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  • Review Article
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Genetics of ANCA-associated vasculitis: role in pathogenesis, classification and management

Nature Reviews Rheumatology volume 18, pages 559–574 (2022)Cite this article

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Abstract

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), that share features of pauci-immune small-vessel vasculitis and the positivity of ANCA targeting proteinase-3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). AAV syndromes are rare, complex diseases and their aetio-pathogenesis is mainly driven by the interaction between environmental and genetic factors. In patients with GPA and MPA, the genetic associations are stronger with ANCA specificity (PR3- versus MPO-ANCA) than with the clinical diagnosis, which, in keeping with the known clinical and prognostic differences between PR3-ANCA-positive and MPO-ANCA-positive patients, supports an ANCA-based re-classification of these disorders. EGPA is also made up of genetically distinct subsets, which can be stratified on ANCA-status (MPO ANCA-positive versus ANCA-negative); these subsets differ in clinical phenotype and possibly in their response to treatment. Interestingly, MPO-ANCA-positive patients with either MPA or EGPA have overlapping genetic determinants, thus strengthening the concept that this EGPA subset is closely related to the other AAV syndromes. The genetics of AAV provides us with essential information to understand its varied phenotype. This Review discusses the main findings of genetic association studies in AAV, their pathogenic implications and their potential effect on classification, management and prognosis.

Key points

  • ANCA-associated vasculitides (AAV) are classified according to clinico-pathological features as granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), and have complex aetio-pathogenetic mechanisms.

  • In GPA and MPA, genetic associations are stronger with ANCA specificity (PR3- or MPO-ANCA) than with the clinical diagnosis.

  • Evidence of a distinct genetic background between PR3-ANCA-positive and MPO-ANCA-positive vasculitis is coherent with the demographic, clinical and prognostic data, and supports a re-classification of AAV according to ANCA specificity.

  • In EGPA, MPO-ANCA-positive and ANCA-negative subsets share associations with loci involved in eosinophilia and asthma, and differ for associations with HLA-DQ, IL-5 and GPA33.

  • The genetic differences between the two EGPA subsets support the ANCA-based dichotomy of this syndrome.

  • ANCA-positive disease, which often displays vasculitic features, is closely related to MPO-ANCA-positive vasculitis, whereas ANCA-negative disease, which shows a higher prevalence of eosinophilic manifestations, may be associated with mucosal barrier dysfunction.

  • Future studies focusing on genotype–phenotype, genotype–prognosis and pharmacogenomics are likely to improve our understanding of AAV and refine our approaches to patient management.

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Fig. 1: Main clinical, imaging and histopathological features of the three AAV syndromes.
Fig. 2: Immunopathogenesis of PR3-ANCA-positive and MPO-ANCA-positive vasculitis.
Fig. 3: Immunopathogenesis of MPO-ANCA-positive and ANCA-negative EGPA.
Fig. 4: Genetic associations in AAV.
Fig. 5: Main demographic and clinical features as well as outcomes in AAV subsets based on their ANCA status along with their genetic associations.

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References

  1. Jennette, J. C. et al. 2012 revised international Chapel Hill consensus conference nomenclature of Vasculitides. Arthritis Rheum. 65, 1–11 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. Lanham, J. G., Elkon, K. B., Pusey, C. D. & Hughes, G. R. Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome. Medicine 63, 65–81 (1984).

    Article  CAS  PubMed  Google Scholar 

  3. Leavitt, R. Y. et al. The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum. 33, 1101–1107 (1990).

    Article  CAS  PubMed  Google Scholar 

  4. Masi, A. T. et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum. 33, 1094–1100 (1990).

    Article  CAS  PubMed  Google Scholar 

  5. Sorensen, S. F., Slot, O., Tvede, N. & Petersen, J. A prospective study of vasculitis patients collected in a five year period: evaluation of the Chapel Hill nomenclature. Ann. Rheum. Dis. 59, 478–482 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Watts, R. et al. Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies. Ann. Rheum. Dis. 66, 222–227 (2007).

    Article  PubMed  Google Scholar 

  7. Robson, J. C. et al. 2022 American College of Rheumatology/European Alliance of Associations for rheumatology classification criteria for granulomatosis with polyangiitis. Arthritis Rheumatol. 74, 393–399 (2022).

    Article  CAS  PubMed  Google Scholar 

  8. Suppiah, R. et al. 2022 American College of Rheumatology/European Alliance of Associations for rheumatology classification criteria for microscopic polyangiitis. Arthritis Rheumatol. 74, 400–406 (2022).

    Article  CAS  PubMed  Google Scholar 

  9. Grayson, P. C. et al. 2022 American College of Rheumatology/European Alliance of Associations for rheumatology classification criteria for eosinophilic granulomatosis with polyangiitis. Arthritis Rheumatol. 74, 386–392 (2022).

    Article  CAS  PubMed  Google Scholar 

  10. Hagen, E. C. et al. Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. EC/BCR Project for ANCA Assay Standardization. Kidney Int. 53, 743–753 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. 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. 318, 1651–1657 (1988).

    Article  CAS  PubMed  Google Scholar 

  12. Goldschmeding, R. et al. Wegener’s granulomatosis autoantibodies identify a novel diisopropylfluorophosphate-binding protein in the lysosomes of normal human neutrophils. J. Clin. Invest. 84, 1577–1587 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jennette, J. C., Hoidal, J. R. & Falk, R. J. Specificity of anti-neutrophil cytoplasmic autoantibodies for proteinase 3. Blood 75, 2263–2264 (1990).

