Pathogenesis and biomarkers in ANCA-associated vasculitis

Abstract

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a group of systemic autoimmune diseases associated with serum ANCA positivity that affect small to medium vessels with inflammation and endothelial injury. This group includes several diseases: granulomatosis with polyangiitis (GPA), microscopic polyangiitis, eosinophilic GPA, and drug-induced AAV. A few AAVs are ANCA negative, but this form has decreased with the increase in detection methods. Different genetic, epigenetic, and environmental risk factors contribute to the pathogenesis of AAV. ANCA’s role in the origin of vasculitis has led to a better grasp of the disease. Research has also improved the treatment, more precisely to tune its intensity, translating into better outcomes. However, there is still a gap to be filled with new potential and testable biomarkers for diagnosis, disease activity, and prognosis, which we discuss here.

Keywords

Pathogenesis / ANCA / ANCA-associated vasculitis / biomarkers

References

[1] Davies DJ,Niall JF.Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology?.Br Med J (Clin Res Ed)1982;285:606 PMCID:PMC1499415

[2] Kitching AR,Basu N.ANCA-associated vasculitis.Nat Rev Dis Primers2020;6:71

[3] Seeliger B,Robson JC.Are the 1990 American College of Rheumatology vasculitis classification criteria still valid?.Rheumatology (Oxford)2017;56:1154-61 PMCID:PMC6251621

[4] Jennette JC,Bacon PA.2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides.Arthritis Rheum2013;65:1-11

[5] Pearce FA,Merkel PA,Watts RA.Global ethnic and geographic differences in the clinical presentations of anti-neutrophil cytoplasm antibody-associated vasculitis.Rheumatology (Oxford)2017;56:1962-9

[6] Furuta S,Arimura Y.Comparison of the Phenotype and Outcome of Granulomatosis with Polyangiitis Between UK and Japanese Cohorts.J Rheumatol2017;44:216-22

[7] Bossuyt X,Arimura Y.Position paper: Revised 2017 international consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis.Nat Rev Rheumatol2017;13:683-92

[8] Puéchal X,Perrodeau É.French Vasculitis Study GroupLong-term outcomes among participants in the WEGENT trial of remission-maintenance therapy for granulomatosis with polyangiitis (Wegener’s) or microscopic polyangiitis.Arthritis Rheumatol2016;68:690-701

[9] Yates M,Bajema IM.EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis.Ann Rheum Dis2016;75:1583-94

[10] Tanna A,Brookes P.Familial granulomatosis with polyangiitis: three cases of this rare disorder in one Indoasian family carrying an identical HLA DPB1 allele.BMJ Case Rep2012;2012:bcr0120125502 PMCID:PMC4545082

[11] Lyons PA,Trivedi S.Genetically distinct subsets within ANCA-associated vasculitis.N Engl J Med2012;367:214-23 PMCID:PMC3773907

[12] Kawasaki A,Hidaka M.Protective role of HLA-DRB1*13:02 against microscopic polyangiitis and MPO-ANCA-positive vasculitides in a Japanese Population: a Case-Control Study.PLoS One2016;11:e0154393 PMCID:PMC4868057

[13] Jones BE,Muthigi A.Gene-specific DNA methylation changes predict remission in patients with ANCA-associated vasculitis.J Am Soc Nephrol2017;28:1175-87 PMCID:PMC5373455

[14] Ciavatta DJ,Preston GA.Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis.J Clin Invest2010;120:3209-19 PMCID:PMC2929711

[15] Nakazawa D,Tomaru U.Pathogenesis and therapeutic interventions for ANCA-associated vasculitis.Nat Rev Rheumatol2019;15:91-101

[16] Laudien M,Podschun R.Nasal carriage of Staphylococcus aureus and endonasal activity in Wegener’s granulomatosis as compared to rheumatoid arthritis and chronic Rhinosinusitis with nasal polyps.Clin Exp Rheumatol2010;28:51-5

[17] Scott J,Mockler D.Environmental risk factors associated with ANCA associated vasculitis: a systematic mapping review.Autoimmun Rev2020;19:102660

[18] Watts RA,Lane SE,Bentham G.Geoepidemiology of systemic vasculitis: comparison of the incidence in two regions of Europe.Ann Rheum Dis2001;60:170-2 PMCID:PMC1753459

[19] Pearce FA,Watts RA,Abhishek A.Novel insights into the aetiology of granulomatosis with polyangiitis-a case-control study using the Clinical Practice Research Datalink.Rheumatology (Oxford)2018;57:1002-10 PMCID:PMC5965083

