of anca associated vasculitis kdigo · vasculitis – patients with non-vasculitic renal disease...
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Pathogenesis and prognosis of ANCA associated vasculitis
Duvuru Geetha,M.D.Johns Hopkins University School of Medicine
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Disclosures
Consultant to ChemoCentryx
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Outline
ØPathogenesis of ANCA vasculitis (experimental and clinical data)
– ANCA– Neutrophils– Complement pathway– Cellular immunity
ØPrognosis of ANCA vasculitis
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UNCNephropathology
Vasculitis Nomenclature
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ANCA types
5
c-ANCA (PR 3) p-ANCA (MPO and others)
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ANCA disease associations
6
Kallenberg CG et al. Kidney Int 1994
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Pathogenesis of ANCA associated vasculitis
Kellenberg Nature Rev Nephrol 2006
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MPO ANCA mouse model
Xiao H et al. J Clin Invest 2002
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Animal model: lessons learned from MPO mouse model
Ø Anti-MPO IgG alone can cause disease
Ø Neutrophils are required &neutrophil priming exacerbates disease
Ø Genetic factors modulate disease activity
Ø Alternative complement pathway is involved
Ø C5a receptor blockade abrogates disease
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Not all MPO ANCA are pathogenic
Roth AJ et al. J Clin Invest 2013
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Neutrophils are required
Xiao H et al. Am J Pathol 2005
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ANCA and pro-inflammatory cytokines react synergistically
Huugen D et al. Am J Pathol 2005
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LPS causes dose dependent increase in renal injury
Huugen D et al. Am J Pathol 2005
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Disease severity is modulated by genetic factors
Xiao H et al. Am J Pathol 2013
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Genetic differences influence neutrophil activation by anti MPO IgG
Xiao H et al. Am J Pathol 2013
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How about PR3 ANCA?
Ø Immunized PR 3 deficient mice with recombinant murine PR3
Ø Mouse developed PR3 antibodies that recognized mouse PR3 on surface of neutrophils
Ø Passive transfer of mouse PR3 antibodies to naive mice
Ø No signs of vasculitis seen in kidneys or lungs
Pfister H et al. Blood 2004
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PR3 ANCA causes vasculitis but no granulomas
Primo VC et al. Clin Exp Imm2010
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PR3 ANCA in mice with humanized immune system
Ø Chimeric mice were generated
Ø Matched chimera mice were treated with human IgG from patients:– anti-PR3 positive renal and lung
vasculitis– patients with non-vasculitic renal
disease– healthy controls.
Ø .
Only anti-PR3 treated mice had pauci-immune proliferative glomerulonephritis and pulmonary vasculitis
Little MA et al. Plos one 2012
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In vitro studies: ANCA induced neutrophil activation
Ø Priming of neutrophils is necessary for ANCA induced activation
Ø Surface expression of MPO and PR3
Ø Fc¥RIIa and Fc¥RIIIb interaction is involved
Ø Release of ROS and lytic enzymes
Ø Conversion of rolling of neutrophils to firm integrin mediated adhesion
Ø Induction of neutrophil cytotoxicity to endothelial cells
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ANCA induced activation of neutrophils
Brouwer et al. KI 1994
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Stimulation of adaptive immune response by activated neutrophils
NETs B cell activating factors
Kessenbrock et al., Nature Med 2009Holden et al. Ann Rheum Dis 2011
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C3(H2O)
C3
C3b
(C5 convertases)
C3bBb(C3 convertase)
fB,fD+
properdin
C5b-9 (MAC)
C5a
C5a
Complement in ANCA vasculitis
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Complement pathway is involved
Xiao H et al. Am J Pathol 2007
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Alternative complement pathway is involved
Xiao H et al. Am J Pathol 2007
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C5a receptor blockade abrogates disease
Xiao H et al. Am J Pathol 2007
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ANCA stimulated neutrophils have increased capacity to activate alternative complement pathway
Increased C3Bbp levels in supernatants from AAV neutrophils
Increased microparticle release from AAV neutrophils
Ohisson S et al., Plos One2019
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Clinical evidence for ANCA pathogenicity
• AAV caused by transplacental passage of MPO ANCA from mother with MPA
• ANCA titers correlate with disease activity and recurrences in subsets of patients
• Efficacy of rituximab and plasma exchange KDIGO
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Clinical evidence for alternative complement pathway activation
• Hypocomplementemia in a subset of patients with severe disease
• Elevated plasma levels of Bb, C3a, C5a, and sC5b–9 and decreased properdin in active disease
• Elevated urinary levels of Bb, C3a, C5a, and C5b–9 in active disease
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Complement activation products in MPO and PR3 AAV
Wu EY et al., Arthritis & Rheumatol 2019
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Clinical evidence for alternative complement pathway activation
• Demonstration of complement pathway products in renal biopsies– C3 can be demonstrated in ANCA GN and correlates with poor renal prognosis– C5b−9, C3d, and factor B, but not C4d, could be detected in active glomerular lesions – C3d and properdin staining was associated with the proportion of cellular crescents
• CLEAR trial: successful use of C5a receptor blocker for remission induction
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T cell involvement in AAV
• Activated T cells can be seen in inflammatory lesions in affected organs, particularly in granulomatous lesions
• Alterations in circulating T cell subsets
• Increased levels of soluble factors indicative of T cell activation detected in plasma of GPA patients
• Numerical and functional alterations in Tregs
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Memory T cells in AAV
Abdulahad WH et al., Kidney Int 2006
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Memory T cells and renal AAV
Abdulahad WH et al., Arthritis & Rheum 2009
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What is the phenotype of these T cells?
