Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Issues in trial design for ANCA-associated and large-vessel vasculitis


Randomized clinical trials (RCTs) have informed the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, although challenges still exist. The evidence base for treating large-vessel vasculitis (LVV) is weaker, but initiatives to standardize diagnostic criteria and outcome measures, and to validate biomarkers in LVV, together with newly initiated RCTs should start to address this need. In this Perspectives, we discuss the prerequisites for RCTs in vasculitis, existing trial evidence, continuing unmet needs, potential therapeutic avenues to explore and considerations in the design of future trials.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Potential therapeutic targets in AAV and LVV.


  1. 1

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

    CAS  Google Scholar 

  2. 2

    Hamour, S., Salama, A. D. & Pusey, C. D. Management of ANCA-associated vasculitis: current trends and future prospects. Ther. Clin. Risk Manag. 6, 253–264 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Robson, J. et al. Damage in the ANCA-associated vasculitides: long-term data from the European Vasculitis Study group (EUVAS) therapeutic trials. Ann. Rheum. Dis.

  4. 4

    Heijl, C. et al. Incidence of malignancy in patients treated for antineutrophil cytoplasm antibody-associated vasculitis: follow-up data from European Vasculitis Study Group clinical trials. Ann. Rheum. Dis. 70, 1415–1421 (2011).

    CAS  Article  Google Scholar 

  5. 5

    Unizony, S. H. et al. Design of the tocilizumab in giant cell arteritis trial. Int. J. Rheumatol. 2013, 912562 (2013).

    Article  Google Scholar 

  6. 6

    US National Library of Medicine. Clinical [online], (2013).

  7. 7

    Walsh, M. et al. Plasma exchange and glucocorticoid dosing in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis (PEXIVAS): protocol for a randomized controlled trial. Trials 14, 73 (2013).

    CAS  Article  Google Scholar 

  8. 8

    US National Library of Medicine. [online], (2013).

  9. 9

    Berry, D. A. Bayesian clinical trials. Nat. Rev. Drug Discov. 5, 27–36 (2006).

    CAS  Article  Google Scholar 

  10. 10

    US National Library of Medicine. [online], (2013).

  11. 11

    Basu, N. et al. EULAR points to consider in the development of classification and diagnostic criteria in systemic vasculitis. Ann. Rheum. Dis. 69, 1744–1750 (2010).

    Article  Google Scholar 

  12. 12

    Craven, A. et al. ACR/EULAR-endorsed study to develop Diagnostic and Classification Criteria for Vasculitis (DCVAS). Clin. Exp. Nephrol. 17, 619–621 (2013).

    CAS  Article  Google Scholar 

  13. 13

    Tervaert, J. W. et al. Association between active Wegener's granulomatosis and anticytoplasmic antibodies. Arch. Intern. Med. 149, 2461–2465 (1989).

    CAS  Article  Google Scholar 

  14. 14

    Seror, R. et al. Adalimumab for steroid sparing in patients with giant-cell arteritis: results of a multicentre randomised controlled trial. Ann. Rheum. Dis.

  15. 15

    Berden, A. E. et al. Histopathologic classification of ANCA-associated glomerulonephritis. J. Am. Soc. Nephrol. 21, 1628–1636 (2010).

    Article  Google Scholar 

  16. 16

    Merkel, P. A. et al. The OMERACT core set of outcome measures for use in clinical trials of ANCA-associated vasculitis. J. Rheumatol. 38, 1480–1486 (2011).

    Article  Google Scholar 

  17. 17

    Direskeneli, H. et al. Development of outcome measures for large-vessel vasculitis for use in clinical trials: opportunities, challenges, and research agenda. J. Rheumatol. 38, 1471–1479 (2011).

    Article  Google Scholar 

  18. 18

    Luqmani, R. A. et al. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM 87, 671–678 (1994).

    CAS  PubMed  Google Scholar 

  19. 19

    de Groot, K., Gross, W. L., Herlyn, K. & Reinhold-Keller, E. Development and validation of a disease extent index for Wegener's granulomatosis. Clin. Nephrol. 55, 31–38 (2001).

    CAS  PubMed  Google Scholar 

  20. 20

    Dolezalova, P. et al. Disease activity assessment in childhood vasculitis: development and preliminary validation of the Paediatric Vasculitis Activity Score (PVAS). Ann. Rheum. Dis. 72, 1628–1633 (2013).

    Article  Google Scholar 

  21. 21

    Exley, A. R. et al. Development and initial validation of the Vasculitis Damage Index for the standardized clinical assessment of damage in the systemic vasculitides. Arthritis Rheum. 40, 371–380 (1997).

    CAS  Article  Google Scholar 

  22. 22

    Suppiah, R. et al. Measurement of damage in systemic vasculitis: a comparison of the Vasculitis Damage Index with the Combined Damage Assessment Index. Ann. Rheum. Dis. 70, 80–85 (2011).

