Vasculitis - From Diagnosis To Treatment

RHEUMATISM AND MUSCULOSKELETAL DISORDERS
VASCULITIS
FROM DIAGNOSIS TO TREATMENT
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RHEUMATISM AND
MUSCULOSKELETAL DISORDERS
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RHEUMATISM AND MUSCULOSKELETAL DISORDERS
VASCULITIS
FROM DIAGNOSIS TO TREATMENT
ROGER M. BROWN
EDITOR
Copyright © 2021 by Nova Science Publishers, Inc.
DOI: https://doi.org/10.52305/DLVW4660
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CONTENTS
Preface vii
Chapter 1 Giant Cell Arteritis 1
Harsha Pattnaik, Nicky N. Chopra,
Adrian A. Jarquin-Valdivia, Rahul Kashyap
and Salim Surani
Chapter 2 Pulmonary Complications of Vasculitis 43
Pahnwat Tonya Taweesedt, Julian Bayati,
Farah Yasmin, Munish Sharma and Salim Surani
Chapter 3 Eosinophilic Granulomatosis with Polyangiitis 89
N. Vobugari, Kejal Gandhi, K. Raja,
Farah Yasmin, Iqbal Ratnani and Salim Surani
Chapter 4 Cardiovascular Complications of Vasculitis 125
Syed Adeel Hassan, Somia Jamal Sheikh,
Iqbal Ratnani and Salim Surani
Chapter 5 Cerebral Vasculitides Associated with Central
Nervous System Herpesviridae Infection 155
Tracey Fan, Alise Carlson, Ahmad Mahadeen
and Richard A. Prayson
vi Contents
Chapter 6 Gastrointestinal Complications of Vasculitis 179

The Dang, Luis O. Chavez, Monica Leon,
Kejal Gandhi, Pahnwat Taweesedt
and Salim Surani
Chapter 7 Hypocomplementic Urticarial
Vasculitis Syndrome 199
Kejal Gandhi, N. Vobugari and Salim Surani
Chapter 8 Pulmonary Capillaritis in
Systemic Lupus Erythematosus 221
Chrong-Reen Wang, Wei-Chieh Lin
and Ming-Fei Liu
Chapter 9 Cerebral Venous Sinus Thrombosis
as a Complication of COVID-19 Vaccination 245
N. Prasad, Salim Surani and Rahul Kashyap
Index 263
PREFACE
Vasculitis refers to diseases that cause blood vessel walls to thicken

and narrow, cutting off blood supply to tissues and organs. Vasculitis
encapsulates several conditions, and the cause of vasculitis is often
unknown. This book explores various forms of vasculitis and options for
treatment. Chapter one includes a detailed description of giant cell arteritis,
a form of vasculitis involving inflammation of the middle and large
arteries, including the latest management strategies. Chapter two concerns
different types of vasculitis affecting the lungs, their signs and symptoms,
treatment, and complications needed for diagnosis. Chapter three deals
with eosinophilic granulomatosis with polyangiitis, a multisystemic
necrotizing vasculitis characterized by allergic rhinitis, asthma, and
peripheral eosinophilia. Chapter four describes the common
pathophysiology and cardiovascular complications arising in different
vasculidities. Chapter five reviews the pathophysiology, epidemiology,
diagnostic investigation, and treatment of infection etiologies of
Herpesviridae associated with vasculitis. Chapter six elucidates the impact
of vasculitis on the gastrointestinal system. Chapter seven explains
hypocomplementic urticarial vasculitis syndrome, defined as presence of
greater than six months of urticaria along with hypocomplementemia and
multi-system manifestations such as recurrent abdominal pain, uveitis,
arthralgia and glomerulonephritis. Chapter eight explicates the use of
viii Roger M. Brown
biologics in treating rheumatology disorders, with rituximab being

recommended in organ-threatening, refractory systemic lupus
erythematosus. Lastly, chapter nine discusses the pathophysiology and
adverse effects of adenoviral vector vaccinations for SARS-CoV-2 and the
importance of identifying the true epidemiology of adverse outcomes
regarding promoting increased acceptance of COVID-19 vaccinations,
while stressing that despite the possibility of adverse outcomes, the
benefits of vaccination outweigh the risks of remaining unvaccinated.
Chapter 1 - Giant Cell Arteritis (GCA) is the inflammation of middle
and large arteries commonly affecting the elderly with a female
preponderance. In this chapter, the authors have included a detailed
description and the latest management. Its diagnosis is muddled by a
constellation of vague manifestations like fever, headache, anemia, high
ESR, which may or may not include the characteristic symptoms due to
ophthalmic arteritis and polymyalgia rheumatica. On temporal artery
biopsy, which remains the gold standard of diagnosis, patchy pan-arteritis,
with focal granulomatous lesions and giant cells, is seen. Recently,
ultrasonography (USG), MRI, and PET scans are being adopted to
optimize the diagnostic process. Corticosteroids remain the mainstay of
treatment and are crucial in retarding the disease process to prevent
blindness. Though methotrexate and various immunosuppressants have
been tried as adjuncts with arguable results, Tocilizumab has been
approved for use in the treatment of GCA. Abatacept and Ustekinumab are
promising new candidates. GCA is an evolving field in terms of diagnosis
and new biological therapies.
Chapter 2 - Vasculitis is an inflammation of the blood vessel. Patients
with connective tissue disease can have a vascular injury which can be
primary or secondary. The primary vasculitis is the inflammation of the
blood vessel, whereas the secondary vasculitis is caused by secondary
condition as connective tissue disease, infection, malignancy or allergy.
Primary vasculitis is defined based on the size of the affected vessel. It can
be large vessel vasculitis as Takayasu arteritis, medium vessel vasculitis as
polyarteritis nodosa, and small-vessel vasculitis which predominantly
affects small vessels. Pulmonary vasculitis is a rare condition with an
Preface ix
incidence rate of 20-100 cases/million/year with a prevalence rate of 150-

450 cases/million/year. Both large and medium vasculitis can cause
pulmonary involvement. The small vessel vasculitis can usually be
categorized into ANCA and immune complex associated vasculitis, both
of which can cause pulmonary involvement. In this chapter, the authors
will discuss briefly vasculitis and then will dive into different types of
vasculitis affecting the lungs, their signs, and symptoms, diagnosis,
treatment, and complications needed for the diagnosis. It is considered a
sleep-related movement disorder. Evidence suggests that bruxism is
centrally mediated and is also found to be associated with sleep-related
breathing disorders, psychiatric disorders, neurological disorders, and
gastroesophageal reflux disease. Other factors including substance use,
medications, or genetic factors can increase the risk of bruxism. Treatment
may be behavioral and pharmacologic approach using the oral or injection
medication, and/or avoidance of predisposing factors. Oral appliances
have been used to reduce the damaging effect of grinding or clenching on
teeth in sleep bruxism.
Chapter 3 - Eosinophilic Granulomatosis with Polyangiitis (EGPA),
previously called Churg-Strauss syndrome (CSS), is a multisystemic
necrotizing vasculitis. It belongs to small to medium size vessel anti-
neutrophil cytoplasmic antibody (ANCA) vasculitis. EGPA is
characterized by allergic rhinitis, asthma, and peripheral eosinophilia.
Involvement of non-pulmonary organs, including the gastrointestinal tract,
kidney, and heart, is not uncommon and has been associated with poor
prognosis as assessed by the revised Five-Factor Score (FFS).
Approximately 10 percent of vasculitis are recognized to have EGPA,
although the epidemiology of EGPA remains unclear. The exact etiology
is unknown. Augmented Th1 and Th2 lymphocyte function, increased
eosinophil recruitment, and decreased eosinophil apoptosis are postulated
as underlying pathogenesis. Diagnosis includes peripheral blood
eosinophilia, usually 5000-9000 eosinophils/microL, and is confirmed by
lung or skin biopsy showing leukoclastic vasculitis. ANCA antibodies are
detected in about 40-60 percent of patients. The primary treatment of
x Roger M. Brown
EGPA is systemic glucocorticoids which has shown to improve 5-year

survival rates to 70-90%.
Chapter 4 - Vasculitis represent a broad spectrum of autoimmune
blood vessel disease, which eventually leads to inflammation-mediated
stenosis, thrombosis, occlusion, and aneurysmal dilation. The incidence of
cardiovascular complications in patients with systemic vasculitis has been
well documented in the literature. Regardless of the initiating trigger,
cardiovascular complications arise secondary to sustained inflammation,
pro-thrombotic states, vascular damage, and accelerated atherosclerosis.
The advances in therapy have improved survival timelines and increased
the rates of cardiovascular morbidity and mortality. In this chapter, based
on the vessel size involvement, the authors discuss the common
pathophysiology and cardiovascular complications arising in various
vasculidities.
Chapter 5 - Herpesviridae is a family of DNA viruses that are
neurotropic and known to cause primary central nervous system (CNS)
infections and devastating neurologic outcomes. Cerebrovascular
complications, including CNS vasculitis, occur rarely but have been
reported as sequelae of herpesvirus infections of the CNS. Much of the
existing literature has been focused on varicella zoster virus (VZV)
associated CNS pathology, including ischemic stroke, aneurysm,
intracranial hemorrhage, carotid dissection, and rarely peripheral artery
disease. Histologically, these infections affect both large and small vessels
and are characterized by thrombosis of the cerebral arteries. They are
distinguished from other vasculitides by arterial infiltration predominantly
by mononuclear and multinucleated giant cells. This chapter will focus
attention on cerebral vasculitides which have been identified in this
population, to review the epidemiology, clinical presentation, imaging
features, and pathologic characteristics of CNS vasculopathy associated
with Herpesviridae infections. The pathophysiology, epidemiology,
diagnostic investigation, and treatment of each infectious etiology will also
be reviewed.
Chapter 6 - Vasculitides are defined by the presence of inflammatory
leukocytes in vessel walls, with 36% of patients presenting with
Preface xi
gastrointestinal manifestations that vary from general and/or postprandial

abdominal pain, nausea, vomiting, and diarrhea. A low-flow
pathophysiologic leads to small bowel obstruction, intussusception,
mesenteric ischemia, ischemic colitis, and massive gastrointestinal
bleeding. Often gastrointestinal vasculitis is a diagnosis of exclusion.
However, patients without significant risk factors for atherosclerotic
vascular disease require an initial lab and imaging workup. An endoscopic
approach is not recommended due to nonspecific findings and an elevated
risk for perforation. The resolution entails symptomatic treatment and
immunosuppressive agents for the underlying vasculitis.
Chapter 7 - Hypocomplementemic Urticarial Vasculitis (HUV) is a
rare vasculitis syndrome which was recognized in 2012 and was revised in
the International Chapel Hill Consensus Conference (CHCC). It is defined
as presence of greater than six months of urticaria along with
hypocomplementemia and multi-systemic manifestations such as recurrent
abdominal pain, uveitis, arthralgia and glomerulonephritis. It is often
associated with obstructive pulmonary diseases such as emphysema, a
major source of morbidity and mortality. Diagnosis of HUV is made by
the presence of antibodies against the complement protein 1q and skin
biopsy. Histopathologically, it is a small vessel disease with perivascular
infiltration of neutrophils. HUV syndrome is also associated with systemic
lupus erythematosus (SLE) and has multiple overlapping features. HUV
syndrome could also be an initial presentation of SLE. However,
angioedema, COPD, and uveitis are more common in HUV syndrome
compared to SLE. HUV is a benign self-limited vasculitis but has a
considerable morbidity burden. Thus, early screening of urticaria patients
is recommended, especially those having dyspnea and proteinuria.
Chapter 8 - There is an increasing trend of biologics usage in treating
rheumatology disorders with rituximab (RTX) being recommended in
organ-threatening, refractory systemic lupus erythematosus (SLE). Diffuse
alveolar hemorrhage (DAH) caused by capillaritis, described first by Sir
William Osler in 1895, is associated with a high mortality in SLE. A
retrospective analysis of DAH was performed in hospitalized adult lupus
patients from January 2006 to June 2019, focusing on the therapeutic
xii Roger M. Brown
modality. Twenty patients (1.8% incidence), 18 females (90%) ages 19 to

67 years (38.3 + 15.0), had 27 DAH episodes with SLEDAI-2K 12 to 33
(20.3 + 6.0) and involved organ numbers 2 to 7 (4.5 + 1.3) at the onset.
High-dose corticosteroids, mechanic ventilator, pulse methylprednisolone,
plasma exchange, cyclophosphamide and extracorporeal membrane
oxygenation were prescribed in all, 15 (75%), 13 (65%), 7 (35%), 6 (30%)
and 3 (15%), respectively. In particular, 5 (25%) received RTX 375 mg/m2
weekly × 4 or fortnightly × 2 with a depletion of circulating B cells, and
all survived without relapse, with 3 carrying a recurrent history. Seven
(35%) succumbed to acute respiratory failure. There was a higher DAH
incidence (3.7%) and mortality rate (73%) in admitted adult lupus patients
before 1998. Despite a better critical care quality in respiratory
dysfunction, this study observes a benefit of the RTX therapy in improving
survival and preventing recurrence in SLE-associated DAH manifestation.
Chapter 9 - This chapter discusses the pathophysiology and adverse
effects of adenoviral vector vaccinations for SARS-CoV-2 and the
importance of identifying the true epidemiology of adverse outcomes
regarding promoting increased acceptance of COVID-19 vaccinations.
This book chapter includes all published studies relating to outcomes after
adenoviral-vector vaccination. The findings described show adenoviral
vector vaccines are associated with an increased risk of thrombosis,
typically with thrombocytopenia. This phenomenon has been termed
vaccine-induced thrombotic thrombocytopenia (VITT). The rate of
thrombotic adverse effects following vaccination remains lower than the
rate of thrombosis following COVID-19 infection. At the current rate of
reported severe adverse outcomes, the benefits of vaccination outweigh the
risks of remaining unvaccinated regardless of the vaccine vector.
In: Vasculitis: From Diagnosis to Treatment ISBN: 978-1-53619-853-9
Editor: Roger M. Brown © 2021 Nova Science Publishers, Inc.
Chapter 1
GIANT CELL ARTERITIS
Harsha Pattnaik1, MD, Nicky N. Chopra2, MD,

Adrian A. Jarquin-Valdivia2, MD,
Rahul Kashyap2,3, MD and Salim Surani3,4,*, MD
1
Lady Hardinge Medical College, New Delhi, India
2
Internal Medicine, TriStar Centennial Medical Center, HCA
Healthcare, Nashville, TN, USA
3
Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
4
Pulmonary, Critical Care & Sleep Medicine,
Texas A&M University, TX, USA
ABSTRACT
Giant Cell Arteritis (GCA) is the inflammation of middle and large

arteries commonly affecting the elderly with a female preponderance. In
this chapter, we have included a detailed description and the latest
management. Its diagnosis is muddled by a constellation of vague
manifestations like fever, headache, anemia, high ESR, which may or
may not include the characteristic symptoms due to ophthalmic arteritis
and polymyalgia rheumatica. On temporal artery biopsy, which remains
*
Corresponding Author’s E-mail: srsurani@hotmail.com.
2 H. Pattnaik, N. N. Chopra, A. A. Jarquin-Valdivia et al.
the gold standard of diagnosis, patchy pan-arteritis, with focal

granulomatous lesions and giant cells, is seen. Recently, ultrasonography
(USG), MRI, and PET scans are being adopted to optimize the diagnostic
process. Corticosteroids remain the mainstay of treatment and are crucial
in retarding the disease process to prevent blindness. Though
methotrexate and various immunosuppressants have been tried as
adjuncts with arguable results, Tocilizumab has been approved for use in
the treatment of GCA. Abatacept and Ustekinumab are promising new
candidates. GCA is an evolving field in terms of diagnosis and new
biological therapies.
Keywords: giant cell arteritis, temporal arteritis, polymyalgia rheumatica,

temporal artery biopsy, tocilizumab, ultrasonography
INTRODUCTION
Giant cell arteritis, also called temporal arteritis, is a granulomatous

vasculitis of medium and large vessels. It is the most common primary
vasculitis in adults and mainly affects elderly with a female predominance
[1]. It has a significantly higher incidence in the Scandinavian populations
[2].
Temporal artery biopsy is the main modality of disease confirmation
in GCA showing characteristic vascular wall pathologic changes [3]. Its
exact etiology and pathogenesis are still not well understood. Vague
manifestations like generalized body ache, malaise, fever, and headache
may elude diagnosis and cause a delay in starting appropriate treatment.
Such delays can lead to irreversible blindness [4], and large vessel
involvement can cause potentially life-threatening complications [5].
Hence, any new-onset headache with generalized body aches and malaise
suggestive of polymyalgia rheumatica in a person >50 years of age should
immediately arouse suspicion for GCA to initiate diagnostic strategies.
Corticosteroids should be started immediately without waiting for the
results of temporal artery biopsy (TAB).
Modern imaging methods like ultrasonography (USG), MRI, and
FDG-PET scans have emerged in recent years. These are non-invasive,
Giant Cell Arteritis 3
fast, and comparable diagnostic efficacy and have been recommended in

the European Alliance of Associations for Rheumatology (EULAR)
guidelines as these can supplement diagnosis and hasten appropriate
management [6].
Glucocorticoids are the treatment of choice for all vasculitides,
including GCA [6]. After the Giant-Cell Arteritis Actemra (GiACTA) trial
in 2017, Federal Drug Agency (FDA) approved Tocilizumab, an anti-IL-6
monoclonal antibody, for GCA as an adjunct to steroids [7]. Continued
research efforts have revitalized the therapy landscape of GCA, which used
to rely heavily, almost solely on steroids for disease suppression. With new
biologics like abatacept and Ustekinumab under consideration now, the
dependency on steroids, which have well-known adverse effects, may be
reduced.
EPIDEMIOLOGY
Giant cell arteritis is the most common primary vasculitis in adults. Its
incidence varies between 15 and 25 cases per 100,000 ≥ 50 years of age
[8, 9] and its incidence increases with increasing age with peak incidence
rates in 70-79 [10, 11]. There is a female preponderance with rates varying
between 2:1 to 4:1 in various studies, with higher ratios seen in Northern
European countries compared to other regions [9, 11–14]. Their
predisposition can explain the higher incidence in women to autoimmune
diseases.
There are apparent ethnic variations in the incidence of GCA.
According to a metanalysis, Scandinavian populations have a significantly
higher incidence (21.57/100,000 aged ≥ 50years) than other populations,
with the lowest incidence seen in East Asian populations (0.34/100,000)
[2]. A higher incidence was observed in Northern Europe (14.6 to
43.6/100,000 aged ≥50 years; as compared to Southern Europe (1.1 to
11.1/100,000) [15]. Buttressing this, Nordberg reported that the incidence
of GCA was threefold higher in Scandinavia relative to the rest of Europe
and was six times higher in Scandinavia compared to East Asia [9].
Denmark has the highest reported incidence of 76.6/100,000 people [2].

Even within the United States, a higher incidence is seen in populations
with Scandinavian ancestry. In Olmsted County, Minnesota, the incidence
is 18.8 per 100,000 aged ≥50 years [11]. In a new study in Ontario, Canada,
the incidence is 25/100,000 aged ≥50 years [16]. This can be due to the
higher Scandinavian ancestry there [9].
Though the genetic susceptibility to GCA is still under investigation,
HLA-DRB1*04 is a potential culprit. An association between GCA and
the HLA-DRB1*04 allele was shown by a meta-analysis [17]. This allele
is relatively common in Northern European ethnicities, which correlates
with the higher incidence of GCA in them and may play a role in its
pathogenesis.
Additionally, the possibility of metabolic factors influencing GCA is
being explored. Some studies showed a decreased risk of GCA in
overweight or obese individuals [18, 19]. A study found negative
associations between fasting blood glucose, serum cholesterol, and
triglycerides with GCA, i.e., these parameters were significantly reduced
in cases compared to the controls [20]. Raised diastolic blood pressure and
smoking was associated with incident GCA/PMR complex [21].
Polymyalgia rheumatica (PMR) is an entity that often coexists with
GCA. 40–60% of GCA patients also had PMR, while 15–20% of PMR
afflicted individuals eventually developed symptoms of GCA [22]. A
systematic literature review found that GCA and PMR are more common
in populations of Northern European ancestry than others, which might
explain their coexistence [23]. On the contrary, a study reported significant
associations for HLA-DRB1*0401and HLA-DRB1*0404 with GCA but did
not find any such pattern in patients with PMR [24]. The reported
incidence and prevalence estimates for PMR were higher than that of GCA
in Caucasians [23]. Such findings make the pathogenesis behind GCA and
its association with PMR murkier.
There are conflicting studies regarding mortality in GCA. One found
higher mortality from vascular diseases because of complications in GCA
cases [25]. Another study refuted this and found no increased mortality in
GCA cases, but they found higher mortality in male GCA patients than
female counterparts [26].
An infectious etiology has also been suggested, which may trigger
hypersensitivity [27]. A study suggested the role of the varicella-zoster
virus in GCA pathogenesis, but its findings have yet to be reproduced [28].
Hence this remains to be determined.
PATHOLOGY AND PATHOPHYSIOLOGY
Giant cell arteritis is a systemic granulomatous vasculitis that affects

large and medium-sized arteries. It is a multifocal, segmental pan-arteritis
[29]. It involves transmural inflammatory infiltrate of CD4+ T cells and
macrophages. Giant cells occur in about half of the cases of GCA.
Additionally, neutrophils, B cells, and eosinophils may also be seen. There
is a fragmentation of internal elastic lamina, granulomas, and hyperplasia
of the intimal layer on histopathology [27, 30, 31, 32].
In GCA, there are various histological patterns of cellular infiltration
with the inflammatory infiltrates being limited to the adventitia, extending
beyond the muscular layer, infiltrating intima but sparing media and the
most common pan-arteritic pattern where inflammatory infiltrates are
present throughout the three arterial layers. Laminar necrosis,
calcifications, and neovascularization are also seen along the internal
elastic lamina. Fibrinoid necrosis and acute thrombosis rarely occur [31,
32].
These might shed some light on the serial pathogenesis of GCA.
Inflammatory cells first come in contact with adventitia since adventitial
involvement is seen in all cases of GCA. Then, these inflammatory cells
further infiltrate the intima, leading to transmural inflammation. These
may then spread horizontally, leading to inflammation interspersed with
normal areas leading to patchy involvement. The reparative process would
lead to fibrotic changes and intimal thickening [31].
There are conflicting reports on the relationship between pathological
features of temporal artery biopsies and disease severity. Some report more
symptoms - headache, jaw claudication, neuro-ophthalmic complications,

abnormalities of temporal arteries on USG, lower serum levels of acute-
phase reactants in transmural inflammation, [32] others did not find any
such correlation [31, 33–37]. There is also a reported relationship between
visual loss and the histopathological finding of giant cells [38, 39].
Glucocorticoids appear to have no significant effect on histopathology
in short-term treatments up to one month on full dose and up to 3 months
on low dose Prednisolone [31, 40]. Hence TAB can be delayed for several
days while emergent steroid therapy is started without compromising the
diagnostic efficacy of TAB. But in patients on long-term steroids, healing
lesions are seen on repeat biopsies [41].
Since TAB is the gold standard for diagnosing GCA [3, 6], there has
been an increased focus on the histopathology of GCA, which has
elucidated multiple stages of pathogenic changes in the vasculature
affected individuals. But the pathophysiology is still shrouded in mystery.
It is well accepted that cell-mediated immunity, especially CD4+ T
cells and macrophages, plays a major role in pathogenesis. Due to an
unknown trigger, dendritic cells are activated and invade the adventitial
layer of arteries. They then release chemokines and interleukins to recruit
helper T cells and activate them, respectively. IL-6 causes CD4+ T cells to
differentiate into Th17 cells, while IL-12 and IL-18 influence other CD4+
T cells to become Th1 cells. Th17 and Th1 cells release IL-17 and IFN-ƴ.
These drive a granulomatous inflammation with macrophage recruitment
and formation of multinucleated giant cells. The macrophages further
produce IL-6 and TNF-α, which cause systemic manifestations like fever,
increased acute phase reactants, and malaise. Macrophages release reactive
oxygen species, which cause vasculature injury by cell membrane
phospholipid peroxidation and activation of metalloproteinases that
destroy the arterial wall layers. Injured vascular smooth muscle cells and
macrophages release Platelet-derived growth factors and vascular
endothelial growth factors that can cause intimal hyperplasia and
angiogenesis, leading to arterial obstruction [42–44].
IL-6 plays a crucial role in the pathophysiology of GCA. A correlation

between levels of IL-6 and GCA disease activity has been demonstrated
[45]. This plays a role in the effectiveness of Tocilizumab in GCA.
Signs and Symptoms
The American College of Rheumatology (ACR) states that for the

diagnosis of GCA, three out of five criteria must be satisfied ((age ⩾50
years, new headache, clinical temporal artery abnormality, ESR ⩾50 mm/1
h, and positive TAB) [12, 46]. Table 1 discusses the various criteria for
GCA.
Table 1 Criteria for classification of GCA. The classic
symptomatology includes headache, jaw claudication, polymyalgia
rheumatica (PMR), and visual impairment [12, 49]. The clinical
manifestations of GCA can be broadly grouped as cranial or extracranial
GCA. Though there is considerable overlap in these groups, the risk and
type of complications and time to diagnose varies. Cranial varieties of
GCA patients are picked up early compared to extracranial varieties, which
take longer to diagnose [50] due to nonspecific symptoms common in other
afflictions of the elderly like generalized myalgia, arthralgia, and fatigue.
The classic case of GCA involves predominantly cranial ischemic
symptoms due to vascular compromise [49]. Involvement of the branches
of external and internal carotid arteries leads to the classic GCA complex
of headache, jaw claudication, visual loss, and scalp tenderness
[8, 12, 49]. Headache is the most common presenting complaint and is
found in more than two-thirds of patients of GCA [51, 52]. It is abrupt
onset, severe, and in the temporal region. Thus, a new onset headache
inpatient ≥50 years should initiate rapid assessment for GCA. Other well-
known symptoms include jaw claudication (seen in up to half of the cases)
[51], [52] and visual disturbances (seen in 15-30% cases) [53]. Rarely
scalp tenderness, tongue claudication, and necrosis may also be seen in
GCA. Tender temporal arteries thickened on palpation with diminished
pulses may be detected on examination [12, 22, 50, 54].
Table 1. Giant Cell Arteritis Classification Criteria
ACR Classification Revised ACR EULAR Consensus for Active

Criteria (1990) Classification Disease in GCA [6]
of GCA [47] Criteria of GCA [48]
Three of the five points In the presence of 3 or Active disease defined as the presence
are required for clinical more points out of 11 of typical signs or symptoms of active
diagnosis of GCA. with at least one point LVV, and at least one of the following:
belonging to domain I a. Current activity on imaging or
along with all entry biopsy
criteria, the diagnosis b. Ischemic complications attributed to
of GCA can be LVV
established. c. Persistently elevated inflammatory
markers
(After other causes have been
excluded)
Age of onset >50 years Entry criteria: Key symptoms:
Localized pain in the Age of onset > 50 New-onset of persistent localized
head years headache
Temporal artery Absence of exclusion (Often in temporal area)
abnormality such as criteria Constitutional symptoms
tenderness to palpation Domain I criteria: (Weight loss >2kg, low-grade fever,
or decreased pulsation. New onset localized fatigue, night sweats)
ESR > 50 mm/h headache (1.p) Jaw/tongue claudication
Abnormal artery biopsy Sudden onset visual Acute visual symptoms
showing vasculitis with disturbance (1.p) (Amaurosis fugax, acute visual loss,
mononuclear cell or Polymyalgia diplopia)
granulomatous Rheumatica (2.p) Symptoms of polymyalgia rheumatic
inflammation, usually Jaw claudication (1.p) Limb claudication
with giant cell infiltrate. Abnormal temporal Key clinical findings:
artery (up to 2.p) Tenderness and/or thickening of
Domain II criteria: superficial temporal arteries with or
Unexplained fever without reduced pulsation
and/or anemia (1.p) Scalp tenderness, bruits (particularly in
ESR > 50 mm/h (1.p) axilla)
Compatible pathology Reduced pulses/blood pressure of the
(up to 2.p) upper limbs
Elevated ESR and/or Pathological finds during
CRP ophthalmologic examination including:
Abnormal artery anterior ischemic optic neuropathy,
biopsy oculomotor cranial nerve palsy/palsies,
central retinal artery occlusion, branch
retinal artery occlusion and/or
choroidal ischemia
The most dreaded visual complication of GCA is irreversible blindness

secondary to retinal infarct. Arteritic anterior ischemic optic neuropathy
(AAION) can cause permanent blindness unless emergent measures are
not taken. The forewarning of AAION is amaurosis fugax, diplopia, and
jaw and tongue claudication. AAION is a sudden painless unilateral or
bilateral loss of vision. On fundoscopy, there are cotton wool spots,
hemorrhages, and pale, edematous optic nerve head. Additionally, central
retinal artery occlusion (CRAO) may also be present [53, 55].
Table 2. Differential Diagnosis of Giant Cell Arteritis Based on

Clinical Findings [47]
Giant Migraine Trigeminal Central Herpes

Cell Headache Neuralgia Retinal Artery Zoster
Arteritis Occlusion Virus
Localized Pain in + + + - +
Head
Tenderness in + +/- +/- - +/-
Temporal Artery
Distribution
Polymyalgia + - - - -
Rheumatica
Visual Disturbance + +/- - + +/-
(Amaurosis fugax,
acute visual loss,
diplopia)
ESR >50 + - - - +/-
Temporal Artery + - - - -
Abnormality on
Biopsy
In extracranial GCA, PMR is the most common association. 40–60%

of those afflicted by GCA also had PMR, while 15–20% of PMR patients
eventually developed GCA symptoms [12, 22]. PMR is the aching and
stiffness of the shoulder and pelvic girdle with predominant proximal
muscle involvement, which worsens in the morning [56]. It is often
attributed to the inflammation of the bursa and extra-articular synovial
structures [22]. PMR dominant forms of GCA may develop visual
impairments if left untreated [57]. The relationship between GCA and
PMR has been explored in the Epidemiology section. Table 2 discusses the
various clinical entities that have overlapping features with GCA.
In GCA, sometimes large vessel involvement is seen. Ischemia of large
vessels can lead to limb claudication [12], infarctions, and stroke in
vertebrobasilar area. Aortitis, aneurysms, and dissections may also develop
as complications [5].
As discussed in the Pathophysiology section, due to the complex
immune cascade of cytokines, systemic effects of inflammation like fever,
fatigue, malaise, anorexia, weight loss, high ESR, and increased C-reactive
protein (CRP) may be seen [12].
Investigations
In the initial workup of a suspected case of GCA, laboratory findings

play a crucial role.
In a meta-analysis, platelet count ≥400 × 103/μL and ESR ≥ 100 mm/h
were associated with GCA, while ESR ≤ 40 mm/h and CRP ≤ 2.5mg/dl
were associated with GCA absence [12]. Patients with increased ESR and
CRP who have visual symptoms must be started on steroids immediately
as per guidelines [3, 6]. Hence a routine workup of Complete Blood Count
with ESR and CRP should be done [12, 50, 58]. But, these should be used
with caution as their absence does not rule out GCA. A study found the
sensitivities of ESR > 50 mm/h, CRP > 20 mg/L, and platelets
>300 × 109/L to be 65.5%, 66.9%, and 71.2% respectively, while
specificities were 57.3%, 67.9%, and 71.2% respectively [58]. Also, when
newly diagnosing GCA, consider performing neck/chest/abdomen CT
angiography to detect other arterial involvement that may need future
monitoring [59].
Temporal Artery Biopsy

Long-segment (>1 cm) temporal artery biopsy is considered the gold
standard for confirming the diagnosis of GCA [3, 6, 46]. All other
modalities of diagnosis are often evaluated against TAB as the control. The
histopathology of various types of lesions seen in TAB at different stages

of the disease has been discussed in the Pathology section of this chapter.
It is widely recommended to do TAB as soon as possible after starting
steroids [3, 6, 46]. Features of GCA are seen on TAB even after starting
glucocorticoids, and hence guidelines recommend doing TAB even after
weeks of steroid use [6]. Full-dose glucocorticoids don’t significantly
decrease the sensitivity of TAB in short-term (<2 weeks) treatments [59]
or low-dose glucocorticoid treatment for up to 3 months [31, 40]. Hence
initiating treatment should take priority above doing a biopsy. The longer
the use of steroids, the more atypical the features of GCA were found [31,
41].
Despite being an irreplaceable part of GCA management, TAB has its
pitfalls. Its sensitivity can vary widely. It has a very high specificity for
diagnosing GCA (up to 100%), but its sensitivity can be as low as 39%
[60]. A meta-analysis reported a sensitivity of 77% against diagnosis made
by ACR criteria [61]. Bayesian analysis using bilateral temporal artery
biopsies found a sensitivity of 87.1% [61]. There may be disagreements on
what GCA looks like under the microscope, even among pathologists due
to subjective perceptions [60]. The false-negative rate in TAB could be due
to skip lesions commonly seen in GCA [62] or improper sampling. To
combat the issue of failed detection of GCA due to segmental involvement
of arteries, USG guided TAB, and bilateral TABs can be considered. A
study was unable to show improvement in sensitivity by doing USG guided
TAB [63] and bilateral TABs didn’t have a significant improvement in
sensitivity over unilateral TAB [64–67]. At present, only unilateral TAB
is recommended as a routine step in the management of GCA. Thus, the
proper methodology must be followed while doing a TAB to make it
optimal. Other limitations of TAB include delayed results, its invasive
nature, and need for skilled surgical manpower. Even though
complications are rare, facial nerve injury and scalp necrosis post-
procedure have been reported [68–73].
Ultrasonography (USG)
Temporal artery USG is now one of the investigations of choice in
GCA diagnosis, being included in the guidelines as a first line modality,
often done before TAB. It is fast, nearly painless, convenient, and non-
invasive [6]. EULAR 2018 guidelines recommend doing TAB only if USG
findings are inconclusive. USG was introduced into the sphere of GCA
diagnosis with the ‘halo’ sign [74] – a circumferential, peri-arterial,
homogeneous, hypoechoic appearance surrounding the inflamed temporal
arteries. It is best appreciated on the luminal side. It reflects vessel wall
edema and increased intimal thickness due to hyperplasia. The sensitivity
and specificity of finding a hypoechoic halo are estimated to be 68% and
81% GCA, respectively [74]. In a metanalysis, USG (halo sign) at
temporal arteries yielded a sensitivity of 77% and specificity of 96%
compared with a clinical diagnosis of GCA [75]. It is considered the
minimum requirement for GCA diagnosis [76]. Another sign is the
‘compression’ sign – the temporal artery is not compressed when applying
pressure with the USG probe [77, 78]. Both halo sign and compression
signs are considered important markers of vasculitis on USG [76].
The halo sign finding decreases following initiation of steroid therapy,
and it has been reported to disappear rapidly in a few weeks [79].
Therefore, USG should be done as the first investigation in a suspected
GCA case. USG could also be used to monitor the treatment response [80].
A study compared TAB vs. USG in GCA diagnosis and found the
specificity of USG was slightly less 81% vs. 77% and sensitivities 93% vs.
91% while [81]. In multiple meta-analyses, USG yields an overall
sensitivity of 68–88% and specificity of 77–91%, compared to TAB (TAB
itself having a sensitivity of 39% and specificity close to 100%) for the
diagnosis of GCA [82–85].
Axillary artery (AA) USG can also supplement GCA diagnosis and
identification of extracranial manifestations. Halo sign can also be seen in
axillary arteries [81]. AAUSG, in addition to TAUSG can increase
sensitivity for GCA from 52 to 71% [86]. Thus, AAUSG can be included
in the diagnostic workup.
Due to comparable sensitivity to TAB and being non-invasive and fast,

USG of temporal arteries can be the initial screening tool to detect
vasculitic changes when GCA is suspected. This can strengthen clinical
suspicion and supplement the early initiation of glucocorticoids. Though
EULAR recommends TAB only if USG is abnormal [6], ACP criteria put
heavy emphasis on TAB, and both should be done to enhance diagnostic
power [46].
MRI
MRI is another imaging method that can play a role in the diagnosis of
GCA. MRI has a sensitivity of 93.6% and specificity of 77.9% for
detection of GCA. It can act as a screening tool since a normal MRI has a
negative predictive value of 98.2% and can help us determine if TAB is
necessary [87].
Several studies using MRI for GCA diagnosis have yielded promising
results, identifying vessel wall thickening and luminal changes in temporal
arteries [87–92]. A meta-analysis found that MRI of cranial arteries
yielded a sensitivity of 73% and specificity of 88% compared to clinical
diagnosis of GCA [75]. MRI is affected when glucocorticoids have been
started. Hence, MRI should be performed within the first week of treatment
initiation to avoid a drop in sensitivity [93].
Due to the potential for contrast agent associated side effects, lack of
universal availability and high costs, MRI is not recommended for first line
use in GCA imaging [6].
PET
EULAR has developed a set of guidelines for imaging in large vessel
vasculitis, which do not include Positron emission tomography/computed
tomography (PET/CT) among the first-line imaging modalities for
diagnosis [6].
High Fluorine-18-fluorodeoxyglucose (FDG) uptake is seen in
lymphocytes and macrophages. As these cells infiltrate the vessel wall in
vasculitis, FDG-PET is a promising diagnostic modality for GCA. It has a
sensitivity and specificity of 92% and 85%, respectively, compared to
TAB [94, 95]. Its negative predictive value (NPV) is 98% and can exclude
patients from undergoing invasive TAB. Compared to clinical diagnosis,
PET/CT has a sensitivity of 71% and specificity of 91% [94]. Other studies
investigating PET reported sensitivities of 67%–77% and specificities of
66%–100% [75].
It can also effectively find moderate to marked aortitis in large vessel
as well as cranial forms of GCA [96]. Aortitis is detected on PET/CT in
almost half of the patients with a positive TAB [97, 98].
While the primary role of FDG-PET in GCA diagnosis has been the
identification of large vessel inflammation, it is not routinely performed
due to radiation exposure, high price tag, and other better imaging
alternatives [98]. FDG uptake, and consequently the sensitivity of PET
decrease significantly after glucocorticoid exposure. Thus, PET/CT should
be performed within three days of initiating steroids [95]. Also, many
patients may show FDG uptake in the large vessels even after completion
of GCA treatment; thus, its utility remains under question [95].
Treatment
Vasculitis treatment aims to subdue the inflammation. The

effectiveness of a treatment can be measured by how well it controls
inflammatory markers like Erythrocyte sedimentation rate (ESR) and C-
reactive protein (CRP). Systemic glucocorticoids remain the mainstay of
GCA treatment [3, 6], and it has been shown that vision loss is less likely
to occur after they have been started [99].
It is widely accepted that daily steroid treatment should be started as
soon as GCA is suspected without waiting for the results of the TAB.
Delaying the initiation of steroids can lead to irreversible blindness and
other ischemic complications. Early initiation of treatment has shown to
improve the outcomes [100]. Moreover, in the short term, glucocorticoids
don’t significantly decrease the sensitivity of TAB, so there should be no
reason to delay treatment [31, 40].
EULAR recommends starting steroids immediately on suspicion of

GCA with an initial dosage of prednisone 1 mg/kg body weight per day
(max. 60 mg) [6]. The dose can then be tapered in a stepwise manner
depending on the patient’s response until the lowest effective dose is
reached. Clinical symptoms, ESR, CRP, and USG, can help monitor the
patient’s response to treatment. [58] In the event of a flare, the dose must
be increased again until the symptoms are under control.
30% to 50% cases need step up in doses again despite an initial good
response [101]. Most patients treated with prednisone monotherapy require
additional dosing because of flares or refractory symptoms, especially if
the drugs were tapered too soon or treatment cessation was intended within
one year of starting [7, 101, 102]. Generally accepted recommendation is
that glucocorticoids can be stopped after a mean duration of treatment of 2
years [6, 103, 104]. However, in 20% to 25% of patients, steroid treatment
may be needed to be continued for much longer and, in some cases,
throughout life [102].
In cranial-GCA with threatened vision loss, it is advised to initiate
intravenous high-dose steroids, [105, 106] after which treatment can be
continued orally as per the dosage schedule recommended by EULAR [6].
Methylprednisolone up to 1000 mg/day for 3-5 days through intravenous
route is recommended, followed by a maintenance dose of 1 mg/kg of
prednisone or 60mg (whichever is lower) [107]. Some authors dispute the
efficacy of high dose iv steroids [108, 109]. However, cases presenting
with amaurosis fugax necessitate high dose treatment due to the high risk
of vision loss [110].
Without prompt treatment, the contralateral eye may lose vision in up
to 60% of patients. But risk of second eye blindness decreases to only 10%
to 20%, if treatment is given [99, 111]. Further, if GCA-induced arterial
stenosis leads to limitation of the blood flow, consider adding daily aspirin.
The elderly patients, is a vulnerable population at risk of a multitude
of complications due to long-term use of steroids. Most patients (up to
95%) develop an adverse event [112, 113] most commonly cataract or
osteoporosis. For each 1g increase in dose, the hazard ratio for adverse
events rises by 3% [114]. These adverse events include fractures, sepsis,
hypertension and diabetes mellitus [112, 113]. In GCA patients on high vs.
low dose of prednisone (30mg or more vs. 5 mg or less; daily), the odds
ratios for complications were: diabetes (4.7), osteoporosis (1.9), fractures
(2.6), glaucoma (3.5), serious infection (3.3), and death (2.1), with many
complications occurring many years after initial treatment and diagnosis
of GCA [115]. Despite such complications, glucocorticoids must be used
in all cases of GCA due to imminent blindness and, though steroid-sparing
drugs are necessary in these cases.
On repeat TAB as a follow-up in patients on high-dose
glucocorticoids, persistent vascular inflammation was seen in 75% of
patients at six months and 44% of patients at 12 months, despite having the
well-controlled clinical disease [116]. Persistence of subclinical
inflammation despite good control of clinical symptoms can lead to relapse
and complications such as aortic aneurysms down the line [117], [118].
Methotrexate
Treatment with methotrexate can be used in addition to steroids as per
EULAR recommendations [6]. A meta-analysis showed that methotrexate
(7.5 to 15 mg/week), when used as a steroid-sparing adjunct, reduced
relapse rate (risk of first and second relapse decreased by 35% and 51%
respectively) and lowered cumulative steroid dose in GCA patients [119].
Another study subsequently reported a decrease in relapse rate of 72% in
the methotrexate group as compared to the steroid monotherapy group
[120].
But a study compared prednisone with 0.15 mg/kg/week MTX
(increased to 0.25 mg/kg/week, for a maximum weekly dosage of 15 mg)
vs. placebo with prednisone and found no difference in the incidence of
treatment failure between the two groups at 12 months, serious morbidity
due to the disease, cumulative steroid doses, or treatment toxicity [121]
which puts the role of methotrexate as an adjunct into question.
Thus, there is conflicting evidence surrounding the efficacy and utility
of methotrexate as an adjunct and steroid-sparing treatment and with its
potential side effects, it should be used with caution.
Interleukin-Receptor Blocking Agents

Some promising biologic treatment options in GCA are Tocilizumab
(interleukin-6), Ustekinumab (interleukin-12/interleukin-23) and
Abatacept (T-lymphocytes). These target the crucial players involved in
the pathogenesis model of GCA.
Tocilizumab
Tocilizumab (TLZ) is an anti-IL-6 monoclonal antibody. It is the most
significant breakthrough in giant cell arteritis treatment in recent years. It
was approved by FDA [7] for the treatment of GCA and is the only biologic
yet for this indication. In selected patients with increased risk for
glucocorticoid-related adverse events as well as in refractory or relapsing
cases of GCA, it is recommended as adjunctive therapy as per EULAR [6].
IL-6 serum levels are elevated in untreated GCA patients [45].
Increased IL-6 levels correlate with disease severity, and levels decrease
in response to steroids. TLZ was first used as a steroid-sparing agent in
2011 and decreased inflammatory indicators while also reducing effective
steroid dose [122].
A 2012 study of refractory/relapsing GCA cases treated with the TLZ
showed that all cases achieved and maintained remission, and the mean
prednisone dose decreased from 20.8 mg/day to 4.1 mg/day.
Complications included mild neutropenia and transaminitis. One death
from myocardial infarction after elective surgery in a patient, with autopsy
evidence of unresolved medium and large vessel vasculitis despite
treatment, was also reported [123].
In another study published in 2015, GCA patients showed persistent
remission in 86% of the enrolled cases. Cessation was reported in three
patients due to various complications like severe neutropenia,
cytomegalovirus infection and recurrent pneumonia. After second
infusion, one death from stroke-related to infectious endocarditis was
reported [124].
A randomized controlled trial followed this in 2016 where GCA
patients received intravenous TLZ 8mg/kg every month and steroids with
a placebo group receiving steroid only. The steroids were gradually tapered
in both groups. 85% reached complete remission by three months in the

TLZ group, while only 40% of the steroid monotherapy group reached
remission. A higher relapse-free survival rate was seen in the TLZ group.
There were more severe adverse events in the steroid monotherapy group
than in the Tocilizumab-steroid co-therapy group. Side effects in the TLZ
group were multiple infections and one case of Stevens-Johnson syndrome
three days after an infusion [125].
The GiACTA trial [7] was the groundbreaking trial that led to the FDA
approval of TLZ as a second line drug in GCA in May 2017. Over a year,
subcutaneous TLZ 162 mg was administered to patients weekly or every
two weeks with a prednisone taper for 52 weeks. The placebo group was
given prednisone and subdivided into two subgroups – one of 52 weeks
taper and the other of 26 weeks taper. Sustained remission of GCA was the
primary outcome. It is defined as the absence of flare and CRP
normalization to <1 mg/dl, both of which were sustained from 3 to 13
months along with adherence to the tapering of prednisone. 56% of the
weekly TLZ group and 53% of every two weeks TLZ group achieved
sustained remission while adhering to the prednisone taper. Still, only 14%
of the placebo group with 26-weeks taper and 18% of the placebo group
with 52-weeks taper achieved sustained remission. There were significant
reductions in total median prednisone doses in the treatment group: 1862
mg in both groups that received TLZ, compared with 3296 mg and 3818
mg in the 26-week and 52-week prednisone taper placebo groups,
respectively. In the two-year follow-up study of the GiACTA trial,
approximately 47% of those who had received TLZ could maintain their
remission over the additional two years [126]. Patients on Tocilizumab had
lower cumulative steroid doses and thus had fewer adverse events. The
treatment groups had fewer serious adverse events compared to steroid-
only groups. Treatment group individuals withdrew from the trial more
than the placebo group, but the difference was relatively small (6% vs. 4%
in 26-week taper and 0% in 52-week taper groups). A complication
reported was that of grade III neutropenia which developed in 4% of TLZ
patients. This study provided satisfactory and robust proof of the efficacy
of TLZ in GCA.
A small 2018 study selected normalization of vessel wall enhancement

on magnetic resonance angiography (MRA) as a parameter to compare the
effectiveness of TLZ+steroid vs. placebo+steroid. They found a very slight
increase in normalizations in TLZ (33%) vs placebo (25%) group. Though
the prognostic significance of MRA is undetermined and uncertain, all
TLZ patients experienced clinical and laboratory remission [127].
The limitations of TLZ are its very expensive price tag, the need for
periodic subcutaneous injections, which can be difficult to self-administer
in the elderly, and the increased risk of infections (especially when
combined with steroids.) But these limitations are surmountable since, in
refractory and relapsing cases of GCA, TLZ shows significant efficacy in
achieving and maintaining remission and decreasing cumulative steroid
dose. EULAR recommends steroids to urgently treat GCA cases soon after
diagnosis and add TLZ as an adjunctive therapy only in
refractory/relapsing cases or in cases where steroid-induced adverse events
are anticipated or already present [6, 112, 113].
Additional Comments on Treatment

Other immunosuppressants (azathioprine, leflunomide,
cyclophosphamide, mycophenolate mofetil, and dapsone have been tried.
But there is no concrete evidence for their use, and guidelines have not
recommended them [128–134]. One study of Azathioprine (150mg/day) in
PMR GCA patients showed a significant reduction in mean steroid dose
[135]. Azathioprine may be an alternative in patients who do not tolerate
Methotrexate, but it is not recommended.
High tissue levels of TNF-α have been demonstrated, which led to
investigations into their use for GCA [136]. Randomized Controlled Trials
of Infliximab [137] and Adalimumab [138] demonstrated no significant
benefit. Though a small RCT of Etanercept showed more patients (50%
versus 12%) were in glucocorticoid-free remission, and the cumulative
steroid dose was significantly lower. Still, these findings should be treated
with caution due to the small study size [139]. The consensus is that these
drugs are ineffective in GCA.
GCA is associated with thrombocytosis and occlusive-ischemic

symptoms; hence EULAR recommends giving amino-salicylic-acid
(ASA) (75 to 150 mg/day) as a platelet aggregation inhibitor in the absence
of contraindications. Studies report the beneficial effect on cardiovascular
and cerebrovascular events in GCA [140, 141]. Physicians should
additionally give proton pump inhibitors when ASA is given with
corticosteroids to prevent gastric ulcers.
New Treatment Developments

The treatment of GCA is an ever-evolving field with multiple ongoing
investigations into finding effective treatment options to supplement and
potentially substitute steroids. Since steroids have negative effects on
elderly patients with potentially life-threatening complications, a safer
alternative is needed.
Abatacept is a recombinant CTLA-4-immunoglobulin fusion protein
that binds to CD80/86 on activated dendritic or antigen-presenting cells,
inhibits its interaction with CD28, and prevents CD4+ T cell activation and
IL-6 production. Essentially, it acts as a negative regulator of T-cell co-
stimulation. In a study in GCA patients, it was found that the one-year
relapse-free survival rate was more than the placebo group (48% vs. 31%),
along with a longer median duration of steroid free remission in the
abatacept group (9.9 vs. 3.9 months) with no significant rise in adverse
events compared to placebo. A low number of participants limited the
study. It has not been FDA-approved for GCA, and further research is
needed to determine efficacy [142].
Ustekinumab is an anti- IL-12 and IL-23 monoclonal antibody which
disrupts Th1 and Th17 immune pathways. In a study of refractory GCA
patients on long-term steroids, Ustekinumab was associated with reducing
the median cumulative steroid dose from 5475 mg to 2790 mg with no
relapse for at least a year [143]. A follow-up study demonstrated a median
daily steroid dose reduction from 20 mg of prednisolone to 5 mg in 52
weeks of starting Ustekinumab [142]. But these findings may be fallacious
as in the natural course of steroid monotherapy, step down to such doses
in possible in 1 year without the use of any adjuncts.
While both Abatacept and Ustekinumab are promising candidates,

additional clinical trials are necessary to evaluate whether these agents are
efficacious enough to be used in routine clinical practice.
Many other biologics have been proposed. Anakinra, an interleukin-
1β blocker, has been used in GCA patients with optimistic results. There
was reported disappearance of aortitis and good steroid-sparing activity
[144, 145]. A RCT is planned for anakinra [146] (ClinicalTrials.gov
identifier: NCT02902731).
Two case reports show Rituximab (anti-CD20 antibody) may be
effective in refractory GCA [147, 148] which is surprising considering
GCA pathogenesis is heavily T-lymphocyte dominated. A role of B
lymphocytes in the pathogenesis of GCA is purported [149, 150]. IL-6, IL-
12 and IL-23 play a major role in GCA inflammation and act through the
JAK-STAT pathway. Thus, the investigative focus is now on JAK
inhibitors. Tofacitinib [150] has shown some promise. Other JAK
inhibitors – Baricitinib [151] (ClinicalTrials.gov identifier:
NCT03026504) and Upadacitinib [152] (ClinicalTrials.gov identifier:
NCT03725202) are currently planned for RCTs.
The search for an effective steroid-sparing biologic is ongoing, has a
bright future.
CONCLUSION
Despite being the most common primary vasculitis in adults, Giant cell
arteritis is still not well understood. Due to the greater importance placed
in TAB, the vascular changes involved are quite well documented. While
the extensive epidemiological studies do provide certain clues, its
etiopathogenesis is still under investigation. A focus on the immunological
and inflammatory process of GCA can help in the search for effective
therapies. PMR symptoms, headache, limb claudication, and fatigue often
go unnoticed due to their protean and relatively nonspecific nature. Visual
symptoms like amaurosis fugax are the warning sign of dangerous
ischemia that should point towards GCA with immediate initiation of
intervention, lest delays lead to permanent vision loss. Other systemic

complications of vasculitis can lead to aneurysms and infarctions. Thus, it
is pertinent to catch cases early and prevent lifelong sequelae or loss of
life. Treatment should begin before confirmation of diagnosis by biopsy.
With the advent of new and extensive imaging technology, the diagnosis
is becoming faster and more convenient, with temporal artery USG slowly
decreasing the heavy reliance on TAB.
Glucocorticoids remain the only drug used in routine practice, playing
a very important role in salvaging vision as well as improving the quality
of life of those afflicted with GCA. Despite being life-saving drugs in
GCA, steroids come with their spectrum of complications, some serious,
especially on chronic use. Methotrexate is an adjunct often used as a
steroid-sparing agent. Various drugs have been investigated in GCA - like
other immunosuppressants (azathioprine, cyclophosphamide, dapsone),
anti-CD20 antibodies (rituximab), anti-interleukin receptor antibodies, and
TNF-α inhibitors (adalimumab, infliximab). Even though they seemed
attractive in theory due to targeting key players in the inflammation of
GCA, they were either ineffective in practice or haven’t been researched
in larger studies yet. Due to limited data on their efficacy, they should not
be used in routine clinical practice. However, Tocilizumab is a
breakthrough drug with significant effectiveness in GCA and is
recommended as the steroid-sparing adjunct in difficult to treat cases of
GCA. Abatacept and Ustekinumab have shown promising results. RCTs
of Anakinra and JAK-STAT inhibitors have been planned due to
encouraging preliminary studies. The field of GCA is going through a
dynamic shift, and tomorrow is sure to bring more effective therapies.
DISCLAIMER
“This research was supported (in whole or in part) by HCA Healthcare

and/or an HCA Healthcare affiliated entity. The views expressed in this
publication represent those of the author(s) and do not necessarily
represent the official views of HCA Healthcare or any of its affiliated

entities.”
REFERENCES
[1] Lyons H. S., V. Quick, A. J. Sinclair, S. Nagaraju, and S. P. Mollan,

“A new era for giant cell arteritis,” Eye 2019 34:6, vol. 34, no. 6,
pp. 1013–1026, Oct. 2019, doi: 10.1038/s41433-019-0608-7.
[2] Li K. J., D. Semenov, M. Turk, and J. Pope, “A meta-analysis of the
epidemiology of giant cell arteritis across time and space,” Arthritis
Research & Therapy 2021 23:1, vol. 23, no. 1, pp. 1–10, Mar. 2021,
doi: 10.1186/S13075-021-02450-W.
[3] Mukhtyar C. et al., “EULAR recommendations for the management
of large vessel vasculitis,” Annals of the Rheumatic Diseases, vol.
68, no. 3, pp. 318–323, Mar. 2009, doi: 10.1136/
ARD.2008.088351.
[4] F. C, C. MC, C. V. B, L. S. A, and G. JM, “Clinical features in
patients with permanent visual loss due to biopsy-proven giant cell
arteritis,” British journal of rheumatology, vol. 36, no. 2, pp. 251–
254, 1997, doi: 10.1093/RHEUMATOLOGY/36.2.251.
[5] Muratore F., G. Pazzola, N. Pipitone, L. Boiardi, and C. Salvarani,
“Large-vessel involvement in giant cell arteritis and polymyalgia
rheumatica,” Clinical and Experimental Rheumatology, vol. 32, no.
SUPPL.82, 2014.
[6] Hellmich B. et al., “2018 Update of the EULAR recommendations
for the management of large vessel vasculitis,” Annals of the
Rheumatic Diseases, vol. 79, no. 1, pp. 19–30, Jan. 2020, doi:
10.1136/ANNRHEUMDIS-2019-215672.
[7] Stone J. H. et al., Trial of Tocilizumab in Giant-Cell Arteritis,
https://doi.org/10.1056/NEJMoa1613849, vol. 377, no. 4, pp. 317–
328, Jul. 2017, doi: 10.1056/NEJMOA1613849.
[8] Weyand C. M. and J. J. Goronzy, “Giant-Cell Arteritis and

Polymyalgia Rheumatica,” The New England journal of medicine,
vol. 371, no. 1, p. 50, Jul. 2014, doi: 10.1056/NEJMCP1214825.
[9] Nordborg E. and C. Nordborg, “Giant cell arteritis: epidemiological
clues to its pathogenesis and an update on its treatment,”
Rheumatology, vol. 42, no. 3, pp. 413–421, Mar. 2003, doi:
10.1093/RHEUMATOLOGY/KEG116.
[10] G. G. MA et al., “Giant cell arteritis in northwestern Spain: a 25-
year epidemiologic study.,” Medicine, vol. 86, no. 2, pp. 61–68,
Mar. 2007, doi: 10.1097/MD.0B013E31803D1764.
[11] Salvarani C., C. S. Crowson, W. M. O’Fallon, G. G. Hunder, and S.
E. Gabriel, “Reappraisal of the epidemiology of giant cell arteritis
in Olmsted County, Minnesota, over a fifty-year period,” Arthritis
Care & Research, vol. 51, no. 2, pp. 264–268, Apr. 2004, doi:
10.1002/ART.20227.
[12] van der Geest K. S. M., M. Sandovici, E. Brouwer, and S. L. Mackie,
“Diagnostic Accuracy of Symptoms, Physical Signs, and
Laboratory Tests for Giant Cell Arteritis: A Systematic Review and
Meta-analysis,” JAMA Internal Medicine, vol. 180, no. 10, p. 1295,
Oct. 2020, doi: 10.1001/JAMAINTERNMED.2020.3050.
[13] Gonzalez-Gay M. A. et al., “Epidemiology of Giant Cell Arteritis
and Polymyalgia Rheumatica,” 2009, doi: 10.1002/art.24459.
[14] Watts R. A., “2. Epidemiology of giant cell arteritis: a critical
review,” Rheumatology, vol. 53, no. suppl_2, pp. i1–i2, Jul. 2014,
doi: 10.1093/RHEUMATOLOGY/KEU183.
[15] Sharma A., A. Mohammad, and C. Turesson, “Incidence and
prevalence of giant cell arteritis and polymyalgia rheumatica: A
systematic literature review,” Seminars in Arthritis and
Rheumatism, vol. 50, no. 5, pp. 1040–1048, Oct. 2020, doi:
10.1016/J.SEMARTHRIT.2020.07.005.
[16] Barra L. et al., “Incidence and prevalence of giant cell arteritis in
Ontario, Canada,” Rheumatology, vol. 59, no. 11, pp. 3250–3258,
Nov. 2020, doi: 10.1093/RHEUMATOLOGY/KEAA095.
[17] Mackie S. L. et al., Association of HLA-DRB1 amino acid residues

with giant cell arteritis: genetic association study, meta-analysis
and geo-epidemiological investigation, 2011, doi: 10.1186/s13075-
015-0692-4.
[18] Jakobsson K. et al., “Body mass index and the risk of giant cell
arteritis-results from a prospective study,” Rheumatology (United
Kingdom), vol. 54, no. 3, pp. 433–440, Mar. 2015, doi: 10.1093/
RHEUMATOLOGY/KEU331.
[19] Tomasson G., J. Bjornsson, Y. Zhang, V. Gudnason, and P. A.
Merkel, “Cardiovascular risk factors and incident giant cell arteritis:
a population-based cohort study,” Scandinavian Journal of
Rheumatology, vol. 48, no. 3, pp. 213–217, May 2019, doi:
10.1080/03009742.2018.1506821.
[20] Wadström K., L. Jacobsson, A. J. Mohammad, K. J. Warrington, E.
L. Matteson, and C. Turesson, “Negative associations for fasting
blood glucose, cholesterol and triglyceride levels with the
development of giant cell arteritis,” Rheumatology, vol. 59, no. 11,
pp. 3229–3236, Nov. 2020, doi: 10.1093/RHEUMATOLOGY/
KEAA080.
[21] Yates M. et al., “Cardiovascular risk factors associated with
polymyalgia rheumatica and giant cell arteritis in a prospective
cohort: EPIC-Norfolk Study,” Rheumatology (Oxford, England),
vol. 59, no. 2, p. 319, Feb. 2020, doi: 10.1093/ RHEUMATOLOGY/
=KEZ289.
[22] S. C, C. F, and H. GG, “Polymyalgia rheumatica and giant-cell
arteritis,” Lancet (London, England), vol. 372, no. 9634, pp. 234–
245, 2008, doi: 10.1016/S0140-6736(08)61077-6.
[23] Sharma A., A. Mohammad, and C. Turesson, “Incidence and
prevalence of giant cell arteritis and polymyalgia rheumatica: A
systematic literature review,” Seminars in Arthritis and
Rheumatism, vol. 50, no. 5, pp. 1040–1048, Oct. 2020, doi:
10.1016/J.SEMARTHRIT.2020.07.005.
[24] Martínez-Taboda V. M. et al., “HLA-DRB1 allele distribution in
polymyalgia rheumatica and giant cell arteritis: Influence on clinical
subgroups and prognosis,” Seminars in Arthritis and Rheumatism,

vol. 34, no. 1, pp. 454–464, Aug. 2004, doi: 10.1016/J.
SEMARTHRIT.2003.12.001.
[25] Aouba A. et al., “Mortality causes and trends associated with giant
cell arteritis: analysis of the French national death certificate
database (1980–2011)Achille Aouba et al. Mortality associated with
GCA,” Rheumatology, vol. 57, no. 6, pp. 1047–1055, Jun. 2018, doi:
10.1093/RHEUMATOLOGY/KEY028.
[26] Andersen J. B., G. Myklebust, G. Haugeberg, A. H. Pripp, and A. P.
Diamantopoulos, “Incidence Trends and Mortality of Giant Cell
Arteritis in Southern Norway,” Arthritis Care & Research, vol. 73,
no. 3, pp. 409–414, Mar. 2021, doi: 10.1002/ACR.24133.
[27] Weyand C. M. and J. J. Goronzy, “Immune mechanisms in medium
and large-vessel vasculitis,” Nature Reviews Rheumatology 2013
9:12, vol. 9, no. 12, pp. 731–740, Nov. 2013, doi:
10.1038/nrrheum.2013.161.
[28] G. D et al., “Prevalence and distribution of VZV in temporal arteries
of patients with giant cell arteritis,” Neurology, vol. 84, no. 19, pp.
1948–1955, May 2015, doi: 10.1212/WNL.00000000 00001409.
[29] Lie J. T., Illustrated Criteria for Histopathologic Classification
Selected Vasculitis Syndromes.
[30] Parker F., L. A. Healey, K. R. Wilske, and G. F. Odland, Light and
Electron Microscopic Studies on Human Temporal Arteries With
Special Reference to Alterations Related to Senescence,
Atherosclerosis and Giant Cell Arteritis.
[31] Hernández-Rodríguez J. et al., “Description and Validation of
Histological Patterns and Proposal of a Dynamic Model of
Inflammatory Infiltration in Giant-cell Arteritis,” Medicine, vol. 95,
no. 8, Mar. 2016, doi: 10.1097/MD.0000000000002368.
[32] C. A et al., “Inflamed temporal artery: histologic findings in 354
biopsies, with clinical correlations,” The American journal of
surgical pathology, vol. 38, no. 10, pp. 1360–1370, 2014, doi:
10.1097/PAS.0000000000000244.
[33] S. D and L. KU, “Temporal arteritis. Comparison of histological and

clinical findings,” Acta ophthalmologica, vol. 72, no. 3, pp. 319–
325, 1994, doi: 10.1111/J.1755-3768.1994.TB02766.X.
[34] ter B. EJ, H. HC, and S. CA, “Relationship between histological
subtypes and clinical characteristics at presentation and outcome in
biopsy-proven temporal arteritis. Identification of a relatively
benign subgroup,” Clinical rheumatology, vol. 26, no. 4, pp. 529–
532, Apr. 2007, doi: 10.1007/S10067-006-0332-0.
[35] M. NC, “Temporal (granulomatous) arteritis: a histopathological
study of 32 cases,” Histopathology, vol. 3, no. 3, pp. 209–221, 1979,
doi: 10.1111/J.1365-2559.1979.TB02998.X.
[36] H. KA, H. GG, L. JT, K. RH, and E. LR, “Temporal arteritis: a 25-
year epidemiologic, clinical, and pathologic study,” Annals of
internal medicine, vol. 88, no. 2, pp. 162–167, 1978, doi:
10.7326/0003-4819-88-2-162.
[37] Bevan A. T., M. S. Dunnill, and M. J. Harrison, “Clinical and biopsy
findings in temporal arteritis.,” Annals of the Rheumatic Diseases,
vol. 27, no. 3, p. 271, 1968, doi: 10.1136/ARD.27.3.271.
[38] A. AT, T. WB, W. GC, and H. TM, “Clinical importance of the
presence of giant cells in temporal arteritis,” Journal of clinical
pathology, vol. 61, no. 5, pp. 669–671, May 2008, doi:
10.1136/JCP.2007.049049.
[39] C. D et al., “Pathological features of temporal arteries in patients
with giant cell arteritis presenting with permanent visual loss,”
Annals of the rheumatic diseases, vol. 68, no. 1, pp. 84–88, Jan.
2009, doi: 10.1136/ARD.2007.084947.
[40] N. J et al., “Influence of previous corticosteroid therapy on temporal
artery biopsy yield in giant cell arteritis,” Seminars in arthritis and
rheumatism, vol. 37, no. 1, pp. 13–19, Aug. 2007, doi:
10.1016/J.SEMARTHRIT.2006.12.005.
[41] Visvanathan S. et al., “Tissue and serum markers of inflammation
during the follow-up of patients with giant-cell arteritis—a
prospective longitudinal study,” Rheumatology (Oxford, England),
vol. 50, no. 11, p. 2061, 2011, doi: 10.1093/RHEUMATOLOGY/

KER163.
[42] Weyand C. M., B. R. Younge, and J. J. Goronzy, “IFN-γ and IL-17
- The Two Faces of T Cell Pathology in Giant Cell Arteritis,”
Current opinion in rheumatology, vol. 23, no. 1, p. 43, Jan. 2011,
doi: 10.1097/BOR.0B013E32833EE946.
[43] S. M et al., “Th1 and Th17 lymphocytes expressing CD161 are
implicated in giant cell arteritis and polymyalgia rheumatica
pathogenesis,” Arthritis and rheumatism, vol. 64, no. 11, pp. 3788–
3798, Nov. 2012, doi: 10.1002/ART.34647.
[44] Ma-Krupa W., M. S. Jeon, S. Spoerl, T. F. Tedder, J. J. Goronzy,
and C. M. Weyand, “Activation of Arterial Wall Dendritic Cells and
Breakdown of Self-tolerance in Giant Cell Arteritis,” The Journal
of Experimental Medicine, vol. 199, no. 2, p. 173, Jan. 2004, doi:
10.1084/JEM.20030850.
[45] R. NE, F. JW, W. AD, H. GG, G. JJ, and W. CM, “Correlation of
interleukin-6 production and disease activity in polymyalgia
rheumatica and giant cell arteritis,” Arthritis and rheumatism, vol.
36, no. 9, pp. 1286–1294, 1993, doi: 10.1002/ART.1780360913.
[46] H. GG et al., “The American College of Rheumatology 1990 criteria
for the classification of giant cell arteritis,” Arthritis and
rheumatism, vol. 33, no. 8, pp. 1122–1128, 1990, doi:
10.1002/ART.1780330810.
[47] Simon S., J. Ninan, and P. Hissaria, “Diagnosis and management of
giant cell arteritis: Major review,” Clinical & Experimental
Ophthalmology, vol. 49, no. 2, pp. 169–185, Mar. 2021, doi:
10.1111/CEO.13897.
[48] W. F, N. N, M. AJ, and T. C, “Evaluation of revised classification
criteria for giant cell arteritis and its clinical phenotypes.,”
Rheumatology (Oxford, England), Apr. 2021, doi: 10.1093/
RHEUMATOLOGY/KEAB353.
[49] L. SM and H. DB, “Giant cell arteritis,” Current opinion in
rheumatology, vol. 14, no. 1, pp. 3–10, 2002, doi:
10.1097/00002281-200201000-00002.
[50] Gonzalez-Gay M. A., S. Barros, M. J. Lopez-Diaz, C. Garcia-

Porrua, A. Sanchez-Andrade, and J. Llorca, “Giant cell arteritis:
Disease patterns of clinical presentation in a series of 240 patients,”
Medicine, vol. 84, no. 5, pp. 269–276, Sep. 2005, doi:
10.1097/01.MD.0000180042.42156.D1.
[51] H. GG, “Giant cell arteritis and polymyalgia rheumatica,” The
Medical clinics of North America, vol. 81, no. 1, pp. 195–219, 1997,
doi: 10.1016/S0025-7125(05)70511-3.
[52] L. SM and H. DB, “Giant cell arteritis,” Current opinion in
rheumatology, vol. 14, no. 1, pp. 3–10, 2002, doi: 10.1097/
00002281-200201000-00002.
[53] G. G. MA et al., “Visual manifestations of giant cell arteritis. Trends
and clinical spectrum in 161 patients,” Medicine, vol. 79, no. 5, pp.
283–292, 2000, doi: 10.1097/00005792-200009000-00001.
[54] B. Dasgupta et al., Guidelines BSR and BHPR guidelines for the
management of giant cell arteritis, doi: 10.1093/rheumatology/
keq039a.
[55] Lee A. W., C. Chen, and S. Cugati, “Temporal arteritis,” Neurology:
Clinical Practice, vol. 4, no. 2, p. 106, 2014, doi: 10.1212/
CPJ.0B013E3182A9C62A.
[56] K. TA and W. KJ, “Polymyalgia rheumatica,” Lancet (London,
England), vol. 381, no. 9860, pp. 63–72, 2013, doi: 10.1016/ S0140-
6736(12)60680-1.
[57] R. RI, M. P, and B. LE, “Development of giant cell (temporal)
arteritis in a patient ‘adequately’ treated for polymyalgia
rheumatica,” Annals of the rheumatic diseases, vol. 36, no. 1, pp.
88–90, 1977, doi: 10.1136/ARD.36.1.88.
[58] Chan F. L. Y., S. Lester, S. L. Whittle, and C. L. Hill, “The utility
of ESR, CRP and platelets in the diagnosis of GCA,” BMC
Rheumatology, vol. 3, no. 1, 2019, doi: 10.1186/S41927-019-0061-
Z.
[59] Maz M. et al., “2021 American College of Rheumatology/Vasculitis
Foundation Guideline for the Management of Giant Cell Arteritis
and Takayasu Arteritis,” Arthritis and Rheumatology, vol. 73, no. 8,

pp. 1349–1365, Aug. 2021, doi: 10.1002/ART.41774.
[60] L. R et al., “The Role of Ultrasound Compared to Biopsy of
Temporal Arteries in the Diagnosis and Treatment of Giant Cell
Arteritis (TABUL): a diagnostic accuracy and cost-effectiveness
study,” Health technology assessment (Winchester, England), vol.
20, no. 90, pp. 1–270, 2016, doi: 10.3310/HTA20900.
[61] R. E, M. C, G. C. S, C. S, and M. A, “Sensitivity of temporal artery
biopsy in the diagnosis of giant cell arteritis: a systematic literature
review and meta-analysis,” Rheumatology (Oxford, England), vol.
59, no. 5, pp. 1011–1020, May 2020, doi: 10.1093/
RHEUMATOLOGY/KEZ385.
[62] Albert D. M., M. C. Ruchman, and J. L. Keltner, “Skip Areas in
Temporal Arteritis,” Archives of Ophthalmology, vol. 94, no. 12, pp.
2072–2077, 1976, doi: 10.1001/ARCHOPHT.1976.03910
040732006.
[63] G. G et al., “Is colour duplex sonography-guided temporal artery
biopsy useful in the diagnosis of giant cell arteritis? A randomized
study,” Rheumatology (Oxford, England), vol. 54, no. 3, pp. 400–
404, Mar. 2015, doi: 10.1093/RHEUMATOLOGY/KEU241.
[64] H. S and H. GG, “Is temporal artery biopsy prudent?,” Mayo Clinic
proceedings, vol. 59, no. 11, pp. 793–796, 1984, doi:
10.1016/S0025-6196(12)65593-1.
[65] B. LR, M. NR, and G. WR, “Efficacy of unilateral versus bilateral
temporal artery biopsies for the diagnosis of giant cell arteritis,”
American journal of ophthalmology, vol. 128, no. 2, pp. 211–215,
Aug. 1999, doi: 10.1016/S0002-9394(99)00101-4.
[66] B. GS, N. G, and N. R, “Rate of discordant findings in bilateral
temporal artery biopsy to diagnose giant cell arteritis,” The Journal
of rheumatology, vol. 36, no. 4, pp. 794–796, Apr. 2009, doi:
10.3899/JRHEUM.080792.
[67] Breuer G. S., G. Nesher, R. Nesher, and G. S. Breuer, “Rate of
Discordant Findings in Bilateral Temporal Artery Biopsy to
Diagnose Giant Cell Arteritis,” J Rheumatol First, 2009, doi:

10.3899/jrheum.080792.
[68] S. ML, “Brow droop after superficial temporal artery biopsy,”
Archives of ophthalmology (Chicago, Ill. : 1960), vol. 104, no. 8, p.
1127, 1986, doi: 10.1001/ARCHOPHT.1986.01050200033026.
[69] B. MT and T. RM, “Partial facial paralysis following temporal
artery biopsy,” Eye (London, England), vol. 14, no. Pt 6, pp. 918–
919, 2000, doi: 10.1038/EYE.2000.257.
[70] Y. MK, H. JC, and M. TJ, “Facial nerve injury: a complication of
superficial temporal artery biopsy,” American journal of
ophthalmology, vol. 152, no. 2, 2011, doi: 10.1016/J.AJO.2011.
02.003.
[71] Rison R. A., “Branch facial nerve trauma after superficial temporal
artery biopsy: a case report,” Journal of Medical Case Reports 2011
5:1, vol. 5, no. 1, pp. 1–3, Jan. 2011, doi: 10.1186/1752-1947-5-34.
[72] M. AP and B. JR, “Brow ptosis after temporal artery biopsy:
incidence and associations,” Ophthalmology, vol. 119, no. 12, pp.
2637–2642, 2012, doi: 10.1016/J.OPHTHA.2012.07.020.
[73] S. SJ, “On the occurrence of necrotising lesions in arteritis
temporalis: review of the literature with a note on the potential risk
of a biopsy,” British journal of plastic surgery, vol. 40, no. 1, pp.
73–82, 1987, doi: 10.1016/0007-1226(87)90015-4.
[74] Schmidt W. A., H. E. Kraft, K. Vorpahl, L. Völker, and E. J.
Gromnica-Ihle, Color Duplex Ultrasonography in the Diagnosis of
Temporal Arteritis, http://dx.doi.org/10.1056/NEJM1997110
63371902, vol. 337, no. 19, pp. 1336–1342, Aug. 2009, doi:
10.1056/NEJM199711063371902.
[75] Duftner C., C. Dejaco, A. Sepriano, L. Falzon, W. A. Schmidt, and
S. Ramiro, “Imaging in diagnosis, outcome prediction and
monitoring of large vessel vasculitis: a systematic literature review
and meta-analysis informing the EULAR recommendations,” RMD
Open, vol. 4, no. 1, p. e000612, Feb. 2018, doi: 10.1136/
RMDOPEN-2017-000612.
[76] Chrysidis S. et al., “Original article: Definitions and reliability

assessment of elementary ultrasound lesions in giant cell arteritis: a
study from the OMERACT Large Vessel Vasculitis Ultrasound
Working Group,” RMD Open, vol. 4, no. 1, 2018, doi: 10.1136/
RMDOPEN-2017-000598.
[77] A. M et al., “Temporal artery compression sign--a novel ultrasound
finding for the diagnosis of giant cell arteritis,” Ultraschall in der
Medizin (Stuttgart, Germany : 1980), vol. 34, no. 1, pp. 47–50,
2013, doi: 10.1055/S-0032-1312821.
[78] Aschwanden M. et al., “The ultrasound compression sign to
diagnose temporal giant cell arteritis shows an excellent
interobserver agreement,” Clinical and experimental rheumatology,
vol. 33, no. 2, Mar. 2015.
[79] H. C et al., “Effects of early corticosteroid treatment on magnetic
resonance imaging and ultrasonography findings in giant cell
arteritis,” Rheumatology (Oxford, England), vol. 51, no. 11, pp.
1999–2003, Nov. 2012, doi: 10.1093/RHEUMATOLOGY/
KES153.
[80] P. C et al., “Ultrasound halo sign as a potential monitoring tool for
patients with giant cell arteritis: a prospective analysis,” Annals of
the rheumatic diseases, p. annrheumdis-2021-220306, Jul. 2021,
doi: 10.1136/ANNRHEUMDIS-2021-220306.
[81] L. R et al., “The Role of Ultrasound Compared to Biopsy of
Temporal Arteries in the Diagnosis and Treatment of Giant Cell
Arteritis (TABUL): a diagnostic accuracy and cost-effectiveness
study,” Health technology assessment (Winchester, England), vol.
20, no. 90, pp. 1–270, 2016, doi: 10.3310/HTA20900.
[82] K. FB, M. MI, S. WA, and I. JP, “Meta-analysis: test performance
of ultrasonography for giant-cell arteritis,” Annals of internal
medicine, vol. 142, no. 5, pp. 359–369, Mar. 2005, doi:
10.7326/0003-4819-142-5-200503010-00011.
[83] Arida A., M. Kyprianou, M. Kanakis, and P. P. Sfikakis, “The
diagnostic value of ultrasonography-derived edema of the temporal
artery wall in giant cell arteritis: a second meta-analysis,” BMC
Musculoskeletal Disorders, vol. 11, p. 44, 2010, doi: 10.1186/ 1471-

2474-11-44.
[84] Duftner C., C. Dejaco, A. Sepriano, L. Falzon, W. A. Schmidt, and
S. Ramiro, “Imaging in diagnosis, outcome prediction and
monitoring of large vessel vasculitis: a systematic literature review
and meta-analysis informing the EULAR recommendations,” RMD
Open, vol. 4, no. 1, p. e000612, Feb. 2018, doi: 10.1136/
RMDOPEN-2017-000612.
[85] R. M et al., “Diagnostic performance of temporal artery ultrasound
for the diagnosis of giant cell arteritis: a systematic review and meta-
analysis of the literature,” Autoimmunity reviews, vol. 18, no. 1, pp.
56–61, Jan. 2019, doi: 10.1016/J.AUTREV.2018.07.012.
[86] Hop H. et al., “Diagnostic value of axillary artery ultrasound in
patients with suspected giant cell arteritis,” Rheumatology (Oxford,
England), vol. 59, no. 12, p. 3676, Dec. 2020, doi: 10.1093/
RHEUMATOLOGY/KEAA102.
[87] R. M et al., “High-Resolution Magnetic Resonance Imaging of
Scalp Arteries for the Diagnosis of Giant Cell Arteritis: Results of a
Prospective Cohort Study,” Arthritis & rheumatology (Hoboken,
N.J.), vol. 69, no. 1, pp. 161–168, Jan. 2017, doi: 10.1002/ART.
39824.
[88] V. S et al., “MRI displays involvement of the temporalis muscle and
the deep temporal artery in patients with giant cell arteritis,”
European radiology, vol. 24, no. 11, pp. 2971–2979, Nov. 2014,
doi: 10.1007/S00330-014-3255-1.
[89] F. P et al., “Evaluation of a 32-channel versus a 12-channel head
coil for high-resolution post-contrast MRI in giant cell arteritis
(GCA) at 3T,” European journal of radiology, vol. 83, no. 10, pp.
1875–1880, Oct. 2014, doi: 10.1016/J.EJRAD.2014.06.022.
[90] G. J, B. T, U. M, F. A, L. M, and M. M, “Diagnostic value of T2-
weighted imaging for the detection of superficial cranial artery
inflammation in giant cell arteritis,” Journal of magnetic resonance
imaging : JMRI, vol. 31, no. 2, pp. 470–474, Feb. 2010, doi:
10.1002/JMRI.22047.
[91] B. TA et al., “Diagnostic value of high-resolution MR imaging in

giant cell arteritis,” AJNR. American journal of neuroradiology, vol.
28, no. 9, pp. 1722–1727, Oct. 2007, doi: 10.3174/AJNR. A0638.
[92] B. TA et al., “Assessment of the cranial involvement pattern of giant
cell arteritis with 3T magnetic resonance imaging,” Arthritis and
10.1002/ART.21226.
[93] Klink T. et al., “giant cell arteritis: Diagnostic Accuracy of MR
Imaging of Superficial Cranial Arteries in Initial Diagnosis-Results
from a Multicenter Trial 1,” Radiology, vol. 273, no. 3, 2014, doi:
10.1148/radiol.14140056.
[94] S. AM et al., “Diagnostic Accuracy of Positron Emission
Tomography/Computed Tomography of the Head, Neck, and Chest
for Giant Cell Arteritis: A Prospective, Double-Blind, Cross-
Sectional Study,” Arthritis & rheumatology (Hoboken, N.J.), vol.
71, no. 8, pp. 1319–1328, Aug. 2019, doi: 10.1002/ART.40864.
[95] Braun J., X. Baraliakos, and M. Fruth, “The role of 18F-FDG
positron emission tomography for the diagnosis of vasculitides,”
Clinical and Experimental Rheumatology, vol. 36, pp. S108–S114,
2018.
[96] B. M et al., “Role of positron emission tomography in the
assessment of disease burden and risk of relapse in patients affected
by giant cell arteritis,” Clinical rheumatology, vol. 39, no. 4, pp.
1277–1281, Apr. 2020, doi: 10.1007/S10067-019-04808-7.
[97] de B. H et al., “Giant-Cell Arteritis: Do We Treat Patients with
Large-Vessel Involvement Differently?,” The American journal of
medicine, vol. 130, no. 8, pp. 992–995, Aug. 2017, doi:
10.1016/J.AMJMED.2017.03.054.
[98] S. AM et al., “Diagnostic Accuracy of Positron Emission
Tomography/Computed Tomography of the Head, Neck, and Chest
for Giant Cell Arteritis: A Prospective, Double-Blind, Cross-
Sectional Study,” Arthritis & rheumatology (Hoboken, N.J.), vol.
71, no. 8, pp. 1319–1328, Aug. 2019, doi: 10.1002/ART.40864.
[99] A. PD, T. JC, M. TJ, K. AR, and H. GG, “Visual prognosis in giant
cell arteritis,” Ophthalmology, vol. 100, no. 4, pp. 550–555, 1993,
doi: 10.1016/S0161-6420(93)31608-8.
[100] Gonzalez-gay M. A. et al., “Permanent Visual Loss and
Cerebrovascular Accidents in Giant Cell Arteritis Predictors and
Response to Treatment,” Arthritis & Rheumatism, vol. 41, no. 8, pp.
1497–1504, 1998, doi: 10.1002/1529-0131.
[101] A. R, M. BE, and B. BA, “Long-term corticosteroid treatment in
giant cell arteritis,” Acta medica Scandinavica, vol. 220, no. 5, pp.
465–469, 1986, doi: 10.1111/J.0954-6820.1986.TB02796.X.
[102] Salvarani C. et al., Epidemiologic and Immunogenetic Aspects of
Polymyalgia Rheumatica and Giant Cell Arteritis in Northern Italy.
[103] P. A, G. SE, O. C, O. WM, and H. GG, “Glucocorticoid therapy in
giant cell arteritis: duration and adverse outcomes,” Arthritis and
rheumatism, vol. 49, no. 5, pp. 703–708, Oct. 2003, doi: 10.1002/
ART.11388.
[104] K. N and E. E, “Diagnosis and management of giant cell arteritis: a
review,” Current opinion in ophthalmology, vol. 21, no. 6, pp. 417–
422, Nov. 2010, doi: 10.1097/ICU.0B013E32833EAE8B.
[105] M. M et al., “Treatment of giant cell arteritis using induction therapy
with high-dose glucocorticoids: a double-blind, placebo-controlled,
randomized prospective clinical trial,” Arthritis and rheumatism,
vol. 54, no. 10, pp. 3310–3318, Oct. 2006, doi: 10.1002/
ART.22163.
[106] R. W and R. FZ, “Giant cell (temporal) arteritis: an overview and
update,” Survey of ophthalmology, vol. 50, no. 5, pp. 415–428, Sep.
2005, doi: 10.1016/J.SURVOPHTHAL.2005.06.011.
[107] M. SL et al., “British Society for Rheumatology guideline on
diagnosis and treatment of giant cell arteritis,” Rheumatology
(Oxford, England), vol. 59, no. 3, pp. E1–E23, Mar. 2020, doi:
10.1093/RHEUMATOLOGY/KEZ672.
[108] P. et al., Chevalet, “A randomized, multicenter, controlled trial
using intravenous pulses of methylprednisolone in the initial
treatment of simple forms of giant cell arteritis: a one year follow-

up study of 164 patients,” J Rheumatol, Jun. 2000.
[109] H. SS and Z. B, “Visual deterioration in giant cell arteritis patients
while on high doses of corticosteroid therapy,” Ophthalmology, vol.
110, no. 6, pp. 1204–1215, Jun. 2003, doi: 10.1016/S0161-
6420(03)00228-8.
[110] Mazlumzadeh M. et al., “Treatment of Giant Cell Arteritis Using
Induction Therapy With High-Dose Glucocorticoids A Double-
Blind, Placebo-Controlled, Randomized Prospective Clinical Trial,”
Arthritis & Rheumatism, vol. 54, no. 10, pp. 3310–3318, 2006, doi:
10.1002/art.22163.
[111] J. F, C. JF, and E. RA, “Temporal arteritis. A 14-year
epidemiological, clinical and prognostic study,” Scottish medical
journal, vol. 24, no. 2, pp. 2127–2132, 1979, doi: 10.1177/0036
93307902400203.
[112] Proven A., S. E. Gabriel, C. Orces, W. M. O’Fallon, and G. G.
Hunder, “Glucocorticoid therapy in giant cell arteritis: Duration and
adverse outcomes,” Arthritis Care & Research, vol. 49, no. 5, pp.
703–708, Oct. 2003, doi: 10.1002/ART.11388.
[113] Chandran A., P. D. Udayakumar, T. A. Kermani, K. J. Warrington,
C. S. Crowson, and E. L. Matteson, “Glucocorticoid Usage in Giant
Cell Arteritis over Six Decades (1950 to 2009),” Clinical and
experimental rheumatology, vol. 33, no. 2 0 89, p. S, Mar. 2015,
Accessed: Jul. 20, 2021. [Online]. Available: /pmc/articles/
PMC4515753/
[114] B. MS et al., “Corticosteroid-related adverse events in patients with
giant cell arteritis: A claims-based analysis,” Seminars in arthritis
and rheumatism, vol. 46, no. 2, pp. 246–252, Oct. 2016, doi:
10.1016/J.SEMARTHRIT.2016.05.009.
[115] W. JC et al., “Serious adverse effects associated with glucocorticoid
therapy in patients with giant cell arteritis (GCA): A nested case-
control analysis,” Seminars in arthritis and rheumatism, vol. 46, no.
6, pp. 819–827, Jun. 2017, doi: 10.1016/J.SEMARTHRIT.
2016.11.006.
[116] M. JJ et al., “Clinical and pathological evolution of giant cell

arteritis: a prospective study of follow-up temporal artery biopsies
in 40 treated patients,” Modern pathology : an official journal of the
United States and Canadian Academy of Pathology, Inc, vol. 30, no.
6, pp. 788–796, Jun. 2017, doi: 10.1038/MODPATHOL. 2017.10.
[117] N. DM, H. GG, C. TJ, M. RL, and M. EL, “Incidence and predictors
of large-artery complication (aortic aneurysm, aortic dissection,
and/or large-artery stenosis) in patients with giant cell arteritis: a
population-based study over 50 years,” Arthritis and rheumatism,
vol. 48, no. 12, pp. 3522–3531, Dec. 2003, doi: 10.1002/
ART.11353.
[118] E. JM, O. WM, and H. GG, “Increased incidence of aortic aneurysm
and dissection in giant cell (temporal) arteritis. A population-based
study,” Annals of internal medicine, vol. 122, no. 7, pp. 502–507,
Apr. 1995, doi: 10.7326/0003-4819-122-7-199504010-00004.
[119] M. AD et al., “Adjunctive methotrexate for treatment of giant cell
arteritis: an individual patient data meta-analysis,” Arthritis and
10.1002/ART.22754.
[120] Leon L. et al., “Treatment with methotrexate and risk of relapses in
patients with giant cell arteritis in clinical practice,” Clinical and
Experimental Rheumatology, vol. 36, pp. S121–S128, 2018.
[121] H. GS et al., “A multicenter, randomized, double-blind, placebo-
controlled trial of adjuvant methotrexate treatment for giant cell
arteritis,” Arthritis and rheumatism, vol. 46, no. 5, pp. 1309–1318,
2002, doi: 10.1002/ART.10262.
[122] Christidis D., S. Jain, and B. das Gupta, “Novel treatment (new
drug/intervention; established drug/procedure in new situation):
Successful use of tocilizumab in polymyalgic onset biopsy positive
GCA with large vessel involvement,” BMJ Case Reports, vol. 2011,
2011, doi: 10.1136/BCR.04.2011.4135.
[123] U. S et al., “Tocilizumab for the treatment of large-vessel vasculitis
(giant cell arteritis, Takayasu arteritis) and polymyalgia
rheumatica,” Arthritis care & research, vol. 64, no. 11, pp. 1720–
1729, Nov. 2012, doi: 10.1002/ACR.21750.
[124] L. J et al., “Tocilizumab in giant cell arteritis: Multicenter open-
label study of 22 patients,” Seminars in arthritis and rheumatism,
vol. 44, no. 6, pp. 717–723, Jun. 2015, doi: 10.1016/J.
SEMARTHRIT.2014.12.005.
[125] V. PM et al., “Tocilizumab for induction and maintenance of
remission in giant cell arteritis: a phase 2, randomised, double-blind,
placebo-controlled trial,” Lancet (London, England), vol. 387, no.
10031, pp. 1921–1927, May 2016, doi: 10.1016/S0140-
6736(16)00560-2.
[126] Stone J. H. et al., “OP0140 Long-Term Outcome of Tocilizumab for
Patients with Giant Cell Arteritis: Results from Part 2 of the Giacta
Trial,” Annals of the Rheumatic Diseases, vol. 78, no. Suppl 2, pp.
145–146, Jun. 2019, doi: 10.1136/ANNRHEUMDIS-2019-
EULAR.2099.
[127] R. S et al., “Magnetic resonance angiography in giant cell arteritis:
results of a randomized controlled trial of tocilizumab in giant cell
arteritis,” Rheumatology (Oxford, England), vol. 57, no. 6, pp. 982–
986, Jun. 2018, doi: 10.1093/RHEUMATOLOGY/KEY015.
[128] Dospinescu P. I. et al., “SAT0362 Mycophenolate Mofetil versus
Methotrexate in the Management of Large Vessel Giant Cell
Arteritis,” Annals of the Rheumatic Diseases, vol. 75, no. Suppl 2,
pp. 798–798, Jun. 2016, doi: 10.1136/ANNRHEUMDIS-2016-
EULAR.4330.
[129] K. H. Ly et al., “Steroid-sparing effect and toxicity of dapsone
treatment in giant cell arteritis: A single-center, retrospective study
of 70 patients,” Medicine (United States), vol. 95, no. 42, 2016, doi:
10.1097/MD.0000000000004974.
[130] Q. L et al., “Role of oral cyclophosphamide in the treatment of giant
cell arteritis,” Rheumatology (Oxford, England), vol. 51, no. 9, pp.
1677–1686, Sep. 2012, doi: 10.1093/RHEUMATOLOGY/
KES127.
[131] de B. H et al., “Is there a place for cyclophosphamide in the

treatment of giant-cell arteritis? A case series and systematic
review,” Seminars in arthritis and rheumatism, vol. 43, no. 1, pp.
105–112, Aug. 2013, doi: 10.1016/J.SEMARTHRIT.2012.12.023.
[132] Loock J. et al., “Treatment of refractory giant cell arteritis with
cyclophosphamide: A retrospective analysis of 35 patients from
three centres,” Clinical and Experimental Rheumatology, vol. 30,
no. SUPPL. 70, 2012.
[133] Adizie T., D. Christidis, C. Dharmapaliah, F. Borg, and B.
Dasgupta, “Efficacy and tolerability of leflunomide in difficult-to-
treat polymyalgia rheumatica and giant cell arteritis: a case series,”
International Journal of Clinical Practice, vol. 66, no. 9, pp. 906–
909, Sep. 2012, doi: 10.1111/J.1742-1241.2012.02981.X.
[134] Diamantopoulos A. P., H. Hetland, and G. Myklebust,
“Leflunomide as a Corticosteroid-Sparing Agent in Giant Cell
Arteritis and Polymyalgia Rheumatica: A Case Series,” BioMed
Research International, vol. 2013, 2013, doi: 10.1155/2013/
120638.
[135] D. S. M and H. BL, “Azathioprine in giant cell arteritis/polymyalgia
rheumatica: a double-blind study,” Annals of the rheumatic
diseases, vol. 45, no. 2, pp. 136–138, 1986, doi:
10.1136/ARD.45.2.136.
[136] H. R. J et al., “Tissue production of pro-inflammatory cytokines (IL-
1beta, TNFalpha and IL-6) correlates with the intensity of the
systemic inflammatory response and with corticosteroid
requirements in giant-cell arteritis,” Rheumatology (Oxford,
England), vol. 43, no. 3, pp. 294–301, Mar. 2004, doi: 10.1093/
RHEUMATOLOGY/KEH058.
[137] H. GS et al., “Infliximab for maintenance of glucocorticosteroid-
induced remission of giant cell arteritis: a randomized trial,” Annals
of internal medicine, vol. 146, no. 9, pp. 621–630, May 2007, doi:
10.7326/0003-4819-146-9-200705010-00004.
[138] S. R et al., “Adalimumab for steroid sparing in patients with giant-
cell arteritis: results of a multicentre randomised controlled trial,”
Annals of the rheumatic diseases, vol. 73, no. 12, pp. 2074–2081,
Dec. 2014, doi: 10.1136/ANNRHEUMDIS-2013-203586.
[139] M. T. VM et al., “A double-blind placebo controlled trial of
etanercept in patients with giant cell arteritis and corticosteroid side
effects,” Annals of the rheumatic diseases, vol. 67, no. 5, pp. 625–
630, May 2008, doi: 10.1136/ARD.2007.082115.
[140] Lee M. S., S. D. Smith, A. Galor, and G. S. Hoffman, “Antiplatelet
and anticoagulant therapy in patients with giant cell arteritis,”
Arthritis & Rheumatism, vol. 54, no. 10, pp. 3306–3309, Oct. 2006,
doi: 10.1002/ART.22141.
[141] Nesher G., Y. Berkun, M. Mates, M. Baras, A. Rubinow, and M.
Sonnenblick, “Low-dose aspirin and prevention of cranial ischemic
complications in giant cell arteritis,” Arthritis & Rheumatism, vol.
50, no. 4, pp. 1332–1337, Apr. 2004, doi: 10.1002/ART.20171.
[142] Langford C. A. et al., “A Randomized, Double-Blind Trial of
Abatacept (CTLA4-IG) for the Treatment of Giant Cell Arteritis,”
Arthritis & rheumatology (Hoboken, N.J.), vol. 69, no. 4, p. 837,
Apr. 2017, doi: 10.1002/ART.40044.
[143] C. R et al., “Ustekinumab for the treatment of refractory giant cell
arteritis,” Annals of the rheumatic diseases, vol. 75, no. 8, pp. 1578–
1579, Aug. 2016, doi: 10.1136/ANNRHEUMDIS-2016-209351.
[144] D. S et al., “Steroid-sparing effect of anakinra in giant-cell arteritis:
a case series with clinical, biological and iconographic long-term
assessments,” Rheumatology (Oxford, England), Mar. 2021, doi:
10.1093/RHEUMATOLOGY/KEAB280.
[145] L. KH, S. J, L. E, M. M, F. O, and F. AL, “Interleukin-1 blockade
in refractory giant cell arteritis,” Joint bone spine, vol. 81, no. 1, pp.
76–78, Jan. 2014, doi: 10.1016/J.JBSPIN.2013.06.004.
[146] Giant Cell Arteritis and Anakinra Trial - Full Text View -
ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT029
02731 (accessed Jul. 20, 2021).
[147] M. B, H. M, B. S, W. M, and T. J, “The first case of a patient with
neutropenia and giant-cell arteritis treated with rituximab,” Clinical
rheumatology, vol. 26, no. 9, pp. 1597–1598, Sep. 2007, doi:

10.1007/S10067-007-0684-0.
[148] Bhatia A., P. Ell, and J. Edwards, “Anti-CD20 monoclonal antibody
(rituximab) as an adjunct in the treatment of giant cell arteritis,”
Annals of the Rheumatic Diseases, vol. 64, no. 7, p. 1099, Jul. 2005,
doi: 10.1136/ARD.2005.036533.
[149] van der G. KS et al., “Serum markers associated with disease
activity in giant cell arteritis and polymyalgia rheumatica,”
Rheumatology (Oxford, England), vol. 54, no. 8, pp. 1397–1402,
May 2015, doi: 10.1093/RHEUMATOLOGY/KEU526.
[150] van der G. KS et al., “Disturbed B cell homeostasis in newly
diagnosed giant cell arteritis and polymyalgia rheumatica,” Arthritis
& rheumatology (Hoboken, N.J.), vol. 66, no. 7, pp. 1927–1938,
2014, doi: 10.1002/ART.38625.
[151] Baricitinib in Relapsing Giant Cell Arteritis - Full Text View -
04 (accessed Jul. 20, 2021).
[152] A Study to Evaluate the Safety and Efficacy of Upadacitinib in
Participants with Giant Cell Arteritis - Full Text View -
202 (accessed Jul. 20, 2021).
Chapter 2
PULMONARY COMPLICATIONS
OF VASCULITIS
Pahnwat Tonya Taweesedt1, Julian Bayati1,

Farah Yasmin2, Munish Sharma1 and Salim Surani3,4*
1
Corpus Christi Medical Center, Corpus Christi, TX, USA
2
Dow Medical College, Dow University of Health Sciences,
Karachi, Pakistan
3
4
ABSTRACT
Vasculitis is an inflammation of the blood vessel. Patients with

connective tissue disease can have a vascular injury which can be primary
or secondary. The primary vasculitis is the inflammation of the blood
vessel, whereas the secondary vasculitis is caused by secondary condition
as connective tissue disease, infection, malignancy or allergy. Primary
vasculitis is defined based on the size of the affected vessel. It can be
* Corresponding Author’s E-mail: srsurani@hotmail.com.

44 Pahnwat Tonya Taweesedt, Julian Bayati, Farah Yasmin et al.
large vessel vasculitis as Takayasu arteritis, medium vessel vasculitis as

polyarteritis nodosa, and small-vessel vasculitis which predominantly
affects small vessels.
Pulmonary vasculitis is a rare condition with an incidence rate of 20-
100 cases/million/year with a prevalence rate of 150-450
cases/million/year. Both large and medium vasculitis can cause
pulmonary involvement. The small vessel vasculitis can usually be
categorized into ANCA and immune complex associated vasculitis, both
of which can cause pulmonary involvement. In this chapter, we will
discuss briefly vasculitis and then will dive into different types of
vasculitis affecting the lungs, their signs, and symptoms, diagnosis,
treatment, and complications needed for the diagnosis. It is considered a
sleep-related movement disorder. Evidence suggests that bruxism is
centrally mediated and is also found to be associated with sleep-related
breathing disorders, psychiatric disorders, neurological disorders, and
gastroesophageal reflux disease. Other factors including substance use,
medications, or genetic factors can increase the risk of bruxism.
Treatment may be behavioral and pharmacologic approach using the oral
or injection medication, and/or avoidance of predisposing factors. Oral
appliances have been used to reduce the damaging effect of grinding or
clenching on teeth in sleep bruxism.
Keywords: pulmonary vasculitis, lung vasculitis, ANCA associated

vasculitis, granulomatosis with polyangiitis, microscopic polyangiitis,
eosinophilic granulomatosis with polyangitis
INTRODUCTION
Systemic vasculitis is a term used to describe a clinicopathological,

various bundles of conditions defined by inflammation of the vascular wall
[1, 2]. The inflammatory process is caused by the immune effector cells
infiltrating the blood vessel and the surrounding tissue. This process leads
to impairment of the blood vessel integrity and narrowing of the lumen
resulting in tissue ischemia and necrosis, ultimately leading to an end-
organ damage [3]. Pulmonary vasculitis is a facet of systemic vasculitis,
referred to as vasculitis syndrome or vasculitides, which includes a broad
variety of different disease entities, all of which encompass inflammation
of the pulmonary vasculature, both arteries, and veins.
Pulmonary Complications of Vasculitis 45
Similar to systemic vasculitis, the vessels involved in pulmonary

vasculitis can vary in size from large elastic vessels to small-caliber vessels
[1, 2, 4, 5]. Among the pulmonary vascular inflammation, the most
frequently affected vessels with small-sized vessels, especially anti-
neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV)
such as microscopic polyangiitis (MPA) and eosinophilic granulomatosis
with polyangiitis (EGPA) [1, 2].
While vasculitis is straightforward to describe, it is not simple to
identify. The presenting signs and symptoms are nonspecific and depend
on the location, size, and type of the blood vessel involved. Additionally,
symptoms usually overlap with other more frequently encountered
diseases that can also be the cause of secondary pulmonary vasculitides,
such as infection, malignancy, or connective tissue diseases [1, 3, 5].
However, the presence of multiple organ system involvements, such as
neurological, cutaneous disease, and renal disease, should raise suspicion
for vasculitis [6]. Once vasculitis has been diagnosed, management is
carried out through the use of immunosuppressive agents and
corticosteroids. Without treatment, pulmonary vasculitis can be fatal.
However, treatment should be tailored to control the disease activity,
symptoms and prevent organ dysfunction while minimizing the side effects
[5, 6].
CLASSIFICATION AND NOMENCLATURE
While vasculitis classification has become more and more elaborated,

some areas remain poorly defined. Certain vasculitis cases with the
nonspecific presentation may still be challenging to assign to a specific
disease group [7]. It is also important to note that classification differs from
nomenclature, as the former aim to categorize illnesses in a broader
framework of medical conditions while the latter mainly deals with names
and definitions of diseases without concentrating on their arrangement [7].
Zeek et al. was the pioneer to carry out vasculitis classification in 1952,
describing five types of vasculitis (Table 1) [8].
Since then, multiple classification systems for vasculitis have been
generated [1, 7]. In 1990, the American College of Rheumatology (ACR)
published a set of classification criteria for seven types of systemic
vasculitis [9, 10]. The goal of ACR for this criteria was to help define
homogeneous groups for epidemiology studies and facilitate comparison
between different therapeutic strategies [10]. Four years later, the Chapel
Hill Consensus Conference (CHCC) defined vasculitis in each condition
[9]. The CHCC nomenclature which was revised in 2012, and now is the
most commonly accepted system (Table 2) [11]. In this nomenclature
system, new names for several diseases were changed, providing better
understanding of the pathophysiology, such as EGPA in place of Churg-
Strauss syndrome and granulomatosis with polyangiitis (GPA) in place of
Wegener’s granulomatosis.
Table 1. Vasculitis classification by Zeek et al. in 1952 [8]
1. Hypersensitivity angiitis
2. Allergic granulomatous angiitis
3. Rheumatic arteritis
4. Periarteritis nodosa
5. Temporal arteritis
Nonetheless, the most popular used approach to classify primary

vasculitis is based on the predominant vessel size (large, medium, and
small) involved [5, 6, 12]. Although the simplicity of this approach might
seem appealing, it has some functional limitations. As in some patients, it
is hard to categorize the diseases that involve more than one size of the
vessels and may lead to misclassification [7]. Currently, well-established
diagnostic criteria for vasculitides do not yet exist [13, 14]. The diagnosis
of vasculitides depends on identifying unique manifestations, imagings,
blood works, and histopathology results [12].
Table 2. The International Chapel Hill Consensus Conference

Nomenclatures of Vasculitides in 2012 [11]
Small-sized vessel vasculitis

Immune complexes related  Immunoglobulin A vasculitis
vasculitides  Cryoglobulinemic vasculitis
 Anti-glomerular basement membrane antibody disease
 Hypocomplementemic urticarial vasculitis
Anti-neutrophil cytoplasmic  Microscopic polyangiitis
antibody positive  Granulomatosis with polyangiitis
 Eosinophilic granulomatosis with polyangiitis/ allergic
angiitis and granulomatosis
Medium-sized vessel vasculitis
 Kawasaki disease
 Polyarteritis nodosa
Large-sized vessel vasculitis
 Takayasu arteritis/Pulseless disease
 Giant cell arteritis/Horton disease/Temporal arteritis
Vasculitis limited to one organ
 Primary central nervous system vasculitis
 Isolated aortitis
 Cutaneous arteritis
 Cutaneous leukocytoclastic vasculitis
Vasculitis related to systemic disease
 Sarcoidosis associated vasculitis
 Lupus associated vasculitis
 Rheumatoid arthritis-associated vasculitis
Vasculitis involving the variable size of vessels
 Cogan’s syndrome
 Behçet disease
Vasculitis due to probable etiologies
 Hepatitis C virus-related cryoglobulinemic vasculitis
 Hepatitis B virus-related vasculitis
 Drug-related immune complex vasculitis
 Drug-related ANCA-associated vasculitis
PREVALENCE
Previous reports showed the prevalence of pulmonary involvement

among patients with primary systemic vasculitis were 89.0% in EGPA, 30-
65.9% in MPA, 64.5-85% in GPA, 4.5-27% in polyarteritis nodosa (PAN),

15-60% in Takayasu arteritis (TA), 9-31% in giant cell arteritis (GCA),
and 5.9% in IgA vasculitis [4, 15, 16].
PATHOPHYSIOLOGY
The etiology of vasculitis is not clearly understood. Presumably, to be

similar to most autoimmune diseases, predisposing factors of vasculitis are
multifactorial. For AAV, antibodies activate neutrophils and monocytes
and promote their migration towards blood vessels resulting in the release
of reactive oxygen species and other enzymes. This process eventually
contributes to the injury and death of endothelial cells and degradation of
the wall [2, 4, 5]. In large arteries, inflammation can result in pain, edema
follows by wall erosion due to the inflammatory cells. While the
inner/sheer pressure leads to dilation and aneurysm, the hyperplasia of
intima and fibrosis of adventitia can lead to stenosis and occlusion [17].
When inflammation presents in vasculitis, the leakage of the red blood cell
into alveolar space may occur causing diffuse alveolar hemorrhage.
Genome-Wide Association Studies and Immunochip studies reported
the association of genetic and vasculitis. Anti-proteinase 3 antibody (anti-
PR3) is found to be associated with HLA-DP (DPB1 and DPA1), serpin
family A member 1 (SERPINA1), and proteinase 3 (PRTN3); anti-
myeloperoxidase antibody (anti-MPO) is noted to be associated with HLA-
DQB1 [18, 19]. Other systemic vasculitides also had genetic associations
such as PTPN22 in GCA, HLA-DRB4 in EGPA, and HLA-B*51 in Behçet
disease [19, 20]. Environmental factors, particularly silica exposure, have
been documented to be associated with anti-MPO positive AAV with lung
involvement [21]. Infectious organisms related to vasculitis have been
reported, e.g., Staphylococcus, Streptococcus, Enterococcus, Parvovirus
B-19, Epstein-Barr virus, and Ross River virus as well as the severe acute
respiratory syndrome-related coronavirus-2 (SARS-CoV-2) [22–24].
Infection is thought to induce the pro-inflammatory cytokines including
tumor necrosis factor-alpha (TNF-α), interferon-gamma. It causes immune
reaction through the response of autoantibodies to microbial or ANCA

formation as the result of human protein mimicry such as complementary
PR3 [25]. Common medications related to vasculitis has been described
such as propylthiouracil (PTU), hydralazine, levamisole, anti-TNF-α, and
immune checkpoint inhibitors [19, 26, 27].
PULMONARY VASCULITIS
Large-Vessel Vasculitis
Giant Cell Arteritis

GCA, also known as Horton disease or temporal arteritis, is a systemic
vasculitis that involves medium to large-size vessels, preferably cranial
branches of the aorta. GCA affects various vessels: subclavian, iliac,
ophthalmic, occipital, and pulmonary arteries. The incidence of giant cell
arteritis (GCA) was 12.3 cases per 100,000 populations per year with age
≥ 50 years and was female predominant [28]. It should be suspected in
patients with age more than 50 years old, who have new-onset headaches
(particularly in the temporal region), acute onset of visual disturbance
(especially transient monocular visual loss), jaw claudication. Many
patients with GCA report constitutional symptoms (15%) [3].
Approximately 9-31% of the cases reported respiratory symptoms, such as
cough, shortness of breath, and sore throat [15, 29, 30]. GCA can lead to
aneurysms and claudication of the upper extremities [31]. Since
polymyalgia rheumatica (PMR) coexist in 40-60% of GCA cases, GCA
symptoms should be obtained when evaluating patients with PMR [31].
Diagnosis of GCA based on ACR required three of five criteria (Table
3) [32]. Elevated sedimentation rate (ESR) and C-reactive protein are
typically found in the majority of the cases (> 90%). Usually, an ESR of
equal or more than 50 mm/h is used as one of the diagnosis criteria. The
gold standard “temporal artery biopsy” usually revealed pan-arteritis of the
media with infiltration of CD4+ lymphocytes, macrophages, and
multinucleated giant cells. Although commonly found on biopsy, the giant
cell is not required to diagnose GCA. In a systematic review of a total of

3092 patients, temporal biopsies had a sensitivity of 77% [33]. False-
negative temporal artery biopsy result in GCA patients can occur up to
44%, which may be due to “skip area” or short length biopsy. Imaging
studies are not required but can evaluate vascular inflammation without
doing the biopsy, which is the gold standard [34]. Meta-analysis showed
that ultrasonography of the temporal artery could detect “Halo” sign,
stenosis, or occlusion in the temporal artery with a sensitivity of 68% and
specificity of 81% when compared to biopsy [35]. Magnetic resonance
angiogram (MRA) and computed tomography with an angiogram (CTA)
can detect large vessel abnormalities in patients with GCA. Moreover,
fluorodeoxyglucose-positron emission tomography use for GCA diagnosis
has a sensitivity of 80% and a specificity of 89% [36].
Pulmonary vasculitis in GCA is rare. It may affect both medium and
large-sized vessels causing pulmonary artery vasculitis, pulmonary artery
thrombosis, pulmonary infarction, alveolar hemorrhage. The uncommon
pulmonary manifestations of GCA include lung nodules, infiltration,
interstitial lung disease (ILD), and pleural effusion [16]. Pleural effusion
in GCA is usually unilateral, exudative, and lymphocytes predominant [3,
37]. Also, idiopathic isolated pulmonary GCA is a rare condition reported
to lead to cor pulmonale [38].
Similar to GCA in general, treatment with high dose systemic
glucocorticoids is the mainstay for GCA with lung involvement. Forty to
sixty mg prednisolone-equivalent/day is recommended to initiate and
continue until symptoms resolve and inflammatory markers decrease.
Symptoms usually improve within 24-48 hours of glucocorticoid
treatment. Taper protocol of prednisolone shall be started once patients are
in remission to reach 15-20 mg/day within few months, then ≤ 5 mg/day
one year, followed by decreasing by 1 mg every 1-2 months [39].
Adjunctive therapies for GCA, including tocilizumab, methotrexate,
leflunomide, abatacept, ustekinumab, and anti-TNF-α have been studies.
Thus far, only tocilizumab has been approved. The Giant-Cell Arteritis
Actemra (GiACTA) trial demonstrated the superiority of prednisolone and
tocilizumab to prednisolone alone in maintaining remission after 52 weeks
of treatment [40]. Steroid sparing therapies may be a benefit in cases with

premorbid diseases, significant glucocorticoid-related side effects, or
relapsing diseases [3].
Table 3. The American College of Rheumatology diagnostic criteria

in 1990 for giant cell arteritis* [32]
1. Age of > 50 years old at the initial presentation

2. New onset of cephalea
3. Diminished pulse of temporal artery
4. Erythrocyte sedimentation rate of ≥ 50 mm/h
5. Abnormal artery biopsy: vasculitis defined by mononuclear cell infiltration or granulomatous
inflammation with multinucleated giant cells
*Need to have at least three criteria for the diagnosis.
5.1.2. Takayasu Arteritis

TA, also known as pulseless disease, is commonly observed in young,
Asian, females (80-90% of cases) [41]. It predominantly affected the aorta
followed by the pulmonary artery. The latter was found in 15-60% of the
patients and may lead to aneurysm, vessel wall thickening, or pulmonary
arterial hypertension [16]. Signs and symptoms include constitutional
symptoms, limb claudication, diminished peripheral pulses, discrepant
blood pressure between both arms, subclavian or aortic bruit/murmur due
to the narrowing or occlusion. The most common site of diminished or
absent pulses was found at the radial artery level [42]. At initial
presentation, the carotid artery's tenderness was reported in 10-30% of the
cases [43]. Dyspnea (14.7%), cough (7.6%), hemoptysis, and chest pain
have been reported. Pulmonary vasculitis, pulmonary artery aneurysm,
pulmonary ischemia, and pulmonary infarction due to stenosis or
thromboembolism were seen in TA [44].
Diagnosis criteria by the 1990 ACR classification criteria for Takayasu
arteritis are composed of the followings: 1. age less than 40 years on the
initial presentation of symptoms, 2. one extremity claudication, 3.
decreased brachial artery pulse, 4. more than 10 mmHg discrepancy of
systolic blood pressure between both upper extremities, 5. subclavian or
aortic murmur, and 6. arteriography reveals decreased lumen size or
occlusion of the aorta or aortic main branches as well as large-sized

proximal arteries of the arms/legs. The diagnosis requires three out of six
criteria to be met. Newer criteria by Ishikawa for TA, was later adjusted
by Sharma et al. (Table 4). The modified Ishikawa criteria showed a 92.5%
sensitivity and 95% specificity [45].
Table 4. The modified Ishikawa criteria for Takayasu arteritis [45]
Major criteria
1. Left mid-subclavian artery stenosis/occlusion
2. Right mid-subclavian artery stenosis/occlusion
3. Signs and symptoms ≥ one month
Minor criteria
1. ESR > 20 mm/h
2. Tenderness on palpation of the carotid artery
3. High blood pressure
4. Aortic regurgitation
5. Occluded pulmonary artery or equivalent
6. Left mid-common carotid stenosis/occlusion
7. Distal brachiocephalic trunk stenosis/occlusion
8. Descending thoracic aorta with narrowing/irregular lumen, dilatation, or aneurysm
9. Abdominal aorta with narrowing/irregular lumen, dilatation, or aneurysm
10. Coronary artery abnormalities
*At least two major or one major and two minor criteria or four minor criteria are required.
Imaging of aorta and pulmonary vessels is essential for the diagnosis

and evaluation of the disease extension. It can be obtained by
arteriography, CTA, MRA, or color doppler ultrasonography.
Transthoracic echocardiography is recommended to assess pulmonary
hypertension. Pulmonary vessel involvement in TA can also be identified
by echocardiography as follows; right pulmonary artery left pulmonary
artery, and right upper lobe artery [46]. Erythrocyte sediment rate (ESR) is
usually elevated more than 20 mm/h but can be within normal level even
in inactive disease [47]. Biopsy result of TA revealed a focal
granulomatous pan-arteritis with lymphocytes, histiocytes, macrophages,
plasma cells, and giant cells [3]. However, a biopsy of the organ
involvement in TA is considered risky and not required for the diagnosis
of TA.
Like GCA, high-dose systemic glucocorticoids (prednisolone 40-60

mg/day) are the therapy of choice in TA. A large cohort of TA reported
that 20-30 mg of prednisolone-equivalent/day might be an adequate dose
for initial treatment of TA with limited vascular involvement. Owing to the
high rate of relapsing, adding steroid-sparing agents is usually
recommended. Nonbiologic disease-modifying antirheumatic drugs such
as methotrexate, azathioprine, mycophenolate mofetil, and biologics
therapies such as tocilizumab have shown benefit in TA treatment [39].
Endovascular intervention or surgical procedure may be considered in
GCA and TA when patients have non-resolving stenosis resulting in
critical ischemia of large aneurysm [39].
Medium-Vessel Vasculitis
Polyarteritis Nodosa
PAN is a systemic necrotizing vasculitis that predominantly involves
a medium-sized artery but may occur among small-sized vessels.
Incidence of PAN varies from 2.4 to 77 cases per million and is decreasing,
possibly related to viral hepatitis incidence in different regions [48, 49].
Age onset of PAN typically ranges from 9-10 years in children and 25-50
years in the adult with peaks at 60 years old [50]. The male gender is more
commonly found to have PAN than the female gender. PAN etiology can
be idiopathic or secondary to other causes such as hepatitis B virus,
hepatitis C virus, and hairy cell leukemia [51]. Patients with PAN usually
presented with constitutional symptoms, including fever (64%), myalgia
(59.4%), and weight loss (48.9%). Approximately 50-80% of PAN
involved skin such as livedo reticularis, palpable purpura, erythema
nodules, and ulceration [50, 52]. Neurological involvement ranges from
32.3-70% commonly affects mono/polyneuropathy of radial, ulnar and
peroneal nerves [53]. PAN involves renal systems in 40.6% of cases and
may result in high blood pressure, renal insufficiency, or infarction. If
glomerulonephritis happens, other diagnoses should be considered as it is
not associated with PAN. PAN affects testicular 10.5% of cases causing
testicular pain [50]. Mesenteric ischemia or bowel perforation can be the

result of gastrointestinal involvement in PAN [3].
Pulmonary involvement in PAN is not common ranging from 4.5-27%
of the cases [15]. Respiratory symptoms of PAN include dyspnea (18.8%),
cough (16.7%; dry cough of 10.4%, productive cough of 6.3%, hemoptysis
of 4.2%), and pleuritic chest pain (4.2%) [21]. Pulmonary arteritis,
bronchial arteritis, pulmonary artery aneurysm, bronchiolitis obliterans,
organizing pneumonia, and diffuse alveolar hemorrhage related to PAN
have been reported [4]. Consolidation and effusion were seen in 5 and 3
out of 28 PAN cases with lung imaging [15].
According to the 1990 ACR criteria, PAN can be diagnosed when
three out of 10 features are met. This criterion gives a sensitivity of 82.2%
and specificity of 86.6% (Table 5) [54].
Table 5. The American College of Rheumatology 1990 criteria for

polyarteritis nodosa diagnosis*[54]
1. Decreased in body weight > 4 kilograms

2. Mottled or reticulated vascular pattern with purplish discoloration of the skin
3. Painful or tenderness of the testicles
4. Soreness, weakness, or tenderness of lower extremities muscles
5. Mono/polyneuropathy
6. Diastolic blood pressure > 90 mmHg
7. Blood urea nitrogen elevation of more than 40 mg/dl or creatinine more than 1.5 mg/dl not
because of another cause
8. Hepatitis B virus infection (acute)
9. Abnormal arterial imaging
10. Granulocytes in the artery wall from the biopsy of the mall or medium-caliber artery
* At least three criteria are needed.
Biopsy of PAN is often needed to help with diagnosis and usually

revealed localized necrotizing medium or small artery with
polymorphonuclear leukocytes. ESR and CRP can be elevated but not
specific for diagnosis in PAN. ANCA antibodies are generally negative in
PAN. Imaging studies include the arteriography of the renal or visceral
artery, which can confirm the PAN abnormalities such as microaneurysm,
which are mostly superior mesenteric artery, constriction, or occlusion
[55]. A newer method such as CTA or MRA can also be used as an

alternative investigation [55].
Treatment options depend on the severity of PAN and infectious
status. While patients who have a mild disease without viral hepatitis can
start the monotherapy using glucocorticoids, patients who have viral
hepatitis should be started with antiviral without glucocorticoids or
immunosuppressants [3]. If patients develop resistance, adding
azathioprine or methotrexate to steroid may be needed. In patients with
moderate-severe PAN without viral hepatitis, glucocorticoids and
immunosuppressive medications are recommended. For patients who have
concomitant viral hepatitis and moderate-severe disease, glucocorticoids
and immunosuppressants are suggested before or together with antiviral
therapy.
Kawasaki Disease
Kawasaki disease is a mucocutaneous lymph node syndrome that
mainly affects medium-sized vessels. Nevertheless, small or large-sized
arteries may also be involved [56]. It often presents in children below five
years [57]. Coronary artery abnormalities can be noted in Kawasaki
disease in the form of dilatation or aneurysm. Also, pulmonary artery
involvement has been reported. Ethnicity may be associated with the
prevalence of lung involvement in Kawasaki disease. While 1.83% and
14.7% of the patients in India and Japan studies presented with pulmonary
abnormalities on chest X-ray, none of the patients in the multicenter study
in Italy have abnormalities on the chest radiographic [57–59]. The most
common finding on chest X-ray in Kawasaki disease is the reticulo-
micronodular pattern. Other chest x-ray findings that have been reported
were peri-bronchial cuffing, ILD, lobar consolidation, atelectasis,
empyema, pneumothorax, and pleural effusion.
Diagnosis can be made solely from clinical features (Table 6) [60].
The disease may be divided into three stages: 1 Acute fever lasting 10-14
days; 2. The sub-acute phase occurs 2-4 weeks after initial presentation
includes periungual desquamation and coronary artery lesions; 3.
Convalescent phase-complete resolution of clinical manifestations.
Respiratory complaints such as cough and tachypnea are rare. There is

limited data regarding the lung biopsy result in Kawasaki disease. It is vital
to early detect Kawasaki disease and initiates the treatment with aspirin
and intravenous immunoglobin (IVIg) as it is proven to decrease coronary
artery complications.
Table 6. The American Heart Association 2004 criteria for

Kawasaki disease [60]
1. Fever ≥ five days

2. Polymorphous exanthem
3. Extremities changes
4. Mucosal changes of the lips and oral cavity
5. Non-purulent bilateral bulbar conjunctival injection
6. Unilateral cervical lymphadenopathy
*The first criteria are needed plus four or more of the following criteria.
Small-Vessel Vasculitis
ANCA-Associated Vasculitis
Granulomatosis with Polyangiitis

GPA, the most frequent AAV, can be found in 210 per million
populations, respectively [61]. It occurs commonly in older adult with a
mean age of 50 and no gender predilection. It is well-known for the
composition of “classic triad”; upper respiratory tract, lower respiratory
tract (alveolar hemorrhage, pulmonary nodules), and glomerulonephritis.
Although, the complete triad was only found at presentation in 28% of the
cases [62]. Otolaryngologic manifestations such as sinusitis, epistaxis,
nasal discharge, otitis media, hearing loss, subglottic stenosis were found
at presentation and during the course of disease in 73% and 92% of the
cases, respectively. The destruction of nasal cartilage in GPA can lead to
characteristic saddle nose deformity. GPA is one of the pulmonary-renal
syndromes, which includes GPA, MPA, Goodpasture, and systemic lupus
erythematosus (SLE). Renal manifestations, commonly rapid progressive
glomerulonephritis, occurred in 18% at the presentation and eventually

went up to 77% during the course of the disease. Respiratory symptoms
include cough, hemoptysis, dyspnea, chest pain, pleuritis present in 25-
64.5% of the GPA cases and can increase to 85% of the GPA cases during
disease [15, 63]. Constitutional symptoms and other organ systems
involvement such as skin (purpura, nodule, ulcers), nervous system
(peripheral/central neuropathy), musculoskeletal system (arthralgia,
myalgia), cardiac system (coronary vasculitis, pericarditis) can be found in
GPA [5].
The criteria for GPA (Table 7) include 1. Oronasal inflammation (ulcer
or discharge), 2. Lung nodules, infiltration or cavities on chest radiograph,
3. Urinary sediment with ≥ five red blood cells/high power field or red
blood cell casts, 4. Granulomatous inflammation on arterial biopsy. With
the two out of four ACR criteria, the sensitivity and specificity were 88%
and 92%, respectively [64].
Table 7. The diagnostic criteria for Granulomatosis with Polyangiitis

by American College of Rheumatology in 1990*[64]
1. Nasal or oral inflammation

2. Abnormal chest X-ray
3. Active urinary sediment
4. Granulomatous inflammation in the biopsy
*At least two criteria are needed.
Imaging studies are recommended as part of the evaluation. The chest

x-ray can be used as an initial investigation, but the CT chest usually gives
better details. Bilateral pulmonary nodules in various sizes, the most
prevalent finding in GPA, occurs in 25-50% of the cases [4, 21]. Lung
nodules/masses with cavitary lesions are typically associated with GPA.
Pulmonary infiltration is also a common presentation in GPA.
Additionally, pulmonary hemorrhage, endobronchial lesion, ILD (23%),
pleural effusion (20-50%), fibrosis (1.9%) were reported in GPA [15, 65,
66]. Among CT chest findings in AAV cases, subglottic stenosis is the
unique finding for GPA [67]. Pulmonary function test (PFT) can reveal
both airflow obstruction (18.3%) or restrictive pattern (16.6%) and reduce

diffusing capacity of lung for carbon monoxide (DLCO) (16.0%) [4, 15].
However, DLCO will be increased if diffuse alveolar hemorrhage presents
in GPA.
Cytoplasmic ANCA (C-ANCA) is known to be specific to an antibody
against proteinase-3 (anti-PR3). While a positive C-ANCA or anti-PR3
were accounted for 85-95% of active systemic disease, a much lower
positive rate is reported when GPA is in partial or complete remission
stage. For C-ANCA examined by immunofluorescence, pooled sensitivity
and specificity are 75.2% and 98.4%, respectively [68]. The pooled
sensitivity and specificity of anti-PR3 are 79.8-86.6% and 96.8-98.3%,
respectively [68]. Antibodies were noted to be related to respiratory
manifestations. Patients with hemoptysis were commonly found to have
positive anti-PR3 GPA [15]. Lung nodules were commonly observed in
patients with ANCA positivity regardless of type [15].
Bronchoscopy with bronchoalveolar lavage may be used to assess
anatomical abnormality, infection, and hemorrhage [5]. Among GPA cases
who underwent a bronchoscopy, stenosis of subglottic, tracheal, and/or
bronchus were seen in 11.1% [15]. Lung biopsy by transbronchial biopsy
is not generally the procedure of choice but may provide the pathologic
evidence if the endobronchial lesion is seen. Open lung biopsies or assisted
video thoracoscopic procedures are usually preferred methods to obtain the
tissue. Histopathologic results from lung biopsies were found to be
compatible with vasculitis in 60.6% of GPA cases [15]. Biopsy in GPA
usually reveals small-medium necrotizing vasculitis (arteritis, venulitis,
capillaritis), granulomatous inflammation (neutrophils, lymphocytes,
plasma cells, macrophages, eosinophils, and giant cells infiltration) with
parenchymal necrosis (micro-abscess or geographic necrosis) [4, 5].
Choice of treatment for AAV depends on the extent of the disease
(limited vs. severe). In limited disease (no organ- or life-threatening
disease), glucocorticoids, plus methotrexate is recommended. Other
combination includes glucocorticoids-cyclophosphamide and
glucocorticoids-rituximab. Severe disease is characterized by any of the
following features: active glomerulonephritis, pulmonary hemorrhage,
cerebral vasculitis, progressive peripheral/cranial neuropathy, orbital

pseudotumor, scleritis, gastrointestinal bleeding related to vasculitis, and
cardiac-related vasculitis. Severe disease required induction follows by
maintenance therapy. Compared to glucocorticoid-cyclophosphamide, the
combination of glucocorticoids and rituximab is non-inferior as the
induction therapy based on the Rituximab versus cyclophosphamide for
induction of remission for ANCA associated vasculitis trial (RAVE) trial
and the Rituximab versus cyclophosphamide in ANCA-associated renal
vasculitis (RITUXVAS) trial [69]. In Plasma Exchange and
Glucocorticoid in Severe ANCA-Associated Vasculitis (PEXIVAS) trial,
plasma exchange for induction treatment did not show significant
improvement of the composite outcome, including death or end-stage renal
disease. Looking at the similar composite outcome in the PEXIVAS trial,
a reduced dose of steroids showed a non-inferior result to standard-dose
steroids. As for maintenance treatment, rituximab is associated with fewer
relapses than azathioprine. Mycophenolate mofetil had a higher relapse
rate when compared to azathioprine [70].
Microscopic Polyangiitis
MPA is an inflammation of the vasculature with necrosis that has little
or no immune deposition. It mainly involves venules, arterioles, and
capillaries. Unlike PAN, medium-sized vessels are not generally affected
in MPA. The prevalence of MPA was 46 cases per million populations
[61]. MPA affects patients with a mean age of 56 and slightly more
common in females. Kidney and pulmonary involvement can be found up
to 80-100% and 30-65.9% of the cases, respectively [4, 5, 15]. Rapidly
progressive glomerulonephritis is the common renal presentation in MPA
[5, 15]. Respiratory symptoms in MPA includes dyspnea (43.5-90%),
cough (37.7-90%), hemoptysis (23.3-79%) and pleuritis (6.4%) [15, 67].
Constitutional symptoms (fever, myalgia, weight loss) are common in
MPA. Skin lesion (purpura, nodules), ear-nose-throat symptoms, and
peripheral neuropathy are reported in MPA.
Perinuclear-ANCA (P-ANCA) is associated with anti-MPO with a
pooled sensitivity of 46.3, 58.1%, and pooled specificity of 91.4% and
95.6%, respectively [68]. The ANCA positivity MPA is not significantly

related to hemoptysis prevalence, pulmonary fibrosis, and nodules [15].
Chest X-ray findings typically show diffuse alveolar infiltration. CT chest
findings, including ground-glass opacity, pulmonary hemorrhage pattern,
reticulation in the peripheral area of the lungs, usual interstitial pneumonia,
and honeycombing, were more prevalent in patients with MPA compared
to other AAV, while lung nodules are uncommon presentation in MPA
[67]. PFT findings in MPA are noted for obstructive pattern in 28.3%,
restrictive pattern in 19.6%, and decreased DLCO in 45.7% of the cases
[15]. Histopathology is the gold standard for MPA diagnosis (Table 8)
which can obtain from the kidney, skin, or lung. Renal biopsies typically
show pauci-immune and necrotizing glomerulonephritis. Hemorrhage,
hemosiderin within alveolar macrophages in air spaces, diffuse
neutrophilic capillaritis are typically seen in lung biopsies.
Table 8. The typical characteristic of Microscopic polyangiitis
1. Pauci-immune necrotizing vasculitis

2. Small vessels predominant
3. Pulmonary-renal syndrome (necrotizing glomerulonephritis and pulmonary capillaritis are
common)
4. Absent of granulomatous inflammation
Eosinophilic Granulomatosis with Polyangiitis

EGPA, also called allergic angiitis and granulomatosis, is a systemic
vasculitis involving small to medium-sized vasculature. EGPA is
characterized by the classic triad of elevated serum eosinophils,
necrotizing inflammation of the vessel, and asthma. EGPA had a
prevalence of 10-45 cases per million and an annual incidence of 0.5-2
cases per million population [22]. The median age onset of EGPA is 49-59
years, and no significant gender preference [71]. EGPA can be divided into
three phases; the initial phase includes atopy, sinusitis, asthma, followed
by the eosinophilic phase, and the last phase is the vasculitic phase.
Peripheral nerves and paranasal sinuses are commonly affected, causing
mononeuritis multiplex (2/3 of the cases), nasal obstruction, nasal polyps,
and nasal crusts. Respiratory symptoms include dyspnea (65.8%), cough

(55.5%) and wheezing [15]. Pleuritis is well recognized and usually occurs
with pericarditis and pleural effusion [72]. Hemoptysis can be seen in 8.2%
but less frequently compared to other small vessel vasculitides (26.7% in
GPA and 23.3% in MPA) [5, 72]. Other organ involvement in EGPA
includes skin (leukoclastic vasculitis, purpura, nodules, urticarial rash),
cardiac system (pericarditis, coronary vasculitis, heart failure, myocardial
infarction), and gastrointestinal system (diarrhea, gastrointestinal
bleeding, perforation, colitis, abdominal pain) [5].
Diagnosis of EGPA can be made by ACR criteria (Table 9) and
another widely used criteria by Lanham et al., which required three out of
three criteria to be met; 1. Asthma, 2. Peak peripheral blood eosinophils >
1.5 x 106/cc, 3. Systemic vasculitis with two or more extrapulmonary organ
involvement [73, 74].
Table 9. Eosinophilic Granulomatosis with Polyangiitis diagnostic

criteria by the American College of Rheumatology*[74]
1. Asthma
2. Serum eosinophils more than 10% of the total white cell counts
3. Mono/polyneuropathy
4. Nonfixed pulmonary infiltration
5. Paranasal sinus abnormalities
6. Extravascular eosinophils on biopsy of blood vessels
* Need at least four criteria for the diagnosis.
ANCA positivity is noted in 30-35% of the cases [5, 56, 71]. Of the
patients with positive ANCA, anti-MPO accounts for 90-100% of the
cases. In contrast to glomerulonephritis, which is more common in ANCA
positive EGPA, cardiac involvement is more common in ANCA negative
EGPA [71]. Lung nodules are more common in anti-PR3 positive patients
(75% vs. 11%) [15]. Imaging of the lungs, including chest X-ray and CT
chest, is commonly used as part of EGPA work-up. It typically presents as
migrating patchy infiltration with peripheral distribution (ground-glass
opacity or consolidation) [71]. Lung nodules and bronchial
wall/interlobular septal thickening were reported. Fibrosis was

documented in 6.3% of EGPA cases [15].
The biopsy findings are different depending on the organ affected.
Necrotizing vasculitis and eosinophil infiltration with necrotizing
granuloma are seen on lung biopsies, while eosinophils infiltration is rarely
reported in peripheral nerve or kidney biopsy. Renal biopsy in EGPA is
usually compatible with pauci-immune focal segmental necrotizing
glomerulonephritis.
The cornerstone treatment of EGPA is glucocorticoids. Additional
immunosuppressive agents should be implemented in EGPA cases with
organ- or life-threatening diseases. Mepolizumab, the only Food and Drug
Administration-approved anti-interleukin-5 agents for EGPA,
demonstrated the benefit of reducing the annual relapse of EGPA by 50%
compared to placebo and reducing steroid requirement [75].
Immune Complex Small Vessel Vasculitis
Anti-Glomerular Basement Membrane Antibody Disease

Anti-glomerular basement membrane (Anti-GBM) antibody disease,
an uncommon small vessel vasculitis, is mediated by circulating anti-GBM
antibodies that specific to the non-collagenous domain of the alpha-3 chain
of collagen type IV, aiming at the capillaries of glomerulus and alveolus
[76]. It occurs in 1/1,000,000 in the bimodal age distribution (thirty
decades vs sixty-seventy decades) and male predominance [12]. Patients
with age less than 30 tend to have more pulmonary involvement, while
older age patients tend to have more isolated renal disease. “Goodpasture
disease” is defined as the disease that comprises glomerulonephritis and
pulmonary hemorrhage causing by anti-GBM antibodies, whereas
“Goodpasture syndrome” is used to characterize the same conditions from
any cause. Rapidly progressive glomerulonephritis is frequently reported
(approximately 90%) which is more common than pulmonary involvement
(25-60%) [56]. Isolated alveolar hemorrhage related to anti-GBM antibody
disease is rare but may occur.
Diagnosis is confirmed by renal biopsy (Table 10), which reveals

crescentic proliferative glomerulonephritis on light microscopy and linear
deposition of Immunoglobulin G in the glomerular membrane on direct
immunofluorescence.
Table 10. The typical characteristic of anti-glomerular basement

membrane antibody disease
Histopathology result
Abundant crescent-shaped glomeruli under light microscopy
Lineal deposition of IgG in the basement membrane of glomeruli under direct immunofluorescence
Anti-basement membrane antibody detecting in blood or histopathology result
Alveolar hemorrhage may be presented
Serologic testing by serum assay for anti-GBM antibodies such as a

direct enzyme-linked immunoassay. Chest imaging is typically showed
bilateral air-space opacities that resembled diffused alveolar hemorrhage
(DAH). Lung biopsy typically revealed alveolar hemorrhage with
pulmonary capillarity [1]. Approximately 20–30% of patients with anti-
GBM antibody disease are also ANCAs-positive (generally anti-MPO).
Standard treatment with glucocorticoids, cytotoxic agents in
combination with plasmapheresis has been used in clinical practice. The
use of plasmapheresis, targeting anti-GBM removal, has been shown to
improved renal function and survival. Among hospitalized patients with
Goodpasture syndrome, 19% needed invasive mechanical ventilation, and
52% required renal replacement therapy [77]. In critically ill cases with
anti-GBM antibody disease, extracorporeal membrane oxygenation and
double lung transplant may be necessary [77] Fortunately, relapsing is
uncommon in anti-GBM antibody disease [78].
IgA Vasculitis
Immunoglobin A vasculitis, or called Henoch-Schönlein purpura, is a
disease of small-sized vessel inflammation with Immunoglobulin A1-
dominant immune deposition. It most affected children (up to 90% of the
cases) and is more common in the male gender. Upper airway infection
frequently precedes the symptoms of IgA vasculitis. Tetrad of disease

includes 1. Palpable purpura in patients without low platelet/coagulopathy,
2. Arthritis/arthralgia, 3. Abdominal pain due to submucosal
hemorrhage/edema 4. IgA vasculitis nephritis.
Respiratory symptoms are rare and occur in 5.9% of the cases (dyspnea
2.6% and cough 3.3%) [15]. The diagnosis criteria, according to the
American College of Rheumatology1990 for IgA vasculitis (Table 11)
showed that both sensitivity and specificity are around 90% [79].
Table 11. IgA vasculitis criteria*[79]
1. Age ≤20 years

2. Tangible purpura
3. Severe abdominal pain
4. Biopsy that shows granulocytes in small vessel walls
*Need at least two criteria.
Pulmonary imaging can be normal or mild interstitial change in a

majority of the cases (89%). Pulmonary hemorrhage, however, is an
exceedingly rare finding in IgA vasculitis and primarily seen in adults and
adolescents. Biopsies are usually obtained from skin or kidneys, which
showed IgA deposition. DLCO has been reported to be consistently low,
which compatible with ILD findings on chest x-ray.
As most of the patients with IgA vasculitis recover without specific
treatment. Therefore, supportive therapy for IgA vasculitis is generally
recommended. Arthritis, arthralgia, edema, and abdominal pain may be
alleviated by anti-inflammatory medications. Glucocorticoids are usually
reserved for severe cases or rare complications such as pulmonary
hemorrhage, orchitis, and cerebral involvement.
Cryoglobulinemic Vasculitis
Cryoglobulinemic vasculitis is a small to medium vessel vasculitis
with cryoglobulin-containing immune complexes deposition. It is a rare
disorder with a prevalence of 1/100,100, female predominance, commonly
found in the fifth decades of age [80]. It has a strong association with
hepatitis C virus infection. The immune complex may precipitate and

cause abnormalities in kidneys (glomerulonephritis), joints (arthralgia),
skin (palpable purpura), or peripheral nerve. Pulmonary involvement is
uncommon (approximately 2% of the cases) [56]. Not only due to immune
complex, cryoglobulin can also cause organ damage by hyper viscosity
syndrome. Cough, shortness of breath, or pleuritic pain were reported
when the lungs are involved. Pulmonary infiltration, fibrosis, organizing
pneumonia, diffuse alveolar hemorrhage was reported on lung imaging.
PFT often showed obstructive patterns and diminished DLCO [16].
Bronchoalveolar lavage is noted for T-lymphocyte predominant [16].
Treatment includes immunosuppressants (glucocorticoids and rituximab
or cyclophosphamide) and plasmapheresis. Anti-viral therapy can be given
together with immunosuppressants in patients with cryoglobulinemic
vasculitis associated with hepatitis C [81].
Hypocomplimentemic Urticarial Vasculitis

