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
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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
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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.
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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.
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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.