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Granulomatosis with polyangiitis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2]Associate Editor(s)-in-Chief: Amandeep Singh M.D.[3]Krzysztof Wierzbicki M.D. [4]Cafer Zorkun, M.D., Ph.D. [5]

Overview

Overview

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief:Amandeep Singh M.D.[2]Cafer Zorkun, M.D., Ph.D. [3]

Overview

Granulomatosis with polyangiitis is a form of vasculitis that affects the lungs, kidneys and other organs. Due to its end-organ damage, it can be a serious disease that requires long-term immune suppression. Granulomatosis with polyangiitis is part of a larger group of vasculitic syndromes, all of which feature the presence of an abnormal type of circulating antibody termed ANCAs (antineutrophil cytoplasmic antibodies) that affect small and medium-size blood vessels. Apart from granulomatosis with polyangiitis, this category includes Churg-Strauss syndrome and microscopic polyangiitis. Although granulomatosis with polyangiitis affects small and medium-sized vessels, it is formally classified as one of the small vessel vasculitides in the Chapel Hill system.The pathogenesis of granulomatosis with polyangiitis is currently unknown. However, several hypothesizes have been made to identify possible links associated with this disease, such as bacterial infections, failure of B-cells to downregulate, and T cell dysfunction. The genetic component of granulomatosis with polyangiitis is not fully known. However, there seems to be a strong correlation between HLA-DPB1 and HLA-DPB2 with granulomatosis with polyangiitis. Granulomatosis with polyangiitis must be differentiated from other diseases that cause purpura, alveolar hemorrhage, fever, arthralgia, myalgia, necrotizing extra-capillary glomerulonephritis, such as microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis.The incidence of granulomatosis with polyangiitis in children ranges form 0.03 to 3.2 per 100,000 per year. The prevalence in the United States is 3 per 100,000 persons. The mean age of diagnosis of granulomatosis with polyangiitis is 58 years. The disease most commonly presents in patients that are either middle aged or elderly. The mean age of diagnosis in children is between the ages of 4 to 17. Males are more commonly affected with granulomatosis with polyangiitis. The overall male to female ratio is approximately 1.2 to 1. In children females are more commonly seen with the disease. Granulomatosis with polyangiitis typically affects Caucasians. Common risk factors in the development of granulomatosis with polyangitis (GPA) are age group of 40-65 years and presence of variant HLA-DPB1*0401 with ANCA. If left untreated, granulomatosis with polyangiitis may progress to morbidity and mortality. Complications of granulomatosis with polyangiitis include, vision loss, subglottic manifestations, hearing loss, renal failure and increased infections with prolonged immunosuppressant therapy. Determination of 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 granulomatosis with polyangiitis. If the patient has renal failure or cutaneous vasculitis, these are the most logical organs to obtain a biopsy from. Rarely, thoracoscopic lung biopsy is required. The symptomatology depends on the system involved. The disease involve ear, nose and throat and cause symptoms of sinusitis, nasal crusting, otitis media, otorrhea, epistaxis. Patients with history of lung involvement presents with hoarseness, Cough, Dyspnea, Stridor, Hemoptysis. Renal involvement presents with cloudy urine with hematuria, edema.The important physical exam findings are ulcerations, palpable purpura and subcutaneous nodules in the skin; conjunctivitis, uveitis, sinusitis, purulent exudate from nares, saddle nose deformity, reduced hearing in the head and neck; pleuritic chest pain and signs of atelectasis in lung examination; and signs of mononeuritis multiplex on neural exam. Laboratory findings consistent with the diagnosis of granulomatosis with polyangiitis include, anti-neutrophil cytoplasmic antibody, elevated blood urea nitrogen, elevated creatinine serum, erythrocyte sedimentation rate, C reactive protein, proteinuria, microscopic hematuria, and red blood casts. An x-ray may be helpful in the diagnosis of granulomatosis with polyangiitis. Findings on an x-ray suggestive of granulomatosis with polyangiitis include 4 patterns as multiple nodules with or without cavitation; pulmonary hemorrhage as airspace opacities; reticulations and nodules and wedge-like consolidation in periphery. In most cases, treatment consists of a combination of a glucocorticoid (a steroid) and a cytotoxic medicine. It includes glucocorticoids, cyclophosphamide, Rituximab, Methotrexate, Azathioprine and when needed with plasmapheresis.

Historical Perspective

Granulomatosis with polyangiitis was first discovered by Peter McBride, a Scottish otolaryngologist, in 1897 when describing a case of rapid destruction of the nose and face. In 1907, Heinz Karl Ernst Klinger added information regarding the anatomical pathology of the disease. However, the full presentation of the disease was later discovered in 2 separate reports in 1936 and 1939 by a German pathologist, Friedrich Wegener. The disease was called pathergic granulomatosis. This led to some confusion with lethal midline granuloma and lymphomatoid granulomatosis. In 1954, it was called as Wegener’s granulomatosis, named after a German pathologist, Friedrich Wegener who described the disease in his detailed report published in 1936. As of November 7, 2010, the name Wegener’s granulomatosis has been changed to Granulomatosis with polyangiitis by the American College of Rheumatology, American Society of Nephrology, and the European League Against Rheumatism. The association between ANCA and Granulomatosis with polyangiitis was made in 1982.

Classification

According to the American College of Rheumatology (ACR) Granulomatosis with polyangiitis is classified using 4 criteria.