Hypocomplimentemic urticarial vasculitis is a small vessel vasculitis
that is associated with anti-C1q antibodies [56]. Due to its rarity,
prevalence is unknown. Base on previously reported cases, it is usually
seen in the fifth decades of life, and most of them are female [82].
Table 12. Diagnostic criteria for hypocomplimentemic

urticarial vasculitis* [83]
Major criteria
1. Chronic urticarial skin lesions
2. Serum hypocomplementemia
Minor criteria
1. Leukoclastic vasculitis proved by biopsy
2. Joint pain/inflammation
3. Occular inflammation (Uvea or episcleral or conjunctiva)
4. Glomerulonephritis
5. Recurrent pain in the abdomen
6. Anti-C1q antibodies
*Both major criteria are needed plus at least two for the minor criteria.
It is characterized by chronic recurrent urticaria (< 6 months), low

serum complements levels (C1q, C3, C4), glomerulonephritis, arthritis,
ocular inflammation, glomerulonephritis, and abdominal pain (Table 12)
[83].
Chronic obstructive lung disease is estimated in 50-61% of the cases
and can commonly progress especially among smokers [82]. Common
respiratory symptoms are dyspnea, wheezing, and cough. CT chest
abnormalities were found in 82%, including centrilobular emphysema,
mosaic attenuation, pleural effusion, and bronchiectasis change.
Pulmonary vasculitis in this disease is thought to be due to anti-C1q
antibody binding and the release of elastase by neutrophils causing
pulmonary emphysema, predominantly in basal zones [84]. There is no
specific treatment for this condition, though glucocorticoids and cytotoxic
agents may be required in severe cases.
Variable-Vessel Vasculitis
Behçet Disease
Behçet disease or Behçet syndrome is a multisystemic vasculitis that
can affect small, medium, or large vessels, both arterial and venous
systems. Even though most of the cases involve large veins. This disease
is generally seen in young patients, particularly in the second to the third
decade of life. It is almost equally reported in both gender and commonly
found in Turkey and other Asian countries [3].
The hallmark of this disease is widely known for recurring aphthous
ulcerations in the mouth and genitalia. Other common presentations can
include inflammatory lesions of the skin (pseudofolliculitis, erythema
nodosum), eyes (uveitis, retinal vasculitis, conjunctivitis), joint (arthritis),
gastrointestinal ulceration, and central nervous system. Superficial
phlebitis, superior vena cava obstruction, thromboembolism have been
reported. Among arterial systems, pulmonary artery involvements,
particularly multiple/bilateral main and lobar pulmonary artery aneurysms,
are commonly reported ranging from 1-33%, followed by aortic
involvement [3]. It is crucial to evaluate for pulmonary artery aneurysm as

a ruptured aneurysm that can lead to fatal outcomes [12].
Respiratory symptoms include hemoptysis, chest pain, cough, and
shortness of breath. Hilar enlargement and perihilar area opacity on the
chest x-ray may give a clue for aneurysm, while wedge-shaped
consolidation may be the sign of pulmonary infarction. CTA or MRA are
recommended to provide a better characteristic of vascular abnormality in
Behçet diseases such as pulmonary artery aneurysm, arterial/venous
thrombosis, pulmonary calcification, pleural effusion secondary to
superior vena cava obstruction, or pulmonary infarction [1]. Biopsy result
is not required but may show lymphocytic infiltration with the necrotizing
area of the vessels’ wall, organizing thrombus with periadventitial fibrotic
tissues or hemorrhagic area.
The International Study Group diagnostic criteria for Behcet’s disease,
commonly used criteria, have a sensitivity and specificity of 95 and 100%
(Table 13) [85]. Next, the International Criteria for Behcet’s disease was
developed in 2006 and was revised in 2010 showed a sensitivity of 87-
96.5% and specificity of 88.9-97.3% [86].
Table 13. The International Study Group diagnostic criteria for

Behcet’s disease*[85]
1. Recurrent oral ulcers

2. Recurrent genital ulcers
3. Ocular lesions
4. Cutaneous lesions
5. Positive pathergy test
*Need the first criteria and at least two of the following criteria.
Treatment of Behçet disease depends on the severity and organ

involvement [87]. Isolated mucocutaneous lesions (oral and genital ulcers)
can be treated with topical glucocorticoids or sucralfate solution while
colchicine is recommended for relapsing prevention. In severe
mucocutaneous involvement, azathioprine, pentoxifylline, dapsone,
interferon-α can be given. Ocular involvement can be started with
azathioprine, cyclosporine, interferon-α, anti-TNF-α agents are usually

recommended. For acute gastrointestinal involvement, glucocorticoids
combined with aminosalicylate or azathioprine are recommended.
Glucocorticoids and NSAIDs can be used for arthritis. For pulmonary
artery aneurysm, primary management with a pulse dose of
glucocorticoids with cyclophosphamide is recommended. Surgical repair
of aneurysm may be required if patients fail medical management.
Vasculitis due to Systemic Disease and Other Causes
Necrotizing Sarcoid Granulomatosis

Necrotizing sarcoid granulomatosis is considered a rare manifestation
of vasculitis, often limited to the lungs but may involve ocular and
neurological systems. Age ranges from 8-68 with a mean age of 42 years.
It is common among the female gender (62%), Caucasian (80%), and non-
smoker (67.6%) [88]. Patients can present with fever (45.4%), dyspnea
(34%), chest pain/pleuritis (38.1%), weight loss (33%), night sweat
(23.75), hemoptysis (10.3%) or even asymptomatic [88]. Chest radiograph
findings include bilateral nodules predominant in lower lungs (64.8%),
solitary nodule/mass (20.5%), hilar/mediastinal lymphadenopathy, pleural
thickening, and pleural effusion [88]. Histologically, sarcoid-like
granulomas, large areas of infarct-like necrosis, and granulomatous
vasculitis are classical findings. Sarcoidosis, GPA, and granulomatous
infections such as tuberculosis are the common differential diagnosis.
However, it is still controversial if this disorder should be considered a part
of vasculitis syndrome or sarcoidosis variant. Patients with this type of
vasculitis usually have excellent outcomes. Surgical resection is
recommended for localized lesions, while glucocorticoid therapy is
suggested for bilateral pulmonary lesions [4].
Systemic Lupus Erythematosus-Related Vasculitis

SLE, an autoimmune disease with multiorgan system involvement,
most frequently affects women of childbearing ages. It the most frequent
connective tissue disease that causes pulmonary vasculitis particularly

capillaritis. It is the result of the direct immune-mediated inflammatory
response of capillaries of the alveoli leading to the increased permeability,
destruction, and eventually DAH. This complication of SLE is rare (<5-
11% of SLE cases) but associated with high mortality. Concurrently, SLE-
related pulmonary vasculitis is frequent found with lupus nephritis. The
most symptoms are fever, while hemoptysis occurs in approximately 50%
of the cases. Chest imaging of typical DAH, bilateral alveolar infiltration,
is seen. Histologically, the finding of alveolar hemorrhage, hemosiderin-
laden macrophages with capillaritis in SLE resembles GPA, MPA, and
Goodpasture syndrome [4]. Not only that, SLE can involve other parts of
pulmonary vasculatures (pulmonary artery hypertension, pulmonary
embolism), lung parenchyma (ILD, pneumonitis), pleural (pleuritis,
pleural effusion), and shrinking lung syndrome [89]. The treatment for
SLE-related pulmonary vasculitis includes intravenous corticosteroids,
cyclophosphamide, rituximab, IVIg, and plasmapheresis [89].
Rheumatoid Arthritis-Related Vasculitis

Rheumatoid arthritis (RA), a chronic systemic autoimmune disease,
mainly presents with articular complaints. Much extra-articular
involvement may be found in the eyes, kidneys, cardiovascular system,
gastrointestinal system, nervous system, and respiratory system.
Pulmonary complications occur in 30-40% of RA cases. Among RA cases
with pulmonary complications, 20-30% of cases can present before
synovitis symptoms [89]. ILD is the most common complication of RA-
related lung disorder. It can also involve bronchus, pleura, pleura, and
rarely pulmonary vasculatures. Rheumatoid factor can produce immune
complexes that may result in vasculitis. RA-related vasculitis affects small
to medium vessels leading to gastrointestinal bleeding, ulcer, nerve
ischemia. RA-related pulmonary vasculitis may occur and can cause
capillaritis. To date, only 6 cases of isolated pulmonary capillaritis causing
DAH in RA have been reported [91]. Glucocorticoid is the primary
treatment for RA-related DAH. Cyclophosphamide, rituximab,
azathioprine, IVIg, and sivelestat have been added to the regimens.
Nonetheless, the fatal outcome has been reported in 2 out of those 6 cases
[91].
Coronavirus Disease 2019-Related Vasculitis

Coronavirus disease 2019 (COVID-19), is caused by SARS-CoV-2,
leading to the recent pandemic. It is known to primarily involved the
respiratory system. Nevertheless, multiple organ systems can be affected.
COVID-19 has been reported to be the cause of inflammation of
endothelium, vasculitis, and angiogenesis. Systemic vasculitis in COVID-
19, particularly systemic cutaneous vasculitis, is thought to be due to viral
infection or immune response [24]. Autopsy finding showed perivascular
lymphocytic inflammation with few areas of intra-vessel wall infiltration
compatible with non-necrotizing lymphocytic vasculitis. Lung biopsies
from suspected/known COVID-19 patients revealed vasculitis,
microthrombi, and alveolar damage [92].
Drug-Induced Pulmonary Vasculitis

Drug-induced vasculitis (DIV) is characterized by necrotizing
inflammation of small to medium-sized blood vessels associated with the
prolonged use of almost all classes of pharmacologic agents. Increasing
research in the field of vasculitis has revealed that a large proportion of
patients with DIV are reported to be ANCA positive induced by certain
drugs. Hence, the presence of ANCA can serve as a warning possibility of
DIV, and in some cases, DIV largely refers to drug-induced AAV [93].
Drug-induced AAV has been associated with a variety of drugs including
PTU, sulfasalazine, anti‐TNF‐α agents, D‐penicillamine, and hydralazine
[94]. It is imperative to discontinue the administration of offending drugs
immediately following the diagnosis of drug-induced AAV, and
administer appropriate immunosuppressive corticosteroid therapy in cases
of vital organ involvement [93].
The pathogenesis of drug-induced AAV has not been studied much in
published literature. However, Deoxyribonuclease I activity reduces in
these patients resulting in the persistence of neutrophil extracellular traps
(NETs) due to weakened degradation that can destroy the tolerance to
MPO leading to generation of P-ANCA [95]. Cytokines, particularly TNF

and interleukin-1 beta, activate neutrophils which present ANCA-specific
antigens. ANCAs attach to the neutrophils via these antigens, and the Fc
region of ANCAs binds to the Fcγ receptor on neutrophils. Consequently,
neutrophils were activated, and NETs were created [96-98]. Matrix
metalloproteinases and histones in NETs induces damage to the vascular
endothelial cells [99, 100].
Drug-induced AAV presents with pulmonary complications
comprising intra-alveolar hemorrhage accompanied by dyspnea, cough,
and hemoptysis [101]. Although the kidney is the most commonly
involved organ, some patients may only present with lung involvement
leading to acute respiratory distress syndrome and interstitial pneumonia
without renal injury [102]. ANCA-positive DAH has been widely
associated with PTU therapy, as activated primed neutrophils release
MPO, which converts PTU into cytotoxic products that cause vascular
injury [103, 104]. Although both C-ANCA and P-ANCA can induce
neutrophil activation, hemorrhagic alveolar capillaritis is more often
encountered in patients with P-ANCA than in those with C-ANCA [101].
Hence, DAH is a relatively well-recognized pulmonary complication
resulting from pulmonary capillaritis associated with PTU-induced
ANCA-positive vasculitic syndrome. However, PTU-induced nonspecific
interstitial pneumonia has also been less commonly reported associated
with cough, dyspnea, and bilateral multifocal consolidation on chest CT
scan [105].
Other drugs such as hydralazine, sulfasalazine, D-penicillamine,
minocycline, and allopurinol have also been reported to cause ANCA-
associated pulmonary vasculitis. DAH has also been observed with D-
penicillamine, allopurinol, phenytoin, cocaine, leukotriene antagonists,
and all-trans retinoic acid therapy. It may occur through any of the three
pathophysiological mechanisms comprising immune-mediated
hypersensitivity, direct attack on the basement membrane of alveolar
capillary, and coagulopathy causing by the pharmacological agent [106].
It is difficult to clinically distinguish DAH of other causes, and a diagnosis
of DIV is only made after a thorough review of medication list. However,
clinical manifestations including cough, shortness of breath or chest

radiograph of infiltration, bronchoalveolar lavage showing blood return all
support the diagnosis [106]. Furthermore, variable histological findings
have revealed in drug-induced DAH comprising diffuse alveolar damage,
veno-occlusive disease, and bland hemorrhage of the lungs. The
management involves the removal of the suspected causative
pharmacological agent, and appropriate immunosuppression for ANCA-
associated vasculitis as previously discussed. However, in cases of all-
trans retinoic acid-related pulmonary capillaritis, medication should be
withdrawn, and a high-dose glucocorticoid should be started. All-trans
retinoic acid may be reintroduced when the syndrome has resolved [106].
CONCLUSION
Pulmonary complications in vasculitis encompass multiple individual

disease entities all of which contribute to inflammation, and blood vessel
destruction within the pulmonary vasculature. Although pulmonary
complications can be found in small to large vessel vasculitis, small-sized
vessels are the most common targets of pulmonary vascular inflammation,
especially AAV. These diseases can be life-threatening. The diagnosis and
management of pulmonary vasculitides remain a challenge for physicians
due to their variable clinical evolution and overlap with infection,
connective tissue diseases, malignancy, and adverse medication reaction.
REFERENCES
[1] Mahmoud, Shamseldeen, Subha Ghosh, Carol Farver, Jason

Lempel, Joseph Azok, and Rahul D. Renapurkar. 2016. “Pulmonary
Vasculitis.” Radiologic Clinics of North America 54 (6): 1097–
1118. https://doi.org/10.1016/j.rcl.2016.05.007.
[2] Lally, Lindsay, and Robert F. Spiera. 2015. “Pulmonary Vasculitis.”

Rheumatic Diseases Clinics of North America 41 (2): 315–31.
https://doi.org/10.1016/j.rdc.2015.01.004.
[3] Adams, Traci N., Da Zhang, Kiran Batra, and John E. Fitzgerald.
2018. “Pulmonary Manifestations of Large, Medium, and Variable
Vessel Vasculitis.” Respiratory Medicine 145 (December): 182–91.
https://doi.org/10.1016/j.rmed.2018.11.003.
[4] Travis, William D., Kevin O. Leslie, and Mary Beth Beasley. 2011.
“10 - Pulmonary Vasculitis and Pulmonary Hemorrhage.” In
Practical Pulmonary Pathology: A Diagnostic Approach (Second
Edition), edited by Kevin O. Leslie and Mark R. Wick, Second
Edition, 339–73. Philadelphia: W. B. Saunders. https://doi.org/
10.1016/B978-1-4160-5770-3.00010-9.
[5] Brown, Kevin K. 2006. “Pulmonary Vasculitis.” Proceedings of the
American Thoracic Society 3 (1): 48–57. https://doi.org/10.1513/
pats.200511-120JH.
[6] Tiwari, Anupama, and Mark Bowling. 2019. “Management of
Pulmonary Vasculitis: A Concise Review.” Clinical Pulmonary
Medicine 26 (2): 46–52. https://doi.org/10.1097/CPM.0000000
000000299.
[7] Mahr, Alfred, and Mathilde de Menthon. 2015. “Classification and
Classification Criteria for Vasculitis: Achievements, Limitations
and Prospects.” Current Opinion in Rheumatology 27 (1): 1–9.
https://doi.org/10.1097/BOR.0000000000000134.
[8] Zeek, Pearl M. 1952. “Periarteritis Nodosa; a Critical Review.”
American Journal of Clinical Pathology 22 (8): 777–90.
https://doi.org/10.1093/ajcp/22.8.777.
[9] Watts, R. A., S. E. Lane, D. G. Scott, W. Koldingsnes, H. Nossent,
M. A. Gonzalez-Gay, C. Garcia-Porrua, and G. A. Bentham. 2001.
“Epidemiology of Vasculitis in Europe.” Annals of the Rheumatic
Diseases 60 (12): 1156–57. https://doi.org/10.1136/ard.60.
12.1156a.
[10] Waller, Rosemary, Azeem Ahmed, Ishita Patel, and Raashid
Luqmani. 2013. “Update on the Classification of Vasculitis.” Best
Practice & Research. Clinical Rheumatology 27 (1): 3–17.

https://doi.org/10.1016/j.berh.2012.12.002.
[11] Jennette, John C., R. J. Falk, P. A. Bacon, N. Basu, M. C. Cid, F.
Ferrario, L. F. Flores-Suarez, et al. 2013. “2012 Revised
International Chapel Hill Consensus Conference Nomenclature of
Vasculitides.” Arthritis and Rheumatism 65 (1): 1–11.
https://doi.org/10.1002/art.37715.
[12] Castañer, Eva, Anna Alguersuari, Xavier Gallardo, Marta Andreu,
Yolanda Pallardó, Josep Maria Mata, and José Ramírez. 2010.
“When to Suspect Pulmonary Vasculitis: Radiologic and Clinical
Clues.” Radiographics: A Review Publication of the Radiological
Society of North America, Inc 30 (1): 33–53. https://doi.org/
10.1148/rg.301095103.
[13] Kitching, A. Richard, Hans-Joachim Anders, Neil Basu, Elisabeth
Brouwer, Jennifer Gordon, David R. Jayne, Joyce Kullman, et al.
2020. “ANCA-Associated Vasculitis.” Nature Reviews. Disease
Primers 6 (1): 71. https://doi.org/10.1038/s41572-020-0204-y.
[14] Yazici, Hasan, and Yusuf Yazici. 2016. “Diagnosis and/or
Classification of Vasculitis: Different?” Current Opinion in
Rheumatology 28 (1): 3–7. https://doi.org/10.1097/BOR.00000000
00000230.
[15] Makhzoum, Jean-Paul, Peter C. Grayson, Cristina Ponte, Joanna
Robson, Ravi Suppiah, Richard A. Watts, Raashid Luqmani, Peter
A. Merkel, Christian Pagnoux, and DCVAS collaborators. 2021.
“Pulmonary Involvement in Primary Systemic Vasculitides.”
Rheumatology (Oxford, England), March. https://doi.org/10.1093/
rheumatology/keab325.
[16] Manganelli, Paolo, Pieranna Fietta, Marina Carotti, Alberto Pesci,
and Fausto Salaffi. 2006. “Respiratory System Involvement in
Systemic Vasculitides.” Clinical and Experimental Rheumatology
24 (2 Suppl 41): S48-59.
[17] Yoshifuji, Hajime. 2019. “Pathophysiology of Large Vessel
Vasculitis and Utility of Interleukin-6 Inhibition Therapy.” Modern
Rheumatology 29 (2): 287–93. https://doi.org/10.1080/14397595.

2018.1546358.
[18] Lyons, Paul A., Tim F. Rayner, Sapna Trivedi, Julia U. Holle,
Richard A. Watts, David R. W. Jayne, Bo Baslund, et al. 2012.
“Genetically Distinct Subsets within ANCA-Associated
Vasculitis.” New England Journal of Medicine 367 (3): 214–23.
https://doi.org/10.1056/NEJMoa1108735.
[19] Acosta-Herrera, Marialbert, Miguel A. González-Gay, Javier
Martín, and Ana Márquez. 2019. “Leveraging Genetic Findings for
Precision Medicine in Vasculitis.” Frontiers in Immunology 10
(August). https://doi.org/10.3389/fimmu.2019.01796.
[20] Vaglio, Augusto, Davide Martorana, Umberto Maggiore, Chiara
Grasselli, Adele Zanetti, Alberto Pesci, Giovanni Garini, et al. 2007.
“HLA-DRB4 as a Genetic Risk Factor for Churg-Strauss
Syndrome.” Arthritis and Rheumatism 56 (9): 3159–66. https://doi.
org/10.1002/art.22834.
[21] Saeki, Takako, Nobuya Fujita, Hiroyo Kourakata, Hajime
Yamazaki, and Syoji Miyamura. 2004. “Two Cases of Hypertrophic
Pachymeningitis Associated with Myeloperoxidase Antineutrophil
Cytoplasmic Autoantibody (MPO-ANCA)-Positive Pulmonary
Silicosis in Tunnel Workers.” Clinical Rheumatology 23 (1): 76–80.
https://doi.org/10.1007/s10067-003-0815-1.
[22] Salvadori, Maurizio, and Aris Tsalouchos, eds. 2018
“Epidemiology and Pathogenesis of ANCA-Associated Vasculitis.”
In Reviews in immunology. Toscana: SM Group Books
[23] Xu, P., S. Lin, L. Wei, and W. Shang. 2014. “Antineutrophil
Cytoplasmic Antibody-Associated Vasculitis Associated with
Epstein-Barr Virus Infection: A Case Report and Review of the
Literature.” Infection 42 (3): 591–94. https://doi.org/10.1007/
s15010-014-0606-4.
[24] Potus, François, Vicky Mai, Marius Lebret, Simon Malenfant,
Emilie Breton-Gagnon, Annie C. Lajoie, Olivier Boucherat,
Sébastien Bonnet, and Steeve Provencher. 2020. “Novel Insights on
the Pulmonary Vascular Consequences of COVID-19.” American
Journal of Physiology. Lung Cellular and Molecular Physiology

319 (2): L277–88. https://doi.org/10.1152/ajplung.00195.2020.
[25] Flores-Suárez, Luis Felipe, Marco A. Alba, Heidegger Mateos-
Toledo, and Natllely Ruiz. 2017. “Pulmonary Involvement in
Systemic Vasculitis.” Current Rheumatology Reports 19 (9): 56.
https://doi.org/10.1007/s11926-017-0682-4.
[26] Jin, Qiuyu, Sam Kant, Jihad Alhariri, and Duvuru Geetha. 2018.
“Levamisole Adulterated Cocaine Associated ANCA Vasculitis:
Review of Literature and Update on Pathogenesis.” Journal of
Community Hospital Internal Medicine Perspectives 8 (6): 339–44.
https://doi.org/10.1080/20009666.2018.1536242.
[27] Ho, Bernard, James Larkin, and Kara Heelan. 2021. “Checkpoint
Inhibitor-Associated Cutaneous Small Vessel Vasculitis: A Review
of the Literature.” Journal of Immunotherapy (Hagerstown, Md.:
1997) 44 (3): 118–21. https://doi.org/10.1097/CJI.0000000000
000352.
[28] Stamatis, Pavlos, Aleksandra Turkiewicz, Martin Englund, Carl
Turesson, and Aladdin J. Mohammad. 2021. “Epidemiology of
Biopsy-Confirmed Giant Cell Arteritis in Southern Sweden - an
Update on Incidence and First Prevalence Estimate.” Rheumatology
(Oxford, England), March. https://doi.org/10.1093/rheumatology/
keab269.
[29] Mahfoudhi, Madiha, Habiba Mamlouk, Sami Turki, and Adel
Kheder. 2015. “[Horton disease revealed by dyspnea].” The Pan
African Medical Journal 20: 248. https://doi.org/10.11604/pamj.
2015.20.248.4656.
[30] Larson, T. S., S. Hall, N. G. Hepper, and G. G. Hunder. 1984.
“Respiratory Tract Symptoms as a Clue to Giant Cell Arteritis.”
Annals of Internal Medicine 101 (5): 594–97. https://doi.org/
10.7326/0003-4819-101-5-594.
[31] Buttgereit, Frank, Christian Dejaco, Eric L. Matteson, and Bhaskar
Dasgupta. 2016. “Polymyalgia Rheumatica and Giant Cell Arteritis:
A Systematic Review.” JAMA 315 (22): 2442–58. https://doi.org/
10.1001/jama.2016.5444.
[32] Hunder, Gene G., Daniel A. Bloch, Beat A. Michel, Mary Betty
Stevens, William P. Arend, Leonard H. Calabrese, Steven M.
Edworthy, et al.1990. “The American College of Rheumatology
1990 Criteria for the Classification of Giant Cell Arteritis.” Arthritis
and Rheumatism 33 (8): 1122–28. https://doi.org/10.1002/
art.1780330810.
[33] Rubenstein, Emma, Carla Maldini, Solange Gonzalez-Chiappe,
Sylvie Chevret, and Alfred Mahr. 2020. “Sensitivity of Temporal
Artery Biopsy in the Diagnosis of Giant Cell Arteritis: A Systematic
Literature Review and Meta-Analysis.” Rheumatology (Oxford,
England) 59 (5): 1011–20. https://doi.org/10.1093/rheumatology/
kez385.
[34] Lopez, Dasha, and Myriam Guevara. 2020. “Use of Ultrasound in
the Diagnosis and Management of the Vasculitides.” Current
Rheumatology Reports 22 (7): 31. https://doi.org/10.1007/s11926-
020-00902-x.
[35] Rinagel, Marina, Emmanuel Chatelus, Sandrine Jousse-Joulin, Jean
Sibilia, Jacques-Eric Gottenberg, François Chasset, and Laurent
Arnaud. 2019. “Diagnostic Performance of Temporal Artery
Ultrasound for the Diagnosis of Giant Cell Arteritis: A Systematic
Review and Meta-Analysis of the Literature.” Autoimmunity
Reviews 18 (1): 56–61. https://doi.org/10.1016/j.autrev.
2018.07.012.
[36] Besson, Florent L., Jean-Jacques Parienti, Boris Bienvenu, John O.
Prior, Sylvie Costo, Gerard Bouvard, and Denis Agostini. 2011.
“Diagnostic Performance of 18F-Fluorodeoxyglucose Positron
Emission Tomography in Giant Cell Arteritis: A Systematic Review
and Meta-Analysis.” European Journal of Nuclear Medicine and
Molecular Imaging 38 (9): 1764–72. https://doi.org/10.1007/
s00259-011-1830-0.
[37] Marie, Isabelle, Philippe Heliot, Jean-François Muir, Françis
Roussel, Hervé Levesque, and Hubert Courtois. 2004. “Pleural
Effusion Revealing Giant Cell Arteritis.” European Journal of
Internal Medicine 15 (2): 125–27. https://doi.org/10.1016/j.ejim.

2004.01.014.
[38] Okubo, Shumpei, Takeyoshi Kunieda, Motomi Ando, Nobuyuki
Nakajima, and Chikao Yutani. 1988. “Idiopathic Isolated
Pulmonary Arteritis with Chronic Cor Pulmonale.” Chest 94 (3):
665–66. https://doi.org/10.1378/chest.94.3.665.
[39] Hellmich, B., A. F. Águeda, S. Monti, and R. Luqmani. 2020.
“Treatment of Giant Cell Arteritis and Takayasu Arteritis—Current
and Future.” Current Rheumatology Reports 22 (12).
https://doi.org/10.1007/s11926-020-00964-x.
[40] Stone, John H., Katie Tuckwell, Sophie Dimonaco, Micki
Klearman, Martin Aringer, Daniel Blockmans, Elisabeth Brouwer,
et al. 2017. “Trial of Tocilizumab in Giant-Cell Arteritis.” New
England Journal of Medicine 377 (4): 317–28. https://doi.org/
10.1056/NEJMoa1613849.
[41] Lupi-Herrera, Eulo, Gustavo Sanchez-Torres, Jorge Marcushamer,
Jorge Mispireta, Simon Horwitz, and Jorge Espino Vela. 1977.
“Takayasu’s Arteritis. Clinical Study of 107 Cases.” American
Heart Journal 93 (1): 94–103. https://doi.org/10.1016/s0002-
8703(77)80178-6.
[42] Serra, Raffaele, Lucia Butrico, Francesco Fugetto, Mariia
Dmitrievna Chibireva, Alberto Malva, Giovanni De Caridi, Mafalda
Massara, Andrea Barbetta, Marco Cannistrà, and Stefano de
Franciscis. 2016. “Updates in Pathophysiology, Diagnosis and
Management of Takayasu Arteritis.” Annals of Vascular Surgery 35
(August): 210–25. https://doi.org/10.1016/j.avsg.2016.02.011.
[43] Mason, Justin C. 2010. “Takayasu Arteritis--Advances in Diagnosis
and Management.” Nature Reviews. Rheumatology 6 (7): 406–15.
https://doi.org/10.1038/nrrheum.2010.82.
[44] Moghaddam, Nima, Bahar Moghaddam, Natasha Dehghan, and
Nathan W. Brunner. 2018. “Isolated Large Vessel Pulmonary
Vasculitis Leading to Pulmonary Artery Aneurysm Formation: A
Case Report and Literature Review.” Pulmonary Circulation 8 (2):
2045894018765346. https://doi.org/10.1177/2045894018765346.
[45] Sharma, B. K., S. Jain, S. Suri, and F. Numano. 1996. “Diagnostic

Criteria for Takayasu Arteritis.” International Journal of
Cardiology 54 (August): S141–47. https://doi.org/10.1016/S0167-
5273(96)88783-3.
[46] Jiang, Wei, Yuanhua Yang, Xiuzhang Lv, Yidan Li, Zhanhong Ma,
and Jifeng Li. 2017. “Echocardiographic Characteristics of
Pulmonary Artery Involvement in Takayasu Arteritis.”
Echocardiography (Mount Kisco, NY) 34 (3): 340–47. https://doi.
org/10.1111/echo.13464.
[47] Kerr, Gail S., Claire W. Hallahan, Joseph Giordano, Randi Y.
Leavitt, Anthony S. Fauci, Menachem Rottem, and Gary S.
Hoffman. 1994. “Takayasu Arteritis.” Annals of Internal Medicine
120 (11): 919–29. https://doi.org/10.7326/0003-4819-120-11-
199406010-00004.
[48] Kanecki, Krzysztof, Aneta Nitsch-Osuch, Pawel Gorynski,
Waldemar Wierzba, Patryk Tarka, and Piotr Tyszko. 2019.
“Polyarteritis Nodosa: Decreasing Incidence in Poland.” Archives of
Medical Science: AMS 15 (5): 1308–12. https://doi.org/10.5114/
aoms.2017.68407.
[49] Guillevin, Loïc, Alfred Mahr, Patrice Callard, Pascal Godmer,
Christian Pagnoux, Emmanuelle Leray, Pascal Cohen, and French
Vasculitis Study Group. 2005. “Hepatitis B Virus-Associated
Polyarteritis Nodosa: Clinical Characteristics, Outcome, and Impact
of Treatment in 115 Patients.” Medicine 84 (5): 313–22.
https://doi.org/10.1097/01.md.0000180792.80212.5e.
[50] Sönmez, Hafize Emine, Berkan Armağan, Gizem Ayan, Kenan
Barut, Ezgi Deniz Batu, Abdulsamet Erden, Serdal Uğurlu, et al.
2019. “Polyarteritis Nodosa: Lessons from 25 Years of Experience.”
Clinical and Experimental Rheumatology 37 Suppl 117 (2): 52–56.
[51] Hasler, Paul, Hansjörg Kistler, and Heini Gerber. 1995.
“Vasculitides in Hairy Cell Leukemia.” Seminars in Arthritis and
Rheumatism 25 (2): 134–42. https://doi.org/10.1016/s0049-
0172(95)80026-3.
[52] Pagnoux, Christian, Raphaèle Seror, Corneliu Henegar, Alfred

Mahr, Pascal Cohen, Véronique Le Guern, Boris Bienvenu, Luc
Mouthon, Loïc Guillevin, and French Vasculitis Study Group. 2010.
“Clinical Features and Outcomes in 348 Patients with Polyarteritis
Nodosa: A Systematic Retrospective Study of Patients Diagnosed
between 1963 and 2005 and Entered into the French Vasculitis
Study Group Database.” Arthritis and Rheumatism 62 (2): 616–26.
[53] Moore, Patricia M. 1995. “Neurological Manifestation of
Vasculitis: Update on Immunopathogenic Mechanisms and Clinical
Features.” Annals of Neurology 37 Suppl 1 (May): S131-141.
https://doi.org/10.1002/ana.410370713.
[54] Lightfoot Jr, Robert W., Beat A. Michel, Daniel A. Bloch, Gene G.
Hunder, Nathan J. Zvaifler, Dennis J. McShane, William P. Arend,
et al. 1990. “The American College of Rheumatology 1990 Criteria
for the Classification of Polyarteritis Nodosa.” Arthritis and
Rheumatism 33 (8): 1088–93. https://doi.org/10.1002/art.17803
30805.
[55] Schmidt, Wolfgang A. 2004. “Use of Imaging Studies in the
Diagnosis of Vasculitis.” Current Rheumatology Reports 6 (3):
203–11. https://doi.org/10.1007/s11926-004-0069-1.
[56] Casal, Ana, Juan Díaz-Garel, Tara Pereiro, María E. Toubes, Jorge
Ricoy, and Luis Valdés. 2018. “Pulmonary Vasculitis.” Journal of
Thoracic Disease 10 (9): 5560–75. https://doi.org/10.21037/
jtd.2018.08.117.
[57] Singh, Surjit, Aman Gupta, Ankur Kumar Jindal, Anju Gupta,
Deepti Suri, Amit Rawat, Pankaj C. Vaidya, and Meenu Singh.
2018. “Pulmonary Presentation of Kawasaki Disease—A
Diagnostic Challenge.” Pediatric Pulmonology 53 (1): 103–7.
https://doi.org/10.1002/ppul.23885.
[58] Falcini, Fernanda, R. Cimaz, G. B. Calabri, P. Picco, G. Martini, M.
G. Marazzi, G. Simonini, and F. Zulian. 2002. “Kawasaki’s Disease
in Northern Italy: A Multicenter Retrospective Study of 250
Patients.” Clinical and Experimental Rheumatology 20 (3): 421–26.
[59] Umezawa, T., T. Saji, N. Matsuo, and K. Odagiri. 1989. “Chest X-

Ray Findings in the Acute Phase of Kawasaki Disease.” Pediatric
Radiology 20 (1–2): 48–51. https://doi.org/10.1007/BF02010633.
[60] Newburger, Jane W., Masato Takahashi, Michael A. Gerber,
Michael H. Gewitz, Lloyd Y. Tani, Jane C. Burns, Stanford T.
Shulman, et al. 2004. “Diagnosis, Treatment, and Long-Term
Management of Kawasaki Disease: A Statement for Health
Professionals from the Committee on Rheumatic Fever,
Endocarditis, and Kawasaki Disease, Council on Cardiovascular
Disease in the Young, American Heart Association.” Pediatrics 114
(6): 1708–33. https://doi.org/10.1542/peds.2004-2182.
[61] Hellmich, Bernhard, Peter Lamprecht, Philip Spearpoint, Dieter
Götte, Angelika Deichmann, Ina Buchholz, Matthias P.
Schönermark, and Peter Rutherford. 2021. “New Insights into the
Epidemiology of ANCA-Associated Vasculitides in Germany:
Results from a Claims Data Study.” Rheumatology (Oxford,
England), January. https://doi.org/10.1093/rheumatology/keaa924.
[62] DeREMEE, R. A., T. J. McDonald, E. G. Harrison, and D. T. Coles.
1976. “Wegener’s Granulomatosis. Anatomic Correlates, a
Proposed Classification.” Mayo Clinic Proceedings 51 (12): 777–
81.
[63] Hoffman, Gary S., Gail S. Kerr, Randi Y. Leavitt, Claire W.
Hallahan, Robert S. Lebovics, William D. Travis, Menachem
Rottem, and Anthony S. Fauci. 1992. “Wegener Granulomatosis:
An Analysis of 158 Patients.” Annals of Internal Medicine 116 (6):
488–98. https://doi.org/10.7326/0003-4819-116-6-488.
[64] Leavitt, Randi Y., Anthony S. Fauci, Daniel A. Bloch, Beat A.
Michel, Gene G. Hunder, William P. Arend, Leonard H. Calabrese
for the Classification of Wegener’s Granulomatosis.” Arthritis and
0807.
[65] Ugan, Yunus, Atalay Doğru, Giray Aynalı, Mehmet Şahin, and
Şevket Ercan Tunç. 2018. “A Clinical Threat in Patients with
Granulomatosis Polyangiitis in Remission: Subglottic Stenosis.”

European Journal of Rheumatology 5 (1): 69–71. https://doi.org/
10.5152/eurjrheum.2017.16025.
[66] Sebastiani, Marco, Andreina Manfredi, Caterina Vacchi, Giulia
Cassone, Paola Faverio, Alberto Cavazza, Nicola Sverzellati, Carlo
Salvarani, and Fabrizio Luppi. 2020. “Epidemiology and
Management of Interstitial Lung Disease in ANCA-Associated
Vasculitis.” Clinical and Experimental Rheumatology 38 Suppl 124
(2): 221–31.
[67] Mohammad, Aladdin J., Kristian H. Mortensen, Judith Babar, Rona
Smith, Rachel B. Jones, Daiki Nakagomi, Pasupathy Sivasothy, and
David R. W. Jayne. 2017. “Pulmonary Involvement in
Antineutrophil Cytoplasmic Antibodies (ANCA)-Associated
Vasculitis: The Influence of ANCA Subtype.” The Journal of
Rheumatology 44 (10): 1458–67. https://doi.org/10.3899/jrheum.
161224.
[68] Guchelaar, Niels A. D., Manon M. Waling, Anviti A. Adhin, Paul
L. A. van Daele, Marco W. J. Schreurs, and Saskia M. Rombach.
2021. “The Value of Anti-Neutrophil Cytoplasmic Antibodies
(ANCA) Testing for the Diagnosis of ANCA-Associated Vasculitis,
a Systematic Review and Meta-Analysis.” Autoimmunity Reviews
20 (1): 102716. https://doi.org/10.1016/j.autrev.2020.102716.
[69] Stone, John H., Peter A. Merkel, Robert Spiera, Philip Seo, Carol
A. Langford, Gary S. Hoffman, Cees G. M. Kallenberg, et al. 2010.
“Rituximab versus Cyclophosphamide for ANCA-Associated
Vasculitis.” The New England Journal of Medicine 363 (3): 221–
32. https://doi.org/10.1056/NEJMoa0909905.
[70] Springer, Jason M., Mohamad A. Kalot, Nedaa M. Husainat, Kevin
W. Byram, Anisha B. Dua, Karen E. James, Yih Chang Lin, et al.
2021. “Granulomatosis with Polyangiitis and Microscopic
Polyangiitis: A Systematic Review and Meta‐Analysis of Benefits
and Harms of Common Treatments.” ACR Open Rheumatology 3
(3): 196–205. https://doi.org/10.1002/acr2.11230.
[71] Furuta, Shunsuke, Taro Iwamoto, and Hiroshi Nakajima. 2019.

“Update on Eosinophilic Granulomatosis with Polyangiitis.”
Allergology International: Official Journal of the Japanese Society
of Allergology 68 (4): 430–36. https://doi.org/10.1016/j.alit.
2019.06.004.
[72] Thompson, Gwen E., Michael Bourne, Marta Casal Moura, Misbah
Baqir, Rodrigo Cartin-Ceba, Ashima Makol, Matthew J. Koster,
Kenneth J. Warrington, Bijan J. Borah, and Ulrich Specks. 2021.
“Pleuritis and Pericarditis in ANCA-Associated Vasculitis.” Chest,
March. https://doi.org/10.1016/j.chest.2021.02.049.
[73] Lanham, John G., Keith B. Elkon, Charles D. Pusey, and Graham
R. Hughes. 1984. “Systemic Vasculitis with Asthma and
Eosinophilia: A Clinical Approach to the Churg-Strauss
Syndrome.” Medicine 63 (2): 65–81. https://doi.org/10.1097/
00005792-198403000-00001.
[74] Masi, Alfonse T., Gene G. Hunder, J. Tetal Lie, Beat A. Michel,
Daniel A. Bloch, William P. Arend, Leonard H. Calabrese et al.
1990. “The American College of Rheumatology 1990 Criteria for
the Classification of Churg-Strauss Syndrome (Allergic
Granulomatosis and Angiitis).” Arthritis and Rheumatism 33 (8):
1094–1100. https://doi.org/10.1002/art.1780330806.
[75] Wechsler, Michael E., Praveen Akuthota, David Jayne, Paneez
Khoury, Amy Klion, Carol A. Langford, Peter A. Merkel, et al.
2017. “Mepolizumab or Placebo for Eosinophilic Granulomatosis
with Polyangiitis.” The New England Journal of Medicine 376 (20):
1921–32. https://doi.org/10.1056/NEJMoa1702079.
[76] Henderson, Scott R., and Alan D. Salama. 2018. “Diagnostic and
Management Challenges in Goodpasture’s (Anti-Glomerular
Basement Membrane) Disease.” Nephrology, Dialysis,
Transplantation: Official Publication of the European Dialysis and
Transplant Association - European Renal Association 33 (2): 196–
202. https://doi.org/10.1093/ndt/gfx057.
[77] Kaewput, Wisit, Charat Thongprayoon, Boonphiphop Boonpheng,
Patompong Ungprasert, Tarun Bathini, Api Chewcharat, Narat
Srivali, Saraschandra Vallabhajosyula, and Wisit Cheungpasitporn.

2020. “Inpatient Burden and Mortality of Goodpasture’s Syndrome
in the United States: Nationwide Inpatient Sample 2003–2014.”
Journal of Clinical Medicine 9 (2): 455. https://doi.org/10.3390/
jcm9020455.
[78] McAdoo, Stephen P., and Charles D. Pusey. 2017. “Anti-
Glomerular Basement Membrane Disease.” Clinical Journal of the
American Society of Nephrology 12 (7): 1162–72. https://doi.org/
10.2215/CJN.01380217.
[79] Mills, John A., Beat A. Michel, Daniel A. Bloch, Leonard H.
Calabrese, Gene G. Hunder, William P. Arend, Steven M. Edworthy
for the Classification of Henoch-Schönlein Purpura.” Arthritis and
330809.
[80] Ferri, Clodoveo, A. L. Zignego, and S. A. Pileri. 2002.
“Cryoglobulins.” Journal of Clinical Pathology 55 (1): 4–13.
https://doi.org/10.1136/jcp.55.1.4.
[81] Davuluri, Srijana, and Pankaj Bansal. 2021. “Cryoglobulinemic
Vasculitis.” In StatPearls. Treasure Island (FL): StatPearls
Publishing. http://www.ncbi.nlm.nih.gov/books/NBK556045/.
[82] Buck, Andrew, Jim Christensen, and Morgan McCarty. 2012.
“Hypocomplementemic Urticarial Vasculitis Syndrome.” The
Journal of Clinical and Aesthetic Dermatology 5 (1): 36–46.
[83] Schwartz, H. R., F. C. McDuffie, L. F. Black, A. L. Schroeter, and
D. L. Conn. 1982. “Hypocomplementemic Urticarial Vasculitis:
Association with Chronic Obstructive Pulmonary Disease.” Mayo
Clinic Proceedings 57 (4): 231–38.
[84] David, Clémence, Marie Jachiet, Marc Pineton de Chambrun, Anne
Sophie Gamez, Anas Mehdaoui, Thierry Zenone, Delphine Gobert,
et al. 2020. “Chronic Obstructive Pulmonary Disease Associated
with Hypocomplementemic Urticarial Vasculitis.” The Journal of
Allergy and Clinical Immunology. In Practice 8 (9): 3222-3224.e1.
https://doi.org/10.1016/j.jaip.2020.05.031.
[85] Ferraz, M. Bosi, S. D. Walter, R. Heymann, and Edgard Atra. 1995.

“Sensitivity and Specificity of Different Diagnostic Criteria for
Behçet’s Disease According to the Latent Class Approach.” British
Journal of Rheumatology 34 (10): 932–35. https://doi.org/10.1093/
rheumatology/34.10.932.
[86] Davatchi, Fereydoun. 2012. “Diagnosis/Classification Criteria for
Behcet’s Disease.” Pathology Research International 2012:
607921. https://doi.org/10.1155/2012/607921.
[87] Hatemi, Gulen, Robin Christensen, Dongsik Bang, Bahram
Bodaghi, Aykut Ferhat Celik, Farida Fortune, Julien Gaudric, et al.
2018. “2018 Update of the EULAR Recommendations for the
Management of Behçet’s Syndrome.” Annals of the Rheumatic
Diseases 77 (6): 808–18. https://doi.org/10.1136/annrheumdis-
2018-213225.
[88] Karpathiou, Georgia, Anna Batistatou, Panagiotis Boglou,
Dimitrios Stefanou, and Marios E. Froudarakis. 2018. “Necrotizing
Sarcoid Granulomatosis: A Distinctive Form of Pulmonary
Granulomatous Disease.” The Clinical Respiratory Journal 12 (4):
1313–19. https://doi.org/10.1111/crj.12673.
[89] Amarnani, Raj, Su-Ann Yeoh, Emma K. Denneny, and Chris
Wincup. 2021. “Lupus and the Lungs: The Assessment and
Management of Pulmonary Manifestations of Systemic Lupus
Erythematosus.” Frontiers in Medicine 7 (January). https://doi.org/
10.3389/fmed.2020.610257.
[90] Figus, Fabiana Assunta, Matteo Piga, Irene Azzolin, Rebecca
McConnell, and Annamaria Iagnocco. 2021. “Rheumatoid Arthritis:
Extra-Articular Manifestations and Comorbidities.” Autoimmunity
Reviews 20 (4): 102776. https://doi.org/10.1016/j.autrev.2021.
102776.
[91] Nakashima, Kazuki, Naoya Nishimura, Toyoshi Yanagihara, Ayaka

Egashira, Naruhiko Ogo, Tatsuma Asoh, Seiji Yoshizawa, and
Takashige Maeyama. 2021. “A Fatal Case of Diffuse Alveolar
Hemorrhage Complicated by Rheumatoid Arthritis.” Respiratory
Medicine Case Reports 32 (February). https://doi.org/10.1016/
j.rmcr.2021.101363.
[92] Calabrese, Fiorella, Federica Pezzuto, Francesco Fortarezza, Paul
Hofman, Izidor Kern, Angel Panizo, Jan von der Thüsen, Sergei
Timofeev, Gregor Gorkiewicz, and Francesca Lunardi. 2020.
“Pulmonary Pathology and COVID-19: Lessons from Autopsy. The
Experience of European Pulmonary Pathologists.” Virchows Archiv,
July, 1–14. https://doi.org/10.1007/s00428-020-02886-6.
[93] Merkel, Peter A. 2001. “Drug-Induced Vasculitis.” Rheumatic
Diseases Clinics of North America 27 (4): 849–62. https://doi.org/
10.1016/s0889-857x(05)70239-8.
[94] Gao, Ying, and Ming-Hui Zhao. 2009. “Review Article: Drug-
Induced Anti-Neutrophil Cytoplasmic Antibody-Associated
Vasculitis.” Nephrology (Carlton, Vic.) 14 (1): 33–41.
https://doi.org/10.1111/j.1440-1797.2009.01100.x.
[95] Nakazawa, Daigo, Haruki Shida, Utano Tomaru, Masaharu
Yoshida, Saori Nishio, Tatsuya Atsumi, and Akihiro Ishizu. 2014.
“Enhanced Formation and Disordered Regulation of NETs in
Myeloperoxidase-ANCA-Associated Microscopic Polyangiitis.”
Journal of the American Society of Nephrology: JASN 25 (5): 990–
97. https://doi.org/10.1681/ASN.2013060606.
[96] Heeringa, Peter, Abraham Rutgers, and Cees G. M. Kallenberg.
2018. “The Net Effect of ANCA on Neutrophil Extracellular Trap
Formation.” Kidney International 94 (1): 14–16. https://doi.org/10.
1016/j.kint.2018.03.010.
[97] Jennette, J. Charles, and Ronald J. Falk. 2014. “Pathogenesis of

Antineutrophil Cytoplasmic Autoantibody-Mediated Disease.”
Nature Reviews. Rheumatology 10 (8): 463–73. https://doi.org/10.
1038/nrrheum.2014.103.
[98] Kessenbrock, Kai, Markus Krumbholz, Ulf Schönermarck, Walter
Back, Wolfgang L. Gross, Zena Werb, Hermann-Josef Gröne,
Volker Brinkmann, and Dieter E. Jenne. 2009. “Netting Neutrophils
in Autoimmune Small-Vessel Vasculitis.” Nature Medicine 15 (6):
623–25. https://doi.org/10.1038/nm.1959.
[99] Kumar, Santhosh V. R., Onkar P. Kulkarni, Shrikant R. Mulay,
Murthy N. Darisipudi, Simone Romoli, Dana Thomasova, Christina
R. Scherbaum, et al. 2015. “Neutrophil Extracellular Trap-Related
Extracellular Histones Cause Vascular Necrosis in Severe GN.”
Journal of the American Society of Nephrology: JASN 26 (10):
2399–2413. https://doi.org/10.1681/ASN.2014070673.
[100] Carmona-Rivera, Carmelo, Wenpu Zhao, Srilakshmi Yalavarthi,
and Mariana J. Kaplan. 2015. “Neutrophil Extracellular Traps
Induce Endothelial Dysfunction in Systemic Lupus Erythematosus
through the Activation of Matrix Metalloproteinase-2.” Annals of
the Rheumatic Diseases 74 (7): 1417–24. https://doi.org/10.1136/
annrheumdis-2013-204837.
[101] Yamauchi, Keiko, Makoto Sata, Jun-Ichi Machiya, Daisuke Osaka,
Toshihiro Wada, Shuichi Abe, Kazuhisa Otake, and Isao Kubota.
2003. “Antineutrophil Cytoplasmic Antibody Positive
Alveolar Haemorrhage during Propylthiouracil Therapy for
Hyperthyroidism.” Respirology (Carlton, Vic.) 8 (4): 532–35.
https://doi.org/10.1046/j.1440-1843.2003.00499.x.
[102] John, R., and A. M. Herzenberg. 2009. “Renal Toxicity of
Therapeutic Drugs.” Journal of Clinical Pathology 62 (6): 505–15.
https://doi.org/10.1136/jcp.2008.058271.
[103] Jiang, Xiaoxia, Gus Khursigara, and Robert L. Rubin. 1994.
“Transformation of Lupus-Inducing Drugs to Cytotoxic Products by
Activated Neutrophils.” Science (New York, N.Y.) 266 (5186): 810–
13. https://doi.org/10.1126/science.7973636.
[104] Schmiedeberg, S. von, C. Goebel, E. Gleichmann, and J. Uetrecht.

1995. “Neutrophils and Drug Metabolism.” Science (New York,
N.Y.) 268 (5210): 585–86. https://doi.org/10.1126/science.7725110.
[105] Lee, Ji Yeon, Jin-Haeng Chung, Yeon Joo Lee, Sung Soo Park, Seo
Yun Kim, Hyeon-Kyoung Koo, Jae Ho Lee, Choon-Taek Lee, and
Ho Il Yoon. 2011. “Propylthiouracil-Induced Nonspecific
Interstitial Pneumonia.” Chest 139 (3): 687–90. https://doi.org/
10.1378/chest.10-1558.
[106] Groskreutz, Dayna J., and Jess Mandel. 2006. “Chapter 15 -
Pulmonary Vasculitis.” In Pulmonary Vascular Disease, edited by
Jess Mandel and Darren Taichman, 237–53. Philadelphia: W.B.
Saunders. https://doi.org/10.1016/B978-1-4160-2246-6.50021-3.
Chapter 3
EOSINOPHILIC GRANULOMATOSIS
WITH POLYANGIITIS
N. Vobugari1,, Kejal Gandhi1, K. Raja2,

Farah Yasmin 3, Iqbal Ratnani4, MD
and Salim Surani5,6,*, MD
1
Department of Medicine, Georgetown University,
Medstar Washington Hospital Center, Washington, DC, USA
2
Department of Pediatric Cardiology, University of Minnesota,
Minneapolis, MN, USA
3
Dow University of Health Science, Karachi, Pakistan
4
Weil Cornell University, Houston Methodist Hospital,
Houston, TX, USA
5
6

Corresponding Author’s E-mail: srsurani@gmail.com.
90 N. Vobugari, K. Gandhi, K. Raja et al.
ABSTRACT
Eosinophilic Granulomatosis with Polyangiitis (EGPA), previously

called Churg-Strauss syndrome (CSS), is a multisystemic necrotizing
vasculitis. It belongs to small to medium size vessel anti-neutrophil
cytoplasmic antibody (ANCA) vasculitis. EGPA is characterized by
allergic rhinitis, asthma, and peripheral eosinophilia. Involvement of
non-pulmonary organs, including the gastrointestinal tract, kidney, and
heart, is not uncommon and has been associated with poor prognosis as
assessed by the revised Five-Factor Score (FFS). Approximately 10
percent of vasculitis are recognized to have EGPA, although the
epidemiology of EGPA remains unclear. The exact etiology is unknown.
Augmented Th1 and Th2 lymphocyte function, increased eosinophil
recruitment, and decreased eosinophil apoptosis are postulated as
underlying pathogenesis. Diagnosis includes peripheral blood
eosinophilia, usually 5000-9000 eosinophils/microL, and is confirmed by
lung or skin biopsy showing leukoclastic vasculitis. ANCA antibodies
are detected in about 40-60 percent of patients. The primary treatment of
EGPA is systemic glucocorticoids which has shown to improve 5-year
survival rates to 70-90%.
Keywords: vasculitis, eosinophilic granulomatosis with polyangiitis,

ANCA associated vasculitis, Churg-Strauss syndrome, asthma,
eosinophilia, ANCA
INTRODUCTION
Eosinophilic granulomatosis with polyangiitis (EGPA) is a

multisystem disease presented as allergic rhinitis, asthma, peripheral
eosinophilia, and peripheral neuropathy.1 EGPA was previously known as
Churg-Strauss syndrome (CSS) or allergic granulomatosis and angiitis.
1
Sharon A Chung et al., “2021 American College of Rheumatology/Vasculitis Foundation
Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated
Vasculitis,” Arthritis Rheumatol 73, no. 8 (2021): 1366–83, https://doi.org/
10.1002/art.41773; A Mahr et al., “Eosinophilic Granulomatosis with Polyangiitis (Churg-
Strauss): Evolutions in Classification, Etiopathogenesis, Assessment and Management,”
Curr. Opin. Rheumatol. 26, no. 1 (August 10, 2014), https://doi.org/
10.1097/BOR.0000000000000015.
Eosinophilic Granulomatosis with Polyangiitis 91
EGPA is included among a group of necrotizing vasculitis of small and

medium-sized systemic arteries.
Other subsets of small and medium sized vasculitis include
polyarteritis nodosa (PAN), granulomatosis with polyangiitis (GPA) and
microscopic polyangiitis (MPA).2 EGPA is differentiated histologically by
eosinophilic tissue infiltration in addition to vasculitis. The knowledge of
EGPA continues to evolve, but many lot of gaps in knowledge persist.
2021 revised American College of Rheumatology/ Vasculitis Foundation
Guidelines defines EGPA among the anti-neutrophil cytoplasmic antibody
(ANCA) vasculitis group along with GPA and MPA, although detectable
ANCA is found in 40-75% of patients with EGPA.3 This chapter reviews
history, epidemiology, etiology, pathogenesis, clinical presentation,
evaluation, diagnostic criteria, and treatment of EGPA as a guide for
clinicians in practice.
HISTORY
In 1951, Jacob Churg and Lotte Strauss first described EGPA in a case
series of 13 patients. These patients presented with a triad of asthma, fever,
blood eosinophilia. Autopsy evidence showed granulomatous necrotizing
vasculitis. This entity was initially called as allergic granulomatosis,
angiitis, and periarteritis nodosa, defined with three characteristic features
of eosinophilic infiltration, necrotizing vasculitis of small and medium-
sized vessels, and extravascular granulomatous inflammation associated
with allergic etiology.4 With further evolving knowledge, in 1984, Lanham
et al. defined EGPA based on bronchial asthma, blood eosinophilia greater
2
Chung et al., “2021 American College of Rheumatology/Vasculitis Foundation Guideline for
the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.”
3
Chung et al.; Mahr et al., “Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss):
Evolutions in Classification, Etiopathogenesis, Assessment and Management”; K A Keogh
and U Specks, “Churg-Strauss Syndrome,” Semin. Respir. Crit. Care Med. 27, no. 2
(August 10, 2006), https://doi.org/10.1055/s-2006-939518.
4
Lotte Strauss Jacob Churg, “Allergic Granulomatosis, Allergic Angiitis, and Periarteritis
Nodosa,” Am. J. Pathol. 27, no. 2 (August 10, 1951): 277, https://www.ncbi.nlm.nih.
gov/pmc/articles/PMC1937314/.
than 1500/ microliter, and vasculitis of at least two extrapulmonary organ

systems.5 In 1990, American College of Rheumatology proposed the
classification criteria, which is the latest diagnostic criteria. This criterion
includes six features asthma, migratory infiltrates in the lung, paranasal
sinus abnormalities, mono or polyneuropathy, peripheral blood
eosinophilia (> 10% of total leukocyte count), eosinophilic tissue
infiltrates, requiring at least four features for diagnosis with 99.7%
specificity and 85% sensitivity for diagnosis.6
EPIDEMIOLOGY
Overall incidence and prevalence of EGPA remain unclear. In a study

period ranging from 1998-2014, the incidence of EGPA in the US was
around 4 cases per million population. In Europe, it ranges from 0.5- 2.7
cases per million. The overall prevalence in the US is 18 cases per million;
in Europe, it ranges from 2-38 cases per million.7 Over the past three
decades, the incidence and prevalence of EGPA is gradually increasing,
possibly due to a genuine increase in incidence or increased awareness and
availability of diagnostic criteria to differentiate the type of vasculitis. The
5
Rebanta K Chakraborty and Narothama R Aeddula, “Churg Strauss Syndrome,” in StatPearls
[Internet] (StatPearls Publishing, 2021), https://www.ncbi.nlm.nih.gov/books/NBK
537099/; J G Lanham et al., “Systemic Vasculitis with Asthma and Eosinophilia: A Clinical
Approach to the Churg-Strauss Syndrome,” Medicine 63, no. 2 (August 10, 1984),
https://doi.org/10.1097/00005792-198403000-00001.
6
A T Masi et al., “The American College of Rheumatology 1990 Criteria for the Classification
of Churg-Strauss Syndrome (Allergic Granulomatosis and Angiitis),” Arthritis Rheum. 33,
no. 8 (August 10, 1990), https://doi.org/10.1002/art.1780330806.
7
the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis”; A J
Mohammad, “An Update on the Epidemiology of ANCA-Associated Vasculitis,”
Rheumatology 59, no. Suppl 3 (August 10, 2020), https://doi.org/10.1093/
rheumatology/keaa089; Mugdha Gokhale et al., “Prevalence of Eosinophilic
Granulomatosis With Polyangiitis and Associated Health Care Utilization Among Patients
With Concomitant Asthma in US Commercial Claims Database,” JCR: Journal of Clinical
Rheumatology 27, no. 3 (August 10, 2021): 107, https://doi.org/10.1097/
RHU.0000000000001198.
trend of patient survival rates is also growing, given better understanding

and evolving treatment patterns of EGPA.8
The median age of EGPA is 40 years.9 Peak age of onset appears to be
rising with increasing age. The peak age range is 55-75 years, per recent
data. In most studies, a higher male predominance is evident. A male:
female ratio ranging 1.07-1.48, with around 0.86 in the US.10 Among the
three ANCA-associated vasculitis, EGPA is the least common.11
ETIOLOGY
The exact pathogenesis is evolving and remains unclear. ANCA

positivity is noted in 40-75% of patients and is therefore unclear if ANCA
has a significant pathogenic role or whether they reflect portion among the
spectrum of EGPA clinical manifestations.12 EGPA continues to be
grouped under ANCA-associated vasculitis per 2021 revised American
College of Rheumatology/ Vasculitis Foundation Guidelines.13 The
existence of ANCA negative EGPA postulates involvement by other
etiologies. Several other abnormalities in immunologic function play a role
in the pathogenesis of EGPA, which includes amplified Th1 and Th2
8
the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis”;
Mohammad, “An Update on the Epidemiology of ANCA-Associated Vasculitis.”
9
Masi et al., “The American College of Rheumatology 1990 Criteria for the Classification of
Churg-Strauss Syndrome (Allergic Granulomatosis and Angiitis)”; M Conron and H L
Beynon, “Churg-Strauss Syndrome,” Thorax 55, no. 10 (August 10, 2000),
https://doi.org/10.1136/thorax.55.10.870.
10
Mohammad, “An Update on the Epidemiology of ANCA-Associated Vasculitis.”
11
Keogh and Specks, “Churg-Strauss Syndrome.”
12
the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis”; Mahr et
al., “Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss): Evolutions in
Classification, Etiopathogenesis, Assessment and Management.”
13
the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.”
lymphocyte function, eosinophilia, tissue recruitment, and decreased

eosinophil apoptotic function.14
Immune Dysfunction
Both innate and adaptive immunity is noted to play a role in the

etiopathogenesis.15 Heightened Th2 responses suggest the prominence of
allergic rhinitis and asthma. Th1 immunity involvement is demonstrated
by angiocentric necrotizing granulomatosis. Eosinophilia is due to a
combination of elevated eosinophil recruitment triggered by Th2 cytokines
and prolonged survival of eosinophils due to inhibition of CD95-mediated
apoptosis.16
Genetic Factors
Polygenic factors may also play a role in the etiopathogenesis of

EGPA. Human Leukocyte Antigen (HLA) class and specific interleukin10
polymorphism are also associated with pathogenesis of EGPA. IL-10-
3575/-1082/-592 TAC haplotype is strongly associated with EGPA
especially, ANCA negative EGPA, and can also help differentiate EGPA
from GPA.17 HLA-DRB1*07 and HLA-DRB4 found to be more prevalent
among patients with EGPA. Increased vasculitic manifestations correlated
with HLA-DRB4 presence, indicating its role as a genetic risk factor for
14
B Hellmich et al., “Update on the Pathogenesis of Churg-Strauss Syndrome,” Clin. Exp.
Rheumatol. 21, no. 6 Suppl 32 (August 11, 2003), https://pubmed.ncbi.
nlm.nih.gov/14740430/.
15
“Analysis of Innate and Adaptive Immune Responses in Eosinophilic Granulomatosis with
Polyangiitis (Churg-Strauss) - ACR Meeting Abstracts,” August 10, 2016,
https://acrabstracts.org/abstract/analysis-of-innate-and-adaptive-immune-responses-in-
eosinophilic-granulomatosis-with-polyangiitis-churg-strauss/ LB - IiDU.
16
Hellmich et al., “Update on the Pathogenesis of Churg-Strauss Syndrome.”
17
S Wieczorek et al., “Functionally Relevant Variations of the Interleukin-10 Gene Associated
with Antineutrophil Cytoplasmic Antibody-Negative Churg-Strauss Syndrome, but Not
with Wegener’s Granulomatosis,” Arthritis Rheum. 58, no. 6 (August 11, 2008),
EGPA.18 HLA-DQ is associated with Myeloperoxidase (MPO) positive

ANCA associated EGPA.19
Drug-Related Factors
Various medications, although rare, such as leukotriene modifying

agents, inhaled glucocorticoids, and omalizumab (monoclonal antibody
inhibiting the binding of IgE to mast cells) are associated with the
pathogenesis of EGPA majority observed in asthma patients when
systemic glucocorticoids dosage was reduced due to the addition of the
above agents in the asthma treatment, postulating the unmasking effects of
underlying EGPA.20 In a review of 181 suspected drug-induced EGPA
case reports from 1997-2003, 90% of cases had leukotriene receptor
18
A Vaglio et al., “HLA-DRB4 as a Genetic Risk Factor for Churg-Strauss Syndrome,” Arthritis
Rheum. 56, no. 9 (August 11, 2007), https://doi.org/10.1002/art.22834.
19
P A Lyons et al., “Genome-Wide Association Study of Eosinophilic Granulomatosis with
Polyangiitis Reveals Genomic Loci Stratified by ANCA Status,” Nat. Commun. 10, no. 1
(August 11, 2019), https://doi.org/10.1038/s41467-019-12515-9.
20
C Le Gall et al., “Inhaled Corticosteroids and Churg-Strauss Syndrome: A Report of Five
Cases,” Eur. Respir. J. 15, no. 5 (2000): 978–81, https://doi.org/10.1034/j.1399-
3003.2000.15e29.x; Stuart E Turvey, Sara O Vargas, and Wanda Phipatanakul, “Churg-
Strauss Syndrome in a 7-Year-Old Receiving Montelukast and Inhaled Corticosteroids,”
Annals of Allergy, Asthma & Immunology, 2003, https://doi.org/10.1016/s1081-
1206(10)62156-4; S A Dyer and W J Geimeier, “A Case Study of Churg Strauss Syndrome
with Montelukast and Inhaled Corticosteroids,” Journal of Allergy and Clinical
Immunology, 2006, https://doi.org/10.1016/j.jaci.2005.12.029; Anne-Marie Ruppert et al.,
“Development of Churg-Strauss Syndrome with Controlled Asthma during Omalizumab
Treatment,” J. Allergy Clin. Immunol. 121, no. 1 (2008): 253–54,
https://doi.org/10.1016/j.jaci.2007.10.040; Salik Nazir et al., “Omalizumab-Associated
Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome),” Ann. Allergy
Asthma Immunol. 118, no. 3 (2017): 372-374.e1, https://doi.org/10.1016/j.anai.
2016.12.003; Luke Nessan Carson, Ashish Pradhan, and Deepak Subramanian,
“Omalizumab-Associated Eosinophilic Granulomatosis with Polyangiitis: Cause or
Coincidence?,” BMJ Case Rep. 14, no. 7 (2021), https://doi.org/10.1136/bcr-2020-240078;
Christine Jaworsky, “Leukotriene Receptor Antagonists and Churg-Strauss Syndrome: An
Association with Relevance to Dermatopathology?,” Journal of Cutaneous Pathology,
2008, https://doi.org/10.1111/j.1600-0560.2008.01050.x.
antagonists as the suspected medication.21 Other medications such as

sulfonamides, macrolides, and diphenylhydantoin are also implicated.22
Cocaine use is also postulated as an unusual etiology of EGPA
vasculitis. ANCA positivity is also noted in the cocaine-induced nasal
septum destructive lesions, unclear if these are separate entities from
EGPA.23 In addition, diagnosis of EGPA in patients using cocaine is
challenging as both can present with acute and chronic eosinophilic
pneumonia.24
PATHOPHYSIOLOGY
The pathogenesis of EGPA continues to evolve. It is majorly divided

into eosinophil-mediated damage or ANCA-induced endothelial injury.
The clinical phenotype depends on the type of endothelial injury.
Eosinophil Mediated Tissue Injury
Both abnormal Th1 and Th2 type immune responses are involved in
pathogenesis. T cell response via Th2 activation and Th9 and Th17
polarization in peripheral blood, activation of B cells, and reduction of
Innate Lymphoid Cell (ILC2) noted on flow cytometry during active
disease. The decrease in serum ILC2 is due to deposition into cells. An
increase in IL-25, Thymic Stromal Lymphopoietin (TSLP) and Thymus
and Activation Regulated Chemokine (TARC), and Th2 related cytokines
21
S Bibby et al., “Association between Leukotriene Receptor Antagonist Therapy and Churg-
Strauss Syndrome: An Analysis of the FDA AERS Database,” Thorax 65, no. 2 (August
11, 2010), https://doi.org/10.1136/thx.2009.120972.
22
Chakraborty and Aeddula, “Churg Strauss Syndrome.”
23
O Wiesner et al., “Antineutrophil Cytoplasmic Antibodies Reacting with Human Neutrophil
Elastase as a Diagnostic Marker for Cocaine-Induced Midline Destructive Lesions but Not
Autoimmune Vasculitis,” Arthritis Rheum. 50, no. 9 (August 11, 2004),
24
R Orriols et al., “Cocaine-Induced Churg-Strauss Vasculitis,” Eur. Respir. J. 9, no. 1 (August
11, 1996), https://doi.org/10.1183/09031936.96.09010175.
in serum indicates the interplay between both innate and adaptive immune
response.25
An initial abnormal Th2 mediated immune activation triggers the
margination of eosinophils. Eosinophilia and eosinophil infiltration result
from increased synthesis, enhanced extravasation, and prolonged survival
of eosinophils.26 IL-3 and IL-5 are eosinophil maturation regulators
indicted by elevated IL-5 levels correlating to active disease and its
suppression with immunosuppressive therapy. Endothelial and epithelial
cells secrete eosinophil-specific chemokines such as CCL17, CCL22,
CCL26 which act on CCR4 receptors of T cells to facilitate recruitment of
eosinophils and effector Th2 cells to organs. The recruited eosinophils
release peroxidases, neurotoxins, and eosinophil major basic proteins
(MBP) mediating direct tissue damage. Eosinophils release cytokines such
as IL-1, IL-3, IL-5, Tissue Like Growth Factor (TGF) beta, which
increases the survival of eosinophils and ongoing tissue destruction.27
ANCA Mediated Tissue Injury
About 40-70% of EGPA patients have the presence of MPO ANCA.28

Proteinase 3 (PR3) ANCA is noted in few percentages of EGPA patients.
MPO ANCA binds to the intracellular MPO antigen of neutrophils. This
25
“Analysis of Innate and Adaptive Immune Responses in Eosinophilic Granulomatosis with
Polyangiitis (Churg-Strauss) - ACR Meeting Abstracts.”
26
Chakraborty and Aeddula, “Churg Strauss Syndrome.”
27
Y Shiota et al., “Serum Interleukin-5 Levels in a Case with Allergic Granulomatous Angiitis,”
Intern. Med. 36, no. 10 (August 11, 1997), https://doi.org/10.2169/
internalmedicine.36.709; B Jakiela et al., “Both Th2 and Th17 Responses Are Involved in
the Pathogenesis of Churg-Strauss Syndrome,” Clin. Exp. Rheumatol. 29, no. 1 Suppl 64
(August 11, 2011), https://pubmed.ncbi.nlm.nih.gov/21470488/; J Zwerina et al., “Eotaxin-
3 in Churg-Strauss Syndrome: A Clinical and Immunogenetic Study,” Rheumatology 50,
no. 10 (August 11, 2011), https://doi.org/10.1093/rheumatology/
keq445.
28
the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis”; Mahr et
al., “Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss): Evolutions in
Classification, Etiopathogenesis, Assessment and Management.”
leads to the generation of reactive oxygen species and proteolytic enzymes

leading to tissue destruction.29
Figure 1. Pathogenesis of eosinophilic granulomatosis with polyangiitis. Allergen is

presented by antigen presenting cell (APC) binds to T cell receptor (TCR) on CD4
T cell triggers both Th1/Th17 and Th2 pathway Th1 activation release
interleukins (IL2, IFN-gamma, IL17) triggers granulomatous vasculitis and tissue
damage. Th2 pathway activates interleukins (IL4, IL5, IL13) activates B cell
release of IgE, IgG4, ANCA), activation of IL25 release of CCR3 and CCL26
eosinophil activation, tissue recruitment and inhibition of apoptosis release of
major basic protein (MBP) and proteolytic enzymes tissue damage.
HISTOPATHOLOGY
The pathology findings in various organs include eosinophilic

infiltration, prominent extensive areas of necrosis, eosinophilic- giant cell
vasculitis of small arteries and veins, interstitial, and perivascular
necrotizing granulomas. The distinctive pattern includes angiitis,
granulomatous or non-granulomatous, and extravascular necrotizing
granulomas, especially eosinophilic infiltrates.30 The histopathology
29
A J Porges et al., “Anti-Neutrophil Cytoplasmic Antibodies Engage and Activate Human
Neutrophils via Fc Gamma RIIa,” J. Immunol. 153, no. 3 (August 11, 1994),
https://pubmed.ncbi.nlm.nih.gov/8027554/.
30
J T Lie, “Illustrated Histopathologic Classification Criteria for Selected Vasculitis Syndromes.
American College of Rheumatology Subcommittee on Classification of Vasculitis,”
Arthritis Rheum. 33, no. 8 (August 11, 1990), https://doi.org/10.
1002/art.1780330804.
findings depend on the stage of the disease. In the pre-vasculitic phase,

tissue infiltration by eosinophils is seen without obvious vasculitis. During
the vasculitis phase, a nondestructive eosinophilic infiltration may be seen.
In the post-vasculitic phase, fibrotic vascular lesions with organized
thrombi, extensive destruction. Eosinophilic infiltration may be absent in
the post-vasculitic phase.
Involvement of organs can range involving a few (pulmonary) to
multisystemic, including pulmonary and extrapulmonary. Extrapulmonary
lesions are found in the gastrointestinal tract, spleen, and heart more
commonly than the kidney, distinguishing between EGPA and GPA.31
In the lung, granulomas have central necrosis with eosinophilic
infiltration with a border of palisading histiocytes and multinucleated giant
cells. Asthmatic bronchitis, eosinophilic pneumonia, vasculitis, and
extravascular granulomas are the different modes of destructive pulmonary
lesions. Pulmonary hemorrhage may also be seen.32
Skin lesions reveal a leukocytoclastic vasculitis with eosinophilic
infiltration, palisading granulomas, and dermal nerve fibers involvement.33
Cardiac biopsy revealed endomyocarditis and not vasculitis, which is
usually fatal.34
31
Chakraborty and Aeddula, “Churg Strauss Syndrome”; Lie, “Illustrated Histopathologic
Classification Criteria for Selected Vasculitis Syndromes. American College of
Rheumatology Subcommittee on Classification of Vasculitis”; A L Katzenstein,
“Diagnostic Features and Differential Diagnosis of Churg-Strauss Syndrome in the Lung.
A Review,” Am. J. Clin. Pathol. 114, no. 5 (August 11, 2000),
https://doi.org/10.1309/F3FW-J8EB-X913-G1RJ.
32
Katzenstein, “Diagnostic Features and Differential Diagnosis of Churg-Strauss Syndrome in
the Lung. A Review.”
33
T Kawakami et al., “Initial Cutaneous Manifestations Consistent with Mononeuropathy
Multiplex in Churg-Strauss Syndrome,” Arch. Dermatol. 141, no. 7 (August 11, 2005),
https://doi.org/10.1001/archderm.141.7.873.
34
T Neumann et al., “Cardiac Involvement in Churg-Strauss Syndrome: Impact of
Endomyocarditis,” Medicine 88, no. 4 (August 11, 2009), https://doi.org/10.
1097/MD.0b013e3181af35a5; C Comarmond et al., “Eosinophilic Granulomatosis with
Polyangiitis (Churg-Strauss): Clinical Characteristics and Long-Term Followup of the 383
Patients Enrolled in the French Vasculitis Study Group Cohort,” Arthritis Rheum. 65, no. 1
(August 11, 2013), https://doi.org/10.1002/art.37721.
Renal lesions include necrotizing crescentic glomerulonephritis,

eosinophilic interstitial nephritis, mesangial glomerulonephritis, and focal
segmental glomerulonephritis.35
CLINICAL PRESENTATION
EGPA clinical presentation can range from involving a few to multi-

organ system. The most commonly involved organ is the lung followed by
skin with presenting symptoms of asthma (90%), rhinitis/sinusitis (48%),
peripheral neuropathy (51%), and skin (40%).36 EGPA can involve any
organ system, including gastrointestinal, cardiovascular, renal, central
nervous systems, and extrapulmonary involvement is associated with
morbidity and mortality in EGPA.
ANCA-positive patients are more likely to have ear, nose, throat
(ENT) manifestations, weight loss, biopsy-proven vasculitis,
glomerulonephritis, leukoclastic capillaries, peripheral neuropathy, and
renal involvement, but less frequent cardiac manifestations than ANCA-
negative patients.37
The clinical spectrum is characterized in three sequential phases,
although all phases do not occur in every patient or can overlap between
35
R A Sinico et al., “Renal Involvement in Churg-Strauss Syndrome,” Am. J. Kidney Dis. 47,
no. 5 (August 11, 2006), https://doi.org/10.1053/j.ajkd.2006.01.026; E J Clutterbuck, D J
Evans, and C D Pusey, “Renal Involvement in Churg-Strauss Syndrome,” Nephrol. Dial.
Transplant 5, no. 3 (August 11, 1990), https://doi.org/10.1093/ndt/5.3.161.
36
Comarmond et al., “Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss): Clinical
Characteristics and Long-Term Followup of the 383 Patients Enrolled in the French
Vasculitis Study Group Cohort”; L Guillevin et al., “Churg-Strauss Syndrome. Clinical
Study and Long-Term Follow-up of 96 Patients,” Medicine 78, no. 1 (August 11, 1999),
https://doi.org/10.1097/00005792-199901000-00003.
37
Vasculitis Study Group Cohort”; V Cottin et al., “Revisiting the Systemic Vasculitis in
Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss): A Study of 157 Patients
by the Groupe d’Etudes et de Recherche Sur Les Maladies Orphelines Pulmonaires and the
European Respiratory Society Taskforce on E,” Autoimmun. Rev. 16, no. 1 (August 11,
2017), https://doi.org/10.1016/j.autrev.2016.09.018.
the phases. These phases include prodromal phase, eosinophilic phase and
vasculitic phase, which are described in the Table 1.38
Table 1. Clinical spectrum of eosinophilic granulomatosis with

polyangiitis (EGPA)
Prodromal phase Nonspecific symptoms- malaise, fever, migrating polyarthralgia and

myalgia (37-57%), weight loss, and refractory asthma.
Upper respiratory symptoms like atopic disease, allergic rhinitis, and
asthma are more common than chronic rhinosinusitis, nasal polyps.
Occurs in the second and third decades of life.
Eosinophilic Peripheral blood eosinophilia and eosinophilic infiltration in tissues,
phase especially lung, gastrointestinal tract, and serosal effusions.
Vasculitic phase Systemic vasculitis of medium and small vessels and vascular and
extravascular granulomatosis, including neurological symptoms.
Occurs after three to nine years from the onset of asthma symptoms.
Organ System Involvement
Upper Respiratory Tract and Pulmonary Manifestations

Asthma is present in almost 90-100% of the patients. Usually
represents one of the early symptoms for the age 30-50-year range.39
EGPA associated asthma is usually adult onset with an eosinophilic
phenotype. Asthma occurs in association with allergic rhinitis, sinusitis,
and nasal polyps. Chronic rhinitis is also common in 75% of cases that
usually occurs in the eosinophilic stage.
Asthma in EGPA might occur before the diagnosis of EGPA and is
usually resistant to conventional treatment, and by the time of diagnosis of
EGPA, these patients are usually steroid dependent. The disease might not
be apparent till systemic steroids are held or stopped. Asthma medications
38
Chakraborty and Aeddula, “Churg Strauss Syndrome”; Lanham et al., “Systemic Vasculitis
with Asthma and Eosinophilia: A Clinical Approach to the Churg-Strauss Syndrome”;
Guillevin et al., “Churg-Strauss Syndrome. Clinical Study and Long-Term Follow-up of 96
Patients.”
39
Vasculitis Study Group Cohort.”
like leukotriene antagonists, inhaled corticosteroids, omalizumab are

associated with EGPA in etiopathogenesis.40 Although it is to be noted that
these treatments are started to reduce the doses of systemic steroids, when
the EGPA symptoms start, unclear if the reducing systemic steroid dose is
unmasking the EGPA symptoms.
Other pulmonary symptoms include pulmonary opacities with
eosinophilia, granulomatous nodules, eosinophilic pleural effusion.
Alveolar hemorrhage is rare and can be associated with ANCA-positive
EGPA.
ENT involvement ranges from allergic rhinitis, nasal polyposis, nasal
obstruction, serous otitis media, recurrent sinusitis in about 40-80% of
patients.41 Chronic serous otitis media and sensorineural hearing loss are
also seen in EGPA and likely reflect the severity of rhinosinusitis.
Gastrointestinal Involvement
Gastrointestinal manifestations occur due to eosinophilic infiltration,
leading to eosinophilic gastroenteritis and mesenteric vasculitis. The
presentation can range from nonspecific symptoms such as nausea,
vomiting, or diarrhea (33-90%) to severe complications like bleeding,
mucosal ulcers, perforation, intestinal obstruction, which are surgical
emergencies (8%) necessitating exploratory laparotomy. Serosal
40
Le Gall et al., “Inhaled Corticosteroids and Churg-Strauss Syndrome: A Report of Five Cases”;
Turvey, Vargas, and Phipatanakul, “Churg-Strauss Syndrome in a 7-Year-Old Receiving
Montelukast and Inhaled Corticosteroids”; Ruppert et al., “Development of Churg-Strauss
Syndrome with Controlled Asthma during Omalizumab Treatment”; Jaworsky,
“Leukotriene Receptor Antagonists and Churg-Strauss Syndrome: An Association with
Relevance to Dermatopathology?”; Bibby et al., “Association between Leukotriene
Receptor Antagonist Therapy and Churg-Strauss Syndrome: An Analysis of the FDA
AERS Database.”
41
Vasculitis Study Group Cohort”; V Seccia et al., “Focus on the Involvement of the Nose
and Paranasal Sinuses in Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss
Syndrome): Nasal Cytology Reveals Infiltration of Eosinophils as a Very Common
Feature,” Int. Arch. Allergy Immunol. 175, no. 1–2 (August 11, 2018), https://doi.org/10.
1159/000484602; I Srouji et al., “Rhinologic Symptoms and Quality-of-Life in Patients
with Churg-Strauss Syndrome Vasculitis,” Am. J. Rhinol. 22, no. 4 (August 11, 2008),
https://doi.org/10.2500/ajr.2008.22.3204; A Bacciu et al., “Ear, Nose and Throat
Manifestations of Churg-Strauss Syndrome,” Acta Otolaryngol. 126, no. 5 (August 11,
2006), https://doi.org/10.1080/00016480500437435.
involvement can present with eosinophilic peritonitis and ascites.

