Granulomatosis with polyangiitis (GPA), formerly known as Wegener’s Granulomatosis (WG), is a long-term systemic disorder that involves both granulomatosis and polyangiitis. It is a form of vasculitis (inflammation of blood vessels) that affects small- and medium-size vessels in many organs but most commonly affects the upper respiratory tract and the kidneys. Therefore, the signs and symptoms of GPA are highly varied and reflect which organs are supplied by the affected blood vessels. Typical signs and symptoms include nosebleeds, stuffy nose and crustiness of nasal secretions, and inflammation of the uveal layer of the eye. Damage to the heart, lungs and kidneys can be fatal.
The cause of GPA is unknown. Genetics have been found to play a role in GPA though the risk of inheritance appears to be low.
GPA treatment depends on the severity of the disease. Severe disease is typically treated with a combination of immunosuppressive medications such as rituximab or cyclophosphamide and high-dose corticosteroids to induce remission and azathioprine, methotrexate, or rituximab to keep the disease in remission. Plasma exchange is also used in severe cases with damage to the lungs, kidneys, or intestines.
The annual incidence of GPA is estimated to be 2.1-14.4 new cases per million people in Europe. GPA is rare in Japanese and African-American populations but occurs more often in people of Northern European descent. The prevalence of GPA in the United States is estimated to be 3 cases per 100,000 people and equally affects men and women.
Signs and Symptoms
Initial signs are extremely variable, and diagnosis can be severely delayed due to the nonspecific nature of the symptoms. In general, rhinitis is the first sign in most people. Involvement of the upper respiratory tract, such as the nose and sinuses, is seen in nearly all people with GPA. Typical signs and symptoms of nose or sinus involvement include crusting around the nose, stuffiness, nosebleeds, runny nose, and saddle-nose deformity due to a perforated septum. Scleritis and conjunctivitis are the most common ocular signs of GPA; involvement of the eyes is common and occurs in slightly more than half of people with the disease.
Kidney: rapidly progressive glomerulonephritis (75%), leading to chronic kidney failure
Upper airway, eye and ear disease:
Ears: conductive hearing loss due to auditory tube dysfunction, sensorineural hearing loss (unclear mechanism)
Oral cavity: strawberry gingivitis, underlying bone destruction with loosening of teeth, non-specific ulcerations throughout oral mucosa
Trachea: subglottal stenosis
Lungs: pulmonary nodules (referred to as “coin lesions”), infiltrates (often interpreted as pneumonia), cavitary lesions, pulmonary haemorrhage causing haemoptysis, and rarely bronchial stenosis.
Arthritis: Pain or swelling (60%), often initially diagnosed as rheumatoid arthritis
Skin: subcutaneous nodules (granulomas) on the elbow, purpura, various others (see cutaneous vasculitis)
Nervous system: occasionally sensory neuropathy (10%) and rarely mononeuritis multiplex
Heart, gastrointestinal tract, brain, other organs: rarely affected.
The cause of GPA is unknown, although microbes, such as bacteria and viruses, as well as genetics have been implicated in its pathogenesis.
Classic microscopic features of GPA include inflammation of blood vessels associated with poorly formed granulomas, necrosis, and many giant cells. Bacterial colonization with Staphylococcus aureus has been hypothesized as an initiating factor of the autoimmunity seen in people with GPA. Several genes involved in the immune system including PTPN22, CTLA4, and human leukocyte antigen genes may influence the risk of developing GPA.
It is now widely presumed that the anti-neutrophil cytoplasmic antibodies (ANCAs) are responsible for the inflammation in GPA. The typical ANCAs in GPA are those that react with proteinase 3, an enzyme prevalent in neutrophil granulocytes. In vitro studies have found that ANCAs can activate neutrophils, increase their adherence to endothelium, and induce their degranulation that can damage endothelial cells. In theory, this phenomenon could cause extensive damage to the vessel wall, in particular of arterioles.
GPA treatment depends on its severity and whether it has caused organ damage.
The standard treatment for severe GPA is to induce remission with immunosuppressants such as rituximab or cyclophosphamide in combination with high-dose corticosteroids. Intravenous “pulse” corticosteroids and plasmapheresis are also recommended if manifestations of severe GPA, such as diffuse alveolar hemorrhage, glomerulonephritis (as seen in pulmonary-renal syndrome), or mesenteric ischemia, are observed. The use of plasmapheresis in those with GPA and acute kidney failure (renal vasculitis) reduces progression to end-stage kidney disease at three months.