Pathophysiology

The pathogenesis of granulomatosis with polyangiitis is currently unknown. However, several hypothesizes have been made to identify possible links associated with this disease, such as bacterial infections, failure of B-cells to downregulate, and T cell dysfunction. The genetic component of granulomatosis with polyangiitis is not fully known. However, there seems to be a strong correlation between HLA-DPB1 and HLA-DPB2 with granulomatosis with polyangiitis.

Differentiating Xyz from Other Diseases

Granulomatosis with polyangiitis must be differentiated from other diseases that cause purpura, alveolar hemorrhage, fever, arthralgia, myalgia, necrotizing extra-capillary glomerulonephritis, such as microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis.

Epidemiology and Demographics

The incidence of granulomatosis with polyangiitis in children ranges form 0.03 to 3.2 per 100,000 per year. The prevalence in the United States is 3 per 100,000 persons. The mean age of diagnosis of granulomatosis with polyangiitis is 58 years. The disease most commonly presents in patients that are either middle aged or elderly. The mean age of diagnosis in children is between the ages of 4 to 17. Males are more commonly affected with granulomatosis with polyangiitis. The overall male to female ratio is approximately 1.2 to 1. In children females are more commonly seen with the disease. Granulomatosis with polyangiitis typically affects Caucasians.

Risk Factors

Common risk factors in the development of granulomatosis with polyangitis (GPA) are age group of 40-65 years and presence of variant HLA-DPB1*0401 with ANCA.

Natural History, Complications, and Prognosis

If left untreated, granulomatosis with polyangiitis may progress to morbidity and mortality. Complications of granulomatosis with polyangiitis include, vision loss, subglottic manifestations, hearing loss, renal failure and increased infections with prolonged immunosuppressant therapy.

Diagnosis

Diagnostic Study of Choice

Determination of 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 granulomatosis with polyangiitis. If the patient has renal failure or cutaneous vasculitis, these are the most logical organs to obtain a biopsy from. Rarely, thoracoscopic lung biopsy is required. 

History and Symptoms

The symptomatology depends on the system involved. The disease involve ear, nose and throat and cause symptoms of sinusitis, nasal crusting, otitis media, Otorrhea, epistaxis. Patients with history of lung involvement presents with hoarseness, cough, dyspnea, stridor, hemoptysis. Renal involvement presents with cloudy urine with hematuria, edema.

Physical Examination

The important physical exam findings are ulcerations, palpable purpura and subcutaneous nodules in the skin; conjunctivitis, uveitis, sinusitis, purulent exudate from nares, saddle nose deformity, reduced hearing in the head and neck; pleuritic chest pain and signs of atelectasis in lung examination; and signs of mononeuritis multiplex on neural exam.

Laboratory Findings

Laboratory findings consistent with the diagnosis of granulomatosis with polyangiitis include, anti-neutrophil cytoplasmic antibody, elevated blood urea nitrogen, elevated creatinine serum, erythrocyte sedimentation rate, C reactive protein, proteinuria, microscopic hematuria, and red blood casts.

X-ray

An x-ray may be helpful in the diagnosis of granulomatosis with polyangiitis. Findings on an x-ray suggestive of granulomatosis with polyangiitis include 4 patterns as multiple nodules with or without cavitation; pulmonary hemorrhage as airspace opacities; reticulations and nodules and wedge-like consolidation in periphery.

CT scan

On chest CT scan, granulomatosis with polyangiitis is characterized by multiple lung nodules, lung consolidations and ground-glass opacities.

Treatment

Medical Therapy

In most cases, treatment consists of a combination of a glucocorticoid (a steroid) and a cytotoxic medicine. It includes glucocorticoids, cyclophosphamide, Rituximab, Methotrexate, Azathioprine and when needed with plasmapheresis.

Historical Perspective

Historical Perspective

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2];Associate Editor(s)-in-Chief: Amandeep Singh M.D.[3]Krzysztof Wierzbicki M.D. [4]Cafer Zorkun, M.D., Ph.D. [5]

Overview

Granulomatosis with polyangiitis was first discovered by Peter McBride, a Scottish otolaryngologist, in 1897 when describing a case of rapid destruction of the nose and face. In 1907, Heinz Karl Ernst Klinger added information regarding the anatomical pathology of the disease. However, the full presentation of the disease was later discovered in 2 separate reports in 1936 and 1939 by a German pathologist, Friedrich Wegener. The disease was called pathergic granulomatosis. This led to some confusion with lethal midline granuloma and lymphomatoid granulomatosis. In 1954, it was called as Wegener’s granulomatosis, named after a German pathologist, Friedrich Wegener who described the disease in his detailed report published in 1936. As of November 7, 2010, the name Wegener’s granulomatosis has been changed to Granulomatosis with polyangiitis by the American College of Rheumatology, American Society of Nephrology, and the European League Against Rheumatism. The association between ANCA and Granulomatosis with polyangiitis was made in 1982.