    Article  CAS  PubMed  Google Scholar 

  14. Franssen, C., Gans, R., Kallenberg, C., Hageluken, C. & Hoorntje, S. Disease spectrum of patients with antineutrophil cytoplasmic autoantibodies of defined specificity: distinct differences between patients with anti-proteinase 3 and anti-myeloperoxidase autoantibodies. J. Intern. Med. 244, 209–216 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Lionaki, S. et al. Classification of antineutrophil cytoplasmic autoantibody vasculitides: the role of antineutrophil cytoplasmic autoantibody specificity for myeloperoxidase or proteinase 3 in disease recognition and prognosis. Arthritis Rheum. 64, 3452–3462 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mahr, A. et al. Revisiting the classification of clinical phenotypes of anti-neutrophil cytoplasmic antibody-associated vasculitis: a cluster analysis. Ann. Rheum. Dis. 72, 1003–1010 (2013).

    Article  PubMed  Google Scholar 

  17. Miloslavsky, E. M. et al. Myeloperoxidase-antineutrophil cytoplasmic antibody (ANCA)-positive and ANCA-negative patients with granulomatosis with polyangiitis (Wegener’s): distinct patient subsets. Arthritis Rheumatol. 68, 2945–2952 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Schirmer, J. H. et al. Myeloperoxidase-antineutrophil cytoplasmic antibody (ANCA)-positive granulomatosis with polyangiitis (Wegener’s) is a clinically distinct subset of ANCA-associated vasculitis: a retrospective analysis of 315 patients from a German vasculitis referral center. Arthritis Rheumatol. 68, 2953–2963 (2016).

    Article  CAS  PubMed  Google Scholar 

  19. Guillevin, L. et al. Churg-Strauss syndrome. Clinical study and long-term follow-up of 96 patients. Medicine 78, 26–37 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Moosig, F. et al. A vasculitis centre based management strategy leads to improved outcome in eosinophilic granulomatosis and polyangiitis (Churg-Strauss, EGPA): monocentric experiences in 150 patients. Ann. Rheum. Dis. 72, 1011–1017 (2013).

    Article  PubMed  Google Scholar 

  21. Sable-Fourtassou, R. et al. Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome. Ann. Intern. Med. 143, 632–638 (2005).

    Article  PubMed  Google Scholar 

  22. Sinico, R. A. et al. Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome. Arthritis Rheum. 52, 2926–2935 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Comarmond, C. et al. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical characteristics and long-term followup of the 383 patients enrolled in the French Vasculitis Study Group cohort. Arthritis Rheum. 65, 270–281 (2013).

    Article  PubMed  Google Scholar 

  24. Moiseev, S. et al. International consensus on ANCA testing in eosinophilic granulomatosis with polyangiitis. Am. J. Respir. Crit. Care Med. https://doi.org/10.1164/rccm.202005-1628SO (2020).

    Article  PubMed  Google Scholar 

  25. Jennette, J. C., Falk, R. J., Hu, P. & Xiao, H. Pathogenesis of antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis. Annu. Rev. Pathol. 8, 139–160 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Halbwachs-Mecarelli, L., Bessou, G., Lesavre, P., Lopez, S. & Witko-Sarsat, V. Bimodal distribution of proteinase 3 (PR3) surface expression reflects a constitutive heterogeneity in the polymorphonuclear neutrophil pool. FEBS Lett. 374, 29–33 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Falk, R. J., Terrell, R. S., Charles, L. A. & Jennette, J. C. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc. Natl Acad. Sci. USA. 87, 4115–4119 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Porges, A. J. et al. Anti-neutrophil cytoplasmic antibodies engage and activate human neutrophils via Fc gamma RIIa. J. Immunol. 153, 1271–1280 (1994).

    CAS  PubMed  Google Scholar 

  29. Savage, C. O., Pottinger, B. E., Gaskin, G., Pusey, C. D. & Pearson, J. D. Autoantibodies developing to myeloperoxidase and proteinase 3 in systemic vasculitis stimulate neutrophil cytotoxicity toward cultured endothelial cells. Am. J. Pathol. 141, 335–342 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Xiao, H. et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J. Clin. Invest. 110, 955–963 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Xiao, H., Schreiber, A., Heeringa, P., Falk, R. J. & Jennette, J. C. Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies. Am. J. Pathol. 170, 52–64 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Schreiber, A. et al. C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis. J. Am. Soc. Nephrol. 20, 289–298 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jayne, D. R. W., Merkel, P. A., Schall, T. J., Bekker, P. & Group, A. S. Avacopan for the treatment of ANCA-associated vasculitis. N. Engl. J. Med. 384, 599–609 (2021).

    Article  CAS  PubMed  Google Scholar 

  34. Mellbye, O. J., Mollnes, T. E. & Steen, L. S. IgG subclass distribution and complement activation ability of autoantibodies to neutrophil cytoplasmic antigens (ANCA). Clin. Immunol. Immunopathol. 70, 32–39 (1994).

    Article  CAS  PubMed  Google Scholar 

  35. Csernok, E. et al. Cytokine profiles in Wegener’s granulomatosis: predominance of type 1 (Th1) in the granulomatous inflammation. Arthritis Rheum. 42, 742–750 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Schonermarck, U., Csernok, E., Trabandt, A., Hansen, H. & Gross, W. L. Circulating cytokines and soluble CD23, CD26 and CD30 in ANCA-associated vasculitides. Clin. Exp. Rheumatol. 18, 457–463 (2000).

    CAS  PubMed  Google Scholar 

  37. Kiene, M. et al. Elevated interleukin-4 and interleukin-13 production by T cell lines from patients with Churg-Strauss syndrome. Arthritis Rheum. 44, 469–473 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Abdulahad, W. H., Stegeman, C. A., Limburg, P. C. & Kallenberg, C. G. Skewed distribution of Th17 lymphocytes in patients with Wegener’s granulomatosis in remission. Arthritis Rheum. 58, 2196–2205 (2008).

