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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

Granulomatosis With Polyangiitis

Priyatha Garlapati; Preeti Rout; Ahmad Qurie.

Author Information and Affiliations

Last Update: August 31, 2024.

Continuing Education Activity

Granulomatosis with polyangiitis is a rare form of vasculitis affecting small

vessels. Hallmark features include necrotizing granulomas and pauci-immune
vasculitis, most commonly affecting the upper respiratory tract, lungs, and
kidneys. Antineutrophil cytoplasmic antibody–associated vasculitis diseases
comprise granulomatosis with polyangiitis, microscopic polyangiitis, and
eosinophilic granulomatosis with polyangiitis. These syndromes share
overlapping etiologies and clinical presentations, particularly granulomatosis
with polyangiitis and microscopic polyangiitis. Due to the variable systemic
manifestations, a high index of suspicion is required for accurate diagnosis.
Despite their rarity, these diseases are associated with significant morbidity and
mortality and have been the focus of numerous recent clinical trials. These trials
have generated extensive data and treatment recommendations. This activity
describes the clinical presentation, evaluation, and treatment of granulomatosis
with polyangiitis, highlighting the role of the interprofessional team in treating
patients with this disease.

Objectives:

Differentiate between granulomatosis with polyangiitis and other forms of

vasculitides, including systemic lupus erythematosus, microscopic
polyangiitis, and eosinophilic granulomatosis with polyangiitis.

Screen patients with upper respiratory tract, lung, and kidney symptoms for
potential signs of granulomatosis with polyangiitis to ensure early detection
and intervention.

Implement evidence-based treatment protocols for managing

granulomatosis with polyangiitis, including the use of immunosuppressive
therapies.

Collaborate with an interprofessional healthcare team, including

rheumatologists, nephrologists, and pulmonologists, to provide
comprehensive care for patients with granulomatosis with polyangiitis.

Access free multiple choice questions on this topic.

Introduction

Granulomatosis with polyangiitis (GPA), formerly known as Wegener's

granulomatosis, is a necrotizing vasculitis affecting small to medium-sized
vessels. GPA is part of a spectrum of disorders known as antineutrophil
cytoplasmic antibody (ANCA)–associated vasculitides. The 3 main ANCA-
associated vasculitides are GPA, microscopic polyangiitis (MPA), and eosinophilic
granulomatosis with polyangiitis (EGPA or Churg-Strauss syndrome). This
classification was established at the 2012 Chapel Hill Consensus Conference on
the Nomenclature of Systemic Vasculitides.[1] GPA is characterized by a
pulmonary-renal syndrome associated with otorhinolaryngological
manifestations.

The first case of GPA was described by German medical student Heinz Klinger in
1931. In 1936, a German pathologist, Friedrich Wegener, described 3 cases of
peculiar small-medium vessel vasculitis with granulomatous inflammation and
identified the disorder as a distinct form of vasculitis. In 1954, Godman and Churg
published a review involving 22 cases, and the disease was universally known as
Wegener's granulomatosis.[2] In 1989, Wegener was awarded a Master Clinician
Prize by the American College of Chest Physicians. In 2000, Wegener's Nazi ties
came to light, and a movement began to rename the disease in the clinical
community. The board of directors of the American College of Rheumatology
(ACR), the American Society of Nephrology, and the European League Against
Rheumatism recommended a switch to disease-descriptive nomenclature. Hence,
the disease was renamed GPA.[3]

Please see StatPearls' companion resources, "ANCA Positive Vasculitis,"

"Microscopic Polyangiitis," and "Eosinophilic Granulomatosis with
Polyangiitis," for more information.

Etiology

Several complex interactions involving genetics and microbes have been

implicated in the etiology of GPA. The presumption that ANCAs are responsible
for inflammation in GPA is now widely accepted. Defective immune-regulatory
responses to environmental factors, such as infection or autoantigens, can lead to
excessive production of cytokines, which in turn may develop inflammatory
granulomatous vascular lesions.[4]

Understanding the 2 primary types of ANCAs—anti-proteinase 3 (PR3) and anti-

myeloperoxidase (MPO)—is crucial for comprehending the disease process. Some
studies suggest that the specific type of ANCA may have better prognostic value
compared to the clinical presentation of the disease. ANCA in GPA typically reacts
with PR3, a serine proteinase prevalent in neutrophil granulocytes. When ANCA
binds to PR3, it activates neutrophils, increasing their adherence to the
endothelium and triggering degranulation, which can damage endothelial cells.
[5] In GPA cases, anti-PR3 is positive in about 75% of cases; anti-MPO antibody is
positive in about 10% of cases; fewer than 10% are ANCA-negative.[5] With MPA,
anti-MPO is positive in about 70% of cases.[3]

