New pathophysiological insights and treatment of ANCA-associated vasculitis
2010; Elsevier BV; Volume: 79; Issue: 6 Linguagem: Inglês
10.1038/ki.2010.472
ISSN1523-1755
AutoresBenjamin Wilde, Pieter van Paassen, Oliver Witzke, Jan Willem Cohen Tervaert,
Tópico(s)Otitis Media and Relapsing Polychondritis
ResumoANCA-associated-vasculitis (AAV) comprises three different diseases entities: Churg–Strauss syndrome, microscopic polyangiitis, and Wegener’s granulomatosis. AAV is an autoimmune disease with complex pathophysiology. Anti-neutrophil cytoplasmic antibodies (ANCAs) with specificity for proteinase-3 (PR3) or myeloperoxidase (MPO) are hallmarks of AAV and have a pivotal role in disease development. In addition to ANCA, the cellular immune system contributes to the pathogenesis of the disease. ANCA-mediated degranulation of neutrophils causes vasculitic damage; T cells drive granuloma formation, promote vasculitic damage by several different pathways, and enhance autoantibody production by B cells. Recently, complementary PR3 and lysosomal membrane protein-2 were suggested as novel autoantigens in AAV. New findings also indicate the importance of complement, danger-associated molecular patterns, and dendritic cells in AAV. This review highlights novel pathophysiological findings in AAV and puts them into context with the current understanding of disease mechanisms. Furthermore, implications for present and new therapeutic strategies are discussed. ANCA-associated-vasculitis (AAV) comprises three different diseases entities: Churg–Strauss syndrome, microscopic polyangiitis, and Wegener’s granulomatosis. AAV is an autoimmune disease with complex pathophysiology. Anti-neutrophil cytoplasmic antibodies (ANCAs) with specificity for proteinase-3 (PR3) or myeloperoxidase (MPO) are hallmarks of AAV and have a pivotal role in disease development. In addition to ANCA, the cellular immune system contributes to the pathogenesis of the disease. ANCA-mediated degranulation of neutrophils causes vasculitic damage; T cells drive granuloma formation, promote vasculitic damage by several different pathways, and enhance autoantibody production by B cells. Recently, complementary PR3 and lysosomal membrane protein-2 were suggested as novel autoantigens in AAV. New findings also indicate the importance of complement, danger-associated molecular patterns, and dendritic cells in AAV. This review highlights novel pathophysiological findings in AAV and puts them into context with the current understanding of disease mechanisms. Furthermore, implications for present and new therapeutic strategies are discussed. ANCA-associated vasculitis (AAV) is a life-threatening autoimmune disease characterized by necrotizing vasculitis of small- and medium-sized vessels.1.Kallenberg C.G. Brouwer E. Weening J.J. et al.Anti-neutrophil cytoplasmic antibodies: current diagnostic and pathophysiological potential.Kidney Int. 1994; 46: 1-15Abstract Full Text PDF PubMed Google Scholar, 2.Jennette J.C. Falk R.J. Andrassy K. et al.Nomenclature of systemic vasculitides. Proposal of an international consensus conference.Arthritis Rheum. 1994; 37: 187-192Crossref PubMed Google Scholar, 3.Lie J.T. Illustrated histopathologic classification criteria for selected vasculitis syndromes.Arthritis Rheum. 1990; 33: 1074-1087Crossref PubMed Google Scholar Pauci-immune necrotizing crescentic glomerulonephritis (NCGN) is commonly observed.3.Lie J.T. Illustrated histopathologic classification criteria for selected vasculitis syndromes.Arthritis Rheum. 1990; 33: 1074-1087Crossref PubMed Google Scholar,4.Tervaert J.W.C. Goldschmeding R. Elema J.D. et al.Autoantibodies against myeloid lysosomal-enzymes in crescentic glomerulonephritis.Kidney Int. 1990; 37: 799-806Abstract Full Text PDF PubMed Google Scholar Anti-neutrophil cytoplasmic antibodies (ANCAs) with specificity for either proteinase-3 (PR3) or myeloperoxidase (MPO) are hallmarks of AAV. AAV comprises three disease types: Wegener’s granulomatosis (WG), Churg–Strauss syndrome (CSS), and microscopic polyangiitis (MPA). The disease types differ with respect to clinical manifestations and histological findings. Granulomatous inflammation is observed in WG and CSS but not in MPA.2.Jennette J.C. Falk R.J. Andrassy K. et al.Nomenclature of systemic vasculitides. Proposal of an international consensus conference.Arthritis Rheum. 