    Article  PubMed  Google Scholar 

  39. Nogueira, E. et al. Serum IL-17 and IL-23 levels and autoantigen-specific Th17 cells are elevated in patients with ANCA-associated vasculitis. Nephrol. Dial. Transplant. 25, 2209–2217 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Fagin, U. et al. Distinct proteinase 3-induced cytokine patterns in Wegener s granulomatosis, Churg-Strauss syndrome, and healthy controls. Clin. Exp. Rheumatol. 29 (1 Suppl 64), S57–S62 (2011).

    PubMed  Google Scholar 

  41. Pinching, A. J. et al. Relapses in Wegener’s granulomatosis: the role of infection. Br. Med. J. 281, 836–838 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Raynauld, J. P., Bloch, D. A. & Fries, J. F. Seasonal variation in the onset of Wegener’s granulomatosis, polyarteritis nodosa and giant cell arteritis. J. Rheumatol. 20, 1524–1526 (1993).

    CAS  PubMed  Google Scholar 

  43. Stegeman, C. A. et al. Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann. Intern. Med. 120, 12–17 (1994).

    Article  CAS  PubMed  Google Scholar 

  44. Grau, R. G. Drug-induced vasculitis: new insights and a changing lineup of suspects. Curr. Rheumatol. Rep. 17, 71 (2015).

    Article  PubMed  Google Scholar 

  45. Watanabe, T. Vasculitis following influenza vaccination: a review of the literature. Curr. Rheumatol. Rev. 13, 188–196 (2017).

    Article  PubMed  Google Scholar 

  46. Prabhahar, A. et al. ANCA-associated vasculitis following ChAdOx1 nCoV19 vaccination: case-based review. Rheumatol. Int. 42, 749–758 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yashiro, M. et al. Significantly high regional morbidity of MPO-ANCA-related angitis and/or nephritis with respiratory tract involvement after the 1995 great earthquake in Kobe (Japan). Am. J. Kidney Dis. 35, 889–895 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Hogan, S. L. et al. Association of silica exposure with anti-neutrophil cytoplasmic autoantibody small-vessel vasculitis: a population-based, case-control study. Clin. J. Am. Soc. Nephrol. 2, 290–299 (2007).

    Article  PubMed  Google Scholar 

  49. Lane, S. E., Watts, R. A., Bentham, G., Innes, N. J. & Scott, D. G. Are environmental factors important in primary systemic vasculitis? A case-control study. Arthritis Rheum. 48, 814–823 (2003).

    Article  PubMed  Google Scholar 

  50. Maritati, F. et al. Occupational exposures and smoking in eosinophilic granulomatosis with polyangiitis: a case-control study. Arthritis Rheumatol. 73, 1694–1702 (2021).

    Article  CAS  PubMed  Google Scholar 

  51. Fujimoto, S. et al. Comparison of the epidemiology of anti-neutrophil cytoplasmic antibody-associated vasculitis between Japan and the UK. Rheumatology 50, 1916–1920 (2011).

    Article  PubMed  Google Scholar 

  52. Watts, R. A. et al. Renal vasculitis in Japan and the UK-are there differences in epidemiology and clinical phenotype? Nephrol. Dial. Transplant. 23, 3928–3931 (2008).

    Article  PubMed  Google Scholar 

  53. Watts, R. A., Hatemi, G., Burns, J. C. & Mohammad, A. J. Global epidemiology of vasculitis. Nat. Rev. Rheumatol. 18, 22–34 (2022).

    Article  PubMed  Google Scholar 

  54. Weiner, M. et al. Proteinase-3 and myeloperoxidase serotype in relation to demographic factors and geographic distribution in anti-neutrophil cytoplasmic antibody-associated glomerulonephritis. Nephrol. Dial. Transplant. 34, 301–308 (2019).

    CAS  PubMed  Google Scholar 

  55. Watts, R. A. et al. Epidemiology of vasculitis in Europe. Ann. Rheum. Dis. 60, 1156–1157 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Mohammad, A. J., Jacobsson, L. T., Mahr, A. D., Sturfelt, G. & Segelmark, M. Prevalence of Wegener’s granulomatosis, microscopic polyangiitis, polyarteritis nodosa and Churg-Strauss syndrome within a defined population in southern Sweden. Rheumatology 46, 1329–1337 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Watts, R. A. et al. Classification, epidemiology and clinical subgrouping of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Nephrol. Dial. Transplant. 30, i14–i22 (2015).

    Article  CAS  PubMed  Google Scholar 

  58. Knight, A., Sandin, S. & Askling, J. Risks and relative risks of Wegener’s granulomatosis among close relatives of patients with the disease. Arthritis Rheum. 58, 302–307 (2008).

    Article  PubMed  Google Scholar 

  59. Manganelli, P., Giacosa, R., Fietta, P., Zanetti, A. & Neri, T. M. Familial vasculitides: Churg-Strauss syndrome and Wegener’s granulomatosis in 2 first-degree relatives. J. Rheumatol. 30, 618–621 (2003).

    PubMed  Google Scholar 

  60. Staels, F. et al. Adult-onset ANCA-associated vasculitis in SAVI: extension of the phenotypic spectrum, case report and review of the literature. Front. Immunol. 11, 575219 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lodi LM, M. V. et al. Type I interferon-related kidney disorders. Kidney Int. 101, 1142–1159 (2022).

