Granulomatosis with Polyangiitis (GPA): Symptoms, Diagnosis, and Management

Granulomatosis with polyangiitis (GPA), previously known as Wegener's granulomatosis, is a rare autoimmune disorder characterized by vasculitis (inflammation of blood vessels) and the formation of granulomas (inflammatory tissue masses). GPA primarily affects small to medium-sized blood vessels in the nose, sinuses, throat, lungs, and kidneys, but can also involve other organs such as the skin, joints, and nerves. This condition can lead to necrosis of the vessel and resultant poor organ perfusion. Eventually, this inflammation can lead to the vessel becoming completely occluded. Chronic inflammation can lead to the formation of granulomas, and ultimately, organ necrosis. Early diagnosis and treatment are crucial to prevent irreversible organ damage and improve patient outcomes.

Understanding GPA

What is GPA?

Granulomatosis with polyangiitis (GPA) is a systemic inflammatory condition, a type of vasculitis, where small blood vessels become inflamed and narrowed, restricting blood flow to vital organs. GPA is one of a group of blood vessel diseases called vasculitis. The affected tissues can develop inflamed areas called granulomas.

Epidemiology and Demographics

GPA is the most common of the three ANCA-associated vasculitides. The annual incidence is approximately 8-10 cases per million, and the prevalence is estimated at 3 cases per 100,000 people. These numbers vary by continent, but GPA is typically more common in colder climates. Men and women are affected equally. Patients are usually white and in their 40s-50s, but GPA can occur at any age or in any race. GPA can present in children under 18 with similar manifestations to the adult GPA, although there exists a female predominance.

Etiology and Pathogenesis

The exact cause of GPA remains unknown, but it is considered an autoimmune disorder. There may be environmental contributing factors such as dust, exposure to silica, smoke, or chemicals. Certain medications may also contribute to the development of the disease.

The pathogenesis of GPA involves the partial, and possibly complete, occlusion of blood vessels, which results in the formation of microabscesses that develop into granulomas over time, ultimately leading to necrotizing granulomatous vasculitis. Unlike in tuberculosis or sarcoidosis, the granulomas in GPA are poorly defined and consist of giant cells surrounded by lymphocytes, plasma cells, and dendritic cells. The presence of these cells damages the submucosa and can eventually penetrate surrounding cartilage and bone.

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The formation of granulomas in GPA begins with the formation of neutrophilic microabscesses. While the initial cause is not completely understood, it is thought that autoantibody development to myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3) ANCA is key in the development of GPA. In persistent GPA, humoral immunity, specifically CD4+ T cells produce IL-17 and IL-23 which contribute to organ injury, particularly in the kidneys. Microbes such as S. aureus could also be involved in the disease process via superantigen stimulation of B and T cells.

Classification

GPA can be broadly categorized into a limited form and a systemic form. The limited form is defined by the absence of renal involvement and is largely isolated to the upper and lower respiratory tracts. The systemic form may involve the kidneys as well as other organs outside of the respiratory tract. There is no gender predilection for the disease, although women are more likely to have the limited form of the disease.

Symptoms of GPA

Symptoms of granulomatosis with polyangiitis (GPA) can vary widely from person to person. Early symptoms may feel like a cold or flu and can last for weeks or longer. The clinical presentation, however, is often nonspecific with varying symptoms from arthralgias to sinusitis. It's important to talk to your doctor about your symptoms. You know how you are feeling better than anyone else. Being aware of your symptoms can help you talk to your doctor about how you're feeling and what treatments may be right for you.

Common Symptoms

The upper respiratory tract (sinuses, nose, ears, and trachea) is the most often involved system, with up to 85% of patients having disease, and 81% of patients having ENT findings as their initial symptoms.

General Symptoms:
- Fever that has no clear cause
- Night sweats
- Fatigue
- Malaise (a general feeling of discomfort, illness, or unease)
- Weight loss
Upper Respiratory Tract Symptoms:
- Chronic sinusitis unresponsive to treatment is the most common presentation
- Sinus pain
- Nasal congestion
- Nasal ulceration
- Epistaxis (nosebleeds)
- Nasal mucosal ulcer
- Nasal granulomatous lesions
- Nasal bridge collapse
- Subglottic or tracheal stenosis
- Hearing loss (can be a presenting feature in an important minority of cases, and can often predate other more characteristic symptoms by several months)
- Ear involvement can vary considerably in its severity, with hearing loss occurring as a result of conductive and sensorineural mechanisms
Lower Respiratory Tract Symptoms:
- Cough (with or without blood in the sputum)
- Hemoptysis (coughing up blood)
- Pleuritic chest pain
- Shortness of breath
- Wheezing
- Stridor
Renal Symptoms:
- Glomerulonephritis (inflammation of the kidney's filtering units)
- Microhematuria (blood in the urine)
- Proteinuria (protein in the urine)
Musculoskeletal Symptoms:
- Arthralgias (joint pain)
- Myalgia (muscle pain)
Ocular Symptoms:
- Eye pain
- Diplopia (double vision)
- Decreased vision
- Decreased peripheral vision/visual field
- Redness
- Scleritis (inflammation of the white part of the eye)
- Keratitis (inflammation of the cornea)
- Uveitis (inflammation of the middle layer of the eye)
- Retinal and choroidal involvement
- Eyelid involvement

