Granulomatosis with polyangiitis (GPA), previously known as Wegener's granulomatosis (WG), is a rare long-term systemic disorder that involves the formation of granulomas and inflammation of blood vessels (vasculitis). It is a form of vasculitis that affects small- and medium-size 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 A nosebleed, also known as epistaxis, is bleeding from the nose. Blood can flow down into the stomach, and cause nausea and vomiting. In more severe cases, blood may come out of both nostrils. Rarely, bleeding may be so significant that low bloo ...

, stuffy nose and crustiness of nasal secretions, and inflammation of the uveal layer of the eye. Damage to the

heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...

, lungs and kidneys can be fatal. The cause of GPA is unknown.

Genetics Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinian friar wor ...

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 control the symptoms of the disease and

azathioprine Azathioprine (AZA), sold under the brand name Imuran, among others, is an immunosuppressive medication. It is used in rheumatoid arthritis, granulomatosis with polyangiitis, Crohn's disease, ulcerative colitis, and systemic lupus erythematosus, ...

, 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 to be 2.1–14.4 new cases per million people in Europe. GPA is rare in Japanese and

African-American African Americans (also referred to as Black Americans and Afro-Americans) are an ethnic group consisting of Americans with partial or total ancestry from sub-Saharan Africa. The term "African American" generally denotes descendants of ensl ...

populations but occurs more often in people of Northern European descent. GPA is estimated to affect 3 cases per 100,000 people in the United States and equally affects men and women.

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 inflammation of the nose is the first sign in most people. Involvement of the

upper respiratory tract The respiratory tract is the subdivision of the respiratory system involved with the process of respiration in mammals. The respiratory tract is lined with respiratory epithelium as respiratory mucosa. Air is breathed in through the nose to t ...

, 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,

nosebleed A nosebleed, also known as epistaxis, is bleeding from the nose. Blood can flow down into the stomach, and cause nausea and vomiting. In more severe cases, blood may come out of both nostrils. Rarely, bleeding may be so significant that low bl ...

s, runny nose, and ''

saddle-nose Saddle nose is a condition associated with nasal trauma, congenital syphilis, relapsing polychondritis, granulomatosis with polyangiitis, cocaine abuse, and leprosy, among other conditions. The most common cause is nasal trauma. It is character ...

'' deformity due to a hole in the septum of the nose. Inflammation of the outer layers of the eye (

scleritis Scleritis is a serious inflammatory disease that affects the white outer coating of the eye, known as the sclera. The disease is often contracted through association with other diseases of the body, such as granulomatosis with polyangiitis or ...

and

episcleritis Episcleritis is a benign, self-limiting inflammatory disease affecting part of the eye called the episclera. The episclera is a thin layer of tissue that lies between the conjunctiva and the connective tissue layer that forms the white of the e ...

) 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 An ear is the organ that enables hearing and, in mammals, body balance using the vestibular system. In mammals, the ear is usually described as having three parts—the outer ear, the middle ear and the inner ear. The outer ear consists of ...

disease: ** Ears: conductive hearing loss due to

auditory tube Auditory means of or relating to the process of hearing: * Auditory system, the neurological structures and pathways of sound perception ** Auditory bulla, part of auditory system found in mammals other than primates ** Auditory nerve, also known ...

dysfunction, sensorineural hearing loss (unclear mechanism) ** Oral cavity: strawberry gingivitis, underlying bone destruction with loosening of teeth, non-specific ulcerations throughout the lining of the mouth * Trachea: subglottal stenosis * Lungs: pulmonary nodules (referred to as "coin lesions"), infiltrates (often interpreted as

pneumonia Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severi ...

), 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, various others (see '' cutaneous vasculitis'') *

Nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes ...

: occasionally

sensory neuropathy Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...

(10%) and rarely

mononeuritis multiplex Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...

Heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...

, gastrointestinal tract,

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...

, other organs: rarely affected.

Causes

The cause of GPA is unknown, although microbes, such as

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...

and

virus A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsk ...

es, as well as genetics have been implicated in its

pathogenesis Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...

