Anti-neutrophil Cytoplasmic Antibody Positive Vasculitis

Anti-neutrophil cytoplasmic antibody (ANCA) positive vasculitis is a group of rare autoimmune diseases that cause inflammation in small blood vessels throughout the body. This inflammation can damage vital organs including the kidneys, lungs, and nervous system, making early diagnosis and treatment essential for preventing serious complications.

Table of contents

• What is ANCA-Associated Vasculitis?
• Types of ANCA-Associated Vasculitis
• Causes and Risk Factors
• Symptoms and Affected Organs
• Diagnosis
• Treatment
• Living with ANCA-Associated Vasculitis

What is ANCA-Associated Vasculitis?

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a group of rare autoimmune diseases that cause inflammation of blood vessels with various manifestations. In healthy people, the immune system produces antibodies that identify and destroy foreign invaders like viruses and bacteria. However, in ANCA-associated vasculitis, the immune system produces abnormal antibodies called autoantibodies, which mistakenly attack healthy cells and tissues in the body.^[1]

These autoantibodies, called ANCAs, target proteins inside white blood cells called neutrophils. Neutrophils are infection-fighting white blood cells that help protect the body from harm. When ANCAs bind to neutrophils, they cause them to become overly activated. These activated neutrophils then bind to the cells lining blood vessels, release toxic substances, and trigger further immune system activation, leading to vascular damage and tissue swelling.^[5]

All types of ANCA-associated vasculitis affect small blood vessels, such as capillaries, venules, and arterioles. Since small blood vessels are present throughout the body, this condition can cause many different symptoms depending on which organs are affected. The disease affects approximately 1 in 50,000 people and is more common in middle-aged white men and women.^[5]

ANCA vasculitis, AAV, antineutrophil cytoplasmic antibody-associated vasculitis

Types of ANCA-Associated Vasculitis

There are three main types of ANCA-associated vasculitis. Each type has distinct characteristics, though they share some common features. Patients are usually diagnosed based on their symptoms and findings under a microscope.^[1]

Granulomatosis with polyangiitis (GPA), formerly known as Wegener granulomatosis, is a disease resulting from inflammation of the blood vessels. In GPA, immune cells can cluster together to form structures called granulomas. This condition most often affects blood vessels in the lungs, sinuses, ears, nose, and throat. It may also affect the kidneys and windpipe.^[2]

Microscopic polyangiitis (MPA) shares many similarities with GPA, but granulomas do not form in this condition. MPA can affect several parts of the body, including the lungs, kidneys, nerves, skin, and joints. The impact on the kidneys may be more severe in MPA, and people with this condition may be more likely to experience bleeding in their lungs.^[2][3]

Eosinophilic granulomatosis with polyangiitis (EGPA), previously known as Churg-Strauss syndrome, usually affects blood vessels in the lungs and sinuses. It may also affect the stomach and intestines, skin, heart, and nervous system. This condition often causes asthma and a high level of white blood cells called eosinophils.^[3]

Other ANCA-associated diseases include drug-induced vasculitis and renal-limited vasculitis, where the disease primarily affects the kidneys.^[1]

Causes and Risk Factors

The exact cause of ANCA-associated vasculitis is currently unknown. Researchers believe that a combination of genetic and environmental factors contributes to the development of these diseases.^[2]

The strongest genetic association has been observed with a family of genes called the major histocompatibility complex (MHC), which contains information to produce proteins with a key role in immune response.^[5]

Environmental factors that may increase the risk for ANCA-associated vasculitis include inhalation of silica, a mineral found in soil that stimulates inflammatory reactions. Exposure to chemical compounds used in farming, such as pesticides, or in industry, such as alcohols and glues, may also increase risk. Some medications, prolonged use of cocaine, and infections with certain viruses and bacteria have also been associated with the development of ANCA-associated vasculitis.^[5]

Anyone can develop these conditions, but they usually develop in people between ages 40 and 50. Males have a slightly higher risk than females.^[14]

Symptoms and Affected Organs

ANCA-associated vasculitis can affect many different parts of the body. Symptoms may develop slowly or quickly, and they may be mild or severe. Because blood vessel damage can occur in various organs, the symptoms depend on which parts of the body are affected.^[3]

General symptoms that are common across all types include fever, fatigue, general malaise, unexplained weight loss or loss of appetite, and general aches and pains.^[4]