    Article  Google Scholar 

  23. 23

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

    CAS  Article  Google Scholar 

  24. 24

    Jones, R. B. et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N. Engl. J. Med. 363, 211–220 (2010).

    CAS  Article  Google Scholar 

  25. 25

    Tarzi, R. M. & Pusey, C. D. Vasculitis: Risks and rewards of treating elderly patients with vasculitis. Nat. Rev. Nephrol. 7, 253–255 (2011).

    Article  Google Scholar 

  26. 26

    Mello, M. M. et al. Preparing for responsible sharing of clinical trial data. N. Engl. J. Med. 369, 1651–1658 (2013).

    CAS  Article  Google Scholar 

  27. 27

    Nisen, P. & Rockhold, F. Access to patient-level data from GlaxoSmithKline clinical trials. N. Engl. J. Med. 369, 475–478 (2013).

    Article  Google Scholar 

  28. 28

    Fauci, A. S., Katz, P., Haynes, B. F. & Wolff, S. M. Cyclophosphamide therapy of severe systemic necrotizing vasculitis. N. Engl. J. Med. 301, 235–238 (1979).

    CAS  Article  Google Scholar 

  29. 29

    Faurschou, M. et al. Malignancies in Wegener's granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients. J. Rheumatol. 35, 100–105 (2008).

    CAS  PubMed  Google Scholar 

  30. 30

    Holle, J. U. et al. Improved outcome in 445 patients with Wegener's granulomatosis in a German vasculitis center over four decades. Arthritis Rheum. 63, 257–266 (2011).

    Article  Google Scholar 

  31. 31

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

    Article  Google Scholar 

  32. 32

    US National Library of Medicine. [online], (2012).

  33. 33

    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).

    CAS  Article  Google Scholar 

  34. 34

    Hogan, S. L. et al. Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis. Ann. Intern. Med. 143, 621–631 (2005).

    Article  Google Scholar 

  35. 35

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

    CAS  Article  Google Scholar 

  36. 36

    Falk, R. J. & Jennette, J. C. ANCA disease: where is this field heading? J. Am. Soc. Nephrol. 21, 745–752 (2010).

    CAS  Article  Google Scholar 

  37. 37

    de Groot, K. et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann. Intern. Med. 150, 670–680 (2009).

    Article  Google Scholar 

  38. 38

    Harper, L. et al. Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up. Ann. Rheum. Dis. 71, 955–960 (2012).

    CAS  Article  Google Scholar 

  39. 39

    Jayne, D. R. et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J. Am. Soc. Nephrol. 18, 2180–2188 (2007).

    CAS  Article  Google Scholar 

  40. 40

    Walsh, M. et al. Long-term follow-up of patients with severe ANCA-associated vasculitis comparing plasma exchange to intravenous methylprednisolone treatment is unclear. Kidney Int. 84, 397–402 (2013).

    CAS  Article  Google Scholar 

  41. 41

    US National Library of Medicine. [online], (2005).

  42. 42

    Little, M. A. et al. Early mortality in systemic vasculitis: relative contribution of adverse events and active vasculitis. Ann. Rheum. Dis. 69, 1036–1043 (2010).

    Article  Google Scholar 

  43. 43

    Watts, R. A., Lane, S. E., Bentham, G. & Scott, D. G. Epidemiology of systemic vasculitis: a ten-year study in the United Kingdom. Arthritis Rheum. 43, 414–419 (2000).

    CAS  Article  Google Scholar 

  44. 44

    Cohen, P. et al. Churg–Strauss syndrome with poor-prognosis factors: A prospective multicenter trial comparing glucocorticoids and six or twelve cyclophosphamide pulses in forty-eight patients. Arthritis Rheum. 57, 686–693 (2007).

    CAS  Article  Google Scholar 

  45. 45

    Cartin-Ceba, R., Fervenza, F. C. & Specks, U. Treatment of antineutrophil cytoplasmic antibody-associated vasculitis with rituximab. Curr. Opin. Rheumatol. 24, 15–23 (2012).

    CAS  Article  Google Scholar 

  46. 46

    Pepper, R. J. et al. Rituximab is effective in the treatment of refractory Churg–Strauss syndrome and is associated with diminished T-cell interleukin-5 production. Rheumatology (Oxford) 47, 1104–1105 (2008).

    CAS  Article  Google Scholar 

  47. 47

    US National Library of Medicine. [online], (2013).

  48. 48

    Weyand, C. M., Liao, Y. J. & Goronzy, J. J. The immunopathology of giant cell arteritis: diagnostic and therapeutic implications. J. Neuroophthalmol. 32, 259–265 (2012).

    Article  Google Scholar 

  49. 49

    Mason, J. C. Takayasu arteritis—advances in diagnosis and management. Nat. Rev. Rheumatol. 6, 406–415 (2010).

