Organ- or life-threatening disease

AAV can result in damage to vital organs such as the lungs, kidneys, nervous system, gastrointestinal system, skin, eyes and heart⁴

The majority of AAV patients have evidence of organ- or life-threatening disease¹

Remission induction

For remission induction of non-organ-threatening AAV,
EULAR/ERA–EDTA recommends glucocorticoids PLUS:^2,3

1. Methotrexate (20–25 mg/week, oral or parenteral)

OR

1. Mycophenolate mofetil (maximum 3 g/day)

Remission induction

For remission induction of new-onset organ-threatening or life-threatening AAV, EULAR/ERA–EDTA recommends glucocorticoids (1 mg/kg/day, maximum 80 mg/day) PLUS:³

1. Cyclophosphamide (2 mg/kg/day, maximum 200 mg/day)

OR

1. Rituximab (375 mg/m²/week for 4 weeks)

Remission

1. Full remission is defined as the absence of disease activity attributable to active disease⁵

2. Qualified by the need for ongoing immunosuppressive therapy, in particular glucocorticoids⁵

The response rate is still variable, and many patients do not get into and stay in full remission^6–8

1. Using standard of care treatment, full remission induction, BVAS/WG of 0 along with no ongoing glucocorticoids, can only be achieved in up to 64% of patients with organ- or life-threatening GPA or MPA at 6 months⁶*

2. Up to 48% and 39% of these patients are still in full remission without glucocorticoids at 1 year and 18 months, respectively^7*†

3. Real-world data from EU patients with GPA or MPA highlight the variable response rate to remission induction therapy with a full response observed in only 18%, 43%, 61% and 59% of patients at 1, 3, 6 and 12 months, respectively^8‡

Remission maintenance

For remission maintenance of AAV,
EULAR/ERA–EDTA recommends low-dose glucocorticoids PLUS:³

1. Azathioprine (2 mg/kg/day)

OR

1. Rituximab

OR

1. Methotrexate

OR

1. Mycophenolate mofetil

Relapse

Relapse refers to any disease previously well-controlled with or without treatment that has become active again²

1. Minor relapse: increase in ≥1 new or worse minor items and no major BVAS items²

2. Major relapse: increase in ≥1 major BVAS item²

Relapse in AAV remains common, with approximately 5–10% of patients experiencing relapses of varying severity each year despite continued immunosuppression.^{3,8–11‡§}

For a major relapse of organ-threatening or life-threatening AAV, EULAR/ERA–EDTA recommends treatment as per new disease with glucocorticoids PLUS:³

1. Cyclophosphamide

OR

1. Rituximab

Refractory

Refractory disease is defined as:³

1. Unchanged or increased disease activity in acute AAV after 4 weeks of treatment with standard therapy in acute AAV

OR

1. Lack of response (<50% reduction in disease activity score, e.g. BVAS or BVAS/WG after 6 weeks of treatment)

OR

1. Chronic, persistent disease (presence of ≥1 major or ≥3 minor items on the disease activity score after >12 weeks of treatment)

For AAV refractory to remission induction therapy,
EULAR/ERA–EDTA recommends switching from:³

1. Cyclophosphamide to rituximab

OR

1. Rituximab to cyclophosphamide

Patients should be managed in close conjunction with, or referred to, an expert centre for further evaluation and potential enrolment in clinical trials³

References & footnotes

AAV, ANCA-associated vasculitis; ANCA, anti-neutrophil cytoplasmic autoantibody; BVAS, Birmingham Vasculitis Activity Score; ERA–EDTA, European Renal Association—European Dialysis and Transplant Association; EU, European Union; EULAR, European League Against Rheumatism; EUVAS, European Vasculitis Study Group; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; MPO, myeloperoxidase; PR3, proteinase 3; RCT, randomised controlled trial; WG, Wegener’s Granulomatosis

*Multicentre, randomised, double-blind, double-dummy, noninferiority trial of rituximab (375 mg/m²/week for 4 weeks; n=99; mean age at symptom onset: 54.0 years; male: 46%; GPA: 75%; MPA: 24%; indeterminate: 1%) vs. cyclophosphamide (2 mg/kg/day; n=98; mean age at symptom onset: 51.5 years; male: 54%; GPA: 76%; MPA: 24%) for remission induction in patients with severe AAV (PR3-/MPO-ANCA positive). Glucocorticoids were tapered off; the primary endpoint was remission of disease (BVAS/WG of 0) without the use of prednisone at 6 months. Patients were enrolled between 30 December 2004 and 30 June 2008;^{6 †}Patients in the rituximab group who completed glucocorticoid tapering and had sustained disease remission (BVAS/WG of 0) received no further active treatment. In the cyclophosphamide group, patients achieving remission between month 3 and month 6 discontinued treatment and initiated azathioprine (2 mg/kg) for the balance of the 18 months;^{7 ‡}Retrospective study reviewing 929 incident AAV patients (GPA: 54%; MPA: 46%; mean age: 56.8 years; male: 53.7%) from four EU countries (399 physicians) who initiated remission induction therapy between November 2014 and February 2017 with data collected at baseline presentation, and after 1, 3, 6 and 12 months of treatment (59% cyclophosphamide, 24% rituximab, 83% glucocorticoids);⁸ §Patients (n=535; median age: 61 years) with newly diagnosed GPA (53%) or MPA (47%; adapted Chapel Hill disease definitions) recruited into four EUVAS RCTs in hospitals in 15 countries between 1995 and 2002.¹⁰