1994; 37: 187-192Crossref PubMed Google Scholar, 5.Masi A.T. Hunder G.G. Lie J.T. et al.The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis).Arthritis Rheum. 1990; 33: 1094-1100Crossref PubMed Google Scholar, 6.Leavitt R.Y. Fauci A.S. Bloch D.A. et al.The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis.Arthritis Rheum. 1990; 33: 1101-1107Crossref PubMed Google Scholar Furthermore, neutrophils are abundantly found in WG-associated inflammation, whereas in CSS eosinophils dominate the inflammatory infiltrate.2.Jennette J.C. Falk R.J. Andrassy K. et al.Nomenclature of systemic vasculitides. Proposal of an international consensus conference.Arthritis Rheum. 1994; 37: 187-192Crossref PubMed Google Scholar,3.Lie J.T. Illustrated histopathologic classification criteria for selected vasculitis syndromes.Arthritis Rheum. 1990; 33: 1074-1087Crossref PubMed Google Scholar CSS and MPA are mostly associated with ANCAs directed against MPO, whereas WG is more associated with ANCAs with specificity for PR3.7.Cohen Tervaert J.W. Limburg P.C. Elema J.D. et al.Detection of autoantibodies against myeloid lysosomal-enzymes – a useful adjunct to classification of patients with biopsy-proven necrotizing arteritis.Am J Med. 1991; 91: 59-66Abstract Full Text PDF PubMed Scopus (0) Google Scholar The pathophysiology of AAV is complex and the humoral as well as the cellular immune system are involved. ANCAs themselves are thought to be pathogenic. Furthermore, ANCAs promote degranulation of neutrophils and monocytes facilitating endothelial damage.8.Falk R.J. Terrell R.S. Charles L.A. et al.Antineutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro.Proc Natl Acad Sci USA. 1990; 87: 4115-4119Crossref PubMed Scopus (0) Google Scholar The endothelium is also activated and thereby neutrophil adherence is enhanced.9.van Paassen P. Tervaert J.W.C. Heeringa P. 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Recent findings on ANCAs, complement, neutrophils, lymphocytes, and dendritic cells (DCs) demand to confine new roles for old players in AAV. Thus, we discuss and illustrate novel insights and the role in the current concept of disease. This review will also highlight and further explain implications for treatment modality. The functional characteristics of ANCAs have been studied in different in vitro and in vivo models providing growing evidence for pathogenicity.12.Gomez-Puerta J.A. Bosch X. Anti-neutrophil cytoplasmic antibody pathogenesis in small-vessel vasculitis: an update.Am J Pathol. 2009; 175: 1790-1798Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar ANCAs bind to neutrophils and endothelial cells having differential but synergistic effects on both cell types. ANCAs bind to membrane-bound PR3/MPO on neutrophils.12.Gomez-Puerta J.A. Bosch X. 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The activation of the neutrophil respiratory burst by anti-neutrophil cytoplasm autoantibody (ANCA) from patients with systemic vasculitis requires tyrosine kinases and protein kinase C activation.Clin Exp Immunol. 1999; 118: 171-179Crossref PubMed Scopus (0) Google Scholar Membrane-bound MPO/PR3 is expressed constitutively by neutrophils and can be enhanced by pro-inflammatory cytokines like tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) (‘priming’).13.van Rossum A.P. Rarok A.A. Huitema M.G. et al.Constitutive membrane expression of proteinase 3 (PR3) and neutrophil activation by anti-PR3 antibodies.J Leukoc Biol. 2004; 76: 1162-1170Crossref PubMed Scopus (0) Google Scholar, 14.Radford D.J. Lord J.M. Savage C.O.S. 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Leucocyte membrane expression of proteinase 3 correlates with disease activity in patients with Wegener’s granulomatosis.Br J Rheumatol. 