Neutrophils from GPA patients are more likely to produce neutrophil

extracellular traps and exhibit lower DNAse I activity, leading to decreased
clearance of neutrophil extracellular traps. Neutrophil extracellular traps are
composed of decondensed chromatin and intracellular granules that capture cell
components.[6][7] Anti-PR3 binds to neutrophils, leading to degranulation,
reactive oxygen species, adhesion to endothelial cells, and secretion of pro-
inflammatory cytokines, especially interleukin-8.[5] Although neutrophils are an
integral part of innate immunity, adaptive immunity responses are also
significant. B-cells specific to PR-3 are associated with disease activity and risk of
relapse.[8]

Genetic associations in GPA include the following:

A defective allele for alpha-1 antitrypsin

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which is involved in

T-cell activation

PR3 gene

Major histocompatibility complex, class II, DP alpha-1 (HLA-DP) gene

Certain types of FC gamma receptor III b on the surface of neutrophils and

macrocytes or monocytes [9]

Infections: In addition to the initiation and exacerbation of the vasculitic process,

infectious agents have also been known to modulate the clinical phenotype of the
disease.

Bacterial: Colonization with Staphylococcus aureus has been hypothesized as

an initiating factor for inflammation observed in GPA because it is
associated with neutrophil extracellular trap release.[6]

Viral: Association with various viruses, including hepatitis C virus,

cytomegalovirus, Epstein-Barr virus, and parvovirus, have been reported.
[10]

Drugs Linked to Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

Certain medications can induce ANCA-associated vasculitis, typically manifesting

as rapidly progressive glomerulonephritis. Specifically, a high MPO titer is
common. Levamisole, which is often found in contaminated cocaine, can cause
the elevation of both anti-MPO and anti-PR3 antibodies, along with other
autoantibodies, skin lesions, and arthralgias. Treatment is the same as that of
other ANCA-associated rapidly progressive glomerulonephritis cases, but possibly
with shorter induction, and prolonged maintenance is typically unnecessary.
Once the drug is discontinued, relapse is uncommon, unlike disease associated
with PR3/MPO. The most common offending medications include these:

Hydralazine

Propylthiouracil and methimazole

Allopurinol

Sulfasalazine

Minocycline
 Penicillamine

Rifampicin

Aminoguanidine

Sofosbuvir

Anti-tumor necrosis factor-alpha therapy for rheumatoid arthritis and

ankylosing spondylitis [11]

Double-Positive Antibody Disease

Also called dual antibody disease, this type of crescentic glomerulonephritis is

associated with a positive ANCA and anti-glomerular basement membrane (GBM)
antibody. Some studies indicate that 10% to 50% of patients with anti-GBM
disease have detectable ANCA, typically anti-MPO. In contrast, up to 10% of
patients with ANCA-associated vasculitis also have circulating anti-GBM
antibodies.[12] Generally, the positive ANCA precedes the anti-GBM
antibodies; therefore, it is postulated that ANCA leads to the anti-GBM antibodies
by exposing epitopes on the GBM. Renal manifestations follow an anti-GBM
pattern, whereas systemic symptoms are similar to those of ANCA vasculitis.[13]
[14] This double-positive characteristic comes into play during treatment
selection.[8][15]

Epidemiology

Among the 3 ANCA-associated vasculitides, GPA is the most common. The annual
worldwide incidence of GPA is estimated to be 10 to 20 cases per million based on
the geographical location. A higher incidence is noted in the colder regions. The
prevalence of GPA in European and American populations is about 120 to 140 per
million.[16] A national study in the Netherlands on ANCA-associated vasculitis
found that 167 patients (73%) were diagnosed with GPA, 54 (24%) with MPA, and
9 (4%) with EGPA. This distribution is similar to other European registries.[17]

GPA is more commonly reported in Whites, although it can be observed in all

racial and ethnic groups. The onset of GPA occurs between 45 and 60 years, but a
small proportion (3%-7%) affects children and adolescents. Children younger
than 18 have a female-to-male predominance of about 2:1, while in adults, the
ratio is 1:1.[18]

Pathophysiology

The etiology of GPA is attributed to ANCA, which causes an immune-mediated

vasculitis of small- and medium-sized vessels, primarily affecting the ears, nose,
throat, lungs, and kidneys. The primary morbidity of the GPA is related to
necrotizing sinusitis, pulmonary capillaritis, and glomerulonephritis.[5]

