Damage and Disease Burden on Quality of Life

Only 11–14% of patients surviving GPA remain without any damage [186]. Among the most frequent complaints and damage after 10 years of follow-up are dyspnea (46% of survivors), hearing loss (30–45%), hypertension (31%), and nasal deformities (23%) [48]. The socio-professional impact of GPA is substantial: only 44% of patients are able to continue or return to work after diagnosis and treatment. Finally, late complications, such as late cancers or early atherosclerosis, responsible for late cardiovascular events, have become frequent and may continue to increase with improved patient survival [91, 187]. Thus, regular cardiovascular monitoring seems essential.

Conclusions

GPA is a severe and potentially life-threatening disease, which often becomes and follows the path of a chronic disease with a risk of relapse in survivors. With proper and prolonged treatment, patient survival exceeds 80% at 5 years. Based on advances in our understanding of the pathogenesis of the disease, and many epidemiological and clinical studies, more effective drugs have been developed over the past decade, and newer ones are upcoming. Rituximab has almost become the standard for both induction, in combination with glucocorticoids, and maintenance therapies, although older immunosuppressive drugs such as cyclophosphamide are still used and, often, useful. New drugs, such as avacopan, will certainly be incorporated into the treatment of patients with GPA, which will allow for a more limited use of glucocorticoids, thus having less complications. Other strategies should increasingly target each manifestation of the disease and, ultimately, each patient, individually. Better treatments to prevent ear, nose, and throat erosive lesions and nasal deformities for subglottic and bronchial stenoses are still needed. More therapeutic trials need to be conducted, on an international level, to further improve the generalizability of results and patient outcomes.

Clinical Vignette

A 30-year-old female was hospitalized for recentonset fatigue and dyspnea. She also had recurrent episodes of sinus and ear pain for the prior 6 months and intermittent nose bleeds. On examination, she had nasal mucosa ulcerations and bilateral chest rales. Initial laboratory tests revealed a hemoglobin level of 6.5 g/dL, a serum creatinine level of 2.0 mg/dL (176 μmol/L), and an erythrocyte sedimentation rate of 78 mm/h. Her urine sediment analysis revealed

microscopic hematuria and several red blood cell casts. A chest computed tomography showed bilateral lung infltrates and nodules, up to 25 mm in diameter. Further tests revealed positive anti-neutrophil cytoplasm antibodies (ANCAs) against proteinase 3 (PR3) in ELISA. A diagnosis of granulomatosis with polyangiitis (GPA) was made, and a treatment with rituximab (1 g on Day 1 and Day 15) and glucocorticoids was initiated. The patient had excellent response to therapy, and, 6 months later, glucocorticoids were stopped. The patient remained asymptomatic, with repeat rituximab infusions (500 mg) every 6 months for maintenance for 2 years.

Four years later, off medications, she presents for a routine follow-up visit. She has had polyarthralgia, moderate leg edema, bloody-tinged rhinorrhea, dry cough, and bilateral ear fullness for the past couple of weeks. Her serum hemoglobin is 12 g/dL, serum creatinine is 3.5 mg/dL (309 μmol/L), and C-reactive protein is >200 mg/L. A diagnosis of GPA relapse is suspected.

References

1.\Falk RJ, Gross WL, Guillevin L, Hoffman G, Jayne DR, Jennette JC, et al. Granulomatosis with polyangiitis (Wegener’s): an alternative name for Wegener’s granulomatosis. J Am Soc Nephrol. 2011;22(4):587–8.

2.\Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 1994;37(2):187–92.

3.\Mohammad AJ, Jacobsson LT, Westman KW, Sturfelt G, Segelmark M. Incidence and survival rates in Wegener’s granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and polyarteritis nodosa. Rheumatology. 2009;48(12):1560–5.

4.\Nilsen AT, Karlsen C, Bakland G, Watts R, Luqmani R, Koldingsnes W. Increasing incidence and prevalence of ANCA-­ associated vasculitis in Northern Norway. Rheumatology (Oxford). 2019;59:2316.

5.\Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116(6):488–98.

6.\Wilde B, van Paasen P, Witzke O, Tervaert JW. New pathophysiological insights and treatment of ANCA-associated vasculitis. Kidney Int. 2011;79(6):599–612.

7.\Demirkaya E, Arici ZS, Romano M, Berard RA, Aksentijevich I. Current state of precision medicine in primary systemic vasculitides. Front Immunol. 2019;10:2813.

8.\Wallace ZS, Stone JH. Personalized medicine in ANCA-­ associated vasculitis ANCA specifcity as the guide? Front Immunol. 2019;10:2855.

9.\Smith RM, Jones RB, Jayne DR. Progress in treatment of ANCA-­ associated vasculitis. Arthritis Res Ther. 2012;14(2):210.

10.\Quinn KA, Gelbard A, Sibley C, Sirajuddin A, Ferrada MA, Chen M, et al. Subglottic stenosis and endobronchial disease

in granulomatosis with polyangiitis. Rheumatology (Oxford). 2019;58(12):2203–11.

11.\Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend WP, et al. The American College of Rheumatology 1990 criteria for the classifcation of Wegener’s granulomatosis. Arthritis Rheum. 1990;33(8):1101–7.

12.\Falk RJ, Gross WL, Guillevin L, Hoffman GS, Jayne DR, Jennette JC, et al. Granulomatosis with polyangiitis (Wegener’s): an alternative name for Wegener’s granulomatosis. Arthritis Rheum. 2011;63(4):863–4.

13.\Jennette J, Falk R, Bacon P, Basu N, Cid M, Ferrario F, et al. 2012 Revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Arthritis Rheum. 2013;65:1.

14.\Craven A, Robson J, Ponte C, Grayson PC, Suppiah R, Judge A, et al. ACR/EULAR-endorsed study to develop Diagnostic and Classifcation Criteria for Vasculitis (DCVAS). Clin Exp Nephrol. 2013;17(5):619–21.

