Granulomatosis with polyangiitis (GPA) is a rare, long-term, systemic disorder that involves the formation of granulomas and inflammation of blood vessels (vasculitis). It is an autoimmune disease and a form of vasculitis that affects small- and medium-sized vessels in many organs, but most commonly affects the upper respiratory tract, lungs, and kidneys. 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 disease was formerly known as Wegener's granulomatosis (WG). The cause of GPA is unknown. Genetics has 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 control the symptoms of the disease, and azathioprine, methotrexate, or rituximab to keep the disease under control. Plasma exchange is also used in severe cases with damage to the lungs, kidneys, or intestines. The number of new cases of GPA each year is estimated at 2.1 to 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. GPA is estimated to affect three cases per 100,000 people in the United States and affects men and women equally. GPA has infrequently been reported in minors.
Signs and symptoms
Initial signs are highly variable, and diagnosis can be severely delayed due to the nonspecific nature of the symptoms. In general, irritation and nasal inflammation are the first signs 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 hole in the septum of the nose. Inflammation of the outer layers of the eye (scleritis and episcleritis) and conjunctivitis are the most common signs of GPA in the eye; 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 disease 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, and nonspecific ulcerations throughout the lining of the mouth Trachea: Subglottal stenosis Lungs: Pulmonary nodules (referred to as "coin lesions"), infiltrates (often interpreted as pneumonia), cavitary lesions, bleeding in the lungs causing a person to cough up blood, and rarely bronchial stenosis Arthritis: Pain or swelling (60%), often initially diagnosed as rheumatoid arthritis Skin: Subcutaneous nodules (granulomas) on the elbow, purpura, and various others (see cutaneous vasculitis) Nervous system: Occasionally sensory neuropathy (10%) and rarely mononeuritis multiplex Heart, gastrointestinal tract, brain, other organs: Rarely affected
Causes The cause of GPA is unknown, although microbes, such as bacteria and viruses, as well as genetics, have been implicated in its pathogenesis.
Pathophysiology Classic microscopic features of GPA include inflammation of blood vessels featuring 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. Antineutrophil cytoplasmic antibodies (ANCAs) are now widely presumed to be 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. This phenomenon could cause extensive damage to the vessel wall, especially to arterioles.
Diagnosis
Granulomatosis with polyangiitis is usually suspected only when a person has had unexplained symptoms for a long period. The determination of ANCAs can aid in diagnosing GPA, but a positive ANCA test is not conclusive, and a negative ANCA test result is insufficient to exclude the diagnosis. More than 90% of people who have GPA test positive for ANCAs. Cytoplasmic-staining ANCAs that react with the enzyme proteinase 3 (cANCA) in neutrophils (a type of white blood cells) are associated with GPA. Involvement of the ears, nose, and throat is more common in granulomatosis with polyangiitis than in the similar condition microscopic polyangiitis. If the person has signs of kidney involvement or cutaneous vasculitis, a biopsy is obtained from the kidneys. Rarely, a thoracoscopic lung biopsy is required. On histopathological examination, a biopsy will show leukocytoclastic vasculitis with necrotic changes and granulomatous inflammation (clumps of typically arranged white blood cells) on microscopy. These granulomas are the main reason for the name granulomatosis with polyangiitis, although they are not an essential feature. Nevertheless, necrotizing granulomas are a hallmark of this disease. Many biopsies can be nonspecific, though, and 50% provide too little information for the diagnosis of GPA.
Classification Granulomatosis with polyangiitis is part of a larger group of vasculitic syndromes called systemic vasculitides or necrotizing vasculopathies, all of which feature an autoimmune attack by an abnormal type of circulating antibody termed ANCAs (antineutrophil cytoplasmic antibodies) against small and medium-sized blood vessels. Apart from GPA, this category includes eosinophilic granulomatosis with polyangiitis (EGPA) and microscopic polyangiitis. Although GPA affects small- and medium-sized vessels, it is formally classified as one of the small-vessel vasculitides in the Chapel Hill system.
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