The formation of granulomas in GPA begins with the development of neutrophilic

microabscesses. The granulomas in GPA ultimately result in partial or total
occlusion of blood vessels. The granulomas in GPA are not well-formed, unlike the
ones in sarcoidosis or tuberculosis, and consist of giant cells surrounded by
plasma cells, lymphocytes, and dendritic cells. These cells can damage the
submucosa and penetrate the surrounding tissues, cartilage, or bone, resulting in
necrosis and permanent deformities.[4][19]

A significant overlap exists between the 3 ANCA-associated vasculitides,

particularly GPA and MPA. MPA is a necrotizing vasculitis primarily involving
small vessels and is less likely to involve the upper airways; pathology does not
demonstrate granulomas. MPA is associated with pulmonary fibrosis, a condition
that is rare in GPA.[20]

Histopathology

Histopathological evaluation of various organs, including kidneys, skin, and

lungs, can be performed to detect vasculitis and immune deposits. The lung is the
most common site for biopsy, followed by renal biopsy.

Lung:

A lung biopsy shows granulomas surrounded by palisading histiocytes and

giant cells with central necrosis. The central necrosis leads to liquefaction or
coagulative necrosis in the lungs with profuse eosinophils and
multinucleated giant cells. Necrotizing or granulomatous vasculitis is found
in small arteries and veins, and the lumens can be occluded by granulomas
or thrombi.[20]

Given the patchy involvement of GPA, targeted lung biopsy is recommended

rather than biopsy without correlation to imaging. CT scans and 18-F-
fluorodeoxyglucose positron emission/CT scans can also be used to identify
active lesions to increase the biopsy yield. Avoiding necrotic areas is also
preferable.[20]

Kidney:

Light microscopy shows necrotizing and crescentic glomerulonephritis.

Cellular, microcellular, and fibrous crescents may all be present,
representing different stages of disease progression. Immunofluorescence
staining is typically negative or very light for immunoglobulins (Ig) or
complement. If present, the small amounts are more likely to be present in a
segmental distribution (unlike the diffuse distribution of immune complex
glomerulonephritis).[21]

The percentage of capsular rupture, fibrous crescents, tubular atrophy, and

interstitial fibrosis are linked with increased progression to end-stage renal
disease.[22]

Please see StatPearls' companion resource, "Rapidly Progressive

Glomerulonephritis," for more information.

History and Physical

GPA typically presents with a triad of symptoms as follows:

 Upper respiratory tract, including sinusitis, crusting rhinitis, saddle nose
deformity, otitis media, mastoiditis, and hearing loss, and lower respiratory
tract, such as lung nodules and alveolar hemorrhage

Systemic vasculitis

Kidney involvement, such as glomerulonephritis [23]

GPA shows a significant overlap with MPA. Alveolar hemorrhage and crescentic
necrotizing glomerulonephritis are also observed in MPA.

Generalized Systemic Symptoms

GPA typically presents with nonspecific symptoms of generalized systemic

disease, including fever, malaise, weight loss, polyarthralgia, and myalgia.[24]

Systemic manifestations are as follows: [24]

Upper respiratory tract involvement: Studies show that approximately 90% of

patients experience upper respiratory tract issues. Early symptoms often include
nasal and sinus pain, sinus stuffiness, purulent nasal discharge, nasal ulcerations,
epistaxis, and otitis media. Clinical signs such as sinusitis, crusting rhinitis, otitis
media, mastoiditis, and hearing loss should alert for GPA. Nasal inflammation can
lead to septal perforation or nasal bridge collapse, causing a saddle nose
deformity.[24]

Lower respiratory tract involvement: Symptoms include cough, hemoptysis,

dyspnea, sometimes pleuritic chest pain, and tracheal obstruction can be noted.
Nearly 50% of patients initially present with bilateral or unilateral pulmonary
infiltrates. Pulmonary nodules (referred to as coin lesions) are common. Pleural
effusion has also been reported in 15% to 20% of cases. Diffuse pulmonary
hemorrhage is a significant cause of morbidity and mortality in these patients.
[25][26]

Renal involvement: Upon presentation, renal involvement is noted in only

10% to 20% of cases, but glomerulonephritis eventually develops in 80% of
patients within 2 years of disease onset. The most common manifestation is
rapidly progressive crescentic glomerulonephritis, leading to chronic kidney
disease or end-stage renal disease.