15.\Hellmich B, Lamprecht P, Spearpoint P, Gotte D, Deichmann A, Buchholz I, et al. New insights into the epidemiology of ANCA-­ associated vasculitides in Germany: results from a claims data study. Rheumatology (Oxford). 2021;60:4868.

16.\Watts RA, Mooney J, Skinner J, Scott DG, Macgregor AJ. The contrasting epidemiology of granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis. Rheumatology (Oxford). 2012;51(5):926–31.

17.\van der Woude FJ. Anticytoplasmic antibodies in Wegener’s granulomatosis. Lancet. 1985;2(8445):48.

18.\Mahr A, Artigues N, Coste J, Aouba A, Pagnoux C, Guillevin L. Seasonal variations in onset of Wegener’s granulomatosis: increased in summer? J Rheumatol. 2006;33(8):1615–22.

19.\Duna GF, Cotch MF, Galperin C, Hoffman DB, Hoffman GS. Wegener’s granulomatosis: role of environmental exposures. Clin Exp Rheumatol. 1998;16(6):669–74.

20.\Reinhold-Keller E, Herlyn K, Wagner-Bastmeyer R, Gut eisch J, Peter HH, Raspe HH, et al. No difference in the incidences of vasculitides between north and south Germany: frst results of the German vasculitis register. Rheumatology (Oxford). 2002;41(5):540–9.

21.\Gatenby PA, Lucas RM, Engelsen O, Ponsonby AL, Clements M. Antineutrophil cytoplasmic antibody-associated vasculitides: could geographic patterns be explained by ambient ultraviolet radiation? Arthritis Rheum. 2009;61(10):1417–24.

22.\Knight A, Sandin S, Askling J. Increased risk of autoimmune disease in families with Wegener’s granulomatosis. J Rheumatol. 2010;37(12):2553–8.

23.\Stone JH. Limited versus severe Wegener’s granulomatosis: baseline data on patients in the Wegener’s granulomatosis etanercept trial. Arthritis Rheum. 2003;48(8):2299–309.

24.\Wieczorek S, Holle JU, Epplen JT. Recent progress in the genetics of Wegener’s granulomatosis and Churg-Strauss syndrome. Curr Opin Rheumatol. 2010;22(1):8–14.

25.\Monach PA, Merkel PA. Genetics of vasculitis. Curr Opin Rheumatol. 2010;22(2):157–63.

26.\Lyons PA, Rayner TF, Trivedi S, Holle JU, Watts RA, Jayne DR, et al. Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med. 2012;367(3):214–23.

27.\Pagnoux C, Springer J. Editorial: Classifying antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides according to ANCA type or phenotypic diagnosis: salt or pepper? Arthritis Rheum. 2016;68(12):2837–40.

28.\Jennette JC, Falk RJ, Gasim AH. Pathogenesis of antineutrophil cytoplasmic autoantibody vasculitis. Curr Opin Nephrol

Dutch Co-Trimoxazole Wegener Study Group. N Engl J Med. 1996;335(1):16–20.

30.\Pendergraft WF III, Preston GA, Shah RR, Tropsha A, Carter CW Jr, Jennette JC, et al. Autoimmunity is triggered by cPR- 3(105-­201), a protein complementary to human autoantigen pro- teinase-­3. Nat Med. 2004;10(1):72–9.

31.\Hamidou MA, Audrain M, Ninin E, Robillard N, Muller JY, Bonneville M. Staphylococcus aureus, T-cell repertoire, and Wegener’s granulomatosis. Joint Bone Spine. 2001;68(5):373–7.

32.\Kain R, Exner M, Brandes R, Ziebermayr R, Cunningham D, Alderson CA, et al. Molecular mimicry in pauciimmune focal necrotizing glomerulonephritis. Nat Med. 2008;14(10):1088–96.

33.\Kronbichler A, Blane B, Holmes MA, Wagner J, Parkhill J, Peacock SJ, et al. Nasal carriage of Staphylococcus pseudintermedius in patients with granulomatosis with polyangiitis. Rheumatology (Oxford). 2019;58(3):548–50.

34.\Rhee RL, Lu J, Bittinger K, Lee JJ, Mattei LM, Sreih AG, et al. Dynamic changes in the nasal microbiome associated with disease activity in patients with granulomatosis with polyangiitis. Arthritis Rheum. 2021;73:1703.

35.\Rhee RL, Sreih AG, Najem CE, Grayson PC, Zhao C, Bittinger K, et al. Characterisation of the nasal microbiota in granulomatosis with polyangiitis. Ann Rheum Dis. 2018;77(10):1448–53.

36.\Wagner J, Harrison EM, Martinez Del Pero M, Blane B, Mayer G, Leierer J, et al. The composition and functional protein subsystems of the human nasal microbiome in granulomatosis with polyangiitis: a pilot study. Microbiome. 2019;7(1):137.

37.\Pfster H, Ollert M, Frohlich LF, Quintanilla-Martinez L, Colby TV, Specks U, et al. Antineutrophil cytoplasmic autoantibodies against the murine homolog of proteinase 3 (Wegener autoantigen) are pathogenic in vivo. Blood. 2004;104(5):1411–8.

38.\Primo VC, Marusic S, Franklin CC, Goldmann WH, Achaval CG, Smith RN, et al. Anti-PR3 immune responses induce segmental and necrotizing glomerulonephritis. Clin Exp Immunol. 2010;159(3):327–37.

39.\Little MA, Al-Ani B, Ren S, Al-Nuaimi H, Leite M Jr, Alpers CE, et al. Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system. PLoS One. 2012;7(1):e28626.

40.\Espy C, Morelle W, Kavian N, Grange P, Goulvestre C, Viallon V, et al. Sialylation levels of anti-proteinase 3 antibodies are associated with the activity of granulomatosis with polyangiitis (Wegener’s). Arthritis Rheum. 2011;63(7):2105–15.

41.\Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221–32.

42.\Jones RB, Ferraro AJ, Chaudhry AN, Brogan P, Salama AD, Smith KG, et al. A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2009;60(7):2156–68.