    Article  Google Scholar 

  62. Jagiello, P. et al. New genomic region for Wegener’s granulomatosis as revealed by an extended association screen with 202 apoptosis-related genes. Hum. Genet. 114, 468–477 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Vaglio, A. et al. HLA-DRB4 as a genetic risk factor for Churg-Strauss syndrome. Arthritis Rheum. 56, 3159–3166 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Mahr, A. D. et al. Alpha1-antitrypsin deficiency-related alleles Z and S and the risk of Wegener’s granulomatosis. Arthritis Rheum. 62, 3760–3767 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Gencik, M., Meller, S., Borgmann, S. & Fricke, H. Proteinase 3 gene polymorphisms and Wegener’s granulomatosis. Kidney Int. 58, 2473–2477 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Jagiello, P. et al. The PTPN22 620W allele is a risk factor for Wegener’s granulomatosis. Arthritis Rheum. 52, 4039–4043 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Willcocks, L. C. et al. Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake. J. Exp. Med. 205, 1573–1582 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Martorana, D. et al. Fcγ-receptor 3B (FCGR3B) copy number variations in patients with eosinophilic granulomatosis with polyangiitis. J. Allergy Clin. Immunol. 137, 1597–1599.e8 (2016).

    Article  CAS  PubMed  Google Scholar 

  69. Husmann, C. A. et al. Genetics of toll like receptor 9 in ANCA associated vasculitides. Ann. Rheum. Dis. 73, 890–896 (2014).

    Article  CAS  PubMed  Google Scholar 

  70. Lyons, P. A. et al. Genetically distinct subsets within ANCA-associated vasculitis. N. Engl. J. Med. 367, 214–223 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Xie, G. et al. Association of granulomatosis with polyangiitis (Wegener’s) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis. Arthritis Rheum. 65, 2457–2468 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Merkel, P. A. et al. Identification of functional and expression polymorphisms associated with risk for antineutrophil cytoplasmic autoantibody-associated vasculitis. Arthritis Rheumatol. 69, 1054–1066 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Lyons, P. A. et al. Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status. Nat. Commun. 10, 5120 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Ciavatta, D. J. et al. Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis. J. Clin. Invest. 120, 3209–3219 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yang, J. et al. Histone modification signature at myeloperoxidase and proteinase 3 in patients with anti-neutrophil cytoplasmic autoantibody-associated vasculitis. Clin. Epigenetics 8, 85 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Jones, B. E. et al. Gene-specific DNA methylation changes predict remission in patients with ANCA-associated vasculitis. J. Am. Soc. Nephrol. 28, 1175–1187 (2017).

    Article  CAS  PubMed  Google Scholar 

  77. Martorana, D. et al. PTPN22 R620W polymorphism in the ANCA-associated vasculitides. Rheumatology 51, 805–812 (2012).

    Article  CAS  PubMed  Google Scholar 

  78. Wieczorek, S. et al. Contrasting association of a non-synonymous leptin receptor gene polymorphism with Wegener’s granulomatosis and Churg-Strauss syndrome. Rheumatology 49, 907–914 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Fanciulli, M. et al. FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nat. Genet. 39, 721–723 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wieczorek, S. et al. Functionally relevant variations of the interleukin-10 gene associated with antineutrophil cytoplasmic antibody-negative Churg-Strauss syndrome, but not with Wegener’s granulomatosis. Arthritis Rheum. 58, 1839–1848 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Kamesh, L. et al. CT60 and +49 polymorphisms of CTLA 4 are associated with ANCA-positive small vessel vasculitis. Rheumatology 48, 1502–1505 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Dahlqvist, J. et al. Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA. Rheumatology https://doi.org/10.1093/rheumatology/keab912 (2021).

    Article  PubMed Central  Google Scholar 

  83. Heckmann, M. et al. The Wegener’s granulomatosis quantitative trait locus on chromosome 6p21.3 as characterised by tagSNP genotyping. Ann. Rheum. Dis. 67, 972–979 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Tsuchiya, N., Kobayashi, S., Hashimoto, H., Ozaki, S. & Tokunaga, K. Association of HLA-DRB1*0901-DQB1*0303 haplotype with microscopic polyangiitis in Japanese. Genes Immun. 7, 81–84 (2006).

    Article  CAS  PubMed  Google Scholar 

  85. Wieczorek, S., Hellmich, B., Gross, W. L. & Epplen, J. T. Associations of Churg-Strauss syndrome with the HLA-DRB1 locus, and relationship to the genetics of antineutrophil cytoplasmic antibody-associated vasculitides: comment on the article by Vaglio et al. Arthritis Rheum. 58, 329–330 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Kawasaki, A. et al. Protective role of HLA-DRB1*13:02 against microscopic polyangiitis and MPO-ANCA-positive vasculitides in a Japanese population: a case-control study. PLoS ONE 11, e0154393 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Tsuchiya, N. et al. Genetic background of Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis: association of HLA-DRB1*0901 with microscopic polyangiitis. J. Rheumatol. 30, 1534–1540 (2003).

    CAS  PubMed  Google Scholar 

  88. Wieczorek, S. et al. A functionally relevant IRF5 haplotype is associated with reduced risk to Wegener’s granulomatosis. J. Mol. Med. 88, 413–421 (2010).

    Article  PubMed  Google Scholar 

  89. Kawasaki, A. et al. Association of ETS1 polymorphism with granulomatosis with polyangiitis and proteinase 3-anti-neutrophil cytoplasmic antibody positive vasculitis in a Japanese population. J. Hum. Genet. 63, 55–62 (2018).

    Article  CAS  PubMed  Google Scholar 

  90. Miyashita, R. et al. Association of killer cell immunoglobulin-like receptor genotypes with microscopic polyangiitis. Arthritis Rheum. 54, 992–997 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Wieczorek, S. et al. Novel association of the CD226 (DNAM-1) Gly307Ser polymorphism in Wegener’s granulomatosis and confirmation for multiple sclerosis in German patients. Genes Immun. 10, 591–595 (2009).