Ophthalmic Manifestations

Ophthalmic features of GPA can occur in up to 60% of patients with the disease and can affect nearly every structure of the eye ranging from the orbit and eyelids, to the retina and optic nerve. Presentations can vary dramatically between patients, and are usually the result of vasculitis of the small vessels supplying the orbit and its structures. Ocular inflammation can lead to severe ocular morbidity resulting in vision loss in up to 8% of patients, but has been reported as high as 37% of patients with inadequately treated disease.

Scleritis: One of the most common and early appearing presentations of GPA and can occur in roughly 50% of patients. This condition typically presents with deep boring pain and erythematous tender eyes which are seen as areas of capillary nonperfusion on ocular examination. Nodular scleritis can also occur.
Keratitis: Especially peripheral ulcerative keratitis, is also a common presentation of GPA. This typically presents with pronounced ocular pain, tearing, photophobia, and reduced vision with corneal stromal infiltration and invading vessels from the limbus being present on examination.
Orbital Involvement: The orbit is commonly involved in GPA often due to contiguous disease in the nasal and paranasal sinuses. Orbital presentations include diplopia, swelling, epiphora, and proptosis due to orbital granuloma. Proptosis is the most common presentation of orbital GPA, and because it is often present concomitantly with respiratory and renal disease, these manifestations together are highly suggestive of the disease. Due to orbital inflammation, patients can present with diplopia as well as pain and restriction with ocular movements. Orbital GPA can also involve the optic nerve resulting in painless optic disc swelling (arteritic anterior ischemic optic neuropathy.
Other Ocular Manifestations: Uveitis is an uncommon finding in GPA occurring in 3% of patients. Retinal and choroidal involvement is also relatively uncommon, being seen in 5-12% of patients. Retinal involvement can also be present with manifestations ranging from isolated cotton wool spots or intra-retinal hemorrhages to branch or central retinal artery and vein occlusions. Retinal artery occlusion can also occur due to vasculitis induced intravascular thrombosis. Eyelid involvement can occur in GPA with a “yellow lid sign” resembling a florid xanthelasma concurrently with orbital inflammation which is especially characteristic of GPA.

Diagnosis of GPA

GPA should be suspected in any person who is between 64-75 years of age presenting with general symptoms of upper respiratory tract and pulmonary involvement as these are the most common symptoms. The broad spectrum of non-specific symptoms that occur in GPA can make diagnosis difficult, leading to delays in treatment. Clinical and imaging findings can guide the site of biopsy to confirm the diagnosis of GPA.

Diagnostic Criteria

The American College of Rheumatology (ACR) has designated a diagnostic criteria for GPA. It involves nasal or oral inflammation characterized by painful/painless oral ulcers, abnormal chest radiographs, urinary sediment with > 5 red blood cells per high power field or red cell casts, and granulomatous inflammation at biopsy with involvement of arterial or arterioles wall. The presence of two out of four of these criteria is 88.2% and 92% sensitive and specific, respectively.

Laboratory Tests

ANCA Testing: One of the most common utilized tests in the diagnosis of GPA is ANCA, and has a high diagnostic utility for ANCA-associated vasculitis: GPA, microscopic polyangiitis (MPO), and eosinophilic granulomatosis. Antibodies reacting with PR3 generate a specific immunofluorescence cytoplasmic (c) pattern (also known as c-ANCA) and antibodies reacting to MPO have a perinuclear (p) staining pattern (also known as p-ANCA). Although 90% of patients with active disease are c-ANCA positive, 40% of patients with limited disease can be negative. In addition, p- ANCA can be positive in GPA patients as well. Measurement of c-ANCA can be done through the conventional antigen specific enzyme-linked immunosorbent assay (ELISA).
Other Blood Tests:
- Complete blood count (CBC)
- Comprehensive metabolic panel
- Erythrocyte sedimentation rate (ESR)
- C-reactive protein (CRP)
- Renal profile
Urine Analysis: Urinalysis is done to look for signs of kidney disease, such as protein and blood in the urine. Sometimes urine is collected over 24 hours to check how the kidneys are working. Urine analysis is positive for red cell casts, indicating likely glomerular involvement.

