Granulomatosis with polyangiitis

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Granulomatosis with polyangiitis
Synonyms Wegener's granulomatosis (WG)
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

Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis (WG),[1][2][3] 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. Damage to the lungs and kidneys can be fatal.

The cause of GPA is unknown.[4] Genetics have been found to play a role in GPA though the risk of inheritance appears to be low.[4]

Treatment requires long-term immunosuppression with medications such as high-dose corticosteroids, rituximab, or cyclophosphamide to induce remission and azathioprine or methotrexate to maintain remission.[1][4]

The annual incidence of GPA 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.[4] The prevalence of GPA in the United States is estimated to be 3 cases per 100,000 people and equally affects men and women.[5]


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,[6] it is formally classified as one of the small vessel vasculitides in the Chapel Hill system.[2]

Signs and symptoms[edit]

Typical saddle nose damage due to granulomatosis with polyangiitis.

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.[7][8]


The cause of GPA is unknown, although microbes, such as bacteria and viruses, as well as genetics have been implicated in its pathogenesis.[8][10]


Inflammation with granuloma formation against a nonspecific inflammatory background is the classical tissue abnormality in all organs affected by GPA.[7]

It is now widely presumed that the anti-neutrophil cytoplasmic antibodies (ANCAs) are responsible for the inflammation in GPA.[7] The typical ANCAs in GPA are those that react with proteinase 3, an enzyme prevalent in neutrophil granulocytes.[4]

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.[7]


Immunofluorescence pattern produced by binding of ANCA to ethanol-fixed neutrophils, from a person with GPA
Photo showing the sclerokeratitis associated 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. Cytoplasmic-staining ANCAs that react with the enzyme proteinase 3 (cANCA) in neutrophils (a type of white blood cell) are associated with GPA.[7]

If the person has kidney failure 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.[7]


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.[11]

  • 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:
  • Biopsy: granulomatous inflammation
    • within the arterial wall or
    • in the perivascular area

According to the Chapel Hill Consensus Conference (CHCC) on the nomenclature of systemic vasculitis (1992), establishing the diagnosis of GPA demands:[12]

Several investigators have compared the ACR and Chapel Hill criteria.[13]


The standard treatment for GPA is to induce remission with immunosuppressants such as rituximab or cyclophosphamide in combination with high-dose corticosteroids.[14] The dose of corticosteroids is generally tapered (decreased) very slowly over the course of several months to reduce the risk of another GPA flare. Rituximab may be substituted for cyclophosphamide in inducing remission since it is similarly effective and has a comparable side effect profile.[14] 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.[15] Trimethoprim/sulfamethoxazole may also help prevent relapse.[15] A systematic review of 84 trials examined the evidence for various treatments in GPA. Many trials include data on pooled groups of people with GPA and microscopic polyangiitis. In this review, cases are divided between localised disease, non-organ threatening, generalized organ-threatening disease and severe kidney vasculitis and immediately life-threatening disease.[16]

  • In generalised non-organ-threatening disease, remission can be induced with methotrexate and steroids, where the steroid dose is reduced after a remission has been achieved and methotrexate used as maintenance.
  • In case of organ-threatening disease, pulsed intravenous cyclophosphamide with steroids is recommended. Once remission has been achieved, azathioprine and steroids can be used to maintain remission.
  • In severe kidney vasculitis, the same regimen is used but with the addition of plasma exchange.
  • In pulmonary haemorrhage, high doses of cyclophosphamide with pulsed methylprednisolone may be used, or alternatively CYC, corticosteroids, and plasma exchange.

Therapy for GPA and MPA has two main components: induction of remission with initial immunosuppressive therapy, and maintenance of remission with immunosuppressive therapy for a variable period to prevent relapse. The mainstay of treatment for granulomatosis with polyangiitis (GPA) is a combination of corticosteroids and cytotoxic agents.

