Granulomatosis with polyangiitis

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Granulomatosis with polyangiitis
Other namesWegener's granulomatosis (WG) (formerly)
Wegener's granulomatosis -b- intermed mag.jpg
Micrograph showing features characteristic of granulomatosis with polyangiitis – a vasculitis and granulomas with multi-nucleated giant cells. H&E stain.
Specialty Immunology, rheumatology   OOjs UI icon edit-ltr-progressive.svg
Causes Autoimmune disease

Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis (WG), [1] [2] [3] [4] [5] after the German physician Friedrich Wegener, 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-size vessels in many organs but most commonly affects the upper respiratory tract, lungs and kidneys. [6] 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. [3] Damage to the heart, lungs and kidneys can be fatal.

Contents

The cause of GPA is unknown. Genetics have a role in GPA though the risk of inheritance appears to be low. [7]

GPA treatment depends on the severity of the disease. [8] 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. [1] [7] [8] Plasma exchange is also used in severe cases with damage to the lungs, kidneys, or intestines. [9]

The number of new cases of GPA each year is estimated to be 2.1–14.4 new cases per million people in Europe. [3] GPA is rare in Japanese and African-American populations but occurs more often in people of Northern European descent. [7] GPA is estimated to affect 3 cases per 100,000 people in the United States and equally affects men and women. [10] GPA has infrequently been reported in minors. [11]

Signs and symptoms

Typical saddle nose damage due to granulomatosis with polyangiitis. Saddle nose 38.jpg
Typical saddle nose damage due to granulomatosis with polyangiitis.

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. [12] [13] Involvement of the upper respiratory tract, such as the nose and sinuses, is seen in nearly all people with GPA. [14] 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. [7] [14] Inflammation of the outer layers of the eye (scleritis and episcleritis [15] [16] ) 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. [6]

Causes

The cause of GPA is unknown, although microbes, such as bacteria and viruses, as well as genetics have been implicated in its pathogenesis. [13] [18]

Pathophysiology

Classic microscopic features of GPA include inflammation of blood vessels associated with poorly formed granulomas, necrosis, and many giant cells. [19] Bacterial colonization with Staphylococcus aureus has been hypothesized as an initiating factor of the autoimmunity seen in people with GPA. [8] Several genes involved in the immune system including PTPN22 , CTLA4 , and human leukocyte antigen genes may influence the risk of developing GPA. [7]

It is now widely presumed that the anti-neutrophil cytoplasmic antibodies (ANCAs) are responsible for the inflammation in GPA. [12] The typical ANCAs in GPA are those that react with proteinase 3, an enzyme prevalent in neutrophil granulocytes. [7] 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. [12]

Diagnosis

Immunofluorescence pattern produced by binding of ANCA to ethanol-fixed neutrophils, from a person with GPA C anca.jpg
Immunofluorescence pattern produced by binding of ANCA to ethanol-fixed neutrophils, from a person with GPA

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. [19] Cytoplasmic-staining ANCAs that react with the enzyme proteinase 3 (cANCA) in neutrophils (a type of white blood cell) are associated with GPA. [12] Involvement of the ears, nose, and throat is more common in granulomatosis with polyangiitis than in the similar condition microscopic polyangiitis. [7]

If the person has signs of kidney involvement or cutaneous vasculitis, a biopsy is obtained from the kidneys. On rare occasions, 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 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. [12]

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 (EGPA) and microscopic polyangiitis. [1] Although GPA affects small- and medium-size vessels, [20] it is formally classified as one of the small vessel vasculitides in the Chapel Hill system. [2]

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. [14] [21]

The left apical region is opacified in a case of granulomatosis with polyangiitis. Granulomatosis with polyangiitis.jpg
The left apical region is opacified in a case of granulomatosis with polyangiitis.

