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Wegener’s Granulomatosis

PHM142 Fall 2013 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson. Wegener’s Granulomatosis. By: Stephanie Dean Adam Joseph Foy Phillip Kim Timmy Lui Oct 23, 2013 PHM142. What is Wegener’s Granulomatosis ?.

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Wegener’s Granulomatosis

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  1. PHM142 Fall 2013 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson Wegener’s Granulomatosis By: Stephanie Dean Adam Joseph Foy Phillip Kim Timmy Lui Oct 23, 2013 PHM142

  2. What is Wegener’s Granulomatosis? • Wegener's granulomatosis (WG) is an auto-immune disease that causes inflammation of blood vessels (vasculitis) • WG commonly affects the upper respiratory tract, kidneys, and lungs. It can affect other organs also, but it isn't as common.

  3. Wegener’s Granulomatosis • It was first noticed by Klinger in 1931 and later by Wegener in 1936, whom this disease is named after. • The criteria for defining WG is: • necrotizing granulomas in the upper and lower respiratory tract • generalized necrotizing vasculitis of small arteries and veins • renal involvement.

  4. The cause of Wegener's granulomatosis • The exact cause of WG isn't definitively known but there is research that show a strong indication that anti-neutrophilcytoplasmicautoantibody (ANCA) plays a significant role in the progression of this disease. • ANCA bind to proteinase3 (PR-3) which are proteins found on the surface of cell membranes of neutrophils and this causes inflammation of blood vessels. • The attachment of ANCA are thought to activate neutrophils and cause them to attach to endothelium which causes the inflammation. • The cause of the elevated levels of ANCA are thought to be attributed to inhaled antigens, genetic predusposition, and host factors. • Environmental factors may include Staphylococcus aureus

  5. Proteinase 3 (PR3) • Mature PR3 has 222 amino acid residues • Serine protease, stored in azurophilic granules within neutrophils • Antigen of ANCA • Some expression on membrane of neutrophil • Genetically determined

  6. How is PR3 activated? • Post-translational modification occurs 1.) Amino-end peptide removed by signal peptidase 2.) Amino-end dipeptide removed by Dipeptidyl peptidase I (DPPI/cathepsin C) • Granules are excreted by neutrophil upon activation • Granular movement to surface caused by cytokines (TNF-alpha) and chemoattractants (IL-8) • ANCAs attack PR3 activating neutrophils, especially those signaled by TNF-alpha

  7. PR3 and WG • Binding of Cytoplasmic-ANCA (C-ANCA) to membrane-bound PR3 leads to overactive neutrophils • increased secretion of reactive oxygen species and proteinases (degranulation) • Ultimately damaging endothelial cells of blood vessels • higher densities of membrane-bound PR3 on neutrophils correlated with WG sensitivity • Likelihood of relapse higher

  8. Decreasing C-ANCA effect • Use of SerpinB1 • inhibits ANCAs by binding with the PR3 on membrane • Inhibit PR3 activity when bound together

  9. Decreasing Membrane Bound PR3 • Use of DPPI inhibitors • Lower DPPI resulted in lower PR3 content within neutrophils • Unprocessed protein produced • Degraded internally in cell or excreted (both in development of neutrophils)

  10. Symptoms • WG mostly affects the upper respiratory tract, kidneys, and lungs due to restricted blood flow • Patients commonly present with : • Chronic sinusitis (67%) • Pulmonary infiltrates (71%) • Chronic cough (34%) • Collapse of nasal support, causing saddle nose deformity (common) • Necrotizing glomerulonephritis (17%)

  11. Diagnosis • Cytoplasmic anti-neutrophilcytoplasmic autoantibody testing (c-ANCA) • fluorescence within cytoplasm suggests presence of PR3 auto-antibodies • Chest Radiography • Identifies pulmonary infiltrates • Renal/Pulmonary Biopsies • Identifies presence of necrotizing granulomas *Only conclusive test to diagnose WG*

  12. Treatment • Common treatment consists of cyclophosphamide (CYC) and corticosteroids • Prednisone • Initial phase is aggressive, second phase designed to prevent remission CYC Prednisone

  13. Problems • CYC has been a proposed carcinogen • After 10 years, relapse rate is about 67% • Survivability rate has not improved much since the 1970s

  14. Future treatments • Relapse may be prevented by maintaining the production of PR3-ANCA and primed neutrophils • Future treatments may target the Th1 response (ex: anti-Il-12)

  15. Summary • Wegener's granulomatosis (WG) is an auto-immune disease that causes inflammation of blood vessels (vasculitis) • Commonly affects the upper respiratory tract, kidneys, and lungs. • The exact cause isn’t known but it is believed anti-neutrophil cytoplasmic autoantibodies (ANCA) binds to its antigen, proteinase 3 • This causes neutrophil to over-release proteinases and reactive oxidative species, damaging endothelial walls • Renal/pulmonary biopsies are the only conclusive diagnostic test for WG • Treatment of WG is normally with cyclophosphamide (CYC) and corticosteroids (commonly prednisone)

