1. Wegener’s Granulomatosis Adrian Boucher, Adrian Bagarich, Sarah Moninhas, Fethi Sedik PHM142 Fall 2014 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

2. Introduction Part of a group of disorders that produce systemic vasculitis – Autoimmune disorder that involves attack triggered by Anti-neutrophilic Cytoplasmic Autoantibody (ANCA) Systemic inflammation of small and medium blood vessels – Formation of granuloma

3. Clinical Symptoms Most affected organs are those that are highly perfused – Respiratory tract, kidneys – Also affects skin, joints, nerves, ears, eyes

4. Anti-neutrophilic Cytoplasmic Autoantibody (ANCA) IgG antibodies that primarily target PR3 in neutrophil – Attack endothelium Generated by B-cells in response to a stimulus

5. Proteinase 3 Found in the granules of neutrophils Serine protease that normally acts in combination with ROS to destroy pathogens

6. Causes

7. ANCA and Infection Superantigen Cell Wall Fragments Neutrophil B-cell Neutrophil

8. ANCA Production B-cell ANCA Antigen Blood Antigen R

9. Neutrophil Priming of Neutrophil TNF-a ANCA PR3

10. PR3/ANCA Complex Neutrophil TNF-a ANCA PR3

11. Complex with Fc Receptor Neutrophil TNF-a ANCA PR3 FcR

12. Localization and Degranulation TNF-a ANCA PR3 ROS

13. Tissue Necrosis TNF-a ANCA PR3 ROS

14. Positive Feedback Properdin Complement Pathway Neutrophil

15. Typical Treatment Course Immunosuppression therapy coupled with supportive treatments – Hemodialysis in case of renal failure – Respiratory support in case of lung hemorrhage – Preventing infection Lugmani, 2014

16. Phases of immune suppression Remission Induction – Aggressive dosing of immunosuppressants Coupled with high doses of corticosteroids to reduce inflammation further – Goal: try to prevent as much irreversible tissue damage (kidneys, lungs) as you can, as quickly as possible – Challenges: Minimizing drug toxicity Co-morbidity Remission Maintenance – Lower, continued doses of immunosuppressant to – Goal: prevent relapse going forward – Challenges: When is it safe to transition from induction to maintenance? Issues with long-term drug exposure/accumulation

17. Cyclophosphamide Cytotoxic alkylating agent, destroys T-cells and B-cells Followed up or coupled with maintenance agents Issues: – Considerable toxicity Infertility, hair loss, nausea/vomiting – Excessive compromise of immunity – High incidence of relapse http://www.unilab.com.ph/files/1713/2323/4729/Cycl ophosphamide_1_g_vial_powder_for_injection.JPG

18. Summary Wegener’s is autoimmune disease caused by Anti- neutrophilic Cytoplasmic Autoantibody (ANCA) ANCA are released by B-cells and target proteinase 3 (PR3) released by neutrophils Binding of ANCA/PR3 complex to Fc receptor results in attack on endothelium by neutrophils This damages the endothelium and results in tissue necrosis The main treatment is immunosuppressant drugs such as cyclophosphamide which destroy T and B cells The goal of treatment is used to achieve remission as there is no curing currently for Wegener’s

19. References http://www.moondragon.org/health/disorders/wegenersgranulomatosis.html#sy mptoms Woof, J. M., & Burton, D. R. (2004). Human antibody–Fc receptor interactions illuminated by crystal structures. Nature Reviews Immunology, 4(2), 89-99. Van der Geld, Y. M., Limburg, P. C., & Kallenberg, C. G. M. (2001). Proteinase 3, Wegener’s autoantigen: from gene to antigen. Journal of leukocyte biology,69(2), 177-190. Chen, M., & Kallenberg, C. G. (2010). ANCA-associated vasculitides—advances in pathogenesis and treatment. Nature Reviews Rheumatology,6(11), 653-664. Lutalo, P. M., & D'Cruz, D. P. (2014). Diagnosis and classification of granulomatosis with polyangiitis (aka Wegener's granulomatosis). Journal of autoimmunity, 48, 94- 98. Jennette, J. C., Falk, R. J., Hu, P., & Xiao, H. (2013). Pathogenesis of antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis.Annual Review of Pathology: Mechanisms of Disease, 8, 139-160.

20. References Tarzi RM, Pusey CD. Current and future prospects in the management of granulomatosis with polyangiitis (Wegener's granulomatosis). Ther Clin Risk Manag. 2014;10:279-93. Luqmani RA. State of the art in the treatment of systemic vasculitides. Front Immunol. 2014;5:471. Walsh M, Flossmann O, Berden A, et al. Risk factors for relapse of antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2012;64(2):542-8. Walton EW. Giant-cell granuloma of the respiratory tract (Wegener's granulomatosis). Br Med J. 1958;2(5091):265-70. Flossmann O, Berden A, De groot K, et al. Long-term patient survival in ANCA-associated vasculitis. Ann Rheum Dis. 2011;70(3):488-94. Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003;349(1):36-44. Harper L, Morgan MD, Walsh M, et al. Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up. Ann Rheum Dis. 2012;71(6):955-60. Little MA, Nightingale P, Verburgh CA, et al. Early mortality in systemic vasculitis: relative contribution of adverse events and active vasculitis. Ann Rheum Dis. 2010;69(6):1036-43.