Gastrointestinal emergencies are associated with poor prognosis and are
the fourth leading cause of death among EGPA patients.42 Rarely, EGPA
can present as necrotizing acalculous cholecystitis, eosinophilic liver
disease and pancreatitis.
Skin Involvement
About 40-60% of patients with EGPA have skin involvement. Skin
involvement is the most common presentation of the vasculitic phase.
Histopathology includes extravascular eosinophils, vasculitis, and
granulomas.43 Skin involvement presents as subcutaneous nodules on the
extensor surfaces of the arm, particularly elbows, hands, and legs.44
Renal Involvement
Renal involvement is variable among EGPA patients. Renal
involvement majorly occurs in ANCA-positive patients. Necrotizing
glomerulonephritis is the most common pathology involved. Others
include eosinophilic interstitial nephritis, mesangial glomerulonephritis,
and focal segmental glomerulonephritis.45 Systemic hypertension can
affect 10-30% of EGPA patients.
Cardiovascular Involvement
Cardiac involvement is one of the severe manifestations of EGPA, and
approximately 50% of deaths among EGPA patients. Cardiac
42
P Fraioli, M Barberis, and G Rizzato, “Gastrointestinal Presentation of Churg Strauss
Syndrome,” Sarcoidosis 11, no. 1 (August 11, 1994), https://pubmed.ncbi.nlm.
nih.gov/8036344/.
43
C Bridges et al., “Cutaneous Manifestations of Childhood Eosinophilic Granulomatosis with
Polyangiitis (CEGPA): A Case-Based Review,” Pediatr. Dermatol. 37, no. 4 (August 11,
2020), https://doi.org/10.1111/pde.14144.
44
Vasculitis Study Group Cohort”; R A Schwartz and J Churg, “Churg-Strauss Syndrome,”
Br. J. Dermatol. 127, no. 3 (August 11, 1992), https://doi.org/10.1111/j.1365-
2133.1992.tb00114.x.
45
Sinico et al., “Renal Involvement in Churg-Strauss Syndrome”; Clutterbuck, Evans, and
Pusey, “Renal Involvement in Churg-Strauss Syndrome.”
manifestations range from impaired ventricular function (50%), mild to

severe valvular abnormalities (73%), pericardial effusions (40%),
endocarditis (59%).46 EGPA with cardiac involvement is less likely to have
ANCA positivity and more likely to have peripheral eosinophilia.
Neurologic Involvement
Peripheral neuropathy involving at least two separate nerve areas or
mononeuritis multiplex (75% of patients). If untreated, this may progress
to symmetric or asymmetric polyneuropathy. Neuropathic pain can also
concur.47 Patients with mononeuritis multiplex are more likely to have
ANCA positivity.48 Other rare manifestations include subarachnoid and
cerebral hemorrhage, cerebral infarction, cranial nerve palsies, cortical
blindness. Ophthalmic manifestations include central retinal artery
occlusion, central retinal vein occlusion, ischemic optic neuropathy,
conjunctival nodules, orbital myositis.49
Musculoskeletal Involvement
Musculoskeletal involvement includes myalgia, migratory
polyarthralgia, arthritis that occurs in 40-50% of the vasculitic phase of
EGPA.50 Myositis can occur rarely.51
46
Neumann et al., “Cardiac Involvement in Churg-Strauss Syndrome: Impact of
Endomyocarditis.”
47
N Hattori et al., “Clinicopathological Features of Churg-Strauss Syndrome-Associated
Neuropathy,” Brain 122 (Pt 3 (August 11, 1999), https://doi.org/10.1093/brain/122.3.427.
48
Cottin et al., “Revisiting the Systemic Vasculitis in Eosinophilic Granulomatosis with
Polyangiitis (Churg-Strauss): A Study of 157 Patients by the Groupe d’Etudes et de
Recherche Sur Les Maladies Orphelines Pulmonaires and the European Respiratory Society
Taskforce on E.”
49
S S Akella et al., “Ophthalmic Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss
Syndrome): A Systematic Review of the Literature,” Ophthal. Plast. Reconstr. Surg. 35,
no. 1 (August 11, 2019), https://doi.org/10.1097/IOP.0000000000001202.
50
Patients.”
51
M E Parent, S Larue, and B Ellezam, “Eosinophilic Granulomatosis with Polyangiitis (Churg-
Strauss Syndrome) Presenting as Diffuse Myositis,” BMC Musculoskelet. Disord. 15
(August 11, 2014), https://doi.org/10.1186/1471-2474-15-388.
Thromboembolic Disease
Venous thromboembolism (VTE) can occur in 8% of the EGPA
patients, similar to other systemic vasculitis.52
Lymphadenopathy
Eosinophilic lymphadenopathy can occur in 30-40% of the EGPA
patients, majorly cervical and axillary lymphadenopathy.53
Table 2. Organ wise range of clinical manifestations in eosinophilic

granulomatosis with polyangiitis (EGPA)
Pulmonary Asthma (90-100%), Pulmonary granulomatous nodules,

eosinophilic pleural effusion, alveolar hemorrhage
Upper respiratory tract Allergic rhinitis, nasal polyposis, nasal obstruction, serous otitis
and Ear, nose, and throat media, recurrent sinusitis, chronic serous otitis media
(ENT)
Gastrointestinal Non-specific (nausea, vomiting, diarrhea), gastrointestinal
bleeding, mucosal ulcers, perforation, intestinal obstruction,
eosinophilic ascites, peritonitis
Skin Subcutaneous granulomatous nodules on arm, elbows, hands, and
legs, vasculitis
Renal Necrotizing glomerulonephritis, eosinophilic interstitial nephritis,
mesangial glomerulonephritis, focal segmental
glomerulonephritis
Cardiovascular Endocarditis, impaired ventricular function, mild to severe
valvular abnormalities, pericardial effusions
Neurologic Mononeuropathy, mononeuritis multiplex, peripheral neuropathy,
subarachnoid or cerebral hemorrhage, Ophthalmic
manifestations- central retinal artery or venous occlusion, optic
neuropathy, conjunctival nodules.
Musculoskeletal Myalgia, migratory polyarthralgia, arthritis, myositis
Thromboembolic Venous thromboembolism
Lymphadenopathy Eosinophilic cervical and axillary lymphadenopathy
52
Y Allenbach et al., “High Frequency of Venous Thromboembolic Events in Churg-Strauss
Syndrome, Wegener’s Granulomatosis and Microscopic Polyangiitis but Not Polyarteritis
Nodosa: A Systematic Retrospective Study on 1130 Patients,” Ann. Rheum. Dis. 68, no. 4
(August 11, 2009), https://doi.org/10.1136/ard.2008.099051.
53
A Churg et al., “Formes Frustes of Churg-Strauss Syndrome,” Chest 108, no. 2 (August 11,
1995), https://doi.org/10.1378/chest.108.2.320.
INVESTIGATIONS
Initial Investigations
Peripheral eosinophilia, high IgE titers and ANCA positivity are the
most common laboratory findings seen in patients with EGPA.
Eosinophilia, though fluctuates, is a persistent finding. Eosinophil
count >1500/mm3 or greater than 10% of peripheral white blood count has
been used in diagnostic criteria. Eosinophils disappear rapidly after start of
corticosteroid treatment. Tissue eosinophilia can be found in patients in
whom peripheral eosinophilia is absent. Patients with absolute eosinophilia
should be evaluated to rule out other causes of eosinophilia. They should
be tested for local parasites, HIV, Vitamin B12 levels and serum tryptase
levels. Peripheral smear must also be obtained to identify blasts or
dysplastic eosinophils.54
High IgE titer is seen in 75% of patients but is non-specific.55
ANCA are found in 30 to 60% of EGPA patients. Majority of the
ANCA antibodies are directed against myeloperoxidase with perinuclear
staining pattern (anti-MPO p-ANCA). Antibodies to PR3 are uncommon
in EGPA. Multiple studies have shown that ANCA positive EGPA patients
have more systemic vasculitis with involvement of kidneys and peripheral
neuropathy whereas ANCA negative patients have more
cardiomyopathy.56
54
Matthieu Groh et al., “Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss) (EGPA)
Consensus Task Force Recommendations for Evaluation and Management,” European
Journal of Internal Medicine 26, no. 7 (2015): 545–53, https://doi.org/
10.1016/j.ejim.2015.04.022.
55
Eveline Y. Wu et al., “Eosinophilic Granulomatosis with Polyangiitis: Clinical Pathology
Conference and Review,” Journal of Allergy and Clinical Immunology: In Practice 6, no.
5 (2018): 1496–1504, https://doi.org/10.1016/j.jaip.2018.07.001.
56
Régis Sablé-Fourtassou et al., “Antineutrophil Cytoplasmic Antibodies and the Churg-Strauss
Syndrome,” Annals of Internal Medicine 143, no. 9 (2005): 632–38,
https://doi.org/10.7326/0003-4819-143-9-200511010-00006.
Other non-specific laboratory findings include elevation of

inflammatory markers, normocytic anemia, positive rheumatoid factor
(RF), normal or elevated complement levels.
Asthma is almost always present at the time of diagnosis. However,
sometimes, it may occur following vasculitis onset. Complete pulmonary
diagnostic evaluation including chest radiography, high-resolution CT
scan and pulmonary function tests should be performed at the time of
diagnosis. Chest X-ray findings are often diverse and includes transient,
patchy opacities without specific distribution pattern. Eosinophilic pleural
effusion is present in 30% of patients.57 HRCT is more sensitive than chest
X-ray and shows patchy infiltrates or consolidation with random
distribution not limiting to a particular segment or lobe. Spirometry will
show findings consistent with asthma.58 Bronchoalveolar lavage (BAL) is
performed in patients with interstitial infiltrates to evaluate for
eosinophilia, diffuse alveolar hemorrhage, malignancy or infection. BAL
would normally show high percentage of eosinophils; however, this
finding is very non-specific. Lung biopsy is only done when none of the
other sites are appropriate for biopsy and HRCT shows presence of
interstitial infiltrates. Lung histopathology in EGPA might show
eosinophilic pneumonia, asthmatic changes, extravascular granulomas, or
vasculitis.
Post-Diagnostic Evaluation
Once EGPA is diagnosed, evaluation of other organs involvement

should be done.
57
S. C. Erzurum et al., “Pleural Effusion in Churg-Strauss Syndrome,” Chest 95, no. 6 (1989):
1357–59, https://doi.org/10.1378/chest.95.6.1357.
58
Lanham et al., “Systemic Vasculitis with Asthma and Eosinophilia: A Clinical Approach to
the Churg-Strauss Syndrome.”
Renal, cardiac or gastro-intestinal involvement are associated with

poor prognosis and requires change in management plans. Thus, patients
should be screened for their involvement early in the disease.
Renal involvement can be evaluated with urinalysis (for proteinuria
and hematuria), serum creatinine and blood urea nitrogen.
Cardiac involvement is the leading cause of mortality in EGPA
patients. Thus, all patients must be screened with basic cardiac
investigations including cardiac troponin, N-terminal pro-brain natriuretic
peptide (NT-proBNP), electrocardiogram (EKG), transthoracic
echocardiogram. Approximately 40% of EGPA patients with normal EKG
were found to have cardiac involvement with echocardiogram. Thus,
echocardiogram is used to evaluate for wall motion abnormalities, valvular
involvement, pericardial effusion, or thrombus. Cardiac MRI and positron
emission tomography (PET) scan are more sensitive than initial screening
and thus, should be performed when EKG or echocardiogram are
abnormal.59
Gastrointestinal involvement, due to vascular necrosis causing
ischemia is associated with poor prognosis. Thus, any patient with
symptoms of abdominal pain, nausea, vomiting, diarrhea, hematochezia,
melena should undergo radiographic or endoscopic investigations. In
asymptomatic patient, routine screening is not recommended.60
Additional investigations should be performed based on symptoms.
Any patient with neuropathy or muscle weakness should undergo
electromyography or nerve conduction studies. CT sinus should be
performed in patients with sinusitis.
59
Robert M. Dennert et al., “Cardiac Involvement in Churg-Strauss Syndrome,” Arthritis and
Rheumatism 62, no. 2 (2010): 627–34, https://doi.org/10.1002/art.27263; Marmursztejn J.
et al., “Impact of Cardiac Magnetic Resonance Imaging for Assessment of Churg-Strauss
Syndrome: A Cross-Sectional Study in 20 Patients,” Clinical and Experimental
Rheumatology 27, no. 1 SUPPL. 52 (2009): S70–76, http://ovidsp.ovid.com/ovidweb.cgi?
T=JS&PAGE=reference&D=emed9&NEWS=N&AN=2009609617.
60
Christian Pagnoux et al., “Presentation and Outcome of Gastrointestinal Involvement in
Systemic Necrotizing Vasculitides,” Medicine 84, no. 2 (2005): 115–28,
https://doi.org/10.1097/01.md.0000158825.87055.0b.
DIAGNOSIS
Diagnosis of EGPA is essential and various diagnostic criteria has

been proposed. Lanham criteria established in 1984 has good sensitivity
and specificity without the need for biopsy.61 Criteria is as follows:
Table 3. Lanham’s criteria for EGPA diagnosis
Asthma
Blood eosinophilia >1500/mm3
Systemic vasculitis involving two or more extra-pulmonary organs
All the three criteria have to be met for diagnosis of EGPA. However,
the diagnostic criteria have certain limitations. First, asthma might follow
and not precede the vasculitis phase. Second, evidence of eosinophilia is
variable and may disappear after starting the glucocorticoids and third,
vasculitis is sometimes hard to confirm with biopsy.
American College of Rheumatology (ACR) provided another
diagnostic criterion which has sensitivity of 85% and specificity of 99.7%.
Four of these six criteria have to be met for the diagnosis of EGPA.62
Table 4. ACR criteria for EGPA diagnosis
Asthma
Eosinophilia > 10%
Neuropathy
Migratory pulmonary infiltrates
Paranasal sinus abnormality
Extravascular eosinophil
61
Lanham et al., “Systemic Vasculitis with Asthma and Eosinophilia: A Clinical Approach to
the Churg-Strauss Syndrome.”
62
Masi et al., “The American College of Rheumatology 1990 Criteria for the Classification of
Churg-Strauss Syndrome (Allergic Granulomatosis and Angiitis).”
TREATMENT
Glucocorticoids is the mainstay of treatment for EGPA. In presence of

severe multi-organ involvement, induction is achieved by pulse dose
methylprednisolone. Otherwise, starting dose is normally 1-2 mg/kg/day
for 2-3 weeks followed by gradual taper. Patients are maintained on
minimal glucocorticoid dose that prevents systemic manifestations and
control asthma.63
Five factor score (FFS) is a prognostic tool as described below
associated with poor prognosis in EGPA patients affecting the therapy of
patients. In patients with FFS ≥ 1, adjunctive treatment with cytotoxic
drugs is recommended. Cyclophosphamide is used in addition to
glucocorticoids in these patients. Cyclophosphamide can be given orally
daily or monthly infusion. Though monthly infusions are associated with
more relapses, it has more compliance and overall decreases long term
morbidity burden. Patients on cyclophosphamide should undergo regular
screening for drug induced neutropenia.64
Maintenance therapy is beneficial to prevent relapses and allowing for
glucocorticoid taper. Maintenance therapy should be started 2-3 weeks
after last cyclophosphamide infusion or few days after oral
cyclophosphamide. Azathioprine and methotrexate are used for
maintenance therapy due to low side effect profile compared to
cyclophosphamide. Methotrexate is less preferred due to its pulmonary
toxicity which would be difficult to differentiate from asthma or
pulmonary eosinophilia. Maintenance therapy is typically for 18-24
months with longer duration in patients with multiple relapses.65
63
Xavier Bosch et al., “Treatment of Antineutrophil Cytoplasmic Antibody-Associated
Vasculitis: A Systematic Review,” Journal of the American Medical Association 298, no.
6 (2007): 655–69, https://doi.org/10.1001/jama.298.6.655.
64
Pascal Cohen et al., “Churg-Strauss Syndrome with Poor-Prognosis Factors: A Prospective
Multicenter Trial Comparing Glucocorticoids and Six or Twelve Cyclophosphamide Pulses
in Forty-Eight Patients,” Arthritis Care and Research 57, no. 4 (2007): 686–93,
65
David Jayne et al., “A Randomized Trial of Maintenance Therapy for Vasculitis Associated
with Antineutrophil Cytoplasmic Autoantibodies,” New England Journal of Medicine 349,
no. 1 (2003): 36–44, https://doi.org/10.1056/nejmoa020286; Christian Pagnoux et al.,
“Azathioprine or Methotrexate Maintenance for ANCA-Associated Vasculitis,” New
Anti-IL5 monoclonal antibodies such as mepolizumab has been

approved for EGPA treatment. Mepolizumab should be used in addition to
glucocorticoids in patients who are not candidate for cyclophosphamide. It
decreases peripheral eosinophil levels and asthma exacerbations.66
Plasma exchange is not recommended and has not shown to improve
survival in patients with multi-organ failure. Plasma exchange should only
be considered in patients with rapidly progressing renal failure and diffuse
alveolar hemorrhage.67
Rituximab, monoclonal antibody against CD20 receptors on B-
lymphocytes, has shown benefits in inducing remission in granulomatosis
with polyangiitis and microscopic polyangiitis. However, data in EGPA
patients is limited to case reports and case series. ANCA positive patients
seem to have better response. Thus, rituximab should be considered only
for ANCA positive EGPA patients with severe renal involvement,
refractory to other cytotoxic drugs.68
Few case series have shown beneficial effects of intravenous
immunoglobulin (IVIG) in disease control in addition to glucocorticoids.
No strong recommendations are available, but IVIG should be considered
in patients with recurrent infections and/or hypogammaglobulinemia.69
England Journal of Medicine 359, no. 26 (2008): 2790–2803, https://doi.org/

10.1056/nejmoa0802311.
66
Kristine Herrmann, Wolfgang L. Gross, and Frank Moosig, “Extended Follow-up after
Stopping Mepolizumab in Relapsing/Refractory Churg-Strauss Syndrome,” Clinical and
Experimental Rheumatology 30, no. SUPPL. 70 (2012).
67
LOïc Guillevin et al., “Lack of Superiority of Steroids Plus Plasma Exchange to Steroids Alone
in the Treatment of Polyarteritis Nodosa and Churg‐Strauss Syndrome,” Arthritis &
Rheumatism 35, no. 2 (1992): 208–15, https://doi.org/10.1002/art.1780350214; Philip J.
Klemmer et al., “Plasmapheresis Therapy for Diffuse Alveolar Hemorrhage in Patients with
Small-Vessel Vasculitis,” American Journal of Kidney Diseases 42, no. 6 (2003): 1149–
53, https://doi.org/10.1053/j.ajkd.2003.08.015.
68
M Koukoulaki, K G C Smith, and D R W Jayne, “Rituximab in Churg-Strauss Syndrome,”
Annals of the Rheumatic Diseases 65, no. 4 (April 1, 2006): 557 LP – 559,
https://doi.org/10.1136/ard.2005.042937.
69
Naomi Tsurikisawa et al., “Treatment of Churg-Strauss Syndrome with High-Dose
Intravenous Immunoglobulin,” Annals of Allergy, Asthma and Immunology 92, no. 1
(2004): 80–87, https://doi.org/10.1016/S1081-1206(10)61714-0.
Interferon alpha is considered second or third line agent. However,

though it has shown some effective remission, it’s use is limited due to its
adverse effects and relapses after discontinuation.70
PROGNOSIS
Clinical remission rates are around 90% and have been steadily
increasing since the last few decades due to the widespread use of systemic
glucocorticoids and immunosuppressive agents for patients with severe
diseases. Approximately 20% of patients relapse. Vasculitis relapses
occurred more frequently in ANCA-positive versus ANCA-negative
patients. Older age, cardiomyopathy, gastrointestinal involvement, low
eosinophil count at diagnosis are predictive of relapses.71
FFS was developed initially in 1996 and then revised in 2011 to predict
survival in EGPA with some change in components. 1996 FFS criteria
include cardiac involvement, gastrointestinal disease (bleeding,
perforation, infarction, pancreatitis), renal insufficiency (plasma creatinine
>1.6 mg/dL, proteinuria, central nervous system involvement. Revised
2011 FFS includes age >65 years, cardiac insufficiency, renal insufficiency
(peak creatinine 1.7 mg/dL), gastrointestinal involvement, absence of ENT
manifestations. Each component is scored as 1. Score >or=1 associated
with 25-45% mortality at five years.72 Due to widespread knowledge and
70
Efstratios Tatsis, Armin Schnabel, and Wolfgang L. Gross, “Interferon-α Treatment of Four
Patients with the Churg-Strauss Syndrome,” Annals of Internal Medicine 129, no. 5 (1998):
370–74, https://doi.org/10.7326/0003-4819-129-5-199809010-00004.
71
Neumann et al., “Cardiac Involvement in Churg-Strauss Syndrome: Impact of
Endomyocarditis”; Comarmond et al., “Eosinophilic Granulomatosis with Polyangiitis
(Churg-Strauss): Clinical Characteristics and Long-Term Followup of the 383 Patients
Enrolled in the French Vasculitis Study Group Cohort”; Guillevin et al., “Churg-Strauss
Syndrome. Clinical Study and Long-Term Follow-up of 96 Patients”; Fraioli, Barberis, and
Rizzato, “Gastrointestinal Presentation of Churg Strauss Syndrome”; L Mouthon, B
Dunogue, and L Guillevin, “Diagnosis and Classification of Eosinophilic Granulomatosis
with Polyangiitis (Formerly Named Churg-Strauss Syndrome),” J. Autoimmun. 48–49
(August 11, 2014), https://doi.org/10.1016/j.jaut.2014.01.018.
72
L Guillevin et al., “Prognostic Factors in Polyarteritis Nodosa and Churg-Strauss Syndrome.
A Prospective Study in 342 Patients,” Medicine 75, no. 1 (August 11, 1996),
https://doi.org/10.1097/00005792-199601000-00003; L Guillevin et al., “The Five-Factor
treatment options for EGPA, survival rates have significantly improved

over the years.
Vasculitis of extrapulmonary organs is notable for morbidity and
mortality associated with EGPA. Cardiac involvement, cerebral
hemorrhage, renal failure, gastrointestinal bleeding, and status asthmaticus
are the major causes of death. Cardiac failure is a cause of death in about
50% of patients.73
Table 5. Five-factor score (FFS) in eosinophilic granulomatosis

with polyangiitis (EGPA)
1996 FFS Revised 2011 FFS

Cardiac involvement Age >65 years
Gastrointestinal disease, including bowel Cardiac insufficiency
infarction, bleeding, perforation, pancreatitis
Renal insufficiency (serum creatinine >1.6 Renal insufficiency (serum creatinine >/= 1.7
mg/dL) mg/dL)
Proteinuria (>1g/day) Gastrointestinal involvement
Central nervous system involvement Absence of ear, nose, throat (ENT)
manifestations
CONCLUSION
Eosinophilic granulomatosis with polyangiitis (EGPA) or Churg-

Strauss syndrome is a multisystemic vasculitis involving eosinophils
characterized by chronic rhinosinusitis, asthma, and peripheral blood
eosinophilia (>/= 1500 cells/microL) or >10 percent eosinophils. In the last
few decades, the enormous knowledge gained has identified the pleiotropic
manifestations of this disease. Given its dichotomous etiopathogenesis and
Score Revisited: Assessment of Prognoses of Systemic Necrotizing Vasculitides Based on

the French Vasculitis Study Group (FVSG) Cohort,” Medicine 90, no. 1 (August 11, 2011),
https://doi.org/10.1097/MD.0b013e318205a4c6.
73
Patients”; Comarmond et al., “Eosinophilic Granulomatosis with Polyangiitis (Churg-
Strauss): Clinical Characteristics and Long-Term Followup of the 383 Patients Enrolled in
the French Vasculitis Study Group Cohort”; Lanham et al., “Systemic Vasculitis with
Asthma and Eosinophilia: A Clinical Approach to the Churg-Strauss Syndrome.”
manifestations, a gold standard diagnosis is lacking. There is a need for

continued research and prospective trials to identify the spectrum of this
disease. Division of EGPA into ANCA-positive versus ANCA-negative
subgroups remains in question. Irrespective of the phenotypic presentation,
the pharmacologic treatment seems to be effective, as seen by increased
remission rates over the last decades. Treatment with glucocorticoids and
immunosuppression continues to be effective treatment options in most
cases. Immunomodulators, plasma exchange, and intravenous
immunoglobulins show modest effects in refractory cases. Early
identification of EGPA, especially in refractory asthmatics, prompt multi-
specialty referral and treatment is imperative for decreasing morbidity,
mortality and improving quality of life in EGPA patients.
REFERENCES
Analysis of Innate and Adaptive Immune Responses in Eosinophilic

Granulomatosis with Polyangiitis (Churg-Strauss) - ACR Meeting
Abstracts, August 10, 2016. https://acrabstracts.org/abstract/
analysis-of-innate-and-adaptive-immune-responses-in-eosinophilic-
granulomatosis-with-polyangiitis-churg-strauss/ LB - IiDU.
Akella, SS, DM Schlachter, EH Black, and A Barmettler. “Ophthalmic
Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss
Syndrome): A Systematic Review of the Literature.” Ophthal. Plast.
Reconstr. Surg. 35, no. 1 (August 11, 2019). https://doi.org/10.1097/
IOP.0000000000001202.
Allenbach, Y, R Seror, C Pagnoux, L Teixeira, P Guilpain, and L
Guillevin. “High Frequency of Venous Thromboembolic Events in
Churg-Strauss Syndrome, Wegener’s Granulomatosis and
Microscopic Polyangiitis but Not Polyarteritis Nodosa: A Systematic
Retrospective Study on 1130 Patients.” Ann. Rheum. Dis. 68, no. 4
(August 11, 2009). https://doi.org/10.1136/ard.2008.099051.
Bacciu, A, S Bacciu, G Mercante, F Ingegnoli, C Grasselli, A Vaglio, E
Pasanisi, et al. “Ear, Nose and Throat Manifestations of Churg-Strauss
Syndrome.” Acta Otolaryngol. 126, no. 5 (August 11, 2006).

https://doi.org/10.1080/00016480500437435.
Bibby, S, B Healy, R Steele, K Kumareswaran, H Nelson, and R Beasley.
“Association between Leukotriene Receptor Antagonist Therapy and
Churg-Strauss Syndrome: An Analysis of the FDA AERS Database.”
Thorax 65, no. 2 (August 11, 2010). https://doi.org/10.1136/thx.
2009.120972.
Bosch, Xavier, Antonio Guilabert, Gerard Espinosa, and Eduard Mirapeix.
“Treatment of Antineutrophil Cytoplasmic Antibody-Associated
Vasculitis: A Systematic Review.” Journal of the American Medical
Association 298, no. 6 (2007): 655–69. https://doi.org/
10.1001/jama.298.6.655.
Bridges, C, MER Shenk, K Martin, and A Launhardt. “Cutaneous
Manifestations of Childhood Eosinophilic Granulomatosis with
Polyangiitis (CEGPA): A Case-Based Review.” Pediatr. Dermatol.
37, no. 4 (August 11, 2020). https://doi.org/10.1111/pde.14144.
Carson, Luke Nessan, Ashish Pradhan, and Deepak Subramanian.
“Omalizumab-Associated Eosinophilic Granulomatosis with
Polyangiitis: Cause or Coincidence?” BMJ Case Rep. 14, no. 7 (2021).
https://doi.org/10.1136/bcr-2020-240078.
Chakraborty, Rebanta K, and Narothama R Aeddula. “Churg Strauss
Syndrome.” In StatPearls [Internet]. StatPearls Publishing, 2021.
https://www.ncbi.nlm.nih.gov/books/NBK537099/.
Chung, Sharon A, Carol A Langford, Mehrdad Maz, Andy Abril, Mark
Gorelik, Gordon Guyatt, Amy M Archer, et al. “2021 American
College of Rheumatology/Vasculitis Foundation Guideline for the
Management of Antineutrophil Cytoplasmic Antibody-Associated
Vasculitis.” Arthritis Rheumatol 73, no. 8 (2021): 1366–83.
Churg, A, M Brallas, SR Cronin, and J Churg. “Formes Frustes of Churg-
Strauss Syndrome.” Chest 108, no. 2 (August 11, 1995).
https://doi.org/10.1378/chest.108.2.320.
Clutterbuck, EJ, DJ Evans, and CD Pusey. “Renal Involvement in Churg-

Strauss Syndrome.” Nephrol. Dial. Transplant 5, no. 3 (August 11,
1990). https://doi.org/10.1093/ndt/5.3.161.
Cohen, Pascal, Christian Pagnoux, Alfred Mahr, Jean Pierre Arène, Luc
Mouthon, Véronique Le Guern, Marie Hélène André, et al. “Churg-
Strauss Syndrome with Poor-Prognosis Factors: A Prospective
Multicenter Trial Comparing Glucocorticoids and Six or Twelve
Cyclophosphamide Pulses in Forty-Eight Patients.” Arthritis Care and
Research 57, no. 4 (2007): 686–93. https://doi.org/10.
1002/art.22679.
Comarmond, C, C Pagnoux, M Khellaf, JF Cordier, M Hamidou, JF
Viallard, F Maurier, et al. “Eosinophilic Granulomatosis with
Polyangiitis (Churg-Strauss): Clinical Characteristics and Long-Term
Followup of the 383 Patients Enrolled in the French Vasculitis Study
Group Cohort.” Arthritis Rheum. 65, no. 1 (August 11, 2013).
Conron, M, and HL Beynon. “Churg-Strauss Syndrome.” Thorax 55, no.
10 (August 10, 2000). https://doi.org/10.1136/thorax.55.10.870.
Cottin, V, E Bel, P Bottero, K Dalhoff, M Humbert, R Lazor, RA Sinico,
et al. “Revisiting the Systemic Vasculitis in Eosinophilic
Granulomatosis with Polyangiitis (Churg-Strauss): A Study of 157
Patients by the Groupe d’Etudes et de Recherche Sur Les Maladies
Orphelines Pulmonaires and the European Respiratory Society
Taskforce on E.” Autoimmun. Rev. 16, no. 1 (August 11, 2017).
https://doi.org/10.1016/j.autrev.2016.09.018.
Dennert, Robert M., Pieter Van Paassen, Simon Schalla, Tatiana
Kuznetsova, Becker S. Alzand, Jan A. Staessen, Sebastiaan Velthuis,
Harry J. Crijns, Jan Willem Cohen Tervaert, and Stephane Heymans.
“Cardiac Involvement in Churg-Strauss Syndrome.” Arthritis and
Rheumatism 62, no. 2 (2010): 627–34. https://doi.org/10.1002/
art.27263.
Dyer, SA, and WJ Geimeier. “A Case Study of Churg Strauss Syndrome
with Montelukast and Inhaled Corticosteroids.” Journal of Allergy and
Clinical Immunology, 2006. https://doi.org/10.1016/j.jaci.

2005.12.029.
Erzurum, SC, GA Underwood, DL Hamilos, and JA Waldron. “Pleural
Effusion in Churg-Strauss Syndrome.” Chest 95, no. 6 (1989): 1357–
59. https://doi.org/10.1378/chest.95.6.1357.
Fraioli, P, M Barberis, and G Rizzato. “Gastrointestinal Presentation of
Churg Strauss Syndrome.” Sarcoidosis 11, no. 1 (August 11, 1994).
Gall, C Le, S Pham, S Vignes, G Garcia, H Nunes, D Fichet, G Simonneau,
P Duroux, and M Humbert. “Inhaled Corticosteroids and Churg-
Strauss Syndrome: A Report of Five Cases.” Eur. Respir. J. 15, no. 5
(2000): 978–81. https://doi.org/10.1034/j.1399-3003.2000.15e29.x.
Gokhale, Mugdha, Christopher F Bell, Scott Doyle, Jolyon Fairburn-
Beech, Jonathan Steinfeld, and Melissa K Van Dyke. “Prevalence of
Eosinophilic Granulomatosis With Polyangiitis and Associated Health
Care Utilization Among Patients With Concomitant Asthma in US
Commercial Claims Database.” JCR: Journal of Clinical
Rheumatology 27, no. 3 (August 10, 2021): 107. https://doi.org/10.
1097/RHU.0000000000001198.
Groh, Matthieu, Christian Pagnoux, Chiara Baldini, Elisabeth Bel, Paolo
Bottero, Vincent Cottin, Klaus Dalhoff, et al. “Eosinophilic
Granulomatosis with Polyangiitis (Churg-Strauss) (EGPA) Consensus
Task Force Recommendations for Evaluation and Management.”
European Journal of Internal Medicine 26, no. 7 (2015): 545–53.
https://doi.org/10.1016/j.ejim.2015.04.022.
Guillevin, L, C Pagnoux, R Seror, A Mahr, L Mouthon, and PL Toumelin.
“The Five-Factor Score Revisited: Assessment of Prognoses of
Systemic Necrotizing Vasculitides Based on the French Vasculitis
Study Group (FVSG) Cohort.” Medicine 90, no. 1 (August 11, 2011).
https://doi.org/10.1097/MD.0b013e318205a4c6.
Guillevin, L, F Lhote, M Gayraud, P Cohen, B Jarrousse, O Lortholary, N
Thibult, and P Casassus. “Prognostic Factors in Polyarteritis Nodosa
and Churg-Strauss Syndrome. A Prospective Study in 342 Patients.”
Medicine 75, no. 1 (August 11, 1996). https://doi.org/10.

1097/00005792-199601000-00003.
Guillevin, L, P Cohen, M Gayraud, F Lhote, B Jarrousse, and P Casassus.
“Churg-Strauss Syndrome. Clinical Study and Long-Term Follow-up
of 96 Patients.” Medicine 78, no. 1 (August 11, 1999). https://doi.
org/10.1097/00005792-199901000-00003.
Guillevin, LOïc, Olivier Fain, François Lhote, Bernard Jarrousse, Du Le
Thi Huong, Annette Bussel, and Anne Leon. “Lack of Superiority of
Steroids Plus Plasma Exchange to Steroids Alone in the Treatment of
Polyarteritis Nodosa and Churg‐Strauss Syndrome.” Arthritis &
Rheumatism 35, no. 2 (1992): 208–15. https://doi.org/10.1002/
art.1780350214.
Hattori, N, M Ichimura, M Nagamatsu, M Li, K Yamamoto, K Kumazawa,
T Mitsuma, and G Sobue. “Clinicopathological Features of Churg-
Strauss Syndrome-Associated Neuropathy.” Brain 122 (Pt 3 (August
11, 1999). https://doi.org/10.1093/brain/122.3.427.
Hellmich, B, S Ehlers, E Csernok, and WL Gross. “Update on the
Pathogenesis of Churg-Strauss Syndrome.” Clin. Exp. Rheumatol. 21,
no. 6 Suppl 32 (August 11, 2003). https://pubmed.ncbi.nlm.nih.
gov/14740430/.
Herrmann, Kristine, Wolfgang L. Gross, and Frank Moosig. “Extended
Follow-up after Stopping Mepolizumab in Relapsing/Refractory
Churg-Strauss Syndrome.” Clinical and Experimental Rheumatology
30, no. SUPPL. 70 (2012).
Jacob Churg, Lotte Strauss. “Allergic Granulomatosis, Allergic Angiitis,
and Periarteritis Nodosa.” Am. J. Pathol. 27, no. 2 (August 10, 1951):
277. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1937314/.
Jakiela, B, M Sanak, W Szczeklik, B Sokolowska, H Plutecka, L
Mastalerz, J Musial, and A Szczeklik. “Both Th2 and Th17 Responses
Are Involved in the Pathogenesis of Churg-Strauss Syndrome.” Clin.
Exp. Rheumatol. 29, no. 1 Suppl 64 (August 11, 2011).
Jaworsky, Christine. “Leukotriene Receptor Antagonists and Churg-
Strauss Syndrome: An Association with Relevance to
Dermatopathology?” Journal of Cutaneous Pathology, 2008.

https://doi.org/10.1111/j.1600-0560.2008.01050.x.
Jayne, David, Niels Rasmussen, Konrad Andrassy, Paul Bacon, Jan
Willem Cohen Tervaert, Jolanta Dadoniené, Agneta Ekstrand, et al.
“A Randomized Trial of Maintenance Therapy for Vasculitis
Associated with Antineutrophil Cytoplasmic Autoantibodies.” New
England Journal of Medicine 349, no. 1 (2003): 36–44.
https://doi.org/10.1056/nejmoa020286.
Katzenstein, AL. “Diagnostic Features and Differential Diagnosis of
Churg-Strauss Syndrome in the Lung. A Review.” Am. J. Clin. Pathol.
114, no. 5 (August 11, 2000). https://doi.org/10.1309/F3FW-J8EB-
X913-G1RJ.
Kawakami, T, Y Soma, K Kawasaki, A Kawase, and M Mizoguchi. “Initial
Cutaneous Manifestations Consistent with Mononeuropathy Multiplex
in Churg-Strauss Syndrome.” Arch. Dermatol. 141, no. 7 (August 11,
2005). https://doi.org/10.1001/archderm.141.7.873.
Keogh, KA, and U Specks. “Churg-Strauss Syndrome.” Semin. Respir.
Crit. Care Med. 27, no. 2 (August 10, 2006). https://doi.org/10.1055/s-
2006-939518.
Klemmer, Philip J, W Chalermskulrat, Michael S Reif, Susan L Hogan,
David C Henke, and Ronald J Falk. “Plasmapheresis Therapy for
Diffuse Alveolar Hemorrhage in Patients with Small-Vessel
Vasculitis.” American Journal of Kidney Diseases 42, no. 6 (2003):
1149–53. https://doi.org/10.1053/j.ajkd.2003.08.015.
Koukoulaki, M, KGC Smith, and DRW Jayne. “Rituximab in Churg-
Strauss Syndrome.” Annals of the Rheumatic Diseases 65, no. 4 (April
1, 2006): 557 LP – 559. https://doi.org/10.1136/ard.2005.
042937.
Lanham, JG, KB Elkon, CD Pusey, and GR Hughes. “Systemic Vasculitis
with Asthma and Eosinophilia: A Clinical Approach to the Churg-
Strauss Syndrome.” Medicine 63, no. 2 (August 10, 1984).
https://doi.org/10.1097/00005792-198403000-00001.
Lie, JT. “Illustrated Histopathologic Classification Criteria for Selected
Vasculitis Syndromes. American College of Rheumatology
Subcommittee on Classification of Vasculitis.” Arthritis Rheum. 33,

no. 8 (August 11, 1990). https://doi.org/10.1002/art.1780330804.
Lyons, PA, JE Peters, F Alberici, J Liley, RMR Coulson, W Astle, C
Baldini, et al. “Genome-Wide Association Study of Eosinophilic
Granulomatosis with Polyangiitis Reveals Genomic Loci Stratified by
ANCA Status.” Nat. Commun. 10, no. 1 (August 11, 2019).
https://doi.org/10.1038/s41467-019-12515-9.
Mahr, A, F Moosig, T Neumann, W Szczeklik, C Taillé, A Vaglio, and J
Zwerina. “Eosinophilic Granulomatosis with Polyangiitis (Churg-
Strauss): Evolutions in Classification, Etiopathogenesis, Assessment
and Management.” Curr. Opin. Rheumatol. 26, no. 1 (August 10,
2014). https://doi.org/10.1097/BOR.0000000000000015.
Marmursztejn, J, Vignaux O, Cohen P, Guilpain P, Pagnoux C, Gouya H,
Mouthon L, Legmann P, Duboc D, and Guillevin L. “Impact of
Cardiac Magnetic Resonance Imaging for Assessment of Churg-
Strauss Syndrome: A Cross-Sectional Study in 20 Patients.” Clinical
and Experimental Rheumatology 27, no. 1 SUPPL. 52 (2009): S70–
76. http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D
=emed9&NEWS=N&AN=2009609617.
Masi, AT, GG Hunder, JT Lie, BA Michel, DA Bloch, WP Arend, LH
Calabrese, SM Edworthy, AS Fauci, and RY Leavitt. “The American
College of Rheumatology 1990 Criteria for the Classification of
Churg-Strauss Syndrome (Allergic Granulomatosis and Angiitis).”
Arthritis Rheum. 33, no. 8 (August 10, 1990). https://doi.org/
10.1002/art.1780330806.
Mohammad, AJ. “An Update on the Epidemiology of ANCA-Associated
Vasculitis.” Rheumatology 59, no. Suppl 3 (August 10, 2020).
https://doi.org/10.1093/rheumatology/keaa089.
Mouthon, L, B Dunogue, and L Guillevin. “Diagnosis and Classification
of Eosinophilic Granulomatosis with Polyangiitis (Formerly Named
Churg-Strauss Syndrome).” J. Autoimmun. 48–49 (August 11, 2014).
https://doi.org/10.1016/j.jaut.2014.01.018.
Nazir, Salik, Niranjan Tachamo, Shoaib Bilal Fareedy, Muhammad Sohail
Khan, and Saroj Lohani. “Omalizumab-Associated Eosinophilic
Granulomatosis with Polyangiitis (Churg-Strauss Syndrome).” Ann.

Allergy Asthma Immunol. 118, no. 3 (2017): 372-374.e1.
https://doi.org/10.1016/j.anai.2016.12.003.
Neumann, T, B Manger, M Schmid, C Kroegel, A Hansch, WA Kaiser, D
Reinhardt, et al. “Cardiac Involvement in Churg-Strauss Syndrome:
Impact of Endomyocarditis.” Medicine 88, no. 4 (August 11, 2009).
https://doi.org/10.1097/MD.0b013e3181af35a5.
Orriols, R, X Muñoz, J Ferrer, P Huget, and F Morell. “Cocaine-Induced
Churg-Strauss Vasculitis.” Eur. Respir. J. 9, no. 1 (August 11, 1996).
https://doi.org/10.1183/09031936.96.09010175.
Pagnoux, Christian, Alfred Mahr, Mohamed A. Hamidou, Jean-Jacques
Boffa, Marc Ruivard, Jean-Pierre Ducroix, Xavier Kyndt, et al.
“Azathioprine or Methotrexate Maintenance for ANCA-Associated
Vasculitis.” New England Journal of Medicine 359, no. 26 (2008):
2790–2803. https://doi.org/10.1056/nejmoa0802311.
Pagnoux, Christian, Alfred Mahr, Pascal Cohen, and Loïc Guillevin.
“Presentation and Outcome of Gastrointestinal Involvement in
Systemic Necrotizing Vasculitides.” Medicine 84, no. 2 (2005): 115–
28. https://doi.org/10.1097/01.md.0000158825.87055.0b.
Parent, ME, S Larue, and B Ellezam. “Eosinophilic Granulomatosis with
Polyangiitis (Churg-Strauss Syndrome) Presenting as Diffuse
Myositis.” BMC Musculoskelet. Disord. 15 (August 11, 2014).
https://doi.org/10.1186/1471-2474-15-388.
Porges, AJ, PB Redecha, WT Kimberly, E Csernok, WL Gross, and RP
Kimberly. “Anti-Neutrophil Cytoplasmic Antibodies Engage and
Activate Human Neutrophils via Fc Gamma RIIa.” J. Immunol. 153,
no. 3 (August 11, 1994). https://pubmed.ncbi.nlm.nih.gov/8027554/.
Ruppert, Anne-Marie, Gerlinde Averous, Daniela Stanciu, Nicolas
Deroide, Sophie Riehm, Vincent Poindron, Gabrielle Pauli, Christian
Debry, and Frédéric de Blay. “Development of Churg-Strauss
Syndrome with Controlled Asthma during Omalizumab Treatment.”
J. Allergy Clin. Immunol. 121, no. 1 (2008): 253–54. https://doi.org/
10.1016/j.jaci.2007.10.040.
Sablé-Fourtassou, Régis, Pascal Cohen, Alfred Mahr, Christian Pagnoux,

Luc Mouthon, David Jayne, Daniel Blockmans, et al. “Antineutrophil
Cytoplasmic Antibodies and the Churg-Strauss Syndrome.” Annals of
Internal Medicine 143, no. 9 (2005): 632–38. https://doi.org/10.7326/
0003-4819-143-9-200511010-00006.
Schwartz, RA, and J Churg. “Churg-Strauss Syndrome.” Br. J. Dermatol.
127, no. 3 (August 11, 1992). https://doi.org/10.1111/j.1365-
2133.1992.tb00114.x.
Seccia, V, C Baldini, M Latorre, M Gelardi, I Dallan, L Cristofani-
Mencacci, S Sellari-Franceschini, ML Bartoli, E Bacci, and P
Paggiaro. “Focus on the Involvement of the Nose and Paranasal
Sinuses in Eosinophilic Granulomatosis with Polyangiitis (Churg-
Strauss Syndrome): Nasal Cytology Reveals Infiltration of
Eosinophils as a Very Common Feature.” Int. Arch. Allergy Immunol.
175, no. 1–2 (August 11, 2018). https://doi.org/10.1159/ 000484602.
Shiota, Y, H Matsumoto, Y Kanehisa, M Tanaka, K Kanazawa, J Hiyama,
T Ono, M Marukawa, and H Mashiba. “Serum Interleukin-5 Levels in
a Case with Allergic Granulomatous Angiitis.” Intern. Med. 36, no. 10
(August 11, 1997). https://doi.org/10.2169/internalmedicine.36.709.
Sinico, RA, L Di Toma, U Maggiore, C Tosoni, P Bottero, E Sabadini, G
Giammarresi, et al. “Renal Involvement in Churg-Strauss Syndrome.”
Am. J. Kidney Dis. 47, no. 5 (August 11, 2006). https://doi.org/
10.1053/j.ajkd.2006.01.026.
Srouji, I, V Lund, P Andrews, and C Edwards. “Rhinologic Symptoms and
Quality-of-Life in Patients with Churg-Strauss Syndrome Vasculitis.”
Am. J. Rhinol. 22, no. 4 (August 11, 2008). https://doi.org/10.
2500/ajr.2008.22.3204.
Tatsis, Efstratios, Armin Schnabel, and Wolfgang L. Gross. “Interferon-α
Treatment of Four Patients with the Churg-Strauss Syndrome.” Annals
of Internal Medicine 129, no. 5 (1998): 370–74. https://doi.org/10.
7326/0003-4819-129-5-199809010-00004.
Tsurikisawa, Naomi, Masami Taniguchi, Hiroshi Saito, Hideo Himeno,
Akihiko Ishibashi, Shunsuke Suzuki, and Kazuo Akiyama. “Treatment
of Churg-Strauss Syndrome with High-Dose Intravenous
Immunoglobulin.” Annals of Allergy, Asthma and Immunology 92, no.

1 (2004): 80–87. https://doi.org/10.1016/S1081-1206(10)61714-0.
Turvey, Stuart E, Sara O Vargas, and Wanda Phipatanakul. “Churg-Strauss
Syndrome in a 7-Year-Old Receiving Montelukast and Inhaled
Corticosteroids.” Annals of Allergy, Asthma & Immunology, 2003.
https://doi.org/10.1016/s1081-1206(10)62156-4.
Vaglio, A, D Martorana, U Maggiore, C Grasselli, A Zanetti, A Pesci, G
Garini, et al. “HLA-DRB4 as a Genetic Risk Factor for Churg-Strauss
Syndrome.” Arthritis Rheum. 56, no. 9 (August 11, 2007).
Wieczorek, S, B Hellmich, L Arning, F Moosig, P Lamprecht, WL Gross,
and JT Epplen. “Functionally Relevant Variations of the Interleukin-
10 Gene Associated with Antineutrophil Cytoplasmic Antibody-
Negative Churg-Strauss Syndrome, but Not with Wegener’s
Granulomatosis.” Arthritis Rheum. 58, no. 6 (August 11, 2008).
Wiesner, O, KA Russell, AS Lee, DE Jenne, M Trimarchi, G Gregorini,
and U Specks. “Antineutrophil Cytoplasmic Antibodies Reacting with
Human Neutrophil Elastase as a Diagnostic Marker for Cocaine-
Induced Midline Destructive Lesions but Not Autoimmune
Vasculitis.” Arthritis Rheum. 50, no. 9 (August 11, 2004).
Wu, Eveline Y., Michelle L. Hernandez, J. Charles Jennette, and Ronald
J. Falk. “Eosinophilic Granulomatosis with Polyangiitis: Clinical
Pathology Conference and Review.” Journal of Allergy and Clinical
Immunology: In Practice 6, no. 5 (2018): 1496–1504. https://doi.org/
10.1016/j.jaip.2018.07.001.
Zwerina, J, C Bach, D Martorana, M Jatzwauk, G Hegasy, F Moosig, J
Bremer, et al. “Eotaxin-3 in Churg-Strauss Syndrome: A Clinical and
Immunogenetic Study.” Rheumatology 50, no. 10 (August 11, 2011).
https://doi.org/10.1093/rheumatology/keq445.
Chapter 4
CARDIOVASCULAR COMPLICATIONS
OF VASCULITIS
Syed Adeel Hassan1, Somia Jamal Sheikh2,

Iqbal Ratnani3, MD and Salim Surani4,5,, MD
1
Department of Medicine, University of Louisville School of
Medicine, Louisville, KY, USA
2
Department of Medicine,
Karachi Medical and Dental College, Karachi, Pakistan
3
Department of Anesthesiology, Weil Cornell University,
Houston Methodist Hospital, Houston, TX, USA
4
5
ABSTRACT
Vasculitis represent a broad spectrum of autoimmune blood vessel

disease, which eventually leads to inflammation-mediated stenosis,

126 Syed Adeel Hassan, Somia Jamal Sheikh, Iqbal Ratnani et al.
thrombosis, occlusion, and aneurysmal dilation. The incidence of

cardiovascular complications in patients with systemic vasculitis has
been well documented in the literature. Regardless of the initiating
trigger, cardiovascular complications arise secondary to sustained
inflammation, pro-thrombotic states, vascular damage, and accelerated
atherosclerosis. The advances in therapy have improved survival
timelines and increased the rates of cardiovascular morbidity and
mortality. In this chapter, based on the vessel size involvement, we
discuss the common pathophysiology and cardiovascular complications
arising in various vasculidities.
Keywords: vasculitis, heart disease, cardiovascular, complications, large

vessel vasculitis, medium vessel vasculitis, small vessel vasculitis,
variable vessel vasculitis
INTRODUCTION
Vasculitis can be defined as a group of heterogeneous disorders

resulting in the intra-mural inflammation and fibrinoid necrosis of the
blood vessel wall [1]. The subsequent vessel narrowing and occlusion
results in ischemia and infarction-mediated organ damage. Owing to its
variable nature of vessel involvement, clinical manifestations of these
vasculidities are broad. Several classification systems have been proposed
based on several international consensus conferences to classify
Vasculitides [2, 3]. However, the most widely accepted classification
stratifies the vasculitides based on the caliber of vessel involvement [4].
These include large-vessel, medium-vessel, and small-vessel vasculidities.
Furthermore, they can also be differentiated based on etiology.
Primary vasculitides refer to vasculitis arising with an unknown etiology.
In contrast, secondary vasculidities arise as a consequence of underlying
systemic disease [5]. These include systemic lupus erythematosus,
scleroderma, sarcoidosis, rheumatoid arthritis, and connective tissue
diseases.
The improvements in medical therapy have changed the outlook of
these diseases to a remitting-relapsing condition. Due to the frequent use
Cardiovascular Complications of Vasculitis 127
of glucocorticoid therapy and improved survival times, cardiovascular

complications now account for the leading cause of mortality in these
patients [6]. Systemic Vasculitis tends to rarely involves the cardiovascular
system. Cardiovascular sequelae are known to arise in about 10% of
patients [7]. However, a higher incidence of cardiovascular complications
has been reported in certain vasculitides, such as Takayasu’s arteritis and
eosinophilic granulomatosis with polyangiitis [7]. From the
clinicopathological perspective, cardiac involvement includes pericarditis,
myocarditis, coronary artery arteritis, intracavitary thrombosis, and
valvular heart disease. However, the incidence of these complications
remains variable for all forms of vasculitis. Diagnostic modalities such as
cardiac MRI, coronary angiography, electrocardiography, and
echocardiography remain the choice of investigations. However, due to
their lack of specificity/sensitivity, diagnosis requires a high degree of
suspicion. The choice of therapy depends on clinical features, vessel
involvement, nature of disease activity, and history of prior damage. In this
chapter, we review the pathophysiology accounting for the development
of cardiovascular sequelae. Furthermore, we discuss the specific spectrum
of cardiovascular involvement in vasculitis.
PATHOPHYSIOLOGY OF COMPLICATIONS
IN VASCULITIDES
Due to the mechanistic variability, the pathophysiology of vasculitis

remains poorly understood [8]. Several studies have depicted the role of
endothelial activation, immunologic dysfunction, and accelerated
atherogenesis in mediating the necrotizing inflammation of blood vessels
[9, 10]. However, the preceding inciting events remain unknown. A
summary of these mechanisms based on vasculitis subtypes is depicted in
Figure 1.
Figure 1. Classification of vasculidities based on pathogenic mechanisms.
Endothelial dysfunction has been implicated in the pathogenesis of

vasculitis [11, 12]. From the physiological perspective, endothelium helps
maintain vascular tone and non-thrombotic environment [12]. In addition,
endothelial cells (EC) also function as an off switch for controlling the
local immune response [13] via the release of adenosine. EC tends to
downregulate neutrophil responses [13]. Furthermore, EC also produces
anti-inflammatory eicosanoids and helps expand the CD4+CD25+FoxP3+
regulatory T-lymphocytes [13]. Several mechanisms of endothelial cell
damage have been reported in the literature. These include complement-
mediated cytotoxicity, antibody-mediated cytotoxicity, and enhanced
cytokine production. [11, 14]. The presence of IgG and IgM anti-
endothelial cell antibodies (AECA) has also been reported [15]. AECA
titers tend to correlate with disease activity [15]. AECA can modulate the
expression of adhesion molecules, chemokines, and cytokines [16]. These
AECA induced-functional changes in the endothelium mediate leukocyte
recruitment and adhesion.
The diagnosis of certain Vasculidites requires isolating specific
autoantibodies such as anti-neutrophil cytoplasmic antibodies (ANCA).
Davies and colleagues first described these autoantibodies in patients with
arbovirus-induced segmental necrotizing glomerulonephritis [17]. These

subgroups of vasculitis are termed ANCA-associated vasculitis (AAVs).
Furthermore, ANCA is also involved in the pathogenesis of vasculidities.
Based on their biochemical target, ANCA can be classified into two
subtypes [18]. These include ANCA against neutrophil myeloperoxidase
(p-ANCA) and neutrophil serine protease 3 (c-ANCA) [18]. Higher levels
of ANCA titers are usually seen during the active course of the disease
[18]. Several in vivo studies have demonstrated the effects of ANCA on
neutrophils and endothelial cells [18].
Figure 2. Priming of neutrophils and ANCA-mediated activation of neutrophils.
As both effector cells and targets of autoimmunity, neutrophils are

pivotal in the injury associated with AAVs. In order to assert injury, the
neutrophils enhance their response magnitude through the phenomenon of
priming [19]. Factors responsible for priming neutrophils include
microbial infections, environmental factors, tumor necrosis factor-alpha,
lipopolysaccharides, interleukin-1, interleukin-18, and granulocyte/
macrophage colony-stimulating factor (Figure 2) [19]. Priming results in
an enhanced neutrophil respiratory burst, increased expression of surface
adhesion molecules, the amplified release of elastase and myeloperoxidase

enzymes, changes in cytoskeletal actin, and delayed apoptosis of
neutrophils [19]. The downstream effects of priming result in increased
tissue damage via prolonged retention at the site of inflammation,
increased recruitment, and a prolonged life span of neutrophils [19].
ANCA activates primed neutrophils and other phagocytes to release
reactive oxygen species and degranulate [11]. The downstream effects
result in neutrophil-mediated endothelial cell lysis [11].
Figure 3. Pathophysiological Mechanisms involved in the development

of Cardiovascular Manifestations in Vasculitides.
Evidence also suggests the role of accelerated atherosclerosis and pro-

thrombotic state in the development of cardiovascular events
[20, 21]. Cytokine-mediated functional changes in the endothelium result
in reduced fibrinolytic potential and activation of extrinsic and intrinsic
coagulation pathways [22]. Cytokines also increase prostacyclin I2 and
platelet-activating factors resulting in clot formation [11]. Increased levels
of matrix metalloproteinases, platelet-derived growth factors, vascular
endothelial-derived growth factors contribute to intimal hyperplasia [23].
Furthermore, elevated levels of C-reactive protein, interleukin-1 beta,
interleukin-6, and TNF-alpha contribute to smooth muscle cell
proliferation and the promotion of coagulation via thrombomodulin-C

[23]. Increased autoantibody production also results in endothelial
damage, which may further predispose to a pro-thrombotic state (Figure
3). MPO-catalyzed pathway of low density lipoprotein (LDL) oxidation is
also enhanced in vasculitis [24]. Accelerated atherosclerosis can also arise
due to inflammation-mediated structural damage, chronic inflammation-
mediated vessel calcification, fibrin, and lipid metabolism dysregulation
[9]. Systemic hypertension and altered baroreceptor sensitivity can also
predispose to accelerated atherosclerosis [9]. Immunosuppressive agents
remain the mainstay of therapy in patients with vasculitis. However, long-
term use of glucocorticoids results in the development of cardiovascular
disease-associated risk factors. These include hyperglycemia,
dyslipidemia, obesity, and hypertension [25].
LARGE VESSEL VASCULITIS
Giant Cell Arteritis
Also known as temporal arteritis is a large vessel granulomatous

vasculitis usually seen in adults over the age of 50 [26]. It is the most
common vasculitis in North America [26]. GCA tends to involve the aorta
and its branches with a well-defined elastic lamina [26]. More
preferentially, it involves the extracranial branches of the carotid artery
[27]. The presence of granulomatous inflammation characterizes lesions,
multinucleated giant cells, vascular infiltrates, vascular media damage, and
intimal hyperplasia [26]. Diagnostic histopathological characteristic
includes a high ratio of CD4/CD8 cells [28]. Based on the pattern of
clinical involvement, GCA can be subdivided into four phenotypes [29].
These include isolated cranial GCA, systemic inflammatory response,
Large vessel disease, and polymyalgia rheumatica [29]. Clinically GCA
presents with fever, weight loss, headache, jaw claudication, tongue
claudication, and proximal muscle stiffness [26]. Complications include
vision loss due to optic nerve ischemia, cranial ischemic insults, and limb
claudication [30].
When compared to TAK, GCA tends to involve the Cardiovascular
system rarely (<5%) [31]. GCA spectrum of cardiovascular involvement
includes pericarditis, pericardial effusion, myocarditis, coronary arteritis,
ascending aortic aneurysm, aortic dissection, and aortic regurgitation
(Table 1) [32-34]. Clinically patients may present with chest pain, dyspnea,
CHF, arrhythmias, and SCD [7]. In an observational cohort study
involving 3048 patients, there was a high risk of developing coronary
artery disease, with the most significant risk being soon after diagnosis
[35]. Although rare, coronary arteritis has also been reported as a rare
complication [32, 34, 36]. Increased predisposition to ischemic heart
disease in GCA has also been demonstrated. In a matched cohort study of
809 patients, 10.5% of patients developed myocardial infarction, and
7.41% developed stroke [37]. Furthermore, compared to controls, patients
with GCA demonstrated a threefold increase in the risk of myocardial
infarction [37]. To date, the most extensive cross-sectional study in Israel
also yielded a higher risk of ischemic heart disease in GCA [38].
Cardiovascular disease risk factors such as hypertension, smoking,
dyslipidemias, and diabetes mellitus are more prevalent in GCA [38].
The subclinical involvement of the aorta leads to the development of
aneurysm and dissection [39]. Aneurysmal formation most commonly
involves the thoracic aorta, but it can also affect the abdominal aorta [39].
Functional aortic regurgitation can arise secondary to an aneurysm of the
ascending aorta [39]. The presence of aneurysms/dissections can also
provide an insight into disease duration [39]. Furthermore, compared with
non-vasculitis patients, GCA patients have more comorbidities and prior
vascular diseases [40]. Myocarditis has been reported in various case
reports [41-43]. Clinically these patients present with chest pain, ECG
changes, and abnormal cardiac enzymes. Subsequentially, CHF ensues as
a complication. Rarely, pericardial involvement in the form of pericarditis
and pericardial effusion has also been reported [44, 45]. Pericarditis
presents with symptoms of pleuritic chest pain, dyspnea, and friction rubs
with evidence of active GCA. However, in 30% of patients, these

symptoms existed without active GCA [45].
Takayasu Arteritis
First described in 1830, Takayasu arteritis (TA) represents an

idiopathic granulomatous chronic inflammatory vasculitis affecting the
pulmonary circulation, aorta, and its major branches in patients younger
than 50 years of age [46, 47]. It is most commonly seen in female patients
[47]. In literature, TA has also been described as pulseless disease,
stenosing aortitis, idiopathic aortitis, aorto-arteritis, and occlusive
thrombo-arteriopathy [47]. TA has a strong propensity for the aortic arch,
subclavian vessels, and the carotids [48]. The associated damage results in
the aneurysmal formation, stenosis, and occlusion of affected vessels [47].
Histopathological lesions in TA are diagnostic for relatively low CD4/CD8
cells [28]. Clinically these patients present with features of vascular injury
and systemic symptoms. Indices of disease activity include clinical
signs/symptoms, erythrocyte sedimentation rate, and the presence of new
arteriographic findings. Patients in the “Pre-pulseless” phase present non-
specific symptoms such as malaise, fever, night sweats, headaches, rashes,
weight loss, and anorexia [31]. The occlusive phase is characterized by
vascular bruits, diminished/absent pulses, blood pressure discrepancies,
chronic mesenteric ischemia, renovascular hypertension, retinopathy,
aortic regurgitation, limb claudication, and neurological features [25].
When compared to GCA, TA has more frequent cardiovascular
involvement [49]. In addition to having a higher risk of morbidity and
mortality, it also carries a poor prognosis [49]. Generally, cardiac
involvement seems to be widespread and diverse. However, the most
frequent cardiac structures involved include the pericardium, myocardium,
valves, and coronary arteries [50]. The occurrence of cardiovascular
manifestations tends to correlate with disease activity [50]. Overall disease
duration of TA is also significantly longer in patients with cardiovascular
involvement [49]. In a retrospective study of 411 patients in China, 164
TA patients (40%) presented with cardiovascular manifestations [49].

Clinical studies indicate variable involvement of the coronary arteries with
upwards of 50% luminal narrowing [50-53]. Coronary luminal occlusions
and stenosis most commonly involve the proximal segments of the
coronary artery and coronary Ostia [54]. However, in a systematic review
targeting 59 studies, the right coronary artery was most commonly
involved, followed by the left coronary artery [55]. Other coronary vessel
lesions include coronary aneurysms, fistulas, local narrowing, and diffuse
narrowing [56]. The pathological involvement of the coronary vessels is
also said to be a strong predictor of mortality in TA [51]. Subsequently,
these patients present with CHF, angina pectoris, myocardial infarction, or
cardiac conduction defects [49].
Valvular involvement in TA has also been well documented [57-60].
In 15-50% of patients, aortic insufficiency (AI) has been well documented
[49, 50, 57, 58]. AI arises due to leaflet separation in the setting of
ascending aortitis, aneurysmal dilation, and inflammation-mediated
structural retraction of the aortic valve [57]. Aneurysmal involvement in
TA is usually diffuse [57]. Other valvular affections in order of frequency
include mitral insufficiency, tricuspid insufficiency, mitral valve prolapse,
aortic stenosis, and pulmonary insufficiency [49]. Regardless of the
valvular involvement location, most cases of insufficiency are clinically
mild [49]. Hypertension, a predisposing risk factor for heart disease, is also
prominent in TA. 74% of patients developed renovascular hypertension
secondary to renal artery stenosis [61]. More commonly, the renal artery
stenosis was bilateral in these patients [61]. Myocardial infarction and
congestive heart failure have also been documented [62, 63]. The cardiac
magnetic resonance or invasive coronary angiography, can diagnose
asymptomatic myocardial ischemia in up to 25% of the patients [64].
Interestingly, acute myocardial infarction has also been known to be the
basic manifestation of TA [65]. Even though pulmonary artery
involvement is noted in 50% of TA patients, only 12.5% of these patients
present with class 1 pulmonary arterial hypertension [66, 67]. The
underlying vascular inflammation predisposes to thrombus formation.
Therefore, there is also an increased risk of intracardiac and intravascular
thrombosis in TA [68]. Pericarditis and Myocarditis have also been

reported in TA [53, 69]. Both myocardial ischemia and aortic valve
disease-account for the most common cause of death in TA (Table 1) [51].
Table 1. Cardiovascular Manifestations in Large Vessel Vasculitis
Large Myocarditis Pericarditis Epicardial Coronary Valvular Thrombus

Vessel Coronary Microcirculation Involvement
Vasculitis Artery Involvement
Involvement
Giant ✅ ✅ ✅ _ ✅ _
Cell
Arteritis
Takayasu ✅ ✅ ✅ _ ✅ ✅
Arteritis
MEDIUM VESSEL VASCULITIS
Polyarteritis Nodosa
The scope of cardiac involvement in Polyarteritis Nodosa (PAN)

ranges from 4%-20% [70-72]. Historically, the incidence of cardiovascular
involvement in PAN has been challenging to establish due to the lack of
differentiation between PAN and microscopic polyangiitis (MPA). In an
autopsy study of 36 PAN patients, coronary arteritis of the small
subepicardial vessels was noted in 50% of patients [73]. Active coronary
arteritis is associated with a poor prognosis [73]. From a
clinicopathological perspective, diffuse interstitial myocarditis,
perivascular fibrosis, subepicardial vessel necrosis, and occlusion are seen
in PAN [73]. Diagnostically, coronary angiography reveals alternating
areas of focal narrowing or occlusion, paving the way for the characteristic
“beads on a string” appearance [74]. Coronary angiitis and hypertension
lead to the development of cardiac failure [57]. The extent of coronary
vessel involvement is limited to myocardial arterioles and proximal main
coronary arteries [75]. Subsequently, myocardial hypertrophy, myocardial
scarring, and left ventricular hypertrophy ensue due to ischemia [57]. In a

retrospective study of 348 patients, the incidence of cardiomyopathy and
coronary angiitis were noted at 7.5% and 6.9%, respectively [72].
Clinically apparent myocardial infarction is only noted in up to 5% of PAN
patients [73]. When PAN is limited to the microvasculature, angiography
is normal. Although rare, fibrinous pericarditis and myocarditis have also
been reported in PAN [73]. Cardiovascular involvement has also been well
described in children. The spectrum of involvement in children includes
mitral valve dysfunction, tricuspid valve dysfunction, pericarditis, and left
ventricular systolic dysfunction [76].
Kawasaki Disease
Kawasaki disease (KD) represents a self-limiting acute systemic

vasculitis affecting medium to small size vessels [77]. KD most commonly
occurs in children under the age of 5 years [77]. In the USA, it also
represents one of the major causes of acquired cardiovascular disease in
children [78]. Clinical studies have frequently reported the development of
coronary artery aneurysms (CAA) as a feared complication [79, 80]. CAA
tends to develop in 12%-25% of untreated children [81]. Based on their
internal diameter, CAA are classified as small (<5 mm), medium (5-8
mm), and giant (> 8 mm) [81]. They are often multiple and have a
predilection for development at the proximal coronary arteries and
bifurcations [82]. Clinical progression of CAA can also vary based on the
anatomical location. Left CAA is more prone to focal stenosis, whereas
right CAA results in lethal thrombosis [83]. Even though 50% of small
CAA undergo spontaneous resolution, structural damage to the vessel wall
persists [84]. Aneurysms with larger internal diameters (>8 mm) seldomly
regress and are at an increased risk of rupture [82]. Coronary artery lesions
in KD increase the risk of long-term mortality [82].
More recently, non-coronary complications have also emerged in KD.

In retrospective studies by Hamza et al., and Gowin et al., reported
pericarditis in 7.8% to 20% of patients, respectively [85, 86]. Pericarditis
with concomitant septated pericardial effusion has also been reported [87].
The pericardial effusion can resolve on its own by the 5th week [88].
Cardiac tamponade secondary to polyserositis can occur during the acute
phase [89]. However, aneurysmal rupture can increase the risk of cardiac
tamponade at any given time during the disease course [89]. Valvular
abnormalities in the acute phase of KD occur due to pan carditis [90].
However, due to coronary ischemia, persistent valvular dysfunction occurs
in the setting of papillary muscle dysfunction [90]. In KD, the most
commonly reported valvular abnormality is the mitral regurgitation [90].
Inflammation-mediated weakening can result in the rupture of chordae
tendinae and the development of mitral regurgitation [91]. To date, the
largest ever single-center study regarding KD reported that 88% of patients
with KD develop mitral valve dysfunction [92]. Printz et al., demonstrated
aortic root dilatation in 10% of patients during the acute phase of KD [88].
The degree of aortic root dilatation was found to correlate with the
coronary artery diameters [88]. This functional impairment of the aorta is
thought to arise due to loss in aortic elasticity and an increase in its stiffness
[93]. Furthermore, myocardial involvement in the form of inflammatory
interstitial infiltrates (myocarditis) has also been observed [94].
Table 2. Cardiovascular Involvement of Medium Vessel Vasculitis
Medium Myocarditis Pericarditis Epicardial Coronary Valvular Thrombus

Involvement
Polyarteritis ✅ ✅ ✅ ✅ _ _
Nodosa
Kawasaki ✅ ✅ ✅ ✅ ✅ ✅
Disease
SMALL VESSEL VASCULITIS
Cryoglobulinemic Vasculitis
Low incidence of cardiovascular involvement has been reported in

cryoglobulinemic vasculitis (CV) (4%-8%) [95]. The spectrum of cardiac
involvement in CV includes acute CHF, myocardial infarction, and
pericarditis [96]. These complications arise due to immune-complex
mediated mechanisms [96]. In addition to the cardiac involvement, other
organ dysfunctions also ensue. CV-induced renal dysfunction eventually
leads to fluid retention and hypertension, which further negatively affects
the heart. Cardiac Angiography may find stenosis or aneurysms of the
coronary arteries [96]. However, more commonly, no abnormalities in the
coronary microvasculature are seen [96].
Eosinophilic Granulomatosis with Polyangiitis
Eosinophilic granulomatosis with polyangiitis (EGPA) represents the

least common ANCA-associated vasculitis. However, cardiac
abnormalities occur most commonly in EGPA (15%-50%) [57, 97].
Cardiac involvement is seen in 75% of adult patients and 44% of affected
children [98]. Regardless of the type and extent, cardiac involvement in
EGPA is deemed a poor prognostic indicator [57]. Most commonly,
pericarditis and cardiomyopathy occur in 15% and 30% of patients,
respectively [99]. EGPA patients may also present with cardiac conduction
disturbances, valvular incompetence, coronary ischemia in the setting of
normal angiography, endomyocardial fibrosis [100]. Cardiac involvement
is usually seen early on during the disease course [57]. Clinically, patients
most commonly present with signs and symptoms of heart failure and
arrhythmia [57].
EGPA can be further classified on the basis of anti-neutrophilic
cytoplasmic antibodies (ANCA). Based on the ANCA status, cardiac
manifestations and symptom onset can vary [97, 101]. It has been reported
that ANCA-negative patients tend to have cardiac involvement more

frequently [97, 101, 102]. ANCA-negative patients also have higher
eosinophil count and shorter duration between diagnosis and onset of
symptoms [57, 97]. A significant number of eosinophils at baseline was
associated with a higher prevalence of dysrhythmias and lower ejection
fraction [103]. Cardiomyopathy, myocarditis, pleural effusion, and
pericardial effusion are more common in the ANCA-negative subset of
patients [97]. The elevated eosinophil counts and their release of
intracellular enzymes cause tissue injury [104]. EGPA also shares similar
histological characteristics as hypereosinophilic syndromes [105].
Clinically, ANCA-negative status is also described as a risk factor for
cardiac involvement [106]. Patients with endomyocardial fibrosis also
have a bleak prognosis [107]. Although subclinical, valvular lesions may
be present in 7% to 30% of patients [100, 108]. The most common valvular
lesions include mitral insufficiency followed by aortic insufficiency [108].
In less than 3% of patients, coronary arteritis and heart block are seen
[109]. Furthermore, intracardiac thrombosis is also rare in EGPA [109].
Interestingly, vasculitic involvement of the myocardium is rarely seen
[57]. During the remission phase, peak-systolic myocardial strain and left
ventricular late gadolinium enhancement can be seen on stress
echocardiography [110]. This suggests subclinical myocardial
involvement during periods of disease inactivity. On EKG, greater
dispersion of corrected QT interval has been noted [111]. Furthermore,
severe cardiac involvement in EGPA can also warrant the need for an
orthotopic heart transplant [112].
Microscopic Polyangiitis
Assessment regarding Cardiac involvement with regards to

microscopic polyangiitis (MPA) has been limited [57]. In a study
conducted by Guillevin et al., cardiac failure and pericardial effusion were
noted in 18% and 11% of patients [113]. Shuai et al., described cardiac
involvement in one-fifth of patients with cardiomyopathy, pericarditis,
aortic incompetence, and cardiac rhythm disturbance as manifestations

[114]. There may also be subclinical myocardial involvement in MPA
[107]. Further studies are needed to characterize cardiovascular
involvement in MPA.
Granulomatosis with Polyangiitis
Granulomatosis with polyangiitis (previously known as Wegner’s

granulomatosis) tends to involve the heartless commonly. Although when
reported, the spectrum of involvement includes valvular dysfunction,
conduction defects, cardiomyopathy, pericarditis, and ischemic heart
disease [115]. Pericarditis and arrhythmias are thought to be the most
common manifestations [57]. In GPA, the arrhythmias occur secondary to
pericardial inflammation-induced sinus node dysfunction [116]. Coronary
arteritis, intracardiac thrombus, and myocarditis seldom occur in 1% to 2%
of patients [57]. Endocardial involvement in GPA also remains rare. In a
review of 20 cases, aortic incompetence was the most common valvular
involvement [117]. Valvular dysfunction occurs due to valvular masses
and valve thickening [57]. Isolated case reports have also reported atrial
and ventricular masses in GPA [118]. Furthermore, an echocardiographic
study also reported wall motion defects, decreased LVEF, pericardial
effusions, and valvular lesions [118].
Table 3. Cardiovascular Involvement of Small Vessel Vasculitis
Small Myocarditis Pericarditis Epicardial Coronary Valvular Thrombus

Involvement
CV _ ✅ ✅ ✅ _ _
EGPA ✅ ✅ ✅ ✅ ✅ ✅
GPA ✅ ✅ ✅ ✅ ✅ ✅
MPA ✅ ✅ ✅ ✅ ✅ ✅
VARIABLE VESSEL VASCULITIS
As per the revised Chapel Hill consensus, Cogan’s syndrome and

Behcet’s disease (BD) represent the most widely known variable vessel
vasculidities [119]. Cardiac involvement in Cogan’s syndrome is reported
to be extremely rare and poorly described. Isolated reports regarding aortic
valve dysfunction, mitral valve dysfunction, aortic root dilatation, and
coronary artery vasculitis have been noted in the literature
[120, 121].
Approximately 6% of patients with BD present with cardiac
involvement [122]. At baseline, 2% of patients tend to have cardiac
involvement [122]. The most common presentations in order of frequency
include pericarditis, valvular dysfunction, myocardial infarction, and
coronary vasculitis [122]. In a retrospective study of 476 Chinese patients,
only 4% of patients had coronary involvement [123]. However, coronary
stenosis, multiple aneurysms, and occlusions were noted [123]. The
subsequent clinical manifestations include angina, acute MI, and
arrhythmias [123]. The most frequently involved coronary vessels include
left circumflex coronary artery (LCX), right coronary artery (RCA), and
left anterior descending artery (LAD) [123]. Clinical studies have also
depicted a strong association of ischemic heart disease in BD [124].
Patients younger than 70 years of age and male gender are at an elevated
risk of ischemic heart disease in BD [124]. Intraventricular thrombi
develop in 19% of BD patients [57]. These thrombi usually develop in the
right side of the heart and are also associated with pulmonary arteritis
[125]. These patients can also clinically mimic infective endocarditis [57].
The underlying platelet activation, hypercoagulability, and impaired
fibrinolysis predispose to endothelial injury and thrombus formation [126].
Other forms of cardiac involvement include endocarditis, endocardial
fibroelastosis, and myocardial aneurysm [122]. Electrophysiological
disturbances have also been seen in BD. Inter-atrial and intra-atrial
conduction delay have been reported in BD [127]. These delays tend to
correlate with CRP levels [127]. Furthermore, widened QRS complex,
increased QT interval, and fragmented QRS complexes are also noted in
these patients [128]. The degree of sympathetic and parasympathetic

dysfunction also tends to correlate with inflammatory markers [129].
Table 4. Spectrum of Cardiovascular involvement

in Behcet’s Disease
Vasculitis Myocarditis Pericarditis Epicardial Coronary Valvular Thrombus

Coronary Microcirculation Involvement
Artery Involvement
Involvement
CV ✅ ✅ ✅ ✅ ✅ ✅
CONCLUSION
Vasculitides represent a heterogeneous group of autoimmune

disorders that can affect the cardiovascular system. They present with a
wide spectrum of cardiovascular involvement. Due to the inflammation-
mediated complications and accelerated premature atherosclerosis.
Pathological and diagnostic studies have depicted frequent subclinical
involvement. Cardiac complications are more common in polyarteritis
nodosa, Takayasu arteritis, and eosinophilic granulomatosis with
polyangiitis. Pericarditis is usually seen in all forms of vasculitides.
However, it is clinically benign in nature. Myocarditis is more common in
EGPA and TAK. In contrast, coronary angiitis is more common in TAK,
PAN, and BD. Treatment options available include immunosuppressive
agents and surgery.
REFERENCES
[1] González-Gay, M. A. and C. García-Porrúa, Epidemiology of the

vasculitides. Rheum Dis Clin North Am, 2001. 27(4): p. 729-49.
[2] Fries, J. F., et al., The American College of Rheumatology 1990

criteria for the classification of vasculitis. Summary. Arthritis
Rheum, 1990. 33(8): p. 1135-6.
[3] Jennette, J. C., et al., Nomenclature of systemic vasculitides.
Proposal of an international consensus conference. Arthritis Rheum,
1994. 37(2): p. 187-92.
[4] Watts, R. A. and D. G. Scott, Classification and epidemiology of the
vasculitides. Baillieres Clin Rheumatol, 1997. 11(2): p. 191-217.
[5] González-Gay, M. A. and C. García-Porrúa, Systemic vasculitis in
adults in northwestern Spain, 1988-1997. Clinical and
epidemiologic aspects. Medicine (Baltimore), 1999. 78(5): p. 292-
308.
[6] Wallace, Z. S., et al., All-cause and cause-specific mortality in
ANCA-associated vasculitis: overall and according to ANCA type.
Rheumatology (Oxford), 2020. 59(9): p. 2308-2315.
[7] Silveira, L. H., Cardiovascular Manifestations of Systemic
Vasculitides. Current Rheumatology Reports, 2020. 22(10).
[8] Weyand, C. M. and J. J. Goronzy, Medium- and large-vessel
vasculitis. N Engl J Med, 2003. 349(2): p. 160-9.
[9] Clifford, A. H. and J. W. Cohen Tervaert, Cardiovascular events and
the role of accelerated atherosclerosis in systemic vasculitis.
Atherosclerosis, 2021. 325: p. 8-15.
[10] Sage, A. P., et al., The role of B cells in atherosclerosis. Nat Rev
Cardiol, 2019. 16(3): p. 180-196.
[11] Pall, A. A. and C. O. Savage, Mechanisms of endothelial cell injury
in vasculitis. Springer Semin Immunopathol, 1994. 16(1): p. 23-37.
[12] Cockwell, P., W. Y. Tse, and C. O. Savage, Activation of
endothelial cells in thrombosis and vasculitis. Scand J Rheumatol,
1997. 26(3): p. 145-50.
[13] Little, M. A. and C. O. Savage, The role of the endothelium in
systemic small vessel vasculitis. Clin Exp Rheumatol, 2008. 26(3
Suppl 49): p. S135-40.
[14] Sais, G., et al., Adhesion molecule expression and endothelial cell
activation in cutaneous leukocytoclastic vasculitis. An
immunohistologic and clinical study in 42 patients. Arch Dermatol,

1997. 133(4): p. 443-50.
[15] Praprotnik, S., et al., Pathogenic role of anti-endothelial cell
antibodies in systemic vasculitis. Wien Klin Wochenschr, 2000.
112(15-16): p. 660-4.
[16] Frampton G, J. D., Perry G J, Lockwood CM, Cameron JS
Autoantibodies to endothelial cells and neutrophil cytoplasmic
antigens in systemic vasculitis. Clin Exp Immunol 1990. 82: p. 227.
[17] Davies, D. J., et al., Segmental necrotising glomerulonephritis with
antineutrophil antibody: possible arbovirus aetiology? Br Med J
(Clin Res Ed), 1982. 285(6342): p. 606.
[18] Kitching, A. R., et al., ANCA-associated vasculitis. Nat Rev Dis
Primers, 2020. 6(1): p. 71.
[19] Condliffe, A. M., E. Kitchen, and E. R. Chilvers, Neutrophil
priming: pathophysiological consequences and underlying
mechanisms. Clin Sci (Lond), 1998. 94(5): p. 461-71.
[20] Hilhorst, M., et al., Patients with antineutrophil cytoplasmic
antibodies associated vasculitis in remission are hypercoagulable. J
Rheumatol, 2013. 40(12): p. 2042-6.
[21] González-Suárez, I., J. J. Ríos-Blanco, and J. Arpa, Accelerated
atherosclerosis in ANCA-associated vasculitis. Acta Neurol Scand,
2017. 136(6): p. 688-693.
[22] Pober, J. S. and R. S. Cotran, Cytokines and endothelial cell biology.
Physiol Rev, 1990. 70(2): p. 427-51.
[23] Shirai, T., et al., Macrophages in vascular inflammation--From
atherosclerosis to vasculitis. Autoimmunity, 2015. 48(3): p. 139-51.
[24] Slot, M. C., et al., Anti-oxidized low-density lipoprotein antibodies
in myeloperoxidase-positive vasculitis patients preferentially
recognize hypochlorite-modified low density lipoproteins. Clin Exp
Immunol, 2007. 149(2): p. 257-64.
[25] Buchman, A. L., Side effects of corticosteroid therapy. J Clin
Gastroenterol, 2001. 33(4): p. 289-94.
[26] Winkler, A. and D. True, Giant Cell Arteritis: 2018 Review.
Missouri medicine, 2018. 115(5): p. 468-470.
[27] Salvarani, C., et al., Polymyalgia rheumatica and giant-cell arteritis.

N Engl J Med, 2002. 347(4): p. 261-71.
[28] Watanabe, R., et al., Pathogenesis of Giant Cell Arteritis and
Takayasu Arteritis-Similarities and Differences. Curr Rheumatol
Rep, 2020. 22(10): p. 68.
[29] de Boysson, H., et al., The different clinical patterns of giant cell
arteritis. Clin Exp Rheumatol, 2019. 37 Suppl 117(2): p. 57-60.
[30] Langford, C. A., Vasculitis. Journal of Allergy and Clinical
Immunology, 2010. 125(2, Supplement 2): p. S216-S225.
[31] Maksimowicz-McKinnon, K., T. M. Clark, and G. S. Hoffman,
Takayasu arteritis and giant cell arteritis: a spectrum within the same
disease? Medicine (Baltimore), 2009. 88(4): p. 221-226.
[32] Lie, J. T., Aortic and extracranial large vessel giant cell arteritis: a
review of 72 cases with histopathologic documentation. Semin
Arthritis Rheum, 1995. 24(6): p. 422-31.
[33] Fateh-Moghadam, S., et al., Pericardial effusion as primary
manifestation of Takayasu arteritis. Int J Cardiol, 2010. 145(1): p.
e33-5.
[34] Säve-Söderbergh, J., et al., Giant cell arteritis as a cause of death.
Report of nine cases. Jama, 1986. 255(4): p. 493-6.
[35] Tomasson, G., et al., Risk for cardiovascular disease early and late
after a diagnosis of giant-cell arteritis: a cohort study. Ann Intern
Med, 2014. 160(2): p. 73-80.
[36] Karger, B. and G. Fechner, Sudden death due to giant cell coronary
arteritis. Int J Legal Med, 2006. 120(6): p. 377-9.
[37] Amiri, N., et al., Increased risk of cardiovascular disease in giant
cell arteritis: a general population–based study. Rheumatology,
2016. 55(1): p. 33-40.
[38] Dagan, A., et al., The Association Between Giant Cell Arteritis and
Ischemic Heart Disease: A Population Based Cross-Sectional Study.
Isr Med Assoc J, 2017. 19(7): p. 411-414.
[39] Nuenninghoff, D. M., et al., Incidence and predictors of large-artery
complication (aortic aneurysm, aortic dissection, and/or large-artery
stenosis) in patients with giant cell arteritis: a population-based

study over 50 years. Arthritis Rheum, 2003. 48(12): p. 3522-31.
[40] Li, L., T. Neogi, and S. Jick, Giant cell arteritis and vascular disease-
risk factors and outcomes: a cohort study using UK Clinical Practice
Research Datalink. Rheumatology (Oxford), 2017. 56(5): p. 753-
762.
[41] Daumas, A., et al., Myopericarditis revealing giant cell arteritis in
the elderly. J Rheumatol, 2012. 39(3): p. 665-6.
[42] Pugnet, G., et al., Giant cell arteritis as a cause of acute myocarditis
in the elderly. J Rheumatol, 2011. 38(11): p. 2497.
[43] Kushnir, A., S.W. Restaino, and M. Yuzefpolskaya, Giant Cell
Arteritis as a Cause of Myocarditis and Atrial Fibrillation. Circ
Heart Fail, 2016. 9(2): p. e002778.
[44] Matsue, Y., et al., A case of giant cell arteritis with massive
pericardial effusion. Heart Vessels, 2011. 26(5): p. 562-4.
[45] Tiosano, S., et al., Pericarditis among giant cell arteritis patients:
From myth to reality. Clin Cardiol, 2018. 41(5): p. 623-627.
[46] Numano, F., et al., Takayasu’s arteritis. Lancet, 2000. 356(9234): p.
1023-5.
[47] Russo, R. A. G. and M. M. Katsicas, Takayasu Arteritis. Front
Pediatr, 2018. 6: p. 265.
[48] Serra, R., et al., Updates in Pathophysiology, Diagnosis and
Management of Takayasu Arteritis. Ann Vasc Surg, 2016. 35: p.
210-25.
[49] Li, J., et al., Clinical Characteristics of Heart Involvement in
Chinese Patients with Takayasu Arteritis. J Rheumatol, 2017.
44(12): p. 1867-1874.
[50] Lee, G. Y., et al., Cardiovascular manifestations of Takayasu
arteritis and their relationship to the disease activity: analysis of 204
Korean patients at a single center. Int J Cardiol, 2012. 159(1): p. 14-
20.
[51] Soto, M. E., et al., Takayasu arteritis: clinical features in 110
Mexican Mestizo patients and cardiovascular impact on survival
and prognosis. Clin Exp Rheumatol, 2008. 26(3 Suppl 49): p. S9-15.
[52] Panja, M., et al., Coronary artery lesions in Takayasu’s arteritis--

clinical and angiographic study. J Assoc Physicians India, 1998.
46(8): p. 678-81.
[53] Maksimowicz-McKinnon, K., T. M. Clark, and G. S. Hoffman,
Limitations of therapy and a guarded prognosis in an American
cohort of Takayasu arteritis patients. Arthritis Rheum, 2007. 56(3):
p. 1000-9.
[54] Matsubara, O., et al., Coronary artery lesions in Takayasu arteritis:
pathological considerations. Heart Vessels Suppl, 1992. 7: p. 26-31.
[55] Yuan, S. M. and H. Z. Lin, Coronary artery involvements in
Takayasu arteritis: systematic review of reports. Gen Thorac
Cardiovasc Surg, 2020. 68(9): p. 883-904.
[56] Endo, M., et al., Angiographic findings and surgical treatments of
coronary artery involvement in Takayasu arteritis. J Thorac
Cardiovasc Surg, 2003. 125(3): p. 570-7.
[57] Miloslavsky, E. and S. Unizony, The heart in vasculitis. Rheum Dis
Clin North Am, 2014. 40(1): p. 11-26.
[58] Zhang, Y., et al., Cardiac Valve Involvement in Takayasu Arteritis
Is Common: A Retrospective Study of 1,069 Patients Over 25
Years. Am J Med Sci, 2018. 356(4): p. 357-364.
[59] Hashimoto, Y., et al., Aortic regurgitation in patients with Takayasu
arteritis: assessment by color Doppler echocardiography. Heart
Vessels Suppl, 1992. 7: p. 111-5.
[60] Zheng, T., et al., Treatment with Corticosteroid and/or
Immunosuppressive Agents before Surgery can Effectively Improve
the Surgical Outcome in Patients with Takayasu’s Arteritis. J Invest
Surg, 2019. 32(3): p. 220-227.
[61] Soto, M. E., et al., Echocardiographic follow-up of patients with
Takayasu’s arteritis: five-year survival. Echocardiography, 2006.
23(5): p. 353-60.
[62] Talwar, K. K., et al., Cardiac involvement in nonspecific
aortoarteritis (Takayasu’s arteritis). Am Heart J, 1991. 122(6): p.
1666-70.
[63] Ishikawa, K. and S. Maetani, Long-term outcome for 120 Japanese

patients with Takayasu’s disease. Clinical and statistical analyses of
related prognostic factors. Circulation, 1994. 90(4): p. 1855-60.
[64] Comarmond, C., et al., Findings of cardiac magnetic resonance
imaging in asymptomatic myocardial ischemic disease in Takayasu
arteritis. Am J Cardiol, 2014. 113(5): p. 881-7.
[65] Ishiyama, Y., et al., New-onset Takayasu’s Arteritis as Acute
Myocardial Infarction. Intern Med, 2018. 57(10): p. 1415-1420.
[66] Cong, X. L., et al., Takayasu’s arteritis: clinical features and
outcomes of 125 patients in China. Clin Rheumatol, 2010. 29(9): p.
973-81.
[67] Panja, M., et al., Cardiac involvement in non-specific aorto-arteritis.
Int J Cardiol, 1992. 34(3): p. 289-95.
[68] Tomasson, G., P. A. Monach, and P. A. Merkel, Thromboembolic
disease in vasculitis. Curr Opin Rheumatol, 2009. 21(1): p. 41-6.
[69] Takeda, N., et al., Takayasu myocarditis mediated by cytotoxic T
lymphocytes. Intern Med, 2005. 44(3): p. 256-60.
[70] Bae, Y. D., et al., Clinical features of polyarteritis nodosa in Korea.
J Korean Med Sci, 2006. 21(4): p. 591-5.
[71] Guillevin, L., et al., Polyarteritis nodosa related to hepatitis B virus.
A prospective study with long-term observation of 41 patients.
Medicine (Baltimore), 1995. 74(5): p. 238-53.
[72] Pagnoux, C., et al., Clinical features and outcomes in 348 patients
with polyarteritis nodosa: a systematic retrospective study of
patients diagnosed between 1963 and 2005 and entered into the
French Vasculitis Study Group Database. Arthritis Rheum, 2010.
62(2): p. 616-26.
[73] Schrader, M. L., J. S. Hochman, and B. H. Bulkley, The heart in
polyarteritis nodosa: a clinicopathologic study. Am Heart J, 1985.
109(6): p. 1353-9.
[74] Stanson, A. W., et al., Polyarteritis nodosa: spectrum of
angiographic findings. Radiographics, 2001. 21(1): p. 151-9.
[75] Holsinger, D. R., P. J. Osmundson, and J. E. Edwards, The heart in
periarteritis nodosa. Circulation, 1962. 25: p. 610-8.
[76] Zöller, B., et al., Risk of subsequent coronary heart disease in

patients hospitalized for immune-mediated diseases: a nationwide
follow-up study from Sweden. PLoS One, 2012. 7(3): p. e33442.
[77] Ramphul, K. and S. G. Mejias, Kawasaki disease: a comprehensive
review. Arch Med Sci Atheroscler Dis, 2018. 3: p. e41-e45.
[78] Singh, S., P. Vignesh, and D. Burgner, The epidemiology of
Kawasaki disease: a global update. Arch Dis Child, 2015. 100(11):
p. 1084-8.
[79] Frey, E. E., et al., Coronary artery aneurysms due to Kawasaki
disease: diagnosis with ultrafast CT. Radiology, 1988. 167(3): p.
725-6.
[80] Joshi, M. and R. Tulloh, Kawasaki disease and coronary artery
aneurysms: from childhood to adulthood. Future Cardiol, 2017.
13(5): p. 491-501.
[81] Newburger, J. W., et al., Diagnosis, treatment, and long-term
management of Kawasaki disease: a statement for health
professionals from the Committee on Rheumatic Fever,
Endocarditis and Kawasaki Disease, Council on Cardiovascular
Disease in the Young, American Heart Association. Circulation,
2004. 110(17): p. 2747-71.
[82] Petrunić, M., et al., Thoracoabdominal and coronary arterial
aneurysms in a young man with a history of Kawasaki disease. J
Vasc Surg, 2009. 50(5): p. 1173-6.
[83] Suzuki, A., et al., Coronary arterial lesions of Kawasaki disease:
cardiac catheterization findings of 1100 cases. Pediatr Cardiol,
1986. 7(1): p. 3-9.
[84] Fukushige, J., et al., Long-term outcome of coronary abnormalities
in patients after Kawasaki disease. Pediatr Cardiol, 1996. 17(2): p.
71-6.
[85] Gowin, E., et al., Cardiac complications in children with Kawasaki
disease in our own experience. Kardiol Pol, 2016. 74(1): p. 75-82.
[86] Hamza, H. S., et al., Acute Kawasaki disease with emphasis on the
echocardiographic profile: A single center experience. Glob Cardiol
Sci Pract, 2017. 2017(3): p. e201727.
[87] Sonçaği, A., et al., Septated pericarditis associated with Kawasaki

disease: a brief case report. Turk J Pediatr, 2007. 49(3): p. 312-4.
[88] Printz, B. F., et al., Noncoronary cardiac abnormalities are
associated with coronary artery dilation and with laboratory
inflammatory markers in acute Kawasaki disease. J Am Coll
Cardiol, 2011. 57(1): p. 86-92.
[89] Mok, G. C., et al., A child with Kawasaki disease who survived after
rupture of a coronary artery aneurysm. Eur J Pediatr, 2003. 162(9):
p. 634-6.
[90] Akagi, T., et al., Valvular heart disease in Kawasaki syndrome:
incidence and natural history. Am Heart J, 1990. 120(2): p. 366-72.
[91] Kitamura, S., et al., Severe mitral regurgitation due to coronary
arteritis of mucocutaneous lymph node syndrome. A new surgical
entity. J Thorac Cardiovasc Surg, 1980. 80(4): p. 629-36.
[92] de La Harpe, M., et al., Thirty Years of Kawasaki Disease: A Single-
Center Study at the University Hospital of Lausanne. Front Pediatr,
2019. 7: p. 11.
[93] Schäfer, M., et al., Children with Kawasaki disease present elevated
stiffness of great arteries: Phase-contrast MRI study. J Magn Reson
Imaging, 2018. 48(5): p. 1228-1236.
[94] Harada, M., et al., Histopathological characteristics of myocarditis
in acute-phase Kawasaki disease. Histopathology, 2012. 61(6): p.
1156-67.
[95] Terrier, B., et al., Presentation and prognosis of cardiac involvement
in hepatitis C virus-related vasculitis. Am J Cardiol, 2013. 111(2):
p. 265-72.
[96] Gorevic, P. D., et al., Mixed cryoglobulinemia: clinical aspects and
long-term follow-up of 40 patients. Am J Med, 1980. 69(2): p. 287-
308.
[97] Comarmond, C., et al., Eosinophilic granulomatosis with
polyangiitis (Churg-Strauss): clinical characteristics and long-term
followup of the 383 patients enrolled in the French Vasculitis Study
Group cohort. Arthritis Rheum, 2013. 65(1): p. 270-81.
[98] Gendelman, S., A. Zeft, and S. J. Spalding, Childhood-onset

eosinophilic granulomatosis with polyangiitis (formerly Churg-
Strauss syndrome): a contemporary single-center cohort. J
Rheumatol, 2013. 40(6): p. 929-35.
[99] Neumann, T., et al., Cardiac involvement in Churg-Strauss
syndrome: impact of endomyocarditis. Medicine (Baltimore), 2009.
88(4): p. 236-243.
[100] Dennert, R. M., et al., Cardiac involvement in Churg-Strauss
syndrome. Arthritis Rheum, 2010. 62(2): p. 627-34.
[101] Keogh, K. A. and U. Specks, Churg-Strauss syndrome: clinical
presentation, antineutrophil cytoplasmic antibodies, and leukotriene
receptor antagonists. Am J Med, 2003. 115(4): p. 284-90.
[102] Sinico, R. A., et al., Prevalence and clinical significance of
antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome.
Arthritis Rheum, 2005. 52(9): p. 2926-35.
[103] Szczeklik, W., et al., Multimodality assessment of cardiac
involvement in Churg-Strauss syndrome patients in clinical
remission. Circ J, 2011. 75(3): p. 649-55.
[104] Gioffredi, A., et al., Eosinophilic granulomatosis with polyangiitis:
an overview. Front Immunol, 2014. 5: p. 549.
[105] Marmursztejn, J., et al., Churg-Strauss syndrome cardiac
involvement evaluated by cardiac magnetic resonance imaging and
positron-emission tomography: a prospective study on 20 patients.
Rheumatology (Oxford), 2013. 52(4): p. 642-50.
[106] Vinit, J., et al., Heart involvement in Churg-Strauss syndrome:
retrospective study in French Burgundy population in past 10 years.
Eur J Intern Med, 2010. 21(4): p. 341-6.
[107] Mavrogeni, S., et al., Detection of coronary artery lesions and
myocardial necrosis by magnetic resonance in systemic necrotizing
vasculitides. Arthritis Rheum, 2009. 61(8): p. 1121-9.
[108] Hazebroek, M. R., et al., Prevalence and prognostic relevance of
cardiac involvement in ANCA-associated vasculitis: eosinophilic
granulomatosis with polyangiitis and granulomatosis with
polyangiitis. Int J Cardiol, 2015. 199: p. 170-9.
[109] León-Ruíz, L., et al., Churg-Strauss syndrome complicated by

endomyocardial fibrosis and intraventricular thrombus. Importance
of the echocardiography for the diagnosis of asymptomatic phases
of potentially severe cardiac complications. Lupus, 2002. 11(11): p.
765-7.
[110] Miszalski-Jamka, T., et al., The mechanics of left ventricular
dysfunction in patients with Churg-Strauss syndrome.
Echocardiography, 2012. 29(5): p. 568-78.
[111] Szczeklik, W., et al., QT dispersion in patients with Churg-Strauss
syndrome. Kardiol Pol, 2011. 69(11): p. 1143-9.
[112] Groh, M., et al., Heart transplantation in patients with eosinophilic
granulomatosis with polyangiitis (Churg-Strauss syndrome). J
Heart Lung Transplant, 2014. 33(8): p. 842-50.
[113] Guillevin, L., et al., Microscopic polyangiitis: clinical and
laboratory findings in eighty-five patients. Arthritis Rheum, 1999.
42(3): p. 421-30.
[114] Shuai, Z. W., et al., Clinical analysis of patients with
myeloperoxidase antineutrophil cytoplasmic antibody-associated
vasculitis. Genet Mol Res, 2015. 14(2): p. 5296-303.
[115] McGeoch, L., et al., Cardiac Involvement in Granulomatosis with
Polyangiitis. J Rheumatol, 2015. 42(7): p. 1209-12.
[116] Forstot, J. Z., et al., Cardiac complications of Wegener
granulomatosis: a case report of complete heart block and review of
the literature. Semin Arthritis Rheum, 1980. 10(2): p. 148-54.
[117] Lacoste, C., et al., Valvular involvement in ANCA-associated
systemic vasculitis: a case report and literature review. BMC
Musculoskelet Disord, 2011. 12: p. 50.
[118] Herbst, A., et al., Cardiac Wegener’s granulomatosis masquerading
as left atrial myxoma. Ann Thorac Surg, 2003. 75(4): p. 1321-3.
[119] Jennette, J. C., et al., 2012 revised International Chapel Hill
Consensus Conference Nomenclature of Vasculitides. Arthritis
Rheum, 2013. 65(1): p. 1-11.
[120] Gasparovic, H., et al., Aortic root vasculitis associated with Cogan’s
syndrome. Ann Thorac Surg, 2011. 92(1): p. 340-1.
[121] Weyn, T., S. Haine, and V. Conraads, Cogan’s syndrome with left
main coronary artery occlusion. Cardiol J, 2009. 16(6): p. 573-6.
[122] Geri, G., et al., Spectrum of cardiac lesions in Behçet disease: a
series of 52 patients and review of the literature. Medicine
(Baltimore), 2012. 91(1): p. 25-34.
[123] Chen, H., et al., Coronary involvement in patients with Behçet’s
disease. Clin Rheumatol, 2019. 38(10): p. 2835-2841.
[124] Yavne, Y., et al., Investigating the link between ischemic heart
disease and Behcet’s disease: A cross-sectional analysis. Int J
Cardiol, 2017. 241: p. 41-45.
[125] Emmungil, H., et al., A rare but serious manifestation of Behçet’s
disease: intracardiac thrombus in 22 patients. Clin Exp Rheumatol,
2014. 32(4 Suppl 84): p. S87-92.
[126] La Regina, M., et al., Behçet’s Disease as a Model of Venous
Thrombosis. Open Cardiovasc Med J, 2010. 4: p. 71-7.
[127] Cansel, M., et al., Assessment of atrial conduction time in patients
with Behçet’s disease. Acta Reumatol Port, 2014. 39(1): p. 29-36.
[128] Sayin, M. R., et al., Assessment of QRS duration and presence of
fragmented QRS in patients with Behçet’s disease. Coron Artery
Dis, 2013. 24(5): p. 398-403.
[129] Borman, P., et al., The subclinic autonomic dysfunction in patients
with Behçet disease: an electrophysiological study. Clin Rheumatol,
2012. 31(1): p. 41-7.
Chapter 5
CEREBRAL VASCULITIDES ASSOCIATED

WITH CENTRAL NERVOUS SYSTEM
HERPESVIRIDAE INFECTION
Tracey Fan1, Alise Carlson1, Ahmad Mahadeen1

and Richard A. Prayson2,*
1
Department of Neurology, Neurological Institute,
Cleveland Clinic, Cleveland, OH, USA
2
Department of Anatomic Pathology,
Pathology & Lab Medicine Institute, Cleveland Clinic,
Cleveland, OH, USA
ABSTRACT
Herpesviridae is a family of DNA viruses that are neurotropic and

known to cause primary central nervous system (CNS) infections and
devastating neurologic outcomes. Cerebrovascular complications,
including CNS vasculitis, occur rarely but have been reported as sequelae
of herpesvirus infections of the CNS. Much of the existing literature has
*
Corresponding Author’s E-mail: praysor@ccf.org.
156 Tracey Fan, Alise Carlson, Ahmad Mahadeen et al.
been focused on varicella zoster virus (VZV) associated CNS pathology,

including ischemic stroke, aneurysm, intracranial hemorrhage, carotid
dissection, and rarely peripheral artery disease. Histologically, these
infections affect both large and small vessels and are characterized by
thrombosis of the cerebral arteries. They are distinguished from other
vasculitides by arterial infiltration predominantly by mononuclear and
multinucleated giant cells. This chapter will focus attention on cerebral
vasculitides which have been identified in this population, to review the
epidemiology, clinical presentation, imaging features, and pathologic
characteristics of CNS vasculopathy associated with Herpesviridae
infections. The pathophysiology, epidemiology, diagnostic investigation,
and treatment of each infectious etiology will also be reviewed.
INTRODUCTION
Herpesviridae is a family of DNA viruses that can infect humans and

other animals. All members have a common, unique, molecular structure.
The viral genome consists of a non-segmented, linear double-stranded
DNA molecule. This is surrounded by an icosahedral nucleocapsid, an
amorphous protein – the “tegument” and a bi-layered lipid envelope.
Embedded within the envelope are several glycoproteins that permit each
virus to elicit a distinct immune response [1].
Regardless of their clinical manifestations, Herpesviridae are globally
distributed and nearly ubiquitous among the human population. Herpes
Simplex Virus (HSV)-1 and HSV-2 infect approximately two-thirds of the
human population without any geographic or seasonal variation. Each of
these viruses has a distinct set of recognized clinical manifestations,
dependent on the age and immune status of the host [1]. Of the over 100
known herpes viruses, humans serve as the primary host for only 8 of these
(human herpesviruses [HHV] 1-8), which are further subdivided into three
subfamilies: α-Herpesviridae, β-Herpesviridae, and γ-Herpesviridae. All
HHV have been reported to produce neurologic disease, either by primary
infection or reactivation of latent disease dictated primarily by the age and
immune status of the host; however, only 5 have consistently been shown
to cause pathologically proven disease (HSV 1/2, Varicella Zoster Virus
[VZV], Cytomegalovirus [CMV] and Epstein-Barr virus [EBV]). The α‐
Cerebral Vasculitides Associated with Central Nervous System … 157
Herpesviridae (HSV-1, HSV-2, VZV) and their association with

inflammatory vasculopathy of the central nervous system were among the
most studied [1–3].
In the central nervous system (CNS), HSV-1 and HSV-2 have both
been found in immunocompetent patients with encephalitis, meningitis and
rarely myelitis. HSV-1 is identified in over 90% of patients with
encephalitis, while HSV-2 accounts for most cases of meningitis including
recurrent aseptic meningitis (Mollaret meningitis) [2]. In addition to
seizures as a frequent complication seen in patients with HSV CNS
infection, a population study has also reported cerebrovascular
complications including 5.6% with ischemic stroke (IS) and 2.7% with
intracranial hemorrhage (ICH) associated with HSV CNS infection [4].
Very rarely, isolated IS due to HSV infection related cerebral vasculitis
and venous sinus thrombosis have also be reported. All these
complications were associated with increased mortality; those with stroke
have a threefold increase in the odds of death [2, 4].
VZV can result in a host of central and peripheral nervous system
complications, usually the result of reactivation of dormant virus in elderly
and immunocompromised patients [1]. Shingles, herpes zoster
ophthalmicus, and zoster oticus occur due to reactivation of latent virus in
sensory root ganglia. Reactivation can also cause CNS disease, and may
manifest as encephalitis (both infectious and post-infectious), cerebellitis
(following primary infection), or myelitis [2, 5]. It is also a well-recognized
cause of inflammatory CNS vasculopathy in children following primary
infection, in adults with shingles in around 60% of cases, or in the absence
of dermatological manifestations. The risk for stroke is higher in patients
with shingles presenting before the age of 40 years [6].
CMV is a well-recognized cause of polyradiculopathy, and together
with EBV can present with encephalitis in immunocompromised
individuals. CMV is also responsible for a well-recognized congenital
neurological syndrome when the pathogen is transmitted through the
placenta during pregnancy [1]. EBV is associated with primary CNS
lymphoma in immunocompromised patients with HIV. There are reports
of HHV-6 being associated with limbic encephalitis and it is frequently
associated with febrile illness in relation to febrile seizures in childhood.

HHV-8, the causative agent of Kaposi’s sarcoma, has been identified in
patients with CNS involvement [2, 7].
Although all 8 types of HHV can infection the nervous system and
cause neurologic disease, this text will focus on the alpha-herpesviruses
(HSV-1, HSV-2, and VZV), which have previously been identified to
cause inflammatory vasculopathy of the CNS [1]. We will discuss the
pathophysiology, clinical features, radiographic and histopathological
findings, and treatment options.
PATHOPHYSIOLOGY
The mechanism(s) by which HHV enter the CNS and damage neuronal
tissue is not fully understood. The extent of damage seen depends greatly
on both the immunocompetency of the host as well as inherent viral
factors, and often results from a combination of direct injury as well as
immune-mediated cell injury [8, 9]. As aforementioned, of the eight types
of HHV, HSV-1, HSV-2, and VZV have been studied the most extensively
with regard to infection of the CNS and development of vasculitic changes.
In the initial phase of infection, the inflammatory cascade activates the
innate immune response. The inflammatory response is characterized by
recruitment of activated leukocytes, which cause necrosis and apoptosis in
infected cells (resulting in tissue damage) [9, 10]. Vasculitis results from
direct infiltration of the blood vessel walls by both T-cells and B-cells,
with interferon-γ serving as an important mediator [11, 12]. Deficiencies
in the immune response may lead to more extensive and widespread
damage.
Histologically, cortical blood vessels may demonstrate angiocentric
chronic inflammation and infiltration of the vessel wall by inflammatory
cells (constituting a non-necrotizing pattern of injury) (Figure 1).
Typically, the vessels are diffusely affected (panarteritis) with a
predilection for the media [12]. Angiocentric inflammation may also exist
without concomitant vessel wall infiltration (Figure 2). Involved areas may
ultimately become necrotic secondary to inflammation, and in severe

cases, inflammation may lead to vessel occlusion or rupture [12]. Cerebral
infarction, resulting from herpes virus infection of the CNS, is
pathologically marked by necrosis and peripheral reactive or hypertrophic
astrocytes surrounding the area of infection (Figure 3). Cowdry (Type A)
intranuclear inclusion bodies or evidence of nuclear immunostaining
(Figure 4) are commonly seen, as is microglial cell proliferation and focal
dystrophic calcification (Figure 5).
In HSV-1 cases, the temporal lobes are most heavily involved (though
it is well known that rapidly evolving infection may lead to bilateral spread
by way of the limbic system) [8]. Post-mortem, viral antigen has been
found to be most highly concentrated in the medial and inferior temporal
lobes, amygdaloid nuclei and hippocampus, olfactory cortex, insular
cortex, and cingulate gyrus [13]. Notably, more diffuse involvement
(including bilateral cortices, cerebellum, and brainstem) has been observed
in immunocompromised hosts [14].
Figure 1. Cortical blood vessel marked by angiocentric chronic inflammation and

infiltration of the vessel wall by inflammatory cells constituting a nonnecrotizing
vasculitic pattern of injury associated with Herpes simplex virus infection
(hematoxylin and eosin, original magnification 400X).
Figure 2. Angiocentric inflammation without infiltration of the vessel wall

(hematoxylin and eosin, original magnification 400X).
Figure 3. Area of infarct adjacent to Herpes simplex associated vasculitis marked by

necrosis and peripheral reactive or hypertrophic astrocytes (hematoxylin and eosin,
original magnification 200X).
Figure 4. Immunostaining with antibody for Herpes simplex virus showing nuclear
staining (hematoxylin and eosin, original magnification 400X).
Figure 5. Microglial cell proliferation and focal dystrophic calcification (arrow) in

Herpes simplex infection (hematoxylin and eosin, original magnification 400).
After the primary infection (chicken pox), VZV remains dormant in

the trigeminal and autonomic ganglions of the head and neck and upon
reactivation, travels transaxonally to cerebral arteries, dural sinuses and
other brain structures. VZV infects a variety of cells within the CNS
including the vascular wall endothelium, spreading transmurally from the
adventitia, where nerves terminate, to the intima. It can cause fibrinoid
necrosis and inflammation, leading to vasospasm, small vessel
vasculopathy and thrombosis. Histologic and immunohistochemical
analyses of infected cerebral vessels shows neointimal thickening from
myofibroblast migration and proliferation that continues for months after
initial VZV infection, leading to stenosis and stroke. It also involves
internal elastic lamina, weakening the vessel wall, and causing aneurysmal
dilation, dissection and hemorrhage. However, VZV-induced
inflammation may also result from either primary infection or virus
reactivation [15], and similar histopathologic changes to those associated
with HSV are seen.
CLINICAL AND IMAGING MANIFESTATIONS OF HERPES

VIRUS INFECTION-RELATED VASCULOPATHY
Herpes Simplex Virus 1 and 2
The most common neurologic manifestation of HSV-1 is encephalitis,

and the most common manifestation of HSV-2 is meningitis. Rarely, HSV-
2 can also cause encephalitis (especially in neonates or
immunocompromised patients) [16, 17]. The signs and symptoms of HSV
CNS infection are largely nonspecific and are related primarily to
meningoencephalitis (which may be associated with acute onset of
headache, fever, neck stiffness and signs of brain dysfunction such as
altered mental status, especially if brain parenchyma is involved, that
progress over the course of several days). Fever is reported as one of the
most frequent features at the presentation, though headache is also present
in up to 90% of cases [18]. Patients may also experience respiratory,
gastrointestinal, and autonomic symptoms including urinary and fecal
incontinence [19]. A United States population study in 2006 demonstrated
that the most common reasons for hospital presentation in patients

ultimately diagnosed with HSV encephalitis were seizures (32%),
abnormal behavior (23%), loss of consciousness (13%), and confusion or
disorientation (13%) [9]. Patients with HSV encephalitis may also exhibit
a variety of focal neurological deficits, including hemiparesis, dysphasia,
aphasia, and focal cranial nerve palsies [20]. Furthermore, there may be
additional emotional and behavioral disturbances including hypomania,
amnesia, and Klüver–Bucy syndrome [21, 22]. Less commonly, HSV-1
infection can cause myelitis (described in only a single case report) [23,
24].
Cerebrovascular disease is an infrequent but reported complication of
HSV CNS infection. Both HSV-1 and HSV-2 are associated with
intracranial hemorrhage (ICH) and ischemic stroke (IS). However, HSV-2
is the predominant herpesvirus known to be strongly associated with
cerebral vasculopathy [4, 25, 26]. Very rarely, venous sinus thrombosis
has been reported as a result of HSV-2 CNS infection [27, 28].
ICH typically occurs as a complication of encephalitis. The clinical
symptoms at the time of presentation are almost exclusively sequelae of
meningoencephalitis, including fever, headache, and altered mental status.
Sometimes, patients can present with new onset of seizure or vomiting due
to elevated intracranial pressure. On brain imaging, hematomas are
typically located adjacent or in approximation to the site of parenchymal
involvement. However, there have been reports of hemorrhage distant
from the primary infectious nidus, without the presence of encephalitis.
Vasculitic changes have not been reported in patients who suffered from
ICH as a secondary complication of encephalitis [27, 28].
IS, on the other hand, can occur as a complication from encephalitis or
as an isolated event due to HSV CNS infection related cerebral
vasculopathy [28]. In patients with IS related to HSV encephalitis, clinical
presentations are similar to those suffering from ICH, with nonspecific
symptoms related to meningoencephalitis. In patients that present with
isolated IS, the presentation is identical to that seen with an acute stroke
with sudden onset of focal neurologic deficits. The onset of deficits is
hyperacute (onset to maximum symptoms within minutes to hours) in
comparison to the symptoms related to encephalitis (which develop over

the course of days). Due to the identical presentation to stroke, at times,
the diagnosis of an underlying HSV infection may be overlooked. The
initial focal deficits vary depending on the specific cerebral vascular
territory involved. The initial brain computed tomography (CT) study may
not reveal any acute changes. On conventional cerebral arterial imaging,
such as CT/magnetic resonance (MR) angiogram or digital subtraction
angiography (DSA), there may be evidence of structural intracranial blood
vessel changes corresponding to the area of stroke, similar to what is seen
in patients with atherosclerotic disease. However, high resolution 3-Telsa
MR vessel wall imaging will reveal concentric gadolinium contrast
enhancement in patients with vasculitis, as opposed to the eccentric
enhancement seen in patients with atherosclerotic changes [26, 29]. The
changes in the intracranial blood vessels have been reported as focal
vascular narrowing or stenosis, and/or pseudoaneurysm and dilation.
Based on the current literature, it is believed that HSV CNS infection only
affects large blood vessels, and it is thought that the virus may have a
predilection for the posterior circulation (as shown in one study), though
changes have also been reported to involve the anterior circulation [27,
28]. The involvement of intracranial vessels can be unifocal or multi-focal.
If undiagnosed and untreated, HSV CNS infection may cause dynamic
imaging features such as worsening stenosis or involvement of blood
vessels in other areas of the brain [27, 28].
Varicella Zoster Virus
Reactivation of VZV, the pathogen of varicella, may also lead to CNS

complications such as myelitis and focal vasculopathies. VZV is a rare
cause of stroke in children that can occur from days to months after the
primary VZV infection. In young children, there is a 3-fold increase in risk
of ischemic stroke with preceding varicella infection [18]. VZV
vasculopathy can affect both immunocompetent and immunocompromised
patients and can be either unifocal or multifocal. Patients with VZV related
vasculitis can present with acute ischemic stroke or transient ischemic

attack [30]. The initial presentation can be related to stroke including acute
hemiplegia or hemisensory loss, aphasia, ataxia, hemianopia, and
monocular vision loss, but can also be associated with nonspecific
symptoms such as headache and changes in mental status. Less frequently,
VZV vasculopathy can cause spinal cord infarction, intracerebral or
subarachnoid hemorrhage, cerebral aneurysm, arterial dissection, and focal
ectasia. VZV has also been reported to be a pathogen capable of causing
giant cell arteritis and venous sinus thrombosis [29–32].
VZV CNS infection related cerebral vasculopathy can cause both large
vessel unifocal granulomatous arteritis and small vessel multifocal
vasculopathy. Large vessel unifocal granulomatous arteritis is usually a
disorder of immunocompetent patients, and neurologic symptoms
typically develop weeks to months following trigeminal zoster.
Importantly, lack of skin lesion(s) does not exclude the diagnosis of VZV,
as 37% of VZV vasculopathy cases develop in patients without rash [35].
The initial MRI brain can be normal. When IS are present, they may be
cortical or subcortical, but typically occur at gray-white junctions [31]. On
conventional cerebral arterial imaging, such as magnetic resonance
angiography (MRA) or computed tomography angiography (CTA), the
involved vessel would show focal narrowing or occlusion of the blood
vessel. Although the presence of stenosis or occlusion is helpful in
diagnosing VZV vasculopathy, a negative CTA/MRA does not exclude the
diagnosis (because changes in small arteries are not detected as readily as
those in large arteries). DSA may improve the diagnostic sensitivity, where
the involved vessels may show focal stenosis with post-stenotic dilation
[36].
Areas of small vessel involvement are typically multifocal and occur
more frequently in immunocompromised patients [37]. The typical
presentations are more subacute in nature, with progressive neurologic
deficits, including headache, fever, mental status changes, and seizures. A
history of herpes zoster rash might precede the symptoms by several weeks
to months. MRI brain may demonstrate multifocal infarcts of different
stages. On brain biopsy, there is histological evidence of productive VZV
infection in the involved vessels including Cowdry A inclusion bodies,

multinucleated giant cells, herpes virions, and both VZV DNA and
antigen. Analysis of the blood vessel itself may reveal abnormal
accumulation of smooth muscle cells and myofibroblasts in the thickened
intima and disrupted media [38]. Early VZV vasculopathy may be
distinguished by the presence of abundant neutrophils in the adventitia that
are absent in late VZV vasculopathy [39].
DIAGNOSIS OF CNS INFECTION OF HERPES VIRUS
Herpes Simplex Virus 1 and 2
The most common reason for delay in therapy is failure to diagnose

HSV CNS infection. Delays in treatment are directly associated with
higher morbidity and mortality for HSV encephalitis, and result in sequelae
of the disease including recurrent ischemia [40]. HSV serologies are
generally not clinically helpful in the acute setting [9]. To diagnose HSV
CNS infection, CSF analysis is required to evaluate for cell count, protein,
glucose, and viral DNA. Previously, the diagnosis of HSV infection in the
CNS required demonstration of intrathecal production of anti-HSV
antibodies, though this has been replaced by CSF polymerase chain
reaction (PCR) tests for both HSV-l and HSV-2 DNA. The PCR test for
HSV is sensitive (98%) and specific (94%) as compared to brain biopsy
[9, 39]. The typical CSF profile in HSV infection includes a moderate
lymphocytic pleocytosis (10–200/mm3), moderately elevated protein (50–
100 mg/dl), normal glucose, and normal or elevated erythrocyte count in
the setting of ICH. However, absence of pleocytosis and false-negative
PCR results are both possible early in the course of HSV encephalitis (and
can be seen in patients who are immunocompromised). The time frame in
which CSF PCR is most likely to result positive is 2-10 days after the onset
of the illness. When there is a high clinical suspicion, the HSV PCR should
be repeated in 3 to 7 days if the initial result is negative [42].
Conventional imaging of the intracranial arteries with CTA, MRA, and

DSA can reveal abnormalities of the vessel lumen, but they are unable to
characterize disease within the vessel wall. It would be difficult to
differentiate the changes due to HSV infection related vasculitis from other
entities such as atherosclerotic disease or arterial dissection. High-
resolution intracranial vessel wall MR imaging in the case of vasculitis
would demonstrate smooth, homogeneous, concentric arterial wall
thickening and enhancement in comparison with the typical nonconcentric
(and often heterogeneous) wall abnormality of atherosclerotic plaque [43].
Brain biopsy remains the gold standard for diagnosis of CNS vasculitis,
but is rarely done in HSV infection related cerebral vasculitis.
Varicella Zoster Virus
When a clinical diagnosis of VZV vasculopathy is suspected and is

corroborated by characteristic lesions on MRI or CT, virological
confirmation is required. CNS infection of VZV can be diagnosed by CSF
analysis with VZV DNA detection by PCR. CSF often shows a
lymphocytic pleocytosis and elevated protein, similar to the CSF profile
seen in other viral CNS infections. In patients with VZV vasculopathy, the
lack of CSF pleocytosis or of angiographic abnormalities should not
preclude the diagnosis of vasculopathy. Indeed, in VZV vasculopathy, up
to 33% of cases may have normal CSF and 30% may have negative
vascular imaging [35]. In patients with encephalitis, CSF VZV PCR test
has a high sensitivity of about 96%. A previous study has shown that VZV
CSF viral load is associated with the severity of the neurological symptoms
[44]. Although in patients with VZV related cerebral vasculitis, the test
sensitivity is as low as 30%, possibly due to a delay of several weeks from
the onset of active VZV infection to the development of CNS symptoms
[45]. VZV vasculopathy is often chronic and protracted; although viral
DNA can be detected by PCR in early disease, detection of anti-VZV IgG
antibody is the best diagnostic test with a diagnostic sensitivity close to
93% [42–44]. The CSF VZV antibody index is calculated to prevent the
possibility of false positive detection of CSF anti-VZV antibodies and is

considered elevated if the index value is greater than 1.5. The index can be
calculated using Reiber’s formula by using contemporaneous VZV
antibodies and total albumin in serum and CSF [44, 45]. Brain biopsy is
rarely used in the case of an unclear diagnosis, but in vasculopathy related
to VZV infection, biopsy would show fibrinoid necrosis, intimal
proliferation, loss of elastic lamina, and a lymphocytic or monocytic
inflammatory infiltrate with surrounding multinucleated giant cells [48].
The diagnostic value of PCR in HSV encephalitis has been shown by
comparison with HSV-positive brain biopsy samples, which has served as
the gold standard for diagnosis; however, a gold standard that shows VZV
in the arterial wall of patients with VZV vasculopathy has not been
established.
TREATMENT
When patients are presenting with symptoms of profound

encephalopathy, seizure, stroke, intracerebral hemorrhage, autonomic
instability, or other symptoms leading to respiratory insufficiency,
hemodynamic stabilization and airway protection must be addressed first.
Following stabilization, empiric intravenous Acyclovir (56.3%) 10-15
mg/Kg (based on ideal body weight and renal function) dosed every 8
hours should be started immediately for any adult with suspected or
confirmed viral encephalitis [42]. Because it is often difficult to discern
etiology at the time of initial presentation, antibacterial coverage should be
started concurrently, based on patient and epidemiologic factors. Choice
of antibiotic therapy and dosing will not be covered here. Treatment should
not be delayed for diagnostic testing. The course of therapy should be
continued for 14-21 days in immunocompetent adults. Neonates and
children (up to age 11 years) are recommended to receive doses of 15-20
mg/Kg for a total course of 21 days. Patients who are
immunocompromised or who have developed resistance to Acyclovir may
require higher doses of Acyclovir and longer duration of treatment. Repeat
CSF PCR in addition to magnetic resonance vessel wall imaging may be

considered to guide duration of treatment [9, 47]. This is an area of
research where further investigation is required.
The use of corticosteroids in the treatment of HSV-related vasculitis is
a contested practice. Clinical evidence in humans is lacking, though
several animal and preclinical studies have suggested potential benefit in
patients with HSVE [9]. One non-randomized retrospective study
suggested that the use of Acyclovir along with corticosteroids may be
associated with improved outcomes, though no large prospective studies
have been performed to date, and none have focused specifically on HSV-
related CNS vasculitis [50].
For treatment of VZV-related encephalitis, intravenous Acyclovir is
recommended (with dosing as outlined previously) for a total of 14 -21
days, based upon level 2 class evidence from treatment studies of HSV
CNS infection, expert opinion, and cases series of VZV vasculopathy. Data
is lacking regarding the treatment duration of IV Acyclovir for more than
21 days, and whether longer treatment would alter outcome or reduce risk
of recurrence. A second course may be required in immunocompromised
patients or patients with recurrent disease, followed by long term oral
antiviral medication. Reversibility of both the stenosis and enhancement
of the blood vessel involved are reported; however, the course of resolution
of vessel inflammation and stenosis is unknown [51]. It is unclear whether
monitoring for resolution of the enhancement is indicative of response to
treatment [52]. Given the arterial inflammation seen on histology,
concurrent treatment with corticosteroids is often recommended but has
not shown any evidence in altering the neurologic outcome. Ganciclovir
may be considered as an alternative [42].
With regards to treatment of other Herpesviridae infections of the
CNS, the Infectious Disease Society of America recommends a
combination of Ganciclovir and Foscarnet for CMV-related infections, as
well as in immunocompromised patients with HHV-6 (with consideration
for treatment in immunocompetent hosts). Corticosteroids may be
considered for patients with EBV infectious, though benefits must be
weighed with potential risks [5]. Acyclovir is not recommended [42].
PROGNOSIS
Complications of VZV and HSV CNS infections have been poorly

characterized, and infections caused by these viruses vary greatly in
severity [15, 51]. Known sequelae of these infections include cerebral
edema, IS, ICH, acute retinal necrosis, cranial nerve palsies, seizures
(including status epilepticus), and auto-immune encephalitis amongst
others.
HSV associated CNS vasculitis is associated with a poor prognosis
(with significant morbidity and mortality), despite recent advances in
diagnostic tools and available therapies. The mortality of untreated HSV-
associated encephalitis is approximately 70%, with nearly all patients
having some residual sequelae of disease, whereas mortality rates as low
as 5-15% have been seen with early intravenous Acyclovir administration
[9]. Immunocompromised hosts have significantly higher morbidity and
mortality [8, 14]. Other factors which may contribute to poorer outcomes
include older age, severity of symptoms at the time of presentation, and
delay in initiation of Acyclovir treatment by more than 48 hours [9, 52].
With regard to VZV infection, several studies have reported presence
of neurological sequelae in up to 50% of patients, with cognitive
impairment and persistent sensorimotor deficits being most common [15,
53, 54]. Little work has been done to characterize the long-term sequelae
and outcomes in patients with VZV-related CNS vasculitis, though less
favorable outcomes have been reported in patients presenting with clinical
features of encephalitis including neuropsychological impairment, focal
seizures, aphasia, and facial paralysis [57].
CONCLUSION
Herpesviridae infections are ubiquitous in the human population. In

addition to the systemic and dermatological manifestations they can cause
infection of the central and peripheral nervous system as well as the
cerebral vasculature resulting in inflammation of the vessel wall.