1998; 37: 901-907Crossref PubMed Google Scholar Priming of neutrophils also enhances adhesion to endothelial cells along with a further increase of membrane MPO/PR3 expression.18.Radford D.J. Savage C.O.S. Nash G.B. Treatment of rolling neutrophils with antineutrophil cytoplasmic antibodies causes conversion to firm integrin-mediated adhesion.Arthritis Rheum. 2000; 43: 1337-1345Crossref PubMed Scopus (97) Google Scholar,19.Schreiber A. Luft F.C. Kettritz R. Membrane proteinase 3 expression and ANCA-induced neutrophil activation.Kidney Int. 2004; 65: 2172-2183Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar Thus, degranulation occurs in close contact with the vascular endothelium, resulting in vasculitic damage (Figure 1). There is ongoing discussion about the role of cytotoxic mediators in endothelial damage. A recent study by Lu et al.20.Lu X. Garfield A. Rainger G.E. et al.Mediation of endothelial cell damage by serine proteases, but not superoxide, released from antineutrophil cytoplasmic antibody-stimulated neutrophils.Arthritis Rheum. 2006; 54: 1619-1628Crossref PubMed Scopus (0) Google Scholar confirmed former experimental evidence suggesting that serine proteases (like PR3 and elastase) are more important than superoxide radicals in mediating cytotoxic damage.21.Westlin W.F. Gimbrone Jr, M.A. Neutrophil-mediated damage to human vascular endothelium. Role of cytokine activation.Am J Pathol. 1993; 142: 117-128PubMed Google Scholar The authors showed in vitro that endothelial cell injury was not prevented by blocking superoxide release. However, inhibition of serine proteases led to less endothelial cell injury. Therefore, ANCA-induced release of proteases seems to be the most important factor for vasculitic damage. Nevertheless, release of reactive oxygen species enhances the activity of serine proteases by inactivating α1-anti-trypsin, which is a potent PR3 inhibitor.22.Weiss S. Tissue destruction by neutrophils.N Engl J Med. 1989; 320: 365-376Crossref PubMed Google Scholar, 23.Dean R.T. Nick H.P. Schnebli H.P. Free radicals inactivate human neutrophil elastase and its inhibitors with comparable efficiency.Biochem Biophys Res Commun. 1989; 159: 821-827Crossref PubMed Scopus (0) Google Scholar, 24.Dolman K.M. Stegeman C.A. van de Wiel B.A. et al.Relevance of classic anti-neutrophil cytoplasmic autoantibody (C-ANCA)-mediated inhibition of proteinase 3-alpha 1-antitrypsin complexation to disease activity in Wegener’s granulomatosis.Clin Exp Immunol. 1993; 93: 405-410Crossref PubMed Google Scholar Binding of ANCAs to endothelial cells might occur via PR3/MPO acting as cofactors or via Fc receptors, but the exact mechanism remains controversial.11.Tervaert J.W. 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Detection of Fcgamma receptors on human endothelial cells stimulated with cytokines tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma).Clin Exp Immunol. 1998; 112: 533-538Crossref PubMed Scopus (0) Google Scholar The interaction of ANCAs with endothelial cells enhances expression of adhesion molecules like E-/P-Selectin and vascular cell adhesion molecule, as shown by several authors.10.Muller Kobold A.C. van Wijk R.T. Franssen C.F. et al.In vitro up-regulation of E-selectin and induction of interleukin-6 in endothelial cells by autoantibodies in Wegener’s granulomatosis and microscopic polyangiitis.Clin Exp Rheumatol. 1999; 17: 433-440PubMed Google Scholar,28.Nagao T. Matsumura M. 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Hu P.Q. et al.Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice.J Clin Invest. 2002; 110: 955-963Crossref PubMed Scopus (798) Google Scholar immunized MPO-knockout mice with murine MPO and transferred anti-MPO-IgG to wild-type and immune-deficient (RAG2−/−) mice. Wild-type and immune-deficient mice developed NCGN, proving a pathogenic role for MPO-ANCA. The importance of neutrophils and the priming process with proinflammatory agents was confirmed in this model.33.Huugen D. Xiao H. van Esch A. et al.Aggravation of anti-myeloperoxidase antibody-induced glomerulonephritis by bacterial lipopolysaccharide: role of tumor necrosis factor-alpha.Am J Pathol. 2005; 167: 47-58Abstract Full Text Full Text PDF PubMed Google Scholar,34.Xiao H. Heeringa P. Liu Z. et al.The role of neutrophils in the induction of glomerulonephritis by anti-myeloperoxidase antibodies.Am J Pathol. 