Granulomatosis With Polyangiitis

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]
(A1)

• 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]
(A1)

• 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.(A1)

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](A1)

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](B3)

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] (B3)

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](A1)

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](A1)

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