    Article  CAS  PubMed  Google Scholar 

  92. Mamegano, K. et al. Association of LILRA2 (ILT1, LIR7) splice site polymorphism with systemic lupus erythematosus and microscopic polyangiitis. Genes Immun. 9, 214–223 (2008).

    Article  CAS  PubMed  Google Scholar 

  93. Wang, H. Y. et al. Risk HLA class II alleles and amino acid residues in myeloperoxidase-ANCA-associated vasculitis. Kidney Int. 96, 1010–1019 (2019).

    Article  CAS  PubMed  Google Scholar 

  94. Elzouki, A. N., Segelmark, M., Wieslander, J. & Eriksson, S. Strong link between the alpha 1-antitrypsin PiZ allele and Wegener’s granulomatosis. J. Intern. Med. 236, 543–548 (1994).

    Article  CAS  PubMed  Google Scholar 

  95. Stanford, S. M. & Bottini, N. PTPN22: the archetypal non-HLA autoimmunity gene. Nat. Rev. Rheumatol. 10, 602–611 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Bottini, N. et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat. Genet. 36, 337–338 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Begovich, A. B. et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am. J. Hum. Genet. 75, 330–337 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kyogoku, C. et al. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am. J. Hum. Genet. 75, 504–507 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Serrano, A. et al. Identification of the PTPN22 functional variant R620W as susceptibility genetic factor for giant cell arteritis. Ann. Rheum. Dis. 72, 1882–1886 (2013).

    Article  CAS  PubMed  Google Scholar 

  100. Tizaoui, K. et al. The role of PTPN22 in the pathogenesis of autoimmune diseases: a comprehensive review. Semin. Arthritis Rheum. 51, 513–522 (2021).

    Article  CAS  PubMed  Google Scholar 

  101. Giscombe, R., Wang, X., Huang, D. & Lefvert, A. K. Coding sequence 1 and promoter single nucleotide polymorphisms in the CTLA-4 gene in Wegener’s granulomatosis. J. Rheumatol. 29, 950–953 (2002).

    CAS  PubMed  Google Scholar 

  102. Zhou, Y. et al. An analysis of CTLA-4 and proinflammatory cytokine genes in Wegener’s granulomatosis. Arthritis Rheum. 50, 2645–2650 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. Slot, M. C. et al. Immunoregulatory gene polymorphisms are associated with ANCA-related vasculitis. Clin. Immunol. 128, 39–45 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Lee, Y. H., Choi, S. J., Ji, J. D. & Song, G. G. CTLA-4 and TNF-α promoter-308 A/G polymorphisms and ANCA-associated vasculitis susceptibility: a meta-analysis. Mol. Biol. Rep. 39, 319–326 (2012).

    Article  CAS  PubMed  Google Scholar 

  105. Takara, M., Kouki, T. & DeGroot, L. J. CTLA-4 AT-repeat polymorphism reduces the inhibitory function of CTLA-4 in Graves’ disease. Thyroid 13, 1083–1089 (2003).

    Article  CAS  PubMed  Google Scholar 

  106. Anjos, S., Nguyen, A., Ounissi-Benkalha, H., Tessier, M. C. & Polychronakos, C. A common autoimmunity predisposing signal peptide variant of the cytotoxic T-lymphocyte antigen 4 results in inefficient glycosylation of the susceptibility allele. J. Biol. Chem. 277, 46478–46486 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Igarashi, K., Kurosaki, T. & Roychoudhuri, R. BACH transcription factors in innate and adaptive immunity. Nat. Rev. Immunol. 17, 437–450 (2017).

    Article  CAS  PubMed  Google Scholar 

  108. Sawalha, A. H. & Dozmorov, M. G. Epigenomic functional characterization of genetic susceptibility variants in systemic vasculitis. J. Autoimmun. 67, 76–81 (2016).

    Article  CAS  PubMed  Google Scholar 

  109. Mahr, A. et al. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): evolutions in classification, etiopathogenesis, assessment and management. Curr. Opin. Rheumatol. 26, 16–23 (2014).

    Article  CAS  PubMed  Google Scholar 

  110. Williams, B. B. et al. Glycoprotein A33 deficiency: a new mouse model of impaired intestinal epithelial barrier function and inflammatory disease. Dis. Model. Mech. 8, 805–815 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. GTEx Consortium. Human genomics. The genotype-tissue expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648–660 (2015).

    Article  PubMed Central  Google Scholar 

  112. Hui, C. C. et al. Thymic stromal lymphopoietin (TSLP) secretion from human nasal epithelium is a function of TSLP genotype. Mucosal Immunol. 8, 993–999 (2015).

    Article  CAS  PubMed  Google Scholar 

  113. Suppiah, R. et al. A model to predict cardiovascular events in patients with newly diagnosed Wegener’s granulomatosis and microscopic polyangiitis. Arthritis Care Res. 63, 588–596 (2011).

    Article  Google Scholar 

  114. de Joode, A. A., Sanders, J. S. & Stegeman, C. A. Renal survival in proteinase 3 and myeloperoxidase ANCA-associated systemic vasculitis. Clin. J. Am. Soc. Nephrol. 8, 1709–1717 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Quintana, L. F. et al. ANCA serotype and histopathological classification for the prediction of renal outcome in ANCA-associated glomerulonephritis. Nephrol. Dial. Transpl. 29, 1764–1769 (2014).

    Article  CAS  Google Scholar 

  116. Bischof, A. et al. Peripheral neuropathy in antineutrophil cytoplasmic antibody-associated vasculitides: Insights from the DCVAS study. Neurol. Neuroimmunol. Neuroinflamm. 6, e615 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Monti, S. et al. Association between age at disease onset of anti-neutrophil cytoplasmic antibody-associated vasculitis and clinical presentation and short-term outcomes. Rheumatology 60, 617–628 (2021).

