| Granulomatosis with polyangiitis | |
|---|---|
| Other names | Wegener's granulomatosis (formerly) |
 | |
| Micrograph showing features characteristic of granulomatosis with polyangiitis – avasculitis andgranulomas with multi-nucleated giant cells.H&E stain. | |
| Specialty | Immunology,internal medicine  |
| Causes | Autoimmune disease |
Granulomatosis with polyangiitis (GPA), is a rare, long-term, systemic disorder that involves the formation ofgranulomas andinflammation of blood vessels (vasculitis).[1][2][3][4][5] It is anautoimmune 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.[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 includenosebleeds, stuffy nose and crustiness of nasal secretions, andinflammation of the uveal layer of the eye.[3] Damage to theheart,lungs, andkidneys can be fatal. The disease was formerly known asWegener's granulomatosis (WG).
The cause of GPA is unknown.Genetics has 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 ofimmunosuppressive medications such asrituximab orcyclophosphamide and high-dosecorticosteroids to control thesymptoms of the disease, andazathioprine,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]
Thenumber of new cases of GPA each year is estimated to be between 2.1 and 14.4 new cases per million people in Europe.[3] GPA is rare inJapanese andAfrican-American populations but occurs more often in people of Northern European descent.[7] GPA is estimated toaffect three cases per 100,000 people in the United States and affects men and women equally.[10] GPA has infrequently been reported in minors.[11]
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.[12][13] Involvement of theupper respiratory tract, such as the nose andsinuses, is seen in nearly all people with GPA.[14][15] Typical signs and symptoms of nose or sinus involvement include crusting around the nose, stuffiness,nosebleeds,runny nose, and "saddle-nose" deformity due to ahole in the septum of the nose.[7][14] Inflammation of the outer layers of the eye (scleritis andepiscleritis[16][17]) andconjunctivitis 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]
The cause of GPA is unknown, although microbes, such asbacteria andviruses, as well as genetics, have been implicated in itspathogenesis.[13][19]
Classic microscopic features of GPA include inflammation of blood vessels associated with poorly formedgranulomas,necrosis, and manygiant cells.[20] Bacterial colonization withStaphylococcus aureus has been hypothesized as an initiating factor of the autoimmunity seen in people with GPA.[8] Several genes involved in theimmune system includingPTPN22,CTLA4, andhuman leukocyte antigen genes may influence the risk of developing GPA.[7]
Antineutrophil cytoplasmic antibodies (ANCAs) now are widely presumed to be responsible for the inflammation in GPA.[12] The typical ANCAs in GPA are those that react withproteinase 3, an enzyme prevalent inneutrophil granulocytes.[7]In vitro studies have found that ANCAs can activateneutrophils, increase their adherence toendothelium, and induce theirdegranulation that can damageendothelial cells. This phenomenon could cause extensive damage to the vessel wall, especially toarterioles.[12]
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 positivity is not conclusive, and negative ANCAs are insufficient to reject the diagnosis. More than 90% of people who have GPA test positive for ANCAs.[20] Cytoplasmic-staining ANCAs that react with the enzyme proteinase 3 (cANCA) inneutrophils (a type ofwhite blood cells) 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 orcutaneous vasculitis, abiopsy is obtained from the kidneys. Rarely, athoracoscopic lung biopsy is required. Onhistopathological examination, a biopsy will show leukocytoclastic vasculitis withnecrotic changes andgranulomatousinflammation (clumps of typically arranged white blood cells) onmicroscopy. 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.[12]
Granulomatosis with polyangiitis is part of a larger group of vasculitic syndromes calledsystemic vasculitides or necrotizing vasculopathies, all of which feature an autoimmune attack by an abnormal type of circulatingantibody termed ANCAs (antineutrophil cytoplasmic antibodies) against small and medium-sizedblood vessels. Apart from GPA, this category includeseosinophilic granulomatosis with polyangiitis (EGPA) andmicroscopic polyangiitis.[1] Although GPA affects small- and medium-sized vessels,[21] it is formally classified as one of the small-vessel vasculitides in the Chapel Hill system.[2]
In 1990, theAmerican College of Rheumatology accepted classification criteria for GPA. These criteria were not intended for diagnosis but for inclusion inrandomized controlled trials. Two or more positive criteria have asensitivity of 88.2% and a specificity of 92.0% of describing GPA.[14][22]
According to theChapel Hill Consensus Conference (CHCC) on the nomenclature of systemic vasculitis (1992), establishing the diagnosis of GPA demands[23]agranulomatous inflammation involving the respiratory tract, and avasculitis of small to medium-sized vessels.