Eye involvement: Eye involvement occurs in more than half of the people with
the disease. Scleritis and conjunctivitis are the most common
manifestations. Scleritis can lead to necrotizing anterior scleritis, eventually
causing blindness. Peripheral ulcerative keratitis is the most significant corneal
complication of GPA that could lead to corneal melt syndrome. Other
manifestations include episcleritis and anterior uveitis. In 10% to 15% of the
patients, orbital masses in the retrobulbar region can occur, known as
pseudotumors. These pseudotumors can cause diplopia, proptosis, or vision loss.
Nasolacrimal duct obstruction is frequently observed in GPA.[27]

Ear involvement: Both conductive and sensorineural hearing loss are typical of
the disease. Conductive hearing loss often results from auditory tube dysfunction
secondary to nasopharyngeal disease. Some individuals may also experience
sensorineural hearing loss and vestibular dysfunction. Middle ear involvement,
including serous otitis media and mastoiditis, is also observed.

Skin: Dermatologic involvement is reported in 50% to 60% of patients with GPA,

with purpura commonly involving the lower extremities. Other common
manifestations, including cutaneous nodules, particularly involving the
olecranon regions, are common and can be mistaken for rheumatoid arthritis.
Less commonly, ulcers, papules, vesicles, and subcutaneous nodules (granulomas)
may occur.

Nervous system: Nervous system involvement is observed in about 30% to 40%

of the patients, with peripheral neuropathies being the most common.
Neuropathy could lead to mononeuritis multiplex. Cranial neuropathies,
pachymeningitis, seizures, and cerebritis have also been reported.

Musculoskeletal: Arthralgia and myalgia are observed in 70% of patients. Joint

symptoms are common, but diagnosis with this alone is rarely made without
other manifestations. Arthralgias are more common compared to arthritis. The
presence of joint pains, along with subcutaneous nodules and rheumatoid factor
positivity, can often lead to misdiagnosis.

Cardiac: Cardiac involvement is not common and involves valvular lesions or

insufficiency, pericarditis, and coronary arteritis.

Childhood GPA

GPA is significantly more common in adults, particularly at older ages, compared

to children. Although the clinical presentation in children is generally similar to
that in adults, one notable difference is the increased risk of subglottic stenosis.
Patients younger than 20 are 5 times more likely than adults to develop subglottic
stenosis, a dangerous complication. Symptoms of tracheobronchial involvement
include hoarseness, cough, dyspnea, stridor, and wheezing. According to the
ARChiVe (A Registry for Children with Vasculitis), which includes 65 children with
GPA, 74% had pulmonary involvement, with 52% experiencing a chronic cough.
[20]

The most common manifestations are upper airway involvement (82%),

nephropathy (65%), and lower respiratory tract disease (61%). Systemic
symptoms are prevalent, occurring in about 73% of cases. Sinonasal disease is
often initially misdiagnosed as allergic rhinitis or rhinosinusitis. The longstanding
disease can lead to the destruction of the nasal cartilage, resulting in saddle-nose
deformity. Other upper airway manifestations include otitis, mastoiditis, oral
ulcers, mucocele, and hearing loss.[20]

Evaluation

Evaluating a patient with suspected GPA involves a complete clinical, laboratory,

radiological, and histopathological assessment. A thorough clinical evaluation is
crucial to determine the sites and extent of disease involvement.

The 2022 ACR/European Alliance of Associations for Rheumatology (EULAR)

classification criteria for GPA includes the following weighted criteria: [28]
 Bloody nasal discharge, nasal crusting, or sinonasal congestion (+3)

Cartilaginous involvement (+2)

Conductive or sensorineural hearing loss (+1)

Cytoplasmic ANCA or anti-PR3 ANCA positivity (+5)

Pulmonary nodules, mass, or cavitation on chest imaging (+2)

Granuloma or giant cells on biopsy (+2)

Inflammation or consolidation of the nasal/paranasal sinuses on imaging

(+1)

Pauci-immune glomerulonephritis (+1)

Perinuclear ANCA or anti-MPO ANCA positivity (−1)

Eosinophil count more than 1×109 cells/L (−4)

After excluding mimics of vasculitis, a patient diagnosed with small- or medium-

vessel vasculitis could be classified as having GPA if the cumulative score is 5 or
more points. When these criteria were tested in the validation dataset, the
sensitivity was 93%, and the specificity was 94%.[28]

Other Diagnostic Criteria

Various diagnostic criteria have been proposed to diagnose GPA and distinguish
the disease from other forms of vasculitis.

The ACR criteria include the following:

Urinary sediment showing red blood cell casts or more than 5 red blood
cells per high-power field,

Abnormal findings on chest radiography

Oral ulcer or nasal discharge

Granulomatous inflammation on biopsy.

