Wegener’s Granulomatosis

Adrian Boucher, Adrian Bagarich, Sarah Moninhas, Fethi Sedik

PHM142 Fall 2014Coordinator: Dr. Jeffrey HendersonInstructor: 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

Cell Wall Fragments

Neutrophil

B-cell

Neutrophil

ANCA Production

B-cell

ANCA

Antigen

Blood

Antigen R

Neutrophil

Priming of NeutrophilTNF-a

ANCA

PR3

PR3/ANCA Complex

Neutrophil

TNF-a

ANCA

PR3

Complex with Fc Receptor

Neutrophil

TNF-a

ANCA

PR3

FcR

Localization and DegranulationTNF-a

ANCA

PR3

ROS

Tissue NecrosisTNF-a

ANCA

PR3

ROS

Positive Feedback

Properdin Complement Pathway

Neutrophil

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

– Excessive compromise of immunity– High incidence of relapse

http://www.unilab.com.ph/files/1713/2323/4729/Cyclophosphamide_1_g_vial_powder_for_injection.JPG

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

References• http://www.moondragon.org/health/disorders/

wegenersgranulomatosis.html#symptoms• 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.

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.