Kidneys and lungs are among the most commonly affected organs. Kidney involvement may cause blood and protein in the urine, making it appear brownish and foamy, along with high blood pressure and fatigue. Lung problems can include respiratory difficulties, shortness of breath, wheezing, coughing, and coughing up blood. Inflammation in the trachea may also lead to a hoarse voice.^[5]

Upper respiratory tract symptoms, affecting the ears, sinuses, nose, and throat, can include sinus inflammation (sinusitis), eye irritation or pain, bloody discharge from the nose, ear pain and infection, and growths called polyps inside the nose.^[3]

Nervous system involvement commonly causes numbness, tingling, burning sensation, and muscle weakness. Patients may also experience headaches, cognitive impairment, and seizures.^[5]

Skin manifestations include rashes, hives, itching, bruises, and palpable purpura (raised purple spots).^[4]

Musculoskeletal symptoms include strong pain in the muscles and joints.^[5]

Gastrointestinal problems may include blood in stools, diarrhea, nausea, vomiting, abdominal pain, and open sores in the mouth.^[5]

Heart involvement can cause chest pain and heart palpitations.^[2]

For approximately 50% of people, even in remission—when symptoms are controlled—vasculitis symptoms can be debilitating. It is important to keep track of signs and symptoms and discuss them with your doctor.^[2]

• Kidneys
• Lungs
• Sinuses
• Ears
• Nose
• Throat
• Skin
• Nerves
• Joints
• Heart
• Eyes
• Stomach
• Intestines

Diagnosis

Diagnosing ANCA-associated vasculitis can be challenging because the disease shares many signs and symptoms with other conditions. Early diagnosis is extremely important for developing a treatment plan that can help manage these conditions.^[2]

A healthcare provider will diagnose ANCA-associated vasculitis through a combination of physical examination, questions about symptoms, and several diagnostic tests. Small-vessel vasculitis should be suspected in any patient who presents with a multisystem disease that is not caused by an infectious or malignant process.^[4]

Blood tests are essential for diagnosis. An ANCA test looks for antineutrophil cytoplasmic antibodies in the blood. The test can detect two main types of ANCAs. The first type, called cANCA, targets a protein called proteinase 3 (PR3). The second type, called pANCA, targets a protein called myeloperoxidase (MPO).^[3]

There are two methods used for ANCA testing. Indirect immunofluorescence (IIF) gives a positive or negative result, showing whether you have the autoantibodies. Enzyme-linked immunosorbent assay (ELISA) helps to identify which specific protein in the neutrophils is being targeted. Using antigen-specific immunochemical assays to characterize ANCA is more specific and more clinically relevant than pattern-based methods.^[4][6]

ANCA serology is positive in about 90% of GPA and MPA cases. However, about 10% of patients with these conditions have negative assays for ANCA. A negative result does not completely rule out these diseases, and ANCA levels do not always correlate with disease activity. Additionally, a positive ANCA result is not solely diagnostic of ANCA-associated vasculitis, as these antibodies can be found in other conditions.^[1][4]

Other blood tests may look for signs of inflammation, such as a high level of C-reactive protein. A complete blood cell count can tell whether you have enough red blood cells.^[15]

Imaging tests can show which blood vessels and organs are affected. These may include X-rays, ultrasounds, CT scans, MRIs, and positron emission tomography (PET) scans. During a procedure called angiography, a special dye is injected into blood vessels and X-rays are taken to show their outlines.^[15]

Tissue biopsy is a procedure in which a healthcare provider removes a small sample of tissue from the affected area of the body. The tissue is then examined under a microscope for signs of vasculitis. This can help confirm the diagnosis and determine the specific type of vasculitis.^[15]

Making the diagnosis as early as possible is crucial, emphasizing the importance of using high-quality ANCA assays. Detailed medical history, physical examination, and exclusion of other causes for the clinical presentation remain essential steps in clinical assessment.^[11]

Treatment

Treatment of ANCA-associated vasculitis aims to control inflammation, prevent organ damage, achieve remission (a period when symptoms are controlled), and prevent relapses. The approach typically involves two phases: induction therapy to bring the disease under control, and maintenance therapy to prevent relapses.^[7]

Induction therapy for life or organ-threatening ANCA-associated vasculitis is a combination of glucocorticoids (corticosteroids) and either rituximab or cyclophosphamide. Rituximab is the preferred choice in relapsing granulomatosis with polyangiitis and microscopic polyangiitis. A rapidly reducing glucocorticoid regimen is now preferred, which reduces the risk of serious infection without loss of effectiveness.^[7]