Pathophysiology

Classic microscopic features of GPA include inflammation of blood vessels associated with poorly formed granulomas, necrosis, and many

giant cell A giant cell (also known as multinucleated giant cell, or multinucleate giant cell) is a mass formed by the union of several distinct cells (usually histiocytes), often forming a granuloma. Although there is typically a focus on the pathologica ...

s. 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

arteriole An arteriole is a small-diameter blood vessel in the microcirculation that extends and branches out from an artery and leads to capillaries. Arterioles have muscular walls (usually only one to two layers of smooth muscle cells) and are the primar ...

Diagnosis

Granulomatosis with polyangiitis is usually suspected only when a person has had unexplained symptoms for a long period of time. Determination of anti-neutrophil cytoplasmic antibodies (ANCAs) can aid in the diagnosis, but positivity is not conclusive and negative ANCAs are not sufficient to reject the diagnosis. More than 90% of people who have GPA test positive for ANCA. Cytoplasmic-staining ANCAs that react with the enzyme proteinase 3 (cANCA) in neutrophils (a type of white blood cell) 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 A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a dise ...

is obtained from the kidneys. On rare occasions, thoracoscopic lung biopsy is required. On histopathological examination, a biopsy will show ''leukocytoclastic vasculitis'' with

necrotic Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...

changes and granulomatous

inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

(clumps of typically arranged white blood cells) on microscopy. These granulomas are the main reason for the name granulomatosis with polyangiitis, although it is not an essential feature. Nevertheless, necrotizing granulomas are a hallmark of this disease. However, many biopsies can be nonspecific 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-size blood vessels. Apart from GPA, this category includes

eosinophilic granulomatosis with polyangiitis Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as allergic granulomatosis, is an extremely rare autoimmune condition that causes inflammation of small and medium-sized blood vessels (vasculitis) in persons with a history of ...

(EGPA) and

microscopic polyangiitis Microscopic polyangiitis is an ill-defined autoimmune disease characterized by a systemic, pauci-immune, necrotizing, small-vessel vasculitis without clinical or pathological evidence of necrotizing granulomatous inflammation. Signs and symptoms C ...

. Although GPA affects small- and medium-size vessels, it is formally classified as one of the small vessel vasculitides in the Chapel Hill system.

Criteria

In 1990, the American College of Rheumatology accepted classification criteria for GPA. These criteria were not intended for diagnosis, but for inclusion in randomized controlled trials. Two or more positive criteria have a sensitivity of 88.2% and a specificity of 92.0% of describing GPA. Granulomatosis with polyangiitis

* Nasal or oral inflammation: ** painful or painless oral ulcers ''or'' ** purulent or bloody nasal discharge * Lungs: abnormal chest X-ray with: ** nodules, ** infiltrates ''or'' ** cavities * Kidneys: urinary sediment with: ** microscopic hematuria ''or'' ** red cell casts * Biopsy: granulomatous inflammation ** within the arterial wall ''or'' ** in the perivascular area According to the

Chapel Hill Consensus Conference The Chapel Hill Consensus Conferences (CHCC) (1994 and 2012) are a pair of international conferences which addressed the need of standardized classification system for systemic vasculitides.Jennette JC; Nomenclature of systemic vasculitides. Propos ...

(CHCC) on the nomenclature of systemic vasculitis (1992), establishing the diagnosis of GPA demands: * a

granulomatous A granuloma is an aggregation of macrophages that forms in response to chronic inflammation. This occurs when the immune system attempts to isolate foreign substances that it is otherwise unable to eliminate. Such substances include infectiou ...

inflammation involving the respiratory tract, and * a vasculitis of small to medium-size vessels. Several investigators have compared the ACR and Chapel Hill criteria.

Treatment

GPA treatment depends on its severity and whether it has caused organ damage.