Cerebrovascular complications and vasculopathy are more commonly seen
with VZV CNS infection but are increasingly recognized to be associated
with both HSV-1 and 2 infections.
Despite improved outcomes, most survivors from herpes virus CNS
infection related cerebrovascular complications have some degree of
neurological deficit. The diagnosis of Herpes virus related vasculopathy is
often missed or delayed, as initial presentation can be nonspecific in the
cases of small vessel vasculopathy or identical to other stroke patients
presenting with large vessel occlusion in the case of large vessel
vasculopathy. Delayed diagnosis can lead to increased risk of recurrent
strokes. The absence of conventional risk factors for stroke and/or a history
suggesting recent infection or reactivation should prompt workup so that
guided therapy can be initiated to prevent recurrence and future morbidity.
Early recognition of vascular complications of CNS Varicella Zoster
is important as treatment with antiviral agents may be beneficial. Specific
therapy for HSV and VZV related vasculopathy includes the use of
intravenous acyclovir for 14-21 days in adults and 21 days in neonates.
Higher or repeated dose and longer duration of therapy may be needed in
patients with recurrent disease or immunocompromised state. Benefit of
concurrent corticosteroid use is still an area of ongoing debate. It is unclear
whether repeat viral PCR testing is helpful and when the optimal timing of
sampling would be. Repeat imaging with CT, MR or DSA is often done to
assess for improvement in vessel caliber and resolution of vessel wall
enhancement but data is lacking to guide this practice. Future studies
should focus on determining the risk of stroke and vasculopathy recurrence
in those patients, length of monitoring for resolution of vasculopathy and
optimized treatment length to minimize the risk of recurrence.
Further research is needed to better characterize patient populations
that are at risk of developing HSV and VZV vasculopathy, given the global
spread of both infections coupled with an aging population and increasing
use of immunosuppressive and modulatory therapies in medicine. Vessel
wall imaging is not yet uniformly available and alternative means of
noninvasive diagnostics are needed to facilitate early recognition of these
debilitating entities. Finally, randomized controlled studies are needed to

guide the use of antiviral medications and to justify the use of
immunosuppressive medications such as corticosteroids in this patient
population.
REFERENCES
[1] Baldwin, KJ; Cummings, CL. “Herpesvirus infections of the nervous

system,” Contin. Lifelong Learn. Neurol., vol. 24, no. 5,
Neuroinfectious Disease, pp. 1349–1369, Oct. 2018.
[2] Chrétien Fabrice, FG; Kum Thong Wong, Leroy R. Sharer,
Catherine Keohane. Infections of the Central Nervous System:
Pathology and Genetics. Wiley, 2020.
[3] Wald Anna, LC. “HSV: persistence in the population: epidemiology,
transmission,” Hum. Herpesviruses Biol. Ther. Immunoprophyl., pp.
656–72, 2007.
[4] Modi, S; Mahajan, A; Dharaiya, D; et al., “Burden of herpes simplex
virus encephalitis in the United States,” J. Neurol., vol. 264, no. 6,
pp. 1204–1208, Jun. 2017.
[5] Nagel, MA; Bubak, AN. “Varicella zoster virus vasculopathy,” J.
Infect. Dis., vol. 218, no. 2, pp. S107–S112, 2018.
[6] Amlie-lefond, C; Gilden, D; Hospital, SC. “Varicella zoster virus: a
not uncommon cause of stroke in children and adults,” J. Stroke
Cerebrovasc. Dis., vol. 25, no. 7, pp. 1561–1569, 2017.
[7] Mohammadpour Touserkani, F; Gaínza-Lein, M; Jafarpour, S; et al.,
“HHV-6 and seizure: a systematic review and meta-analysis,” J.
Med. Virol., vol. 89, no. 1. John Wiley and Sons Inc., pp. 161–169,
Jan. 01, 2017.
[8] Kumar, R. “Understanding and managing acute encephalitis,”
F1000Research, vol. 9. F1000 Research Ltd, 2020.
[9] Bradshaw, MJ; Venkatesan, A. “Herpes simplex virus-1 encephalitis
in adults: pathophysiology, diagnosis, and management,”
Neurotherapeutics, vol. 13, no. 3, pp. 493–508, 2016.
[10] Lundberg, P; Ramakrishna, C; Brown, J. et al., “The immune

response to herpes simplex virus type 1 infection in susceptible mice
is a major cause of central nervous system pathology resulting in fatal
encephalitis,” J. Virol., vol. 82, no. 14, pp. 7078–7088, Jul. 2008.
[11] Presti, RM; Pollock, JL; Dal Canto, AJ; et al., “Interferon γ regulates
acute and latent murine cytomegalovirus infection and chronic
disease of the great vessels,” J. Exp. Med., vol. 188, no. 3, pp. 577–
588, Aug. 1998.
[12] Kelley, RE. “Central nervous system vasculitis,” Front. Biosci., vol.
9. pp. 946–955, 2004.
[13] Esiri, MM. “Herpes simplex encephalitis. an immunohistological
study of the distribution of viral antigen within the brain,” J. Neurol.
Sci., vol. 54, no. 2, pp. 209–226, 1982.
[14] Tan, IL; McArthur, JC; Venkatesan, A; et al., “Atypical
manifestations and poor outcome of herpes simplex encephalitis in
the immunocompromised,” Neurology, vol. 79, no. 21, pp. 2125–
2132, Nov. 2012.
[15] Alvarez, JC; Alvarez, J; Tinoco, J; et al., “Varicella zoster virus
meningitis and encephalitis: an understated cause of central nervous
system infections.,” Cureus, vol. 12, no. 11, p. e11583, Nov. 2020.
[16] Momméja-Marin, H; Lafaurie, M; Scieux, C; et al., “Herpes simplex
virus type 2 as a cause of severe meningitis in immunocompromised
adults,” Clin. Infect. Dis., vol. 37, no. 11, pp. 1527–1533, Dec. 2003.
[17] Whitley, R; Arvin, A; Prober, C; et al., “Predictors of morbidity and
mortality in neonates with herpes simplex virus Infections,” N. Engl.
J. Med., vol. 324, no. 7, pp. 450–454, Feb. 1991.
[18] Steiner, I; Benninger, F. “Manifestations of herpes virus infections
in the nervous system,” Neurol. Clin., vol. 36, no. 4. pp. 725–738,
Nov. 01, 2018.
[19] Michael Scheld, CMMMW; MD, Richard J. Whitley MD. Infections
of the Central Nervous System. Wolter Kluwer, 2014.
[20] Whitley, RJ. “Herpes simplex encephalitis: adolescents and adults,”
Antiviral Research, vol. 71, no. 2-3 SPEC. ISS. Antiviral Res, pp.
141–148, Sep. 2006.
[21] Hart, RP; Kwentus, JA; Frazier, RB. et al., “Natural history of
Kluver-Bucy syndrome after treated herpes encephalitis,” South.
Med. J., vol. 79, no. 11, pp. 1376–1378, 1986.
[22] Fisher, CM. “Hypomanic symptoms caused by herpes simplex
encephalitis,” Neurology, vol. 47, no. 6, pp. 1374–1378, 1996.
[23] Figueroa, D; Isache, C; Sands, M; et al., “An unusual case of acute
transverse myelitis caused by HSV-1 infection,” IDCases, vol. 5, pp.
29–31, 2016.
[24] Nakajima, H; Furutama, D; Kimura, F; et al., “Herpes simplex virus
myelitis: clinical manifestations and diagnosis by the polymerase
chain reaction method,” Eur. Neurol., vol. 39, no. 3, pp. 163–167,
Apr. 1998.
[25] Ule, ATG. “Acute necrotizing Herpes-encephalitis presenting
ischemic brain infarct,” Zentralbl Allg Pathol, vol. 111, no. 3, pp.
282–288, 1973.
[26] Küker, W; Gaertner, S; Nägele, T; et al., “Vessel wall contrast
enhancement: a diagnostic sign of cerebral vasculitis,” Cerebrovasc.
Dis., vol. 26, no. 1, pp. 23–29, Jul. 2008.
[27] Hauer, L; Pikija, S; Schulte, EC; et al., “Cerebrovascular
manifestations of herpes simplex virus infection of the central
nervous system: A systematic review,” J. Neuroinflammation, vol.
16, no. 1, 2019.
[28] Fan, TH; Khoury, J; Cho, SM; et al., “Cerebrovascular complications
and vasculopathy in patients with herpes simplex virus central
nervous system infection,” J. Neurol. Sci., vol. 419, Dec. 2020.
[29] Swartz, RH; Bhuta, SS; Farb, RI; et al., “Intracranial arterial wall
imaging using high-resolution 3-Tesla contrast-enhanced MRI,”
Neurology, vol. 72, no. 7, pp. 627–634, Feb. 2009.
[30] Chow, FC; Marra, CM; Cho, TA. “Cerebrovascular disease in central
nervous system infections.,” Semin. Neurol., vol. 31, no. 3, pp. 286–
306, Jul. 2011.
[31] Gilden, D; Cohrs, RJ; Mahalingam, R; et al., “Varicella zoster virus
vasculopathies: diverse clinical manifestations, laboratory features,
pathogenesis, and treatment,” Lancet Neurol., vol. 8, no. 8. Lancet

Neurol, pp. 731–740, Aug. 2009.
[32] Chan, J; Bergstrom, RT; Lanza, DC; et al., “Lateral sinus thrombosis
associated with zoster sine herpete,” Am. J. Otolaryngol. - Head
Neck Med. Surg., vol. 25, no. 5, pp. 357–360, Sep. 2004.
[33] Salazar, R; Russman, AN; Nagel, MA; et al., “Varicella zoster virus
ischemic optic neuropathy and subclinical temporal artery
involvement,” Arch. Neurol., vol. 68, no. 4, pp. 517–520, Apr. 2011.
[34] Mathias, M; Nagel, MA; Khmeleva, N; et al., “VZV multifocal
vasculopathy with ischemic optic neuropathy, acute retinal necrosis
and temporal artery infection in the absence of zoster rash,” J.
Neurol. Sci., vol. 325, no. 1–2, pp. 180–182, Feb. 2013.
[35] Nagel, MA; Cohrs, RJ; Mahalingam, R; et al., “The varicella zoster
virus vasculopathies: clinical, CSF, imaging, and virologic features,”
Neurology, vol. 70, no. 11, pp. 853–860, 2008.
[36] Russman, AN; Lederman, RJ; Calabrese, LH. et al., “Multifocal
varicella-zoster virus vasculopathy without rash,” Arch. Neurol., vol.
60, no. 11, pp. 1607–1609, Nov. 2003.
[37] Ortiz, GA; Koch, S; Forteza, A; et al., “Ramsay Hunt syndrome
followed by multifocal vasculopathy and posterior circulation
strokes,” Neurology, vol. 70, no. 13 PART 1, pp. 1049–1051, 2008.
[38] Gilden, DH; Kleinschmidt-DeMasters, BK; Wellish, M; et al.,
“Varicella zoster virus, a cause of waxing and waning vasculitis: The
New England Journal of Medicine case 5-1995 revisited,”
Neurology, vol. 47, no. 6, pp. 1441–1446, 1996.
[39] Dal Canto, AJ; Swanson, PE; O’Guin, AK; et al., “IFN-γ action in
the media of the great elastic arteries, a novel immunoprivileged
site,” J. Clin. Invest., vol. 107, no. 2, 2001.
[40] Hughes, P; Jackson, A. “Delays in initiation of acyclovir therapy in
herpes simplex encephalitis,” Can. J. Neurol. Sci., vol. 39, no. 5, pp.
644–648, Sep. 2012.
[41] Lakeman, FD; Whitley, RJ; Whitley, RJ. et al., “Diagnosis of herpes
simplex encephalitis: Application of polymerase chain reaction to
cerebrospinal fluid from brain-biopsied patients and correlation with

disease,” J. Infect. Dis., vol. 171, no. 4, pp. 857–863, 1995.
[42] Tunkel, AR; Glaser, CA; Bloch, KC; et al., “The management of
encephalitis: Clinical practice guidelines by the Infectious Diseases
Society of America,” Clin. Infect. Dis., vol. 47, no. 3, pp. 303–327,
Aug. 2008.
[43] Mandell, DM; Mossa-Basha, M; Qiao, Y; et al., “Intracranial vessel
wall MRI: principles and expert consensus recommendations of the
American Society of Neuroradiology,” Am. J. Neuroradiol., vol. 38,
no. 2., pp. 218–229, Feb. 01, 2017.
[44] Grahn, A; Studahl, M. “Varicella-zoster virus infections of the
central nervous system - Prognosis, diagnostics and treatment,” J.
Infect., vol. 71, no. 3. W.B. Saunders Ltd, pp. 281–293, 2015.
[45] Nagel, MA; Forghani, B; Mahalingam, R; et al., “The value of
detecting anti-VZV IgG antibody in CSF to diagnose VZV
vasculopathy,” Neurology, vol. 68, no. 13, pp. 1069–1073, 2007.
[46] Nagel, MA; Gilden, DH. “The protean neurologic manifestations of
varicella-zoster virus infection,” Cleve. Clin. J. Med., vol. 74, no. 7.
pp. 489–504, 2007.
[47] Jacobi, C; Lange, P; Reiber, H. “Quantitation of intrathecal
antibodies in cerebrospinal fluid of subacute sclerosing
panencephalitis, herpes simplex encephalitis and multiple sclerosis:
Discrimination between microorganism-driven and polyspecific
immune response,” J. Neuroimmunol., vol. 187, no. 1–2, pp. 139–
146, Jul. 2007.
[48] Schmidbauer, M; Budka, H; Pilz, P; et al., “Presence, distribution
and spread of productive varicella zoster virus infection in nervous
tissues.,” Brain, vol. 115, (Pt 2), pp. 383–98, Apr. 1992.
[49] Padrick, MM; Maya, MM; Fan, Z; et al., “Magnetic resonance vessel
wall imaging in central nervous system vasculitides: a case series,”
Neurologist, vol. 25, no. 6, pp. 174–177, Nov. 2020.
[50] Kamei, S; Sekizawa, T; Shiota, H; et al., “Evaluation of combination
therapy using aciclovir and corticosteroid in adult patients with
herpes simplex virus encephalitis,” J. Neurol. Neurosurg.

Psychiatry, vol. 76, no. 11, pp. 1544–1549, Nov. 2005.
[51] Silver, B; Nagel, MA; Mahalingam, R; et al., “Varicella zoster virus
vasculopathy: a treatable form of rapidly progressive multi-infarct
dementia after 2 years’ duration,” J. Neurol. Sci., vol. 323, no. 1–2,
pp. 245–247, Dec. 2012.
[52] Cheng-Ching, E; Jones, S; Hui, FK; et al., “High-resolution MRI
vessel wall imaging in varicella zoster virus vasculopathy,” J.
Neurol. Sci., vol. 351, no. 1–2, pp. 168–173, Apr. 2015.
[53] Rozenberg, F. “Herpes simplex virus and central nervous system
infections: Encephalitis, meningitis, myelitis,” Virologie, vol. 24, no.
5. pp. 283–294, Sep. 01, 2020.
[54] Raschilas, F; Wolff, M; Delatour, F; et al., “Outcome of and
prognostic factors for herpes simplex encephalitis in adult patients:
Results of a multicenter study,” Clin. Infect. Dis., vol. 35, no. 3, pp.
254–260, Aug. 2002.
[55] Persson, A; Bergström, T; Lindh, M; et al., “Varicella-zoster virus
central nervous system disease-viral load, clinical manifestations and
sequels,” J. Clin. Virol., vol. 46, no. 3, pp. 249–253, 2009.
[56] De Broucker, T; Mailles, A; Chabrier, S; et al., “Acute varicella
zoster encephalitis without evidence of primary vasculopathy in a
case-series of 20 patients,” Clin. Microbiol. Infect., vol. 18, no. 8, pp.
808–819, May 2012.
[57] Becerra, JCL; Sieber, R; Martinetti, G; et al., “Infection of the central
nervous system caused by varicella zoster virus reactivation: A
retrospective case series study,” Int. J. Infect. Dis., vol. 17, no. 7, Jul.
2013.
Chapter 6
GASTROINTESTINAL COMPLICATIONS
OF VASCULITIS
The Dang1, Luis O. Chavez1, Monica Leon2,

Kejal Gandhi3, Pahnwat Taweesedt4
and Salim Surani5,6,*
1
Department of Internal Medicine,
Texas Tech University Health Science Center, El Paso, TX, USA
2
Department of General Surgery, Centro Medico ABC,
Ciudad de Mexico, Mexico
3
Department of Medicine,
Georgetown University/Medstar Washington Hospital Center,
Washington, DC, USA
4
Department of Medicine, Corpus Christi Medical Center,
Corpus Christi, TX, USA
5
6
*
180 The Dang, Luis O. Chavez, Monica Leon et al.
ABSTRACT
Vasculitides are defined by the presence of inflammatory leukocytes

in vessel walls, with 36% of patients presenting with gastrointestinal
manifestations that vary from general and/or postprandial abdominal
pain, nausea, vomiting, and diarrhea. A low-flow pathophysiologic leads
to small bowel obstruction, intussusception, mesenteric ischemia,
ischemic colitis, and massive gastrointestinal bleeding. Often
gastrointestinal vasculitis is a diagnosis of exclusion. However, patients
without significant risk factors for atherosclerotic vascular disease
require an initial lab and imaging workup. An endoscopic approach is not
recommended due to nonspecific findings and an elevated risk for
perforation. The resolution entails symptomatic treatment and
immunosuppressive agents for the underlying vasculitis.
Keywords: vasculitis, gastrointestinal, takayasu arteritis, giant cell

arteritis, polyarteritis nodosa, Kawasaki disease, behcet’s disease
INTRODUCTION
Vasculitides are a wide array of diseases defined by the international

Chapel Hill Consensus Conference (CHCC) as the presence of
inflammatory leukocytes in vessel walls with resulting damage to
subsequent feeding structures. Ischemia and necrosis often are byproducts
of the loss in vessel integrity and compromise of the lumen patency. It is
with little surprise then that the gastrointestinal system, a combination of
highly vascularized structures, can be impacted either in isolation or in
combination with multiple organs, often resulting in rapidly fatal diseases.
As our understanding of the pathogenesis evolves, the disease names
and definitions of the vasculitides change as well. As discussed earlier, the
international Chapel Hill Consensus Conference is the most widely used
nomenclature system to specify the names and definitions for vasculitis1.
Organized by a standardized classification based upon the predominant
1
John C Jennette et al., “2012 Revised International Chapel Hill Consensus Conference
Nomenclature of Vasculitides,” 2013.
Gastrointestinal Complications of Vasculitis 181
size of vessels involved, vasculitides are broken down into large-vessel,

medium-vessel, small vessel, variable vessel, single organ, vasculitis
associated with systemic disease, and vasculitis associated with probable
etiology. However, it should be kept in mind that in any instance of
vasculitis, there may be a slight overlap in the size of arteries involved.
Since 1994, there have been revisions in the CHCC, with significant
changes occurring in 2012 towards using disease names that describe the
pathophysiologic understanding of the condition rather than the previous
eponyms2. In replacing Churg-Strauss syndrome, now eosinophilic
granulomatosis with polyangiitis is used. In place of Wegener’s
granulomatosis, granulomatosis with polyangiitis is used. In place of
Henoch-Schonlein purpura, immunoglobulin A vasculitis is used.
Hypocomplementemic urticarial vasculitis is now alternatively named
anti-C1q vasculitis. And essential cryoglobulinemic vasculitis is also
known as cryoglobulinemic vasculitis.
The most prevalent vasculitides with gastrointestinal involvement are
immunoglobulin A vasculitis, antineutrophil cytoplasmic autoantibody
associated vasculitis, polyarteritis nodosa, and Behcet syndrome. In
retrospective studies, it was found that at least 31% of patients with
vasculitis suffered from gastrointestinal symptoms, with the leading cause
of death being gastrointestinal bleeding, peritonitis, and pancreatitis3.
Despite vasculitis being classified by the size of involved vessels, the
symptom manifestation is often nonspecific. It can range from abdominal
pain, nausea, vomiting, diarrhea, and/or gross or occult blood in the stool.
Gross bleeding is more often seen in the terminal colon due to location.
Still, it is difficult to clinically determine given some cases of small bowel
vasculitis result in gross bleeding as well. Thus, a diagnosis based solely
on gastrointestinal symptoms is extremely challenging, given these
nonspecific manifestations. Despite improvements in the survival of
patients with vasculitis, due to advances in medical and surgical
2
Cord H Sunderkötter et al., “Nomenclature of Cutaneous Vasculitis: Dermatologic Addendum
to the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of
Vasculitides,” Arthritis & Rheumatology 70, no. 2 (2018): 171–84.
3
L Guillevin et al., “Clinical Findings and Prognosis of Polyarteritis Nodosa and Churg-Strauss
Angiitis: A Study in 165 Patients,” Rheumatology 27, no. 4 (1988): 258–64.
treatments, gastrointestinal manifestations remain a very serious problem.

This chapter focuses on the gastrointestinal manifestations and
management of systemic vasculitides.
LARGE-VESSEL VASCULITIS
Per the CHCC, Takayasu and Giant cell arteritis, also known as
temporal arteritis, comprise this category. As derived from their category,
both predominantly affect the aorta and/or its major primary branches.
While Takayasu can result in extensive pan-aortitis, Giant cell arteritis has
a predilection for the carotid branches, including the superficial temporal
artery. Both vasculitides have women primarily affected; however, with
Takayasu, the age of onset is typically before the age of 30 years, most
predominant in Asians, while Giant cell arteritis has an incidence that
peaks after 70 years and most commonly affects white individuals.
Symptoms related to Takayasu tend to be subacute, often leading to a
delay in diagnosis up to years, which allows for vascular disease to
progress silently. Consequently, the arterial disease is often the first sign
for symptomatic Takayasu, with the most common clinical finding being
an auscultated bruit4. Gastrointestinal involvement is rare in Takayasu
arteritis given primarily aortic involvement. Still, stenosis or occlusions of
the celiac trunk, superior mesenteric artery, or the inferior mesenteric
artery can occur with the subsequent involvement of the small intestine,
large intestine, spleen, or liver. This mesenteric ischemia can result in
gastrointestinal hemorrhage.
Given its predilection for the branches of the carotid, Giant cell
arteritis rarely affects the mesenteric vessels. In addition to this, given the
delayed age of onset, it is often clinically difficult to differentiate
symptoms from atherosclerosis versus vasculitis versus abdominal aortic
aneurysms or dissection. Infarction of the large bowel has been described
4
Gail S Kerr et al., “Takayasu Arteritis,” Annals of Internal Medicine 120, no. 11 (1994): 919–
29.
in rare cases, where the clinical presentation was nonspecific fever with
abdominal pain versus acute abdomen. Even rarer cases have described
tongue necrosis with presenting dysphagia, lingual pain, and swelling as a
byproduct of giant cell arteritis. At least one-third of patients with Giant
cell arteritis are found to have asymptomatic liver enzyme abnormalities,
primarily a markedly elevated alkaline phosphatase, most likely secondary
to injury to the bile duct epithelial cells due to adjacent arteritis5.
Table 1. Vasculitides with gastrointestinal involvement
Vasculitis Gastrointestinal Manifestation

Large-vessel Vasculitides
Takayasu arteritis Occlusions/Stenosis of the aorta and its primary branches resulting
in ischemia
Abdominal bruits
Giant cell arteritis Markedly elevated alkaline phosphatase
Asymptomatic elevated transaminase levels
Medium-vessel Vasculitides
Polyarteritis nodosa Nonspecific abdominal pain
Hepatitis B Virus coinfection
Occlusions of the hepato-splenic vessel system
Kawasaki disease Fever, abdominal pain, vomiting
Pseudo-obstructions on imaging
Self-limited disease
Small-vessel Vasculitides
ANCA-associated Patchy intestinal infarctions, mucosal ulcerations, perforations
vasculitis Granulomatosis with polyangiitis mimics IBD, granulomatous
ulcerations of the large bowel. It can also mimic cancer with
pancreatic lesions
IgA Vasculitis Mucosal purpura w/associated bleeds
Bowel wall edema with resulting infarcts, perforations, or
intussusception
Cryoglobulinemic Intestinal ischemia
Vasculitis Acute pancreatitis
Acute cholecystitis
Behcet disease Ileocecal ulcers that can mimic IBD
Intestinal ischemia most often in the mesenteric vessels
Occlusions of the hepato-splenic vessel system
Glucocorticoids are the mainstay treatment for active Takayasu

arteritis or Giant cell arteritis. However, glucocorticoid dependency with
5
Jason Xu, Einar S Björnsson, and Vinay Sundaram, “Severe Cholestatic Hepatitis Due to Large
Vessel Vasculitis: Report of Two Cases,” Gastroenterology Report 6, no. 1 (2018): 68–71.
relapse remains a common obstacle for management of large vessel

vasculitis with gastrointestinal involvement. Methotrexate remains the first
line glucocorticoid sparing agent, with cyclophosphamide and
mycophenolate mofetil being used in refractory cases6. Tocilizumab seems
to be a more effective treatment for Giant cell arteritis. A few open-label
studies, and small randomized controlled trials showed sustained remission
at one year, with most patients being able to stop the glucocorticoid
treatment7.
MEDIUM-VESSEL VASCULITIS
Kawasaki disease and Polyarteritis nodosa comprise this category.

Kawasaki disease, also termed mucocutaneous lymph node syndrome
is one of the most common vasculitides of childhood, only rarely occurring
in adults, and therefore can be clinically difficult to work up. Lasting on
average 12 days without therapy, it is typically a harmless self-limited
condition8. Patients with gastrointestinal involvement usually present
pseudo-obstruction on a wide array of radiological studies, including plain
radiographs, ultrasonography, and computed tomography. Patients
classically present with fever, abdominal pain, and vomiting. These
symptoms can often delay the diagnosis of Kawasaki disease by causing
unnecessary invasive investigative procedures such as surgery and/or
endoscopy9.
6
Medha Soowamber, Adam V Weizman, and Christian Pagnoux, “Gastrointestinal Aspects of
Vasculitides,” Nature Reviews Gastroenterology & Hepatology 14, no. 3 (2017): 185–94.
7
Peter M Villiger et al., “Tocilizumab for Induction and Maintenance of Remission in Giant Cell
Arteritis: A Phase 2, Randomised, Double-Blind, Placebo-Controlled Trial,” The Lancet
387, no. 10031 (2016): 1921–27.
8
Brian W McCrindle et al., “Diagnosis, Treatment, and Long-Term Management of Kawasaki
Disease: A Scientific Statement for Health Professionals from the American Heart
Association,” Circulation 135, no. 17 (2017): e927–99.
9
Claudia Colomba et al., “Intestinal Involvement in Kawasaki Disease,” The Journal of
Pediatrics 202 (2018): 186–93.
Polyarteritis nodosa involves the medium-sized muscular arteries with

occasional case reports of involvement of small muscular arteries. The
largest risk factor for polyarteritis nodosa is hepatitis B virus infection,
with higher incidence rates observed in endemic regions due to infection
or without vaccination. Nonspecific abdominal pain with varying
intensities is the characteristic presentation, most likely secondary to
transmural necrotizing inflammation of the mesenteric vessels, which
causes small bowel ischemia10. Occlusion of the hepato-splenic vessel
system, Budd-Chiari syndrome, can also be seen with polyarteritis nodosa
with resultant liver or splenic infarction. As with any other gastrointestinal
vasculitis, nausea, vomiting, diarrhea, hematochezia, and melena are other
symptoms seen. Upon endoscopic evaluation, jejunal ulcers can be found
in up to 5% of patients with polyarteritis nodosa.
Polyarteritis nodosa has an exceeding good survival rate, and treatment
can be guided using the 1996 Five-Factor Score. In severe forms of non-
HBV gastrointestinal manifestations, treatment should be initiated using
cyclophosphamide, with high dose glucocorticoids followed by
azathioprine or methotrexate after induction11. For non-severe cases,
glucocorticoids alone can achieve sustained remission in up to 50% of
patients12. For cases of HBV-associated vasculitis antiviral therapy should
be enlisted to manage the underlying disease, with glucocorticoids added
on in severe scenarios. Luckily, management of Kawasaki disease is
primarily through aspirin and intravenous immunoglobulin, with repeat
intravenous immunoglobulin infusions for those who do not respond to
initial therapy13.
10
Soowamber, Weizman, and Pagnoux, “Gastrointestinal Aspects of Vasculitides.”
11
Armando De Virgilio et al., “Polyarteritis Nodosa: A Contemporary Overview,” Autoimmunity
Reviews 15, no. 6 (2016): 564–70.
12
Maxime Samson et al., “Long-Term Follow-up of a Randomized Trial on 118 Patients with
Polyarteritis Nodosa or Microscopic Polyangiitis without Poor-Prognosis Factors,”
Autoimmunity Reviews 13, no. 2 (2014): 197–205.
13
Jane W Newburger et al., “Diagnosis, Treatment, and Long-Term Management of Kawasaki
Disease: A Statement for Health Professionals from the Committee on Rheumatic Fever,
Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young,
American Heart Association,” Circulation 110, no. 17 (2004): 2747–71.
SMALL-VESSEL VASCULITIS
ANCA-associated vasculitis, IgA vasculitis, Cryoglobulinemic

vasculitis, and Behcet’s disease compromise this category. Such diseases
typically affect the small vessels, including capillaries, venules, arterioles,
and small arteries.
Antineutrophil cytoplasm antibody (ANCA) associated vasculitides
not only can affect small vessels but also medium-sized arteries as well. It
is further categorized between microscopic polyangiitis, granulomatosis
with polyangiitis, and eosinophilic granulomatosis with polyangiitis.
Marked by the anti-proteinase 3 ANCA, Granulomatosis with
polyangiitis is best known for its involvement of the upper and lower
respiratory tract and kidneys. Any part of the gastrointestinal tract can
reflect involvement; however, the small intestine and lower bowels are
most affected. As high as 11% of patients with granulomatosis with
polyangiitis present with active clinical gastrointestinal symptoms.
However, as many as 24% of cases show gastrointestinal involvement on
autopsy14,15. Such symptoms range from transient abdominal pain with
ulcerations to bloody diarrhea and intestinal perforations. Imaging is
typically nonspecific, and endoscopic evaluation reveals only shallow
transversely oriented ulcerations sometimes described as granulomatous,
as well as generalized ischemic changes noted.
Microscopic polyangiitis, more commonly seen in Asian populations,
presents with gastrointestinal manifestations in up to 30 percent of patients.
Unlike its counterparts, granulomatous inflammation is typically absent,
and it is marked by its ANCA activity against myeloperoxidase. Alongside
the typical abdominal pain, nausea, vomiting, and diarrhea, in rare cases,
14
Christian Pagnoux et al., “Presentation and Outcome of Gastrointestinal Involvement in
Systemic Necrotizing Vasculitides: Analysis of 62 Patients with Polyarteritis Nodosa,
Microscopic Polyangiitis, Wegener Granulomatosis, Churg-Strauss Syndrome, or
Rheumatoid Arthritis-Associated Vasculitis,” Medicine 84, no. 2 (2005): 115–28.
15
Sami Akbulut, “Multiple Ileal Perforations in a Patient with Wegener’s Granulomatosis: A
Case Report and Literature Review,” Journal of Gastrointestinal Surgery 16, no. 4 (2012):
857–62.
colonic ischemic ulcers, peritonitis, and bowel perforations can also be

seen16.
In patients with Eosinophilic granulomatosis with polyangiitis, up to
23% of patients developed gastrointestinal involvement upon a
retrospective cohort review17. Typically associated with late-onset asthma,
eosinophilia, or skin purpura, diagnosis is difficult to make. Very rarely do
patients have detectable serum ANCAs, and there is ANCA activity
against myeloperoxidase when present. Mesenteric artery vasculitis is the
most common explanation for gastrointestinal manifestations in
Eosinophilic granulomatosis with polyangiitis, leading to bowel infarcts
and perforations within the small intestine. Eosinophilic infiltration into
the gastrointestinal tract can elicit pain, motility disorders, and
obstructions. Such infiltrations can result in ulcer formations which are
primary sources of bleeding within the tract. In rare cases, Eosinophilic
granulomatosis with polyangiitis has been found to present with IBD.
IgA vasculitis is most commonly seen in children prior to the age of
10 years. 75% of patients with IgA vasculitis have gastrointestinal
manifestations, with most manifestations being self-limited. Colicky
abdominal postprandial pain is one of the most common presentations with
IgA vasculitis, followed by gastrointestinal bleeding from mucosal and
submucosal vasculitis. Endoscopic evaluation often reveals petechial
lesions, diffuse mucosal redness, and hemorrhagic erosions. Most
interestingly, the extent of skin purpura to the upper extremities has been
found to be associated with an increased risk of gastrointestinal bleeding18.
Cryoglobulinemic vasculitis is hallmarked by cryoglobulins, which
are circulating immunoglobulins that precipitate at temperatures below
16
Pagnoux et al., “Presentation and Outcome of Gastrointestinal Involvement in Systemic
Necrotizing Vasculitides: Analysis of 62 Patients with Polyarteritis Nodosa, Microscopic
Polyangiitis, Wegener Granulomatosis, Churg-Strauss Syndrome, or Rheumatoid Arthritis-
Associated Vasculitis.”
17
C Comarmond et al., “Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss):
Clinical Characteristics and Long-Term Followup of the 383 Patients Enrolled in the
French Vasculitis Study Group Cohort,” Arthritis Rheum. 65, no. 1 (August 2013),
18
Eon Jeong Nam et al., “Gastrointestinal Bleeding in Adult Patients with Henoch–Schönlein
Purpura,” Endoscopy 46, no. 11 (2014): 981–86.
37C and dissolve upon rewarming. Given such temperature restraints,

there is difficulty with obtaining accurate laboratory detection. There are
three subtypes of cryoglobulins: Type 1, Type II, and Type III as shown in
Table 2.
Given technical difficulties assessing cryoglobulins, an isolated
hypocomplementemia of C4 with a positive rheumatoid factor strongly
suggests the presence of cryoglobulins. HCV infection is the leading cause
for cryoglobulinemia, with up to 50% of patients infected with HCV,
having circulating cryoglobulins19. Gastrointestinal involvement with
Cryoglobulinemic vasculitis is associated with high morbidity, given
symptoms ranging from abdominal pain and bloody stools to intestinal
perforations and intestinal ischemia. HCV patients with Cryoglobulinemic
vasculitis often show progression to cirrhosis, with hepatocellular
carcinoma seen less frequently than those without. Treatment is often
pointed towards the underlying disorder either with antivirals for HCV
infection, lymphoma-directed therapies, etc.
Table 2. Types of Cryoglobulins
Types Monoclonal Polyclonal Associated diseases

Type I Monoclonal IgG or - Lymphoproliferative
IgM disorders
Type II (MC) Monoclonal IgM Polyclonal IgG HCV, autoimmune
disorders,
lymphoproliferative
disorders
Type III (MC) - Polyclonal IgG and Infectious disease (HCV)
IgM
MC = Mixed Cryoglobulinemia; HCV = Hepatitis C Virus
As one can see, severe gastrointestinal involvement is more prevalent

in small-vessel vasculitis, ranging from bleeding, perforation, pancreatitis,
and thus more associated with poor outcomes20. Milder manifestations
19
Franco Dammacco et al., “The Expanding Spectrum of HCV-Related Cryoglobulinemic
Vasculitis: A Narrative Review,” Clinical and Experimental Medicine 16, no. 3 (2016):
233–42.
20
Loïc Guillevin et al., “Treatment of Polyarteritis Nodosa and Microscopic Polyangiitis with
Poor Prognosis Factors: A Prospective Trial Comparing Glucocorticoids and Six or Twelve
include protein-losing enteropathy, cholecystitis, and appendicitis. Such

patients suspected to have severe gastrointestinal disease must receive
glucocorticoids combined with a secondary immunosuppressant. In
addition to urgent medical therapy, surgery is sometimes required
depending on the severity of involvement.
VARIABLE-VESSEL VASCULITIS
Comprised of Behcet’s disease and Cogan syndrome. These

vasculitides affect any vessel of any size within the venous or arterial
circulation.
Behcet’s disease is best known for its recurrent oral and/or genital
aphthous ulcers, most commonly seen within Asian and Mediterranean
regions. It is most interesting that through a cross-sectional cohort
comparison, the frequency of gastrointestinal involvement varied from
32% in Taiwan, 50-60% in Japan, 37-43% in the USA, and 2.8% in
Turkey. Clinical symptoms varied from general vomiting, dyspepsia,
diarrhea, melena, and severe anorexia or abdominal pain with perforations
requiring surgical intervention21. Two forms of intestinal Behcet’s disease
can be distinguished: mucosal ulcers secondary to neutrophilic infiltrations
that mimic IBD and intestinal ischemia with infarction due to large-vessel
vasculitis, most notably the mesenteric vessels. While any part of the
gastrointestinal tract can be involved, by nature of the vasculitis, most
typically, the terminal ileum and ileocecal junction are involved. In rare
instances, occlusion of the vena cava can result in esophageal varices22.
Three types of ulcers have been related to Behcet’s disease, the first being
Cyclophosphamide Pulses in Sixty‐five Patients,” Arthritis Care & Research: Official

Journal of the American College of Rheumatology 49, no. 1 (2003): 93–100.
21
Cailin Sibley et al., “Behcet Syndrome Manifestations and Activity in the United States versus
Turkey—a Cross-Sectional Cohort Comparison,” The Journal of Rheumatology 41, no. 7
(2014): 1379–84.
22
Hiroshi Orikasa et al., “A Case of Behçet’s Disease with Occlusion of Both Caval Veins and
‘Downhill’ Esophageal Varices,” Journal of Gastroenterology 29, no. 4 (1994): 506–10.
volcano ulcers, which have the highest risk for perforation, followed by
geographic and aphthous ulcers.
The primary foundation for Behcet’s disease management is
colchicine; however this only addresses oral and genital ulcers. A wide
array of medical management can be employed for gastrointestinal
manifestations, such as glucocorticoids, sulfasalazine, azathioprine,
cyclophosphamide, or even infliximab. In cases of perforation, of course,
surgery is required for repair.
SINGLE-ORGAN VASCULITIS
Isolated gastrointestinal single-organ vasculitis has been reported in a

wide array of organs associated with the gastrointestinal tract, including
the esophagus, stomach, small intestine, large intestine, gallbladder,
appendix, and pancreas. 67% of patients in a small case series presented
with acute abdomen requiring surgical intervention, suggesting possible
diagnostic bias23. For the most part, most cases of gastrointestinal single
organ vasculitis resolve after excision without the need for
immunosuppressive therapy24.
VASCULITIS ASSOCIATED WITH SYSTEMIC DISEASE
This category is broken down into rheumatoid vasculitis and systemic

lupus erythematosus. Patients with longstanding erosive rheumatoid
arthritis often develop rheumatoid vasculitis. While common on autopsy
reports, the development of rheumatoid vasculitis is an extremely rare
condition. Typically presents as mesenteric ischemia.
23
Carlo Salvarani et al., “Localized Vasculitis of the Gastrointestinal Tract: A Case Series,”
Rheumatology 49, no. 7 (2010): 1326–35.
24
Salvarani et al.
Vasculitis associated with systemic lupus erythematosus often impacts

small and medium-sized vessels and, therefore, the gastrointestinal system.
Intermittent abdominal pain alongside nausea, vomiting, diarrhea, fever
and gastrointestinal bleeding is often the heralding sign for vasculitis
associated with systemic lupus erythematosus.
As discussed above, typical presentations for vasculitis involving the

gastrointestinal tract are primarily secondary to mesenteric ischemia
and/or ischemic colitis with resulting infarction. Often it is challenging to
determine the clinical signs of vasculitis with ischemia vs. infarction due
to nonspecific symptoms. A low flow state within the vasculature results
in abdominal pain, either acute or chronic, with even the potential for
postprandial abdominal pain and weight loss to occur as well. Nausea,
vomiting, and diarrhea are very common generalized symptoms as well.
More specific presentations include obstruction secondary to strictures,
intussusception from edema and/or hemorrhage, massive gastrointestinal
bleeds as described above, or thrombus formation that results in bowel
ischemia or hepatic ischemia.
The signs of ischemic colitis secondary to vasculitis are no different
from ischemic colitis caused by other etiologies, presenting with red flags
such as abdominal pain with tenderness over the affected bowel, rectal
bleeding, and generalized hemodynamic instability.
Acute mesenteric ischemia, either acute or chronic, is possibly the
most alarming issue associated with gastrointestinal vasculitis. Often
presenting with pain out of proportion to the abdominal examination,
infarction results in perforation, which results in peritonitis and can quickly
require surgical interventions.
DIAGNOSTIC EVALUATION
Gastrointestinal vasculitis should be considered a diagnosis of

exclusion and is to be suspected in any patient with clinical features of
abdominal ischemia without any history or evidence to support the source
of symptoms. In this setting, the absence of atherosclerotic risk factors
without an established diagnosis of vasculitis should lead to further
diagnostic workup. With no known history of vasculitis, dominating
gastrointestinal symptoms warrants additional testing, including
laboratory workup, vascular imaging, and possibly endoscopy.
A broad approach should be taken for laboratory workup; a complete
blood count, blood cultures, serum lactate, liver chemistry panel,
serologies for viral hepatitis, serum cryoglobulins, serum creatinine, and
urinalysis with sediment should be initially evaluated to help establish the
extent of organ involvement. Often erythrocyte sedimentation rate and C-
reactive protein are included in the workup, but there is insufficient
evidence to support its use case in evaluation for gastrointestinal vasculitis;
this is predominantly up to the Clinicians’ clinical judgment. Similarly,
specific serologic testing may aid in the diagnosis when underlying
vasculitis is unknown, although it is not always necessary in the
preliminary workup.
The preferred imaging technique is computed tomography
angiography of the abdomen with intravenous contrast, as it provides a
detailed survey of the abdominal anatomy to suggest different pathologies.
Endoscopic evaluation is typically not necessary, and in fact, is usually
nonspecific. Biopsies rarely help confirm a diagnosis of vasculitis; in fact,
in one retrospective cohort study, only 5% of patients with known
gastrointestinal vasculitis were positively diagnosed on their biopsy
samples25. This is mostly in part to the fact that biopsies taken
endoscopically are almost never deep enough to sample blood vessels.
Endoscopy’s main use case is to eliminate other diagnoses by evaluating
25
Eun Jeong Gong et al., “Endoscopic Findings of Upper Gastrointestinal Involvement in
Primary Vasculitis,” Gut and Liver 10, no. 4 (2016): 542.
the gross mucosa for findings suggestive of ischemia. However, these

findings places endoscopy procedure at high risk and should be
approached with caution due to the risk of perforation. Air insufflation
should be kept to a minimum to avoid unnecessary distension.
TREATMENT AND MANAGEMENT
There have been significant advances in immunosuppressive

medications and surgical management of vasculitides. However, it remains
a challenging diagnosis as clinical decompensation can occur swiftly.
Overall, there are two major means of managing gastrointestinal vasculitis:
treating the underlying vasculitis with immunosuppressive agents and
symptomatic management of gastrointestinal symptoms.
Glucocorticoids are the mainstay immunosuppressive treatment for
most gastrointestinal vasculitides, often requires high-dose induction pulse
given their cost advantage when compared to other newer market
immunosuppressives. However, one must always keep in mind that patient
glucocorticoid-dependency and relapse can be challenging and concerning
during the tapering process once the patient is out of the acute phase
period26,2728. For this reason, there has been recent research into
glucocorticoid-sparing immunosuppressive agents such as methotrexate,
cyclophosphamide, mycophenolate mofetil, and anti-TNF agents, as
currently they are indicated in refractory cases but are encouraged to be
started as a co-agent in most clinical cases. On a case-by-case basis,
endoscopic and surgical procedures maybe necessary when clinically
warranted, such as in episodes of secondary mesenteric ischemia. In rare
cases, such as proven Kawasaki disease or Cryoglobulinemic vasculitis,
one can get away with more specific treatment modalities that address the
26
Soowamber, Weizman, and Pagnoux, “Gastrointestinal Aspects of Vasculitides.”
27
Soowamber, Weizman, and Pagnoux.
28
Gary S Hoffman et al., “Treatment of Glucocorticoid‐resistant or Relapsing Takayasu Arteritis
with Methotrexate,” Arthritis & Rheumatism 37, no. 4 (1994): 578–82.
originating disease, either with aspirin and immunoglobulin therapy vs.

hepatitis C or B virus treatment regiments respectively.
CONCLUSION
Gastrointestinal manifestations in systemic vasculitides are a broad-

spectrum topic with many differing symptoms that make it challenging for
a clinician. As with the aforementioned diseases, abdominal pain can often
be an early heralding sign of an increasingly dangerous presentation. In
patients with known systemic vasculitis, the clinician should always be
wary and monitor as even the mildest presenting symptom can be occult
sign of something more sinister. The diagnosis of vasculitis is challenging
in patients with underlying undiagnosed vasculitis, however, once a
diagnosis is established, treatments must be started promptly with
immunosuppressants and symptomatic management, and sometimes even
surgical or endoscopic interventions if indicated. Despite changes within
the last few decades, morbidity and mortality associated with severe
gastrointestinal manifestations remain high. Within an inpatient setting,
effective management of vasculitis and its gastrointestinal manifestations
require close interdisciplinary collaboration from all specialists.
REFERENCES
Akbulut, Sami. “Multiple Ileal Perforations in a Patient with Wegener’s

Granulomatosis: A Case Report and Literature Review.” Journal of
Gastrointestinal Surgery, 16, no. 4, (2012), 857–62.
Colomba, Claudia, Simona La Placa, Laura Saporito, Giovanni Corsello,
Francesco Ciccia, Alice Medaglia, Benedetta Romanin, Nicola Serra,
Paola Di Carlo, Antonio Cascio. “Intestinal Involvement in Kawasaki
Disease.” The Journal of Pediatrics, 202, (2018), 186–93.
Comarmond, C; Pagnoux, C; Khellaf, M; Cordier, JF; Hamidou, M;

Viallard, JF; Maurier, F; et al. “Eosinophilic Granulomatosis with
Polyangiitis (Churg-Strauss): Clinical Characteristics and Long-Term
Followup of the 383 Patients Enrolled in the French Vasculitis Study
Group Cohort.” Arthritis Rheum., 65, no. 1 (August 2013).
Dammacco, Franco, Vito Racanelli, Sabino Russi, Domenico Sansonno.
“The Expanding Spectrum of HCV-Related Cryoglobulinemic
Vasculitis: A Narrative Review.” Clinical and Experimental Medicine,
16, no. 3, (2016), 233–42.
Gong, Eun Jeong, Joo Hyun Chun Do Hoon Kim, Ji Yong Ahn, Kwi-Sook
Choi, Kee Wook Jung, Jeong Hoon Lee, Kee Don Choi, Ho June Song,
Gin Hyug Lee, Hwoon-Yong Jung. “Endoscopic Findings of Upper
Gastrointestinal Involvement in Primary Vasculitis.” Gut and Liver,
10, no. 4, (2016), 542.
Guillevin, L; Huong Du, LETHI; Godeau, P; Jais, Ph, Wechsler, B.
“Clinical Findings and Prognosis of Polyarteritis Nodosa and Churg-
Strauss Angiitis: A Study in 165 Patients.” Rheumatology, 27, no. 4,
(1988), 258–64.
Guillevin, Loïc, Pascal Cohen, Alfred Mahr, Jean‐Pierre Arène, Luc
Mouthon, Xavier Puéchal, Edouard Pertuiset, Brigitte Gilson,
Mohamed Hamidou, Patricia Lanoux. “Treatment of Polyarteritis
Nodosa and Microscopic Polyangiitis with Poor Prognosis Factors: A
Prospective Trial Comparing Glucocorticoids and Six or Twelve
Cyclophosphamide Pulses in Sixty‐five Patients.” Arthritis Care &
Research: Official Journal of the American College of Rheumatology,
49, no. 1, (2003), 93–100.
Hoffman, Gary S; Randi Y Leavitt, Gail S Kerr, Menachem Rottem,
Michael C Sneller, Anthony S Fauci. “Treatment of Glucocorticoid‐
resistant or Relapsing Takayasu Arteritis with Methotrexate.” Arthritis
& Rheumatism, 37, no. 4, (1994), 578–82.
Jennette, John C; Falk, RJ; Bacon, PA; Basu, N; Cid, MC; Ferrario, F;
Flores-Suarez, LF; Gross, WL; Guillevin, L; Hagen, EC 2012 Revised
International Chapel Hill Consensus Conference Nomenclature of

Vasculitides, 2013.
Kerr, Gail S; Claire W Hallahan, Joseph Giordano, Randi Y Leavitt,
Anthony S Fauci, Menachem Rottem, Gary S Hoffman. “Takayasu
Arteritis.” Annals of Internal Medicine, 120, no. 11, (1994), 919–29.
McCrindle, Brian W; Anne H Rowley, Jane W Newburger, Jane C Burns,
Anne F Bolger, Michael Gewitz, Annette L Baker, Mary Anne
Jackson, Masato Takahashi, Pinak B Shah. “Diagnosis, Treatment, and
Long-Term Management of Kawasaki Disease: A Scientific Statement
for Health Professionals from the American Heart Association.”
Circulation, 135, no. 17, (2017), e927–99.
Nam, Eon Jeong, Gun Woo Kim, Jong Wan Kang, Churl Hyun Im, Seong
Woo Jeon, Chang-Min Cho, Ji Yun Jeong, Ji Young Park, Yun Jin
Jang, Young Mo Kang. “Gastrointestinal Bleeding in Adult Patients
with Henoch–Schönlein Purpura.” Endoscopy, 46, no. 11, (2014),
981–86.
Newburger, Jane W; Masato Takahashi, Michael A Gerber, Michael H
Gewitz, Lloyd Y Tani, Jane C Burns, Stanford T Shulman, Ann F
Bolger, Patricia Ferrieri, Robert S Baltimore. “Diagnosis, Treatment,
and Long-Term Management of Kawasaki Disease: A Statement for
Health Professionals from the Committee on Rheumatic Fever,
Endocarditis and Kawasaki Disease, Council on Cardiovascular
Disease in the Young, American Heart Association.” Circulation, 110,
no. 17, (2004), 2747–71.
Orikasa, Hiroshi, Yutaka Ejiri, Shuzo Suzuki, Hidemasa Ishikawa,
Masayuki Miyata, Katsutoshi Obara, Tomoe Nishimaki, Reiji
Kasukawa. “A Case of Behçet’s Disease with Occlusion of Both Caval
Veins and ‘Downhill’ Esophageal Varices.” Journal of
Gastroenterology, 29, no. 4, (1994), 506–10.
Pagnoux, Christian, Alfred Mahr, Pascal Cohen, Loïc Guillevin.
“Presentation and Outcome of Gastrointestinal Involvement in
Systemic Necrotizing Vasculitides: Analysis of 62 Patients with
Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener
Granulomatosis, Churg-Strauss Syndrome, or Rheumatoid Arthritis-

Associated Vasculitis.” Medicine, 84, no. 2, (2005), 115–28.
Salvarani, Carlo, Kenneth T Calamia, Cynthia S Crowson, Dylan V Miller,
Aaron W Broadwell, Gene G Hunder, Eric L Matteson, Kenneth J
Warrington. “Localized Vasculitis of the Gastrointestinal Tract: A
Case Series.” Rheumatology, 49, no. 7, (2010), 1326–35.
Samson, Maxime, Xavier Puéchal, Herve Devilliers, Camillo Ribi, Pascal
Cohen, Boris Bienvenu, Marc Ruivard, Benjamin Terrier, Christian
Pagnoux, Luc Mouthon. “Long-Term Follow-up of a Randomized
Trial on 118 Patients with Polyarteritis Nodosa or Microscopic
Polyangiitis without Poor-Prognosis Factors.” Autoimmunity Reviews,
13, no. 2, (2014), 197–205.
Sibley, Cailin, Yusuf Yazici, Koray Tascilar, Nafiz Khan, Yasmin Bata,
Hasan Yazici, Raphaela Goldbach-Mansky, Gulen Hatemi. “Behcet
Syndrome Manifestations and Activity in the United States versus
Turkey—a Cross-Sectional Cohort Comparison.” The Journal of
Rheumatology, 41, no. 7, (2014), 1379–84.
Soowamber, Medha, Adam V Weizman, Christian Pagnoux.
“Gastrointestinal Aspects of Vasculitides.” Nature Reviews
Gastroenterology & Hepatology, 14, no. 3, (2017), 185–94.
Sunderkötter, Cord H; Bernhard Zelger, Ko‐Ron Chen, Luis Requena,
Warren Piette, J Andrew Carlson, Jan Dutz, Peter Lamprecht, Alfred
Mahr, Elisabeth Aberer. “Nomenclature of Cutaneous Vasculitis:
Dermatologic Addendum to the 2012 Revised International Chapel
Hill Consensus Conference Nomenclature of Vasculitides.” Arthritis
& Rheumatology, 70, no. 2, (2018), 171–84.
Villiger, Peter M, Sabine Adler, Stefan Kuchen, Felix Wermelinger, Diana
Dan, Veronika Fiege, Lukas Bütikofer, Michael Seitz, Stephan
Reichenbach. “Tocilizumab for Induction and Maintenance of
Remission in Giant Cell Arteritis: A Phase 2, Randomised, Double-
Blind, Placebo-Controlled Trial.” The Lancet, 387, no. 10031, (2016),
1921–27.
Virgilio, Armando De, Antonio Greco, Giuseppe Magliulo, Andrea Gallo,

Giovanni Ruoppolo, Michela Conte, Salvatore Martellucci, Marco De
Vincentiis. “Polyarteritis Nodosa: A Contemporary Overview.”
Autoimmunity Reviews, 15, no. 6, (2016), 564–70.
Xu, Jason, Einar S Björnsson, Vinay Sundaram. “Severe Cholestatic
Hepatitis Due to Large Vessel Vasculitis: Report of Two Cases.”
Gastroenterology Report, 6, no. 1, (2018), 68–71.
Chapter 7
HYPOCOMPLEMENTIC URTICARIAL
VASCULITIS SYNDROME
Kejal Gandhi1, N. Vobugari1 and Salim Surani2,3,*, MD

1
Department of Medicine, Georgetown University/
Medstar Washington Hospital Center, Washington, DC, USA
2
3
ABSTRACT
Hypocomplementemic Urticarial Vasculitis (HUV) is a rare

vasculitis syndrome which was recognized in 2012 and was revised in
the International Chapel Hill Consensus Conference (CHCC). It is
defined as presence of greater than six months of urticaria along with
hypocomplementemia and multi-systemic manifestations such as
recurrent abdominal pain, uveitis, arthralgia and glomerulonephritis. It is
often associated with obstructive pulmonary diseases such as
emphysema, a major source of morbidity and mortality. Diagnosis of
HUV is made by the presence of antibodies against the complement
*
200 Kejal Gandhi, N. Vobugari and Salim Surani
protein 1q and skin biopsy. Histopathologically, it is a small vessel

disease with perivascular infiltration of neutrophils. HUV syndrome is
also associated with systemic lupus erythematosus (SLE) and has
multiple overlapping features. HUV syndrome could also be an initial
presentation of SLE. However, angioedema, COPD, and uveitis are more
common in HUV syndrome compared to SLE. HUV is a benign self-
limited vasculitis but has a considerable morbidity burden. Thus, early
screening of urticaria patients is recommended, especially those having
dyspnea and proteinuria.
Keywords: HUVS, vasculitis, hypocomplementemia, urticarial vasculitis,

skin biopsy
INTRODUCTION
Urticarial vasculitis (UV) is characterized by inflammation of dermal

capillaries and post-capillary venules. UV can be divided into two types
based on complement levels. It is classified as Normocomplemetic
urticarial vasculitis (NUV) and hypocomplementemic urticarial vasculitis
(HUV). NUV is mostly idiopathic, whereas HUV can be either primary or
secondarily associated with systemic diseases such as systemic lupus
erythematosus (SLE), Sjogren’s syndrome, drug hypersensitivity, or
hematologic malignancies. HUV is further classified as HUV syndrome
(HUVS) when urticaria and hypocomplementemia last for more than six
months with multi-organ involvement. HUVS, also known as McDuffe
syndrome, was first described by McDuffe et al. in 4 patients in 1973,
characterized urticaria with persistent hypocomplementemia associated
with systemic manifestations such as angioedema, arthritis,
glomerulonephritis, pulmonary complications, and recurrent abdominal
pain1.
1
George Payerle et al., “Scholar (3),” Annals of Tourism Research, 2015, http://www.
ncbi.nlm.nih.gov/pubmed/25926610%5Cnhttp://www.pubmedcentral.nih.gov/articlerende
r.fcgi?artid=PMC4492060%0Ahttp://www.sciencedirect.com/science/article/pii/S016073
8315000444.
Hypocomplementic Urticarial Vasculitis Syndrome 201
EPIDEMIOLOGY
In patients with chronic urticaria, 5-10% are found to have UV2. The
incidence and prevalence of HUVS are unknown as it is UV’s rare and
severe presentation3. HUVS is found in 7-8% of SLE patients, whereas
54% of HUVS patients are diagnosed with SLE in the follow-up period4.
Most patients are white, with female predominance being eight times than
male5. HUVS has its peak in the fourth decade compared to UV, which is
found to rise in the fifth decade6.
PATHOPHYSIOLOGY
The pathophysiology of HUVS is unclear. In general, urticarial

vasculitis (UV) is implicated by the deposition of immune complexes
formed in the blood into the vasculature wall. An abnormal immune
response results in antigen-autoantibody aggregates, which can deposit in
various body regions such as skin, joints, vessels, and kidney glomeruli,
which can then trigger the complement pathway. UV is a leukocytoclastic
vasculitis that occurs by type III hypersensitivity vasculitis7. The antigen
2
Jeffrey J Wisnieski, “Urticarial Vasculitis,” Current Opinión in Rheumatology 12, no. 1 (2000):
24–31.
3
Luis J Jara et al., “Hypocomplementemic Urticarial Vasculitis Syndrome,” Current
Rheumatology Reports 11, no. 6 (2009): 410.
4
Kenan Aydogan et al., “Hypocomplementemic Urticarial Vasculitis: A Rare Presentation of
Systemic Lupus Erythematosus” (Wiley Online Library, 2006); M D Davis et al.,
“Clinicopathologic Correlation of Hypocomplementemic and Normocomplementemic
Urticarial Vasculitis.,” Journal of the American Academy of Dermatology 38, no. 6 Pt 1
(1998): 899–905.
5
Jeffrey J Wisnieski et al., “Hypocomplementemic Urticarial Vasculitis Syndrome. Clinical and
Serologic Findings in 18 Patients.,” Medicine 74, no. 1 (1995): 24–41.
6
Andrew Buck, Jim Christensen, and Morgan McCarty, “Hypocomplementemic Urticarial
Vasculitis Syndrome: A Case Report and Literature Review,” The Journal of Clinical and
Aesthetic Dermatology 5, no. 1 (January 2012): 36–46, https://pubmed.ncbi.
nlm.nih.gov/22328958.
7
Dana Baigrie et al., “Leukocytoclastic Vasculitis.” (Treasure Island (FL), 2021); Pavel Kolkhir
et al., “Management of Urticarial Vasculitis: A Worldwide Physician Perspective.,” The
World Allergy Organization Journal 13, no. 3 (March 2020): 100107,
https://doi.org/10.1016/j.waojou.2020.100107.
and autoantibodies are identified in few cases (e.g., hepatitis B)8, whereas
in most cases of UV, these are not defined.
Urticaria and UV are identified as continuum processes and classified
based on histopathological criteria into Normocomplementemic Urticarial
Vasculitis (NUV), Hypocomplementemic Urticarial Vasculitis (HUV),
and HUV syndrome (HVUS) with multisystem involvement9. In HVUS, a
collagen-like region on C1q acts as antigen receptor. The IgG autoantibody
that develops against the C1q antigen is termed as C1q preceptin10. The
pathogenesis of these antigens and autoantibodies is still unclear. These
antigen-antibody complexes activate the classical complement cascade by
activating a series of proteins upon forming the immunocomplexes in the
blood. C3 convertase (C4b2b) cleaves the C3. Subsequently, the C3b
component of cleaved C3 binds to C3 convertase (C4b2b) to form the C5
protein. C3a and C5a attract phagocytes to the deposited site by increasing
vascular permeability and releasing proteolytic enzymes leading to tissue
destruction and inflammation. C3a and C5a formed from cleaved C3 and
C5 cause mast cell degranulation resulting in urticarial eruptions. Thus,
activating the classical complement pathway leads to laboratory findings
of low C1q, C4, and variably decreased C3 levels11. The exact mechanism
of pulmonary involvement in HUVS is unclear. It is postulated that anti-
8
J L Dienstag et al., “Urticaria Associated with Acute Viral Hepatitis Type B: Studies of
Pathogenesis.,” Annals of Internal Medicine 89, no. 1 (July 1978): 34–40,
https://doi.org/10.7326/0003-4819-89-1-34.
9
Buck, Christensen, and McCarty, “Hypocomplementemic Urticarial Vasculitis Syndrome: A
Case Report and Literature Review”; R R Jones et al., “Urticaria and Vasculitis: A
Continuum of Histological and Immunopathological Changes.,” The British Journal of
Dermatology 108, no. 6 (June 1983): 695–703, https://doi.org/10.1111/j.1365-2133.
1983.tb01082.x.
10
M Trendelenburg et al., “Hypocomplementemic Urticarial Vasculitis or Systemic Lupus
Erythematosus?,” American Journal of Kidney Diseases : The Official Journal of the
National Kidney Foundation 34, no. 4 (October 1999): 745–51,
https://doi.org/10.1016/S0272-6386(99)70402-6; J J Wisnieski and G B Naff, “Serum IgG
Antibodies to C1q in Hypocomplementemic Urticarial Vasculitis Syndrome.,” Arthritis
and Rheumatism 32, no. 9 (September 1989): 1119–27, https://doi.org/10.1002/anr.
1780320910.
11
Prabhu Nesargikar, B Spiller, and R Chavez, “The Complement System: History, Pathways,
Cascade and Inhibitors,” European Journal of Microbiology and Immunology 2, no. 2
(2012): 103–11; Buck, Christensen, and McCarty, “Hypocomplementemic Urticarial
Vasculitis Syndrome: A Case Report and Literature Review.”
C1q autoantibodies cross-react with surfactants and may be responsible for

the pulmonary involvement in HVUS12.
Binding of collagen like component C1q antigenic protein to IgG auto Anti C1q
antibody leads ro activation of classical complement pathway which results in
activation and release of C3a and C5a. These complements activate the neutrophil
extravasation, increasing vascular permeability and releasing proteolytic enzymes
leading to tissue destruction and inflammation. C3a and C5a formed from cleaved
C3 and C5 cause mast cell degranulation resulting in urticarial eruptions.
Figure 1. Pathogenesis of Hypocomplementemic Urticarial Vasculitis.
Histopathological findings in HUVS are similar to any

leukocytoclastic vasculitis (LCV)13. The deposition of neutrophils and
phagocytes occurs by increased vascular permeability, especially the
postcapillary venules, by injury and swelling of endothelial cells. This
inflammation leads to extravasation of red blood cells, deposition of
fragmented leukocytes with nuclear debris, fibrin deposition in and around
blood vessels. This perivascular infiltrate is composed chiefly of
neutrophils, and fibrinoid deposition leads to direct vessel damage14.
Interestingly, removing immune complexes by plasmapheresis has been
demonstrated to temporarily lead to the resolution of the urticarial lesions.
Another hypothesis is the release of cytokines like IL-1 in the
pathogenesis of UV. The role of IL-1 signaling in disease pathogenesis is
implicated from the excellent treatment response to anakinra (an IL-1
12
Wolfgang Grotz et al., “Hypocomplementemic Urticarial Vasculitis Syndrome: An
Interdisciplinary Challenge,” Deutsches Arzteblatt International 106, no. 46 (November
2009): 756–63, https://doi.org/10.3238/arztebl.2009.0756.
13
Dana Baigrie et al., “Leukocytoclastic Vasculitis,” 2018.
14
Jara et al., “Hypocomplementemic Urticarial Vasculitis Syndrome.”
receptor antagonist)15. Genetic factors are also considered in the

development of HVUS. DNASE1L3 mutations result in loss of function
from nonsense mutation of exon skipping leading to missing functional
protein. DNASE1L3 mutations are identified in HVUS. A different loss of
function mutation in DNASE1L3 is also observed in SLE patients16.
HUVS and Systemic Lupus Erythematous (SLE) have overlapping
features17. The IgG autoantibody, which binds only to the collagen-like
region of Clq, was found in 100% of the HVUS patients and 35% of the
SLE patients, which raises the question of HVUS is, in fact, a subset of
SLE18.
The most prominent clinical finding of HUVS is chronic and recurrent

urticaria. Thus, clinical findings can be divided into cutaneous and extra-
cutaneous manifestations.
Cutaneous Manifestations
Urticarial plaques associated with UV can be characterized as:
15
C Botsios et al., “Non-Complementaemic Urticarial Vasculitis: Successful Treatment with the
IL-1 Receptor Antagonist, Anakinra.,” Scandinavian Journal of Rheumatology (England,
2007), https://doi.org/10.1080/03009740600938647.
16
Z Birsin Ozçakar et al., “DNASE1L3 Mutations in Hypocomplementemic Urticarial Vasculitis
Syndrome.,” Arthritis and Rheumatism 65, no. 8 (August 2013): 2183–89,
17
Trendelenburg et al., “Hypocomplementemic Urticarial Vasculitis or Systemic Lupus
Erythematosus?”
18
J J Wisnieski and S M Jones, “IgG Autoantibody to the Collagen-like Region of Clq in
Hypocomplementemic Urticarial Vasculitis Syndrome, Systemic Lupus Erythematosus,
and 6 Other Musculoskeletal or Rheumatic Diseases.,” The Journal of Rheumatology 19,
no. 6 (June 1992): 884–88.
 They can be found anywhere in the body and do not have any
predilection for legs, like palpable purpura seen in other vasculitis.
 Urticarial wheals in HUVS patients are recurrent lasting for more
than 24 hours and resolves into purpura or hyperpigmentation19.
 In a series of 57 patients in HUV, urticarial lesions were found
both pruritic and painful, whereas general urticaria is more
pruritic20.
 HUVS is associated with angioedema in 50% of patients due to
inflammation involving capillary or postcapillary venules of
deeper layers of dermis and submucosa. Angioedema could be a
presenting symptom for HUVS21.
 On biopsy, UV lesions are have characteristic findings of
leukocytoclastic vasculitis. Immunohistochemistry will
demonstrate complement deposition along with vessel wall or
endothelium, whereas in SLE, patients are typically found to have
deposits along the basal membrane (lupus band)22.
Extra-Cutaneous Manifestations
Joints
Arthralgia and arthritis are the most common presentations of HUVS,
with 50% occurrence accompanying the cutaneous disease.
19
D R Mehregan, M J Hall, and L E Gibson, “Urticarial Vasculitis: A Histopathologic and
Clinical Review of 72 Cases.,” Journal of the American Academy of Dermatology 26, no.
3 Pt 2 (March 1992): 441–48, https://doi.org/10.1016/0190-9622(92)70069-r.
20
Marie Jachiet et al., “The Clinical Spectrum and Therapeutic Management of
Hypocomplementemic Urticarial Vasculitis: Data from a French Nationwide Study of
Fifty-Seven Patients.,” Arthritis & Rheumatology (Hoboken, N.J.) 67, no. 2 (February
2015): 527–34, https://doi.org/10.1002/art.38956.
21
Buck, Christensen, and McCarty, “Hypocomplementemic Urticarial Vasculitis Syndrome: A
Case Report and Literature Review.”
22
Grotz et al., “Hypocomplementemic Urticarial Vasculitis Syndrome: An Interdisciplinary
Challenge.”
Arthralgia is migratory and transient involving joints of hands, elbows,

hands, knees, and ankles. Jaccoud’s arthropathy characterized by typical
deformities of rheumatoid arthritis such as swan-neck deformity, ulnar
deviation, and subluxation without radiologic evidence of joint
destruction, is seen in HUVS. Patients with Jaccoud’s arthropathy are
found to have an increased risk of mitral and aortic valvulopathy, thus
warranting early echocardiographic screening23.
Pulmonary Manifestations
Lungs are involved in 50% of the HUVS patients. COPD is the major
cause of morbidity and mortality in these patients24. Clinically, it can
present as dyspnea, hemoptysis, pleurisy, tracheal stenosis, and coughing.
The most common clinical presentation is either COPD or asthma. Though
smoking has been a confounding factor, HUVS associated emphysema has
lung involvement greater than expected from the level of smoking25.
COPD is also manifested in UV patients who are non-smokers, though
smoking can accelerate the disease process. Pulmonary involvement is
thought to be due to vasculitis causing the neutrophilic release of elastase,
leading to emphysematous changes26. Basilar hyperlucency, an unusual
radiographic finding seen in patients with alpha-1 antitrypsin deficiency,
has also been associated with HUVS27.
23
E Palazzo et al., “Hypocomplementemic Urticarial Vasculitis Syndrome, Jaccoud’s Syndrome,
Valvulopathy: A New Syndromic Combination.,” The Journal of Rheumatology 20, no. 7
(1993): 1236–40.
24
Wisnieski et al., “Hypocomplementemic Urticarial Vasculitis Syndrome. Clinical and
Serologic Findings in 18 Patients.”
25
Grotz et al., “Hypocomplementemic Urticarial Vasculitis Syndrome: An Interdisciplinary
Challenge.”
26
H R Schwartz et al., “Hypocomplementemic Urticarial Vasculitis: Association with Chronic
Obstructive Pulmonary Disease.,” in Mayo Clinic Proceedings, vol. 57, 1982, 231–38.
27
Ziad Ghamra and James K Stoller, “Basilar Hyperlucency in a Patient with Emphysema Due
to Hypocomplementemic Urticarial Vasculitis Syndrome,” Respiratory Care 48, no. 7
(2003): 697–99.
Renal Manifestations
Renal involvement occurs in 50% of HUVS patients and is manifested

as proteinuria and microscopic hematuria28. Histologically, renal biopsy is
non-specific, and findings include proliferative glomerulonephritis, focal
necrotizing vasculitis, crescentic glomerulonephritis, membranous
involvement, and tubulointerstitial nephritis29. The pattern of renal
pathophysiology is indistinguishable for lupus nephritis.
Gastrointestinal Manifestations
Gastrointestinal symptoms are seen in one-third of HUVS patients,

including recurrent abdominal pain, nausea, vomiting, diarrhea thought to
be due to vasculitis involving the GI tract30.
Ocular Manifestations
Approximately 30% of HUVS patients have ophthalmologic

manifestations and present as episcleritis, conjunctivitis, or uveitis31.
28
German Ramirez, Sabiha R Saba, and Luis Espinoza, “Hypocomplementemic Vasculitis and
Renal Involvement,” Nephron 45, no. 2 (1987): 147–50.
29
Marleen Renard, Carine Wouters, and Willem Proesmans, “Rapidly Progressive
Glomerulonephritis in a Boy with Hypocomplementaemic Urticarial Vasculitis,” European
Journal of Pediatrics 157, no. 3 (1998): 243–45; Leah Balsam et al., “Crescentic
Glomerulonephritis Associated with Hypocomplementemic Urticarial Vasculitis
Syndrome,” American Journal of Kidney Diseases 52, no. 6 (2008): 1168–73.
30
Nicholas A Soter, “Urticarial Venulitis,” Dermatologic Therapy 13, no. 4 (2000): 400–408.
31
J M Corwin and J Baum, “Iridocyclitis in Two Patients with Hypocomplementemic Cutaneous
Vasculitis.,” American Journal of Ophthalmology 94, no. 1 (July 1982): 111–13,
https://doi.org/10.1016/0002-9394(82)90202-1.
Cardiovascular Manifestations
Cardiac involvement is rare in HUVS but can have valvulopathy,

especially in patients with joint deformities32.
Neurologic Manifestations
CNS manifestations are again rare but can present as seizures, cranial
nerve palsies, or peripheral neuropathy33. The most common pathology is
pseudotumor cerebri34. However, aseptic meningitis, transverse myelitis
can also occur35.
DIAGNOSIS
Diagnostic criteria for HUVS have been shown in Table 1. The patient
should meet both the significant criteria and at least two minor criteria for
diagnosing HUVS36.
32
L Hong et al., “Atypical Fatal Hypocomplementemic Urticarial Vasculitis with Involvement
of Native and Homograft Aortic Valves in an African American Man.,” The Journal of
Allergy and Clinical Immunology 106, no. 6 (December 2000): 1196–98,
https://doi.org/10.1067/mai.2000.110805.
33
Massimiliano Filosto et al., “Idiopathic Hypocomplementemic Urticarial Vasculitis-Linked
Neuropathy,” Journal of the Neurological Sciences 284, no. 1–2 (2009): 179–81.
34
C L Ludivico, A R Myers, and K Maurer, “Hypocomplementemic Urticarial Vasculitis with
Glomerulonephritis and Pseudotumor Cerebri.,” Arthritis and Rheumatism 22, no. 9
(September 1979): 1024–28, https://doi.org/10.1002/art.1780220912.
35
H Tanaka et al., “Chronic Urticaria Associated with Aseptic Meningitis: An Atypical Urticarial
Vasculitis?,” Acta Paediatrica Japonica : Overseas Edition 39, no. 1 (February 1997): 64–
68, https://doi.org/10.1111/j.1442-200x.1997.tb03558.x; G Bolla et al., “Acute Transverse
Myelitis and Primary Urticarial Vasculitis.,” Clinical Rheumatology 17, no. 3 (1998): 250–
52, https://doi.org/10.1007/BF01451059.
36
Schwartz et al., “Hypocomplementemic Urticarial Vasculitis: Association with Chronic
Obstructive Pulmonary Disease.”
Table 1. Diagnostic Criteria for HUVS syndrome
Major Criteria
Persistent urticaria for more than six months
Hypocomplementemia
Minor Criteria
Dermal vein inflammation (biopsy-proven)
Arthralgia or Arthritis
Mild Glomerulonephritis
Uveitis or episcleritis
Recurrent abdominal pain
Positive C1q precipitin test by immunodiffusion with decreased C1q levels
Schwartz et al. described the diagnostic criteria for HUVS. To meet

the hypocomplementemia criteria, complements should be repeated on two
or more occasions for several months during the disease’s active and
quiescent phase before they are determined to be expected. Exclusion
criteria includes significant cryoglobulinemia, elevated anti-dsDNA titer,
Sm antibodies, hepatitis B viremia, C1 esterase inhibitor deficiency, or
inherited complement deficiency.
Skin biopsy is essential for diagnosis, and microscopic evaluation can
show hallmark findings such as leukocytoclastic vasculitis (LCV), which
is characterized by endothelial disruption, extravasation of erythrocytes,
and fibrin deposition intermixed with interstitial infiltrates consisting of
neutrophils and lymphocytes with occasional eosinophils. In addition to
routine histologic evaluation, the direct immunofluorescent study should
be performed. In HUVS patients, direct immunofluorescence shows
immunoglobulin and complement deposition in the blood vessel wall and
endothelium37.
Initial laboratory evaluation includes complete blood count,
erythrocyte sedimentation rate, complement levels such as C3, C4, C1q
and CH50, urea, serum creatinine, liver function tests, chest radiograph,
37
Mark D P Davis and Jerry D Brewer, “Urticarial Vasculitis and Hypocomplementemic
Urticarial Vasculitis Syndrome,” Immunology and Allergy Clinics 24, no. 2 (2004): 183–
213.
immunoglobulins, and cryoglobulins. Decreased C1q levels due to the

presence of anti-C1q antibodies are characteristic for HUVS38. Other tests
such as anti-double stranded DNA, anti-Sm antibody, anti-SSA/SSB
antibodies, or antiphospholipid antibodies are obtained to rule out
associated diseases. HUVS and SLE have many overlapping features;
however, angioedema, COPD, and uveitis are more common in HUVS
patients. Also, the presence of anti-dsDNA should rule out HUVS39.
HUVS is also known to be associated with hematologic malignancies, such
as Hodgkin and non-Hodgkin lymphomas40.
MANAGEMENT
There is no established treatment guideline for HUVS. Treatment is

based on the severity and degree of systemic involvement.
For patients with only cutaneous manifestations, antihistamines could
provide significant relief from pruritis41, whereas NSAIDs can be used to
manage arthritis/arthralgias42. However, if the systemic disease is present,
more aggressive medications are indicated.
For patients who do not respond to antihistamines and NSAIDs,
systemic glucocorticoids with or without dapsone are typically used as
initial therapy. The initial dose of glucocorticoids is mainly 0.5 to 1
mg/kg/day, adjusted weekly based on the patient’s symptoms and disease
38
R E Berg, G R Kantor, and W F Bergfeld, “Urticarial Vasculitis.,” International Journal of
Dermatology 27, no. 7 (September 1988): 468–72, https://doi.org/10.1111/j.1365-
4362.1988.tb00921.x.
39
Davis and Brewer, “Urticarial Vasculitis and Hypocomplementemic Urticarial Vasculitis
Syndrome.”
40
José María Calvo-Romero, “Diffuse Large B Cell Lymphoma in a Patient with
Hypocomplementemic Urticarial Vasculitis,” Journal of Postgraduate Medicine 49, no. 3
(2003): 252.
41
J P Callen and S Kalbfleisch, “Urticarial Vasculitis: A Report of Nine Cases and Review of
the Literature.,” The British Journal of Dermatology 107, no. 1 (July 1982): 87–93,
https://doi.org/10.1111/j.1365-2133.1982.tb00295.x.
42
Mehregan, Hall, and Gibson, “Urticarial Vasculitis: A Histopathologic and Clinical Review
of 72 Cases.”
activity43. Dapsone is used for patients who develop recurrence with

glucocorticoid taper and is used as initial therapy to maintain remission in
these patients44. Dapsone acts by suppressing the neutrophil activity, which
is described in urticarial pathogenesis. It can reduce the rate of the
progression of lung disease in HUVS if started early in the disease course45.
In HUVS, pentoxifylline has also been shown to act synergistically with
dapsone to provide clinical improvement46. Colchicine and
hydroxychloroquine can also provide symptomatic and serologic
improvement in patients47.
In patients with systemic involvement, higher doses of glucocorticoids
with other immunosuppressive agents have been used. Cyclosporine A has
been effectively used in HUVS patients with renal and pulmonary
involvement48. Azathioprine is also markedly beneficial when used in
combination with prednisone in HUVS patients having renal and
cutaneous manifestations49. Cyclophosphamide and dexamethasone have
been used in refractory cases, whereas mycophenolate mofetil has shown
benefits as monotherapy after initial treatment with glucocorticoids and
cyclophosphamide50.
43
Callen and Kalbfleisch, “Urticarial Vasculitis: A Report of Nine Cases and Review of the
Literature.”
44
Jayne Schiff Fortson et al., “Hypocomplementemic Urticarial Vasculitis Syndrome
Responsive to Dapsone,” Journal of the American Academy of Dermatology 15, no. 5
(1986): 1137–42.
45
Arnold R Eiser et al., “Sustained Dapsone-Induced Remission of Hypocomplementemic
Urticarial Vasculitis: A Case Report,” Angiology 48, no. 11 (1997): 1019–22.
46
W Nürnberg, J Grabbe, and B M Czarnetzki, “Urticarial Vasculitis Syndrome Effectively
Treated with Dapsone and Pentoxifylline.,” Acta Dermato-Venereologica 75, no. 1 (1995):
54–56.
47
L R Lopez et al., “The Hypocomplementemic Urticarial-Vasculitis Syndrome: Therapeutic
Response to Hydroxychloroquine.,” The Journal of Allergy and Clinical Immunology 73,
no. 5 Pt 1 (May 1984): 600–603, https://doi.org/10.1016/0091-6749(84)90518-9.
48
A T Tejani et al., “Cyclosporine A Induced Remission of Relapsing Nephrotic Syndrome in
Children.,” Kidney International 33, no. 3 (March 1988): 729–34, https://doi.org/
10.1038/ki.1988.59; Wisnieski, “Urticarial Vasculitis.”
49
Ramirez, Saba, and Espinoza, “Hypocomplementemic Vasculitis and Renal Involvement.”
50
M Worm, W Sterry, and G Kolde, “Mycophenolate Mofetil Is Effective for Maintenance
Therapy of Hypocomplementaemic Urticarial Vasculitis,” British Journal of Dermatology
143, no. 6 (2000): 1324.
In several patients with HUVS and SLE, refractory to multiple

therapies, rituximab has been used with variable success51. IVIG and
plasma exchange has also been tried in refractory disease without proven
efficacy52.
PROGNOSIS
Patients with hypocomplementemia have more severe disease and

significant morbidity burden and mortality associated with it. However,
the major cause of mortality in COPD and its complications. Rarely, these
patients die due to direct consequences of HUVS, even in the setting of
multi-system involvement53.
CONCLUSION
HUVS has significant morbidity and mortality associated with it.