Several investigators have compared the ACR and Chapel Hill criteria.[24]
In 2022, the American College of Rheumatology and the European Alliance of Associations for Rheumatology updated the classification criteria for GPA.[25]
GPA treatment depends on its severity and whether it has caused organ damage.[8]
The standard treatment for severe GPA is to induce remission with immunosuppressants such asrituximab orcyclophosphamide in combination with high-dosecorticosteroids.[8][26]Plasmapheresis is sometimes recommended for very severe manifestations of GPA, such asdiffuse alveolar hemorrhage and rapidly progressiveglomerulonephritis (as seen inpulmonary-renal syndrome).[5][9] The use of plasmapheresis in those with GPA andacute kidney failure (renal vasculitis) might reduce progression toend-stage kidney disease at three months.[9]
Oral and intravenous cyclophosphamide are both effective for the 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, includinginfertility,inflammation and bleeding from the bladder, andbladder 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 ofabnormally 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, so 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.[26][27] The dose of corticosteroids is generally tapered (decreased) very slowly over 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 maintaining remission and preventing subsequent GPA flares. Less-toxic immunosuppressing medications such asrituximab,methotrexate,azathioprine,leflunomide, ormycophenolate mofetil are used.[28]TNF inhibitors, such asetanercept, appear to be ineffective and are not recommended for routine use.[8]
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 include 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 2015Cochrane review did not confirm fewer relapses with trimethoprim/sulfamethoxazole treatment.[8][9]
Before modern treatments, the two-year survival was under 10%. The average survival was five months.[13][29] Death usually resulted fromuremia orrespiratory failure.[13] The revised five-factor score is associated with five-year mortality from GPA and is based on these criteria: Age greater than 65 years, cardiac symptoms, gastrointestinal involvement, chronic kidney disease, and the absence of ear, nose, and throat symptoms.[7]
With corticosteroids and cyclophosphamide, five-year survival is over 80%.[13] Long-term complications are common (86%), mainlychronic kidney failure, hearing loss, anddeafness.[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 people can lead relatively normal lives and remain in remission for 20+ years after treatment.[30]
Theincidence is 10–20 cases per million per year.[31][32] It is exceedingly rare in Japan and amongAfrican Americans.[32]
Scottishotolaryngologist Peter McBride (1854–1946) first described the condition in 1897 in aBritish Medical Journal article entitled "Photographs of a case of rapid destruction of the nose and face".[33] Heinz Karl Ernst Klinger (born 1907) added information on theanatomical pathology. An early name for the disease was pathergic granulomatosis.[34] The disease is still sometimes confused withlethal midline granuloma andlymphomatoid granulomatosis, both malignantlymphomas.[35]
The full clinical picture was first presented byFriedrich Wegener (1907–1990), aGermanpathologist, in two reports in 1936 and 1939, leading to the eponymous name Wegener's granulomatosis or Wegener granulomatosis (English:/ˈvɛɡənər/).[10] In 2011, theAmerican College of Rheumatology, theAmerican Society of Nephrology, and theEuropean League Against Rheumatism resolved to change the name to granulomatosis with polyangiitis, given Wegener's association with theNazi Party.[36]