2005; 167: 39-45Abstract Full Text Full Text PDF PubMed Google Scholar The current rat MPO-vasculitis model shows a varying and inconsistent disease phenotype. Therefore, Little et al.35.Little M.A. Smyth L. Salama A.D. et al.Experimental autoimmune vasculitis: an animal model of anti-neutrophil cytoplasmic autoantibody-associated systemic vasculitis.Am J Pathol. 2009; 174: 1212-1220Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar recently modified this rat model by using adjuvants to enhance immunization, resulting in experimental vasculitis with robust and reproducible disease expression. Pfister et al.36.Pfister H. Ollert M. Frohlich L.F. et al.Antineutrophil cytoplasmic autoantibodies against the murine homolog of proteinase 3 (Wegener autoantigen) are pathogenic in vivo.Blood. 2004; 104: 1411-1418Crossref PubMed Scopus (190) Google Scholar could not successfully establish a similar model for PR3-ANCA. Wild-type mice receiving anti-PR3-IgG did not develop glomerulonephritis or human AAV features. Interestingly, in a recent study by Primo et al.,37.Primo V.C. Marusic S. Franklin C.C. et al.Anti-PR3 immune responses induce segmental and necrotizing glomerulonephritis.Clin Exp Immunol. 2010; 159: 327-337Crossref PubMed Scopus (46) Google Scholar anti-PR3-induced immune responses elicited NCGN in mice prone to autoimmunity, demonstrating that PR3 immune responses in general can cause vasculitis and NCGN. However, a certain genetic background predisposing to autoimmunity seems to be indispensable.37.Primo V.C. Marusic S. Franklin C.C. et al.Anti-PR3 immune responses induce segmental and necrotizing glomerulonephritis.Clin Exp Immunol. 2010; 159: 327-337Crossref PubMed Scopus (46) Google Scholar Hattar et al.38.Hattar K. Oppermann S. Ankele C. et al.c-ANCA induce neutrophil-mediated lung injury: a model of acute Wegener’s granulomatosis.Eur Respir J. 2010; 36: 187-195Crossref PubMed Scopus (0) Google Scholar confirmed the pathogenic potential of anti-PR3 antibodies in an elegant model using isolated rat lungs. Perfusion of these lungs with neutrophils and antibodies against PR3 but not with control IgG resulted in edema formation resembling acute lung injury. In summary, there is convincing evidence from both in vitro and in vivo experiments that ANCAs are pathogenic. In the late 1980s, it was discovered that PR3 was the main antigen for cytoplasmic-ANCA, whereas MPO was shown to be the antigenic target of perinuclear-ANCA in patients with vasculitis.4.Tervaert J.W.C. Goldschmeding R. Elema J.D. et al.Autoantibodies against myeloid lysosomal-enzymes in crescentic glomerulonephritis.Kidney Int. 1990; 37: 799-806Abstract Full Text PDF PubMed Google Scholar, 7.Cohen Tervaert J.W. Limburg P.C. Elema J.D. et al.Detection of autoantibodies against myeloid lysosomal-enzymes – a useful adjunct to classification of patients with biopsy-proven necrotizing arteritis.Am J Med. 1991; 91: 59-66Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 39.Cohen Tervaert J.W. Damoiseaux J. Fifty years of antineutrophil cytoplasmic antibodies (ANCA) testing: do we need to revise the international consensus statement on testing and reporting on ANCA?.APMIS. 2009; 117: 55-59Crossref Scopus (0) Google Scholar, 40.Tervaert J.W. Goldschmeding R. Elema J.D. et al.Association of autoantibodies to myeloperoxidase with different forms of vasculitis.Arthritis Rheum. 1990; 33: 1264-1272Crossref PubMed Google Scholar, 41.Falk R.J. Jennette J.C. Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis.N Engl J Med. 1988; 318: 1651-1657Crossref PubMed Google Scholar, 42.Goldschmeding R. van der Schoot C.E. ten Bokkel Huinink D. et al.Wegener’s granulomatosis autoantibodies identify a novel diisopropylfluorophosphate-binding protein in the lysosomes of normal human neutrophils.J Clin Invest. 1989; 84: 1577-1587Crossref PubMed Google Scholar, 43.Niles J.L. McCluskey R.T. Ahmad M.F. et al.Wegener’s granulomatosis autoantigen is a novel neutrophil serine proteinase.Blood. 1989; 74: 1888-1893Crossref PubMed Google Scholar, 44.Jenne D.E. Tschopp J. Ludemann J. et al.Wegener’s autoantigen decoded.Nature. 