    Article  PubMed  Google Scholar 

  118. Moiseev, S. et al. Association of venous thromboembolic events with skin, pulmonary and kidney involvement in ANCA-associated vasculitis: a multinational study. Rheumatology 60, 4654–4661 (2021).

    Article  CAS  PubMed  Google Scholar 

  119. Hauer, H. A. et al. Renal histology in ANCA-associated vasculitis: differences between diagnostic and serologic subgroups. Kidney Int. 61, 80–89 (2002).

    Article  PubMed  Google Scholar 

  120. Bettiol, A. et al. Risk of acute arterial and venous thromboembolic events in eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Eur. Respir. J. 57, 2004158 (2021).

    Article  CAS  PubMed  Google Scholar 

  121. Knight, A., Sandin, S. & Askling, J. Increased risk of autoimmune disease in families with Wegener’s granulomatosis. J. Rheumatol. 37, 2553–2558 (2010).

    Article  PubMed  Google Scholar 

  122. Draibe, J. & Salama, A. D. Association of ANCA associated vasculitis and rheumatoid arthritis: a lesser recognized overlap syndrome. Springerplus 4, 50 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Itikyala, S., Pattanaik, D. & Raza, S. Systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic antibody-associated vasculitis (AAV) overlap syndrome: case report and review of the literature. Case Rep. Rheumatol. 2019, 5013904 (2019).

    PubMed  PubMed Central  Google Scholar 

  124. Martin-Nares, E., Zuniga-Tamayo, D. & Hinojosa-Azaola, A. Prevalence of overlap of antineutrophil cytoplasmic antibody associated vasculitis with systemic autoimmune diseases: an unrecognized example of poliautoimmunity. Clin. Rheumatol. 38, 97–106 (2019).

    Article  PubMed  Google Scholar 

  125. Dendrou, C. A., Petersen, J., Rossjohn, J. & Fugger, L. HLA variation and disease. Nat. Rev. Immunol. 18, 325–339 (2018).

    Article  CAS  PubMed  Google Scholar 

  126. Rahmattulla, C. et al. Genetic variants in ANCA-associated vasculitis: a meta-analysis. Ann. Rheum. Dis. 75, 1687–1692 (2016).

    Article  PubMed  Google Scholar 

  127. Vafiadis, P. et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat. Genet. 15, 289–292 (1997).

    Article  CAS  PubMed  Google Scholar 

  128. Stanescu, H. C. et al. Risk HLA-DQA1 and PLA2R1 alleles in idiopathic membranous nephropathy. N. Engl. J. Med. 364, 616–626 (2011).

    Article  CAS  PubMed  Google Scholar 

  129. Stegeman, C. A. Anti-neutrophil cytoplasmic antibody (ANCA) levels directed against proteinase-3 and myeloperoxidase are helpful in predicting disease relapse in ANCA-associated small-vessel vasculitis. Nephrol. Dial. Transpl. 17, 2077–2080 (2002).

    Article  CAS  Google Scholar 

  130. Walsh, M. et al. Risk factors for relapse of antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 64, 542–548 (2012).

    Article  CAS  PubMed  Google Scholar 

  131. Mohammad, A. J. et al. Pulmonary involvement in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis: the influence of ANCA subtype. J. Rheumatol. 44, 1458–1467 (2017).

    Article  PubMed  Google Scholar 

  132. Tanna, A. et al. Long-term outcome of anti-neutrophil cytoplasm antibody-associated glomerulonephritis: evaluation of the international histological classification and other prognostic factors. Nephrol. Dial. Transpl. 30, 1185–1192 (2015).

    Article  CAS  Google Scholar 

  133. Mohammad, A. J. & Segelmark, M. A population-based study showing better renal prognosis for proteinase 3 antineutrophil cytoplasmic antibody (ANCA)-associated nephritis versus myeloperoxidase ANCA-associated nephritis. J. Rheumatol. 41, 1366–1373 (2014).

    Article  PubMed  Google Scholar 

  134. Menez, S. et al. Predictors of renal outcomes in sclerotic class anti-neutrophil cytoplasmic antibody glomerulonephritis. Am. J. Nephrol. 48, 465–471 (2018).

    Article  CAS  PubMed  Google Scholar 

  135. Trivioli, G. et al. Slowly progressive anti-neutrophil cytoplasmic antibody-associated renal vasculitis: clinico-pathological characterization and outcome. Clin. Kidney J. 14, 332–340 (2021).

    Article  CAS  PubMed  Google Scholar 

  136. Flossmann, O. et al. Long-term patient survival in ANCA-associated vasculitis. Ann. Rheum. Dis. 70, 488–494 (2011).

    Article  PubMed  Google Scholar 

  137. Wallace, Z. S. et al. All-cause and cause-specific mortality in ANCA-associated vasculitis: overall and according to ANCA type. Rheumatology 59, 2308–2315 (2020).

    Article  CAS  PubMed  Google Scholar 

  138. Segelmark, M., Elzouki, A. N., Wieslander, J. & Eriksson, S. The PiZ gene of α1-antitrypsin as a determinant of outcome in PR3-ANCA-positive vasculitis. Kidney Int. 48, 844–850 (1995).

    Article  CAS  PubMed  Google Scholar 

  139. Chang, D. Y., Luo, H., Zhou, X. J., Chen, M. & Zhao, M. H. Association of HLA genes with clinical outcomes of ANCA-associated vasculitis. Clin. J. Am. Soc. Nephrol. 7, 1293–1299 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Chen, D. et al. Immunological interaction of HLA-DPB1 and proteinase 3 in ANCA vasculitis is associated with clinical disease activity. J. Am. Soc. Nephrol. https://doi.org/10.1681/ASN.2021081142 (2022).