  • Medications
  • Side effect treatments
  • Plasma exchange
  • Kidney transplant


Before modern treatments, the 2-year mortality was over 90% and average survival five months.[8][17] Death usually resulted from uremia or respiratory failure.[8]

With corticosteroids and cyclophosphamide, 5-year survival is over 80%.[8] Long-term complications are common (86%), mainly chronic kidney failure, hearing loss, and deafness.[7]

Today, drug toxicity is managed more carefully and long-term remissions are possible. Some patients are able to lead relatively normal lives and remain in remission for 20+ years after treatment.[18]


The incidence is 10–20 cases per million per year.[16][19] It is exceedingly rare in Japan and in African Americans.[19]


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".[20] Heinz Karl Ernst Klinger (born 1907) added information on the anatomical pathology. An early name for the disease was pathergic granulomatosis.[21] The disease is still sometimes confused with lethal midline granuloma and lymphomatoid granulomatosis, both malignant lymphomas.[22]

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 name Wegener's granulomatosis or Wegener granulomatosis (English: /ˈvɛɡənər/).[5] 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 and worked in an office where medical experiments were conducted on Jewish people.[23] In addition, their data 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 data raised serious concerns about Wegener's professional conduct. They suggest that the eponym should be abandoned and propose "ANCA-associated granulomatous vasculitis."[24] The authors have since campaigned for other medical eponyms to be abandoned, too.[25] 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.[26] Currently, the old name is still widely used despite the consensus to adopt the change.[27]

See also[edit]