Historical Perspective

Discovery

  • Granulomatosis with polyangitis was first discovered by Peter McBride, a Scottish otolaryngologist, in 1897.[1]
  • In 1907, Heinz Karl Ernst Klinger added information regarding the anatomical pathology of the disease.
  • The disease was called pathergic granulomatososis.[2] This led to some confusion with lethal midline granuloma and lymphomatoid granulomatosis.[3]
  • In 1954, it was called as Wegener’s granulomatosis [4], named after a German pathologist, Friedrich Wegener who described the disease in his detailed report published in 1936.[5]
  • Due to concerns with Wegener’s professional conduct, Alexander Woywodt and Eric Matteson abandoned the name and changed to “ANCA-associated granulomatous vasculitis.”[6]
  • As of November 7, 2010, the name Wegener’s granulomatosis has been changed to Granulomatosis with polyangitis by the American College of Rheumatology, American Society of Nephrology, and the European League Against Rheumatism.[7][8]

Landmark Events in the Development of Treatment Strategies

Famous Cases

  • The following are a few famous cases of disease name:
    • Heinrich Hertz, famous German physicist who worked on electromagnetic waves[16]

References

  1. ↑ Friedmann I (1982). “McBride and the midfacial granuloma syndrome. (The second ‘McBride Lecture’, Edinburgh, 1980)”. The Journal of laryngology and otology. 96 (1): 1–23. PMID 7057076.
  2. ↑ Fienberg R (1955). “Pathergic granulomatosis”. Am. J. Med. 19 (6): 829–31. doi:10.1016/0002-9343(55)90150-9. PMID 13275478.
  3. ↑ Mendenhall WM, Olivier KR, Lynch JW Jr, Mendenhall NP (2006). “Lethal midline granuloma-nasal natural killer/T-cell lymphoma”. Am J Clin Oncol. 29 (2): 202–6. doi:10.1097/01.coc.0000198738.61238.eb. PMID 16601443.
  4. ↑ GODMAN GC, CHURG J (December 1954). “Wegener’s granulomatosis: pathology and review of the literature”. AMA Arch Pathol. 58 (6): 533–53. PMID 13217569.
  5. ↑ Wegener F. Ueber generalisierte septische Gefäßerkrankungen [About generalised septic vascular diseases], Verh Deut Pathol Ges , 1936, vol. 29 (pg. 202-10)
  6. ↑ Woywodt A, Matteson EL (2006). “Wegener’s granulomatosis–probing the untold past of the man behind the eponym”. Rheumatology (Oxford). 45 (10): 1303–6. doi:10.1093/rheumatology/kel258. PMID 16887845.
  7. ↑ Falk RJ, Gross WL, Guillevin L, Hoffman GS, Jayne DR, Jennette JC; et al. (2011). “Granulomatosis with polyangiitis (Wegener’s): an alternative name for Wegener’s granulomatosis”. Arthritis Rheum. 63 (4): 863–4. doi:10.1002/art.30286. PMID 21374588.
  8. ↑ Woywodt A, Haubitz M, Haller H, Matteson EL (2006). “Wegener’s granulomatosis”. Lancet. 367 (9519): 1362–6. doi:10.1016/S0140-6736(06)68583-8. PMID 16631915.
  9. ↑ Davies DJ, Moran JE, Niall JF, Ryan GB (1982). “Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology?”. Br Med J (Clin Res Ed). 285 (6342): 606. PMC 1499415. PMID 6297657.
  10. ↑ van der Woude FJ, Rasmussen N, Lobatto S, Wiik A, Permin H, van Es LA, van der Giessen M, van der Hem GK, The TH (February 1985). “Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener’s granulomatosis”. Lancet. 1 (8426): 425–9. PMID 2857806.
  11. ↑ Harman, Lynn E.; Margo, Curtis E. (1998). “Wegener’s Granulomatosis”. Survey of Ophthalmology. 42 (5): 458–480. doi:10.1016/S0039-6257(97)00133-1. ISSN 0039-6257.
  12. ↑ Helmchen U, Kneissler U, Prall F (1996). “[ANCA-associated forms of vasculitis]”. Verh Dtsch Ges Pathol (in German). 80: 38–45. PMID 9065053.
  13. ↑ “Wegener’s granulomatosis and anti neutrophil cytoplasm antibodies (ANCA). Proceedings of a symposium. Zweibrücken, 1990”. APMIS Suppl. 19: 1–68. 1990. PMID 2285525.
  14. ↑ Pradhan VD, Badakere SS, Ghosh K, Almeida A (July 2005). “ANCA: serology in Wegener’s granulomatosis”. Indian J Med Sci. 59 (7): 292–300. PMID 16062016.
  15. ↑ Langford CA (May 2011). “Cyclophosphamide as induction therapy for Wegener’s granulomatosis and microscopic polyangiitis”. Clin. Exp. Immunol. 164 Suppl 1: 31–4. doi:10.1111/j.1365-2249.2011.04364.x. PMC 3095863. PMID 21447129.
  16. ↑ Feldmann H (June 2005). “[A historic case of Wegener’s granulomatosis: the physicist who discovered the electromagnetic waves: Heinrich Hertz]”. Laryngorhinootologie (in German). 84 (6): 426–31. doi:10.1055/s-2004-826062. PMID 15940574.

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Classification

Classification

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2];Associate Editor(s)-in-Chief: Amandeep Singh M.D.[3]Krzysztof Wierzbicki M.D. [4]

Overview

According to the American College of Rheumatology (ACR) Granulomatosis with polyangiitis is classified using 4 criteria.

Classification

According to the American College of Rheumatology (ACR) Granulomatosis with polyangiitis is classified by 4 criteria. They are:[1]

American College of Rheumatology (ACR) Classification of Granulomatosis with polyangiitis
Abnormal urinary sediment ( red cell casts or > 5 red blood cells per hpf)
Abnormal Chest radiography findings (nodules, cavities, or fixed infiltrates)
Nasal discharge or oral ulcers
Biopsy that presents with granulomatous inflammation

2 out of 4 criteria are needed to distinguish Granulomatosis with polyangiitis from other vasculitides, with a senstivity of 88% and senstivity of 92%.

References

  1. ↑ Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend WP; et al. (1990). “The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis”. Arthritis Rheum. 33 (8): 1101–7. PMID 2202308.