The presence of 2 or more of the 4 criteria mentioned above is associated with a

92% specificity and 88% sensitivity.[25]

The ELK (E for ears, nose, and throat or upper respiratory tract; L for lung; and K
for kidney) proposed by DeRemee uses ANCA to diagnose. According to these
criteria, any typical manifestation involving the ELK, along with positive c-ANCA
or typical histopathological finding, qualifies for a diagnosis of GPA.[26]

Antineutrophil Cytoplasmic Antibody Testing

Although ANCA serology is essential for diagnosing ANCA-associated vasculitis,

the diagnosis cannot rely solely on ANCA testing, as positive results may also be
found in other inflammatory conditions. Often, these ANCAs are not specific to
PR3 or MPO; therefore, they cannot be visualized by the more specific
immunoassay techniques. Instead, they may be visualized by the less specific
immunofixation method.[29] Some less-specific ANCA antigens include cathepsin
G, lactoferrin, elastase, defensin, α-enolase, moesin, leukocidin, and bactericidal
permeability–increasing protein. The pathogenicity of these antigens is believed
to be low.[3]

ANCA serology for MPO or PR3 is positive in about 90% of GPA and MPO cases,
whereas it is positive in about 40% of EGPA cases.[30] A study found that GPA is
80% positive for anti-PR3, 15% positive for anti-MPO, and 5% ANCA-negative.[3]
Anti-PR3 antibodies are about 90% sensitive for diagnosing GPA.[5][31] Although
considered sensitive and specific for GPA, ANCA positivity has also been noted in
15% to 20% of patients with systemic lupus erythematosus, especially those with
lupus nephritis.[7]

Lysosome-associated membrane protein-2 (LAMP-2) is a protein that is believed

to provide structural integrity to lysosomes and help prevent autodigestion.
LAMP-2 antibodies are particularly interesting in ANCA-associated vasculitis
because they are found in patients with MPO and PR3 antibodies and may
contribute to the disease pathology. In addition, LAMP-2 antibodies have been
found in patients with active ANCA-associated vasculitis who are negative for
antibodies to MPO and PR3. Some evidence also suggests that LAMP-2 antibodies
correlate better with active disease compared to MPO/PR3 antibodies.[32]

ANCA can also be negative in some cases, particularly localized disease

presentations. A study involving patients with localized GPA found that only 46%
of patients were ANCA-positive and that ANCA positivity did not correlate with
the risk of relapse, transition to systemic disease, or refractoriness to treatment.
[33] Another study found that PR3 levels correlated with disease activity in only
about 25% of cases, suggesting that PR3 levels alone should not be used to
measure clinical activity or response to treatment; interactions with other
proteins may also be relevant.[5]

Antigen-specific immunoassays are considered more sensitive compared to

indirect immunofluorescence and are the more commonly used method in most
places. Please see StatPearls' companion resource, "Antinuclear Cytoplasmic
Antibody," for more information.

Radiology

Radiological evaluation of the sinuses, lungs, trachea, and orbits can be

performed to assess the sites and extent of involvement. A chest x-ray and
computed tomography (CT) scan of the lungs can be performed to identify
pulmonary lesions and hemorrhage, which can help differentiate GPA from MPA.

A chest x-ray is abnormal in about 89% of cases. Nodular lesions are the most
common radiologic finding. In children, these nodules typically range in size from
1 to 4 cm, while in adults, they can range from 1 to 10 cm. Without treatment, the
nodules enlarge and can cavitate.[20]

Given the patchy involvement of GPA, a targeted lung biopsy is recommended. CT

scans and 18-F-fluorodeoxyglucose positron emission/CT scans can also be used to
identify active lesions, increasing the biopsy yield. When performing biopsies, it
is preferable to avoid necrotic areas to ensure accurate diagnosis.[20]
Treatment / Management

The ACR and EULAR are developing criteria for treating ANCA-associated
vasculitis. Based on new clinical trial data, recent recommendations propose
classifying the disease as either organ/life-threatening or not, rather than severe
or not severe categories. Examples of organ/life-threatening disease
manifestations include glomerulonephritis, pulmonary hemorrhage, cardiac
involvement, or retro-orbital disease. Examples of non-organ/life-threatening
processes include skin involvement, myositis, and non-cavitating pulmonary
nodules.[31]

The treatment of GPA involves the use of immunosuppressive agents in a variety

of combinations. Treatment is classified into 2 phases—the induction phase and
the maintenance phase. Commonly used agents are cyclophosphamide,
glucocorticoids, rituximab, azathioprine, methotrexate, and plasmapheresis if
indicated.

The recommendations listed here apply to both GPA and MPA. EGPA involves a
different recommendation set. One key difference between GPA and MPA is
patients diagnosed with the clinical syndrome of GPA and PR3-ANCA positivity
have an increased relapse risk compared to patients clinically diagnosed with
MPA or who are MPO-positive. Persistent ANCA positivity despite clinical
remission is also associated with relapse.[31] Although immunosuppression
therapy longer than 24 months is associated with a decreased relapse risk, the
increased infectious risk may not warrant this longer treatment course.

The following are key points from the 2022 EULAR recommendations for
managing ANCA-associated vasculitis.[31]

For new-onset organ/life-threatening GPA (and MPA), induce remission with

glucocorticoids and rituximab or cyclophosphamide. Rituximab is preferred
for relapsing disease. No significant differences have been found between 2-
and 4-dose rituximab infusions.[34]

For new-onset non-organ/life-threatening GPA, induce remission with

glucocorticoids and rituximab. In some cases, methotrexate and
mycophenolate mofetil can be substituted for rituximab. Cyclophosphamide
is not preferred due to increased adverse effects, although it is equally
effective. A lower dose of prednisolone (0.5 mg/kg/d) can also be considered.

The induction regimen should use oral glucocorticoids at a dose of 50 to 75

mg of prednisolone daily (weight-dependent). Prednisolone should be
tapered to 5 mg daily for 4 to 5 months.

Avacopan is an oral C5a receptor antagonist that helps block neutrophil

attraction and activation. The ADVOCATE trial demonstrated that
avacopan can be used to induce remission along with rituximab or
cyclophosphamide, effectively reducing glucocorticoid exposure. Avacopan
was Food and Drug Administration-approved in 2021 for the treatment of
severe ANCA-associated vasculitis.[35]
 Plasma exchange can be used to induce remission in patients with
glomerulonephritis and a creatinine level of more than 3.39 mg/dL
(300 μmol/L). Routine use of plasma exchange for alveolar hemorrhage in
GPA (and MPA) is not recommended. However, plasma exchange is often
used as salvage therapy, particularly in patients with a creatinine of more
than 5.7 mg/dL.[36] A meta-analysis suggests that although plasma exchange
may reduce the risk of end-stage renal disease, it also increases the risk of
infections within the first year.[37]

For maintenance of remission, rituximab is recommended. Azathioprine or

methotrexate can also be considered, but their use should be reserved for
patients with eGFR more than 60 mL/min/1.73m2.[36]

For new-onset disease, maintenance should be continued for 24 to 48

months after the onset of remission. A longer treatment duration should be
considered for patients with relapsing disease.

Clinical assessment rather than ANCA or CD+19 B-cell levels should guide
treatment decisions.

If rituximab is used, serum immunoglobulin levels should be measured

before each dose.

For patients on rituximab, cyclophosphamide, or high-dose glucocorticoids,

prophylaxis with trimethoprim-sulfamethoxazole should be administered.

Rituximab Versus Cyclophosphamide

According to the RAVE and RITUXIVAS trials, rituximab was found to be non-
inferior to daily cyclophosphamide for the induction of remission in ANCA-
associated vasculitis, with a potential advantage in relapsing disease. Notably,
cyclophosphamide is considered to have a faster onset of action compared to
rituximab, which should be considered when rapid symptom control is necessary.
[30][38][39] In the RITUXIVAS trial, intravenous cyclophosphamide was
administered during the first six weeks due to the high prevalence of rapidly
progressive glomerulonephritis. The study evaluated rituximab's effectiveness in
maintaining immunosuppression and its impact on long-term prognosis.

Another consideration is that although the combination of cyclophosphamide and

high-dose glucocorticoids is effective in 90% of ANCA-associated vasculitis cases,
the 1-year mortality is about 15%, primarily related to active vasculitis and
infections. Rituximab has not been associated with significantly increased
infectious risks or profound leukopenia when used for rheumatoid arthritis and
non-Hodgkin lymphoma; however, studies have not shown it to have lower rates
of early severe adverse events compared to cyclophosphamide.[39]

The KDIGO 2021 guidelines suggest considering rituximab and cyclophosphamide

if serum creatinine exceeds 4.0; however, the ACR and EULAR guidelines do not
endorse this approach.[36]

Additional Therapeutics
Plasmapheresis: Plasmapheresis is considered in cases of rapidly declining
kidney function, presence of positive anti-glomerular basement membrane
antibodies, or pulmonary hemorrhage complicated by respiratory compromise
that does not respond to intravenous glucocorticoids.