  1. ^ a b c Singer, O; McCune, WJ (May 2017). "Update on maintenance therapy for granulomatosis with polyangiitis and microscopic polyangiitis". Current Opinion in Rheumatology (Review). 29 (3): 248-53. doi:10.1097/BOR.0000000000000382. PMID 28306595. 
  2. ^ a b Lopalco, G; Rigante, D; Venerito, V; Emmi, G; Anelli, MG; Lapadula, G; Iannone, F; Cantarini, L (June 2016). "Management of Small Vessel Vasculitides". Current Rheumatology Reports (Review). 18 (6): 36. doi:10.1007/s11926-016-0580-1. PMID 27118389. 
  3. ^ a b Yates, M; Watts, R (February 2017). "ANCA-associated vasculitis". Clinical Medicine (London, England) (Review). 17 (1): 60-64. doi:10.7861/clinmedicine.17-1-60. PMID 28148583. 
  4. ^ a b c d e Millet, A; Pederzoli-Ribeil, M; Guillevin, L; Witko-Sarsat, V; Mouthon, L (August 2013). "Antineutrophil cytoplasmic antibody-associated vasculitides: is it time to split up the group?". Annals of The Rheumatic Diseases (Review). 72 (8): 1273-9. doi:10.1136/annrheumdis-2013-203255. PMID 23606701. 
  5. ^ a b Pakalniskis, MG; Berg, AD; Policeni, BA; Gentry, LR; Sato, Y; Moritani, T; Smoker, WR (December 2015). "The Many Faces of Granulomatosis With Polyangiitis: A Review of the Head and Neck Imaging Manifestations". AJR. American Journal of Roentgenology (Review). 205 (6): W619-29. doi:10.2214/AJR.14.13864. PMID 26587951. 
  6. ^ Gota, CE (May 2013). "Granulomatosis with Polyangiitis (GPA): Vasculitis". Merck Manual Professional. Merck Sharp & Dohme Corp. Retrieved 16 March 2014. 
  7. ^ a b c d e f g Seo P, Stone JH (July 2004). "The antineutrophil cytoplasmic antibody-associated vasculitides". The American Journal of Medicine. 117 (1): 39–50. doi:10.1016/j.amjmed.2004.02.030. PMID 15210387. 
  8. ^ a b c d e Berden A, Göçeroglu A, Jayne D, Luqmani R, Rasmussen N, Bruijn JA, Bajema I (January 2012). "Diagnosis and management of ANCA associated vasculitis". BMJ. 344: e26. doi:10.1136/bmj.e26. PMID 22250224. 
  9. ^ Marzano, AV; Balice, Y; Tavecchio, S; Desimine, C; Colombo, A; Berti, E (April 2015). "Granulomatous vasculitis". Giornale Italiano di Dermatologia e venerologia (Review). 150 (2): 193-202. PMID 25791629. 
  10. ^ Tracy, CL; Papadopoulos, PJ; Bye, MR; Connolly, H; Goldberg, E; O'Brian, RJ; Sharma, GD; Talavera, F; Toder, DS; Valentini, RP; Windle, ML; Wolf, RE (10 February 2014). Diamond, HS, ed. "Granulomatosis with Polyangiitis". Medscape Reference. WebMD. Retrieved 16 March 2014. 
  11. ^ Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend WP, Calabrese LH, Fries JF, Lie JT, Lightfoot RW (August 1990). "The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis". Arthritis and Rheumatism. 33 (8): 1101–7. doi:10.1002/art.1780330807. PMID 2202308. 
  12. ^ Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, Hagen EC, Hoffman GS, Hunder GG, Kallenberg CG (February 1994). "Nomenclature of systemic vasculitides. Proposal of an international consensus conference". Arthritis and Rheumatism. 37 (2): 187–92. doi:10.1002/art.1780370206. PMID 8129773. 
  13. ^ Bruce IN, Bell AL (April 1997). "A comparison of two nomenclature systems for primary systemic vasculitis". British Journal of Rheumatology. 36 (4): 453–8. doi:10.1093/rheumatology/36.4.453. PMID 9159539. 
  14. ^ a b Schönermarck, U; Gross, WL; de Groot, K (January 2014). "Treatment of ANCA-associated vasculitis". Nature Reviews. Nephrology (Review). 10 (1): 25-36. doi:10.1038/nrneph.2013.225. PMID 24189648. 
  15. ^ a b Tracy, CL; Papadopoulos, PJ; Bye, MR; Connolly, H; Goldberg, E; O'Brian, RJ; Sharma, GD; Talavera, F; Toder, DS; Valentini, RP; Windle, ML; Wolf, RE (10 February 2014). Diamond, HS, ed. "Granulomatosis with Polyangiitis Treatment & Management". Medscape Reference. WebMD. Retrieved 16 March 2014. 
  16. ^ a b Bosch X, Guilabert A, Espinosa G, Mirapeix E (August 2007). "Treatment of antineutrophil cytoplasmic antibody associated vasculitis: a systematic review". JAMA. 298 (6): 655–69. doi:10.1001/jama.298.6.655. PMID 17684188. 
  17. ^ Smith RM, Jones RB, Jayne DR (April 2012). "Progress in treatment of ANCA-associated vasculitis" (PDF). Arthritis Research & Therapy. 14 (2): 210. doi:10.1186/ar3797. PMC 3446448Freely accessible. PMID 22569190. 
  18. ^ "Vasculitis Foundation » Granulomatosis with Polyangiitis (GPA/Wegener's)". Retrieved 2016-03-16. 
  19. ^ a b Cartin-Ceba R, Peikert T, Specks U (December 2012). "Pathogenesis of ANCA-associated vasculitis". Current Rheumatology Reports. 14 (6): 481–93. doi:10.1007/s11926-012-0286-y. PMID 22927039. 
  20. ^ Friedmann I (January 1982). "McBride and the midfacial granuloma syndrome. (The second 'McBride Lecture', Edinburgh, 1980)". The Journal of Laryngology and Otology. 96 (1): 1–23. doi:10.1017/s0022215100092197. PMID 7057076. 
  21. ^ Fienberg R (December 1955). "Pathergic granulomatosis". The American Journal of Medicine. 19 (6): 829–31. doi:10.1016/0002-9343(55)90150-9. PMID 13275478. 
  22. ^ Mendenhall WM, Olivier KR, Lynch JW, Mendenhall NP (April 2006). "Lethal midline granuloma-nasal natural killer/T-cell lymphoma". American Journal of Clinical Oncology. 29 (2): 202–6. doi:10.1097/01.coc.0000198738.61238.eb. PMID 16601443. 
  23. ^ Lubitz MG (February 2018). "Granulomatosis With Polyangiitis-A Moral Impetus for Change". JAMA Otolaryngology-- Head & Neck Surgery. 144 (2): 101. doi:10.1001/jamaoto.2017.2140. PMID 29121164. 
  24. ^ Woywodt A, Matteson EL (October 2006). "Wegener's granulomatosis--probing the untold past of the man behind the eponym". Rheumatology. 45 (10): 1303–6. doi:10.1093/rheumatology/kel258. PMID 16887845. 
  25. ^ Woywodt A, Matteson E (September 2007). "Should eponyms be abandoned? Yes". BMJ. 335 (7617): 424. doi:10.1136/bmj.39308.342639.AD. PMC 1962844Freely accessible. PMID 17762033. 
  26. ^ Falk RJ, Gross WL, Guillevin L, Hoffman G, Jayne DR, Jennette JC, Kallenberg CG, Luqmani R, Mahr AD, Matteson EL, Merkel PA, Specks U, Watts R (April 2011). "Granulomatosis with polyangiitis (Wegener's): an alternative name for Wegener's granulomatosis". Annals of the Rheumatic Diseases. 70 (4): 704. doi:10.1136/ard.2011.150714. PMID 21372195. 
  27. ^ Lubitz MG (February 2018). "Granulomatosis With Polyangiitis-A Moral Impetus for Change". JAMA Otolaryngology-- Head & Neck Surgery. 144 (2): 101. doi:10.1001/jamaoto.2017.2140. PMID 29121164. 

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