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ANCA-Associated Vasculitis
Introduction
Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides are a heterogeneous group of rare autoimmune conditions that cause inflammation of blood vessels with various manifestations. This group includes 3 main diseases—granulomatosis with polyangiitis (GPA), formerly known as Wegener granulomatosis; eosinophilic granulomatosis with polyangiitis (EGPA), previously known as Churg-Strauss syndrome; and microscopic polyangiitis (MPA). Other ANCA-associated diseases include drug-induced vasculitis and renal-limited vasculitis.
Please see StatPearls' companion resources, "Granulomatosis with Polyangiitis," "Eosinophilic Granulomatosis with Polyangiitis," "Microscopic Polyangiitis," and "Rapidly Progressive Glomerulonephritis," for further information.
Etiology
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Etiology
The link between the clinical syndromes, such as GPA, EGPA, and MPA, and ANCA was established in 1988 when the sera of patients with crescentic glomerulonephritis were found to bind to neutrophils in 2 recognizable patterns—perinuclear or diffusely throughout the cytoplasm. Further examination revealed that these patterns correlated with 2 types of antibodies—perinuclear staining (P-ANCA) corresponds primarily with neutrophil myeloperoxidase (MPO) and cytoplasmic staining (C-ANCA) primarily against neutrophil proteinase 3 (PR3).[1][2][3] The aforementioned clinical syndromes are typically positive for either of those antibodies.
ANCA serology is positive in about 90% of GPA and MPO cases, whereas it is positive in about 30% of EGPA cases.[4] Anti-PR3 antibodies are about 90% sensitive for GPA.[5][6] Although 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, and other autoimmune conditions.[7]
C-ANCA with extranuclear cytoplasmic staining is 90% PR3-reactive and 10% MPO-reactive; P-ANCA with staining around the nucleus is 90% MPO-reactive and 10% PR3-reactive.[8]
Epidemiology
The peak onset of ANCA-associated vasculitides typically occurs between 45 and 60, with a slight male prevalence that varies by specific condition. Among the 3 main types of ANCA-associated vasculitides, GPA is the most common, followed by MPA and EGPA. Higher incidence rates are observed in colder regions. The prevalence of GPA in European and American populations is about 120 to 140 per million.[9][10] A national study in the Netherlands found that 167 patients (73%) were diagnosed with GPA, 54 patients (24%) with MPA, and 9 patients (4%) with EGPA. This distribution is similar to other European registries.[11]
Globally, the estimated incidence rates are 130 per million for GPA, 20 per million for MPA, and 1 to 3 per million for EGPA. GPA is more common than MPA in populations of European descent, whereas MPA is more common in China and Japan.[12]
Pathophysiology
Several complex interactions involving genetics and microbes have been implicated in the etiology of GPA. ANCA is responsible for inflammation in ANCA-associated vasculitis. Defective immune-regulatory responses to environmental insults, such as infection or autoantigens, can lead to excessive production of cytokines, ultimately resulting in the formation of inflammatory granulomatous vascular lesions.[13]
Understanding the 2 primary ANCA types—anti-PR3 and anti-MPO—is essential for comprehending the disease process. Some studies suggest that the type of antibody may have better prognostic value than the clinical syndrome patterns themselves. ANCA in GPA typically reacts with PR3, a serine proteinase prevalent in neutrophil granulocytes. ANCA activates neutrophils, which leads to increased adherence to endothelium and induces their degranulation, which can damage endothelial cells. 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.[6] With MPA, anti-MPO is positive in about 70% of cases.[12]
Neutrophils from patients with GPA are more likely to produce neutrophil extracellular traps and have lower DNAse I activity, leading to decreased NET clearance. Neutrophil extracellular traps are composed of decondensed chromatin and intracellular granules that capture cell components.[7][14] ANCA binds to neutrophils, leading to degranulation, reactive oxygen species, adhesion to endothelial cells, and secretion of pro-inflammatory cytokines, especially interleukin-8.[6] Although neutrophils are integral to innate immunity, adaptive immunity responses are also noteworthy. B-cells specific to PR3 are correlated with disease activity and risk of relapse.[15]