Pulse steroids: Pulse steroids have not been shown more effective compared to
oral steroids, and observational data suggest an increased risk of infection
without added benefit.[31]

Methotrexate: The use of methotrexate for the induction of disease remission

rather than cyclophosphamide has also been studied, and 2015 EULAR
recommendations suggest methotrexate only for mild and non-organ-threatening
diseases. In addition, a low threshold to switch from methotrexate to stronger
immunosuppressive may be warranted.[30]

Mycophenolate mofetil: Mycophenolate mofetil is recommended primarily for

anti-MPO-positive disease and is less preferred in cases with anti-PR3 positivity.
[36]

Key Trials Informing Treatment for ANCA-Associated Vasculitis

The ADVOCATE trial compared the use of avacopan to glucocorticoids (along with
rituximab or cyclophosphamide) and found greater renal recovery and increased
remission at 1 year in the avacopan group. Although glucocorticoids were still
used in the avacopan group, the dose was reduced by about two-thirds, resulting
in fewer infections and serious adverse events in this group.[31][35]

The RITUXVAS trial assessed the efficacy of combining rituximab with

cyclophosphamide for induction compared to cyclophosphamide with
azathioprine for maintenance and found higher adverse events/infections in the
combination group after 2 years. Another randomized controlled trial
investigating combination therapy is ongoing (NCT03942887).[21][36]

The MYCYC trial comparing mycophenolate mofetil to cyclophosphamide showed

higher relapse rates with mycophenolate mofetil. As a result, mycophenolate
mofetil is recommended only if rituximab or cyclophosphamide is not tolerated.
[30]

The MAINRITSAN and RITAZAREM trials demonstrated the superiority of

rituximab to azathioprine for maintenance therapy. Rituximab biosimilars have
shown similar performance to rituximab in clinical trials.[31]

The REMAIN, AZA-ANCA, and MAINRITSAN-3 trials all showed reduced relapse
and end-stage renal disease with maintenance immunosuppression (both
azathioprine and rituximab were studied) lasting 36 to 48 months compared to
18 to 36 months.[31][34]

Maintenance therapy is initiated once remission is achieved, typically within 3

months. Patients are transitioned to maintenance therapy to avoid relapses. The
preference for agent selection depends on whether the patient has been newly
diagnosed or has more than 1 relapse. Other factors that influence the choice of
the maintenance agent used include a prior history of toxicity or comorbidity that
increases the risk of toxicity to a particular agent. Maintenance therapy typically
lasts 12 to 36 months after remission, but in high-risk patients, it may be
continued indefinitely.

Patients with drug-induced ANCA vasculitis typically do not require maintenance

therapy.[31]

Refractory disease lacks standardized treatment recommendations. As noted

above, plasmapheresis and IVIG have been used as salvage therapy. The use of
alemtuzumab in refractory ANCA-associated vasculitis was appraised in the open-
label ALLEVIATE trial and found complete or partial remission in 5 of 12 patients
(42%) at 1 year.[34]

Double antibody-positive disease occurs in about 10% of patients with rapidly

progressive glomerulonephritis, where they test positive for both ANCA and anti-
GBM antibodies. The clinical significance is that these patients may significantly
benefit from plasmapheresis, as recommended for anti-GBM disease.[31]

Differential Diagnosis

Due to the multisystemic nature of GPA, the differential diagnosis is

broad. Several conditions that can mimic GPA must be ruled out before a
definitive diagnosis can be made.

Other forms of ANCA-associated vasculitis:

MPA

Churg-Strauss syndrome

Drug-induced ANCA-associated vasculitis

Renal-limited vasculitis

Mixed cryoglobulinemia

Polyarteritis nodosa

Immunoglobulin A vasculitis (Henoch-Schönlein purpura)

Goodpasture syndrome

Other autoimmune disorders:

Systemic lupus erythematosus

Sarcoidosis

Rheumatoid arthritis

Amyloidosis

Infections:

Infective endocarditis

Sepsis

Mycobacterial infections
 Disseminated fungal infections

Disseminated gonococcal infection

Streptococcal pneumonia with glomerulonephritis

Malignancies:

Lymphomatoid granulomatosis

Lymphomas

Castleman's disease

Carcinomatosis

Miscellaneous:

Idiopathic pulmonary alveolar hemorrhage

Pertinent Studies and Ongoing Trials

Neutrophil surface SEMA4D is a potential therapeutic target for ANCA-associated

vasculitis, as it is a negative regulator of neutrophil activation.[40]

Cathepsin C is another potential therapeutic target, as it plays a role in the

maturation of PR3. Inhibiting cathepsin C could potentially reduce autoantigen
PR3 and anti-PR3 ANCA levels.[5]

Toxicity and Adverse Effect Management

The immunosuppressive agents used in the treatment of GPA have significant

adverse effects and can cause complications potentially worse than the disease
itself. The most common adverse effects are as follows:

Glucocorticoids

Hypertension

Diabetes mellitus

Arrhythmias

Gastrointestinal bleeding

Cataract

Glaucoma

Avascular necrosis of bone

Osteoporosis

Methotrexate

Hepatotoxicity

Stomatitis

Pneumonitis
 Bone marrow suppression

Cyclophosphamide

Bone marrow suppression

Infections

Gonadal toxicity

Hemorrhagic cystitis

Bladder carcinoma

Hyponatremia due to SIADH (syndrome of inappropriate antidiuretic

hormone secretion)

Myelodysplasia

Rituximab

Progressive multifocal leukoencephalopathy

Infusion reactions

Opportunistic infections

Late-onset neutropenia

Prognosis

A study found that after a median follow-up of 28 months, patients with a urine
protein-to-creatine ratio of more than 0.05 g/mmol were significantly associated
with a risk of kidney failure and death. Persistent hematuria was also associated
with worse outcomes, although to a lesser extent.[41]

GPA is associated with significant morbidity and mortality either due to

irreversible organ dysfunction or due to the consequences of intensive/prolonged
use of glucocorticoids and immunosuppressive agents. The average life
expectancy for a patient with GPA without any treatment is 5 months, with a 1-
year survival rate of less than 20%.[22] More than 80% of treated patients have
recently survived at least 8 to 9 years. This improvement in survival rates is
particularly notable as the disease primarily affects individuals older than 65.
With advances in treatment, patients also have a higher long-term survival rate
and have been able to lead a relatively normal life.[27]

Complications

Common complications due to the disease itself include the following:

Hearing loss

Permanent vision loss

Saddle nose deformity or septal perforation

Acute hypoxic respiratory failure due to diffuse pulmonary hemorrhage

 Chronic kidney disease and end-stage renal disease

Mononeuritis multiplex

Increased risk of heart disease, diabetes, and hypertension due to the

vasculitis process and its treatment

Complications due to immunosuppressive treatment include the following:

(please refer to the Toxicity and Adverse Effect Management for more
information)

Infections

Cancers, including lymphomas and myelodysplastic syndromes

Infusion reactions and death

Deterrence and Patient Education

Living with GPA can be extremely challenging. Patients often face fatigue, pain,
disease-related complications, medication side effects, and emotional stress, all of
which can significantly impact their well-being, work, and personal relationships.
Sharing experiences and difficulties with clinicians, family, and friends and
connecting with them through a support group can help immensely. Due to the
multisystemic nature of GPA, patients typically require care from multiple
healthcare providers, making it crucial to adhere to follow-up appointments and
treatment plans. Keeping a journal to track medications and appointments can be
a helpful tool in managing the complexities of the condition.

Enhancing Healthcare Team Outcomes

Providing patient-centered care for individuals with GPA requires a collaborative

effort among healthcare professionals, including clinicians, advanced practice
practitioners, pharmacists, and other healthcare providers. Healthcare providers
must possess the necessary clinical skills and expertise when diagnosing,
evaluating, and treating this complex multisystemic condition, including
proficiency in interpreting laboratory and radiological findings and recognizing
potential complications.

GPA is a multisystemic disease that requires an interprofessional team to cover

the broad spectrum of organ involvement. Rheumatologists, pulmonologists,
otolaryngologists, pathologists, radiologists, pharmacists, cardiologists, and
nephrologists play crucial roles in managing GPA. Effective communication
among these team members is key to successful patient care. Nurses are critical
in monitoring vital checks and measuring urine output. They also provide
immediate care to the patient and monitor them closely during infusions for
adverse effects. Many patients with GPA often see multiple specialists,
underscoring the importance of a coordinated, collaborative effort. Effective
interprofessional communication fosters a collaborative environment where
information is shared, questions are encouraged, and concerns are addressed
promptly.
Lastly, care coordination is crucial in ensuring seamless and efficient patient care.
Clinicians, advanced practitioners, pharmacists, and other healthcare providers
must collaborate to streamline the patient's journey, from diagnosis through
treatment and follow-up. This coordination minimizes errors, reduces delays, and
enhances patient safety, ultimately leading to improved outcomes. By prioritizing
the well-being and satisfaction of those affected by GPA, care coordination plays a
vital role in delivering patient-centered care.

Review Questions

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Disclosure: Priyatha Garlapati declares no relevant financial relationships with ineligible
companies.

Disclosure: Preeti Rout declares no relevant financial relationships with ineligible companies.

Disclosure: Ahmad Qurie declares no relevant financial relationships with ineligible companies.

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