    Article  Google Scholar 

  50. 50

    US National Library of Medicine. [online]. (2009).

  51. 51

    Diamantopoulos, A. P. et al. Diagnostic value of color Doppler ultrasonography of temporal arteries and large vessels in giant cell arteritis: a consecutive case series. Arthritis Care Res. (Hoboken) 66, 113–119 (2014).

    Article  Google Scholar 

  52. 52

    Misra, R. et al. Development and initial validation of the Indian Takayasu Clinical Activity Score (ITAS2010). Rheumatology (Oxford) 52, 1795–1801 (2013).

    Article  Google Scholar 

  53. 53

    Hoffman, G. S. et al. Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis: a randomized trial. Ann. Intern. Med. 146, 621–630 (2007).

    Article  Google Scholar 

  54. 54

    Martinez-Taboada, V. M. et al. A double-blind placebo controlled trial of etanercept in patients with giant cell arteritis and corticosteroid side effects. Ann. Rheum. Dis. 67, 625–630 (2008).

    CAS  Article  Google Scholar 

  55. 55

    Mahr, A. D. et al. Adjunctive methotrexate for treatment of giant cell arteritis: an individual patient data meta-analysis. Arthritis Rheum. 56, 2789–2797 (2007).

    CAS  Article  Google Scholar 

  56. 56

    Hoffman, G. S. et al. A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum. 46, 1309–1318 (2002).

    CAS  Article  Google Scholar 

  57. 57

    Jover, J. A. et al. Combined treatment of giant-cell arteritis with methotrexate and prednisone. A randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 134, 106–114 (2001).

    CAS  Article  Google Scholar 

  58. 58

    Spiera, R. F. et al. A prospective, double-blind, randomized, placebo controlled trial of methotrexate in the treatment of giant cell arteritis (GCA). Clin. Exp. Rheumatol. 19, 495–501 (2001).

    CAS  PubMed  Google Scholar 

  59. 59

    Dasgupta, B. et al. BSR and BHPR guidelines for the management of giant cell arteritis. Rheumatology (Oxford) 49, 1594–1597 (2010).

    Article  Google Scholar 

  60. 60

    US National Library of Medicine. [online], (2013).

  61. 61

    Comarmond, C. et al. Anti TNF-α in refractory Takayasu's arteritis: cases series and review of the literature. Autoimmun. Rev. 11, 678–684 (2012).

    CAS  Article  Google Scholar 

  62. 62

    Abisror, N. et al. Tocilizumab in refractory Takayasu arteritis: a case series and updated literature review. Autoimmun. Rev. 12, 1143–1149 (2013).

    CAS  Article  Google Scholar 

  63. 63

    Youngstein, T. et al. Serial analysis of clinical and imaging indices reveals prolonged efficacy of TNF-α and IL-6 receptor targeted therapies in refractory Takayasu arteritis. Clin. Exp. Rheumatol. CER6558 (2013).

  64. 64

    De Groot, K. et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 52, 2461–2469 (2005).

    CAS  Article  Google Scholar 

  65. 65

    Faurschou, M. et al. Brief report: long-term outcome of a randomized clinical trial comparing methotrexate to cyclophosphamide for remission induction in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 64, 3472–3477 (2012).

    CAS  Article  Google Scholar 

  66. 66

    Specks, U. et al. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N. Engl. J. Med. 369, 417–427 (2013).

    CAS  Article  Google Scholar 

  67. 67

    Jayne, D. et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N. Engl. J. Med. 349, 36–44 (2003).

    CAS  Article  Google Scholar 

  68. 68

    Hiemstra, T. F. et al. Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial. JAMA 304, 2381–2388 (2010).

    CAS  Article  Google Scholar 

  69. 69

    Pagnoux, C. et al. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N. Engl. J. Med. 359, 2790–2803 (2008).

    CAS  Article  Google Scholar 

  70. 70

    The Wegener's granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener's granulomatosis. N. Engl. J. Med. 352, 351–361 (2005).

  71. 71

    Metzler, C. et al. Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of remission in Wegener's granulomatosis. Rheumatology (Oxford) 46, 1087–1091 (2007).

    CAS  Article  Google Scholar 

Download references


R.M.T. gratefully acknowledges salary support from an Arthritis Research UK Clinician Scientist Fellowship. The authors acknowledge support from the Imperial NIHR Biomedical Research Centre.

Author information




R.M.T. and J.C.M. researched data for and wrote the article. All authors made equal contributions to discussion of content and reviewing/editing the manuscript before submission.

Corresponding author

Correspondence to Ruth M. Tarzi.

Ethics declarations

Competing interests

C.D.P. has received a research grant from GlaxoSmithKline. R.M.T. and J.C.M. declare no competing interests.

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tarzi, R., Mason, J. & Pusey, C. Issues in trial design for ANCA-associated and large-vessel vasculitis. Nat Rev Rheumatol 10, 502–510 (2014).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing