The pathogenesis of ANCA vasculitis: genetics to new...
Transcript of The pathogenesis of ANCA vasculitis: genetics to new...
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The pathogenesis of ANCA vasculitis: genetics
to new treatments
David Jayne
University of Cambridge, UK
SARAA, Durban, 2019
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Wegener
“In the investigation of sepsis with vessel
changes a striking disease picture
can be distinguished”
Verhandlungen der Deutschen Pathologischen
Gesellschaft 1937;29:202-10
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Jennette et al, Arthritis Rheum 2012
Chapel Hill Consensus 2012
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Granulomatosis with
Polyangitis (GPA)
PR3>>MPO-ANCA
70% renal
Microscopic polyangitis
(MPA)
MPO>PR3
90% renal
EGPA
MPO (40%)
15% renal
ANCA vasculitis – overlapping phenotypes
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Epidemiology
GPA
MPA
Incidence 3/100,000
Prevalence 42/100,000
Berti A et al, Arthritis Rheumatol 2017
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ANCA vasculitis and survival
Heijl C et al, RMD Open 2017
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Pathogenesis
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Genetics GPA/MPA
➢ Associate better with ANCA subtype than clinical diagnosis
– PR3-ANCA:
• HLA DP, PRTN3 (encodes for PR3)
– MPO-ANCA:
• HLA DQ
– Both
• SERPINA1 encodes for alpha 1 anti-trypsin (PR3 inhibitor)
• PTPN22 T cell activation
Lyons P et al, New Engl J Med 2012; Merkel P et al, Arthritis Rheumatol 2016
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Genetics EGPA
Lyons P et al, Nature Communications Med 2018
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EGPA pathogenesis
Falk R et al, J All Clin Immunol 2018
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ANCA
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Environment
Davies D et al, Brit Med J 1982
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Fc
FcgR+
ICAM
CD11/CD18+
F(ab’)2
PR3/MPO+
b2Fcg
ANCA
Functional response(Superoxide production)
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MPO-ANCA splenocytes in Rag-/- miceXiao et al, JCI, 2002
Pulmonary arteritis, capillaritis and granulomata
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Neutrophil extracellular traps (NETs)
Kessenbrock et al, Nature Med 2009
ANCA induce NETS NETs contain PR3/MPO NETs co-localise with neutrophil injury
ANCA
Control
PR3
MPO
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Macrophage extracellular traps promoted by
platelet activation in acute kidney injury
Okubo et al, Nature Med 2018
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B and T cells
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B cells at sites of GPA inflammation
CD20+ Bcells CD138+ plasma cells
Zhao et al. Rheumatology 2012
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Activated B cells and activating cytokines in
GPA
BAFFr and BAFF/BLyS APRIL
Zhao et al. Rheumatology 2012
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McClure & Jayne, Nature Rev Nephrology 2018
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T cell dysregulation
➢Th1 cytokines
➢Th17 expansion
– PR3 specific
– Il 17, 23 increase
➢Tfh expansion
– IL 15, IL 21 increase
➢Tregs
– Functionally deficient
Interaction with
Granulomata
B cells
Monocyte/macrophages
Vascular endothelium
Bacterial antigens
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Complement
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Guo et al, Clin J Am Soc Nephrol 2014
Complement in ANCA Vasculitis
C3d
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Biomarkers of complement activation in nephritis
Gou et al, Kidney Int 2013
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C5a receptor blockade prevents vasculitis
C5aR -/- C5aR +/+
Xiao et al. J Am Soc Nephrol 2014
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Chen, Jayne & Zhao, Nature Rev Nephrol 2017
Platelets
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Infection
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Salmela A et al, Rheumatology 2017
Nasal Staphylococcus Aureus carriage and relapse
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Antibiotic therapy
➢ Trimethoprim-sulfamethoxazole was associated with a
decreased relapse rate in patients with GPA10
Stegeman C et al, New Engl J Med 1996
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Association with disease
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Thrombosis
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Anti-plasminogen antibodies in AAV
➢ Autoantibodies to
– fibrinogen (25%) and tissue plasminogen activator (18%)
➢ Retard fibrinolysis in vitro
➢ Associated with more necrosis and renal failure
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Furuta & Jayne, Kidney Int 2012
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Newer treatments
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Severe disease
Rapidly progressive glomerulonephritis Diffuse alveolar haemorrhage
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Plasma exchange (PEXIVAS)
Hazard Ratio 0.86 (95% CI 0.65 – 1.13; p= 0.27)
PLEX: 100 (28%) No PLEX: 109 (31%)
Walsh, Merkel & Jayne, Submitted
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Mycophenolate mofetil vs. cyclophosphamide
(MYCYC)
➢ Proportion in remission at 6 months
MMF
n=70
IV CYC
n=70
Difference
(90% CI)p-value
Primary 46 (66%) 48 (69%) -3% (-16 to 10) 0.05
Jones et al, Ann Rheum Dis 2018
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
1 2
MPO MPO
PRSPRS
MMF CYC
Re
lap
se
pro
po
rtio
n
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Methods of targeting B cells
McClure & Jayne, Nature Rev Nephrology 2018
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Rituximab, a B cell depleting monoclonal antibody
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Rituximab –in relapsing GPA/MPA
41
Smith R et al, Am Coll Rheum (abstract) 2017
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Rituximab vs. azathioprine (MAINRITSAN)
Guillevin, et al. N Engl J Med. 2014
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Relapse after rituximab: B cells and ANCA
➢ 1/3 relapse before B cells
recovery
➢ 1/2 ANCA negative at
relapse
– 9/11 converting from ANCA
negative to positive relapsed
Alberici et al, Rheumatology 2014
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Rituximab and hypogammaglobulinemia
0
5
10
15
20
25
30
35
Pre-RTX Post-RTX
Per
centa
ge
Mild 5-7
Moderate 3-5
Severe <3
Roberts et al, J Autoimmunity 2014
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Jayne D et al, Arthitis Rheumatol 2018
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Complement inhibition
Jayne D et al. J Am Soc Nephrol 2017
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Avacopan (CCX168) vs. prednisolone
Proteinuria
Jayne D et al. J Am Soc Nephrol 2017
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Cytokine inhibition
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Mepolizumab vs placebo in EGPA
Study week
Placebo Mepolizumab100
BL
80
60
40
20
0
4 8 12 16 20 24 28 32 36 40 44 48 52 56 60
End of treatment period
Wechsler et al New Engl J Med 2017, Steinfeld et al. J All Clin Immunol 2018
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Conclusions
➢ ANCA vasculitis is a Class II restricted autoimmune disease
– Genetics associate with ANCA serotype
– EGPA, difference between ANCA +/-
➢ T/B cell dependent, neutrophil driven inflammation
– Rituximab has been revolutionary
– High risk of immunodeficiency in AAV
➢ Convincing evidence of alternate complement pathway activity
– Novel therapeutic target
– Potential alternative to steroid
? Nature of barrier defects and microbial drive
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PR3-ANCA vasculitis MPO-ANCA vasculitis
EGPA
With ANCA
ANCA vasculitis – classification by serotype
EGPA
Without ANCA
GPA
Without ANCA
MPA
Without ANCA
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Acknowledgements
CambridgeFederico Alberici
Stella Burns
Fausta Catapano
Afzal Chaudhry
Shunsuke Furuta
Pani Gopulani
Rachel Jones
Andreas Kronbichler
Paul Lyons
Helena Marco
Daiki Nakagomi
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