1. Yates M, Watts R. Clin Med (Lond) 2017;17(1):60–4.

2. Ntatsaki E, et al. Rheumatology (Oxford) 2014;53(12):2306–9.

3. Yates M, et al. Ann Rheum Dis 2016;75(9):1583–94.

4. Al-Hussain T, et al. Adv Anat Pathol 2017;24(4):226–34.

5. Hellmich B, et al. Ann Rheum Dis 2007;66(5):605–17.

6. Stone JH, et al. N Engl J Med 2010;363(3):221–32.

7. Specks U, et al. N Engl J Med 2013;369(5):417–27.

8. Rutherford P, et al. Variable response to induction therapy and significant burden of treatment adverse events over the first 12 months in incident ANCA-associated vasculitis (AAV) patients – a study of routine clinical practice in the EU. Poster presented at: ACR/ARHP 2018, 19–24 October 2018, Chicago, IL, USA (abstract 2724).

9. Rutherford PA, et al. Patients with relapsing ANCA-associated vasculitis (AAV) experience unmet needs around remission induction and therapy related adverse events. Poster presented at: ASN 2018, 23–28 October 2018, San Diego, CA, USA (abstract SA-PO402).

10. Walsh M, et al. Arthritis Rheum 2012;64(2):542–8.

11. Smith RM, et al. Arthritis Res Ther 2012;14(2):210.

References & footnotes

AAV, ANCA-associated vasculitis; AE, adverse event; ANCA, anti-neutrophil cytoplasmic autoantibody; EU, European Union; EUVAS, European Vasculitis Study Group; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; RCT, randomised controlled trial

*Patients (n=524) with newly diagnosed GPA or MPA (adapted Chapel Hill disease definitions) recruited into four EUVAS RCTs in 42 hospitals in 11 European countries and Mexico between 1995 and 2005, and followed for 1 year;¹ †Systematic literature review of 33 studies published between 1 January 2007 and 30 January 2018 containing data on glucocorticoid-related AEs (any untoward medical occurrence) and serious AEs (defined in European Medicines Agency CPMP/ICH/377/95) which threaten life or function;^{2 ‡}Retrospective study reviewing 929 incident AAV patients (GPA: 54%; MPA: 46%; mean age: 56.8 years; male: 53.7%) from four EU countries (399 physicians) who initiated remission induction therapy between November 2014 and February 2017 with data collected at baseline presentation, and after 1, 3, 6 and 12 months of treatment (59% cyclophosphamide, 24% rituximab, 83% glucocorticoids).³

1. Little MA, et al. Ann Rheum Dis 2010;69(6):1036−43.

2. Rutherford PA, et al. Adverse events due to glucocorticoids in ANCA-associated vasculitis are frequent but reporting should improve. Poster presented at: ASN 2018, 23–28 October 2018, San Diego, CA, USA (abstract SA-PO405).

3. Rutherford P, et al. Variable response to induction therapy and significant burden of treatment adverse events over the first 12 months in incident ANCA-associated vasculitis (AAV) patients – a study of routine clinical practice in the EU. Poster presented at: ACR/ARHP 2018, 19–24 October 2018, Chicago, IL, USA (abstract 2724).

References & footnotes

AE, adverse event; ANCA, anti-neutrophil cytoplasmic autoantibody; CI, confidence interval; EUVAS, European Vasculitis Study Group; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; RCT, randomised controlled trial; VDI, Vasculitis Damage Index; UK, United Kingdom

*Patients (n=524) with newly diagnosed GPA or MPA (adapted Chapel Hill disease definitions) recruited into four EUVAS RCTs in 42 hospitals in 11 European countries and Mexico between 1995 and 2005, and followed for 1 year;^{1 †}Patients (n=735 recruited; mean age: 57.6 years) with newly diagnosed GPA (54.8%) or MPA (45.2%; adapted 1994 Chapel Hill disease definitions, clinical presentation, and positive ANCA serology and/or histology) recruited into six EUVAS RCTs between 1995 and 2009. Long-term follow-up data (n=535 eligible patients; GPA: 52.5%; MPA: 47.5%; mean age: 57.7 years) were available from four RCTs (n=467/535 with data available; mean follow-up: 7.3 years) with VDI data from 302/535 patients (GPA: 55.3%; MPA: 44.7%; mean age: 56.8 years; mean follow-up: 7.1 years) and VDI + glucocorticoid data from 296/535 patients (GPA: 56.1%; MPA: 43.9%: mean age: 56.6 years);^{2,3 ‡}Data collected from patients with a first diagnosis of incident GPA (n=465; mean age: 60.3 years) and non-GPA matched (sex, age, year of birth and GPA diagnosis year) controls (n=4613: mean age: 60.3 years) from the UK (The Health Improvement Network) between 1992 and 2013. Mortality data were obtained from the 2003–13 cohort.⁴

1. Little MA, et al. Ann Rheum Dis 2010;69(6):1036−43.

2. Robson J, et al. Ann Rheum Dis 2015;74(1):177–84.

3. Robson J, et al. Rheumatology 2015;54(3):471–81.

4. Wallace ZS, et al. Semin Arthritis Rheum 2016;45(4):483–9.

References & footnotes

AAV, ANCA-associated vasculitis; ANCA, anti-neutrophil cytoplasmic autoantibody

1. Little MA, et al. Ann Rheum Dis 2010;69(6):1036−43.

2. Salvadori M, Tsalouchos A. World J Nephrol 2018;7(3):71–83.

3. Jennette JC, Nachman PH. Clin J Am Soc Nephrol 2017;12(10):1680–91.