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