43.\Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, et al. Rituximab versus cyclophosphamide in ANCA-­associated renal vasculitis. N Engl J Med. 2010;363(3):211–20.

44.\Hong Y, Eleftheriou D, Hussain AA, Price-Kuehne FE, Savage CO, Jayne D, et al. Anti-neutrophil cytoplasmic antibodies stimulate release of neutrophil microparticles. J Am Soc Nephrol. 2012;23(1):49–62.

45.\Pang YP, Casal Moura M, Thompson GE, Nelson DR, Hummel AM, Jenne DE, et al. Remote activation of a latent epitope in an autoantigen decoded with simulated B-factors. Front Immunol. 2019;10:2467.

46.\Xiao H, Dairaghi DJ, Powers JP, Ertl LS, Baumgart T, Wang Y, et al. C5a receptor (CD88) blockade protects against MPO-ANCA GN. J Am Soc Nephrol. 2014;25(2):225–31.

47.\Chen M, Kallenberg CG. ANCA-associated vasculitides--ad- vances in pathogenesis and treatment. Nat Rev Rheumatol. 2010;6(11):653–64.

48.\Abdou NI, Kullman GJ, Hoffman GS, Sharp GC, Specks U, McDonald T, et al. Wegener’s granulomatosis: survey of 701 patients in North America. Changes in outcome in the 1990s. J Rheumatol. 2002;29(2):309–16.

49.\Pagnoux C, Wolter NE. Vasculitis of the upper airways. Swiss Med Wkly. 2012;142:w13541.

50.\Langford CA, Sneller MC, Hallahan CW, Hoffman GS, Kammerer WA, Talar-Williams C, et al. Clinical features and therapeutic management of subglottic stenosis in patients with Wegener’s granulomatosis. Arthritis Rheum. 1996;39(10):1754–60.

51.\Hervier B, Pagnoux C, Renaudin K, Masseau A, Pottier P, Planchon B et al. [Endobronchial stenosis in Wegener’s granulomatosis]. Rev Med Interne 2006;27:453.

52.\Devaney KO, Travis WD, Hoffman G, Leavitt R, Lebovics R, Fauci AS. Interpretation of head and neck biopsies in Wegener’s granulomatosis. A pathologic study of 126 biopsies in 70 patients. Am J Surg Pathol. 1990;14(6):555–64.

53.\Duna GF, Calabrese LH. Limitations of invasive modalities in the diagnosis of primary angiitis of the central nervous system. J Rheumatol. 1995;22(4):662–7.

54.\Cordier JF, Valeyre D, Guillevin L, Loire R, Brechot JM. Pulmonary Wegener’s granulomatosis. A clinical and imaging study of 77 cases. Chest. 1990;97(4):906–12.

55.\Russell B, Mohan S, Chahal R, Carette S, Pagnoux C. Prognostic signifcance of cavitary lung nodules in granulomatosis with polyangiitis (Wegener’s): a clinical imaging study of 225 patients. Arthritis Care Res. 2018;70(7):1082–9.

56.\Mohammad AJ, Mortensen KH, Babar J, Smith R, Jones RB, Nakagomi D, et al. Pulmonary involvement in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis: the in uence of ANCA subtype. J Rheumatol. 2017;44(10):1458–67.

57.\Iudici M, Pagnoux C, Courvoisier DS, Cohen P, Hamidou M, Aouba A, et al. Granulomatosis with polyangiitis: study of 795 patients from the French Vasculitis Study Group registry. Semin Arthritis Rheum. 2021;51(2):339–46.

58.\Papo M, Sinico RA, Teixeira V, Venhoff N, Urban ML, Iudici M, et al. Signifcance of PR3-ANCA positivity in eosinophilic granulomatosis with polyangiitis (Churg-Strauss). Rheumatology (Oxford). 2020;60:4355.

59.\Kawashima H, Utsugi A, Shibamiya A, Iida K, Mimura N, Ohashi H, et al. Consideration concerning similarities and differences between ANCA-associated vasculitis and IgG-4-related diseases: case series and review of literature. Immunol Res. 2019;67(1):99–107.

60.\Danlos FX, Rossi GM, Blockmans D, Emmi G, Kronbichler A, Durupt S, et al. Antineutrophil cytoplasmic antibody-associated vasculitides and IgG4-related disease: a new overlap syndrome. Autoimmun Rev. 2017;16(10):1036–43.

61.\Berden AE, Ferrario F, Hagen EC, Jayne DR, Jennette JC, Joh K, et al. Histopathologic classifcation of ANCA-associated glomerulonephritis. J Am Soc Nephrol. 2010;21(10):1628–36.

62.\Villa-Forte A, Hoffman GS. Wegener’s granulomatosis presenting with a renal mass. J Rheumatol. 1999;26(2):457–8.

63.\Dufour JF, Le Gallou T, Cordier JF, Aumaitre O, Pinede L, Aslangul E, et al. Urogenital manifestations in Wegener granulomatosis: a study of 11 cases and review of the literature. Medicine (Baltimore). 2012;91(2):67–74.

64.\Faurschou M, Mellemkjaer L, Sorensen IJ, Thomsen BS, Dreyer L, Baslund B. Cancer preceding Wegener’s granulomatosis: a case-control study. Rheumatology (Oxford). 2009;48(4):421–4.

65.\Faurschou M, Sorensen IJ, Mellemkjaer L, Loft AG, Thomsen BS, Tvede N, et al. Malignancies in Wegener’s granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients. J Rheumatol. 2008;35(1):100–5.

66.\Pagnoux C, Guillevin L. Peripheral neuropathy in systemic vasculitides. Curr Opin Rheumatol. 2005;17(1):41–8.

67.\Seror R, Mahr A, Ramanoelina J, Pagnoux C, Cohen P, Guillevin L. Central nervous system involvement in Wegener granulomatosis. Medicine (Baltimore). 2006;85(1):54–65.

