The pathogenesis of ANCA vasculitis: genetics to new...
Transcript of The pathogenesis of ANCA vasculitis: genetics to new...
The pathogenesis of ANCA vasculitis: genetics
to new treatments
David Jayne
University of Cambridge, UK
SARAA, Durban, 2019
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
Jennette et al, Arthritis Rheum 2012
Chapel Hill Consensus 2012
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
Epidemiology
GPA
MPA
Incidence 3/100,000
Prevalence 42/100,000
Berti A et al, Arthritis Rheumatol 2017
ANCA vasculitis and survival
Heijl C et al, RMD Open 2017
Pathogenesis
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
Genetics EGPA
Lyons P et al, Nature Communications Med 2018
EGPA pathogenesis
Falk R et al, J All Clin Immunol 2018
ANCA
Environment
Davies D et al, Brit Med J 1982
Fc
FcgR+
ICAM
CD11/CD18+
F(ab’)2
PR3/MPO+
b2Fcg
ANCA
Functional response(Superoxide production)
MPO-ANCA splenocytes in Rag-/- miceXiao et al, JCI, 2002
Pulmonary arteritis, capillaritis and granulomata
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
Macrophage extracellular traps promoted by
platelet activation in acute kidney injury
Okubo et al, Nature Med 2018
B and T cells
B cells at sites of GPA inflammation
CD20+ Bcells CD138+ plasma cells
Zhao et al. Rheumatology 2012
Activated B cells and activating cytokines in
GPA
BAFFr and BAFF/BLyS APRIL
Zhao et al. Rheumatology 2012
McClure & Jayne, Nature Rev Nephrology 2018
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
Complement
Guo et al, Clin J Am Soc Nephrol 2014
Complement in ANCA Vasculitis
C3d
Biomarkers of complement activation in nephritis
Gou et al, Kidney Int 2013
C5a receptor blockade prevents vasculitis
C5aR -/- C5aR +/+
Xiao et al. J Am Soc Nephrol 2014
Chen, Jayne & Zhao, Nature Rev Nephrol 2017
Platelets
Infection
Salmela A et al, Rheumatology 2017
Nasal Staphylococcus Aureus carriage and relapse
Antibiotic therapy
➢ Trimethoprim-sulfamethoxazole was associated with a
decreased relapse rate in patients with GPA10
Stegeman C et al, New Engl J Med 1996
Association with disease
Thrombosis
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
Furuta & Jayne, Kidney Int 2012
Newer treatments
Severe disease
Rapidly progressive glomerulonephritis Diffuse alveolar haemorrhage
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
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
Methods of targeting B cells
McClure & Jayne, Nature Rev Nephrology 2018
Rituximab, a B cell depleting monoclonal antibody
Rituximab –in relapsing GPA/MPA
41
Smith R et al, Am Coll Rheum (abstract) 2017
Rituximab vs. azathioprine (MAINRITSAN)
Guillevin, et al. N Engl J Med. 2014
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
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
Jayne D et al, Arthitis Rheumatol 2018
Complement inhibition
Jayne D et al. J Am Soc Nephrol 2017
Avacopan (CCX168) vs. prednisolone
Proteinuria
Jayne D et al. J Am Soc Nephrol 2017
Cytokine inhibition
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
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
PR3-ANCA vasculitis MPO-ANCA vasculitis
EGPA
With ANCA
ANCA vasculitis – classification by serotype
EGPA
Without ANCA
GPA
Without ANCA
MPA
Without ANCA
Acknowledgements
CambridgeFederico Alberici
Stella Burns
Fausta Catapano
Afzal Chaudhry
Shunsuke Furuta
Pani Gopulani
Rachel Jones
Andreas Kronbichler
Paul Lyons
Helena Marco
Daiki Nakagomi
Els van der Peer
Luis Quintana
Darren Roberts
Ken Smith
Rona Smith
Joanna Tieu
Peter Merkel
Michael Walsh
Chen Au Peh
Carmel Hawley