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Pathophysiology

Pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2] Associate Editor(s)-in-Chief: Amandeep Singh M.D.[3]Krzysztof Wierzbicki M.D. [4]Cafer Zorkun, M.D., Ph.D. [5]Amandeep Singh M.D.[6]

Overview

The pathogenesis of granulomatosis with polyangiitis is currently unknown. However, several hypothesizes have been made to identify possible links associated with this disease, such as bacterial infections, failure of B-cells to downregulate, and T cell dysfunction. The genetic component of granulomatosis with polyangiitis is not fully known. However, there seems to be a strong correlation between HLA-DPB1 and HLA-DPB2 with granulomatosis with polyangiitis.

Pathogenesis

The pathogenesis of granulomatosis with polyangiitis is currently unknown. However, several suggestions have been made to identify possible links associated with the disease, such as bacterial infections, failure of B-cells to downregulate, and T cell dysfunction.

Role of bacterial antigens

Role of auto-immunity

  • Another possible cause of this disease is the failure of B cells to downregulate ANCA autoimmunity because of CD19 dysregulation at two stages.
  • The first is CD19 naïve B cells, the dysregulation of CD19 B naïve cells may result in B cells to be autoreactive and have the ability to activate themselves.
  • Another stage of dysregulation is CD19 memory B cells, this allows increased sensitive to reactivate B cells.[2]

Dysfunction of T regulator cells

Neutrophil activation

Genetics

  • The genetic component of granulomatosis with polyangiitis is not fully known.
  • However, there seems to be a strong correlation between HLA-DPB1 and HLA-DPB2 with granulomatosis with polyangiitis.[5]
    • HLA-DP1*401 is the strongest predictor especially when associated with ANCA.[6][7]
  • The genetic inheritance of Granulomatosis with polyangiitis is not common.[8]

Associated Conditions

The following conditions are associated with Granulomatosis with polyangiitis:

Gross Pathology

  • Granulomatosis with polyangiitis-Case courtesy of Dr. Yale Rosen[12]
    Granulomatosis with polyangiitis-Case courtesy of Dr. Yale Rosen[12]
  • Granulomatosis with polyangiitis- By Yale Rosen from USA [13]
    Granulomatosis with polyangiitis- By Yale Rosen from USA [13]

Microscopic Pathology

  • On microscopic histopathology analysis,the characteristic findings of GPA are:are characteristic findings of Granulomatosis with polyangiitis.[14][15]
    • Focal and segmental necrotizing glomerulitis
    • Presence of non-caseating granuloma
    • Necrotizing vasculitis
    • Varied multinucleated giant cells at times
  • Granulomatosis with polyangiitis[16]
    Granulomatosis with polyangiitis[16]

References

  1. ↑ Kain R, Exner M, Brandes R, Ziebermayr R, Cunningham D, Alderson CA; et al. (2008). “Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis”. Nat Med. 14 (10): 1088–96. doi:10.1038/nm.1874. PMC 2751601. PMID 18836458.
  2. ↑ Culton DA, Nicholas MW, Bunch DO, Zhen QL, Kepler TB, Dooley MA; et al. (2007). “Similar CD19 dysregulation in two autoantibody-associated autoimmune diseases suggests a shared mechanism of B-cell tolerance loss”. J Clin Immunol. 27 (1): 53–68. doi:10.1007/s10875-006-9051-1. PMID 17195045.
  3. ↑ Noone D, Hebert D, Licht C (2016). “Pathogenesis and treatment of ANCA-associated vasculitis-a role for complement”. Pediatr Nephrol.   ( ):  . doi:10.1007/s00467-016-3475-5. PMID 27596099.
  4. ↑ van Rossum AP, Limburg PC, Kallenberg CG (2005). “Activation, apoptosis, and clearance of neutrophils in Wegener’s granulomatosis”. Ann N Y Acad Sci. 1051 ( ): 1–11. doi:10.1196/annals.1361.041. PMID 16126939.
  5. ↑ Xie G, Roshandel D, Sherva R, Monach PA, Lu EY, Kung T; et al. (2013). “Association of granulomatosis with polyangiitis (Wegener’s) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis”. Arthritis Rheum. 65 (9): 2457–68. doi:10.1002/art.38036. PMC 4471994. PMID 23740775.
  6. ↑ https://ghr.nlm.nih.gov/condition/granulomatosis-with-polyangiitis#sourcesforpage
  7. ↑ Jagiello P, Gencik M, Arning L, Wieczorek S, Kunstmann E, Csernok E, Gross WL, Epplen JT (April 2004). “New genomic region for Wegener’s granulomatosis as revealed by an extended association screen with 202 apoptosis-related genes”. Hum. Genet. 114 (5): 468–77. doi:10.1007/s00439-004-1092-z. PMID 14968360.
  8. ↑ Knight A, Sandin S, Askling J (2008). “Risks and relative risks of Wegener’s granulomatosis among close relatives of patients with the disease”. Arthritis Rheum. 58 (1): 302–7. doi:10.1002/art.23157. PMID 18163522.
  9. ↑ Langlois V, Lesourd A, Girszyn N, Ménard JF, Levesque H, Caron F; et al. (2016). “Antineutrophil Cytoplasmic Antibodies Associated With Infective Endocarditis”. Medicine (Baltimore). 95 (3): e2564. doi:10.1097/MD.0000000000002564. PMC 4998285. PMID 26817911.
  10. ↑ Kalluri R, Meyers K, Mogyorosi A, Madaio MP, Neilson EG (1997). “Goodpasture syndrome involving overlap with Wegener’s granulomatosis and anti-glomerular basement membrane disease”. J Am Soc Nephrol. 8 (11): 1795–800. PMID 9355084.
  11. ↑ WALTON EW (1958). “Giant-cell granuloma of the respiratory tract (Wegener’s granulomatosis)”. Br Med J. 2 (5091): 265–70. PMC 2026251. PMID 13560836.
  12. ↑ Case courtesy of Dr. Yale Rosen. https://radiopaedia.org/cases/8950 Accessed on March 29, 2018
  13. ↑ (Wegener’s granulomatosis Uploaded by CFCF) [CC BY-SA 2.0 (https://creativecommons.org/licenses/by-sa/2.0)]
  14. ↑ Lie JT (1990). “Illustrated histopathologic classification criteria for selected vasculitis syndromes. American College of Rheumatology Subcommittee on Classification of Vasculitis”. Arthritis Rheum. 33 (8): 1074–87. PMID 1975173.
  15. ↑ Muller K, Lin JH (2014). “Orbital granulomatosis with polyangiitis (Wegener granulomatosis): clinical and pathologic findings”. Arch Pathol Lab Med. 138 (8): 1110–4. doi:10.5858/arpa.2013-0006-RS. PMC 4140401. PMID 25076302.
  16. ↑ Libre pathology. https://librepathology.org/wiki/Granulomatosis_with_polyangiitis Accessed on March 29, 2018