    Article  PubMed  Google Scholar 

  141. Ohlsson, S., Bakoush, O., Tencer, J., Torffvit, O. & Segelmark, M. Monocyte chemoattractant protein 1 is a prognostic marker in ANCA-associated small vessel vasculitis. Mediators Inflamm. 2009, 584916 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Jönsson, N., Erlandsson, E., Gunnarsson, L., Pettersson, A. & Ohlsson, S. Monocyte chemoattractant protein-1 in antineutrophil cytoplasmic autoantibody-associated vasculitis: biomarker potential and association with polymorphisms in the MCP-1 and the CC chemokine receptor-2 gene. Mediators Inflamm. 2018, 6861257 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Comarmond, C. et al. Pulmonary fibrosis in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis: a series of 49 patients and review of the literature. Medicine 93, 340–349 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Alba, M. A. et al. Interstitial lung disease in ANCA vasculitis. Autoimmun. Rev. 16, 722–729 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Zhao, W. et al. Clinical features and prognosis of microscopic polyangiitis with usual interstitial pneumonia compared with idiopathic pulmonary fibrosis. Clin. Respir. J. 13, 460–466 (2019).

    Article  PubMed  Google Scholar 

  146. Namba, N. et al. Association of MUC5B promoter polymorphism with interstitial lung disease in myeloperoxidase-antineutrophil cytoplasmic antibody-associated vasculitis. Ann. Rheum. Dis. 78, 1144–1146 (2019).

    Article  PubMed  Google Scholar 

  147. Seibold, M. A. et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N. Engl. J. Med. 364, 1503–1512 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Juge, P. A. et al. MUC5B promoter variant and rheumatoid arthritis with interstitial lung disease. N. Engl. J. Med. 379, 2209–2219 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Morgan, M. D. et al. Increased incidence of cardiovascular events in patients with antineutrophil cytoplasmic antibody-associated vasculitides: a matched-pair cohort study. Arthritis Rheum. 60, 3493–3500 (2009).

    Article  PubMed  Google Scholar 

  150. Kang, A. et al. High incidence of arterial and venous thrombosis in antineutrophil cytoplasmic antibody-associated vasculitis. J. Rheumatol. 46, 285–293 (2019).

    Article  CAS  PubMed  Google Scholar 

  151. Malik, R. et al. Common coding variant in SERPINA1 increases the risk for large artery stroke. Proc. Natl Acad. Sci. USA 114, 3613–3618 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Markus, H. S. et al. Evidence HDAC9 genetic variant associated with ischemic stroke increases risk via promoting carotid atherosclerosis. Stroke 44, 1220–1225 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Malhotra, R. et al. HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype. Nat. Genet. 51, 1580–1587 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Jones, R. B. et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis: 2-year results of a randomised trial. Ann. Rheum. Dis. 74, 1178–1182 (2015).

    Article  CAS  PubMed  Google Scholar 

  155. Stone, J. H. et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N. Engl. J. Med. 363, 221–232 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Smith, R. M. et al. Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis. Ann. Rheum. Dis. 79, 1243–1249 (2020).

    Article  CAS  PubMed  Google Scholar 

  157. Walsh, M. et al. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis. N. Engl. J. Med. 382, 622–631 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Yates, M. et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann. Rheum. Dis. 75, 1583–1594 (2016).

    Article  CAS  PubMed  Google Scholar 

  159. Hessels, A. C. et al. Clinical outcome in anti-neutrophil cytoplasmic antibody-associated vasculitis and gene variants of 11beta-hydroxysteroid dehydrogenase type 1 and the glucocorticoid receptor. Rheumatology 58, 447–454 (2019).

    Article  CAS  PubMed  Google Scholar 

  160. Quax, R. A. et al. Glucocorticoid sensitivity in health and disease. Nat. Rev. Endocrinol. 9, 670–686 (2013).

    Article  CAS  PubMed  Google Scholar 

  161. van Rossum, E. F. et al. Identification of the BclI polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids in vivo and body mass index. Clin. Endocrinol. 59, 585–592 (2003).

    Article  Google Scholar 

  162. Alberici, F. et al. Association of a TNFSF13B (BAFF) regulatory region single nucleotide polymorphism with response to rituximab in antineutrophil cytoplasmic antibody-associated vasculitis. J. Allergy Clin. Immunol. 139, 1684–1687.e10 (2017).

    Article  CAS  PubMed  Google Scholar 

  163. Nossent, J. C., Lester, S., Zahra, D., Mackay, C. R. & Rischmueller, M. Polymorphism in the 5′ regulatory region of the B-lymphocyte activating factor gene is associated with the Ro/La autoantibody response and serum BAFF levels in primary Sjogren’s syndrome. Rheumatology 47, 1311–1316 (2008).

    Article  CAS  PubMed  Google Scholar 

  164. Fabris, M. et al. The TTTT B lymphocyte stimulator promoter haplotype is associated with good response to rituximab therapy in seropositive rheumatoid arthritis resistant to tumor necrosis factor blockers. Arthritis Rheum. 65, 88–97 (2013).

    Article  CAS  PubMed  Google Scholar 

  165. Taylor, R. P. & Lindorfer, M. A. Drug insight: the mechanism of action of rituximab in autoimmune disease-the immune complex decoy hypothesis. Nat. Clin. Pract. Rheumatol. 3, 86–95 (2007).

    Article  CAS  PubMed  Google Scholar 

  166. Lim, S. H. et al. Fc gamma receptor IIb on target B cells promotes rituximab internalization and reduces clinical efficacy. Blood 118, 2530–2540 (2011).

