Current therapies
Treatment has improved, but treatment-related complications remain common.
Treatment pathway
AAV is a long-term condition with a relapsing
course that needs long-term immunosuppresive therapy1-3
- Organ- or life-threatening disease
- Remission
- Relapse
- Refractory
Treatment-related infection is the leading cause of acute mortality1,2
Treatment-related infection is the
leading cause of acute mortality1,2
In the first year after a GPA or MPA diagnosis, 50% of the early mortality risk is due to treatment-related infection1*
A systematic literature review of glucocorticoid-related AEs in AAV clinical studies published between 1 January 2007 and 30 January 2018 identified infection as the leading cause of mortality, with the highest frequency observed during early induction treatment.2†
Real-world data confirm that treatment-related infections are common with 27%, 28%, 23% and 20% of GPA and MPA patients experiencing an infection at 1, 3, 6 and 12 months following the commencement of remission induction therapy, respectively.3‡
References & footnotes
Organ damage in AAV
GPA and MPA patients accumulate organ damage from a
combination of vasculitis activity and glucocorticoid-related AEs1–3
Long-term and repeated high-dose glucocorticoid use is associated with an increased risk of new onset/worsening of diabetes mellitus, hypertension, osteoporosis, avascular necrosis of bone, malignancy, cataracts and other debilitating side effects.1,2*† In a study following newly diagnosed GPA and MPA patients for up to 7 years, the frequency of damage, including potentially treatment-related damage, rose over time (p<0.01).2†
High levels of long-term vasculitis damage were independently associated with increased cumulative glucocorticoid use (p=0.016).3†
This serious morbidity translates into a significantly increased mortality risk, with a hazard ratio of 2.41 (95% CI: 1.74–3.34) in GPA patients compared with age- and sex-matched controls.2–4†‡
References & footnotes
New therapies and innovative strategies are needed1,2
New therapies and innovative strategies that provide a better balance between AAV disease control and the risk of drug-related toxicity than current treatment options are urgently needed1,2
"Ongoing advances in understanding ANCA disease
mechanisms, and development of more effective, less
toxic, and more targeted therapies, undoubtedly will
lead to even better outcomes in the future."3
– Jennette JC, Nachman PH. Clin J Am Soc Nephrol 2017
Remission-induction regimens using low-dose glucocorticoids or no glucocorticoids are warranted2
"Biologic therapies that target specific cellular and
molecular components of the autoimmune response
and the mediators of inflammatory injury may be
more effective and less toxic."3
– Jennette JC, Nachman PH. Clin J Am Soc Nephrol 2017
References & footnotes
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
Methotrexate (20–25 mg/week, oral or parenteral)
OR
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
Cyclophosphamide (2 mg/kg/day, maximum 200 mg/day)
OR
Rituximab (375 mg/m2/week for 4 weeks)
Remission
Full remission is defined as the absence of disease activity attributable to active disease5
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 remission6–8
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*
Up to 48% and 39% of these patients are still in full remission without glucocorticoids at 1 year and 18 months, respectively7*†
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, respectively8‡
Remission maintenance
For remission maintenance of AAV,
EULAR/ERA–EDTA recommends low-dose glucocorticoids PLUS:3
Azathioprine (2 mg/kg/day)
OR
Rituximab
OR
Methotrexate
OR
Mycophenolate mofetil
Relapse
Relapse refers to any disease previously well-controlled with or without treatment that has become active again2
Minor relapse: increase in ≥1 new or worse minor items and no major BVAS items2
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
Cyclophosphamide
OR
Rituximab
Refractory
Refractory disease is defined as:3
Unchanged or increased disease activity in acute AAV after 4 weeks of treatment with standard therapy in acute AAV
OR
Lack of response (<50% reduction in disease activity score, e.g. BVAS or BVAS/WG after 6 weeks of treatment)
OR
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
Cyclophosphamide to rituximab
OR
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
Yates M, Watts R. Clin Med (Lond) 2017;17(1):60–4.
Ntatsaki E, et al. Rheumatology (Oxford) 2014;53(12):2306–9.
Yates M, et al. Ann Rheum Dis 2016;75(9):1583–94.
Al-Hussain T, et al. Adv Anat Pathol 2017;24(4):226–34.
Hellmich B, et al. Ann Rheum Dis 2007;66(5):605–17.
Stone JH, et al. N Engl J Med 2010;363(3):221–32.
Specks U, et al. N Engl J Med 2013;369(5):417–27.
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).
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).
Walsh M, et al. Arthritis Rheum 2012;64(2):542–8.
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
Little MA, et al. Ann Rheum Dis 2010;69(6):1036−43.
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).
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
Little MA, et al. Ann Rheum Dis 2010;69(6):1036−43.
Robson J, et al. Ann Rheum Dis 2015;74(1):177–84.
Robson J, et al. Rheumatology 2015;54(3):471–81.
Wallace ZS, et al. Semin Arthritis Rheum 2016;45(4):483–9.
References & footnotes
AAV, ANCA-associated vasculitis; ANCA, anti-neutrophil cytoplasmic autoantibody
Little MA, et al. Ann Rheum Dis 2010;69(6):1036−43.
Salvadori M, Tsalouchos A. World J Nephrol 2018;7(3):71–83.
Jennette JC, Nachman PH. Clin J Am Soc Nephrol 2017;12(10):1680–91.
Introduction to AAV
AAV is a rare, severe small vessel vasculitis that affects multiple organs and has a high acute mortality risk
Disease mechanism
The interaction between the activated alternative complement pathway, neutrophils and C5a is at the heart of vasculitic damage in AAV
Current therapies
Treatment has improved but treatment-related complications remain common
Patient experience
AAV is an emotional journey from the patient's perspective
Investigate AAV
Take the interactive challenge to assess your understanding of AAV. Fully interactive version available on desktop only