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 [16]
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 the release of neutrophil extracellular traps.[14]
- Viral: Association with various viruses, including hepatitis C virus, cytomegalovirus, Epstein-Barr virus, and parvovirus, have been reported.[17]
Drugs Linked to ANCA-Associated Vasculitis
Certain medications can induce ANCA-associated vasculitis, typically manifesting as rapidly progressive glomerulonephritis (RPGN). 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 RPGN cases, but possibly with shorter induction, and prolonged maintenance is typically unnecessary. Once the drug is discontinued, relapse is uncommon, unlike GPA/MPA. The most common offending medications include these:
- Hydralazine
- Propylthiouracil and methimazole
- Allopurinol
- Sulfasalazine
- Minocycline
- Penicillamine
- Rifampicin
- Aminoguanidine
- Sofosbuvir
- Anti-tumor necrosis factor-alpha (TNF-α) therapy for rheumatoid arthritis and ankylosing spondylitis [18]
Double-Positive Antibody Disease
Also called dual antibody disease, this type of crescentic glomerulonephritis is associated with a positive ANCA and anti-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.[19] 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.[20][21] This double-positive characteristic comes into play during treatment selection.[15][22]
Histopathology
Immunohistology typically reveals few or no immunoglobulin and complement deposits, so these conditions are called pauci-immune vasculitides.
- Granulomatosis with polyangiitis: A lung tissue biopsy shows evidence of vasculitis and necrotizing granuloma formation, which are characteristic of this disease. However, kidney biopsy does not show granulomas.
- Microscopic polyangiitis: Biopsy shows capillaritis without granuloma formation, leukocytoclastic changes, and crescentic glomerulonephritis in the kidneys.
- Eosinophilic granulomatosis with polyangiitis: Biopsy shows necrotizing vasculitis with eosinophilic infiltrates and eosinophilic granulomas.[23][24][25]
History and Physical
Patients with ANCA vasculitides typically present with symptoms such as fatigue, fever, and weight loss. However, these conditions can manifest in various clinical syndromes, as outlined below.
Granulomatosis With Polyangiitis
- GPA typically involves the upper and lower respiratory tracts and kidneys.
- Upper respiratory tract symptoms include bloody nasal discharge, nasal ulceration, sinusitis, and chronic otitis media. Damage of the nasal cartilage can cause the characteristic saddle nose deformity.
- Symptoms of the lower respiratory tract secondary to lung nodules and alveolar hemorrhage sometimes can be severe and fatal. Rarely it can cause tracheal stenosis.
- Renal involvement can cause rapidly progressive renal failure. The patient can present with high blood pressure, new-onset proteinuria, and active urinary sediments (hematuria, leukocyturia).[26][27][28]
- Around 90% of patients with multisystemic active GPA have ANCA positivity. Thus, an absence of ANCA does not necessarily rule out the diagnosis.
Microscopic Polyangiitis
- MPA causes necrotizing vasculitis of small vessels without granuloma formation, and it manifests commonly as glomerulonephritis that manifests with signs and symptoms of acute renal failure. Of note, kidney involvement is almost ubiquitous in MPA.
- Lung involvement in MPA is less common compared to GPA. When it does occur, it typically presents as capillaritis, causing severe alveolar bleeding. In addition, MPA can also cause pulmonary fibrosis.
- Around 90% of patients are ANCA-positive.
- In some cases, the disease is only limited to renal involvement without immunoglobulin and complement deposition, a condition sometimes called renal-limited MPA.[29]
Eosinophilic Granulomatosis With Polyangiitis
- EGPA can cause eosinophilic granulomatous lesions involving the skin, cardiac, gastrointestinal tract, and peripheral nervous system.[30]
- ANCA, both PR3 and MPO, have been associated with variable frequencies in these patients.