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Causes

Causes

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2] Associate Editor(s)-in-Chief: Krzysztof Wierzbicki M.D. [3]

Overview

Currently there are no established causes for Granulomatosis with polyangiitis. However, it has been hypothesized that infection, environmental toxins, and genetics may play a role in disease progression.

Causes

Currently there are no established causes for Granulomatosis with polyangiitis. However, it has been hypothesized that infection, environmental toxins, and genetics may play a role in disease progression.

References

Differentiating Wegener’s granulomatosis from other Diseases

Differentiating Wegener’s granulomatosis from other Diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2]Associate Editor(s)-in-Chief: Krzysztof Wierzbicki M.D. [3]

Overview

Granulomatosis with polyangiitis must be differentiated from other diseases that cause purpura, alveolar hemorrhage, fever, arthralgia, myalgia, necrotizing extra-capillary glomerulonephritis, such as Microscopic polyangiitis and Eosinophilic granulomatosis with polyangiitis.[1]

Differentiating Granulomatosis with polyangiits from other Diseases

Granulomatosis with polyangiitis must be differentiated from other diseases that cause purpura, alveolar hemorrhage, necrotizing extra-capillary glomerulonephritis, such as Microscopic polyangiitis and Eosinophilic granulomatosis with polyangiitis.[1][2]

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis serological findings
Eosinophilic granulomatosis with polyangiitis Granulomatosis with polyangiitis Microscopic polyangiitis
Cytoplasmic ANCA (cANCA) 90% positive
Perinuclear ANCA (pANCA) 30 to 40% positive 60 to 80% positive
Myeloperoxidase antigen 40% sensitivity 10% sensitivity 30% sensitivity
Proteinase 3 antigen <5% sensitivity 70-80% sensitivity 60% sensitivity

Differentiating Granulomatosis with polyangiitis from other diseases

Granulomatosis with polyangiitis must be differentiated from other diseases that cause purpura, alveolar hemorrhage, fever, arthralgia, myalgia, necrotizing extra-capillary glomerulonephritis and include:[1]

  • mononeuritis multiplex
  • venous thrombosis
  • necrotizing vasculitis of small-sized vessels
  • ear nose throat involvement

Differential diagnosis

Causes of

lung cavities

Differentiating Features Differentiating radiological findings Diagnosis

confirmation

  • Pulmonary nodules with cavities and infiltrates are a frequent manifestation on CXR
  • CXR and CT demonstrates cavities in the upper lobe of the lung
  • Sputum smear positive for acid-fast bacilli
  • Nucleic acid amplification tests (NAAT) is used on sputum or any sterile fluid .
  • Any age group
  • Acute, fulminant life threating complication of prior infection
  • >100.4F fever, with hemodynamic instability
  • Worsening pneumonia-like symptoms
  • CBC is positive for causative organism
  • Children and elderly are at risk
  • Empyema appears lenticular in shape and has a thin wall with smooth luminal margins
  • Elderly females of 40-50 age group
  • Manifestation of rheumatoid arthritis
  • Presents with other systemic symptoms including symmetric arthritis of the small joints of the hands and feet with morning stiffness are common manifestations.
  • Pulmonary nodules with cavitation are located in the upper lobe (Caplan syndrome) on Xray.
  • On CXR, bilateral adenopathy and coarse reticular opacities are seen.
  • CT of the chest demonstrates extensive hilar and mediastinal adenopathy
  • Additional findings on CT include fibrosis (honeycomb, linear, or associated with bronchial distortion), pleural thickening, and ground-glass opacities.[9]
  • Common appearance on CT is patchy consolidation,often accompanied by ground-glass opacities and nodules.[13]
  • Exclusively afflicts smokers, with a peak age of onset of between 20 and 40 years.
  • Clinical presentation varies, but symptoms generally include months of dry cough, fever, night sweats and weight loss.
  • Skin is involved in 80% of the cases, scaly erythematous rash is typical.
  • Thin-walled cystic cavities are the usual radiographic manifestation, observed in over 50% of patients by either CXR or CT scans.[15]
  • Biopsy of the lung