[20] Gómez-Puerta JA,Costenbader KH.The association between silica exposure and development of ANCA-associated vasculitis: systematic review and meta-analysis.Autoimmun Rev2013;12:1129-35 PMCID:PMC4086751

[21] Lane SE,Bentham G,Scott DG.Are environmental factors important in primary systemic vasculitis?.Arthritis Rheum2003;48:814-23

[22] Stamp LK,Francis J.Association between environmental exposures and granulomatosis with polyangiitis in Canterbury, New Zealand.Arthritis Res Ther2015;17:333 PMCID:PMC4657282

[23] Brinkmann V,Goosmann C.Neutrophil extracellular traps kill bacteria.Science2004;303:1532-5

[24] Sangaletti S,Chiodoni C.Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity.Blood2012;120:3007-18

[25] Hakkim A,Amann K.Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis.Proc Natl Acad Sci U S A2010;107:9813-8 PMCID:PMC2906830

[26] Nakazawa D,Tomaru U.Enhanced formation and disordered regulation of NETs in myeloperoxidase-ANCA-associated microscopic polyangiitis.J Am Soc Nephrol2014;25:990-7 PMCID:PMC4005303

[27] Hiwa R,Arase N.Myeloperoxidase/HLA Class II complexes recognized by autoantibodies in microscopic polyangiitis.Arthritis Rheumatol2017;69:2069-80

[28] Leacy E,Little MA.Pathogenesis of ANCA-associated vasculitis: an emerging role for immunometabolism.Rheumatology (Oxford)2020;59:iii33-41

[29] Kronbichler A,Denicolò S.Immunopathogenesis of ANCA-associated vasculitis.Int J Mol Sci2020;21:7319 PMCID:PMC7584042

[30] Xiao H,Heeringa P,Jennette JC.Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies.Am J Pathol2007;170:52-64 PMCID:PMC1762697

[31] Schreiber A,Jennette JC,Luft FC.C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis.J Am Soc Nephrol2009;20:289-98 PMCID:PMC2637051

[32] Nakazawa D,Kusunoki Y.The responses of macrophages in interaction with neutrophils that undergo NETosis.J Autoimmun2016;67:19-28

[33] Chen M.ANCA-associated vasculitides--advances in pathogenesis and treatment.Nat Rev Rheumatol2010;6:653-64

[34] Stegeman C,de Jong P.Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener’s granulomatosis.Am J Ophthalmol1996;122:606

[35] Polzer K,Neumann T.Eotaxin-3 is involved in Churg-Strauss syndrome--a serum marker closely correlating with disease activity.Rheumatology (Oxford)2008;47:804-8

[36] Csernok E.Usefulness of vasculitis biomarkers in the era of the personalized medicine.Autoimmun Rev2020;19:102514

[37] Brogan P.Vasculitis update: pathogenesis and biomarkers.Pediatr Nephrol2018;33:187-98 PMCID:PMC5769819

[38] Roth AJ,Hess JJ.Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis.J Clin Invest2013;123:1773-83 PMCID:PMC3613913

[39] Lally L.Biomarkers in ANCA-associated vasculitis.Curr Rheumatol Rep2013;15:363

[40] Morris AD,Martin FL,Dhaygude AP.Biomarkers in ANCA-associated vasculitis: potential pitfalls and future prospects.Kidney3602021;2:586-97

[41] Domingues VM,Santos J.ANCA-positive vasculitis: clinical implications of ANCA types and titers.Rev Assoc Med Bras (1992)2016;62:434-40

[42] Suwanchote S,Rodsaward P.Anti-neutrophil cytoplasmic antibodies and their clinical significance.Clin Rheumatol2018;37:875-84

[43] FijoŁek J.Antineutrophil cytoplasmic antibodies (ANCA) - their role in pathogenesis, diagnosis, and treatment monitoring of ANCA-associated vasculitis.Cent Eur J Immunol2020;45:218-27 PMCID:PMC7792441

[44] Gou SJ,Chen M.Epitope analysis of anti-myeloperoxidase antibodies in patients with ANCA-associated vasculitis.PLoS One2013;8:e60530 PMCID:PMC3618278

[45] Renn JH,Chueh CM,Lan TH.Bone mass in schizophrenia and normal populations across different decades of life.BMC Musculoskelet Disord2009;10:1 PMCID:PMC2642755

[46] Fussner LA,Schroeder DR.Rituximab in ANCA-Associated Vasculitis-Immune Tolerance Network Research GroupFactors determining the clinical utility of serial measurements of antineutrophil cytoplasmic antibodies targeting proteinase 3.Arthritis Rheumatol2016;68:1700-10 PMCID:PMC7137903