Imaging Studies

Chest X-ray: Chest X ray radiographs are usually the first imaging modality to suggest the diagnosis in the setting of upper airways (sinusitis, nasal mucosal ulcer, nasal granulomatous lesions, nasal bridge collapse, and subglottic or tracheal stenosis) and lower respiratory tract involvement (cough, wheezing, hemoptysis, and stridor). Radiographic signs reported include nodules, mass lesions, or cavitation.
CT Scan: CT has greater sensitivity and specify for GPA findings. Manifestations are similar to those present on radiographs, but since CT is more sensitive and specific, pulmonary involvement has been studied in greater detail using CT.
- Nodules and masses: most common manifestation in 40-70% of patients can be single or multiple and can range from millimeters to > 10 cm. Consolidations greater than 3 cm were considered masses. A study by Lorhrmann et al. found that nodules were bilateral in 70% of patients with GCA.
- Cavitation has been found in 22% of nodules greater than 2 cm. Cavities can get infected and will be characterized by air fluid levels.
- Lesions greater than 2 cm and they tend to be thick walled with irregular margins. CT imaging can also show areas of consolidation and ground glass opacities in the setting of GPA as a result of alveolar hemorrhage, necrotic alveolar cellular infiltrate.
- Diffuse alveolar hemorrhage can occur in 10% of patients, and is characterized by bilateral and diffuse consolidation sparing the subpleural lung. This can lead to interlobular septal thickening due to lymphatic’s congestion. These findings may mimic pneumonia, acute respiratory distress syndrome, tuberculosis, or pulmonary edema.
FDG PET/CT Scan: FDG tracer that marks glucose metabolism has been used to provide information regarding tissue metabolism in the setting of cancer and active inflammatory lesions and diseases. A case reports has documented extensive FDG uptake in nasal lung lesions on combined PET/CT. In this case, the PR3 ANCA antibody were negative at time of pulmonary lesions, but were elevated a year after, allowing a diagnosis 1 year after. This indicates that FDG uptake on CT/PET scan and ANCA elevation are not mutually exclusive and can show early detection of GPA prior to ANCA elevations. In addition, a study by Frary et al. has shown that FDG PET/CT scan is able to distinguish between actual GPA and concurring comorbidities such as cancer and infection. Diagnostic probability for FDG PET/CT with respect to comorbidity was 90% sensitive and 81% specific, positive predictive and negative predictive values were 75% and 93% respectively. In this study FDG PET/CT scan effectively rules our comorbidities correctly, except for a case of a urinary tract infection, which represents a limitation. However, this is an important finding as immunosuppressive therapy is a modality for treatment in GPA and is contraindicated in the setting of a comorbidity such as cancer or infection.
CT scan of the sinuses may also be done to see signs of bone damage in the paranasal structure.

Biopsy

Clinical and imaging findings can guide the site of biopsy to confirm the diagnosis of GPA. Any affected organ can be a potential site for biopsy. Lung tissue is the most common biopsies organ. Renal biopsy can show focal segmental necrotizing glomerulonephritis with proliferation of pauci-immune crescentic formation. It can be associated with microhematuria and proteinuria. Orbital histopathology can show fat disruption, characterized by fay fat necrosis with free vacuoles, lipid laden-macrophages, as well as giant cells. These findings were accompanied by active or pre-existing fibrosis. There also be granulomatous and acute inflammation with polymorphonuclear cells or eosinophils.

Treatment of GPA

The treatment regimen for GPA varies based on numerous disease and patient factors and from physician to physician. The choice of treatment for GPA depends on the organs affected and disease severity. Early treatment is important. Most people improve with medicines to slow or stop the inflammation.

Initial Assessment

In choosing treatment, it is advised that one first determines whether the patient has GPA which is life- or organ-threatening or not. After this determination, treatment should be based upon whether it is the initial presentation of the disease, a presentation of refractory disease, of relapsing disease, or if presentation is for maintenance of disease.