Abdulahad WH et al., Arthritis & Rheum 2008Nogueira E at al., NDT 2010
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IL17 promotes ANCA GN
Gan PY et al. JASN 2010
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Mediation of extra-vascular inflammation
Jennette JC, Falk RJ. Quart J Med, Presse Med 2013, 42:493-8.
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ANCA vasculitis: Pathogenesis and treatment targets
Jennette JC, Falk RJ. Quart J Med, Presse Med 2013, 42:493-8.
Adaptive Immune response Innate Immune response
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Prognosis of ANCA associated vasculitisKDIGO
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Immunosuppression has improved patient survival rate
• 535 AAV patients: 1995 to 2002
• Median FU:5.2 years
• Overall mortality ratio among AAV patients compared to controls was 2.6 (95% CI 2.2-3.1, p< 0.0001)
• Predictors of death: older age, higher BVAS and worse renal function
Flossmann Oet al, Ann Rheum Dis 2011
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Mortality in AAV: Meta-analysis
• 3338 patients and 1091 deaths (1966-2009)
• 2.7 fold increased risk of death in AAV patients compared to general population
Tan JA, et al. Ann Rheum Dis 2017
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Mortality and disease phenotype
Heijl C, et al. RMDOpen 2017
Significantly increased mortality in AAV, p<0.001
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Improved patient survival over time: US data
Steinberg AW et al., Ann of Int Med 2019
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Causes of early and late mortality in AAV
Flossmann O, et al. Ann Rheum Dis 2011
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AAV patients face high morbidity
Most common VDI items Treatment related VDI items
Robson J et al, Rheumatology 2015
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Current treatment prevents lung damage more effectively than renal damage
Most common VDI items
Robson J et al, Rheumatology 2015
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Clinical predictors of ESRD in AAV patients
Wester Trejo MAC et al., Rheumatology 2019
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Histologic predictors for ESRD in AAV
Berden AE et al., J Am Soc Nephrol 2010
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Improvement in trends in ESRD over time
Rhee RL et al, Arthritis &Rheum 2016
Adjusted curveKaplan-Meier curve
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No change in trends in risk of relapse over time
Rhee RL et al, Arthritis &Rheum 2016
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Causes of early and late mortality in AAV
Flossmann O, et al. Ann Rheum Dis 2011
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Infections in AAV
Mohammad AJ et al., J Rheum 2017
No difference in infection rates In early vs recent cohort
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Rituximab and hypogammaglobulinemia
Antibody InductiontherapyN=52
Maintenance therapyN=237
IgG 6 (4,8) 0.6 (-0.2,1.4)
IgA 5 (2,9) 5 (3,6)
IgM 16 (13,19) 9 (8,11)
Roberts DM et al., J Autoimmunity 2015Cortazar B et al., Arthritis & Rheum 2017
Mean percent decline in Ig
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Infection type in AAV and recommendations for prevention
• Respiratory infections, esp. Staph aureus
• C. Difficile
• Opportunistic infections: PJP, HZ, CMV
• Hepatitis B reactivation
• PML
• Decrease/withdraw immunosuppression in those at risk for infection and low relapse risk
• Vaccination for Influenza and Pneumococcus
• Prophylaxis with trimethoprim-sulfamethoxazole
• Surveillance with CBC, renal function and immunoglobulins
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Risk of cardiovascular disease is increased in AAV
• EUVAS data: 14% of 535 patients had at least one CV events over a 5 year follow up
• Age, diastolic hypertension and ANCA type are predictive of CV risk
Suppiah R et al., Arthritis Care Res 2011Morgan MD et al.Arthritis & Rheum 2009
AAV patients have higher risk of cardiovascular events than those with matched CKD
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Risk of cardiovascular disease is increased in AAV
Houben EE et al, Rheumatology 2018
Patients with AAV have an increase in cardiovascular risk of 65%
KDIGO
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Risk of malignancy increased in AAV
Heijl C et al, Ann Rheum Dis 2011
KDIGO
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AAV and malignancy risk
• 138 patients with mean FU of 9.7 years
• 36 developed 85 malignancies, 61 of which were NMSC cancers
Malignancy risk increased compared to general population
Rahmattulla C et al.Arthritis & Rheum 2015
KDIGO
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AAV and malignancy risk decreases with less use of cyclophosphamide
Risk decreased over timeNo increase in risk when CYC use was less than one year
Rahmattulla C et al.Arthritis & Rheum 2015
KDIGO
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Does rituximab decrease the risk of malignancy
van Daalen et al, Ann Rheum Dis 2017
KDIGO
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Patients treated with only rituximab had no increased malignancy risk compared to general population
van Daalen et al, Ann Rheum Dis 2017
KDIGO
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Relative risk of malignancy and treatment category
Malignancy risk in CYC treated patients was 4.61 fold higher than in RTX treated patients
van Daalen et al, Ann Rheum Dis 2017
KDIGO
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Malignancy risk and cumulative dose of CYC and RTX
van Daalen et al, Ann Rheum Dis 2017
KDIGO
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Quality of life and ANCA vasculitis
Basu Net al, Ann Rheum Dis 2014
410 ANCA patients318 chronic disease controls 470 healthy controls
KDIGO
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Closing remarks
• MPO ANCA is pathogenic in in vivo and in vitro studies
• PR3 ANCA associated disease is more complex with effector T cells and infectious triggers
• We have become good at controlling active disease at expense of increasing co-morbidities
• Future challenges: – Refinement of induction therapy– Targeted therapies – Relapse prevention– Management of disease and treatment associated co-morbidities– Addressing patient priorities
KDIGO