[47] Schönermarck U,Csernok E.Prevalence and spectrum of rheumatic diseases associated with proteinase 3-antineutrophil cytoplasmic antibodies (ANCA) and myeloperoxidase-ANCA.Rheumatology (Oxford)2001;40:178-84

[48] Mahr A,Varet H.French Vasculitis Study Group (FVSG) and the European Vasculitis Society (EUVAS)Revisiting the classification of clinical phenotypes of anti-neutrophil cytoplasmic antibody-associated vasculitis: a cluster analysis.Ann Rheum Dis2013;72:1003-10

[49] Lionaki S,Hogan SL.Classification of antineutrophil cytoplasmic autoantibody vasculitides: the role of antineutrophil cytoplasmic autoantibody specificity for myeloperoxidase or proteinase 3 in disease recognition and prognosis.Arthritis Rheum2012;64:3452-62 PMCID:PMC3462364

[50] Pepper RJ,Caplin B.RAVE-Immune Tolerance Network Research GroupAssociation of serum calprotectin (S100A8/A9) level with disease relapse in proteinase 3-antineutrophil cytoplasmic antibody-associated vasculitis.Arthritis Rheumatol2017;69:185-93 PMCID:PMC5839649

[51] Kessenbrock K,Schönermarck U.Netting neutrophils in autoimmune small-vessel vasculitis.Nat Med2009;15:623-5 PMCID:PMC2760083

[52] Manojlovic M,Jonasdottir A.Microparticles expressing myeloperoxidase as potential biomarkers in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV).J Mol Med (Berl)2020;98:1279-86 PMCID:PMC7447662

[53] Lange C,Moosig F.Immune stimulatory effects of neutrophil extracellular traps in granulomatosis with polyangiitis.Clin Exp Rheumatol2017;35 Suppl 103:33-9

[54] Barnado A,Oates JC.At the bedside: neutrophil extracellular traps (NETs) as targets for biomarkers and therapies in autoimmune diseases.J Leukoc Biol2016;99:265-78 PMCID:PMC6608010

[55] Lieberthal JG,Carette S.Vasculitis Clinical Research Consortiumurinary biomarkers in relapsing antineutrophil cytoplasmic antibody-associated vasculitis.J Rheumatol2013;40:674-83 PMCID:PMC4505819

[56] Tam FW,George A.Urinary monocyte chemoattractant protein-1 (MCP-1) is a marker of active renal vasculitis.Nephrol Dial Transplant2004;19:2761-8

[57] Ohlsson S,Tencer J,Segelmark M.Monocyte chemoattractant protein 1 is a prognostic marker in ANCA-associated small vessel vasculitis.Mediators Inflamm2009;2009:584916 PMCID:PMC2706009

[58] O’Reilly VP,Kennedy C.Urinary soluble CD163 in active renal vasculitis.J Am Soc Nephrol2016;27:2906-16 PMCID:PMC5004645

[59] Nagai M,Ebihara I,Shimohata H.Serum levels of the soluble haemoglobin scavenger receptor CD163 in MPO-ANCA-associated renal vasculitis.Scand J Rheumatol2016;45:397-403

[60] Monach PA,Tomasson G.Serum proteins reflecting inflammation, injury and repair as biomarkers of disease activity in ANCA-associated vasculitis.Ann Rheum Dis2013;72:1342-50 PMCID:PMC4982463

[61] Dallos T,Strehl J.CCL17/thymus and activation-related chemokine in Churg-Strauss syndrome.Arthritis Rheum2010;62:3496-503

[62] Vaglio A,Manger B.IgG4 immune response in Churg-Strauss syndrome.Ann Rheum Dis2012;71:390-3

[63] Pepper RJ,Chavele KM.Leukocyte and serum S100A8/S100A9 expression reflects disease activity in ANCA-associated vasculitis and glomerulonephritis.Kidney Int2013;83:1150-8 PMCID:PMC3675710

[64] Szczeklik W,Mastalerz L.12-hydroxy-eicosatetraenoic acid (12-HETE): a biomarker of Churg-Strauss syndrome.Clin Exp Allergy2012;42:513-22

[65] Henes FO,Bley TA.Correlation of serum level of high mobility group box 1 with the burden of granulomatous inflammation in granulomatosis with polyangiitis (Wegener’s).Ann Rheum Dis2011;70:1926-9

[66] Brogan PA.Endothelial microparticles and the diagnosis of the vasculitides.Intern Med2004;43:1115-9

