Wegener`s granulomatosis

Wegener’s Granulomatosis Adrian Boucher, Adrian Bagarich, Sarah Moninhas, Fethi Sedik

PHM142 Fall 2014 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

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

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

Anti-neutrophilic Cytoplasmic Autoantibody (ANCA) • IgG antibodies that primarily target PR3 in neutrophil – Attack endothelium

• Generated by B-cells in response to a stimulus

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

Causes

ANCA and Infection Superantigen B-cell

Cell Wall Fragments

Neutrophil

Neutrophil

ANCA Production

Blood B-cell

Antigen R Antigen ANCA

Priming of Neutrophil

TNF-a ANCA PR3

Neutrophil

PR3/ANCA Complex

TNF-a ANCA PR3

Neutrophil

Complex with Fc Receptor TNF-a ANCA PR3 FcR

Neutrophil

Localization and Degranulation TNF-a ANCA PR3 ROS

Tissue Necrosis TNF-a ANCA PR3 ROS

Positive Feedback

Neutrophil

Properdin

Complement Pathway

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

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

Cyclophosphamide • Cytotoxic alkylating agent, destroys T-cells and B-cells • Followed up or coupled with maintenance agents • Issues: http://www.unilab.com.ph/files/1713/2323/4729/Cycl ophosphamide_1_g_vial_powder_for_injection.JPG

– Considerable toxicity • Infertility, hair loss, nausea/vomiting

– Excessive compromise of immunity – High incidence of relapse

Summary • Wegener’s is autoimmune disease caused by Antineutrophilic 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

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, 9498. 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.

References •

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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.