According to the Chapel Hill Consensus Conference (CHCC) on the nomenclature of systemic vasculitis (1992), establishing the diagnosis of GPA demands: [22]

Several investigators have compared the ACR and Chapel Hill criteria. [23]

In 2022, American College of Rheumatology and the European Alliance of Associations for Rheumatology updated the classification criteria for GPA. [24]

Treatment

GPA treatment depends on its severity and whether it has caused organ damage. [8]

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. [8] [25] Plasmapheresis is sometimes recommended for very severe manifestations of GPA, such as diffuse alveolar hemorrhage and rapidly progressive glomerulonephritis (as seen in pulmonary-renal syndrome). [5] [9] The use of plasmapheresis in those with GPA and acute kidney failure (renal vasculitis) might reduce progression to end-stage kidney disease at three months. [9]

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. [8] 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. [8] However, pulsed intravenous cyclophosphamide may be associated with a higher risk of GPA relapse when compared to oral cyclophosphamide. [8] 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. [8]

Rituximab may be substituted for cyclophosphamide to induce remission since it is similarly effective and has a comparable side effect profile. [25] [26] 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. [27] TNF inhibitors, such as etanercept, appear to be ineffective and are not recommended for routine use. [8]

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. [14] If perforation of the nasal septum occurs (or saddle nose deformity), then surgical repair is recommended. [14]

Trimethoprim/sulfamethoxazole has been proposed to help prevent relapse though a 2015 Cochrane review did not confirm fewer relapses with trimethoprim/sulfamethoxazole treatment. [8] [9]

Prognosis

Before modern treatments, the 2-year survival was under 10% and average survival five months. [13] [28] Death usually resulted from uremia or respiratory failure. [13] 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. [7]

With corticosteroids and cyclophosphamide, 5-year survival is over 80%. [13] Long-term complications are common (86%), mainly chronic kidney failure, hearing loss, and deafness. [12] 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. [7]

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. [29]

Epidemiology

The incidence is 10–20 cases per million per year. [30] [31] It is exceedingly rare in Japan and in African Americans. [31]

History

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". [32] Heinz Karl Ernst Klinger (born 1907) added information on the anatomical pathology. An early name for the disease was pathergic granulomatosis. [33] The disease is still sometimes confused with lethal midline granuloma and lymphomatoid granulomatosis, both malignant lymphomas. [34]

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/ ). [10] 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, given Wegener's association with the Nazi Party. [35]

See also

Related Research Articles

<span class="mw-page-title-main">Vasculitis</span> Medical disorders that destroy blood vessels by inflammation

Vasculitis is a group of disorders that destroy blood vessels by inflammation. Both arteries and veins are affected. Lymphangitis is sometimes considered a type of vasculitis. Vasculitis is primarily caused by leukocyte migration and resultant damage. Although both occur in vasculitis, inflammation of veins (phlebitis) or arteries (arteritis) on their own are separate entities.

<span class="mw-page-title-main">Eosinophilic granulomatosis with polyangiitis</span> Medical condition

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 airway allergic hypersensitivity (atopy).

<span class="mw-page-title-main">Polyarteritis nodosa</span> Systemic necrotizing inflammation of medium-sized muscular arteries

Polyarteritis nodosa (PAN) is a systemic necrotizing inflammation of blood vessels (vasculitis) affecting medium-sized muscular arteries, typically involving the arteries of the kidneys and other internal organs but generally sparing the lungs' circulation. Small aneurysms are strung like the beads of a rosary, therefore making this "rosary sign" an important diagnostic feature of the vasculitis. PAN is sometimes associated with infection by the hepatitis B or hepatitis C virus. The condition may be present in infants.

<span class="mw-page-title-main">Fibrinoid necrosis</span> Deposition of fibrin within blood vessel walls

Fibrinoid necrosis is a pathological lesion that affects blood vessels, and is characterized by the occurrence of endothelial damage, followed by leakage of plasma proteins, including fibrinogen, from the vessel lumen; these proteins infiltrate and deposit within the vessel walls, where fibrin polymerization subsequently ensues.

<span class="mw-page-title-main">Glomerulonephritis</span> Term for several kidney diseases

Glomerulonephritis (GN) is a term used to refer to several kidney diseases. Many of the diseases are characterised by inflammation either of the glomeruli or of the small blood vessels in the kidneys, hence the name, but not all diseases necessarily have an inflammatory component.

<span class="mw-page-title-main">Rituximab</span> Biopharmaceutical drug

Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, idiopathic thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis and Epstein–Barr virus-positive mucocutaneous ulcers. It is given by slow intravenous infusion.