    Article  PubMed  Google Scholar 

  167. Ruyssen-Witrand, A. et al. Fcγ receptor type IIIA polymorphism influences treatment outcomes in patients with rheumatoid arthritis treated with rituximab. Ann. Rheum. Dis. 71, 875–877 (2012).

    Article  CAS  PubMed  Google Scholar 

  168. Cartin-Ceba, R. et al. The pharmacogenomic association of Fcγ receptors and cytochrome P450 enzymes with response to rituximab or cyclophosphamide treatment in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheumatol. 69, 169–175 (2017).

    Article  CAS  PubMed  Google Scholar 

  169. Schirmer, J. H. et al. Cyclophosphamide treatment-induced leukopenia rates in ANCA-associated vasculitis are influenced by variant CYP450 2C9 genotypes. Pharmacogenomics 17, 367–374 (2016).

    Article  CAS  PubMed  Google Scholar 

  170. Cartin-Ceba, R., Keogh, K. A., Specks, U., Sethi, S. & Fervenza, F. C. Rituximab for the treatment of Churg-Strauss syndrome with renal involvement. Nephrol. Dial. Transpl. 26, 2865–2871 (2011).

    Article  CAS  Google Scholar 

  171. Mohammad, A. J. et al. Rituximab for the treatment of eosinophilic granulomatosis with polyangiitis (Churg-Strauss). Ann. Rheum. Dis. 75, 396–401 (2016).

    Article  CAS  PubMed  Google Scholar 

  172. Teixeira, V., Mohammad, A. J., Jones, R. B., Smith, R. & Jayne, D. Efficacy and safety of rituximab in the treatment of eosinophilic granulomatosis with polyangiitis. RMD Open 5, e000905 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Wechsler, M. E. et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N. Engl. J. Med. 376, 1921–1932 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Bettiol, A. et al. Mepolizumab for eosinophilic granulomatosis with polyangiitis: a European multicenter observational study. Arthritis Rheumatol. 74, 295–306 (2022).

    Article  CAS  PubMed  Google Scholar 

  175. Alberici, F. et al. FCGR3B polymorphism predicts relapse risk in eosinophilic granulomatosis with polyangiitis. Rheumatology 59, 3563–3566 (2020).

    Article  PubMed  Google Scholar 

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Acknowledgements

We gratefully thank Dr. Giovanni M. Rossi for providing the histological images included in Fig. 1.

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Authors and Affiliations

  1. Department of Biomedical Experimental and Clinical Sciences “Mario Serio”, University of Florence, Florence, Italy

    Giorgio Trivioli & Augusto Vaglio

  2. Nephrology and Dialysis Unit, Meyer Children’s Hospital, Florence, Italy

    Giorgio Trivioli, Michelangelo Tesi & Augusto Vaglio

  3. Institute of Parasitology and Biomedicine “López-Neyra”, CSIC, Granada, Spain

    Ana Marquez

  4. Medical Genetics Unit, Department of Diagnostics, University Hospital of Parma, Parma, Italy

    Davide Martorana

  5. CoreLab Unit, Research Center, University Hospital of Parma, Parma, Italy

    Davide Martorana

  6. Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK

    Andreas Kronbichler & Paul A. Lyons

  7. Vasculitis and Lupus Service, Department of Renal Medicine, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

    Andreas Kronbichler

  8. Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK

    Paul A. Lyons

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Contributions

All authors researched data for the article. A.V., G.T., D.M., M.T. and A.K. contributed substantially to discussion of the content. A.V., G.T., A.M., D.M., A.K. and P.A.L. wrote the article. G.T., A.M., M.T., A.K. and P.A.L. reviewed and/or edited the manuscript before submission.

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Nature Reviews Rheumatology thanks Ingeborg Bajema, Stephen McAdoo and the other, anonymous, reviewer for their contribution to the peer review of this work.

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Related links

Abatacept for the Treatment of Relapsing, Non-Severe, Granulomatosis With Polyangiitis (Wegener’s): https://clinicaltrials.gov/ct2/show/NCT02108860

Rituximab and Belimumab Combination Therapy in PR3 Vasculitis (COMBIVAS): https://clinicaltrials.gov/ct2/show/NCT03967925

Supplementary information

Glossary

DNA methylation

An epigenetic mechanism involved in the regulation of gene expression through the transfer of a methyl group to the 5′-carbon of a cytosine.

Histone marks

Covalent post-translational modifications of histone proteins that affect chromatin structure and, consequently, gene expression.

Linkage disequilibrium

Non-random association of alleles at different loci because of their physical proximity on a chromosome.

Luciferase reporter assay

An assay used to determine the allele-specific effects of a genetic variant on the expression of a target gene by measuring luminescence emitted by a reporter gene.

Pleiotropy-informed conditional false discovery rate

A method of exploiting the shared similarities between two diseases to detect additional genetic loci common to both.

Mendelian randomization

An approach that uses genetic variation as an instrumental variable to explore the causal relationship between risk factors and clinical traits.

BOLT-REML

A computationally efficient method for carrying out variance component analyses of large GWAS data sets. Such an approach allows an estimation of the variance of a trait that is explained by aggregated sets of SNPs rather than simply testing the significance of individual loci.

Whole-genome/-exome sequencing

The analysis of either the entire genomic sequence of an individual or, in the case of exome sequencing, the protein-coding regions of the genome.

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Trivioli, G., Marquez, A., Martorana, D. et al. Genetics of ANCA-associated vasculitis: role in pathogenesis, classification and management. Nat Rev Rheumatol 18, 559–574 (2022). https://doi.org/10.1038/s41584-022-00819-y

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