Thus, early screening of patients with chronic urticaria and mild systemic
symptoms can decrease the rate of disease progression. Hence, a high
suspicion for HUVS from a diagnostic standpoint is essential.
51
R Mallipeddi and C E H Grattan, “Lack of Response of Severe Steroid-Dependent Chronic
Urticaria to Rituximab.,” Clinical and Experimental Dermatology (England, May 2007),
https://doi.org/10.1111/j.1365-2230.2007.02365.x; C Mukhtyar et al., “Refractory
Urticarial Vasculitis Responsive to Anti-B-Cell Therapy.,” The British Journal of
Dermatology (England, February 2009), https://doi.org/10.1111/j.1365-2133.2008.
08990.x.
52
Philippe Grimbert et al., “Renal Transplantation in a Patient with Hypocomplementemic
Urticarial Vasculitis Syndrome,” American Journal of Kidney Diseases 37, no. 1 (2001):
144–48; P Staubach-Renz et al., “[Hypocomplementemic urticarial vasculitis syndrome.
Successful therapy with intravenous immunoglobulins].,” Der Hautarzt; Zeitschrift fur
Dermatologie, Venerologie, und verwandte Gebiete 58, no. 8 (August 2007): 693–97,
https://doi.org/10.1007/s00105-007-1301-5.
53
N P Sanchez et al., “The Clinical and Histopathologic Spectrums of Urticarial Vasculitis:
Study of Forty Cases.,” Journal of the American Academy of Dermatology 7, no. 5
(November 1982): 599–605, https://doi.org/10.1016/s0190-9622(82)70139-2.
REFERENCES
Aydogan, Kenan, Serap Koran Karadogan, Saduman Balaban Adim, and

Şukran Tunali. “Hypocomplementemic Urticarial Vasculitis: A Rare
Presentation of Systemic Lupus Erythematosus.” Wiley Online
Library, 2006.
Baigrie, Dana, Pankaj Bansal, Amandeep Goyal, and Jonathan S Crane.
“Leukocytoclastic Vasculitis.” Treasure Island (FL), 2021.
———. “Leukocytoclastic Vasculitis,” 2018.
Balsam, Leah, Mohammed Karim, Frederick Miller, and Sofia Rubinstein.
“Crescentic Glomerulonephritis Associated with Hypo-
complementemic Urticarial Vasculitis Syndrome.” American Journal
of Kidney Diseases 52, no. 6 (2008): 1168–73.
Berg, R E, G R Kantor, and W F Bergfeld. “Urticarial Vasculitis.”
International Journal of Dermatology 27, no. 7 (September 1988):
468–72. https://doi.org/10.1111/j.1365-4362.1988.tb00921.x.
Bolla, G, P Disdier, D Verrot, L Swiader, L Andrac, J R Harlé, J Pouget,
and P J Weiller. “Acute Transverse Myelitis and Primary Urticarial
Vasculitis.” Clinical Rheumatology 17, no. 3 (1998): 250–52.
https://doi.org/10.1007/BF01451059.
Botsios, C, P Sfriso, L Punzi, and S Todesco. “Non-Complementaemic
Urticarial Vasculitis: Successful Treatment with the IL-1 Receptor
Antagonist, Anakinra.” Scandinavian Journal of Rheumatology.
England, 2007. https://doi.org/10.1080/03009740600938647.
Buck, Andrew, Jim Christensen, and Morgan McCarty.
“Hypocomplementemic Urticarial Vasculitis Syndrome: A Case
Report and Literature Review.” The Journal of Clinical and Aesthetic
Dermatology 5, no. 1 (January 2012): 36–46. https://pubmed.
ncbi.nlm.nih.gov/22328958.
Callen, J P, and S Kalbfleisch. “Urticarial Vasculitis: A Report of Nine
Cases and Review of the Literature.” The British Journal of
Dermatology 107, no. 1 (July 1982): 87–93. https://doi.org/10.
1111/j.1365-2133.1982.tb00295.x.
Calvo-Romero, José María. “Diffuse Large B Cell Lymphoma in a Patient

with Hypocomplementemic Urticarial Vasculitis.” Journal of
Postgraduate Medicine 49, no. 3 (2003): 252.
Corwin, J M, and J Baum. “Iridocyclitis in Two Patients with
Hypocomplementemic Cutaneous Vasculitis.” American Journal of
Ophthalmology 94, no. 1 (July 1982): 111–13. https://doi.org/10.
1016/0002-9394(82)90202-1.
Davis, M D, Mazen S Daoud, Brian Kirby, Lawrence E Gibson, and R S
Rogers 3rd. “Clinicopathologic Correlation of Hypocomplementemic
and Normocomplementemic Urticarial Vasculitis.” Journal of the
American Academy of Dermatology 38, no. 6 Pt 1 (1998): 899–905.
Davis, Mark D P, and Jerry D Brewer. “Urticarial Vasculitis and
Hypocomplementemic Urticarial Vasculitis Syndrome.” Immunology
and Allergy Clinics 24, no. 2 (2004): 183–213.
Dienstag, J L, A R Rhodes, A K Bhan, A M Dvorak, M C Jr Mihm, and J
R Wands. “Urticaria Associated with Acute Viral Hepatitis Type B:
Studies of Pathogenesis.” Annals of Internal Medicine 89, no. 1 (July
1978): 34–40. https://doi.org/10.7326/0003-4819-89-1-34.
Eiser, Arnold R, Parikshit Singh, Harvey M Shanies, and Harvey M
Shanies. “Sustained Dapsone-Induced Remission of
Hypocomplementemic Urticarial Vasculitis: A Case Report.”
Angiology 48, no. 11 (1997): 1019–22.
Filosto, Massimiliano, Tiziana Cavallaro, Giorgio Pasolini, Laura Broglio,
Marta Tentorio, Mariasofia Cotelli, Sergio Ferrari, and Alessandro
Padovani. “Idiopathic Hypocomplementemic Urticarial Vasculitis-
Linked Neuropathy.” Journal of the Neurological Sciences 284, no. 1–
2 (2009): 179–81.
Fortson, Jayne Schiff, John J Zone, M Elizabeth Hammond, and Gerald C
Groggel. “Hypocomplementemic Urticarial Vasculitis Syndrome
Responsive to Dapsone.” Journal of the American Academy of
Dermatology 15, no. 5 (1986): 1137–42.
Ghamra, Ziad, and James K Stoller. “Basilar Hyperlucency in a Patient
with Emphysema Due to Hypocomplementemic Urticarial Vasculitis
Syndrome.” Respiratory Care 48, no. 7 (2003): 697–99.
Grimbert, Philippe, Klaus Schulte, Claude Buisson, Dominique Desvaux,

Christophe Baron, Myriam Pastural, Djamel Dhamane, Philippe
Remy, Bertrand Weil, and Philippe Lang. “Renal Transplantation in a
Patient with Hypocomplementemic Urticarial Vasculitis Syndrome.”
American Journal of Kidney Diseases 37, no. 1 (2001): 144–48.
Grotz, Wolfgang, Hideo A Baba, Jan U Becker, and Martin W Baumgärtel.
“Hypocomplementemic Urticarial Vasculitis Syndrome: An
Interdisciplinary Challenge.” Deutsches Arzteblatt International 106,
no. 46 (November 2009): 756–63. https://doi.org/10.3238/
arztebl.2009.0756.
Hong, L, F Wackers, M Dewar, M Kashgarian, and P W Askenase.
“Atypical Fatal Hypocomplementemic Urticarial Vasculitis with
Involvement of Native and Homograft Aortic Valves in an African
American Man.” The Journal of Allergy and Clinical Immunology
106, no. 6 (December 2000): 1196–98. https://doi.org/10.1067/mai.
2000.110805.
Jachiet, Marie, Béatrice Flageul, Alban Deroux, Alain Le Quellec,
François Maurier, Florence Cordoliani, Pascal Godmer, et al. “The
Clinical Spectrum and Therapeutic Management of
Hypocomplementemic Urticarial Vasculitis: Data from a French
Nationwide Study of Fifty-Seven Patients.” Arthritis & Rheumatology
(Hoboken, N.J.) 67, no. 2 (February 2015): 527–34.
Jara, Luis J, Carmen Navarro, Gabriela Medina, Olga Vera-Lastra, and
Miguel A Saavedra. “Hypocomplementemic Urticarial Vasculitis
Syndrome.” Current Rheumatology Reports 11, no. 6 (2009): 410.
Jones, R R, B Bhogal, A Dash, and J Schifferli. “Urticaria and Vasculitis:
A Continuum of Histological and Immunopathological Changes.” The
British Journal of Dermatology 108, no. 6 (June 1983): 695–703.
https://doi.org/10.1111/j.1365-2133.1983.tb01082.x.
Kolkhir, Pavel, Hanna Bonnekoh, Emek Kocatürk, Michihiro Hide, Martin
Metz, Mario Sánchez-Borges, Karoline Krause, and Marcus Maurer.
“Management of Urticarial Vasculitis: A Worldwide Physician
Perspective.” The World Allergy Organization Journal 13, no. 3
(March 2020): 100107. https://doi.org/10.1016/j.waojou. 2020.

100107.
Lopez, L R, K C Davis, P F Kohler, and A L Schocket. “The
Hypocomplementemic Urticarial-Vasculitis Syndrome: Therapeutic
Response to Hydroxychloroquine.” The Journal of Allergy and
Clinical Immunology 73, no. 5 Pt 1 (May 1984): 600–603.
https://doi.org/10.1016/0091-6749(84)90518-9.
Ludivico, C L, A R Myers, and K Maurer. “Hypocomplementemic
Urticarial Vasculitis with Glomerulonephritis and Pseudotumor
Cerebri.” Arthritis and Rheumatism 22, no. 9 (September 1979): 1024–
28. https://doi.org/10.1002/art.1780220912.
Mallipeddi, R, and C E H Grattan. “Lack of Response of Severe Steroid-
Dependent Chronic Urticaria to Rituximab.” Clinical and
Experimental Dermatology. England, May 2007. https://doi.org/10.
1111/j.1365-2230.2007.02365.x.
Mehregan, D R, M J Hall, and L E Gibson. “Urticarial Vasculitis: A
Histopathologic and Clinical Review of 72 Cases.” Journal of the
American Academy of Dermatology 26, no. 3 Pt 2 (March 1992): 441–
48. https://doi.org/10.1016/0190-9622(92)70069-r.
Mukhtyar, C, S Misbah, J Wilkinson, and P Wordsworth. “Refractory
Urticarial Vasculitis Responsive to Anti-B-Cell Therapy.” The British
Journal of Dermatology. England, February 2009. https://doi.org/
10.1111/j.1365-2133.2008.08990.x.
Nesargikar, Prabhu, B Spiller, and R Chavez. “The Complement System:
History, Pathways, Cascade and Inhibitors.” European Journal of
Microbiology and Immunology 2, no. 2 (2012): 103–11.
Nürnberg, W, J Grabbe, and B M Czarnetzki. “Urticarial Vasculitis
Syndrome Effectively Treated with Dapsone and Pentoxifylline.” Acta
Dermato-Venereologica 75, no. 1 (1995): 54–56.
Ozçakar, Z Birsin, Joseph 2nd Foster, Oscar Diaz-Horta, Ozgur
Kasapcopur, Yao-Shan Fan, Fatoş Yalçınkaya, and Mustafa Tekin.
“DNASE1L3 Mutations in Hypocomplementemic Urticarial
Vasculitis Syndrome.” Arthritis and Rheumatism 65, no. 8 (August
2013): 2183–89. https://doi.org/10.1002/art.38010.
Palazzo, E, P Bourgeois, O Meyer, M De Bandt, M Kazatchkine, and M F

Kahn. “Hypocomplementemic Urticarial Vasculitis Syndrome,
Jaccoud’s Syndrome, Valvulopathy: A New Syndromic
Combination.” The Journal of Rheumatology 20, no. 7 (1993): 1236–
40.
Payerle, George, R. C. Team, George Payerle, Sokoloff D, Sara Dolnicar,
Alexander Chapple, Alexander W Pastuszak, and Run Wang. “Scholar
(3).” Annals of Tourism Research, 2015. http://www.ncbi.
nlm.nih.gov/pubmed/25926610%5Cnhttp://www.pubmedcentral.nih.
gov/articlerender.fcgi?artid=PMC4492060%0Ahttp://www.sciencedi
rect.com/science/article/pii/S0160738315000444.
Ramirez, German, Sabiha R Saba, and Luis Espinoza.
“Hypocomplementemic Vasculitis and Renal Involvement.” Nephron
45, no. 2 (1987): 147–50.
Renard, Marleen, Carine Wouters, and Willem Proesmans.
“Rapidly Progressive Glomerulonephritis in a Boy with
Hypocomplementaemic Urticarial Vasculitis.” European Journal of
Pediatrics 157, no. 3 (1998): 243–45.
Sanchez, N P, R K Winkelmann, A L Schroeter, and C H Dicken. “The
Clinical and Histopathologic Spectrums of Urticarial Vasculitis: Study
of Forty Cases.” Journal of the American Academy of Dermatology 7,
no. 5 (November 1982): 599–605. https://doi.org/ 10.1016/s0190-
9622(82)70139-2.
Schwartz, H R, F C McDuffie, L F Black, A L Schroeter, and D L Conn.
“Hypocomplementemic Urticarial Vasculitis: Association with
Chronic Obstructive Pulmonary Disease.” In Mayo Clinic
Proceedings, 57:231–38, 1982.
Soter, Nicholas A. “Urticarial Venulitis.” Dermatologic Therapy 13, no. 4
(2000): 400–408.
Staubach-Renz, P, E von Stebut, W Bräuninger, M Maurer, and K

Steinbrink. “[Hypocomplementemic urticarial vasculitis syndrome.
Successful therapy with intravenous immunoglobulins].” Der
Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte
Gebiete 58, no. 8 (August 2007): 693–97. https://doi.org/10.
1007/s00105-007-1301-5.
Tanaka, H, S Waga, Y Kakizaki, K Sugimoto, K Nomura, and M
Yokoyama. “Chronic Urticaria Associated with Aseptic Meningitis:
An Atypical Urticarial Vasculitis?” Acta Paediatrica Japonica :
Overseas Edition 39, no. 1 (February 1997): 64–68. https://doi.org/
10.1111/j.1442-200x.1997.tb03558.x.
Tejani, A T, K Butt, H Trachtman, M Suthanthiran, C J Rosenthal, and M
R Khawar. “Cyclosporine A Induced Remission of Relapsing
Nephrotic Syndrome in Children.” Kidney International 33, no. 3
(March 1988): 729–34. https://doi.org/10.1038/ki.1988.59.
Trendelenburg, M, S Courvoisier, P J Späth, S Moll, M Mihatsch, P Itin,
and J A Schifferli. “Hypocomplementemic Urticarial Vasculitis or
Systemic Lupus Erythematosus?” American Journal of Kidney
Diseases : The Official Journal of the National Kidney Foundation 34,
no. 4 (October 1999): 745–51. https://doi.org/10.1016/S0272-
6386(99)70402-6.
Wisnieski, J J, and S M Jones. “IgG Autoantibody to the Collagen-like
Region of Clq in Hypocomplementemic Urticarial Vasculitis
Syndrome, Systemic Lupus Erythematosus, and 6 Other
Musculoskeletal or Rheumatic Diseases.” The Journal of
Rheumatology 19, no. 6 (June 1992): 884–88.
Wisnieski, J J, and G B Naff. “Serum IgG Antibodies to C1q in
Hypocomplementemic Urticarial Vasculitis Syndrome.” Arthritis and
Rheumatism 32, no. 9 (September 1989): 1119–27. https://doi.org/
10.1002/anr.1780320910.
Wisnieski, Jeffrey J. “Urticarial Vasculitis.” Current Opinión in
Rheumatology 12, no. 1 (2000): 24–31.
Wisnieski, Jeffrey J, Alan N Baer, Jim Christensen, Thomas R Cupps,

Douglas N Flagg, J Verrier Jones, Paul L Katzenstein, E R McFadden,
James J McMillen, and Michael A Pick. “Hypocomplementemic
Urticarial Vasculitis Syndrome. Clinical and Serologic Findings in 18
Patients.” Medicine 74, no. 1 (1995): 24–41.
Worm, M, W Sterry, and G Kolde. “Mycophenolate Mofetil Is Effective
for Maintenance Therapy of Hypocomplementaemic Urticarial
Vasculitis.” British Journal of Dermatology 143, no. 6 (2000): 1324.
Chapter 8
PULMONARY CAPILLARITIS
IN SYSTEMIC LUPUS ERYTHEMATOSUS
Chrong-Reen Wang1,*, Wei-Chieh Lin2

and Ming-Fei Liu1
1
Divisions of Rheumatology, Department of Internal Medicine,
National Cheng Kung University Hospital, Tainan, Taiwan
2
Critical Care Medicine, Department of Internal Medicine,
National Cheng Kung University Hospital, Tainan, Taiwan
ABSTRACT
There is an increasing trend of biologics usage in treating

rheumatology disorders with rituximab (RTX) being recommended in
organ-threatening, refractory systemic lupus erythematosus (SLE).
Diffuse alveolar hemorrhage (DAH) caused by capillaritis, described
first by Sir William Osler in 1895, is associated with a high mortality in
SLE. A retrospective analysis of DAH was performed in hospitalized
adult lupus patients from January 2006 to June 2019, focusing on the
therapeutic modality. Twenty patients (1.8% incidence), 18 females
(90%) ages 19 to 67 years (38.3 + 15.0), had 27 DAH episodes with
*
Corresponding Author’s E-mail: wangcr@mail.ncku.edu.tw.
222 Chrong-Reen Wang, Wei-Chieh Lin and Ming-Fei Liu
SLEDAI-2K 12 to 33 (20.3 + 6.0) and involved organ numbers 2 to 7

(4.5 + 1.3) at the onset. High-dose corticosteroids, mechanic ventilator,
pulse methylprednisolone, plasma exchange, cyclophosphamide and
extracorporeal membrane oxygenation were prescribed in all, 15 (75%),
13 (65%), 7 (35%), 6 (30%) and 3 (15%), respectively. In particular, 5
(25%) received RTX 375 mg/m2 weekly × 4 or fortnightly × 2 with a
depletion of circulating B cells, and all survived without relapse, with 3
carrying a recurrent history. Seven (35%) succumbed to acute respiratory
failure. There was a higher DAH incidence (3.7%) and mortality rate
(73%) in admitted adult lupus patients before 1998. Despite a better
critical care quality in respiratory dysfunction, this study observes a
benefit of the RTX therapy in improving survival and preventing
recurrence in SLE-associated DAH manifestation.
Keywords: acute respiratory failure, B cell depletion, diffuse alveolar

hemorrhage, rituximab, systemic lupus erythematosus
INTRODUCTION
The recent development of biologics and oral small molecules

targeting the pathogenic mechanisms like immune cells and pro-
inflammatory cytokines has revolutionized the therapy of rheumatology
disorders [1]. In particular, rituximab (RTX), a chimeric monoclonal
antibody (mAb) containing murine light/heavy chain variable region and
human IgG1 kappa constant region sequences, has specificity against the
B-lymphocyte transmembrane protein CD20. Since the first approval of
RTX use in indolent B-cell non-Hodgkin lymphoma by the United States
Food and Drug Administration in 1997, these biologics have changed the
treatment of B-cell malignancy with the prolongation of disease
progression and overall survival time [2]. Clinical indication has extended
to the rheumatologic diseases like rheumatoid arthritis and anti-neutrophil
cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) including
granulomatosis with polyangiitis and microscopic polyangiitis [3].
Polyclonal B-cell hyper-reactivity is involved in the pathogenesis of
systemic lupus erythematosus (SLE), with the capacity of B cells to
produce pathogenic antibodies after differentiating antibody-secreting
Pulmonary Capillaritis in Systemic Lupus Erythematosus 223
plasma cells [4]. In addition, through the secretion of pro-inflammatory

cytokines/chemokines and the function as antigen-presenting cells to
present autoantigens to T cells, B cells can perpetuate the disease
development and augment the inflammatory response. Targeting the
antibody-dependent and -independent roles of B cells without board
immunosuppression in SLE has brought RTX use into clinical practice [5].
This therapeutic mAb promotes a rapid, long-term depletion of circulating
and tissue-associated B lymphocytes, resulting in a lower recruitment of
such effectors at the site of immune complex deposition, further reducing
tissue inflammation and damage [3]. There were two large-scale
randomized placebo-controlled trials examining the efficacy of RTX
therapy in lupus patients [6, 7]. In the EXPLORER trial, despite not
achieving the primary endpoint (clinical remission based on activity
score), B-cell depletion was confirmed with reduced anti-dsDNA and
improved complement levels [6]. In the LUNAR trial with lupus nephritis
(LN), patients receiving RTX failed to achieve the primary outcome (better
overall renal responses) [7]; however, further analysis with longer
observation time, demonstrated a reduction in proteinuria and a decreased
need for rescue cyclophosphamide therapy [8]. Nevertheless, the RTX use
is recommended as a therapeutic option in LN by the American College of
Rheumatology (ACR) and European League against Rheumatism
(EULAR) guidelines [9, 10]. Furthermore, in the 2019 update of EULAR
recommendations for SLE management, RTX usage is considered in
organ-threatening, refractory lupus patients [11]. Recently, we have
reported the beneficial effects of RTX usage for the life-threatening SLE
presentations resistant to the standard management including
antiphospholipid syndrome with warfarin therapy failure, diffuse alveolar
hemorrhage (DAH) and lupus myocarditis [12-15]. Although B-cell
depletion based on the RTX therapy is not yet licensed in SLE, this
biologic is of most interest to practicing rheumatologists as it represents a
new approach in treating patients with severe, difficult-to-treat activity.
Pulmonary manifestation in SLE can be related to therapeutic
complication or disease activity, and half of the patients have such a
presentation in their clinical course [16]. There are fatal lung complications
like opportunistic infection due to prior usage of higher daily

corticosteroids dosage. Lung involvement is an important indicator of the
overall prognosis, being associated with more than a two-fold increase in
mortality [17]. Notably, there are infrequently encountered life-threatening
presentations like acute lupus pneumonitis, pulmonary
embolism/infraction and DAH, a clinical condition with the accumulation
of intra-alveolar red blood cells (RBCs) due to capillaritis [14, 18]. The
DAH manifestation, first described by Sir William Osler in his long-term
observation on lupus patients in 1895 [19], leads to acute respiratory
dysfunction associated with a high mortality in most reported series despite
aggressive therapeutic regimens [16]. Indeed, there is a requirement for
new alternative or combined therapeutics to treat the lethal SLE-associated
DAH manifestation.
Characteristic DAH manifestations in lupus patients have been
reported from the National Cheng Kung University Hospital (NCKUH)
[14, 20], a 1,200-bed medical center providing the tertiary service to 6
million people in southern Taiwan. There is an increasing trend of
biologics’ use in miscellaneous rheumatology disorders in this area [21-
26]. In this study, a retrospective review was performed in admitted adult
lupus patients for the DAH presentation, focusing on the therapeutic
modality, especially for RTX usage. English literature was reviewed for
larger-scale case series of SLE-associated DAH and RTX-treated case
reports.
MATERIALS AND METHODS
Selection of Patients
A retrospective review of medical records was carried out in

hospitalized patients who fulfilled the ACR Revised Criteria for SLE
Classification [27], excluding pediatric SLE under the age of 18, at the
NCKUH from January 2006 to June 2019 with permission from the
institutional review board. Lupus patients with DAH manifestation
received the further analysis. DAH was defined as new bilateral pulmonary
infiltrate on chest images (x-ray or computed tomography), abrupt
hemoglobin (Hb) levels drop at least 1.5 g/dL without concomitant
bleeding elsewhere, and one of the following presentations: hemoptysis,
hypoxemia, documentation of bloody appearance in bronchoalveolar
lavage (BAL) fluid, or histopathological evidences of capillaritis or
alveolar hemorrhage with hemosiderin-laden macrophages [14, 20].
Recurrent DAH was defined as a new episode after the complete resolution
of previous DAH events with normal chest images.
Collection of Data
Demographic data including age/sex and disease duration was

recorded. The disease activity (SLEDAI-2K) [28] was calculated at the
onset of DAH. Further analyses included characteristics of DAH
(symptoms, dropping Hb, blood gas, BAL, lung biopsy), concurrent SLE-
related clinical/laboratory data and the outcome of DAH (survival, death).
Medication profiles comprised corticosteroids, immunosuppressants
(cyclophosphamide) and biologics (rituximab), and therapeutic procedures
contained extracorporeal membrane oxygenation (ECMO), mechanic
ventilator and plasma exchange. Corticosteroid dosages were converted to
average daily prednisolone equivalents adjusted by body weight, and high-
dose was defined as 1 to 2 mg/kg/day. Pulse methylprednisolone was 0.5
or one gram methylprednisolone parentally for 3 consecutive days.
Moreover, demographic, clinical, laboratory and medication profiles were
compared in SLE-associated DAH patients observed before 1998 with
those after 2006, and between survivors with deaths after 2006.
Therapeutic indication, regimen and response were analyzed in patients
receiving the RTX therapy.
Review of Literature
English literature from PubMed was reviewed for larger-scale case

series (patients number at least 5) in the DAH manifestation of lupus
patients since 1984 and case reports of such patients receiving the RTX
therapy since 2007.
Statistical Analyses
Results in this study were presented as mean + standard deviation for

continuous variables and as percentages for categorical variables.
Numerical data between two groups were compared by the Mann-Whitney
test, and differences in categorical data between two groups were analyzed
by chi-square test. All P values were two-tailed, and the values less than
0.05 were considered significant in this study.
RESULTS
After 2006, 20 out of 1,130 hospitalized lupus patients (1.8%

incidence), 18 female (90%) aged 19 to 67 years (38.3 + 15.0), had the
DAH manifestation (Table 1). There was an SLE disease period from
initial presentation to 27 years (7.5 + 7.9), SLEDAI-2K 12 to 33 (20.3 +
6.0), recurrent DAH in 4 (2 to 4 episodes) with a total of 27 episodes in
this study, LN in 19 (95%) with nephrotic syndrome in 11 (55%) and acute
renal failure in 14 (70%), neuropsychiatric presentation in 10 (50%, 5
seizure, 4 organic brain syndrome, one psychosis), involved organ
numbers 2 to 7 (4.5 + 1.3), and mortality in 7 (35%) due to acute respiratory
failure. For laboratory data, there were dropping Hb 2.0 to 6.1 g/dL (3.4 +
1.4), thrombocytopenia in 15 (75%), presence of anti-dsDNA in 11 (55%)
and hypocomplementemia in 16 (80%). For therapeutic modality, all
received high-dose corticosteroids, 13 (65%) with pulse
methylprednisolone, 6 (30%) with pulse cyclophosphamide, 5 (25%) with
the RTX therapy, 15 with mechanic ventilator (75%), 7 (35%) with plasma
exchange, and 3 (15%) with ECMO owing to a resistance to the ventilator
usage (a fractional inspired O2 1.0 with a positive end-expiratory pressure
of at least 14 cm H2O). In particular, 10 had the presence of anti-
phospholipid antibodies (anti-2 glycoprotein I, anti-cardiolipin and/or
lupus anticoagulant) and 3 had a history of antiphospholipid syndrome.
There was a bloody appearance in BAL fluid in 11 patients (55%). Despite
no observed capillaritis in 3 patients (15%) receiving the lung biopsy, all
had the findings of alveolar hemorrhage with characteristic hemosiderin-
laden macrophages (Figure 1).
Figure 1. Alveolar hemorrhage with hemosiderin-laden macrophages (arrows),

hematoxylin and eosin, original magnification ×400.
As compared with a 3.7% incidence of DAH manifestation in 300

admitted adult lupus patients and a 73% mortality rate before 1998, there
was a lower incidence (1.8%) and mortality rate (35.0%) after 2006.
Regarding the clinical characteristics and laboratory data, the only
parameter with the significant difference was lower levels of dropping Hb
at the onset of DAH from hospitalized patients before 1998 in comparison
with those admitted after 2006. For the medication and procedure profiles,
RTX and ECMO were not available in our hospital before 1998.
Table 1. Comparison of DAH in hospitalized adult SLE patients

before 1998 with after 2006
Before 1998 After 2006 P value

Demographic feature
Total SLE patients number 300 1,130
DAH patients number 11 20
Incidence 3.7% 1.8% 0.045
Age (years) 29.0 + 11.2 38.3 + 15.0 NS
Female 10 (90.9%) 18 (90.0%) NS
Clinical characteristic
Disease period (years) 1.8 + 2.0 7.5 + 7.9 NS
First manifestation 3 (27.3%) 5 (25.0%) NS
Activity (SLEDAI-2K) 19.0 + 5.1 20.3 + 6.0 NS
Fever 4 (36.4%) 11 (55.0%) NS
Hemoptysis 9 (81.8%) 14 (70.0%) NS
Recurrence of DAH 3 (27.3%) 4 (20.0%) NS
Lupus nephritis 11 (100.0%) 19 (95.0%) NS
Nephrotic syndrome 8 (72.7%) 11 (55.0%) NS
Acute renal failure 9 (81.8%) 14 (70.0%) NS
Neuropsychiatric 6 (54.6%) 10 (50.0%) NS
Antiphospholipid syndrome 3 (27.3%) 3 (15.0%) NS
Involved organ numbers 4.1 + 1.3 4.5 + 1.3 NS
Mortality 8 (72.7%) 7 (35.0%) 0.044
Laboratory data
Hypoxemia 11 (100%) 20 (100%) NS
Hemoglobulin drop (g/dl) 2.3 + 0.7 3.4 + 1.4 0.022
Thrombocytopenia 6 (54.6%) 15 (75.0%) NS
Anti-dsDNA 7 (63.6%) 11 (55.0%) NS
Anti-phospholipid 4 (36.4%) 10 (50.0%) NS
Hypocomplementemia 9 (81.8%) 16 (76.5%) NS
Therapeutic profile
High-dose corticosteroid 11 (100%) 20 (100%) NS
Methylprednisolone pulse 8 (76.9%) 13 (65.0%) NS
Cyclophosphamide pulse 0 (0%) 6 (30.0%) NS
Rituximab usage 0 (0%) 5 (25.0%) NS
Plasma exchange 0 (0%) 7 (35.0%) 0.026
Mechanic ventilator 9 (81.8%) 15 (70.6%) NS
ECMO 0 (0%) 3 (15.0%) NS
NS: not significant.
Table 2. Miscellaneous parameters of 20 lupus patients

with the DAH manifestation
Survivor Death P value

Demographic feature
Patients number 13 7
Age (years) 39.2 + 15.2 36.4 + 15.5 NS
Female 12 (92.3%) 6 (85.7%) NS
Clinical characteristic
Disease period (years) 8.9 + 7.7 3.9 + 4.8 NS
First manifestation 2 (15.4%) 3 (42.9%) NS
Activity (SLEDAI-2K) 19.3 + 6.4 22.0 + 5.2 NS
Hemoptysis 11 (84.6%) 3 (42.9%) NS
Recurrence of DAH 4 (30.8%) 0 (0%) NS
Lupus nephritis 12 (92.3%) 7 (100%) NS
Nephrotic syndrome 8 (61.5%) 4 (57.1%) NS
Acute renal failure 9 (69.2%) 5 (71.4%) NS
Acute myocarditis 2 (15.4%) 1 (14.3%) NS
Neuropsychiatric 6 (46.2%) 4 (57.1%) NS
Antiphospholipid syndrome 2 (18.2%) 1 (14.3%) NS
Involved organ numbers 4.2 + 1.4 5.0 + 1.0 NS
Infection complication 9 (69.2%) 6 (85.7%) NS
Laboratory data
Hemoglobulin drop (g/dl) 3.2 + 1.2 3.8 + 1.7 NS
eGFR (ml/min/1.73 m2) 39.1 + 30.4 27.6 + 31.7 NS
Thrombocytopenia 8 (61.5%) 7 (100%) NS
Anti-dsDNA 7 (53.8%) 4 (57.1%) NS
Anti-phospholipid 8 (61.5%) 2 (28.6%) NS
Anti-neutrophil cytoplasm 2 (15.4%) 1 (14.3%) NS
Hypocomplementemia 10 (76.9%) 6 (85.7%) NS
Therapeutic profile
High-dose corticosteroid 13 (100%) 7 (100%) NS
Methylprednisolone pulse 7 (53.8%) 6 (83.3%) NS
Cyclophosphamide pulse 5 (38.5%) 1 (14.3%) NS
Rituximab usage 5 (38.5%) 0 (0%) 0.058*
Plasmapheresis 5 (38.5%) 2 (28.6%) NS
Mechanic ventilator 8 (61.5%) 7 (100%) NS
ECMO 0 (0%) 3 (42.9%) 0.011
* Marginal significance, NS: not significant.
Further comparison between survivors and deaths after 2006 is shown

in Table 2. There was no difference in demographic feature, clinical
characteristic and laboratory data. For the therapeutic modality, 5 treated

with RTX survived but 3 receiving the ECMO expired. In particular,
despite 3 with the presence of ANCAs specific to myeloperoxidase, they
had no other AAV-related clinical presentations.
Table 3. Clinical/medication profiles in SLE-related DAH

from 25 larger-scale reports
No. Year Study *Case no./ #Age/Sex LN NP MR MP CYC Pl RTX Rf

type Incidence
1 1984 S/R 6/NR 30/F 83% 83% NR 50% 17% 17% Nil Nil 29
2 1985 S/R 12/1.6% 23/F 100% 67% 58% 92% 25% 8% Nil Nil 30
3 1991 S/R 5/5.3% 34/F 80% NR NR 40% 80% Nil 60% Nil 31
4 1993 S/R 8/1.4% 38/F 75% 63% 38% 25% 88% 63% Nil Nil 32
5 1997 S/R 34/5.4% 35/F 94% 32% 15% 62% 74% 6% 6% Nil 33
6 1997 S/R 10/1.4% 27/F 80% 40% 20% 40% 80% 70% 40% Nil 34
7 1997 S/R 15/3.7% 30/F 66% 93% 40% 53% 95% 68% 37% Nil 35
8 1998 S/R 13/4.3% 26/F 92% 100% 62% 77% 77% 15% Nil Nil 20
9 2000 S/R 6/NR 28/F 83% 83% 17% 50% 100% 33% 83% Nil 36
10 2000 S/R 7/1.0% 31/F 82% 70% 10% Nil 82% 73% 6% Nil 37
11 2001 S/R 7/NR 26/F 100% 100% 29% 57% 67% 33% Nil Nil 38
12 2002 S/R 8/0.5% 37/F 100% 100% 38% 50% 100% 13% 38% Nil 39
13 2004 S/R 22/1.5% 32/F 91% 77% 32% 36% 86% 86% 50% Nil 40
14 2007 S/R 7/5.7% 24/F 71% 71% 14% 14% 100% 100% 57% Nil 41
15 2008 S/P 13/0.6% 22/F 92% NR NR 31% 57% 7% Nil Nil 42
16 2010 S/R 29/1.4% 31/F 86% 90% NR 62% 79% 69% 10% Nil 43
17 2011 S/R 21/1.4% 30/F 91% 76% 48% 62% NR 38% 67% Nil 44
18 2011 S/R 22/9.0% 25/F 76% 100% 24% 68% NR 59% Nil 9% 45
19 2012 S/R 28/1.6% 23/F 82% 79% 18% 39% 100% 57% 18% Nil 46
20 2014 M/R 50/NR 23/F 98% 79% 26% 48% NR 49%* Nil 6% 47
21 2015 S/R 22/2.2% 37/NR 36% 9% Nil 45% 41% 18% 14% 48
22 2016 S/R 7/1.6% 43/100% 71% 14% 29% 100% 29% 29% Nil 49
23 2017 S/R 24/2.9% 30/F 100% 54% NR 29% NR 17% 33% Nil 50
24 2018 S/R 17/2.0% 38/F 88% 94% 47% 35% 71% 35% 43% 24% 14
25 2018 M/R 19/2.2% 13/F 74% 84% 21% 47% 95% 47% Nil Nil 51
* Published reports with case numbers at least 5, #Average age in studied patients.
CYC: cyclophosphamide, F: female, LN: lupus nephritis, M: multiple-institute, MP:
methylprednisolone pulse, MR: mortality rate, NP: neuropsychiatric, NR: not reported, P:
prospective, Pl: plasmapheresis, R: retrospective, Rf: reference, S: single-institute.
Table 4. DAH manifestation in SLE receiving the RTX therapy

in English literature
No. Year Age Clinical Therapeutic Concurrent Outcome of Ref

/Sex indication regimen treatment DAH/SLE
1 2007 24F rDAH 375 mg/m2 × 4 w hCS, CP, IVIG, MP, Relapse free, 52
Pl lower activity
2 2008 29F rDAH 500 mg × 3 FN hCS, CP, CsA, Relapse free 53
MMF
3 2009 19F DAH and 375 mg/m2 × 1 hCS, CP, MP Relapse free, 54
recurrence lower activity
4 2009 24F rDAH 375 mg/m2 × 2 hCS, CP, MP, Pl, Relapse free 55
FN FVIIa
5 2010 52F DAH, early 1000 mg × 2 FN hCS, CP, MP Relapse free, 56
regimen lower activity
6 2011 18M DAH, CYC 375 mg/m2 ×2 FN hCS, MMF, MP Relapse free, 57
intolerance lower activity
7 2012 23F rDAH 1000 mg × 2 FN hCS, CP, MP Relapse free, 58
lower activity
8 2014 27F DAH, multi- 1000 mg × 2 FN hCS, CP, MP Relapse free, 59
organic flare lower activity
9 2015 52F rDAH 375 mg/m2 × 5 w hCS, IVIG, MP, Pl Relapse free 60
10 2015 37F DAH, multi- 500 mg × 2 w hCS, MP Relapse free 61
organic flare
11 2017 24M rDAH 1000 mg × 2 FN, hCS, MMF Relapse free 62
every year, 6 m
and 4 m
12 2017 25M DAH, multi- 375 mg/m2 × 4 w hCS, MMF Relapse free, 63
organic flare lower activity
13 2018 30F DAH, multi- 500 mg × 2 w CP, IVIG, Pl Relapse free 64
organic flare
CP: cyclophosphamide pulse, hCS: high-dose corticosteroids, CsA: cyclosporine A,
F: female, FN: fortnightly, IVIG: intravenous immunoglobulin, m: months, MMF: mycophenolate
mofetil, MP: methylprednisolone pulse, Pl: plasmapheresis, FVIIa: activated factor VII, r:
recurrent, Ref: reference, w: weekly.
Table 3 demonstrates the clinical and medication profiles in SLE-

related DAH from 25 larger-scale reports with patients from Europe, Latin
America, USA and Asia including China, Japan, Singapore, South Korea
and Taiwan (two reports from our hospital) [14, 20, 29-51]. Twenty-two
studies used a monocentric/retrospective analysis method. Lower
incidence (less than 3%) in younger female with LN is a common
characteristic in reported patients. There was a higher mortality rate (at

least 25%) in nearly 90% of reported series despite the aggressive
therapeutic modalities. In particular, there is a study from pediatric patients
(age younger than 19) with clinical and laboratory characteristics similar
to adult victims [51]. Notably, 4 case series included the RTX therapy with
2 to 4 patients as a therapeutic modality [14, 45, 47, 48]. Thirteen cases,
mostly young females, received the RTX treatment for their first attack or
recurrent DAH events as well as multi-organic flare (Table 4) [52-64].
Their RTX regimens included 375 mg/m2, 500 mg, or 1000 mg weekly or
fortnightly administration. All had survival outcomes without relapse and
lower disease activity. Except for one report [64], all received the high-
dose corticosteroids combined therapy. Notably, there was no concurrent
usage of cyclophosphamide in 5 cases [57, 60-63].
Table 5. Indication, regimen and response in SLE-associated DAH

with RTX therapy
No. RTX RTX B cells DAH Response Side FU Medications

indication regimen depletion outcome Activity* effect# time@ at/after DAH
1 rDAH, flare 375 mg/m2 × Yes, 2/L Survived, 18 to 6 Yes 86 m hCs/Cs
(LN, NP, 2, fortnightly no recurrence
MV, Tp)
2 rDAH, flare 375 mg/m2 × Yes, 0/L Survived, 26 to 4 Nil 58 m hCs, CP, MP/
(LN, Tp, NP) 4, weekly no recurrence Cs
3 DAH, flare 375 mg/m2 × Yes, 3/L Survived, 15 to 8 Nil 34 m hCs/Cs
+
(DV, HA, 2, fortnightly with rDAH
DCM)
4 rDAH, flare 375 mg/m2 × Yes, 1/L Survived, 27 to 7 Yes 12 m hCs, CP, MP/
(LN, Tp, NP) 2, fortnightly no recurrence Cs, CP
5 DAH, flare 375 mg/m2 × Yes, 0/L Survived 33 to 6 Yes 6 m hCs/Cs
(LN, NP, LH, 4, weekly
LM, Tp, DV)
* Calculation of SLEDAI-2K after the RTX therapy; #Respiratory and/or urinary tract infection
episodes; @ Follow-up after the RTX infusion; +B cell count 64/l at the recurrence of DAH.
DCM: dilated cardiomyopathy with acute heart failure, Cs: corticosteroid, CP: cyclophosphamide
pulse, DV: dermal vasculitis, FU: follow-up, h: high-dose, HA: hemolytic anemia, MP:
methylprednisolone pulse, LH: lupus hepatitis, LM: lupus myocarditis, LN: lupus nephritis, m:
month, MV: mesenteric vasculitis, NP: neuropsychiatric, r: recurrent, Tp: thrombocytopenia.
Table 5 showed the indication, regimen and response of RTX usage in

5 patients from our series including 2 with their first DAH attack, 3 with
recurrent events and all with lupus flare. The RTX regimen was 375 mg/m2
weekly × 4 or fortnightly × 2, resulting in a depletion of B cells with
circulating CD19+ lymphocytes 0 to 3/L. During the DAH event, in
addition to the RTX infusion, all had concomitant usage of high-dose
corticosteroids and 2 received pulse cyclophosphamide therapy. All
survived, and there was no recurrence with a follow-up period of 6 to 86
months (39.2 + 33.2). A relapse of DAH together with a flare of activity
was noted in case no. 3, 34 months after the RTX therapy with a B-cell
count rising to 64/L. Pulse methylprednisolone and cyclophosphamide
were prescribed with a recovery of DAH and reduced lupus activity.
Notably, there was a significant decrease in SLEDAI-2K after the RTX
therapy (before versus after, 23.6 + 7.6 to 6.2 + 1.5, P = 0.008). There were
observed respiratory and/or urinary tract infection episodes after the RTX
therapy; however, these patients also received the high-dose
corticosteroids or plus cyclophosphamide treatment.
DISCUSSION
We compared the DAH manifestation in hospitalized adult lupus

patients in NCKUH between different time cohorts, before 1988 and after
2006, and identified a significant decrease in the incidence and mortality
after 2006, implying a better recent control of disease activity. Except for
variable levels of dropping Hb at the DAH onset, there were no differences
between two periods in demographic, clinical, and laboratory parameters.
Regarding the therapeutic modality, cyclophosphamide therapy and
plasma exchange were not used before 1988; however, there were deaths
in admitted patients receiving such treatments after 2006. Further
comparison was made between survivors and deaths in admitted lupus
patients after 2006. No differences were identified in demographic, clinical
and laboratory profiles. Despite the availability of ECMO and RTX after
2006, there were no survivors in 3 cases using the ECMO device, whereas
no deaths were identified in 5 cases receiving RTX therapy. Although

better critical care quality can contribute to lower mortality in hospitalized
patients after 2006, our long-term observation in different time cohorts
suggests a beneficial role of RTX usage in improving the survival in the
SLE-associated DAH manifestation.
The lung tissues from lupus patients with the DAH manifestation
reveal the presence of pulmonary capillaritis with necrosis of vessel walls
and deposition of immune complex along the alveolar and blood vessel
walls, suggesting the role of antibody-secreting plasma cells derived from
differentiated B cells [65]. Besides the suppression on the production of
antibodies and immune complexes, other RTX action mechanisms
including the inhibition of autoantigens presentation and
cytokines/chemokines secretion by B cells can contribute to the therapeutic
responses [4]. Furthermore, RTX has been administrated successfully as
an alternative therapeutics to cyclophosphamide in the SLE-associated
DAH manifestation [57, 60-63]. In the present study, in addition to high-
dose corticosteroids, cases no. 1, 3 and 5 received RTX infusion without
the concurrent cyclophosphamide usage, resulting in a recovery of DAH.
There are miscellaneous RTX regimens for the SLE-associated DAH
manifestation (Table 4). Two therapeutic schedules, 375 mg/m2 weekly ×
4 and fortnightly × 2, were used in our patients with the depletion of
circulating B cells despite the result of 0/L only from the weekly
administration regimen.
Notably, one 2014 Mexico multi-centric series including RTX as the
therapeutic modality has a death outcome in all treated cases [47], whereas
a 2015 United States monocentric cohort demonstrates the survival result
in all patients receiving this biologic [48]. In this series, similar to the 2015
United States study, RTX usage has the beneficial effects in patient
survival and recurrence prevention. Interestingly, therapeutic results of LN
to immunosuppressive agents are variable among different ethnic groups
with a poor response in Hispanics as compared with Asians [66].
Moreover, the racial factor has been considered to be involved in clinical
responses to the RTX therapy in lupus patients [67]. The therapeutic effect
of RTX in SLE-associated DAH can be further evaluated by carrying a
large-scale internationally collaborative study among different racial

groups.
In this study, a significantly lower survival was identified in patients
using the ECMO device, reflecting their clinic severity in the DAH
manifestation. The risk factor analyses failed to identify other differences
between the survivors and deaths. Indeed, such analyses are usually limited
by lower patient numbers in published series due to the rarity of DAH
manifestation in SLE. In the largest multi-centric retrospective series from
Mexico with 50 patients, the mortality-related clinical factors include
infection complication, renal failure, thrombocytopenia and the usage of
ventilator. The mechanic ventilators are indicated in the development of
DAH due to a rapid accumulation of intra-alveolar RBCs, leading to acute
respiratory failure with severe hypoxemia [16]. For severe pulmonary
dysfunction refractory to ventilators, ECMO has been increasingly used as
a rescue therapy [68]; however, all 3 patients in this series receiving such
a device succumbed to the respiratory failure. Since ECMO requires
systemic anticoagulation to maintain the circuit patency, any condition
accompanied by a significant bleeding risk like DAH has been regarded as
a relative contraindication [69]. Nevertheless, with lower anticoagulation
levels under the improved biocompatibility of newer circuit components,
ECMO usage can reduce the severe impairment in the gas exchange while
minimizing the risk of bleeding [70]. Notably, several successful cases of
ECMO-supported SLE-associated DAH have been published with survival
to decannulation and discharge [69, 70].
ANCA with the specificity to myeloperoxidase was detected in 15%
of patients from the present series. Despite the occurrence of DAH in AAV
disorders like microscopic polyangitis [71], AAV and SLE are different
clinical settings with distinct pathogenic mechanisms. Vasculitis
manifestation can be identified in lupus patients but not corresponding to
the AAV classification criteria. Except the DAH manifestation, our
ANCA-positive patients had no other AAV-related presentations, and their
hypocomplementemia was not in the AAV laboratory profile [72].
Targeting B cells with RTX is an effective regimen to induce remission in
AAV patients [73]. Although AAV-associated DAH patients requiring the
ventilator support were excluded from the clinical trial, a combined

regimen of RTX and cyclophosphamide may have the beneficial effects in
these cases [73, 74].
Finally, half of the patients in this study had positive aPL and 3 had an
earlier diagnosis of SLE-associated APS. Despite the regular usage of an
anticoagulant in 2 cases, there was no warfarin overdose with their target
INR between 2 to 3 at the DAH onset, and the anticoagulant usage was
discontinued during the DAH event. In addition, there were no identified
thromboembolisms during their DAH episodes. In the primary APS, DAH
presentation is regarded as a non-thrombotic inflammatory process [75],
and early administration of RTX has been considered as an alternative to
cyclophosphamide for the induction of remission, either alone or in
combination with other immunosuppressants [74]. In this series, the RTX
therapy was prescribed alone in a SLE-associated APS patient (case no.3)
without the concurrent usage of cyclophosphamide, achieving a recovery
in her DAH manifestation.
In conclusion, despite the aggressive therapeutic regimens, high
mortality is still observed in SLE-associated DAH manifestation, a
therapeutic challenge to the rheumatologists. In this monocentric
retrospective study with larger patient numbers, we observed the beneficial
effects of the RTX therapy in improving survival and preventing
recurrence in SLE-associated DAH manifestation.
ACKNOWLEDGMENTS
The authors are indebted to doctors and nurses at the NCKUH involved
in the diagnosis and management of reported patients, and Dr. Hung-Wen
Tsai at the Pathology Department of NCKUH for providing the
histopathological analyses of the biopsied lung tissues. This study received
no grant or financial support from any funding agency or commercial
source which could create a potential conflict of interest.
REFERENCES
[1] Sarzi-Puttini P, Ceribelli A, Marotto D, Batticciotto A, Atzeni F.

Systemic rheumatic diseases: From biological agents to small
molecules. Autoimmun Rev 2019; 18: 583-592.
[2] Salles G, Barrett M, Foà R, et al. Rituximab in B-Cell hematologic
malignancies: A review of 20 years of clinical experience. Adv Ther
2017; 34:2232-2273.
[3] Schioppo T, Ingegnoli F. Current perspective on rituximab in
rheumatic diseases. Drug Des Devel Ther 2017; 11:2891-2904.
[4] Dörner T, Giesecke C, Lipsky PE. Mechanisms of B cell
autoimmunity in SLE. Arthritis Res Ther 2011; 13:243.
[5] McCarthy EM, Sutton E, Nesbit S, et al. Short-term efficacy and
safety of rituximab therapy in refractory systemic lupus
erythematosus: results from the British Isles Lupus Assessment
Group Biologics Register. Rheumatology 2018; 57:470-479.
[6] Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety of
rituximab in moderately-to-severely active systemic lupus
erythematosus: the randomized, double-blind, phase II/III systemic
lupus erythematosus evaluation of rituximab trial. Arthritis Rheum
2010; 62:222-233.
[7] Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab
in patients with active proliferative lupus nephritis: the Lupus
Nephritis Assessment with Rituximab study. Arthritis Rheum 2012;
64:1215-1226.
[8] Gomez Mendez LM, Cascino MD, Garg J, et al. Peripheral blood B
cell depletion after rituximab and complete response in lupus
nephritis. Clin J Am Soc Nephrol 2018; 13:1502-1509.
[9] Hahn BH, McMathon MA, Wilkinson A, et al. American College of
Rheumatology Guidelines for screening, treatment, and
management of lupus nephritis. Arthritis Care Res 2012; 64:797-
808.
[10] Bertsias GK, Tektonidou M, Amoura Z, et al. Joint European League
Against Rheumatism and European Renal Association–European
Dialysis and Transplant Association recommendations for the

management of adult and pediatric lupus nephritis. Ann Rheum Dis
2012; 71:1771-1782.
[11] Fanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the
EULAR recommendations for the management of systemic lupus
erythematosus. Ann Rheum Dis 2019; 78:736-745.
[12] Wang CR, Liu MF. Rituximab usage in systemic lupus
erythematosus-associated antiphospholipid syndrome: a single
center experience. Semin Arthritis Rheum 2016; 46:102-108.
[13] Wang CR, Weng CT, Liu MF. Monocentric experience of
rituximab therapy in systemic lupus erythematosus-associated
antiphospholipid syndrome with warfarin therapy failure. Semin
Arthritis Rheum 2017; 47:e7-e8.
[14] Wang CR, Liu, MF, Weng CT, Lin WC, Li WT, Tsai HW. Systemic
lupus erythematosus-associated diffuse alveolar hemorrhage: a
monocentric experience in Han Chinese patients. Scand J Rheumatol
2018; 47:392-399.
[15] Wang CR, Tsai YS, Li WT. Lupus myocarditis receiving the
rituximab therapy-a monocentric retrospective study. Clin
Rheumatol 2018; 37:1701-1707.
[16] Mittoo S, Fell CD. Pulmonary manifestations of systemic lupus
erythematosus. Semin Respir Crit Care Med 2014; 35:249-254.
[17] Mira-Avendano IC, Abril A. Pulmonary manifestations of Sjögren
syndrome, systemic lupus erythematosus, and mixed connective
tissue disease. Rheum Dis Clin North Am 2015; 41:263-277.
[18] Weng CT, Chung TJ, Liu MF, et al. A retrospective study of
pulmonary infarction in patients with systemic lupus erythematosus
from southern Taiwan. Lupus 2011; 20:876-885.
[19] Osler W. On the visceral manifestations of the erythema exudativum
mutiforme. Am J Med Sci 1895; 110:629-646.
[20] Liu MF, Lee JH, Weng TH, Lee YY. Clinical experience of 13 cases
with severe pulmonary hemorrhage in systemic lupus erythematosus
with active nephritis. Scand J Rheumatol 1998; 27:291-295.
[21] Wang CR, Weng CT, Lee CT, Huang KY, Hsu SM, Liu MF. Rare
occurrence of inflammatory bowel disease in a cohort of Han
Chinese ankylosing spondylitis patients- a single institute study. Sci
Rep 2017; 7:13165.
[22] Wang CR. Successful treatment of refractory juvenile
dermatomyositis with adalimumab. J Clin Rheum 2017; 23:174-175.
[23] Wang CR, Chiu YC, Chen YC. Successful treatment of refractory
neutropenia in Felty’s syndrome with rituximab. Scand J Rheumatol
2018; 47:340-341.
[24] Wang CR, Yang CC. Adalimumab therapy in hepatitis B virus-
negative polyarteritis nodosa: A case report. Medicine 2018;
97:e11053.
[25] Wang CR, Tsai Ys, Tsai HW. Acute myocarditis in anti-neutrophil
cytoplasmic antibody-positive microscopic polyangiitis patients
receiving the rituximab therapy. J Rheumatol 2019; 46:1645-1646.
[26] Wang CR, Chen YC, Peng SL, Hsu SM. Blurred vision and diplopia
caused by sarcoidosis orbital involvement. J Clin Rheumatol 2020;
8: e298-299.
[27] Hochberg MC. Updating the American college of rheumatology
revised criteria for the classification of systemic lupus
erythematosus. Arthritis Rheum 1997; 40:1725.
[28] Gladman DD, Ibanez D, Urowitz MB. Systemic Lupus
Erythematosus Disease Activity Index 2000. J Rheumatol 2002;
29:288-291.
[29] Carette S, Macher AM, Nussbaum A, et al. Severe, acute pulmonary
disease in patients with systemic lupus erythematosus: ten years of
experience at the National Institutes of Health. Semin Arthritis
Rheum 1984; 14:52-59.
[30] Abud-Mendoza C, Diaz-Jouanen E, Alarcón-Segovia D. Fatal
pulmonary hemorrhage in systemic lupus erythematosus.
Occurrence without hemoptysis. J Rheumatol 1985; 12:558-561.
[31] Onomura K, Nakata H, Tanaka Y, Tsuda T. Pulmonary hemorrhage
in patients with systemic lupus erythematosus. J Thorac Imaging
1991; 6:57-61.
[32] Schwab EP, Schumacher HR Jr, Freundlich B, et al. Pulmonary

alveolar hemorrhage in systemic lupus erythematosus. Semin
Arthritis Rheum 1993; 23:8-15.
[33] Barile LA, Jara LJ, Medina-Rodriguez F, García-Figueroa JL,
Miranda-Limón JM. Pulmonary hemorrhage in systemic lupus
erythematosus. Lupus 1997; 6:445-448.
[34] Koh WH, Thumboo J, Boey ML. Pulmonary hemorrhage in oriental
patients with systemic lupus erythematosus. Lupus 1997; 6:713-716.
[35] Zamora MR, Warner ML, Tuder R, Schwarz MI. Diffuse alveolar
hemorrhage and systemic lupus erythematosus. Clinical
presentation, histology, survival, and outcome. Medicine 1997;
76:192-202.
[36] Lee CK, Koh JH, Cha HS, et al. Pulmonary alveolar hemorrhage in
patients with rheumatic diseases in Korea. Scand J Rheumatol 2000;
29:288-294.
[37] Santos-Ocampo AS, Mandell BF, Fessler BJ. Alveolar hemorrhage
in systemic lupus erythematosus: presentation and management.
Chest 2000; 118:1083-1090.
[38] Lee JG, Joo KW, Chung WK, et al. Diffuse alveolar hemorrhage in
lupus nephritis. Clin Nephrol 2001; 55:282-288.
[39] Chang MY, Fang JT, Chen YC, et al. Diffuse alveolar hemorrhage
in systemic lupus erythematosus: a single center retrospective study
in Taiwan. Ren Fail 2002; 24:791-802.
[40] Badsha H, Teh CL, Kong KO, Lian TY, Chang HH. Pulmonary
hemorrhage in systemic lupus erythematosus. Semin Arthritis
Rheum 2004; 33:414-421.
[41] Cañas C, Tobón GJ, Granados M, et al. Diffuse alveolar hemorrhage
in Colombian patients with systemic lupus erythematosus. Clin
Rheumatol 2007; 26:1947-1949.
[42] Rojas-Serrano J, Pedroza J, Regalado J, et al. High prevalence of
infections in patients with systemic lupus erythematosus and
pulmonary hemorrhage. Lupus 2008; 17:295-299.
[43] Shen M, Zeng X, Tian X, et al. Diffuse alveolar hemorrhage in

systemic lupus erythematosus: a retrospective study in China. Lupus
2010; 19:1326-1330.
[44] Kwok SK, Moon SJ, Ju JH, et al. Diffuse alveolar hemorrhage in
systemic lupus erythematosus: risk factors and clinical outcome:
results from affiliated hospitals of Catholic University of Korea.
Lupus 2011; 20:102-107.
[45] Martínez-Martínez MU, Abud-Mendoza C. Predictors of mortality
in diffuse alveolar hemorrhage associated with systemic lupus
erythematosus. Lupus 2011; 20:568-574.
[46] Araujo DB, Borba EF, Silva CA, et al. Alveolar hemorrhage: distinct
features of juvenile and adult onset systemic lupus erythematosus.
Lupus 2012; 21:872-877.
[47] Martinez-Martinez MU, Sturbaum AK, Alcocer-Varela J, et al.
Factors associated with mortality and infections in patients with
systemic lupus erythematosus with diffuse alveolar hemorrhage. J
Rheumatol 2014; 41:1656-1661.
[48] Kazzaz NM, Coit P, Lewis EE, et al. Systemic lupus erythematosus
complicated by diffuse alveolar hemorrhage: risk factors, therapy
and survival. Lupus Sci Med 2015; 2:e000117.
[49] Andrade C, Mendonça T, Farinha F, et al. Alveolar hemorrhage in
systemic lupus erythematosus: a cohort review. Lupus 2016; 25:75-
80.
[50] Kim D, Choi J, Cho SK, et al. Clinical characteristics and outcomes
of diffuse alveolar hemorrhage in patients with systemic lupus
erythematosus. Semin Arthritis Rheum 2017; 46:782-787.
[51] Blay G, Rodrigues JC, Ferreira JCO, et al. Diffuse alveolar
hemorrhage in childhood-onset systemic lupus erythematosus: a
severe disease flare with serious outcome. Adv Rheumatol 2018;
58:39.
[52] Gillis JZ, Dall’era M, Gross A, Yazdany J, Davis J. Six refractory
lupus patients treated with rituximab: a case series. Arthritis Rheum
2007; 57:538-542.
[53] Nellessen CM, Pöge U, Brensing KA, Sauerbruch T, Klehr HU,

Rabe C. Diffuse alveolar hemorrhage in a systemic lupus
erythematosus patient successfully treated with rituxi-mab: a case
report. Nephrol Dial Transplant 2008; 23:385-386.
[54] Pinto LF, Candia L, Garcia P, et al. Effective treatment of refractory
pulmonary hemorrhage with monoclonal anti-CD20 antibody
(rituximab). Respiration 2009; 78:106-109.
[55] Todd DJ, Costenbader KH. Dyspnoea in a young woman with active
systemic lupus erythematosus. Lupus 2009; 18:777-784.
[56] Narshi CB, Haider S, Ford CM, Isenberg DA, Giles IP. Rituximab
as early therapy for pulmonary hemorrhage in systemic lupus
erythematosus. Rheumatology 2010; 49:392-394.
[57] Pottier V, Pierrot M, Subra JF, et al. Successful rituximab therapy in
a lupus patient with diffuse alveolar hemorrhage. Lupus 2011;
20:656-659.
[58] Martínez-Martínez MU, Abud-Mendoza C. Recurrent diffuse
alveolar hemorrhage in a patient with systemic lupus erythematosus:
long-term benefit of rituximab. Lupus 2012; 21:1124-1127.
[59] Gonzalez-Echavarri C, Pernas B, Ugarte A, Ruiz-Irastorza G. Severe
multiorganic flare of systemic lupus erythematosus successfully
treated with rituximab and cyclophosphamide avoiding high doses
of prednisone. Lupus 2014; 23:323-326.
[60] Tse JR, Schwab KE, McMahon M, Simon W. Rituximab: an
emerging treatment for recurrent diffuse alveolar hemorrhage in
[61] Na JO, Chang SH, Seo KH, et al. Successful early rituximab
treatment in a case of systemic lupus erythematosus with potentially
fatal diffuse alveolar hemorrhage. Respiration 2015; 89:62-65.
[62] Aakjaer S, Bendstrup E, Ivarsen P, Madsen LB. Continous
Rituximab treatment for recurrent diffuse alveolar hemorrhage in a
patient with systemic lupus erythematosus and antiphosholipid
syndrome. Respir Med Case Rep 2017; 22:263-265.
[63] Montes-Rivera G, Ríos G, Vilá LM. Efficacy of rituximab in a

systemic lupus erythematosus patient presenting with diffuse alveo-
lar hemorrhage. Case Rep Rheumatol 2017; 2017:6031053.
[64] Hsu BC, Huang WN, Lai KL. B-cell-depleting therapy for diffuse
alveolar hemorrhage in systemic lupus erythematosus. J Formos
Med Assoc 2018: 117:944-945.
[65] Green RJ, Ruoss SJ, Kraft SA, Duncan SR, Berry GJ, Raffin TA.
Pulmonary capillaritis and alveolar hemorrhage. Update on
diagnosis and management. Chest 1996; 110:1305-1316.
[66] Rivera TL, Belmont HM, Malani S, et al. Current therapies for lupus
nephritis in an ethnically heterogeneous cohort. J Rheumatol 2009;
36:298-305.
[67] Leone A, Sciascia S, Kamal A, Khamashta M. Biologicals for the
treatment of systemic lupus erythematosus: current status and
emerging therapies. Expert Rev Clin Immunol 2015; 11:109-116.
[68] Betit P. Technical Advances in the Field of ECMO. Respir Care
2018; 63:1162-1173.
[69] Patel JJ, Lipchik RJ. Systemic lupus-induced diffuse alveolar
hemorrhage treated with extracorporeal membrane oxygenation: a
case report and review of the literature. J Intensive Care Med 2014;
29:104-9.
[70] Abrams D, Agerstrand CL, Biscotti M, et al. Extracorporeal
membrane oxygenation in the management of diffuse alveolar
hemorrhage. ASAIO J 2015; 61:216-218.
[71] Greco A, De Virgilio A, Rizzo MI, et al. Microscopic polyangiitis:
Advances in diagnostic and therapeutic approaches. Autoimmun Rev
2015; 14:837-844
[72] Sen D, Isenberg DA. Antineutrophil cytoplasmic autoantibodies in
[73] Stone JH, Merkel PA, Spiera R, et al. Rituximab versus
cyclophosphamide for ANCA-associated vasculitis. N Engl J Med
2010; 363:221-232.
[74] Lally L, Spiera RF. Pulmonary vasculitis. Rheum Dis Clin North Am
2015; 41:315-331.
[75] Yachoui R, Sehgal R, Amlani B, Goldberg JW. Antiphospholipid
antibodies-associated diffuse alveolar hemorrhage. Semin Arthritis
Rheum 2015; 44:652-657.
Chapter 9
CEREBRAL VENOUS SINUS THROMBOSIS