References

  1. ↑ 1.0 1.1 1.2 Pagnoux C (2016). “Updates in ANCA-associated vasculitis”. Eur J Rheumatol. 3 (3): 122–133. doi:10.5152/eurjrheum.2015.0043. PMID 27733943.
  2. ↑ Kallenberg CG, Heeringa P, Stegeman CA (2006). “Mechanisms of Disease: pathogenesis and treatment of ANCA-associated vasculitides”. Nat Clin Pract Rheumatol. 2 (12): 661–70. doi:10.1038/ncprheum0355. PMID 17133251.
  3. ↑ 3.0 3.1 Langford CA, Hoffman GS (1999). “Rare diseases.3: Wegener’s granulomatosis”. Thorax. 54 (7): 629–37. PMC 1745525. PMID 10377211.
  4. ↑ Lee KS, Kim TS, Fujimoto K, Moriya H, Watanabe H, Tateishi U, Ashizawa K, Johkoh T, Kim EA, Kwon OJ (2003). “Thoracic manifestation of Wegener’s granulomatosis: CT findings in 30 patients”. Eur Radiol. 13 (1): 43–51. doi:10.1007/s00330-002-1422-2. PMID 12541109.
  5. ↑ 5.0 5.1 Chaudhuri MR (1973). “Primary pulmonary cavitating carcinomas”. Thorax. 28 (3): 354–66. PMC 470041. PMID 4353362.
  6. ↑ Mouroux J, Padovani B, Elkaïm D, Richelme H (1996). “Should cavitated bronchopulmonary cancers be considered a separate entity?”. Ann. Thorac. Surg. 61 (2): 530–2. doi:10.1016/0003-4975(95)00973-6. PMID 8572761.
  7. ↑ Onn A, Choe DH, Herbst RS, Correa AM, Munden RF, Truong MT, Vaporciyan AA, Isobe T, Gilcrease MZ, Marom EM (2005). “Tumor cavitation in stage I non-small cell lung cancer: epidermal growth factor receptor expression and prediction of poor outcome”. Radiology. 237 (1): 342–7. doi:10.1148/radiol.2371041650. PMID 16183941.
  8. ↑ Baughman RP, Teirstein AS, Judson MA, Rossman MD, Yeager H, Bresnitz EA, DePalo L, Hunninghake G, Iannuzzi MC, Johns CJ, McLennan G, Moller DR, Newman LS, Rabin DL, Rose C, Rybicki B, Weinberger SE, Terrin ML, Knatterud GL, Cherniak R (2001). “Clinical characteristics of patients in a case control study of sarcoidosis”. Am. J. Respir. Crit. Care Med. 164 (10 Pt 1): 1885–9. doi:10.1164/ajrccm.164.10.2104046. PMID 11734441.
  9. ↑ Brauner MW, Grenier P, Mompoint D, Lenoir S, de Crémoux H (1989). “Pulmonary sarcoidosis: evaluation with high-resolution CT”. Radiology. 172 (2): 467–71. doi:10.1148/radiology.172.2.2748828. PMID 2748828.
  10. ↑ Murphy J, Schnyder P, Herold C, Flower C (1998). “Bronchiolitis obliterans organising pneumonia simulating bronchial carcinoma”. Eur Radiol. 8 (7): 1165–9. doi:10.1007/s003300050527. PMID 9724431.
  11. ↑ 11.0 11.1 Al-Ghanem S, Al-Jahdali H, Bamefleh H, Khan AN (2008). “Bronchiolitis obliterans organizing pneumonia: pathogenesis, clinical features, imaging and therapy review”. Ann Thorac Med. 3 (2): 67–75. doi:10.4103/1817-1737.39641. PMC 2700454. PMID 19561910.
  12. ↑ Cordier JF, Loire R, Brune J (1989). “Idiopathic bronchiolitis obliterans organizing pneumonia. Definition of characteristic clinical profiles in a series of 16 patients”. Chest. 96 (5): 999–1004. PMID 2805873.
  13. ↑ Lee KS, Kullnig P, Hartman TE, Müller NL (1994). “Cryptogenic organizing pneumonia: CT findings in 43 patients”. AJR Am J Roentgenol. 162 (3): 543–6. doi:10.2214/ajr.162.3.8109493. PMID 8109493.
  14. ↑ Suri HS, Yi ES, Nowakowski GS, Vassallo R (2012). “Pulmonary langerhans cell histiocytosis”. Orphanet J Rare Dis. 7: 16. doi:10.1186/1750-1172-7-16. PMC 3342091. PMID 22429393.
  15. ↑ Moore AD, Godwin JD, Müller NL, Naidich DP, Hammar SP, Buschman DL, Takasugi JE, de Carvalho CR (1989). “Pulmonary histiocytosis X: comparison of radiographic and CT findings”. Radiology. 172 (1): 249–54. doi:10.1148/radiology.172.1.2787035. PMID 2787035.

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Epidemiology and Demographics

Epidemiology and Demographics

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2]Associate Editor(s)-in-Chief: Krzysztof Wierzbicki M.D. [3]Amandeep Singh M.D.[4]

Overview

The incidence of Granulomatosis with polyangiitis in children ranges form 0.03 to 3.2 per 100,000 per year. The prevalence in the United States is 3 per 100,000 persons. The mean age of diagnosis of granulomatosis with polyangiitis is 58 years. The disease most commonly presents in patients that are either middle aged or elderly. The mean age of diagnosis in children is between the ages of 4 to 17. Males are more commonly affected with Granulomatosis with polyangiitis. The overall male to female ratio is approximately 1.2 to 1. In children females are more commonly seen with the disease. Granulomatosis with polyangiitis typically affects Caucasians.