- Drug-induced ANCA vasculitis
- Several medications, such as propylthiouracil, methimazole, carbimazole, hydralazine, and minocycline, have been linked to the development of ANCA-associated vasculitis.
- This drug-induced form often causes constitutional symptoms such as arthralgias, fatigue, and skin rash.
- However, the full range of clinical features, including rapidly progressive renal failure and alveolar hemorrhage, can also occur.
Evaluation
The diagnosis of vasculitis requires a high index of suspicion due to its rarity and multisystemic nature. Obtaining a detailed history and performing a thorough physical examination are essential for managing vasculitis. A complete workup is required to establish the diagnosis, rule out other causes, and evaluate the severity of the disease and organ involvement. To establish the diagnosis, a combination of clinical assessment with serological testing is needed, and a tissue biopsy many times confirms the diagnosis.
Patients with GPA may demonstrate a C-ANCA pattern (with positive anti-PR3 antibodies) in addition to signs and symptoms of vasculitis. Although typical clinical features and serology can be sufficient for diagnosis, a tissue biopsy is often performed due to the high-risk nature of the treatment. A tissue biopsy of GPA shows vasculitis with necrotizing granulomas, except for a kidney biopsy, which only shows evidence of vasculitis without granulomas.[31][32]
In MPA, serology is typically positive for anti-MPO antibodies with a P-ANCA pattern in about 70% of cases, positive for PR3-ANCA in about 20% of cases, and ANCA-negative in 10% of cases.[12]
In EGPA, serology is positive for MPO in about 35% of cases and for anti-PR3 in about 5% of cases. However, around 60% of patients are ANCA-negative.[12] The characteristics of EGPA include patients having eosinophilia in their peripheral blood and in the tissues that are affected. The absence of eosinophilia should cast doubt on the diagnosis.[33]
In drug-induced ANCA-associated vasculitis, a detailed medication history is crucial. Many medications are linked to this condition, including propylthiouracil, methimazole, carbimazole, hydralazine, minocycline, allopurinol, penicillamine, procainamide, thiamazole, clozapine, phenytoin, rifampicin, cefotaxime, isoniazid, and indomethacin.
Patients should also be tested for antinuclear antibodies and anti-glomerular basement membrane antibodies, as systemic lupus erythematosus and Goodpasture syndrome (anti-glomerular basement membrane disease) can present similar clinical signs and symptoms. In addition, infections such as infective endocarditis and chronic hepatitis should be excluded, as they can also mimic the presentation of vasculitis.
To assess disease activity, inflammatory markers, persistence of ANCA antibodies, and kidney function (including urea and electrolytes, urine protein quantification, and urine microscopy) should be monitored. Disease activity can be tracked by clinical tools such as the Birmingham Vasculitis Activity Score (BVAS), which helps evaluate changes over time.[34][35]
Treatment / Management
Treatment for ANCA vasculitides typically begins with induction of remission to avoid or slow down organ involvement. The definition of remission has been standardized by the European Vasculitis Society/European League Against Rheumatism (EUVAS/EULAR) group, a no-detectable disease activity using a recognized scoring tool, such as BVAS.[36]
Induction of remission is typically achieved with cyclophosphamide in addition to high-dose steroids. In cases with life-threatening diseases or severe kidney involvement, plasma exchange is used along with induction treatment.[37][38] Recently, intravenous rituximab has been used for remission induction due to its fewer side effects compared to cyclophosphamide while providing the same therapeutic effect. Studies have demonstrated that rituximab has the same efficacy as cyclophosphamide in remission induction.[39][40] In patients with disease relapse, the RAVE study (rituximab versus cyclophosphamide for ANCA-associated vasculitis) showed that rituximab is superior to cyclophosphamide. In this study, 67% of patients achieved remission at 6 months versus 42% of patients treated with cyclophosphamide.[40] In some cases, methotrexate or mycophenolate mofetil may be used for remission induction, particularly in patients without evidence of organ or life-threatening disease.(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. 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.[41]
Differential Diagnosis
Small vessel vasculitides are classified into ANCA-associated vasculitides and immune complex vasculitides.