[67] Clarke LA,Eleftheriou D.Endothelial injury and repair in systemic vasculitis of the young.Arthritis Rheum2010;62:1770-80

[68] Erdbruegger U,Hertel B.Diagnostic role of endothelial microparticles in vasculitis.Rheumatology (Oxford)2008;47:1820-5

[69] Eleftheriou D,Klein NJ.Thromboembolic disease in systemic vasculitis is associated with enhanced microparticle-mediated thrombin generation.J Thromb Haemost2011;9:1864-7

[70] Eleftheriou D,Hong Y,Brogan PA.Endothelial injury in childhood stroke with cerebral arteriopathy: a cross-sectional study.Neurology2012;79:2089-96 PMCID:PMC3511928

[71] Woywodt A,de Groot K,Haller H.Circulating endothelial cells as markers for ANCA-associated small-vessel vasculitis.Lancet2003;361:206-10

[72] Závada J,Pytlík R,Tesar V.Reduced number of endothelial progenitor cells is predictive of early relapse in anti-neutrophil cytoplasmic antibody-associated vasculitis.Rheumatology (Oxford)2009;48:1197-201

[73] Cantin L,Marcotte F,Ducharme A.Coronary artery noninvasive imaging in adult Kawasaki disease.Clin Imaging2009;33:181-7

[74] van Dam LS,Bredewold EW.Proteinase-3-anti-neutrophil cytoplasmic antibodies (PR3-ANCAs) predict relapses in ANCA-associated vasculitis patients after rituximab.Nephrol Dial Transplant2020;gfaa066

[75] Smith RM,Guerry MJ.Rituximab for remission maintenance in relapsing antineutrophil cytoplasmic antibody-associated vasculitis.Arthritis Rheum2012;64:3760-9

[76] Bunch DO,Khandoobhai NB.Decreased CD5⁺ B cells in active ANCA vasculitis and relapse after rituximab.Clin J Am Soc Nephrol2013;8:382-91 PMCID:PMC3586963

[77] Unizony S,Phippard DJ.Peripheral CD5+ B cells in antineutrophil cytoplasmic antibody-associated vasculitis.Arthritis Rheumatol2015;67:535-44 PMCID:PMC4497572

[78] Bader L,Nossent J.B-lymphocyte activating factor levels are increased in patients with Wegener’s granulomatosis and inversely correlated with ANCA titer.Clin Rheumatol2010;29:1031-5

[79] Dolff S,Wilde B.Th17 cells in renal inflammation and autoimmunity.Autoimmun Rev2019;18:129-36

[80] von Borstel A,Heeringa P.Circulating CD24hiCD38hi regulatory B cells correlate inversely with the ThEM17 cell frequency in granulomatosis with polyangiitis patients.Rheumatology (Oxford)2019;

[81] Guillevin L,Karras A.Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. A prospective study in 117 patients.La Presse Médicale2013;42:679

[82] Li K,Zhang Y.Tyrosine kinase Fyn promotes osteoarthritis by activating the β-catenin pathway.Ann Rheum Dis2018;77:935-43

[83] Wang Y,Zhang N.Reduced activated regulatory T cells and imbalance of Th17/activated Treg cells marks renal involvement in ANCA-associated vasculitis.Mol Immunol2020;118:19-29

[84] Deng J,Fonseca VR,Yu D.T follicular helper cells and T follicular regulatory cells in rheumatic diseases.Nat Rev Rheumatol2019;15:475-90

[85] Gou SJ,Wang C,Chen M.Alternative complement pathway activation products in urine and kidneys of patients with ANCA-associated GN.Clin J Am Soc Nephrol2013;8:1884-91 PMCID:PMC3817906

[86] Tesar V.Avacopan in the treatment of ANCA-associated vasculitis.Expert Opin Investig Drugs2018;27:491-6

[87] Yuan J,Huang J,Chen M.C5a and its receptors in human anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis.Arthritis Res Ther2012;14:R140 PMCID:PMC3446523

[88] Gou SJ,Chen M,Zhao MH.Circulating complement activation in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis.Kidney Int2013;83:129-37

[89] Jayne DRW,Schall TJ.ADVOCATE Study GroupAvacopan for the Treatment of ANCA-Associated Vasculitis.N Engl J Med2021;384:599-609

[90] Manenti L,Gnappi E.Association of serum C3 concentration and histologic signs of thrombotic microangiopathy with outcomes among patients with ANCA-associated renal vasculitis.Clin J Am Soc Nephrol2015;10:2143-51 PMCID:PMC4670755