  16. References • Faurschou, M. et al. Malignancies in Wegener's granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients. The Journal of Reheumatology. 2008. 35. 100 • Reinhold-Keller, E. et al. An interdisciplinary approach to the care of patients with Wegenerʼs granulomatosis: Long‐term outcome in 155 patients. Arthritis and Rheumatism. 2000. 43. 1021 • Khan, A. R. et al. Wegener's granulomatosis: treatment and survival characteristics in a high‐prevalence southern hemisphere region. Internal Medicine Journal. 2012. 42. 23 • Schinlder, A. M. Wegener's Granulomatosis vasculitis and granuloma. Autoimmune Review. 2010. 9. 483 Images Cyclophosphamide. Drugs Information Online. Accessed October 7, 2013 from http://www.drugs.com/pro/cyclophosphamide.html Deltasone. RxList. Accessed October 7, 2013 from http://www.rxlist.com/deltasone-drug.htm

  17. References • Weeda, L.W. and Coffery, S.A.. Wegener's Granulomatosis. Oral Maxillofacial Surgery. (2008). 643-649 • Seo, P. and Stone, J.H.. The AntineutrophilCytoplasmic Antibody - Associated Vasculitides. The American Journal of Medicine. (2004). 117: 39-50 • Langford, C.A.. Wegener Granulomatosis. The American Journal of the Medical Sciences. (2001). 321: 76-82 • Images • The potential role of ANCAs and cytokines in neutrophil-mediated vascular injury. expert reviews in molecular medicine. Accessed October 16, 2013. http://journals.cambridge.org/fulltext_content/ERM/ERM7_08/S146239940500921Xsup005.htm • Wegener's Granulotosis. Vasculitis Foundation. Accessed October 16, 2013. http://elms.readyhosting.com/Classes/Web%20Design/JosephGay/ABOUT.HTML

  18. References • Lynch, Joseph P., and Henry Tazelaar. "Wegener Granulomatosis (Granulomatosis with Polyangiitis): Evolving Concepts in Treatment." Seminar in Respiratory and Critical Care Medicine. 32.3 (2011): 274-97. • Marzano, A.V., Y. Balice, M. Papini, R. Testa, E. Berti, and C. Crosti. "Localized Wegener's granulomatosis." Journal of the European Academy of Dermatology and Venereology. 25.12 (2011): 1466-70. • Millet, Arnaud, MagaliPederzoli-Ribeil, LoicGuillevin, et al. "Antineutrophilcytoplasmic antibody-associated vasculitides: is it time to split up the group?." Ann Rheum Dis. 72. (2013): 1273-79. • Korkmaz, Brice, Adam Lesner, Stephanie Letast, et al. "Neutrophilproteinase 3 and dipeptidyl peptidase I (cathepsin C) as pharmacological targets in granulomatosis with polyangiitis (Wegener granulomatosis)." Seminars in Immunopathology. 35.4 (2013): 411-21. • Images • van der Geld, Y.M., P.C. Limburg, and G.M. Kallenberg. "Proteinase 3, Wegener's autoantigen: from gene to antigen." Journal of Leukocyte Biology. 69.2 (2001): 177-90. Print.

  19. References • Papadopoulos, Particia J. "Wegener Granulomatosis ." Wegener Granulomatosis. Medscape, 12 Aug. 2013. Web. 15 Oct. 2013. <http://emedicine.medscape.com/article/332622-overview>. • Schriber, Andrew, MD. "Wegener's Granulomatosis: MedlinePlus Medical Encyclopedia." U.S National Library of Medicine. U.S. National Library of Medicine, 22 Mar. 2013. Web. 15 Oct. 2013. <http://www.nlm.nih.gov/medlineplus/ency/article/000135.htm>. • Langford, Carol A., MD. "Granulomatosis with Polyangiitis (Wegener's)." Granulomatosis with Polyangiitis (Wegener's). American College of Rheumatology, June 2012. Web. 15 Oct. 2013. <https://www.rheumatology.org/Practice/Clinical/Patients/Diseases_And_Conditions/Granulomatosis_with_Polyangiitis_%28Wegener_s%29/>. • "ANCA/MPO/PR3 Antibodies." Lab Tests Online. American Association for Clinical Chemistry, 21 Dec. 2011. Web. 15 Oct. 2013. <http://labtestsonline.org/understanding/analytes/anca/tab/test>. Images: • http://bestpractice.bmj.com/best-practice/monograph/1094/resources/image/bp/10.html • http://www.facedoctornyc.com/procedures/saddle-nose-deformity.php

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