Severe disease

The standard treatment for severe GPA is to induce remission with immunosuppressants such as rituximab or cyclophosphamide in combination with high-dose corticosteroids. Plasmapheresis is sometimes recommended for very severe manifestations of GPA, such as

diffuse alveolar hemorrhage Pulmonary hemorrhage (or pulmonary haemorrhage) is an acute bleeding from the lung, from the upper respiratory tract and the trachea, and the pulmonary alveoli. When evident clinically, the condition is usually massive.glomerulonephritis Glomerulonephritis (GN) is a term used to refer to several kidney diseases (usually affecting both kidneys). Many of the diseases are characterised by inflammation either of the glomeruli or of the small blood vessels in the kidneys, hence the ...

(as seen in pulmonary-renal syndrome). The use of plasmapheresis in those with GPA and

acute kidney failure Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in kidney function that develops within 7 days, as shown by an increase in serum creatinine or a decrease in urine output, or both. Causes of AKI are c ...

(renal vasculitis) might reduce progression to

end-stage kidney disease Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...

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,

leflunomide Leflunomide, sold under the brand name Arava among others, is an immunosuppressive disease-modifying antirheumatic drug ( DMARD), used in active moderate-to-severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibi ...

, or

mycophenolate mofetil Mycophenolic acid (MPA) is an immunosuppressant medication used to prevent rejection following organ transplantation and to treat autoimmune conditions such as Crohn's disease and lupus. Specifically it is used following kidney, heart, and liv ...

are used. TNF inhibitors, such as

etanercept Etanercept, sold under the brand name Enbrel among others, is a biologic medical product that is used to treat autoimmune diseases by interfering with tumor necrosis factor (TNF), a soluble inflammatory cytokine, by acting as a TNF inhibitor. It ...

, appear to be ineffective and are not recommended for routine use.

Limited disease

In generalized 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 Trimethoprim/sulfamethoxazole, sold under the brand name Bactrim among others, is a fixed-dose combination antibiotic medication used to treat a variety of bacterial infections. It consists of one part trimethoprim to five parts sulfamethoxa ...

has been proposed to help prevent relapse though a 2015 Cochrane review did not confirm fewer relapses with trimethoprim/sulfamethoxazole treatment.

Prognosis

Before modern treatments, the 2-year survival was under 10% and average survival five months. Death usually resulted from uremia or

respiratory failure Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a rise ...

. 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.

Epidemiology

The incidence is 10–20 cases per million per year. It is exceedingly rare in Japan and in African Americans.

History

Scottish

otolaryngologist Otorhinolaryngology ( , abbreviated ORL and also known as otolaryngology, otolaryngology–head and neck surgery (ORL–H&N or OHNS), or ear, nose, and throat (ENT)) is a surgical subspeciality within medicine that deals with the surgical a ...

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 Friedrich Wegener (7 April 1907, Varel – 9 July 1990, Lübeck, ) was a German pathologist who is notable for his description of a rare disease originally referred to Wegener disease and now referred to as granulomatosis with polyangiitis. Alth ...

(1907–1990), a German pathologist, in two reports in 1936 and 1939, leading to the eponymous name ''Wegener's granulomatosis'' or ''Wegener granulomatosis'' (). In 2011, the American College of Rheumatology (ACR), the American Society of Nephrology (ASN) and the

European League Against Rheumatism The European Alliance of Associations for Rheumatology (EULAR) formerly the European League Against Rheumatism is a European non-governmental organization which represents the people with arthritis/rheumatism, health professional and scientific so ...

(EULAR) resolved to change the name to granulomatosis with polyangiitis, given Wegener's association with the

Nazi Party The Nazi Party, officially the National Socialist German Workers' Party (german: Nationalsozialistische Deutsche Arbeiterpartei or NSDAP), was a far-right political party in Germany active between 1920 and 1945 that created and supported t ...

References

External links

{{Glomerular disease Arthritis Autoimmune diseases Disorders of fascia Lung disorders Nephrology Rheumatology Steroid-responsive inflammatory conditions Systemic connective tissue disorders Vascular-related cutaneous conditions