Epidemiology

Incidence

  • The incidence of Granulomatosis with polyangiitis in Europe ranges from 3 to 14.4 per million per year.[1]
  • The incidence of Granulomatosis with polyangiitis in children ranges form 0.03 to 3.2 per 100,000 per year.[2]

Prevalence

  • The prevalence of Granulomatosis with polyangiitis in Europe ranges from 23.7 to 160 per million persons.[1]
  • The prevalence in the United States is 3 per 100,000 persons.[3][4]

Demographics

The rate distribution of Granulomatosis with polyangiitis varies upon age, sex, and race.

Age

  • Patients of all age groups may develop Granulomatosis with polyangiitis.
  • The mean age of diagnosis of granulomatosis with polyangiitis is 58 years.
  • The incidence of the disease in female patients is 70 to 79 years of age and in male patients older than 80 years.[1]
  • The disease most commonly presents in patients that are either middle aged or elderly.[5][6][7]
  • The mean age of diagnosis of Granulomatosis with polyangiitis in children is between the ages of 4 to 17. However, the disease is rarely seen in children.[2]

Gender

  • Males are more commonly affected with Granulomatosis with polyangiitis.
  • The overall male to female ratio is approximately 1.2 to 1.[1]
  • In children females are more commonly seen with the disease.[8]

Race

  • Granulomatosis with polyangiitis typically affects Caucasians.
  • Other races can be affected, however the rate is lower than that of Caucasians.[1][9]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Catanoso M, Macchioni P, Boiardi L, Manenti L, Tumiati B, Cavazza A; et al. (2014). “Epidemiology of granulomatosis with polyangiitis (Wegener’s granulomatosis) in Northern Italy: a 15-year population-based study”. Semin Arthritis Rheum. 44 (2): 202–7. doi:10.1016/j.semarthrit.2014.05.005. PMID 24932888.
  2. ↑ 2.0 2.1 Cabral DA, Uribe AG, Benseler S, O’Neil KM, Hashkes PJ, Higgins G; et al. (2009). “Classification, presentation, and initial treatment of Wegener’s granulomatosis in childhood”. Arthritis Rheum. 60 (11): 3413–24. doi:10.1002/art.24876. PMID 19877069.
  3. ↑ Cotch MF, Hoffman GS, Yerg DE, Kaufman GI, Targonski P, Kaslow RA (1996). “The epidemiology of Wegener’s granulomatosis. Estimates of the five-year period prevalence, annual mortality, and geographic disease distribution from population-based data sources”. Arthritis Rheum. 39 (1): 87–92. PMID 8546743.
  4. ↑ Muller K, Lin JH (2014). “Orbital granulomatosis with polyangiitis (Wegener granulomatosis): clinical and pathologic findings”. Arch Pathol Lab Med. 138 (8): 1110–4. doi:10.5858/arpa.2013-0006-RS. PMC 4140401. PMID 25076302.
  5. ↑ Koldingsnes W, Nossent H (2000). “Epidemiology of Wegener’s granulomatosis in northern Norway”. Arthritis Rheum. 43 (11): 2481–7. doi:10.1002/1529-0131(200011)43:11<2481::AID-ANR15>3.0.CO;2-6. PMID 11083271.
  6. ↑ Watts RA, Lane SE, Bentham G, Scott DG (2000). “Epidemiology of systemic vasculitis: a ten-year study in the United Kingdom”. Arthritis Rheum. 43 (2): 414–9. doi:10.1002/1529-0131(200002)43:2<414::AID-ANR23>3.0.CO;2-0. PMID 10693883.
  7. ↑ Gonzalez-Gay MA, Garcia-Porrua C, Guerrero J, Rodriguez-Ledo P, Llorca J (2003). “The epidemiology of the primary systemic vasculitides in northwest Spain: implications of the Chapel Hill Consensus Conference definitions”. Arthritis Rheum. 49 (3): 388–93. doi:10.1002/art.11115. PMID 12794795.
  8. ↑ Bohm M, Gonzalez Fernandez MI, Ozen S, Pistorio A, Dolezalova P, Brogan P; et al. (2014). “Clinical features of childhood granulomatosis with polyangiitis (wegener’s granulomatosis)”. Pediatr Rheumatol Online J. 12: 18. doi:10.1186/1546-0096-12-18. PMC 4041043. PMID 24891844.
  9. ↑ Mohammad AJ, Jacobsson LT, Mahr AD, Sturfelt G, Segelmark M (2007). “Prevalence of Wegener’s granulomatosis, microscopic polyangiitis, polyarteritis nodosa and Churg-Strauss syndrome within a defined population in southern Sweden”. Rheumatology (Oxford). 46 (8): 1329–37. doi:10.1093/rheumatology/kem107. PMID 17553910.

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Risk Factors

Risk Factors

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2]Associate Editor(s)-in-Chief: Amandeep Singh M.D.[3]

Overview

Common risk factors in the development of granulomatosis with polyangitis(GPA) are age group of 40-65 years and presence of variant HLA-DPB1*0401 with ANCA.