Glucocorticoids are medications that limit inflammation and its effects. While effective, extended use can increase the risk of osteoporosis, weight gain, diabetes, muscle weakness, ulcers and gastritis, and infection. Healthcare providers carefully monitor the types and doses of medicines to develop a treatment plan that limits both the symptoms of the disease and treatment-related side effects.^[12]

Rituximab is a medication that works by depleting B-cells, which are involved in producing antibodies. It has become an important treatment option for ANCA-associated vasculitis. Recent studies have shown that the presence of PR3-ANCA (rather than MPO-ANCA) indicates a better response to rituximab than to cyclophosphamide, but also a much higher relapse risk, making ongoing maintenance therapy necessary.^[8]

Cyclophosphamide is an immunosuppressive medication that has been used for many years to treat ANCA-associated vasculitis. While effective, it can have significant side effects, and treatment protocols have been optimized through clinical trials.^[7]

Plasma exchange is a procedure that may be considered in patients with severe kidney impairment and diffuse alveolar hemorrhage (bleeding in the lungs). Although plasma exchange did not improve the combined outcome of death and end-stage kidney disease in one major trial, a meta-analysis concluded that it may reduce the risk of end-stage kidney disease at 12 months and should be considered in patients presenting with very high serum creatinine levels.^[7]

Avacopan is a newer medication that can be used early in the disease course. It works as a complement inhibitor and represents a targeted therapy approach based on improved understanding of disease mechanisms.^[7]

Maintenance therapy is essential after achieving remission. Fixed-interval repeat-dose rituximab for 24 to 48 months is more effective than azathioprine or methotrexate and permits glucocorticoid discontinuation within 6 months of starting therapy. Relapse risk increases after rituximab withdrawal. Understanding the risks and consequences of relapse and the risks of secondary immunodeficiency with rituximab helps physicians make informed decisions about treatment duration.^[7]

For eosinophilic granulomatosis with polyangiitis, interleukin 5 inhibitors such as mepolizumab have been approved and shown to be effective.^[7]

If the disease goes into remission, treatments can be carefully withdrawn, but patients and their clinical teams need to watch carefully for signs that the vasculitis has returned. Relapse is common with GPA and MPA and is often associated with significant harm.^[12]

Living with ANCA-Associated Vasculitis

With recent advances in treatment, most patients with ANCA-associated vasculitis are able to achieve remission and bring their disease under control, often for extended periods. However, most patients are also likely to relapse at least once. Managing the disease involves balancing the benefits of long-term therapy with its associated complications.^[12]

Emotional support is important, as ANCA-associated vasculitis, like most chronic conditions, can cause feelings of fear, stress, anxiety, and depression. Patients should discuss any changes in mood with their doctors. A physician or counselor may recommend additional medication to ease emotional discomfort. Support groups can also help patients make lifestyle adjustments that accompany the disease. Family and friends provide vital support, and it is important to keep loved ones involved with the disease state and informed about changes in therapy.^[12]

Dietary modifications may be recommended depending on how the body is affected by the disease or treatment. Patients with high blood pressure may need to reduce salt intake. Those with kidney failure may need to restrict protein and potassium intake. Patients on glucocorticoid therapies who develop osteoporosis or diabetes will need to monitor their diet with the help of a healthcare professional.^[12]

Monitoring symptoms is crucial. Keeping a notebook or journal can help organize conversations with doctors and take control of treatment. It is important to tell your doctor about any new or worsening symptoms. About 80% to 90% of patients with ANCA-associated vasculitis have kidney or other organ-threatening signs and symptoms, which can be considered severe active disease.^[2]

Regular follow-up with healthcare providers is essential. Routine monitoring of kidney function, protein in the urine, ANCA levels, and immunoglobulin levels should be performed at baseline and during follow-up. The use of prophylactic antibiotics in susceptible patients and timely vaccination schedules should be discussed with healthcare providers.^[11]

Patients should be aware of potential complications. These diseases can cause serious, potentially life-threatening complications if they damage organs like the lungs, kidneys, or heart. Severe ANCA-associated vasculitis can cause bleeding in the lungs, lung scarring, nerve damage, kidney failure, and heart failure.^[14]