68.\De Luna G, Terrier B, Kaminsky P, Le Quellec A, Maurier F, Solans R, et al. Central nervous system involvement of granulomatosis with polyangiitis: clinical-radiological presentation distinguishes different outcomes. Rheumatology (Oxford). 2015;54(3):424–32.

69.\Pagnoux C, Guillevin L. Neurologic manifestations of ANCA-­ associated vasculitides and polyarteritis nodosa. In: Erkan D, Levine SR, editors. The neurologic involvement in systemic autoimmune disorders. Amsterdam: Elsevier Science; 2004. p. 131–60.

70.\Francès C, Lê Thi Huong D, Piette JC, Saada V, Boisnic S, Wechsler B, et al. Wegener’s granulomatosis. Dermatological manifestations in 75 cases with clinicopathologic correlation. Arch Dermatol. 1994;130(7):861–7.

71.\Barksdale SK, Hallahan CW, Kerr GS, Fauci AS, Stern JB, Travis WD. Cutaneous pathology in Wegener’s granulomatosis. A clinicopathologic study of 75 biopsies in 46 patients. Am J Surg Pathol. 1995;19(2):161–72.

72.\Watkins AS, Kempen JH, Choi D, Liesegang TL, Pujari SS, Newcomb C, et al. Ocular disease in patients with ANCA-positive vasculitis. J Ocul Biol Dis Infor. 2009;3(1):12–9.

73.\Walton EW. Giant-cell granuloma of the respiratory tract (Wegener’s granulomatosis). Br Med J. 1958;2:265–70.

74.\McGeoch L, Carette S, Cuthbertson D, Hoffman GS, Khalidi N, Koening CL, et al. Cardiac involvement in granulomatosis with polyangiitis. J Rheumatol. 2015;42(7):1209–12.

75.\Pagnoux C, Guillevin L. Cardiac involvement in small and medium-sized vessel vasculitides. Lupus. 2005;14(9):718–22.

76.\Pagnoux C, Mahr A, Cohen P, Guillevin L. Presentation and outcome of gastrointestinal involvement in systemic necrotizing vasculitides: analysis of 62 patients with polyarteritis nodosa, microscopic polyangiitis, Wegener granulomatosis, Churg-Strauss syndrome, or rheumatoid arthritis-associated vasculitis. Medicine (Baltimore). 2005;84(2):115–28.

77.\Gendreau S, Porcher R, Thoreau B, Paule R, Maurier F, Goulenok T, et al. Characteristics and risk factors for poor outcome in patients with systemic vasculitis involving the gastrointestinal tract. Semin Arthritis Rheum. 2021;51(2):436–41.

78.\Tao JJ, Agarwal A, Cuperfain AB, Pagnoux C. Granulomatosis with polyangiitis presenting as pancreatic disease. BMJ Case Rep. 2021;14(3):e241033.

79.\Clowse ME, Copland SC, Hsieh TC, Chow SC, Hoffman GS, Merkel PA, et al. Ovarian reserve diminished by oral cyclophosphamide therapy for granulomatosis with polyangiitis (Wegener’s). Arthritis Care Res. 2011;63(12):1777–81.

80.\Ross C, D’Souza R, Pagnoux C. Pregnancy outcomes in systemic vasculitides. Curr Rheumatol Rep. 2020;22(10):63.

81.\Pagnoux C, Le Guern V, Goffnet F, Diot E, Limal N, Pannier E, et al. Pregnancies in systemic necrotizing vasculitides: report on 12 women and their 20 pregnancies. Rheumatology (Oxford). 2011;50(5):953–61.

82.\Nguyen V, Wuebbolt D, Pagnoux C, D’Souza R. Pregnancy outcomes in women with primary systemic vasculitis: a retrospective study. J Matern Fetal Neonatal Med. 2019;34:1–7.

83.\Machen L, Clowse ME. Vasculitis and pregnancy. Rheum Dis Clin N Am. 2017;43(2):239–47.

84.\Allenbach Y, Seror R, Pagnoux C, Teixeira L, Guilpain P, Guillevin L. High frequency of venous thromboembolic events in Churg-­Strauss syndrome, Wegener’s granulomatosis and microscopic polyangiitis but not polyarteritis nodosa: a systematic retrospective study on 1130 patients. Ann Rheum Dis. 2009;68(4):564–7.

85.\Merkel PA, Lo GH, Holbrook JT, Tibbs AK, Allen NB, Davis JC Jr, et al. Brief communication: high incidence of venous thrombotic events among patients with Wegener granulomatosis: the Wegener’s Clinical Occurrence of Thrombosis (WeCLOT) Study. Ann Intern Med. 2005;142(8):620–6.

86.\Berti A, Matteson EL, Crowson CS, Specks U, Cornec D. Risk of cardiovascular disease and venous thromboembolism among patients with incident ANCA-associated vasculitis: a 20-year population-­based cohort study. Mayo Clin Proc. 2018;93:697.

87.\Liapi M, Jayne D, Merkel PA, Segelmark M, Mohammad AJ. Venous thromboembolism in ANCA-associated vasculitis. A population-based cohort study. Rheumatology (Oxford). 2021;60:4616.

88.\Moiseev S, Kronbichler A, Makarov E, Bulanov N, Crnogorac M, Direskeneli H, et al. Association of venous thromboembolic events with skin, pulmonary and kidney involvement in ANCA-­ associated vasculitis: a multinational study. Rheumatology (Oxford). 2021;60:4654.

89.\Berden AE, Nolan SL, Morris HL, Bertina RM, Erasmus DD, Hagen EC, et al. Anti-plasminogen antibodies compromise fbrinolysis and associate with renal histology in ANCA-associated vasculitis. J Am Soc Nephrol. 2010;21(12):2169–79.

90.\Borowiec A, Hadzik-Blaszczyk M, Kowalik I, Rusinowicz T, Krupa R, Jankowski J, et al. High incidence of venous thromboembolism but not of coronary artery disease in granulomatosis with polyangiitis in frst years after diagnosis. Sarcoidosis Vasc Diffuse Lung Dis. 2019;36(3):202–8.