Oral and intravenous cyclophosphamide are both effective for induction of GPA remission. Oral cyclophosphamide at a dose of 2 mg/kg/day was the standard treatment for many years; this regimen resulted in complete remission in more than 75% of people with GPA but is associated with significant toxicities including infertility, inflammation and bleeding from the bladder, and bladder cancer. In contrast, administering pulsed doses of intravenous cyclophosphamide is equally effective for inducing remission, results in a lower cumulative dose, and decreases the incidence of abnormally low white blood cell counts by one-third. However, pulsed intravenous cyclophosphamide may be associated with a higher risk of GPA relapse when compared to oral cyclophosphamide. Due to a high frequency of abnormally low white blood cell counts seen with cyclophosphamide treatment, Pneumocystis jirovecii pneumonia is a common complication and prophylaxis against this pathogen is recommended.
Rituximab may be substituted for cyclophosphamide to induce remission since it is similarly effective and has a comparable side effect profile. The dose of corticosteroids is generally tapered (decreased) very slowly over the course of several months to reduce the risk of another GPA flare. After a person with GPA has successfully undergone induction and gone into remission, the treatment goal then shifts to maintenance of remission and preventing subsequent GPA flares. Less toxic immunosuppressing medications such as rituximab, methotrexate, azathioprine, leflunomide, or mycophenolate mofetil are used. TNF inhibitors, such as etanercept, appear to be ineffective and are not recommended for routine use.
In generalised non-organ-threatening disease, remission can be achieved with a combination of methotrexate and corticosteroids, where the steroid dose is reduced after a remission has been achieved and methotrexate is used as maintenance therapy. Treatment measures for localised GPA of the nose and sinuses includes nasal irrigation, nasal corticosteroids, and antibiotics if infection occurs. If perforation of the nasal septum occurs (or saddle nose deformity), then surgical repair is recommended.
Trimethoprim/sulfamethoxazole has been proposed to help prevent relapse though a 2015 Cochrane review did not confirm fewer relapses with trimethoprim/sulfamethoxazole treatment.
Before modern treatments, the 2-year survival was under 10% and average survival five months. Death usually resulted from uremia or respiratory failure. The revised Five-factor score is associated with 5-year mortality from GPA and is based on the following criteria: age greater than 65 years, cardiac symptoms, gastrointestinal involvement, chronic kidney disease, and the absence of ears, nose, and throat symptoms.
With corticosteroids and cyclophosphamide, 5-year survival is over 80%. Long-term complications are common (86%), mainly chronic kidney failure, hearing loss, and deafness. The risk of relapse is increased in people with GPA who test positive for anti-PR3 ANCA antibodies and is higher than the relapse risk for microscopic polyangiitis.
Today, medication toxicity is managed more carefully and long-term remissions are possible. Some affected individuals are able to lead relatively normal lives and remain in remission for 20+ years after treatment.
The incidence is 10–20 cases per million per year. It is exceedingly rare in Japan and in African Americans.
Scottish otolaryngologist Peter McBride (1854–1946) first described the condition in 1897 in a BMJ article entitled “Photographs of a case of rapid destruction of the nose and face”. Heinz Karl Ernst Klinger (born 1907) added information on the anatomical pathology. An early name for the disease was pathergic granulomatosis. The disease is still sometimes confused with lethal midline granuloma and lymphomatoid granulomatosis, both malignant lymphomas.
The full clinical picture was first presented by Friedrich Wegener (1907–1990), a German pathologist, in two reports in 1936 and 1939, leading to the eponymous name Wegener’s granulomatosis or Wegener granulomatosis (English: /ˈvɛɡənər/).
In 2006, Alexander Woywodt (Preston, United Kingdom) and Eric Matteson (Mayo Clinic, US) investigated Wegener’s past, and discovered that he was, at least at some point of his career, a follower of the Nazi regime. He was a member of the Sturmabteilung paramilitary group and worked in an office where medical experiments were conducted on Jewish people. In addition, their research indicate that Wegener was wanted by Polish authorities and that his files were forwarded to the United Nations War Crimes Commission. Furthermore, Wegener worked in close proximity to the genocide machinery in Łódź. Their research raised serious concerns about Wegener’s professional conduct. They suggested that the eponym be abandoned and proposed “ANCA-associated granulomatous vasculitis” as an alternative name. The authors have since campaigned for other medical eponyms to be abandoned as well. In 2011, the American College of Rheumatology (ACR), the American Society of Nephrology (ASN) and the European League Against Rheumatism (EULAR) resolved to change the name to granulomatosis with polyangiitis. The old name remains widely used despite the consensus to adopt the change.