1990; 346: 520Crossref PubMed Google Scholar The range of ANCA subtypes expanded and additional autoantigens recognized by ANCAs were found.45.Kain R. Exner M. Brandes R. et al.Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis.Nat Med. 2008; 14: 1088-1096Crossref PubMed Scopus (288) Google Scholar Recent findings bring up a new hypothesis on the induction of ANCAs by immune responses against Gram-positive or Gram-negative bacteria.39.Cohen Tervaert J.W. Damoiseaux J. Fifty years of antineutrophil cytoplasmic antibodies (ANCA) testing: do we need to revise the international consensus statement on testing and reporting on ANCA?.APMIS. 2009; 117: 55-59Crossref Scopus (0) Google Scholar,45.Kain R. Exner M. Brandes R. et al.Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis.Nat Med. 2008; 14: 1088-1096Crossref PubMed Scopus (288) Google Scholar Pendergraft et al.46.Pendergraft W.F. Preston G.A. Shah R.R. et al.Autoimmunity is triggered by cPR-3(105-201), a protein complementary to human autoantigen proteinase-3.Nat Med. 2004; 10: 72-79Crossref PubMed Scopus (250) Google Scholar investigated the role of complementary peptides in WG. The authors hypothesized that the initial immune response in WG is directed against the complementary protein PR3 (cPR3) and that anti-PR3 antibodies evolve during a secondary anti-idiotypic immune response (Figure 2). According to this hypothesis, antibodies forming the humoral immune response against cPR3 would serve as antigenic target for a secondary immune response (‘anti-idiotypic response,’ Figure 2).47.McGuire K.L. Holmes D.S. Role of complementary proteins in autoimmunity: an old idea re-emerges with new twists.Trends Immunol. 2005; 26: 367-372Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Anti-idiotypic antibodies not only react to anti-cPR3-antibodies but also to the sense protein PR3. Out of 34 WG patients, 7 (20%) had detectable antibodies against cPR3 that indeed formed idiotypic pairs with anti-PR3 antibodies. Injection of cPR3 in mice resulted in anti-cPR3 and anti-PR3 antibodies as predicted. Interestingly, cPR3 mRNA transcripts were only found in leukocytes from WG patients but not from healthy controls or lupus patients. Whether these cPR3 transcripts are of exogenous or endogenous origin remains to be solved. However, pathogens like Staphylococcus aureus bear genetic sequences that are complementary to the human PR3 gene, pointing to an exogenous origin of cPR3 transcripts. Indeed, chronic nasal carriage of S. aureus has been demonstrated to increase the risk for disease relapse.48.Stegeman C.A. Tervaert J.W.C. Sluiter W.J. et al.Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis.Ann Intern Med. 1994; 120: 12-17Crossref PubMed Google Scholar Moreover, WG patients treated with cotrimoxazole are less prone to relapse, and in some cases even remission can be induced by applying cotrimoxazole as monotherapy.49.Stegeman C.A. Cohen Tervaert J.W. de Jong P.E. et al.Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener’s granulomatosis.New Engl J Med. 1996; 335: 16-20Crossref PubMed Scopus (0) Google Scholar,50.Popa E.R. Tervaert J.W. The relation between Staphylococcus aureus and Wegener’s granulomatosis: current knowledge and future directions.Intern Med. 2003; 42: 771-780Crossref PubMed Google Scholar The mechanism proposed by Pendergraft et al.46.Pendergraft W.F. Preston G.A. Shah R.R. et al.Autoimmunity is triggered by cPR-3(105-201), a protein complementary to human autoantigen proteinase-3.Nat Med. 2004; 10: 72-79Crossref PubMed Scopus (250) Google Scholar defines a pivotal, novel role for a specific ANCA subtype but needs further confirmation. In addition, the clinical relevance and importance to disease pathogenesis needs to be defined and remains unclear. Recently, Kain et al.45.Kain R. Exner M. Brandes R. et al.Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis.Nat Med. 2008; 14: 1088-1096Crossref PubMed Scopus (288) Google Scholar reported the discovery of autoantibodies against lysosomal membrane protein-2 (LAMP-2) in patients with AAV-associated NCGN. They provided in vitro and in vivo evidence for the relevance of these antibodies to disease pathogenesis and linked them with infectious pathogens. Anti-LAMP-2 antibodies were only found in patients with active ANCA-associated NCGN. Interestingly, anti-LAMP-2 antibodies were also detectable in several patients with NCGN lacking PR3-ANCA or MPO-ANCA. Moreover, patients with localized AAV lacking renal involvement were generally negative for anti-LAMP-2 as were disease controls and healthy controls. Furthermore, Wistar Kyoto rats injected with antibodies to LAMP-2 developed crescentic pauci-immune glomerulonephritis. Anti-LAMP-2 crossreacted with FimH, which is part of the fimbriae of Gram-negative pathogens. Accordingly, immunization with FimH led to development of crescentic glomerulonephritis in rats. Altogether, these results suggest that AAV-associated crescentic glomerulonephritis might be triggered by bacterial infection eliciting an immune response to a previously unidentified, novel autoantigen. However, according to our own published observations, disease onset or relapse of AAV is linked to Gram-positive bacteria like S. aureus and not to infections with Gram-negative bacteria.48.Stegeman C.A. Tervaert J.W.C. Sluiter W.J. et al.Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis.Ann Intern Med. 1994; 120: 12-17Crossref PubMed Google Scholar,51.Stegeman C. Cohen Tervaert J. Kallenberg C. Co-trimoxazole and Wegener’s granulomatosis: more than a coincidence?.Nephrol Dial Transplant. 1997; 12: 652-655Crossref PubMed Scopus (0) Google Scholar Thus, the findings by Kain et al.45.Kain R. Exner M. Brandes R. et al.Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis.Nat Med. 2008; 14: 1088-1096Crossref PubMed Scopus (288) Google Scholar need to be confirmed in other patient cohorts. HNE (human neutrophil elastase) belongs to the chymotrypsin family of serine proteases. ANCAs with specificity to HNE are rarely and infrequently detected in patients with vasculitis.52.Tervaert J.W. Mulder L. Stegeman C. et al.Occurrence of autoantibodies to human leucocyte elastase in Wegener’s granulomatosis and other inflammatory disorders.Ann Rheum Dis. 1993; 52: 115-120Crossref PubMed Google Scholar Importantly, HNE-ANCA might be of use for diagnosing cocaine-induced midline destructive disease and/or drug-induced AAV.53.Wiesner O. Russell K.A. Lee A.S. et al.Antineutrophil cytoplasmic antibodies reacting with human neutrophil elastase as a diagnostic marker for cocaine-induced midline destructive lesions but not autoimmune vasculitis.Arthritis Rheum. 2004; 50: 2954-2965Crossref PubMed Scopus (0) Google Scholar Dolman et al.54.Dolman K.M. Gans R.O. Vervaat T.J. et al.Vasculitis and antineutrophil cytoplasmic autoantibodies associated with propylthiouracil therapy.Lancet. 1993; 342: 651-652Abstract PubMed Scopus (284) Google Scholar detected anti-HNE antibodies frequently in patients developing vasculitis during treatment with propylthiouracil. These findings were confirmed by others showing an association of ANCA with the administration of antithyroid drugs.55.Slot M.C. Links T.P. Stegeman C.A. et al.Occurrence of antineutrophil cytoplasmic antibodies and associated vasculitis in patients with hyperthyroidism treated with antithyroid drugs: a long-term followup study.Arthritis Rheum. 2005; 53: 108-113Crossref PubMed Scopus (0) Google Scholar Pauci-immunity is a hallmark of ANCA-associated vasculitis, and deposition of immune complexes or complement factors is considered to be absent.2.Jennette J.C. Falk R.J. Andrassy K. et al.Nomenclature of systemic vasculitides. Proposal of an international consensus conference.Arthritis Rheum. 1994; 37: 187-192Crossref PubMed Google Scholar However, accumulating evidence suggests that the complement pathway is involved in disease pathogenesis.56.Hu C.H. O’Loughlin S. Winkelmann R.K. Cutaneous manifestations of Wegener granulomatosis.Arch Dermatol. 1977; 113: 175-182Crossref PubMed Google Scholar, 57.Van Timmeren M.M. Chen M. Heeringa P. Review article: pathogenic role of complement activation in anti-neutrophil cytoplasmic auto-antibody-associated vasculitis.Neph
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