The interaction between the activated alternative complement pathway, neutrophils and C5a is at the heart of vasculitic damage in AAV.1
The initial causes of AAV are currently unclear.2,3 Predisposing factors such as microbial infection, genetic influence, environmental agents and specific drugs are all fundamental to the development of AAV.2,3
Exposure to silica, pesticides, fumes, construction materials, hydrocarbon (cleaning agents, paint, diesel), drugs (propylthiouracil, hydralazine, D-penicillamine, cefotaxime, minocycline, anti-TNF agents, phenytoin) and certain psychoactive agents may all cause AAV.2,3
References & footnotesANCA involvement
Loss of immune tolerance to ANCA antigens and development of ANCA by plasma cells1
ANCA are most commonly directed against the neutrophil lysosomal enzymes PR3 and MPO in GPA and MPA, respectively1-5
AAV, ANCA-associated vasculitis; ANCA, anti-neutrophil cytoplasmic autoantibody;
TNF, tumour necrosis factor
Bekker P, et al. PLoS One 2016;11(10):e0164646.
Hutton HL, et al. Semin Nephrol 2017;37(5):418–35.
Al-Hussain T, et al. Adv Anat Pathol 2017;24(4):226–34.
ANCA, anti-neutrophil cytoplasmic autoantibody; GPA, granulomatosis with polyangiitis; IL, interleukin; MPA, microscopic polyangiitis; MPO, myeloperoxidase; NETS, neutrophil extracellular traps; PR3, proteinase 3; R, receptor; TNF, tumour necrosis factor
Hutton HL, et al. Semin Nephrol 2017;37(5):418–35.
Al-Hussain T, et al. Adv Anat Pathol 2017;24(4):226–34.
Chen M, et al. Medicine (Baltimore) 2008;87(4):203–9.
Lionaki S, et al. Arthritis Rheum 2012;64(10):3452–62.
Pagnoux C. Eur J Rheumatol 2016;3(3):122–33.
Jennette JC, Nachman PH. Clin J Am Soc Nephrol 2017;12(10):1680–91.
von Borstel A, et al. Autoimmun Rev 2018;17(4):413–21.
AAV, ANCA-associated vasculitis; ANCA, anti-neutrophil cytoplasmic autoantibody;
C-terminal, carboxy terminal; MAC, membrane attack complex; R, receptor
Bekker P, et al. PLoS One 2016;11(10):e0164646.
Thurman JM, Holers VM. J Immunol 2006;176(3):1305–10.
Figueroa JE, Densen P. Clin Microbiol Rev 1991;4(3):359–95.
Jennette JC, Nachman PH. Clin J Am Soc Nephrol 2017;12(10):1680–91.
Jennette JC, et al. Semin Nephrol 2013;33(6):557–64.
Dick J, et al. Kidney Int 2018;93(3):615–25.
Gerard C, et al. Annu Rev Immunol 1994;12:775–808.
Li R, et al. FASEB J 2013;27(3):855–64.
Monk PN, et al. Br J Pharmacol 2007;152(4):429–48.
Cain SA, Monk PN. J Biol Chem 2002;277(9):7165–9.