91.\Pagnoux C, Chironi G, Simon A, Guillevin L. Atherosclerosis in ANCA-associated vasculitides. Ann N Y Acad Sci. 2007;1107:11–21.

92.\Barreto P, Pagnoux C, Luca L, Aouizerate J, Ortigueira I, Cohen P, et al. Dorsal prevertebral lesions in Wegener granulomatosis: report on four cases. Joint Bone Spine. 2011;78(1):88–91.

93.\Perichon S, Pagnoux C, Seror R, Dassonville L, Mangouka L, Cohen P et al. [Periostitis in systemic necrotizing vasculitides: study of the 4 cases identifed among the 1762 patients of the FVSG database and review of the literature]. Presse Med 2010;39(7–8): e165–73.

94.\Hellmich B, Flossmann O, Gross WL, Bacon P, Cohen-Tervaert JW, Guillevin L, et al. EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis: focus on anti-neutrophil cytoplasm antibody-associated vasculitis. Ann Rheum Dis. 2007;66(5):605–17.

95.\de Groot K, Rasmussen N, Bacon PA, Tervaert JW, Feighery C, Gregorini G, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005;52(8):2461–9.

96.\Hoffman GS. Immunosuppressive therapy is always required for the treatment of limited Wegener’s granulomatosis. Sarcoidosis Vasc Diffuse Lung Dis. 1996;13(3):249–52.

97.\Holle JU, Gross WL, Holl-Ulrich K, Ambrosch P, Noelle B, Both M, et al. Prospective long-term follow-up of patients with localised Wegener’s granulomatosis: does it occur as persistent disease stage? Ann Rheum Dis. 2010;69(11):1934–9.

98.\Pagnoux C, Stubbe M, Lifermann F, Decaux O, Pavic M, Berezne A, et al. Wegener’s granulomatosis strictly and persistently localized to one organ is rare: assessment of 16 patients from the French Vasculitis Study Group database. J Rheumatol. 2011;38(3):475–8.

99.\Ozen S, Pistorio A, Iusan SM, Bakkaloglu A, Herlin T, Brik R, et al. EULAR/PRINTO/PRES criteria for Henoch-Schonlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classifcation criteria. Ann Rheum Dis. 2010;69(5):798–806.

100.\Cabral DA, Canter DL, Muscal E, Nanda K, Wahezi DM, Spalding SJ, et al. Comparing presenting clinical features in 48 children with microscopic polyangiitis to 183 children who have granulomatosis with polyangiitis (Wegener’s): an ARChiVe Cohort study. Arthritis Rheum. 2016;68(10):2514–26.

101.\Akikusa JD, Schneider R, Harvey EA, Hebert D, Thorner PS, Laxer RM, et al. Clinical features and outcome of pediatric Wegener’s granulomatosis. Arthritis Rheum. 2007;57(5):837–44.

102.\Milman N, Smith CD. Cutaneous vasculopathy associated with cocaine use. Arthritis Care Res. 2011;63(8):1195–202.

103.\Koldingsnes W, Nossent JC. Baseline features and initial treatment as predictors of remission and relapse in Wegener’s granulomatosis. J Rheumatol. 2003;30(1):80–8.

104.\Izzedine H, Cacoub P, Launay-Vacher V, Bagnis C, Deray G. Lymphopenia in Wegener’s granulomatosis. A new clinical activity index? Nephron. 2002;92(2):466–71.

105.\Bossuyt X, Cohen Tervaert JW, Arimura Y, Blockmans D, Flores-­ Suarez LF, Guillevin L, et al. Position paper: revised 2017 international consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis. Nat Rev Rheumatol. 2017;13(11):683–92.

106.\Mendel A, Ennis D, Go E, Bakowsky V, Baldwin C, Benseler SM, et al. CanVasc consensus recommendations for the management of antineutrophil cytoplasm antibody-associated vasculitis: 2020 update. J Rheumatol. 2020;48:555.

107.\Specks U. The growing complexity of the pathology associated with cocaine use. J Clin Rheumatol. 2011;17(4):167–8.

108.\Levy JB, Hammad T, Coulthart A, Dougan T, Pusey CD. Clinical features and outcome of patients with both ANCA and anti-GBM antibodies. Kidney Int. 2004;66(4):1535–40.

109.\Unlu C, Willems M, Ten Berge IJ, Legemate DA. Aortitis with aneurysm formation as a rare complication of Wegener’s granulomatosis. J Vasc Surg. 2011;54(5):1485–7.

110.\Duna GF, Galperin C, Hoffman GS. Wegener’s granulomatosis. Rheum Dis Clin N Am. 1995;21(4):949–86.

111.\Hamidou MA, Moreau A, Toquet C, El Kouri D, de Faucal P, Grolleau JY. Temporal arteritis associated with systemic necrotizing vasculitis. J Rheumatol. 2003;30(10):2165–9.

112.\Luqmani RA, Bacon PA, Moots RJ, Janssen BA, Pall A, Emery P, et al. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM. 1994;87(11):671–8.

113.\Stone JH, Hoffman GS, Merkel PA, Min YI, Uhlfelder ML, Hellmann DB, et al. A disease-specifc activity index for Wegener’s granulomatosis: modifcation of the Birmingham Vasculitis Activity Score. International Network for the Study of the Systemic Vasculitides (INSSYS). Arthritis Rheum. 2001;44(4):912–20.

114.\de Groot K, Gross WL, Herlyn K, Reinhold-Keller E. Development and validation of a disease extent index for Wegener’s granulomatosis. Clin Nephrol. 2001;55(1):31–8.

115.\Guillevin L, Lhote F, Gayraud M, Cohen P, Jarrousse B, Lortholary O, et al. Prognostic factors in polyarteritis nodosa and Churg-­ Strauss syndrome. A prospective study in 342 patients. Medicine (Baltimore). 1996;75(1):17–28.