<span class="mw-page-title-main">Myeloperoxidase</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">Anti-neutrophil cytoplasmic antibody</span> Group of autoantibodies

Anti-neutrophil cytoplasmic antibodies (ANCAs) are a group of autoantibodies, mainly of the IgG type, against antigens in the cytoplasm of neutrophils and monocytes. They are detected as a blood test in a number of autoimmune disorders, but are particularly associated with systemic vasculitis, so called ANCA-associated vasculitides (AAV).

Microscopic polyangiitis is an autoimmune disease characterized by a systemic, pauci-immune, necrotizing, small-vessel vasculitis without clinical or pathological evidence of granulomatous inflammation.

<span class="mw-page-title-main">Friedrich Wegener</span> German pathologist (1907–1990)

Friedrich Wegener was a German pathologist who is notable for being a high-ranking Nazi physician and for his description of a rare disease originally referred to Wegener disease and now referred to as granulomatosis with polyangiitis. Although this disease was known before Wegener's description, from the 1950s onwards it was generally referred to as Wegener's granulomatosis.

p-ANCA Type of autoantibody

p-ANCA, or MPO-ANCA, or perinuclear anti-neutrophil cytoplasmic antibodies, are antibodies that stain the material around the nucleus of a neutrophil. They are a special class of anti-neutrophil cytoplasmic antibodies.

<span class="mw-page-title-main">Rapidly progressive glomerulonephritis</span> Medical condition

Rapidly progressive glomerulonephritis (RPGN) is a syndrome of the kidney that is characterized by a rapid loss of kidney function, with glomerular crescent formation seen in at least 50% or 75% of glomeruli seen on kidney biopsies. If left untreated, it rapidly progresses into acute kidney failure and death within months. In 50% of cases, RPGN is associated with an underlying disease such as Goodpasture syndrome, systemic lupus erythematosus or granulomatosis with polyangiitis; the remaining cases are idiopathic. Regardless of the underlying cause, RPGN involves severe injury to the kidneys' glomeruli, with many of the glomeruli containing characteristic glomerular crescents.

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Pulmonary-renal syndrome (PRS) is a rare medical syndrome in which respiratory failure involving bleeding in the lungs and kidney failure (glomerulonephritis) occur. PRS is associated with a high rate of morbidity and death. The term was first used by Goodpasture in 1919 to describe the association of respiratory and kidney failure.

Pauci-immune vasculitis is a form of vasculitis that is associated with minimal evidence of hypersensitivity upon immunofluorescent staining for IgG. Often, this is discovered in the setting of the kidney.

<span class="mw-page-title-main">Systemic vasculitis</span> Medical condition

Necrotizing vasculitis, also called systemic necrotizing vasculitis, is a general term for the inflammation of veins and arteries that develops into necrosis and narrows the vessels.

<span class="mw-page-title-main">Lupus vasculitis</span> Medical condition

Lupus vasculitis is one of the secondary vasculitides that occurs in approximately 50% of patients with systemic lupus erythematosus (SLE).

Vasculitic neuropathy is a peripheral neuropathic disease. In a vasculitic neuropathy there is damage to the vessels that supply blood to the nerves. It can be as part of a systemic problem or can exist as a single-organ issue only affecting the peripheral nervous system (PNS). It is diagnosed with the use of electrophysiological testing, blood tests, nerve biopsy and clinical examination. It is a serious medical condition that can cause prolonged morbidity and disability and generally requires treatment. Treatment depends on the type but it is mostly with corticosteroids or immunomodulating therapies.

<span class="mw-page-title-main">Avacopan</span> Chemical compound

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<span class="mw-page-title-main">J. Charles Jennette</span> Doctor, academic, and author

J. Charles Jennette is a physician, nephropathologist, academic, and author. He served as Kenneth M. Brinkhous Distinguished Professor and Chair of Pathology and Laboratory Medicine at the University of North Carolina at Chapel Hill School of Medicine, and Chief of Pathology and Laboratory Medicine Services at UNC Hospitals from 1999 to 2019.

References

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