Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis is a group of rare autoimmune conditions causing inflammation in the body’s small blood vessels. This inflammation, known as vasculitis, results from the immune system mistakenly attacking healthy tissue. The condition is grouped under the umbrella term ANCA-associated vasculitis (AAV) due to the presence of specific self-reactive antibodies in the blood. Understanding whether this disease is passed down through families is important for its management.
Understanding How ANCA Vasculitis Damages the Body
The mechanism of ANCA vasculitis involves neutrophils, a specific type of white blood cell. Patients with AAV produce autoantibodies, known as ANCA, that target two proteins inside neutrophils: proteinase 3 (PR3) or myeloperoxidase (MPO). The presence of these antibodies causes the neutrophils to become overly active and bind to the inner lining of the small blood vessels.
Once activated, the neutrophils release toxic substances and enzymes that cause direct damage and inflammation to the blood vessel walls. This process leads to swelling, narrowing, or blockage of the vessels, restricting blood flow and damaging surrounding tissues and organs. Since small blood vessels are present throughout the body, AAV can affect multiple organ systems.
The condition is broadly categorized into three main subtypes, distinguished by the pattern of organ involvement and the specific ANCA present.
Granulomatosis with Polyangiitis (GPA)
GPA frequently affects the upper and lower respiratory tracts, including the nose, sinuses, and kidneys.
Microscopic Polyangiitis (MPA)
MPA commonly targets the kidneys and lungs, but generally lacks the granulomatous inflammation seen in GPA.
Eosinophilic Granulomatosis with Polyangiitis (EGPA)
EGPA often involves the lungs, and is characterized by asthma and a high number of eosinophils.
AAV can cause widespread damage and a variety of symptoms, including skin lesions, nerve damage, and severe kidney impairment. Kidney involvement, often called ANCA glomerulonephritis, can cause blood and protein to leak into the urine, potentially leading to kidney failure. Lung damage may manifest as shortness of breath or life-threatening bleeding into the air sacs (alveolar hemorrhage).
Is ANCA Vasculitis Inherited?
ANCA vasculitis is not classified as a directly inherited (Mendelian) disease passed simply from parent to child. Instead, the condition is considered multifactorial, resulting from a complex interaction between a person’s genetic makeup and environmental exposures. Although family clusters of AAV have been reported, these cases are rare, indicating that a simple hereditary pattern is not the cause for most individuals.
The genetic component involves an inherited susceptibility to the disease, not a guarantee of developing it. Studies have identified specific genetic variations that increase risk, particularly within the human leukocyte antigen (HLA) complex. The HLA genes, located on chromosome 6, play a major role in regulating the immune system’s ability to recognize self versus non-self. Different AAV subtypes are linked to different HLA alleles; for instance, HLA-DQ variations are associated with MPA, while HLA-DP variations are linked to GPA.
Other non-HLA genes related to immune function, such as those encoding PR3 and alpha-1-antitrypsin, also contribute to the genetic risk profile. These factors influence which ANCA antibody type (PR3 or MPO) an individual develops, correlating with the clinical type of vasculitis. However, having these predisposing genes only increases the likelihood and does not ensure the onset of the disease.
Environmental factors are thought to act as triggers that initiate the autoimmune response in genetically susceptible individuals. Infections, particularly with bacteria like Staphylococcus aureus, have been implicated, as chronic carriage in the nose is common in patients with GPA. Exposure to certain chemicals and pollutants, such as silica dust, air pollution, and specific medications, is also associated with an increased risk of AAV. The disease is ultimately caused by this combination of genetic predisposition and an environmental event that disrupts the immune system’s tolerance.
Confirming the Diagnosis: The Role of the ANCA Test
Confirming ANCA vasculitis relies on specialized laboratory testing combined with a patient’s clinical symptoms. The most specific diagnostic procedure is the ANCA blood test, which identifies the presence of the self-reactive antibodies. This test helps distinguish AAV from other forms of vasculitis and similar autoimmune conditions.
Two primary methods are used for ANCA testing: indirect immunofluorescence (IIF) and immunoassay. The IIF technique involves mixing a patient’s serum with neutrophils on a slide; the resulting staining pattern indicates the type of ANCA present. A cytoplasmic pattern (c-ANCA) is associated with PR3 antibodies, while a perinuclear pattern (p-ANCA) is seen with MPO antibodies.
Immunoassays, such as the Enzyme-Linked Immunosorbent Assay (ELISA), quantify the levels of anti-PR3 and anti-MPO antibodies. A positive result for either PR3-ANCA or MPO-ANCA is suggestive of AAV, especially when clinical signs of vasculitis are present. A definitive diagnosis often requires a tissue biopsy from an affected organ to visualize the inflammation and damage to the small blood vessels.
Current Approaches to Treatment
Treatment for ANCA vasculitis is divided into two phases: induction of remission and maintenance of remission. The initial phase, induction, focuses on rapidly controlling severe inflammation and halting organ damage caused by the active disease. This is achieved using potent immunosuppressive medications, often involving high-dose corticosteroids to quickly reduce inflammation.
In addition to corticosteroids, patients receive a strong immunosuppressant, typically cyclophosphamide or rituximab. Cyclophosphamide is a traditional chemotherapy agent that suppresses the entire immune system. Rituximab is a biologic drug that specifically targets and depletes the B-cells responsible for producing the ANCA antibodies. Both drugs are effective in achieving remission, though rituximab may be preferred for relapsing disease.
Once the disease is controlled and the patient is in remission, treatment shifts to the maintenance phase, a long-term strategy designed to prevent relapse. The goal is to use lower-dose medications to keep the immune system quiet while minimizing side effects. Common maintenance drugs include lower doses of rituximab or traditional oral immunosuppressants like azathioprine or methotrexate.
Studies show that rituximab is superior to azathioprine in preventing relapses, leading specialists to favor it for maintenance therapy. Treatment is individualized based on the specific AAV subtype, the ANCA antibody type, and the patient’s risk of relapse. While modern treatments have improved patient outcomes, AAV is a chronic condition requiring continuous management, as the goal is sustained remission rather than a complete cure.