Risk Factors

Common Risk Factors

  • Common risk factors in the development of granulomatosis with polyangitis(GPA) include:
    • Age= 40-65 years
    • Genetic= HLA DPB1[1]
      • Variant  HLA-DPB1*0401 in those associated with ANCA [2][3]
    • Infection leading to granulomas[4]

Less Common Risk Factors

  • Less common risk factors in the development of granulomatosis with polyangitis(GPA) include:
    • Exposure to silica[5]

References

  1. ↑ Wieczorek S, Holle JU, Epplen JT (January 2010). “Recent progress in the genetics of Wegener’s granulomatosis and Churg-Strauss syndrome”. Curr Opin Rheumatol. 22 (1): 8–14. doi:10.1097/BOR.0b013e3283331151. PMID 19864953.
  2. ↑ https://ghr.nlm.nih.gov/condition/granulomatosis-with-polyangiitis#sourcesforpage
  3. ↑ Jagiello P, Gencik M, Arning L, Wieczorek S, Kunstmann E, Csernok E, Gross WL, Epplen JT (April 2004). “New genomic region for Wegener’s granulomatosis as revealed by an extended association screen with 202 apoptosis-related genes”. Hum. Genet. 114 (5): 468–77. doi:10.1007/s00439-004-1092-z. PMID 14968360.
  4. ↑ Spagnolo P, Richeldi L, du Bois RM (December 2008). “Environmental triggers and susceptibility factors in idiopathic granulomatous diseases”. Semin Respir Crit Care Med. 29 (6): 610–9. doi:10.1055/s-0028-1101271. PMID 19221959.
  5. ↑ Hogan SL, Cooper GS, Savitz DA, Nylander-French LA, Parks CG, Chin H, Jennette CE, Lionaki S, Jennette JC, Falk RJ (March 2007). “Association of silica exposure with anti-neutrophil cytoplasmic autoantibody small-vessel vasculitis: a population-based, case-control study”. Clin J Am Soc Nephrol. 2 (2): 290–9. doi:10.2215/CJN.03501006. PMC 4049534. PMID 17699427.
Screening

Screening

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2]Associate Editor(s)-in-Chief: Krzysztof Wierzbicki M.D. [3]Amandeep Singh M.D.[4]

Overview

There is insufficient evidence to recommend routine screening for granulomatosis with polyangiitis.

Screening

Currently, there are no screening protocols for Granulomatosis with polyangiitis.

References

Natural History, Complications and Prognosis

Natural History, Complications and Prognosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2]Associate Editor(s)-in-Chief: Amandeep Singh M.D.[3]Krzysztof Wierzbicki M.D. [4]

Overview

If left untreated, Granulomatosis with polyangiitis may progress to morbidity and mortality. Complications of Granulomatosis with polyangiitis include, vision loss, subglottic manifestations, hearing loss, renal failure and increased infections with prolonged immunosuppressant therapy.

Natural History

If left untreated, Granulomatosis with polyangiitis may progress to morbidity and mortality as soon as 4 weeks, with an average estimated mortality of 5 months.[1]

Complications

Possible complications of Granulomatosis with polyangiitis include:

Prognosis

In the past the prognosis of Granulomatosis with polyangiitis was fatal with a 1 year survival rate of 18%. Today, the prognosis of Granulomatosis with polyangiitis has improved with the introduction of corticosteroids and cyclophosphamide.[6]

The following are favorable prognostic factors:

The following are poor prognostic factors:

The current survival rate of Granulomatosis with polyangiitis is estimated to be 95% in 1 year, 83% in 5 years, and 65% in 10 years.[7]

References

  1. ↑ WALTON EW (1958). “Giant-cell granuloma of the respiratory tract (Wegener’s granulomatosis)”. Br Med J. 2 (5091): 265–70. PMC 2026251. PMID 13560836.
  2. ↑ Kubaisi B, Abu Samra K, Foster CS (2016). “Granulomatosis with polyangiitis (Wegener’s disease): An updated review of ocular disease manifestations”. Intractable Rare Dis Res. 5 (2): 61–9. doi:10.5582/irdr.2016.01014. PMC 4869584. PMID 27195187.
  3. ↑ Laudien M (2015). “Orphan diseases of the nose and paranasal sinuses: Pathogenesis – clinic – therapy”. GMS Curr Top Otorhinolaryngol Head Neck Surg. 14 ( ): Doc04. doi:10.3205/cto000119. PMC 4702053. PMID 26770278.
  4. ↑ Bavelloni A, Piazzi M, Raffini M, Faenza I, Blalock WL (2015). “Prohibitin 2: At a communications crossroads”. IUBMB Life. 67 (4): 239–54. doi:10.1002/iub.1366. PMID 25904163.
  5. ↑ Masiak A, Struk-Panfill M, Zdrojewski Z (2015). “Infectious complication or exacerbation of granulomatosis with polyangiitis?”. Reumatologia. 53 (5): 286–91. doi:10.5114/reum.2015.55833. PMC 4847319. PMID 27407261.
  6. ↑ Pierrot-Deseilligny Despujol C, Pouchot J, Pagnoux C, Coste J, Guillevin L (2010). “Predictors at diagnosis of a first Wegener’s granulomatosis relapse after obtaining complete remission”. Rheumatology (Oxford). 49 (11): 2181–90. doi:10.1093/rheumatology/keq244. PMID 20675708.
  7. ↑ Mohammad AJ, Jacobsson LT, Westman KW, Sturfelt G, Segelmark M (2009). “Incidence and survival rates in Wegener’s granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and polyarteritis nodosa”. Rheumatology (Oxford). 48 (12): 1560–5. doi:10.1093/rheumatology/kep304. PMID 19797309.

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Diagnosis

Diagnosis

Diagnostic Criteria | History and Symptoms | Physical Examination | Laboratory Findings | Chest X Ray | CT | Other Diagnostic Studies

Treatment

Treatment

Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies

Case Studies

Case Studies

Case #1

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