Granulomatosis with polyangiitis (GPA) is a rare autoimmune disease that causes inflammation of the blood vessels (vasculitis), primarily affecting small and medium-sized vessels. Formerly known as Wegener’s granulomatosis, GPA leads to the formation of granulomas, clusters of immune cells that can damage tissues and organs.

GPA most often affects the sinuses, lungs, and kidneys, but it can involve other organs, including the skin, eyes, joints, and nerves. If left untreated, it can progress rapidly and lead to organ failure.

In my experience, GPA is one of those conditions that often masquerades as something more common, like a sinus infection or pneumonia, until symptoms escalate and reveal the underlying autoimmune process.

Analogy: Imagine the immune system as a well-trained team of firefighters. In GPA, the team mistakenly attacks healthy blood vessels and tissues, starting fires instead of putting them out. This causes scarring and blockage in the organs those vessels supply.

The exact cause of GPA is not fully understood, but it is believed to be an autoimmune disorder. In an autoimmune disease, the body’s immune system, which is designed to identify and eliminate foreign invaders like bacteria and viruses, becomes dysregulated. It loses its ability to distinguish between “self” and “non-self” and begins to produce antibodies that attack its own healthy tissues.

In the case of GPA, the immune system produces a specific type of autoantibody called ANCA (Anti-Neutrophil Cytoplasmic Antibody). Most people with active GPA have a particular subtype of ANCA called c-ANCA, which targets a protein within our own white blood cells called Proteinase 3 (PR3). It is believed that these PR3-ANCAs play a direct role in causing the disease. They activate a type of white blood cell called a neutrophil, causing it to stick to the walls of small blood vessels and release destructive enzymes and inflammatory chemicals. This attack is what initiates the vasculitis and tissue damage that define the disease (Vasculitis Foundation, n.d.). Why the immune system begins producing these harmful autoantibodies in the first place remains a central focus of ongoing research.

Clinically, I think of GPA as a “perfect storm”, genetics, immune system misfires, and possible environmental triggers all play a role in setting it off.

GPA is not inherited directly and not passed person-to-person. It develops when the immune system turns against the body’s blood vessels, but why it happens in one person and not another remains unclear. While research suggests that certain genetic factors may make an individual more susceptible to developing the disease, it does not run in families in a predictable way.

The leading theory is that GPA develops as a result of a two-step process in a genetically predisposed individual:

1. Genetic Susceptibility: A person is born with certain genes that may make their immune system more likely to become dysregulated.
2. Environmental Trigger: It is believed that an external event, most likely an infection, acts as a trigger that “switches on” the abnormal immune response in this susceptible person.

Some studies have investigated a potential link between chronic nasal infection with the bacterium Staphylococcus aureus and the triggering of GPA, but this relationship is complex and not fully proven (American College of Rheumatology, 2023). For most patients, the specific trigger that initiates the disease is never identified. GPA can affect people of all ages but most commonly begins in middle age, between 40 and 65, and it affects men and women equally.

Patients often ask, “Did I do something to cause this?” The answer is no, it’s an unpredictable immune disorder that develops silently until symptoms emerge.

GPA symptoms vary based on which organs are affected. The onset can be gradual or sudden, and the early symptoms are often vague and can mimic those of a common infection, which frequently leads to a delay in diagnosis.

The most common signs and symptoms can be grouped by the areas they affect:

Upper Respiratory Tract (Nose, Sinuses, and Ears)

These are often the first signs of the disease.

• Severe, Chronic Sinusitis: Persistent sinus pain, pressure, and congestion that does not respond to standard treatments like antibiotics.
• Nasal Problems: Frequent and severe nosebleeds, crusting inside the nose, and sometimes a saddle nose deformity, which is a collapse of the bridge of the nose due to damage to the cartilage.
• Ear Problems: Chronic ear infections, fluid in the middle ear, and hearing loss.

Lungs (Lower Respiratory Tract)

• A persistent cough, which may be dry or may produce bloody phlegm (hemoptysis).
• Shortness of breath or wheezing.
• Chest discomfort.

Kidneys

Kidney involvement is one of the most serious features of GPA and can be life-threatening if not treated. Critically, it is often “silent” in its early stages. As the damage progresses, signs may include:

• Blood in the urine (hematuria), which may be visible or microscopic.
• Foamy urine, a sign of protein in the urine (proteinuria).
• Swelling in the legs (edema).
• Untreated kidney vasculitis leads to rapidly progressive glomerulonephritis and, ultimately, kidney failure.