The three pathways of complement activation (classical, lectin and alternative) result in the formation of C3a, C3b, C5a and C5b-91
The alternative complement pathway is constantly ticking over through the spontaneous breakdown of C3 to C3b.2 It is the dysregulation of this pathway that is relevant in AAV1
C5 convertase formed during the amplification loop cleaves C5 into C5a and C5b1
C5b combines with complement components C6, C7, C8 and C9 to form C5b-9, also known as the terminal complement complex or membrane attack complex1
C5b-9 is needed for host resistance to encapsulated bacterial infections, such as Neisseria meningitides1,3
C5a is the downstream terminal effector molecule in the complement cascade and a potent pro-inflammatory mediator critical in AAV1,4
Rapid induction of the expression of adhesion molecules on the cell surface that causes leukocyte chemotaxis1
Further exposure of ANCA antigens at the neutrophil cell surface facilitates subsequent neutrophil activation5
New data suggest C5aR1 plays a role in promoting autoimmunity to ANCA antigens and increasing ANCA production6
C5a also mediates inflammation by stimulating vascular permeability, neutrophil degranulation, and release of lysosomal proteases and oxidative free radicals1,7
C5L2 activation does not play a role in AAV; in other conditions, it has a currently unclear pattern of pro- and anti-inflammatory actions1,8
C5a is rapidly degraded by removal of the C-terminal arginine, forming C5a des Arg with approximately 10-fold reduced activity on C5aR11,9
C5a des Arg binds with high affinity to the C5L2 receptor, and is subsequently internalised and degraded1,10
AAV, ANCA-associated vasculitis; ANCA, anti-neutrophil cytoplasmic autoantibody
Hutton HL, et al. Semin Nephrol 2017;37(5):418–35.
Bekker P, et al. PLoS One 2016;11(10):e0164646.
Little MA, et al. Ann Rheum Dis 2010;69(6):1036−43.
Rutherford P, et al. Patient experience in ANCA-associated vasculitis evolves over time from diagnosis and both benefits and adverse impacts are felt with current therapy. Poster presented at: ACR/ARHP 2018, 19–24 October 2018, Chicago, IL, USA (abstract 2723).
Rutherford P, et al. Arthritis Rheumatol 2018(Suppl 10[Abstract 2723]).
Robson JC, et al. Rheumatol Int 2018;38(4):675–82.
Berlin, 5-8 June 2021
Dublin, 3-6 April 2022
Renal disease during maintenance treatment in ANCA associated vasculitis (AAV) remains a problem and glucocorticoid use is high
PosterCountry differences exist in the treatment of ANCA associated vasculitis (AAV but high dose and prolonged glucocorticoid use is observed across Europe
PosterMaintenance treatment for ANCA-associated vasculitis (AAV) in real world practice in Germany - reality of vasculitis remission, relapse and burden of disease.
PosterSignificant burden of disease during maintenance treatment of ANCA-associated vasculitis (AAV) patients in real world practice in Europe.
PosterMaintenance treatment for ANCA-associated vasculitis in real world practise in Europe – reality of vasculitis remission and relapse and significant burden of disease.
PresentationPatterns of drug treatment for maintenance phase of ANCA-associated vasculitis (AAV) in real world practise in Europe – prolonged glucocorticoid use is common and various treatment regimes are used.
PosterInterviews with Three Key Opinion Leaders
European Medical Journal articleAdverse events and infections as major concerns with remission induction therapy of ANCA-associated vasculitis.
PosterHigh burden of disease for AAV patients in Germany - a claims study.
PosterRenal damage in ANCA-associated vasculitis in incident and relapsing patients.
Slide deckComorbidity, adverse events and infections are major concerns in real world management of ANCA-associated vasculitis.
Abstract PosterVariable response to induction therapy and significant burden of treatment adverse events over the first 12 months of remission induction treatment in ANCA-associated vasculitis patients.
PosterEconomic burden of ANCA-associated vasculitis in Germany - a claims data study.
PosterAdverse events due to high-dose glucocorticoids - lessons from ANCA-associated vasculitis and other inflammatory diseases.
PosterSeverity and response to induction therapy in new and relapsing ANCA-associated vasculitis patients - real world practice data.
PosterManagement of ANCA-associated vasculitis in the UK: a complex pathway of patient referral, diagnosis, and treatment.
PosterPatient Experience in ANCA-Associated Vasculitis - Challenges from Diagnosis and Need for New Approaches.
Abstract PosterPatients with Relapsing ANCA-Associated Vasculitis (AAV) Experience Unmet Needs around Remission Induction and Therapy Related Adverse Events.
Abstract PosterReal World Experience in ANCA-Associated Vasculitis (AAV) – A Complex Pathway of Patient Referral, Diagnosis, and Management.
Abstract Poster
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