116.\Guillevin L, Pagnoux C, Seror R, Mahr A, Mouthon L, Le Toumelin P. The Five-Factor Score revisited: assessment of prognoses of systemic necrotizing vasculitides based on the French Vasculitis Study Group (FVSG) cohort. Medicine (Baltimore). 2011;90(1):19–27.

117.\Suppiah R, Flossman O, Mukhtyar C, Alberici F, Baslund B, Brown D, et al. Measurement of damage in systemic vasculitis: a comparison of the Vasculitis Damage Index with the Combined Damage Assessment Index. Ann Rheum Dis. 2011;70(1):80–5.

118.\Flossmann O, Berden A, de Groot K, Hagen C, Harper L, Heijl C, et al. Long-term patient survival in ANCA-associated vasculitis. Ann Rheum Dis. 2011;70(3):488–94.

119.\Merkel PA, Aydin SZ, Boers M, Direskeneli H, Herlyn K, Seo P, et al. The OMERACT core set of outcome measures for use in clinical trials of ANCA-associated vasculitis. J Rheumatol. 2011;38(7):1480–6.

120.\Mukhtyar C, Guillevin L, Cid MC, Dasgupta B, de Groot K, Gross W, et al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis. 2009;68(3):310–7.

121.\Walsh M, Merkel PA, Peh CA, Szpirt WM, Puechal X, Fujimoto S, et al. Plasma exchange and glucocorticoids in severe ANCA-­ associated vasculitis. N Engl J Med. 2020;382(7):622–31.

122.\McGregor JAC, Hogan SL, Hu Y, Jennette CE, Falk RJ, Nachman PH. GC use beyond 6 months does not prevent relapses but increases risk of infection. Clin Exp Immunol. 2011;164(Suppl 1):60–1.

123.\WGET. Wegener’s Granulomatosis Etanercept Trial Research Group. Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med. 2005;352(4):351–61.

124.\Walsh M, Merkel PA, Mahr A, Jayne D. Effects of duration of glucocorticoid therapy on relapse rate in antineutrophil cytoplasmic antibody-associated vasculitis: a meta-analysis. Arthritis Care Res. 2010;62(8):1166–73.

125.\Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniene J, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003;349(1):36–44.

126.\Guillevin L, Cordier JF, Lhote F, Cohen P, Jarrousse B, Royer I, et al. A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegener’s granulomatosis. Arthritis Rheum. 1997;40(12):2187–98.

127.\Monach PA, Arnold LM, Merkel PA. Incidence and prevention

2010;62(1):9–21.

cyclophosphamide­ -­treated patients with systemic necrotizing vasculitides. Arthritis Rheum. 2011;63(5):1435–45.

129.\de Groot K, Harper L, Jayne DR, Flores Suarez LF, Gregorini G, Gross WL, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-­ associated vasculitis: a randomized trial. Ann Intern Med. 2009;150(10):670–80.

130.\Harper L, Morgan MD, Walsh M, Hoglund P, Westman K, Flossmann O, et al. Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up. Ann Rheum Dis. 2012;71(6):955–60.

131.\Pagnoux C, Mahr A, Hamidou MA, Boffa JJ, Ruivard M, Ducroix JP, et al. Azathioprine or methotrexate maintenance for ANCA-­associated vasculitis. N Engl J Med. 2008;359(26): 2790–803.

132.\Specks U, Merkel PA, Seo P, Spiera R, Langford CA, Hoffman GS, et al. Effcacy of remission-induction regimens for ANCA-­ associated vasculitis. N Engl J Med. 2013;369(5):417–27.

133.\Holle JU, Dubrau C, Herlyn K, Heller M, Ambrosch P, Noelle B, et al. Rituximab for refractory granulomatosis with polyangiitis (Wegener’s granulomatosis): comparison of effcacy in granulomatous versus vasculitic manifestations. Ann Rheum Dis. 2011;71:327.

134.\Unizony S, Villarreal M, Miloslavsky EM, Lu N, Merkel PA, Spiera R, et al. Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type. Ann Rheum Dis. 2016;75(6):1166–9.

135.\Pepper RJ, McAdoo SP, Moran SM, Kelly D, Scott J, Hamour S, et al. A novel glucocorticoid-free maintenance regimen

for anti-neutrophil cytoplasm antibody-associated vasculitis. Rheumatology (Oxford). 2019;58(2):260–8.

136.\Farrah TE, Prendecki M, Hunter RW, Lahiri R, Cairns TD, Pusey CD, et al. Glucocorticoid-free treatment of severe anti-­ neutrophil cytoplasm antibody-associated vasculitis. Nephrol Dial Transplant. 2020;36:739.

137.\Sanders JS, Slot MC, Stegeman CA. Maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003;349(21):2072–3; author reply 3.

138.\Gopaluni S, Smith RM, Lewin M, McAlear CA, Mynard K, Jones RB, et al. Rituximab versus azathioprine as therapy for maintenance of remission for anti-neutrophil cytoplasm antibody-­ associated vasculitis (RITAZAREM): study protocol for a randomized controlled trial. Trials. 2017;18(1):112.

139.\Guillevin L, Pagnoux C, KarrasA, Khouatra C,Aumaitre O, Cohen P, et al. Rituximab versus azathioprine for maintenance in ANCA-­ associated vasculitis. N Engl J Med. 2014;371(19):1771–80.

140.\Smith RM, Jayne DR, Merkel PA. A randomized, controlled trial of rituximab versus azathioprine after induction of remission with rituximab for patients with ANCA associated vasculitis and relapsing disease. Arthritis Rheum. 2019;71(S10):1384–5.

141.\Charles P, Terrier B, Perrodeau E, Cohen P, Faguer S, Huart A, et al. Comparison of individually tailored versus fxed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2). Ann Rheum Dis. 2018;77(8):1143–9.

142.\Charles P, Dechartres A, Terrier B, Cohen P, Faguer S, Huart A, et al. Reducing the initial number of rituximab maintenance-­therapy infusions for ANCA-associated vasculitides: randomized-­trial post-hoc analysis. Rheumatology (Oxford). 2020;59(10):2970–5.

143.\Villa-Forte A, Clark TM, Gomes M, Carey J, Mascha E, Karafa MT, et al. Substitution of methotrexate for cyclophosphamide in Wegener granulomatosis: a 12-year single-practice experience. Medicine (Baltimore). 2007;86(5):269–77.

144.\Holle JU, Gross WL, Latza U, Nolle B, Ambrosch P, Heller M, et al. Improved outcome in 445 patients with Wegener’s granulomatosis in a German vasculitis center over four decades. Arthritis Rheum. 2011;63(1):257–66.

145.\Reinhold-Keller E, Beuge N, Latza U, de Groot K, Rudert H, Nolle B, et al. An interdisciplinary approach to the care of patients with Wegener’s granulomatosis: long-term outcome in 155 patients. Arthritis Rheum. 2000;43(5):1021–32.

146.\Stassen PM, Derks RP, Kallenberg CG, Stegeman CA. Thiopurinemethyltransferase (TPMT) genotype and TPMT activity in patients with anti-neutrophil cytoplasmic antibody-­ associated vasculitis: relation to azathioprine maintenance treatment and adverse effects. Ann Rheum Dis. 2009;68(5):758–9.

147.\Metzler C, Miehle N, Manger K, Iking-Konert C, de Groot K, Hellmich B, et al. Elevated relapse rate under oral methotrexate versus le unomide for maintenance of remission in Wegener’s granulomatosis. Rheumatology (Oxford). 2007;46(7):1087–91.

148.\Nowack R, Gobel U, Klooker P, Hergesell O, Andrassy K, van der Woude FJ. Mycophenolate mofetil for maintenance therapy of Wegener’s granulomatosis and microscopic polyangiitis: a pilot study in 11 patients with renal involvement. J Am Soc Nephrol. 1999;10(9):1965–71.

149.\Langford CA, Talar-Williams C, Sneller MC. Mycophenolate mofetil for remission maintenance in the treatment of Wegener’s granulomatosis. Arthritis Rheum. 2004;51(2):278–83.

150.\Hiemstra TF, Walsh M, Mahr A, Savage CO, de Groot K, Harper L, et al. Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibodyassociated vasculitis: a randomized controlled trial. JAMA. 2010;304(21):2381–8.

151.\Charles P, Perrodeau E, Samson M, Bonnotte B, Hamidou M, Agard C, et al. Comparison between long-term and conventional

rituximab-maintenance treatments: results of a placebo-controlled randomized trial. Arthritis Rheum. 2019;71(S10):4655–6.

152.\DeRemee RA. Trimethoprim-sulphamethoxazole for the treatment of Wegener’s granulomatosis. Rheumatology (Oxford). 2003;42(2):396; author reply 7.

153.\de Groot K, Reinhold-Keller E, Tatsis E, Paulsen J, Heller M, Nolle B, et al. Therapy for the maintenance of remission in sixty-fve patients with generalized Wegener’s granulomatosis. Methotrexate versus trimethoprim/sulfamethoxazole. Arthritis Rheum. 1996;39(12):2052–61.

154.\Song GG, Lee YH. Comparative effcacy and safety of mycophenolate mofetil versus cyclophosphamide in patients with active antineutrophil cytoplasmic antibody-associated vasculitis: a meta-­ analysis of randomized trials. Z Rheumatol. 2020;80:425.

155.\Jayne DR, Chapel H, Adu D, Misbah S, O’Donoghue D, Scott D, et al. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. QJM. 2000;93(7):433–9.

156.\Jayne DR, Gaskin G, Rasmussen N, Abramowicz D, Ferrario F, Guillevin L, et al. Randomized trial of plasma exchange or high-­ dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol. 2007;18(7):2180–8.

157.\Jayne DRW, Bruchfeld AN, Harper L, Schaier M, Venning MC, Hamilton P, et al. Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitis. J Am Soc Nephrol. 2017;28(9):2756–67.

158.\Merkel PA, Niles J, Jimenez R, Spiera RF, Rovin BH, Bomback A, et al. Adjunctive treatment with avacopan, an oral C5a receptor inhibitor, in patients with antineutrophil cytoplasmic antibody-­associated vasculitis. ACR Open Rheumatol. 2020;2(11):662–71.

159.\Jayne DRW, Merkel PA, Schall TJ, Bekker P, Group AS. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med. 2021;384(7):599–609.

160.\Ennis D, Yeung RS, Pagnoux C. Long-term use and remission of granulomatosis with polyangiitis with the oral C5a receptor inhibitor avacopan. BMJ Case Rep. 2020;13(10):e236236.

161.\Langford CA, Monach PA, Specks U, Seo P, Cuthbertson D, McAlear CA, et al. An open-label trial of abatacept (CTLA4-Ig) in non-severe relapsing granulomatosis with polyangiitis (Wegener’s). Ann Rheum Dis. 2014;73(7):1376–9.

162.\Monti S, Delvino P, Riboli M, Rebuff C, Xoxi B, De Silvestri A, et al. The role of Trimethoprim/sulfamethoxazole in reducing relapses and risk of infections in ANCA-associated vasculitis: a meta-analysis. Rheumatology (Oxford). 2021;60:3553.

163.\Kronbichler A, Kerschbaum J, Gopaluni S, Tieu J, Alberici F, Jones RB, et al. Trimethoprim-sulfamethoxazole prophylaxis prevents severe/life-threatening infections following rituximab in antineutrophil cytoplasm antibody-associated vasculitis. Ann Rheum Dis. 2018;77(10):1440–7.

164.\Walsh M, Chaudhry A, Jayne D. Long-term follow-up of relapsing/refractory anti-neutrophil cytoplasm antibody associated vasculitis treated with the lymphocyte depleting antibody alemtuzumab (CAMPATH-1H). Ann Rheum Dis. 2008;67(9):1322–7.

165.\Flossmann O, Jayne DR. Long-term treatment of relapsing Wegener’s granulomatosis with 15-deoxyspergualin. Rheumatology (Oxford). 2010;49(3):556–62.

166.\Booth A, Harper L, Hammad T, Bacon P, Griffth M, Levy J, et al. Prospective study of TNFalpha blockade with in iximab in anti-­ neutrophil cytoplasmic antibody-associated systemic vasculitis. J Am Soc Nephrol. 2004;15(3):717–21.

167.\Silva F, Seo P, Schroeder DR, Stone JH, Merkel PA, Hoffman GS, et al. Solid malignancies among etanercept-treated patients with granulomatosis with polyangiitis (Wegener’s): long-term followup of a multicenter longitudinal cohort. Arthritis Rheum. 2011;63(8):2495–503.

168.\Pagnoux C, Guillevin L. How can patient care be improved beyond medical treatment? Best Pract Res Clin Rheumatol. 2005;19(2):337–44.

169.\Holvast A, de Haan A, van Assen S, Stegeman CA, Huitema MG, Huckriede A, et al. Cell-mediated immune responses to in u- enza vaccination in Wegener’s granulomatosis. Ann Rheum Dis. 2010;69(5):924–7.

170.\Saad CG, Borba EF, Aikawa NE, Silva CA, Pereira RM, Calich AL, et al. Immunogenicity and safety of the 2009 non-adjuvanted in uenza A/H1N1 vaccine in a large cohort of autoimmune rheumatic diseases. Ann Rheum Dis. 2011;70(6):1068–73.

171.\Seror R, Pagnoux C, Ruivard M, Landru I, Wahl D, Riviere S, et al. Treatment strategies and outcome of induction-refractory Wegener’s granulomatosis or microscopic polyangiitis: analysis of 32 patients with frst-line induction-refractory disease in the WEGENT trial. Ann Rheum Dis. 2010;69(12):2125–30.

172.\Faurschou M, Mellemkjaer L, Sorensen IJ, Svalgaard Thomsen B, Dreyer L, Baslund B. Increased morbidity from ischemic heart disease in patients with Wegener’s granulomatosis. Arthritis Rheum. 2009;60(4):1187–92.

173.\Little MA, Nightingale P, Verburgh CA, Hauser T, De Groot K, Savage C, et al. Early mortality in systemic vasculitis: relative contribution of adverse events and active vasculitis. Ann Rheum Dis. 2010;69(6):1036–43.

174.\Casian A, Walsh M, Berden A, Jayne D. Alveolar haemorrhage in ANCA-AAV: an analysis of EUVAS trials. Clin Exp Immunol. 2011;164(Suppl 1):113.

175.\Pagnoux C, Hogan SL, Chin H, Jennette JC, Falk RJ, Guillevin L, et al. Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis: comparison of two independent cohorts. Arthritis Rheum. 2008;58(9):2908–18.

176.\Walsh M, Flossmann O, Berden A, Westman K, Hoglund P, Stegeman C, et al. Risk factors for relapse of antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2012;64(2):542–8.

177.\Lionaki S, Blyth ER, Hogan SL, Hu Y, Senior BA, Jennette CE, et al. Classifcation of antineutrophil cytoplasmic autoantibody vasculitides: the role of antineutrophil cytoplasmic autoantibody specifcity for myeloperoxidase or proteinase 3 in disease recognition and prognosis. Arthritis Rheum. 2012;64(10):3452–62.

178.\Slot MC, Tervaert JW, Boomsma MM, Stegeman CA. Positive classic antineutrophil cytoplasmic antibody (C-ANCA) titer at switch to azathioprine therapy associated with relapse in proteinase 3-related vasculitis. Arthritis Rheum. 2004;51(2):269–73.

179.\Lurati-Ruiz F, Spertini F. Predictive value of antineutrophil cytoplasmic antibodies in small-vessel vasculitis. J Rheumatol. 2005;32(11):2167–72.

180.\Finkielman JD, Merkel PA, Schroeder D, Hoffman GS, Spiera R, St Clair EW, et al. Antiproteinase 3 antineutrophil cytoplasmic antibodies and disease activity in Wegener granulomatosis. Ann Intern Med. 2007;147(9):611–9.

181.\Stegeman CA. 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 Transplant. 2002;17(12):2077–80.

182.\Boomsma MM, Stegeman CA, van der Leij MJ, Oost W, Hermans J, Kallenberg CG, et al. Prediction of relapses in Wegener’s granulomatosis by measurement of antineutrophil cytoplasmic antibody levels: a prospective study. Arthritis Rheum. 2000;43(9):2025–33.

183.\Tomasson G, Grayson PC, Mahr AD, Lavalley M, Merkel PA. Value of ANCA measurements during remission to predict a relapse of ANCA-associated vasculitis - a meta-analysis. Rheumatology (Oxford). 2012;51(1):100–9.

184.\Kemna MJ, Damoiseaux J, Austen J, Winkens B, Peters J, van Paassen P, et al. ANCA as a predictor of relapse: useful in patients

with renal involvement but not in patients with nonrenal disease. J Am Soc Nephrol. 2015;26(3):537–42.

185.\Monach PA, Merkel PA. Genetics of vasculitis. Curr Opin Rheumatol. 2011;22(2):157–63.

186.\Seo P, Min YI, Holbrook JT, Hoffman GS, Merkel PA, Spiera R, et al. Damage caused by Wegener’s granulomatosis and its

treatment: prospective data from the Wegener’s Granulomatosis Etanercept Trial (WGET). Arthritis Rheum. 2005;52(7):2168–78.

187.\Houben E, Mendel A, van der Heijden JW, Simsek S, Bax WA, Carette S, et al. Prevalence and management of cardiovascular risk factors in ANCA-associated vasculitis. Rheumatology (Oxford). 2019;58(12):2333–5.