Medications

Glucocorticoids: Patients with milder disease are commonly prescribed glucocorticoids such as prednisone in combination with another medication such as methotrexate to control inflammation and induce remission of disease. Prednisone is given along with other medicines that slow down the immune response. These are given through the vein for 3 to 5 days at the beginning of treatment.
Immunosuppressants:
- Rituximab: For patients with ocular manifestations of GPA, rituximab should be considered. In a recent study, rituximab was shown to effectively induce remission in treatment-refractory ocular manifestations of GPA. Patients with ocular manifestations that are receiving rituximab should be monitored closely, as exacerbation of symptoms may occur. Patients with severe disease may be prescribed the biologic drug rituximab, used in conjunction with glucocorticoids. Another option for those with severe disease is cyclophosphamide-a chemotherapy-type drug that blocks abnormal growth of certain cells in the body. It is used in combination with glucocorticoids.
- Cyclophosphamide: With respect to cyclophosphamide, there is similar efficacy between DO and IV administration in remission induction; however, pulsed IV cyclophos… Cyclophosphamide is usually limited to a three- to six-month period, then replaced with less toxic drugs such as methotrexate, azathioprine or mycophenolate mofetil.
- Methotrexate and Azathioprine: For milder disease other medicines that slow down the immune response such as methotrexate or azathioprine may be used.
Maintenance Medications: Once the disease is in remission, patients will need to continue taking maintenance medications such as azathioprine, methotrexate or rituximab, to keep the disease under control. The dose of glucocorticoids is usually tapered during remission.
Avacopan (Tavneos ®): In 2021, the medication avacopan (Tavneos ®) was approved by the FDA as an adjunctive treatment in adults for severe, active ANCA-associated vasculitis (specifically GPA and MPA) in combination with standard therapy including glucocorticoids. Avacopan (Tavneos®) may help to reduce exposure to glucocorticoids.

Other Treatments

Intravenous (IV) immunoglobulin G (IG): Intravenous (IV) immunoglobulin G (IG) has been considered as an alternative for patients with persistent ocular involvement, though there have been no conclusive results supporting or opposing its usage.
Plasmapheresis: Some individuals may experience kidney failure, which is a serious complication that requires dialysis and/or a kidney transplant. A rarely used treatment option for those with very serious GPA affecting the kidneys or lungs is “plasmapheresis.” Plasmapheresis is a dialysis-like procedure that clears proteins from the plasma of the blood and replaces it with plasma from a donor, or with a plasma substitute. It can help the kidneys get better. This treatment filters the portion of your blood that contains disease-producing substances. You receive fresh plasma or a protein made by the liver (albumin), which allows your body to produce new plasma.

Monitoring

Patients with ocular manifestations that are receiving rituximab should be monitored closely, as exacerbation of symptoms may occur.

Differential Diagnosis

Differential diagnosis is broad due to the varied presentations of the disease. It can include other forms of ANCA associated vasculitis such as Churg Strauss syndrome and MPA, infections, malignancies, as well as granulomatous and autoimmune disorders.

Complications

Granulomatosis with polyangiitis (GPA) can lead to other health conditions called complications. The complications depend on which organs or body parts the disease affects.

Kidney failure
Eye swelling
Lung failure
Coughing up blood
Nasal septum perforation (hole inside the nose)
Side effects from medicines used to treat the disease
Tissue damage in the lungs, airways, and the kidneys.
Kidney involvement may result in blood in the urine and kidney failure. Kidney disease can quickly get worse. Kidney function may not improve, even when the condition is controlled by medicines.
If untreated, kidney failure and possibly death occur in most cases.

Coping and Support

You're likely to get better after treatment for granulomatosis with polyangiitis (GPA). Even so, you might feel stress about the disease coming back or the damage it can cause.

Understand your condition. Learn all that you can about GPA. The knowledge may help you deal with complications, medicine side effects and relapses.
Talk with your healthcare professional.
Build a strong support system. Family and friends can help you cope. And you might find it helpful and comforting to talk with other people who are living with the condition.
Support groups with others who suffer from similar diseases may help people with the condition and their families learn about the diseases and adjust to the changes associated with the treatment.

Prognosis

Without treatment, people with severe forms of this disease can die within a few months. With treatment, the outlook for most patients is good. Most people who receive corticosteroids and other medicines that slow the immune response get much better. Most people with GPA are treated with ongoing medicines to prevent relapse for at least 12 to 24 months.

When to Contact a Medical Professional

Contact your provider if:

You develop chest pain and shortness of breath.
You cough up blood.
You have blood in your urine.
You have other symptoms of this disorder.
If your symptoms are getting worse, tell your main healthcare professional.

Prevention

There is no known prevention.

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