Immune complex vasculitides can present signs and symptoms similar to ANCA-associated vasculitides, but they are distinguished histopathologically by abundant immune complex deposition in affected tissues. These conditions can be caused by infections such as hepatitis B, hepatitis C, HIV, or endocarditis. They can also be caused by autoimmune conditions such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome. Cryoglobulinemia is one of the immune complex vasculitides that is caused by chronic hepatitis C infection.
Antiglomerular basement membrane disease (Goodpasture syndrome) can mimic ANCA vasculitis, affecting kidneys and lungs. Approximately 10% to 40% of patients with anti-glomerular basement membrane disease test positive for ANCA (dual positivity), which indicates a higher risk of relapse.
Atrial myxoma can also present with symptoms such as fatigue, fever, weight loss, purpuric skin rash, neurological involvement, and lung injury due to embolization.
Malignancy rarely can mimic vasculitis, either through direct involvement of blood vessels, as observed in lymphoma, or as a paraneoplastic syndrome.[42][43]
Prognosis
The prognosis for ANCA vasculitis has significantly improved, with 1-year mortality rates decreasing from 80% to 10%, and patients now achieve prolonged remission. However, relapses remain common, particularly in patients with GPA, where recurrence occurs in more than 50% of cases within 5 years.
Complications
Complications are caused either by the disease itself or as a result of its treatment.
Disease-related complications include the aforementioned manifestations and organ involvement, such as lungs, kidneys, and peripheral nerves. In addition, the patients are at increased risk for hypertension, coronary artery disease, myocardial infarction, mouth ulcers, and cerebrovascular disease.
Treatment-related complications include malignancy, chemical cystitis, marrow failure, gonadal failure, diabetes, and osteoporosis.[44][45][46]
Deterrence and Patient Education
Patients should be educated about the disease, its treatment, and its adverse effects. Key educational subjects are as follows:
Vasculitis refers to inflammation of the blood vessels, which can lead to vessel damage. As blood vessels carry oxygen and nutrients to body tissues, their damage can harm the affected tissues.
There are various types of vasculitis, some of which are medication-induced, while others occur without a known cause.
Symptoms of vasculitis include fatigue, muscle pain, fever, cough, hemoptysis, abdominal pain, blood in urine or weakness, and numbness in hands or feet.
Treatment for vasculitis includes steroids along with other medications that suppress the immune system, such as cyclophosphamide or rituximab.
Enhancing Healthcare Team Outcomes
The multisystemic nature of vasculitis, particularly ANCA-associated vasculitis, necessitates the involvement of an interprofessional healthcare team to ensure comprehensive patient care. ANCA-associated vasculitis often affects multiple organs, most notably the lungs and kidneys. The participation of rheumatologists, nephrologists, pulmonologists, pharmacologists, and nurses in patient care helps decrease the morbidity of the disease. Rheumatologists are essential for managing the overall disease process and coordinating care. Nephrologists are critical in monitoring and treating renal involvement, including rapidly progressive glomerulonephritis. Pulmonologists are vital for assessing and addressing pulmonary complications, such as alveolar hemorrhage and interstitial lung disease.
Pharmacologists are essential in optimizing medication regimens and balancing the efficacy of immunosuppressive therapies with adverse effects. Nurses provide critical support in patient education, monitoring for adverse effects, and ensuring adherence to treatment plans. This coordinated approach allows for early detection of complications, personalized treatment adjustments, and overall improvement in patient outcomes, reducing the morbidity associated with vasculitis. Collaboration among these specialists enhances patient care and contributes to a more holistic approach to managing this complex disease.
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