Constitutional (“Whole Body”) Symptoms

• Unexplained fever
• Drenching night sweats
• Profound fatigue and a general feeling of being unwell (malaise)
• Loss of appetite and unintentional weight loss

Other Possible Symptoms

• Joints: Aching or swollen joints (arthritis).
• Skin: Rashes, sores, or small, purplish bumps (palpable purpura).
• Eyes: Redness, pain, blurry vision, or, in severe cases, vision loss from inflammation of the sclera (scleritis) or other parts of the eye.
• Nerves: Numbness, tingling, or weakness in the limbs from nerve damage.

In practice, I’ve seen GPA go undiagnosed for months in patients with stubborn sinus infections, until they develop kidney problems or lung symptoms that raise red flags.

Diagnosis

GPA can be challenging to diagnose early because its symptoms mimic common infections or allergies. The process requires a high index of suspicion from a doctor and a combination of blood tests, imaging, and, most importantly, a tissue biopsy.

1. Medical History and Physical Exam: A doctor will take a detailed history of the wide-ranging symptoms and perform a thorough physical examination.
2. ANCA Blood Test: This is the most important blood test for diagnosis. A positive test for c-ANCA with antibodies specifically against PR3 (PR3-ANCA) is found in up to 90% of patients with active, generalized GPA and is highly specific for the disease.
3. Urine and Kidney Function Tests: A urinalysis is done to look for blood and protein, and blood tests are done to check creatinine levels to assess kidney function.
4. Imaging Studies: A chest X-ray and, more definitively, a high-resolution CT scan of the chest are used to look for characteristic signs in the lungs, such as nodules or cavities. A CT scan of the sinuses is also standard.
5. Biopsy (The Gold Standard): A biopsy of an affected tissue provides the definitive diagnosis. A small piece of tissue is taken from an area like the sinus passages, the lung, or the kidney. A pathologist then examines the tissue under a microscope, looking for the classic combination of vasculitis, granulomas, and tissue damage that confirms GPA.

I often remind patients that diagnosing GPA is like solving a puzzle. It takes input from labs, imaging, and sometimes tissue to see the full picture.

Treatment

GPA treatment focuses on suppressing the immune system to stop vessel inflammation and prevent further organ damage. Early and aggressive treatment can induce remission and prevent complications. Treatment is managed by a specialist, usually a rheumatologist, and often involves a multidisciplinary team.

The treatment is typically divided into two phases:

1. Induction of Remission

This phase involves using powerful immunosuppressive medications to quickly get the severe, life-threatening inflammation under control.

• High-Dose Corticosteroids: Medications like prednisone are given initially to rapidly reduce inflammation.
• Rituximab: This is a modern, first-line therapy. It is a biologic medication (a monoclonal antibody) that targets and depletes a type of immune cell called the B-cell, which is responsible for producing the harmful ANCAs.
• Cyclophosphamide: This is a powerful chemotherapy drug that is also used as an immunosuppressant. It has historically been a cornerstone of GPA treatment and remains a highly effective first-line option, especially in cases of very severe organ involvement.

For patients with severe kidney failure or bleeding in the lungs, a procedure called plasma exchange (plasmapheresis) may be used to rapidly remove the ANCAs from the bloodstream.

2. Maintenance of Remission

Once the disease is brought under control, the high-dose steroids are tapered down, and the patient is switched to a less toxic long-term medication to keep the disease in remission. This maintenance therapy typically lasts at least two to three years, and sometimes longer. Common maintenance medications include:

• Rituximab (given as periodic infusions every six months).
• Methotrexate.
• Azathioprine.
• Mycophenolate mofetil.

Because these treatments all suppress the immune system, patients must be carefully monitored for side effects and are at an increased risk of developing infections.

In my clinical experience, the response to treatment is usually fast, but the long-term challenge is preventing relapse, which happens in up to 50% of patients. Careful follow-up is key.

Granulomatosis with Polyangiitis is a rare, complex, and serious autoimmune disease that can cause devastating damage to the sinuses, lungs, and kidneys if left unchecked. Its vague and varied initial symptoms often make it a diagnostic challenge, mimicking more common infections. However, the discovery of the ANCA blood test and the development of highly effective immunosuppressive therapies have revolutionized the prognosis for this once-fatal disease. Today, GPA is considered a treatable, chronic condition. Patients often feel empowered once they receive a diagnosis, because with the right treatment team and regular care, GPA is not only manageable, but remission is possible.

American College of Rheumatology. (2023). Granulomatosis with polyangiitis. Retrieved from https://rheumatology.org/patients/granulomatosis-polyangiitis

Mayo Clinic. (2024). Granulomatosis with polyangiitis (Wegener’s granulomatosis). Retrieved from https://www.mayoclinic.org/diseases-conditions/granulomatosis-with-polyangiitis/symptoms-causes/syc-20351088

Vasculitis Foundation. (n.d.). Granulomatosis with Polyangiitis (GPA). Retrieved from https://www.vasculitisfoundation.org/education/forms/granulomatosis-with-polyangiitis-gpa/