AS A COMPLICATION
OF COVID-19 VACCINATION
N. Prasad1,*, MD, Salim Surani2,3, MD,

and Rahul Kashyap1,2, MD
1
Department of Internal Medicine, Centennial Medical Center -
TriStar Division, HCA Healthcare, Nashville, TN, USA
2
3
ABSTRACT
This chapter discusses the pathophysiology and adverse effects of

adenoviral vector vaccinations for SARS-CoV-2 and the importance of
identifying the true epidemiology of adverse outcomes regarding
promoting increased acceptance of COVID-19 vaccinations. This book
chapter includes all published studies relating to outcomes after
*
Corresponding Author’s E-mail: Navin.Prasad@hcahealthcare.com.
246 N. Prasad, Salim Surani and Rahul Kashyap
adenoviral-vector vaccination. The findings described show adenoviral

vector vaccines are associated with an increased risk of thrombosis,
typically with thrombocytopenia. This phenomenon has been termed
vaccine-induced thrombotic thrombocytopenia (VITT). The rate of
thrombotic adverse effects following vaccination remains lower than the
rate of thrombosis following COVID-19 infection. At the current rate of
reported severe adverse outcomes, the benefits of vaccination outweigh
the risks of remaining unvaccinated regardless of the vaccine vector.
Keywords: cerebral venous sinus thrombosis; COVID-19; vaccine-

induced thrombotic thrombocytopenia; adenovirus; vaccination
This research was supported (in whole or in part) by HCA Healthcare

and/or an HCA Healthcare affiliated entity. The views expressed in this
publication represent those of the author(s) and do not necessarily
represent the official views of HCA Healthcare or any of its affiliated
entities.
INTRODUCTION
As of late August 2021, the COVID-19 pandemic has affected more

than 211 million people worldwide and claimed the lives of over 4.4
million people [31]. By the end of 2020, vaccines capable of protecting
recipients against SARS-CoV-2 began distribution among the public after
being granted emergency authorization. The first vaccines were vaccines
using an mRNA vector manufactured by Pfizer-BioNTech and Moderna,
followed by vaccines using an adenovirus vector manufactured by Oxford-
AstraZeneca and Johnson and Johnson. While the rollout of mRNA
vaccines proceeded with few if any major adverse outcomes [1, 22],
vaccination via AstraZeneca’s adenoviral vector vaccine was put on pause
after reports began to surface of severe thromboembolic events within
weeks of the first dose.
Cerebral venous sinus thrombosis (CVST) is a coagulopathic
condition of the brain’s venous drainage system, which can result in
serious morbidity and/or mortality [Stam]. Its prevalence increased in
Cerebral Venous Sinus Thrombosis … 247
2021. The rise in cases was attributed to certain vaccines, and cases were
reported through government websites and various case studies during the
pandemic. Though rare, vaccination against COVID-19 using an
adenovirus vector has been recognized by the scientific community as a
risk factor for thrombotic complications. Vaccination against COVID-19
decreases the risk of thrombosis compared to the risk of thrombosis
following viral infection. However, as the reported cases of CVST as a
complication from adenoviral vector vaccination continue to grow, public
trust in vaccinations overall is decreasing [9].
While there are several promising options currently employed in
different parts of the world, the adenoviral vector vaccines have the
potential to increase vaccination access to people around the world who
would otherwise not have the option. Adenoviral vaccines are the preferred
vaccine deployed in developing countries, which often lack the cold chain
technology required to store mRNA vaccines. In the case of
Ad26.COV2·S, developed by Johnson and Johnson, the single dosing
schedule allows twice as many people to be protected against the virus for
the same number of shots given in a set period, compared to two-dose
vaccines. COVID-19 Vaccines Global Access (COVAX), a global
initiative to provide equitable vaccine access internationally, primarily
distributes these adenoviral vector vaccines as a result [3].
CVST is a complication of adenoviral vector vaccination that was first
reported through government systems in March 2021. This finding came
one month after emergency authorization was granted by local
governments in an attempt to mass distribute vaccinations as early as
possible. Astra-Zeneca’s ChAdOx1 nCOV-19 was emergently authorized
in Europe, while Johnson and Johnson’s Ad26.COV2·S was emergently
authorized in the USA. CVST following adenoviral-vector vaccination has
been recognized to occur in conjunction characteristically with atypical
thrombocytopenia; this condition has been termed vaccine-induced
thrombosis-thrombocytopenia (VITT).
BACKGROUND
CVST Excluding COVID-19
Excluding the contributions of SARS-CoV-2 or the vaccines against

it, CVST has a widely variable estimated incidence of around 4-28.5 cases
per million persons and is the cause of ~0.5-1% of all strokes [21, 27]. The
median age of onset is around 37 years, and females are more likely to be
affected than males 3:1. Nearly all patients will have predisposing risk
factors such as acquired and genetic hypercoagulable and prothrombotic
conditions, including oral contraceptives, pregnancy, malignancy,
infection, and mechanical instrumentation. The most common presenting
symptoms include severe headache, seizures, encephalopathy, and/or focal
neurological deficits. The majority of patients will have good outcomes,
whereas up to 20% of patients may suffer chronic morbidity or otherwise
mortality. Thrombocytopenia is not an associated finding in non-vaccine
mediated CVST.
Epidemiology of CVST during COVID-19
The TriNetX global health collaborative clinical research platform is a

federated electronic health records network recording anonymized data
from 59 healthcare organizations, primarily in the USA. In one study using
the database, researchers analyzed 667,551 patients with COVID-19 and
65,796,480 without COVID-19. This study found the odds of developing
CVST were 4.1 times greater in patients with COVID-19 than those
without the infection, with an incidence of 62.9 cases per million people
after COVID-19 and 15.5 cases per million people without COVID-19
[12]. The study’s findings of CVST in the general, non-COVID population
are consistent with established literature reporting of the disease’s
incidence [20, 21, 27].
Table 1. Reports of adenovirus vector vaccine-induced thrombosis-thrombocytopenia and cerebral venous
sinus thrombosis
Author / Agency Region Vaccine Cases of VITT Age(s) / Age Vaccination Time Cases of CVST
Range (years) Range (days)
Oliver [20] USA Ad26.COV2.S 6 18-48 6-13 6
See et al., [26] USA Ad26.COV2.S 12 18-60 6-15 12
Muir et al.,* [17] USA Ad26.COV2.S 1 48 14 1
Sadoff et al., [23] USA Ad26.COV2.S 1 25 19 1
Total (USA subgroup) Ad26.COV2.S 18* 18*
MHRA [15] UK ChAdOx1 nCOV- 309 18-93 Data not available 116
19
Jamme et al., [13] France ChAdOx1 nCOV- 1 69 11 1
19
D’Agostino et al., [7] Italy ChAdOx1 nCOV- 1 54 12 1
19
Castelli et al., [2] Italy ChAdOx1 nCOV- 1 50 9 1
19
Greinacher et al., [10] Germany ChAdOx1 nCOV- 11 22-49 6-16 9
19
Table 1. (Continued)
Author / Agency Region Vaccine Cases of VITT Age(s) / Age Vaccination Time Cases of CVST
Range (years) Range (days)
Wolf et al., [30] Germany ChAdOx1 nCOV- 3 22-46 7-17 3
19
Tiede et al., [29] Germany ChAdOx1 nCOV- 5 41-67 5-11 1
19
Schultz et al., [24] Norway ChAdOx1 nCOV- 5 32-54 7-10 4
19
Total (Europe subgroup) ChAdOx1 nCOV- 336 136
19
Adenoviral vector vaccines combined 354 154
CDC = Centers for Disease Control (USA)
MHRA = Medicines and Healthcare products Regulatory Agency
USA = United States of America UK = United Kingdom
*Muir et al., is included in both See et al., and CDC
Epidemiology of CVST/VITT after COVID-19

Infection Versus Vaccination
The incidence of CVST and VITT following adenoviral vector

vaccination continues to be studied, but observational retrospective studies
as of April 2021 have given a preliminary estimate. There have been at
least 136 cases of CVST and 336 cases of VITT following these
vaccinations reported to the European Medicines Agency (EMA; Table 1).
The rate of CVST for AstraZeneca’s ChAdOx1 nCOV-19 in the European
Union has been estimated as 5.0 cases (4.3 to 5.8) per million doses [4].
Using this estimated rate, the incidence of CVST is 12.6 times higher post-
COVID-19 infection compared to post-vaccination. VITT rate was ~12.3
per million doses, meaning VITT induces CVST in 40.7% of patients.
Fewer cases of VITT have been recorded in the US, which is reported
through the federal government website for Vaccine Adverse Event
Reporting System (VAERS). As of the end of April 2021, 18 cases of
VITT with CVST have been reported in the US following vaccination with
Johnson and Johnson’s Ad26.COV2·S, an estimated 2.25 cases per million
doses (Table 1) [20]. While case numbers remain under-reported and
continue to be established, a comparison between the rates of VITT/CVST
for the two vaccines should not be attempted.
Risk Factors for VITT/CVST
Observational studies on CVST following adenoviral-vector

vaccination have elicited several associated risk factors: onset of disease
within two weeks of vaccination, female, and under 60 years of age.
Studies have not controlled for these risk factors are predispositions to
coagulopathy, such as young females who take oral combined
contraceptives. In light of this consideration, the UK Joint Commission on
Vaccination and Immunization recommended persons under 30 years of
age be offered an alternative to adenoviral vector vaccination, especially
for females. Apart from this vaccine option in this specific population, the
EMA affirms that for patients of all age and risk groups, the potential
benefits of vaccination far outweigh the potential harms [14]. While under-
reporting events may be confounding the epidemiology, worldwide rates
of VITT remain low overall.
PATHOPHYSIOLOGY
SARS-CoV-2 and Human Immune Response
The vigorous immune response of the human body to SARS-CoV-2

infection has been evident since the beginning of the pandemic. Clinically
significant COVID-19 is typically marked by an upper respiratory
symptom phase, a pulmonary/pneumonia phase, and an inflammatory
phase with multiple organ involvement. The inflammatory phase has been
linked largely to the spike glycoproteins which present on the virus’
surface. The vaccines against the virus contain replication-incompetent
adenoviral vectors, human Ad26.COV2.S (Johnson and Johnson) and
chimpanzee ChAdOx1 nCoV-19 (AstraZeneca), which encode the spike
glycoprotein on SARS-CoV-2 [28]. Cellular and humoral immunity
against the spike proteins reduces the inflammatory phase significantly,
allowing for a decrease in inflammatory-mediated events such as
thrombosis. This straightforward explanation has been the case so far for
the mRNA vaccines. The role of adenoviral vectors in promoting CVST
and VITT illustrates that these vectors generate a unique response by the
human body.
COVID-19 Vaccination and the Human Immune Response
The mechanism of adenoviral vector entry into host cells is well-

established, even with introducing the SARS-CoV-2 spike proteins into the
equation. The adenovirus life cycle proceeds first with cell infection,
followed by viral uncoating into the host cell’s cytosol before the
adenoviral DNA enters the cell nucleus and uses the host’s proteins to
transcribe its genes. The spike gene is transcribed inside the nucleus and
then exported as mRNA. Back in the host cell’s cytosol, this mRNA is
translated into the spike protein [5]. Some theories have been proposed to
explain which part of the process may deviate from the traditional
vaccination blueprint and instead contribute to thrombosis. This remains
an ongoing focus of basic science investigation.
A definitive mechanism for why adenoviral vectors contribute to an
increased thrombosis rate is poorly understood and has yet to be
scientifically proven. One currently proposed pathophysiology of VITT is
the production of platelet-activating antibodies against platelet factor 4
(PF4), as the generation of anti-PF4 antibodies in heparin-induced
thrombocytopenia (HIT). In clinical studies, VITT has been associated
with elevated levels of these autoantibodies [10, 25]. The proposed
pathway includes Fc gamma-receptor-mediated platelet activation by
antibodies targeting PF4 and leading to thrombotic events; this occurs
through a combination of thrombocytopenia secondary to platelet
consumption and increased levels of thrombin generated from the
activation of monocytes [10].
More recently, an international collaborative of scientists was able to
demonstrate that the thrombotic events surrounding adenoviral vector
vaccines are not provoked by spike protein antibodies [11]. Other
mechanisms have been suggested in turn, such as an increased distribution
of the novel vaccines to the brain, as seen in animal studies for ChAdOx1
nCOV-19, which leads to spike protein production in the brain and thus an
autoimmune response predisposing to thrombosis [16].
ADVERSE EFFECTS OF VACCINATION
Adenoviral vector vaccinations have been implicated in a spectrum of

thrombotic and vasculitis events, earning the title “Vaccine-induced
thrombotic thrombocytopenia” (VITT). To date, CVST has been the most
common clinically-presenting thrombotic event related to VITT, and due
to its serious morbidity and mortality, it is also the most concerning. The
mortality of CVST in the general population prior to the COVID-19
pandemic is 5-10% [Oliver, Ferro]. Studies of CVST in patients with
COVID-19 show that the estimated mortality rate is 20% [15, 20, 21]. The
mortality incidence after VITT from Astra-Zeneca’s vaccine is 18% [28].
Clinical Features of CVST
The predominant clinical features of CVST include headache (the

most common presenting symptom) and focal neurological deficits.
Headache has been estimated to occur in two out of three patients with this
condition, making it a relatively sensitive but not specific finding that does
not always merit an extensive neurologic workup. In CVST, the venous
occlusion causes backflow into the drainage system, causing cerebral
edema, seizures, cerebral infarction, intracranial hemorrhage, venous
hypertension, decreased CSF absorption, and/or increased intracranial
pressure [8, 27]. Non-COVID-19-associated CVST classically has a
gradual onset of symptoms while the venous system adapts with collateral
vessels. In acutely-triggered, more rapidly-developed CVST such as from
COVID-19 or VITT, the onset of symptoms is more likely to be more acute
and severe due to less collateralization [8]. When intracranial pressure can
increase faster, it predisposes patients to brain herniation and resulting in
severe brain injury and/or death.
Spectrum of Thromboses after Vaccination
Thrombosis following novel vaccines has been found in arteries and

veins in multiple locations in the body, including the lungs as pulmonary
emboli, abdomen as splanchnic and portal vein thromboses, and elsewhere,
such as internal jugular vein thromboses [26]. Table 1 includes 14
published case reports and series from the USA and Europe; this sample
represents all peer-reviewed published literature on VITT following
adenoviral vector vaccination as of April 2021. A combined analysis of the

patients in this table shows 354 cases of VITT, of which 154 experienced
CVST (43.5%). This rate of CVST with VITT is comparable to the 40.7%
rate determined by the Department of Health and Social Care, as earlier
described [4].
While Table 1 lists the subgroup sample sizes for each of the two
vaccines, comparisons cannot be made between the two through this
analysis or any other. The USA studies specifically looked at CVST as a
result of VITT, while the European studies looked more broadly at VITT
with or without CVST. It is also difficult to generalize the incidence among
the general population of either VITT or VITT-induced CVST using these
data, as there were no control groups with which to compare.
MANAGEMENT OF VITT
Diagnosis
The diagnosis of CVST is made with MRI with magnetic resonance

venography (MRV), the most sensitive test for this disease. If MRI/MRV
is not readily available, high-resolution CT or CT venography can be used,
although there is a higher rate of false-negative results [6, 27]. If MRI or
CT venography fails to establish a definitive diagnosis, cerebral
angiography may be indicated. Compared to imaging studies, angiography
provides better details of the cerebral veins, making it useful for diagnosing
rare cases of isolated thrombosis of the cortical veins without sinus
thrombosis [6].
Treatment
The treatment of VITT mirrors that for heparin-induced

thrombocytopenia with special consideration of CVST. Heparin is the
first-line treatment for CVST; however, patients often are positive for PF4
antibodies as previously described. Thus, when PF4 antibodies are found,

anticoagulation must be provided with agents other than heparin, such as a
direct-acting thrombin or factor ten inhibitor. Heparin is avoided to prevent
the generation of more immune complexes and subsequent worsening
thrombocytopenia. However, anticoagulant treatment has raised
controversy because of the high rate of hemorrhagic conversion, around
40% of all patients, even prior to initiation of anticoagulation [8].
Immunosuppressive modalities have been attempted, such as
intravenous immunoglobulin (IVIG) or steroids, although the evidence for
their efficacy in VITT is limited [28]. While anticoagulation is a mainstay
of treatment, provisional guidelines, including guidance from the
International Society on Thrombosis and Hemostasis (ISTH), recommend
considering IVIG in addition to anticoagulation [19]. In HIT, IVIG has the
ability to inhibit anti-PF4 antibodies and reduce platelet activation by
binding the Fc receptor. It should be noted that IVIG for HIT is not
included in the American Society of Hematology 2018 guidelines [3].
When anticoagulation is not suitable or fails to achieve therapeutic goals,
consultation for a direct endovascular procedure should be pursued.
FUTURE RESEARCH
VITT’s future directions include analyzing populations without

selection bias, as is currently the case with reporting through VAERS. This
way, researchers can determine the value of PF4 antibodies and the specific
comorbidities that may predispose patients to VITT.
Since there is currently no data about people who did not develop
CVST/VITT after a COVID-19 vaccine for comparison, we cannot yet
definitively state that the vaccine is the cause of the PF4 antibodies
thrombocytopenia, or thrombosis. Continued and improved reporting of
adverse effects should be pursued internationally so that the true incidence
of VITT can be determined, as well as any potential contributing factors.
Deciphering the exact mechanism whereby adenoviral vector vaccines
generate VITT while mRNA vaccines do not is another route of further
research. Identifying the specific components of these novel vaccines that

trigger VITT is the key to understanding the mechanism and how best to
treat these events and hopefully prevent them from occurring. With the
high likelihood of booster doses being needed to protect against more
aggressive variants or otherwise in the face of waning immunity, future
research should also be performed with monitoring of the incidence of
adverse effects after multiple doses of these originally-one dose vaccines.
Head-to-head comparisons between available vaccines is another future
avenue of research, especially with respect to side-effect profile.
CONCLUSION
There is an established association between adenoviral vector

vaccinations and VITT, with CVST carrying some of the most serious
adverse outcomes. As the scientific community around the world continues
to study further reporting of these events, clinicians and researchers will
be able to determine a more accurate incidence, which currently appears to
be more common than in the general population yet less common than after
COVID-19 infection. It remains widely accepted that the risks of
remaining unvaccinated outweigh the risks of adverse effects from
vaccination, which carry tremendous benefit by protecting against
COVID-19. Future research should be focused on understanding what
specific components of these vaccines contribute to adverse effects that are
not seen in their mRNA counterparts so that adenoviral vector vaccines
can continue to be distributed efficiently and safely to countries that would
otherwise lack access.
REFERENCES
[1] Baden, Lindsey., Hana Sahly, Brandon Essink, Karen Kotloff,

Sharon Frey, Rich Novak, David Diemert, et al. “Efficacy and Safety
of the mRNA-1273 SARS-CoV-2 Vaccine.” New England Journal

of Medicine, 384(5) (February 2021): 403-416. https://doi.org/
10.1056/nejmoa2035389.
[2] Castelli, Gian Paolo., Claudio Pognani, Carlo Sozzi, Massimo
Franchini, and Luigi Vivona. “Cerebral venous sinus thrombosis
associated with thrombocytopenia post-vaccination for COVID-19.”
Critical Care. 25(1) (April 2021): 137. https://doi.org/10.1186/s
13054-021-03572-y.
[3] Cuker Adam., Gowthami Arepally, Beng Chong, Douglas Cines,
Andreas Greinacher, Yves Gruel, Lori Linkins, et al. “American
Society of Hematology 2018 guidelines for management of venous
thromboembolism: heparin-induced thrombocytopenia.” Blood
Advances. 2 (November 2018): 3360-3392. https://dx.doi.org/
10.1182%2Fbloodadvances.2018024489.
[4] Department of Health and Social Care. “JCVI statement on use of
the AstraZeneca COVID-19 vaccine: 7 April 2021.” Gov.UK, April
23, 2021. https://www.gov.uk/government/publications/use-of-the-
astrazeneca-covid-19-vaccine-jcvi-statement/jcvi-statement-on-use-
of-the-astrazeneca-covid-19-vaccine-7-april-2021.
[5] Doerfler, Walter and Petra Böhm. Adenoviruses: Model and Vectors
in Virus-Host Interactions. Springer-Verlag, Berlin Heidelberg,
2003.
[6] Dormont, Didier., Rene Anxionnat, Serge Evrard, C Louaille,
Jacques Chiras, C Marsault. “MRI in cerebral venous thrombosis.”
Journal of Neuroradiology. 21 (April 1994):81-99. PMID: 8014661.
[7] D’Agostino, Vincenzo., Ferdinando Caranci, Alberto Negro, Valeria
Piscitelli, Bernadino Tuccillo, Fabrizio Fasano, Giovanni Sirabella,
et al. “A rare case of cerebral venous thrombosis and disseminated
intravascular coagulation temporally associated to the COVID-19
vaccine administration.” Journal of Personalized Medicine. 11(4)
(April 2021): 285. https://doi.org/10.3390/jpm11040285.
[8] Ferro Jose, Patrícia Canhão, Jan Stam, Marie-Germaine Bousser,
Fernando Barinagarrementeria, ISCVT Investigators. “Prognosis of
cerebral vein and dural sinus thrombosis: results of the International
Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT).”

Stroke. 35 (March 2004): 664–670. https://doi.org/10.1161/01.
str.0000117571.76197.26.
[9] Frankovic, Kathy. “Decision to pause Johnson and Johnson vaccine
causes public confidence in vaccine to sink.” YouGovAmerica, April
15, 2021. https://today.yougov.com/topics/politics/articles-reports/
2021/04/15/johnson-johnson-vaccine-confidence.
[10] Greinacher, Andreas., Thomas Thiele, Theodore E Warkentin, Karin
Weisser, Paul A Kyrle, and Sabine Eichinger. “Thrombotic
thrombocytopenia after ChAdOx1 nCov-19 vaccination.” New
England Journal of Medicine. 384(22) (June 2021): 2092–2101.
https://doi.org/10.1056/nejmoa2104840.
[11] Greinacher, Andreas., Kathleen Selleng, Julia Mayerle, Raghavendra
Palankar, Jan Wesche, Sven Reiche, Andrea Aebischer, Theodore E
Warkentin, et al. “Anti-SARS-CoV-2 Spike Protein and Anti-
Platelet Factor 4 Antibody Response Induced by COVID-19 Disease
and ChAdOx1 nCov-19 vaccination.” Blood. (July 2021).
https://doi.org/10.1182/blood.2021012938.
[12] Hinduja, Archana., Nalleballe Krishna, Sukanthi Kovvuru, and Omar
Hussein. “Impact of cerebral venous sinus thrombosis associated
with COVID-19.” Journal of Neurological Science. 425 (June
2021):117448. https://dx.doi.org/10.1016%2Fj.jns.2021.117448.
[13] Jamme, Matthieu., Elie Mosnino, Jan Hayon. “Fatal cerebral venous
sinus thrombosis after COVID-19 vaccination.” Intensive Care
Medicine. 47 (May 2021): 790-791.
[14] Mahase, Elisabeth. “AstraZeneca vaccine: Blood clots are
“extremely rare” and benefits outweigh risks, regulators conclude.”
British Medical Journal. 373 (April 2021):931. https://doi.org/
10.1136/bmj.n931.
[15] Medicine & Healthcare products Regulatory Agency. “Coronavirus
Vaccine - Weekly Summary of Yellow Card Reporting.” Gov.UK,
April 2021. https://www.gov.uk/government/publications/
coronavirus-covid-19-vaccine-adverse-reactions/coronavirus-
vaccine-summary-of-yellow-card-reporting.
[16] Merchant, Hamid. “Might post-injection distribution of COVID

vaccines to the brain explain the rare fatal events of cerebral venous
sinus thrombosis (CVST)?” British Medical Journal Online. (April
2021) 373.
[17] Muir, Kate-Lynn., Avyakta Kallam, Scott Koepsell, and Krishna
Gundabolu. “Thrombotic thrombocytopenia after Ad26.COV2.S
vaccination.” New England Journal of Medicine. 384(20) (April
2021): 1964–1965. https://doi.org/10.1056/nejmc2105869.
[18] Muster, Viktoria. Thomas Gary, Reinhard B Raggam, Albert
Wölfler, Marianne Brodmann. “Pulmonary embolism and
thrombocytopenia following ChAdOx1 vaccination.” Lancet.
397(10287) (May 2021): 1842. https://doi.org/10.1016/s0140-
6736(21)00871-0.
[19] Oliver, Sara. “Risk/Benefit assessment of thrombotic
thrombocytopenic events after Janssen COVID-19 vaccines:
Applying Evidence to Recommendation Framework.” Center for
Disease Control and Prevention, Advisory Committee on
Immunization Practices Meeting, April 23, 2021. https://www.cdc.
gov/vaccines/acip/meetings/downloads/slides-2021-04-23/06-
COVID-Oliver-508.pdf.
[20] Oliver, Sara and Tom Shimabukuro. “Johnson & Johnson/Janssen
COVID19 Vaccine and Cerebral Venous Sinus Thrombosis with
Thrombocytopenia - Update for Clinicians on Early Detection and
Treatment.” Centers for Disease Control and Prevention, April 15,
2021.
https://emergency.cdc.gov/coca/calls/2021/callinfo_041521.asp.
[21] Nazy, Ishac., Ulrich Sachs, Donald M. Arnold, Steven McKenzie,
Phil Choi, Karina Althaus, Maria Therese Ahlen, Ruchika Sharma,
Rachael Grace, Tamam Bakchoul. “Recommendations for the
clinical and laboratory diagnosis of vaccine-induced immune
thrombotic thrombocytopenia (VITT) for SARS-CoV-2 infections:
communication from the ISTH SSC Subcommittee on Platelet
Immunology.” Journal of Thrombosis and Haemostasis. 19 (April
2021): 1585-1588. https://doi.org/10.1111/jth.15341.
[22] Polack, Fernando., Stephen Thomas, Nicholas Kitchin, Judith

Absalon, Alejandra Gurtman, Stephen Lockhart, John Perez, et al.
“Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine.”
New England Journal of Medicine, 383(27) (December 2020): 2603-
2615. https://doi.org/10.1056/nejmoa2034577.
[23] Sadoff, Jerald., Kourtney Davis, and Macaya Douoguih.
“Thrombotic thrombocytopenia after Ad26.COV2. S vaccination —
Response from the manufacturer.” New England Journal of
Medicine. 384(20) (May 2021) 1965–1966. https://doi/org/
10.1056/NEJMc2106075.
[24] Schultz, Nina., Ingvild H Sørvoll, Annika E Michelsen, Ludvig A
Munthe, Fridtjof Lund-Johansen, Maria T Ahlen, Markus
Wiedmann. “Thrombosis and thrombocytopenia after ChAdOx1
nCoV-19 vaccination.” New England Journal of Medicine. 384 (22)
(June 2021): 2124–2130. https://doi.org/10.1056/nejmoa2104882.
[25] Scully, Marie., Deepak Singh, Robert Lown, Anthony Poles, Tom
Solomon, Marcel Levi, David Goldblatt, Pavel Kotoucek, William
Thomas, and William Lester. “Pathologic antibodies to platelet
factor 4 after chadox1 ncov-19 vaccination.” New England Journal
of Medicine. 384 (June 2021):2202-2211. https://doi.org/10.1056/
NEJMoa2105385.
[26] See, Isaac., John Su, Allison Lale, Emily Jane Woo, Alice Guh, Tom
Shimabukuro, Michael Streiff, et al. “US case reports of cerebral
venous sinus thrombosis with thrombocytopenia After
Ad26.COV2.S vaccination, March 2 to April 21, 2021.” Journal of
the American Medical Association. 325(24) (June 2021):2448-2456.
https://doi.org/10.1001/jama.2021.7517.
[27] Stam, Jan. “Thrombosis of the cerebral veins and sinuses.” New
England Journal of Medicine, 352 (April 2005): 1791–1798.
https://doi.org/10.1056/NEJMra042354.
[28] Thakur, Kiran., Arina Tamborsk, Greta K. Wood, Emily McNeill,
David Roh, Imo J. Akpan, Eliza C. Miller, et al. “Clinical review of
cerebral venous thrombosis in the context of COVID-19
vaccinations: Evaluation, management, and scientific questions.”
Journal of Neurological Science. 427 (August 2021):117532.

https://dx.doi.org/10.1016%2Fj.jns.2021.117532.
[29] Tiede, Andreas., Ulrich Sachs, Andreas Czwalinna, Sonja
Werwitzke, Rolf Bikker, Joachim Krauss, Frank Donnerstag, et al.
“Prothrombotic immune thrombocytopenia after COVID-19
vaccine.” Blood. (April 2021). https://doi.org/10.1182/blood.
2021011958.
[30] Wolf, Marc., Beate Luz, Ludwig Niehaus, Pervinder Bhogal,
Hansjörg Bäzner and Hans Henkes. “Thrombocytopenia and
intracranial venous sinus thrombosis after “COVID-19 vaccine
AstraZeneca” exposure.” Journal of Clinical Medicine. 10(8) (April
2021): 1599.
[31] World Health Organization. “COVID-19 Weekly Epidemiological
Update.” World Health Organization, August 24, 2021. https://www.
who.int/emergencies/diseases/novel-coronavirus-2019/situation-
reports.
INDEX
allergic rhinitis, vii, ix, 90, 94, 101, 102

A
alveolar macrophage, 60
amaurosis, 9, 15, 21
abatacept, viii, 2, 3, 17, 20, 21, 22, 40, 50
amaurosis fugax, 8, 9, 15, 21
acute mesenteric ischemia, 191
anakinra, 21, 22, 40, 203, 204, 213
acute renal failure, 226
ANCA associated vasculitis, 44, 59, 90
acute respiratory distress syndrome, 71
anemia, viii, 1, 8, 107
acute respiratory failure, xii, 222, 226, 235
aneurysm, x, 37, 48, 51, 52, 53, 54, 55, 67,
acyclovir, 168, 169, 170, 171, 175
68, 132, 141, 145, 150, 156
adalimumab, 19, 22, 39, 239
angioedema, xi, 200, 205, 210
adaptive immune response, 97
angiogenesis, 6, 70
adenovirus, 246, 247, 249, 252
angiogram, 50, 164
adults, 2, 3, 21, 64, 131, 143, 157, 168,
angiography, 10, 19, 38, 127, 134, 135,
171, 172, 173, 184
138, 164, 165, 192, 255
adventitia, 5, 48, 162, 166
ankylosing spondylitis, 239
adverse effects, viii, xii, 3, 36, 112, 245,
anorexia, 10, 133, 189
256, 257
antibiotic, 168
AECA, 128
antibody, ix, 21, 45, 47, 48, 58, 62, 63, 66,
age, 2, 3, 7, 49, 51, 56, 59, 60, 62, 64, 68,
90, 91, 128, 144, 152, 161, 167, 176,
93, 101, 112, 131, 133, 136, 141, 156,
186, 202, 203, 210, 222, 234, 239, 242
157, 168, 170, 182, 187, 224, 225, 230,
anticoagulant, 40, 236, 256
232, 248, 251
anticoagulation, 235, 256
aging population, 171
antigen, 20, 97, 98, 159, 166, 173, 201,
airflow obstruction, 58
202, 223
264 Index
antigen-presenting cells, 20, 223 asthma, vii, ix, 60, 61, 83, 90, 91, 92, 94,
antihistamines, 210 95, 100, 101, 102, 105, 107, 109, 110,
anti-inflammatory medications, 64 111, 113, 117, 119, 121, 123, 187, 206
antineutrophil cytoplasmic autoantibody asymptomatic, 68, 108, 134, 148, 152, 183
associated vasculitis, 181 atherosclerosis, x, 126, 130, 142, 143, 144,
antiphospholipid antibodies, 210 182
antiphospholipid syndrome, 223, 227, 238 atherosclerotic vascular disease, xi, 180
antiviral agents, 171 autoantibodies, 49, 128, 202, 243, 253
antiviral therapy, 55, 185 azathioprine, 19, 22, 39, 53, 55, 59, 67, 69,
anti-VZV IgG antibody, 167, 176 110, 121, 185, 190, 211
aorta, 49, 51, 52, 131, 132, 133, 137, 182,
183
B
aortic insufficiency, 134, 139
aortic regurgitation, 132, 133
B cell depletion, 222, 237
aortic stenosis, 134
baricitinib, 21, 41
aortic valve, 134, 141
basement membrane, 47, 62, 63, 71
aphasia, 163, 165, 170
Behcet disease, 183
aphthous ulcers, 189
Behcet syndrome, 181, 189, 197
apoptosis, ix, 90, 94, 98, 130, 158
beneficial effect, 20, 111, 223, 234, 236
arrhythmias, 138, 140, 141
benefits, viii, xii, 111, 169, 211, 246, 259
arterial hypertension, 51, 134
benign, xi, 27, 142, 200
arteries, vii, viii, 1, 5, 6, 7, 8, 11, 12, 13,
bias, 190, 256
26, 27, 44, 48, 52, 55, 91, 98, 134, 150,
bilateral, 9, 11, 30, 56, 63, 66, 68, 69, 71,
165, 167, 175, 181, 185, 186, 254
134, 159, 225
arteriography, 51, 52, 54
bile, 183
arterioles, 59, 135, 186
bile duct, 183
arteritic anterior ischemic optic
biocompatibility, 235
neuropathy, 9
biopsy, viii, ix, xi, 1, 2, 8, 10, 22, 23, 27,
arteritis, viii, 1, 2, 3, 5, 21, 24, 25, 27, 28,
30, 31, 37, 49, 51, 52, 54, 56, 57, 58, 61,
29, 31, 32, 35, 36, 37, 38, 39, 40, 44, 46,
62, 63, 65, 90, 99, 100, 107, 109, 165,
47, 48, 49, 51, 52, 54, 58, 127, 132, 133,
166, 167, 168, 192, 200, 205, 207, 209,
135, 139, 140, 141, 142, 145, 146, 147,
225, 227
148, 150, 165, 180, 182, 183
bleeding, 102, 112, 113, 181, 187, 188,
artery, viii, x, 1, 2, 5, 7, 8, 10, 11, 12, 22,
191, 225, 235
26, 27, 30, 31, 32, 33, 37, 49, 50, 51, 52,
blindness, viii, 2, 9, 14, 15, 16, 104
53, 54, 55, 66, 105, 127, 131, 134, 136,
blood, vii, viii, x, 4, 8, 15, 25, 43, 44, 45,
137, 141, 145, 147, 149, 150, 151, 153,
46, 48, 51, 52, 54, 57, 61, 63, 70, 72, 91,
156, 175, 182, 187
101, 106, 108, 125, 126, 127, 133, 158,
arthralgia, vii, xi, 7, 57, 64, 65, 199
159, 164, 165, 166, 169, 192, 201, 202,
arthritis, 27, 36, 38, 39, 47, 66, 68, 69, 104,
203, 209, 225, 234, 237, 259, 262
105, 200, 205, 210
blood cultures, 192
assessment, 7, 30, 32, 34, 147, 151, 260
Index 265
blood flow, 15 133, 135, 136, 137, 138, 140, 142, 143,
blood pressure, 8, 51, 52, 54, 133 145, 146, 149, 185, 196, 208
blood supply, vii cardiovascular disease, 131, 136, 145
blood urea nitrogen, 108 cardiovascular morbidity, x, 126
blood vessels, 48, 61, 70, 127, 158, 164, cardiovascular system, 69, 127, 142
192, 203 central nervous system, x, 47, 66, 100, 112,
bowel, xi, 54, 113, 180, 181, 182, 183, 185, 155, 157, 173, 174, 176, 177
187, 191 central retinal artery occlusion, 8, 9, 104
bowel obstruction, xi, 180 central retinal vein occlusion, 104
bowel perforation, 54, 187 cerebellitis, 157
brain, 104, 108, 118, 162, 163, 164, 165, cerebellum, 159
166, 168, 173, 174, 176, 226, 246, 253, cerebral aneurysm, 165
254, 260 cerebral arteries, x, 156, 161
brain herniation, 254 cerebral edema, 170, 254
brain structure, 162 cerebral hemorrhage, 104, 105, 113
brainstem, 159 cerebral venous sinus thrombosis, vi, 245,
breathing, ix, 44 246, 249, 258, 259, 260, 261
bronchial asthma, 91 cerebrospinal fluid, 176
bronchiectasis, 66 cerebrovascular complications, 157, 171
bronchiolitis, 54 chemokines, 6, 97, 128, 223, 234
bronchitis, 99 chicken pox, 161
bronchoscopy, 58 childhood, 149, 158, 184, 241
bronchus, 58, 69 children, 53, 55, 63, 136, 138, 149, 157,
164, 168, 172, 187
cholecystitis, 103, 183, 189
C
Churg-Strauss syndrome (CSS), ix, 46, 75,
83, 90, 91, 92, 93, 94, 95, 96, 97, 99,
C1q preceptin, 202
100, 101, 102, 103, 104, 105, 106, 107,
calcification, 67, 131, 159, 161
108, 109, 110, 111, 112, 113, 114, 115,
caliber, 45, 54, 126, 171
116, 117, 118, 119, 120, 121, 122, 123,
carbon monoxide, 58
151, 152, 181, 186, 187, 197
cardiac catheterization, 149
circulation, 164, 175, 189
cardiac enzymes, 132
classification, 7, 28, 45, 46, 51, 92, 126,
cardiac involvement, 61, 104, 108, 112,
143, 180, 235
127, 133, 135, 138, 139, 141, 150, 151
claudication, 6, 7, 8, 9, 10, 21, 49, 51, 131,
cardiac structure, 133
133
cardiac tamponade, 137
clinical diagnosis, 8, 12, 13, 14, 167
cardiomyopathy, 106, 112, 136, 138, 139,
clinical judgment, 192
140, 232
clinical presentation, x, 29, 91, 100, 151,
cardiovascular, v, vii, x, 20, 25, 69, 81,
156, 163, 183, 206, 230
100, 103, 105, 125, 126, 127, 130, 132,
clinical symptoms, 16, 163
clinical trials, 21
266 Index
complement, xi, 107, 128, 199, 200, 201, cyclosporine, 68, 231
202, 203, 205, 209, 223 cytokines, 10, 39, 48, 94, 96, 97, 128, 203,
complications, v, vi, vii, ix, x, 2, 4, 6, 7, 8, 222, 223, 234
10, 11, 14, 15, 16, 17, 20, 22, 40, 43, 44, cytomegalovirus, 17, 156, 173
56, 64, 69, 71, 72, 102, 125, 126, 127, cytoplasm, 45, 186, 229
131, 137, 138, 142, 149, 152, 155, 157, cytotoxic agents, 63, 66
164, 170, 171, 174, 179, 200, 212, 223,
247
D
compression sign, 12, 32
computed tomography, 13, 50, 164, 165,
deaths, 103, 225, 229, 233, 235
184, 192, 225
deposition, 59, 63, 64, 96, 201, 203, 205,
conduction, 108, 134, 138, 140, 141, 153
209, 223, 234
connective tissue, viii, 43, 45, 69, 72, 126,
destruction, 56, 69, 72, 97, 98, 99, 202, 203
238
detection, 11, 13, 33, 167, 188
coronary arteries, 133, 135, 136, 138
diagnostic criteria, 46, 51, 57, 61, 67, 91,
coronary artery aneurysms, 136, 149
92, 106, 109, 209
coronary artery disease, 132
diarrhea, xi, 61, 102, 105, 108, 180, 181,
coronary heart disease, 149
185, 186, 189, 191, 207
corticosteroid therapy, 27, 36, 70, 144
diastolic blood pressure, 4
corticosteroids, viii, xii, 2, 20, 45, 69, 95,
differential diagnosis, 68
102, 116, 117, 123, 169, 172, 222, 224,
diffuse alveolar hemorrhage, xi, 48, 54, 58,
225, 226, 231, 232, 233, 234
65, 86, 107, 111, 119, 221, 222, 223,
cough, 49, 51, 54, 56, 57, 59, 61, 64, 66,
238, 240, 241, 242, 243, 244
67, 71, 72
dilated cardiomyopathy, 232
COVID-19, vi, viii, xii, 70, 75, 86, 245,
dilation, x, 48, 126, 134, 150, 162, 164,
246, 247, 248, 251, 252, 254, 256, 257,
165
258, 259, 260, 261, 262
disease activity, 7, 28, 41, 45, 127, 128,
Cowdry, 159, 166
133, 146, 211, 223, 225, 232, 233
cranial nerve, 8, 104, 163, 170, 208
disease progression, 212, 222
creatinine, 54, 108, 112, 113, 192, 209
diseases, vii, 45, 46, 51, 62, 67, 72, 112,
crescentic glomerulonephritis, 100, 207
126, 149, 180, 186, 188, 194, 200, 210,
cross-sectional study, 132
222, 262
cryoglobulinemic vasculitis, 47, 64, 84,
disorder, ix, 44, 64, 68, 69, 165, 188
138, 181, 183, 186, 187, 188, 193, 195
dispersion, 139, 152
CSF analysis, 166, 167
disseminated intravascular coagulation,
CSF polymerase chain reaction, 166
258
CSF VZV antibody index, 167
distribution, 25, 26, 61, 62, 107, 173, 176,
cyclophosphamide, xii, 19, 22, 38, 39, 58,
246, 253, 260
65, 68, 69, 82, 110, 111, 116, 184, 185,
DNA, x, 155, 156, 166, 167, 210, 253
189, 190, 193, 195, 211, 222, 223, 225,
dosage, 15, 16, 95, 224
226, 228, 229, 230, 231, 232, 233, 234,
dosing, 15, 168, 169, 247
236, 242, 243
Index 267
drugs, 15, 16, 19, 22, 53, 70, 71, 110, 111 evidence, 16, 17, 19, 58, 91, 109, 133, 159,
dyspnea, xi, 54, 57, 59, 61, 64, 66, 68, 71, 164, 165, 169, 177, 192, 206, 256
76, 132, 200, 206
F
E
facial nerve, 11, 31
edema, 12, 32, 48, 64, 183, 191 fever, viii, 1, 2, 6, 8, 10, 53, 55, 59, 68, 69,
encephalitis, 157, 162, 163, 166, 167, 168, 91, 101, 131, 133, 162, 163, 165, 183,
169, 170, 172, 173, 174, 175, 176, 177 184, 191
endothelial cells, 48, 71, 128, 129, 143, fibrin, 131, 203, 209
144, 203 fibrinoid necrosis, 5, 126, 162, 168
endothelium, 70, 128, 130, 143, 162, 205, fibrosis, 48, 57, 60, 65, 135, 138, 139, 152
209 five-factor score (FFS), ix, 90, 110, 112,
eosinophil, ix, 62, 90, 94, 96, 97, 98, 109, 113, 117, 185
111, 112, 139 formation, 6, 49, 130, 132, 133, 134, 141,
eosinophil count, 112, 139 191
eosinophilia, vii, ix, 83, 90, 91, 92, 94, 97, foscarnet, 169
101, 102, 104, 106, 107, 109, 110, 113, functional changes, 128, 130
119, 187 fusion, 20
eosinophilic granuloma, vii, 44, 45, 90, 98,
101, 105, 113, 127, 142, 151, 152, 181,
G
186
eosinophilic granulomatosis with
gadolinium, 139, 164
polyangiitis (EGPA), vii, ix, 45, 46, 47,
ganciclovir, 169
48, 60, 61, 62, 90, 91, 92, 93, 94, 95, 96,
gastroenteritis, 102
97, 98, 99, 100, 101, 102, 103, 104, 105,
gastroesophageal reflux, ix, 44
106, 107, 108, 109, 110, 111, 112, 113,
gastrointestinal, vi, vii, ix, xi, 54, 59, 61,
114, 117, 127, 138, 139, 140, 142, 150,
66, 68, 69, 90, 99, 100, 101, 102, 103,
151, 152, 181, 186, 187
105, 108, 112, 113, 117, 121, 162, 179,
eosinophilic pneumonia, 96, 99, 107
180, 181, 182, 183, 184, 185, 186, 187,
eosinophils, ix, 5, 58, 60, 61, 62, 90, 94,
188, 189, 190, 191, 192, 193, 194, 195,
97, 99, 103, 106, 107, 113, 139, 209
196, 197, 207
epidemiologic, 24, 27, 143, 168
gastrointestinal bleeding, xi, 59, 61, 69,
epidemiology, vii, ix, x, xii, 23, 24, 46, 90,
105, 113, 180, 181, 187, 191
91, 143, 149, 156, 172, 245, 252
gastrointestinal involvement, 54, 68, 112,
episcleritis, 207, 209
181, 183, 184, 186, 187, 188, 189
etanercept, 19, 40
gastrointestinal tract, ix, 90, 99, 101, 186,
ethnic groups, 234
187, 189, 190, 191
etiology, ix, x, 2, 5, 48, 53, 90, 91, 96, 126,
giant cell arteritis (GCA), v, vii, viii, 1, 2,
156, 168, 181
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,
268 Index
27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, hepatitis, 53, 55, 65, 148, 150, 185, 192,
38, 39, 40, 41, 47, 48, 49, 50, 51, 53, 76, 194, 202, 209, 232, 239
77, 78, 131, 132, 133, 135, 144, 145, herpes, 156, 157, 159, 165, 171, 172, 173,
146, 165, 180, 182,183, 184, 197 174, 175, 176, 177
glomerulonephritis, vii, xi, 53, 56, 58, 59, herpes simplex, 172, 173, 174, 175, 176,
61, 62, 63, 65, 66, 100, 103, 105, 144, 177
199, 200, 207 herpes simplex virus, 156, 159, 161, 162,
glucocorticoids, x, 11, 13, 14, 15, 16, 35, 166, 172, 173, 174, 177
50, 53, 55, 58, 62, 63, 65, 66, 67, 90, 95, herpes zoster ophthalmicus, 157
109, 110, 111, 112, 114, 131, 185, 189, herpesviridae, v, vii, x, 155, 156, 169, 170
190, 210, 211 history, xii, 91, 127, 149, 150, 165, 171,
granulomas, 5, 68, 98, 99, 103, 107 174, 192, 222, 227
granulomatosis with polyangiitis, 44, 46, HSV-1, 157, 158, 159, 162, 163, 171, 174
47, 91, 111, 140, 151, 181, 183, 186, HSV-2, 156, 157, 158, 162, 163, 166
187, 222 hyperplasia, 5, 6, 12, 48, 130, 131
granulomatous, viii, 2, 5, 6, 8, 27, 46, 51, hypersensitivity, 5, 71, 200, 201
52, 57, 58, 60, 68, 85, 91, 97, 98, 102, hypertension, 16, 69, 103, 131, 132, 133,
105, 122, 131, 133, 165, 183, 186 134, 135, 138, 254
granulomatous arteritis, 165 hypocomplementemia, vii, xi, 65, 188, 199,
granulomatous vasculitis, 2, 5, 68, 98, 131 200, 209, 212, 226, 228, 229, 235
guidelines, 3, 10, 11, 12, 13, 19, 29, 176, hypocomplementemic urticarial vasculitis
223, 256, 258 (HUV), xi, 47, 84, 181, 199, 200, 201,
202, 203, 204, 205, 206, 207, 208, 209,
210, 211, 212, 213, 214, 215, 216, 217,
H
218, 219
hairy cell leukemia, 53
halo sign, 12, 32 I
headache, viii, 1, 2, 6, 7, 8, 9, 21, 131, 162,
163, 165, 248, 254 IgA vasculitis, 48, 64, 186, 187
heart block, 139, 152 immune activation, 97
heart disease, 126, 127, 132, 134, 140, 141, immune reaction, 49
145, 149, 150, 153 immune response, 70, 96, 128, 156, 158,
heart failure, 61, 138, 232 173, 176, 201, 252
hemoptysis, 51, 54, 57, 58, 59, 60, 67, 68, immunocompromised, 157, 159, 162, 164,
69, 71, 206, 225, 239 165, 166, 168, 169, 171, 173
hemorrhage, x, xi, 48, 50, 54, 56, 57, 58, immunofluorescence, 58, 63, 209
60, 62, 63, 64, 65, 69, 71, 72, 73, 99, immunoglobulin, 20, 111, 181, 185, 194,
102, 104, 105, 107, 111, 113, 119, 156, 209, 231, 256
157, 162, 163, 165, 168, 182, 191, 221, immunoglobulin A vasculitis, 47, 181
222, 223, 225, 227, 238, 239, 240, 241, immunoglobulins, 187, 210
242, 243, 244, 254 immunosuppression, 72, 114, 223
Index 269
immunosuppressive agent, xi, 45, 62, 112, intranuclear inclusion bodies, 159
142, 180, 193, 211, 234 intravenous immunoglobulins, 114, 212,
impairments, 9 218
improvements, 126, 181 intussusception, xi, 180, 183, 191
in vivo, 129 ischemia, xi, 8, 21, 44, 51, 53, 54, 69, 108,
incidence, ix, x, xii, 2, 3, 4, 16, 31, 37, 44, 126, 132, 133, 135, 136, 137, 138, 166,
49, 53, 60, 92, 126, 127, 135, 138, 150, 180, 182, 183, 185, 188, 189, 190, 191,
182, 185, 201, 221, 226, 227, 231, 233, 192, 193
248, 251, 254, 255, 256, 257 ischemic colitis, xi, 180, 191
induction, 35, 38, 59, 110, 185, 193, 236
infarction, 50, 51, 53, 67, 104, 112, 113,
J
126, 132, 134, 159, 165, 189, 191, 238,
254
jaw claudication, 6, 7, 8, 49, 131
infection, vii, viii, xii, 16, 17, 43, 45, 58,
joint destruction, 206
63, 72, 107, 156, 157, 158, 159, 161,
162, 163, 164, 165, 166, 167, 169, 170,
171, 173, 174, 175, 185, 188, 224, 235, K
246, 248, 251, 252, 257
inflammation, vii, viii, x, 1, 5, 6, 8, 9, 10, Kawasaki disease, 47, 55, 56, 80, 81, 136,
14, 16, 21, 22, 27, 33, 43, 44, 48, 50, 51, 137, 149, 150, 180, 183, 184, 185, 193,
57, 58, 59, 60, 63, 65, 66, 70, 72, 91, 194, 196
125, 126, 127, 130, 131, 134, 140, 142, Korea, 148, 240, 241
144, 158, 159, 160, 162, 169, 171, 185,
186, 200, 202, 203, 205, 209, 223 L
inflammatory bowel disease, 239
inflammatory cells, 5, 48, 158, 159 large intestine, 182, 190
infliximab, 19, 22, 39, 190 large vessel vasculitis, viii, 13, 17, 23, 31,
initiation, 12, 13, 14, 21, 170, 175, 256 32, 33, 44, 72, 74, 126, 131, 135, 183,
injury, iv, viii, 6, 11, 31, 43, 48, 71, 96, 184, 198
129, 133, 139, 141, 143, 158, 159, 183, lesions, viii, 2, 6, 11, 31, 32, 55, 57, 65, 66,
203, 254 67, 68, 96, 99, 100, 131, 133, 134, 136,
interleukin-1, 17, 21, 40, 71, 94, 123, 129, 139, 140, 147, 149, 151, 153, 167, 183,
130 187, 203, 205
interleukin-18, 129 leukocytes, x, 54, 158, 180, 203
interstitial lung disease, 50 leukocytoclastic vasculitis, 47, 99, 143,
interstitial nephritis, 100, 103, 105 201, 203, 205, 209, 213
interstitial pneumonia, 60, 71 leukotriene antagonists, 71, 102
intestinal obstruction, 102, 105 liver, 103, 182, 183, 185, 192, 209
intestinal perforation, 186, 188 liver disease, 103
intima, 5, 48, 162, 166 liver function tests, 209
intracerebral hemorrhage, 168 lung vasculitis, 44
intracranial pressure, 163, 254
270 Index
lupus, xi, 69, 191, 205, 207, 221, 223, 224, methylprednisolone, xii, 35, 110, 222, 225,
226, 227, 229, 230, 232, 233, 234, 235, 226, 230, 231, 232, 233
237, 238, 240, 241, 242, 243 microscopic polyangiitis, 44, 45, 47, 59,
lupus anticoagulant, 227 60, 82, 86, 91, 105, 111, 114, 135, 139,
lupus erythematosus, 191, 237, 238, 241 152, 185, 186, 187, 188, 195, 196, 197,
lymph, 56, 68, 105 222, 239, 243
lymphadenopathy, 56, 68, 105 mitral insufficiency, 134, 139
lymphocytes, 13, 17, 21, 28, 49, 50, 52, 58, mitral regurgitation, 137, 150
111, 128, 209, 223, 233 mitral valve, 134, 136, 137, 141
lymphoma, 157, 188, 222 mitral valve prolapse, 134
molecular structure, 156
monoclonal antibody, 3, 17, 20, 41, 95,
M
111, 222
mononeuritis multiplex, 60, 104, 105
macrophages, 5, 6, 13, 49, 52, 58, 69, 225,
morbidity, xi, 16, 100, 110, 113, 114, 133,
227
166, 170, 171, 173, 188, 194, 199, 206,
magnetic resonance, 19, 32, 33, 34, 134,
212, 246, 248, 254
148, 151, 164, 165, 169, 255
mortality, x, xi, 4, 69, 100, 108, 112, 113,
malaise, 2, 6, 10, 101, 133
114, 126, 127, 133, 136, 143, 157, 166,
malignancy, viii, 43, 45, 72, 107, 222, 248
170, 173, 194, 199, 206, 212, 221, 224,
management, vii, viii, 1, 3, 11, 23, 28, 29,
226, 227, 230, 232, 233, 235, 236, 241,
35, 45, 68, 72, 108, 149, 172, 176, 182,
246, 248, 254
184, 185, 190, 193, 194, 223, 236, 237,
mortality rate, xii, 170, 222, 227, 230, 232,
238, 240, 243, 258, 261
254
mechanical ventilation, 63
myalgia, 7, 53, 57, 59, 101, 104
media, 5, 49, 102, 105, 131, 158, 166, 175
mycophenolate mofetil, 19, 38, 53, 59,
median, 18, 20, 60, 93, 248
184, 193, 211, 219, 231
medical, 36, 45, 68, 126, 181, 189, 190,
myelitis, 157, 163, 164, 174, 177, 208, 213
224
myocardial infarction, 17, 61, 132, 134,
medication, ix, 44, 71, 72, 96, 169, 225,
136, 138, 141
227, 230, 231
myocardial ischemia, 134
medicine, 24, 27, 32, 34, 37, 39, 144, 171
myocardial necrosis, 151
medium vessel vasculitis, viii, 44, 64, 126,
myocarditis, 127, 132, 135, 137, 139, 140,
135, 137
142, 146, 148, 150, 223, 229, 232, 238,
meningitis, 157, 162, 173, 177, 208, 218
239
mental status change, 165
myocardium, 133, 139
mental status changes, 165
mesenteric vessels, 182, 183, 185, 189
meta-analysis, 4, 10, 11, 13, 16, 23, 25, 30, N
31, 32, 33, 37, 172
methotrexate, viii, 2, 16, 19, 22, 37, 38, 50, nasal polyp, 60, 101, 102, 105
53, 55, 58, 110, 121, 184, 185, 193, 195
Index 271
nausea, xi, 102, 105, 108, 180, 181, 185, pathogenesis, ix, 2, 4, 5, 6, 17, 21, 24, 28,
186, 191, 207 70, 90, 91, 93, 94, 95, 96, 128, 129, 175,
necrosis, 5, 7, 11, 44, 58, 59, 68, 98, 99, 180, 202, 203, 211, 222
108, 126, 135, 158, 159, 160, 162, 168, pathology, x, 8, 26, 27, 37, 98, 103, 156,
170, 175, 180, 183, 234 173, 208
necrotizing glomerulonephritis, 60, 62, 129 pathophysiological, 71, 144
necrotizing vasculitis, vii, ix, 53, 58, 60, pathophysiology, vii, x, xii, 6, 7, 46, 126,
90, 91, 207 127, 156, 158, 172, 201, 207, 245, 253
nephritis, 64, 69, 207, 223, 228, 229, 230, pathway, 21, 98, 131, 201, 202, 203, 253
232, 237, 238, 240, 243 perforation, xi, 61, 102, 105, 112, 113, 180,
nerve, 31, 62, 65, 69, 99, 104, 108 188, 190, 191, 193
nervous system, 57, 69, 113, 158, 172, 173 pericardial effusion, 104, 105, 108, 132,
neuropathy, 8, 9, 57, 59, 104, 105, 108, 137, 139, 140, 146
175 pericarditis, 57, 61, 127, 132, 136, 137,
neutropenia, 17, 18, 40, 110, 239 138, 139, 140, 141, 150
neutrophils, xi, 5, 48, 58, 66, 71, 97, 129, peripheral blood, ix, 61, 90, 92, 96, 113
166, 200, 203, 209 peripheral nervous system, 157, 170
nodules, 50, 53, 56, 57, 58, 59, 60, 61, 68, peripheral neuropathy, 59, 90, 100, 105,
102, 103, 104, 105 106, 208
plasma cells, 52, 58, 223, 234
plasmapheresis, 63, 65, 69, 203, 230, 231
O
platelet aggregation, 20
pleural effusion, 50, 55, 57, 61, 66, 67, 68,
obstruction, 6, 60, 102, 105, 184, 191
69, 102, 105, 107, 139
obstructive lung disease, 66
pleuritic chest pain, 54, 132
occlusion, x, 8, 48, 50, 51, 52, 54, 105,
pleuritis, 57, 59, 68, 69
126, 133, 135, 153, 159, 165, 171, 189,
polyarteritis nodosa, viii, 44, 47, 48, 53,
254
54, 79, 80, 91, 105, 111, 112, 114, 117,
organ, viii, xi, 44, 45, 47, 52, 57, 58, 61,
118, 135, 137, 142, 148, 180, 181, 183,
62, 65, 67, 70, 71, 92, 100, 110, 111,
184, 185, 186, 187, 188, 195, 196, 197,
126, 138, 181, 190, 192, 200, 221, 223,
198, 239
226, 228, 229, 252
polymerase, 166, 174, 175
otitis media, 56, 102, 105
polymerase chain reaction, 166, 174, 175
overlap, 7, 45, 72, 100, 181
polymyalgia rheumatica, viii, 1, 2, 4, 7, 8,
9, 23, 24, 25, 28, 29, 35, 38, 39, 41, 49,
P 76, 131, 145
population, x, 15, 25, 37, 60, 92, 145, 146,
pain, vii, xi, 8, 48, 51, 54, 57, 61, 64, 65, 151, 156, 157, 162, 170, 172, 248, 251,
66, 67, 68, 104, 108, 132, 180, 181, 183, 254, 255, 257
184, 185, 186, 187, 188, 189, 191, 194, prednisone, 15, 16, 17, 18, 211, 242
199, 200, 207, 209 prognosis, ix, 26, 35, 90, 103, 108, 110,
pancreatitis, 103, 112, 113, 181, 183, 188 133, 135, 139, 146, 147, 150, 170, 224
272 Index
pro-inflammatory, 39, 48, 222, 223 rheumatoid arthritis, 47, 69, 85, 86, 126,
proliferation, 131, 159, 161, 162, 168 186, 187, 190, 197, 206, 222
proteinuria, xi, 108, 112, 200, 207, 223 rituximab, viii, xi, 21, 22, 40, 41, 58, 65,
pulmonary circulation, 133 69, 82, 111, 119, 212, 216, 221, 222,
pulmonary diseases, xi, 199 225, 228, 229, 237, 238, 239, 241, 242,
pulmonary embolism, 69, 224 243
pulmonary function test, 107
pulmonary hypertension, 52
S
pulmonary vasculitis, viii, 44, 45, 49, 50,
51, 66, 69, 70, 71, 72, 73, 74, 78, 80, 88,
sarcoidosis, 47, 68, 103, 117, 126, 239
244
SARS, viii, xii, 48, 70, 245, 246, 248, 252,
purpura, 53, 57, 59, 61, 63, 64, 65, 183,
258, 259, 260
187, 205
SARS-CoV, viii, xii, 48, 70, 245, 246, 248,
252, 258, 259, 260
R seizures, 157, 158, 163, 165, 170, 208, 248,
254
reactive oxygen, 6, 48, 98, 130 sensitivity, 11, 12, 13, 14, 50, 52, 54, 57,
receptor, 22, 71, 95, 151, 202, 204, 253, 58, 59, 64, 67, 92, 109, 127, 131, 165,
256 167
recommendations, iv, 16, 23, 31, 33, 111, sensorineural hearing loss, 102
176, 223, 238 serum, 4, 6, 17, 27, 60, 63, 66, 96, 106,
recovery, 233, 234, 236 108, 113, 168, 187, 192, 209
recurrence, xii, 169, 171, 211, 222, 231, sinusitis, 56, 60, 100, 101, 102, 105, 108
232, 233, 234, 236 skin, ix, xi, 53, 54, 57, 60, 61, 64, 65, 66,
remission, 17, 18, 19, 20, 38, 39, 50, 58, 90, 100, 103, 165, 187, 200, 201
59, 111, 112, 114, 139, 144, 151, 184, skin biopsy, ix, xi, 90, 200, 209
185, 211, 223, 235, 236 small vessel vasculitis, ix, 44, 62, 65, 76,
renal artery stenosis, 134 126, 138, 140, 143
renal dysfunction, 138 stenosis, x, 15, 37, 48, 50, 51, 52, 53, 56,
renal failure, 111, 113, 228, 229, 235 57, 58, 125, 133, 134, 136, 138, 141,
renal replacement therapy, 63 146, 162, 164, 165, 169, 182, 206
resolution, xi, 33, 34, 55, 107, 136, 164, steroid, 6, 11, 12, 14, 15, 16, 17, 18, 19, 20,
167, 169, 171, 174, 177, 180, 203, 225, 21, 22, 38, 39, 40, 51, 53, 55, 62, 101,
255 212, 216
respiratory dysfunction, xii, 222, 224 stroke, x, 10, 17, 132, 156, 157, 162, 163,
respiratory failure, xii, 222, 226, 235 164, 168, 171, 172, 259
response, 12, 15, 17, 39, 49, 69, 96, 111, surgical intervention, 189, 190, 191
129, 131, 158, 169, 203, 223, 225, 232, survival, x, xii, 18, 20, 63, 90, 93, 94, 97,
233, 234, 237, 252, 253 111, 112, 126, 127, 146, 147, 181, 185,
rheumatic diseases, 27, 29, 32, 39, 40, 237, 222, 225, 232, 234, 235, 236, 240, 241
240
Index 273
symptoms, vii, viii, ix, 1, 4, 6, 7, 8, 9, 10, 226, 227, 231, 232, 233, 234, 235, 236,
15, 20, 21, 44, 45, 49, 50, 51, 52, 53, 54, 237, 238, 239, 241, 242, 243
57, 59, 61, 64, 66, 67, 69, 100, 101, 102, thrombocytopenia, xii, 226, 232, 235, 246,
108, 132, 133, 138, 139, 162, 163, 165, 247, 249, 253, 255, 256, 258, 259, 260,
167, 168, 170, 174, 181, 182, 184, 185, 261, 262
186, 188, 189, 191, 192, 193, 194, 207, thrombocytosis, 20
210, 212, 225, 254 thrombomodulin, 131
syndrome, vii, ix, xi, 44, 46, 47, 60, 62, 63, thrombosis, x, xii, 5, 50, 67, 126, 127, 135,
65, 66, 68, 69, 71, 72, 90, 113, 141, 150, 136, 139, 143, 156, 157, 162, 163, 165,
151, 152, 153, 157, 163, 174, 175, 181, 175, 246, 247, 249, 252, 253, 255, 256,
189, 199, 200, 202, 209, 212, 218, 226, 258, 259, 260, 261, 262
228, 229, 238, 239, 242 thrombus, 67, 108, 134, 140, 141, 152,
systemic lupus erythematosus, vi, viii, xi, 153, 191
56, 68, 85, 87, 126, 190, 191, 200, 201, time frame, 166
202, 204, 213, 218, 221, 222, 237, 238, tissue, viii, 19, 43, 44, 58, 91, 92, 94, 97,
239, 240, 241, 242, 243 98, 99, 130, 139, 158, 202, 203, 223
systemic vasculitis, x, 44, 45, 46, 47, 49, TNF, 6, 19, 22, 48, 50, 68, 70, 71, 130, 193
60, 61, 70, 76, 83, 92, 100, 101, 104, TNF-α, 6, 19, 22, 48, 50, 68
105, 106, 107, 109, 113, 116, 119, 126, tocilizumab, viii, 2, 3, 7, 17, 18, 22, 23, 37,
127, 136, 143, 144, 152, 194 38, 50, 53, 78, 184, 197
systolic blood pressure, 51 tofacitinib, 21
treatment, vii, viii, ix, x, 2, 3, 11, 12, 13,
14, 15, 16, 17, 18, 20, 24, 32, 35, 36, 37,
T
38, 39, 40, 41, 44, 45, 50, 53, 56, 58, 62,
63, 64, 66, 69, 90, 91, 93, 95, 101, 106,
Takayasu arteritis, viii, 30, 37, 44, 47, 48,
110, 111, 113, 114, 149, 156, 158, 166,
51, 52, 78, 79, 133, 135, 142, 145, 146,
168, 169, 170, 171, 175, 176, 183, 185,
147, 148, 182, 183, 193, 195, 196
193, 203, 210, 211, 222, 231, 232, 233,
temporal arteritis, 2, 27, 29, 30, 31, 36, 46,
237, 239, 242, 243, 255, 256
47, 49, 131, 182
temporal artery biopsy, viii, 1, 2, 10, 27,
30, 31, 49, 77 U
temporal artery USG, 12, 22
therapeutic approaches, 243 ultrasonography, viii, 2, 32, 50, 52, 184
therapeutic effect, 234 ultrasonography (USG), viii, 2, 6, 11, 12,
therapeutic goal, 256 13, 15, 31, 32, 50, 52, 184
therapeutics, 224, 234 underlying mechanisms, 144
therapy, x, xii, 3, 6, 12, 18, 35, 36, 40, 53, United Kingdom, 25, 250
59, 64, 65, 68, 71, 97, 110, 126, 131, upadacitinib, 21, 41
147, 166, 168, 171, 175, 184, 185, 189, upper respiratory tract, 56
190, 194, 210, 212, 218, 222, 223, 225, urinary tract, 232, 233
urinary tract infection, 232, 233
274 Index
urticaria, vii, xi, 66, 199, 200, 201, 202, venous sinus thrombosis, 157, 163, 165,
204, 205, 208, 209, 212, 214, 215, 216, 246, 249, 258, 259, 260, 261, 262
218 venules, 59, 186, 200, 203, 205
urticarial vasculitis (UV), vii, xi, 65, 199, vessel involvement, 2, 10, 23, 37, 52, 126,
200, 201, 202, 203, 204, 205, 206, 207, 127, 135, 165
208, 209, 210, 211, 212, 213, 214, 215, vessels, viii, x, 2, 10, 14, 44, 45, 46, 47, 49,
216, 217, 218, 219 50, 52, 53, 55, 59, 60, 66, 67, 69, 72, 91,
ustekinumab, viii, 2, 3, 17, 20, 21, 22, 40, 101, 133, 134, 135, 136, 141, 156, 158,
50 162, 164, 165, 166, 173, 181, 186, 191,
uveitis, vii, xi, 66, 199, 207, 210 201, 254
viral infection, 70, 247
virus infection, 54, 65, 159, 174, 176, 185
V
viruses, x, 155, 156, 170
vision, 9, 14, 15, 22, 132, 165, 239
vaccination, vi, viii, xii, 185, 245, 246,
vision loss, 14, 15, 22, 132, 165
247, 249, 250, 251, 252, 253, 254, 255,
visual, 6, 7, 8, 9, 10, 21, 23, 27, 29, 35, 36,
257, 258, 259, 260, 261
49
vaccine, xii, 246, 247, 248, 249, 251, 254,
visual disturbances, 7
256, 258, 259, 260, 262
visual loss, 6, 7, 8, 9, 23, 27, 35, 49
vaccine-induced thrombotic
visual symptoms, 8, 10, 21
thrombocytopenia, xii, 246, 253
vomiting, xi, 102, 105, 108, 163, 180, 181,
valvular heart disease, 127
183, 184, 185, 186, 189, 191, 207
variable vessel vasculitis, 73, 126, 141
varicella Zoster Virus, 156, 164, 167
vascular diseases, 4, 132 W
vascular wall, 2, 44, 162
vasculature, 6, 44, 59, 60, 72, 171, 191, weight loss, 10, 53, 59, 68, 100, 101, 131,
201 133, 191
vasculitides, x, 3, 34, 44, 45, 46, 47, 48, 61, wheezing, 61, 66
72, 126, 127, 142, 143, 151, 156, 176, worldwide, 246, 252
180, 181, 182, 184, 186, 189, 193, 194
vector, viii, xii, 245, 246, 247, 249, 250,
Z
251, 252, 253, 255, 256, 257
vein, 209, 254, 258
zoster oticus, 157
venography, 255

Vasculitis - From Diagnosis To Treatment

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RHEUMATISM AND MUSCULOSKELETAL DISORDERS

FROM DIAGNOSIS TO TREATMENT

Additional books and e-books in this series can be found

FROM DIAGNOSIS TO TREATMENT

NOTICE TO THE READER

Library of Congress Cataloging-in-Publication Data

ISBN:  HERRN

Published by Nova Science Publishers, Inc. † New York

Chapter 6 Gastrointestinal Complications of Vasculitis 179

Vasculitis refers to diseases that cause blood vessel walls to thicken

biologics in treating rheumatology disorders, with rituximab being

incidence rate of 20-100 cases/million/year with a prevalence rate of 150-

EGPA is systemic glucocorticoids which has shown to improve 5-year

gastrointestinal manifestations that vary from general and/or postprandial

modality. Twenty patients (1.8% incidence), 18 females (90%) ages 19 to

GIANT CELL ARTERITIS

Harsha Pattnaik1, MD, Nicky N. Chopra2, MD,

Giant Cell Arteritis (GCA) is the inflammation of middle and large

the gold standard of diagnosis, patchy pan-arteritis, with focal

Keywords: giant cell arteritis, temporal arteritis, polymyalgia rheumatica,

Giant cell arteritis, also called temporal arteritis, is a granulomatous

fast, and comparable diagnostic efficacy and have been recommended in

Denmark has the highest reported incidence of 76.6/100,000 people [2].

PATHOLOGY AND PATHOPHYSIOLOGY

Giant cell arteritis is a systemic granulomatous vasculitis that affects

symptoms - headache, jaw claudication, neuro-ophthalmic complications,

IL-6 plays a crucial role in the pathophysiology of GCA. A correlation

Signs and Symptoms

The American College of Rheumatology (ACR) states that for the

Table 1. Giant Cell Arteritis Classification Criteria

ACR Classification Revised ACR EULAR Consensus for Active

The most dreaded visual complication of GCA is irreversible blindness

Table 2. Differential Diagnosis of Giant Cell Arteritis Based on

Giant Migraine Trigeminal Central Herpes

In extracranial GCA, PMR is the most common association. 40–60%

In the initial workup of a suspected case of GCA, laboratory findings

Temporal Artery Biopsy

histopathology of various types of lesions seen in TAB at different stages

Due to comparable sensitivity to TAB and being non-invasive and fast,

Vasculitis treatment aims to subdue the inflammation. The

EULAR recommends starting steroids immediately on suspicion of

Interleukin-Receptor Blocking Agents

in both groups. 85% reached complete remission by three months in the

A small 2018 study selected normalization of vessel wall enhancement

Additional Comments on Treatment

GCA is associated with thrombocytosis and occlusive-ischemic

New Treatment Developments

While both Abatacept and Ustekinumab are promising candidates,

intervention, lest delays lead to permanent vision loss. Other systemic

“This research was supported (in whole or in part) by HCA Healthcare

represent the official views of HCA Healthcare or any of its affiliated

[1] Lyons H. S., V. Quick, A. J. Sinclair, S. Nagaraju, and S. P. Mollan,

[8] Weyand C. M. and J. J. Goronzy, “Giant-Cell Arteritis and

[17] Mackie S. L. et al., Association of HLA-DRB1 amino acid residues

subgroups and prognosis,” Seminars in Arthritis and Rheumatism,

[33] S. D and L. KU, “Temporal arteritis. Comparison of histological and

vol. 50, no. 11, p. 2061, 2011, doi: 10.1093/RHEUMATOLOGY/

[50] Gonzalez-Gay M. A., S. Barros, M. J. Lopez-Diaz, C. Garcia-

and Takayasu Arteritis,” Arthritis and Rheumatology, vol. 73, no. 8,

Diagnose Giant Cell Arteritis,” J Rheumatol First, 2009, doi:

[76] Chrysidis S. et al., “Original article: Definitions and reliability

Musculoskeletal Disorders, vol. 11, p. 44, 2010, doi: 10.1186/ 1471-

[91] B. TA et al., “Diagnostic value of high-resolution MR imaging in

ISBN: HERRN