Understand AAV

Our understanding of AAV (ANCA-associated vasculitis) is increasing

Understand AAV

Our understanding of AAV (ANCA-associated vasculitis) is increasing

Understand AAV

Our understanding of AAV (ANCA-associated vasculitis) is increasing

Introduction to AAV

Incidence & prevalence

AAV is a rare, severe small vessel vasculitis that affects multiple organs and has a high acute mortality risk.¹

Types of AAV

The two most common subtypes of AAV are granulomatosis with polyangiitis (GPA, previously called Wegener’s) and microscopic polyangiitis (MPA). The other subtype is eosinophilic granulomatosis with polyangiitis (EGPA, previously called Churg-Strauss syndrome).^2,3This website will focus mainly on GPA and MPA.

AAV is a rare disease²

Global prevalence: 30–218 per million⁴
European incidence: 13–20 per million per year^2,4

AAV occurrence

AAV can affect both younger and older people, but is rare in children and young people and incidence rises with age^2,5
AAV occurs slightly more frequently in men (annual incidence rate approximately 60%) than in women^2,5

References & footnotes

Abbreviations

AAV, ANCA-associated vasculitis; ANCA, anti-neutrophil cytoplasmic antibody; EGPA, eosinophilic granulomatosis with polyangiitis; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis

References

Hutton HL, et al. ANCA-Associated Vasculitis: Pathogenesis, Models, and Preclinical Testing. Semin Nephrol 2017;37(5):418–35.
Watts RA, et al. Classification, epidemiology and clinical subgrouping of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Nephrol Dial Transplant 2015;30(Suppl 1):i14–22.
Yates M, et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis 2016;75(9):1583–94.
Mohammad AJ. An update on the epidemiology of ANCA-associated vasculitis. Rheumatology (Oxford) 2020;59:iii42–50.
Watts RA, et al. Epidemiology of systemic vasculitis: a ten-year study in the United Kingdom. Arthritis Rheum 2000;43(2):414–9.
Watts RA, et al. The global burden of anti-neutrophil cytoplasmic antibody vasculitis: High but unquantified. Rheumatology (Oxford) 2017;56(9):1439–40.

GCC-AVA-2500012 | Date of preparation: October 2025

Introduction to AAV

Incidence & prevalence

AAV is a rare, severe small vessel vasculitis that affects multiple organs and has a high acute mortality risk.¹

Types of AAV

AAV is a rare disease²

Global prevalence: 30–218 per million⁴
European incidence: 13–20 per million per year^2,4

AAV occurrence

AAV can affect both younger and older people, but is rare in children and young people and incidence rises with age^2,5
AAV occurs slightly more frequently in men (annual incidence rate approximately 60%) than in women^2,5

References & footnotes

Abbreviations

References

Hutton HL, et al. ANCA-Associated Vasculitis: Pathogenesis, Models, and Preclinical Testing. Semin Nephrol 2017;37(5):418–35.
Watts RA, et al. Classification, epidemiology and clinical subgrouping of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Nephrol Dial Transplant 2015;30(Suppl 1):i14–22.
Yates M, et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis 2016;75(9):1583–94.
Mohammad AJ. An update on the epidemiology of ANCA-associated vasculitis. Rheumatology (Oxford) 2020;59:iii42–50.
Watts RA, et al. Epidemiology of systemic vasculitis: a ten-year study in the United Kingdom. Arthritis Rheum 2000;43(2):414–9.
Watts RA, et al. The global burden of anti-neutrophil cytoplasmic antibody vasculitis: High but unquantified. Rheumatology (Oxford) 2017;56(9):1439–40.

GCC-AVA-2500012 | Date of preparation: October 2025

Introduction to AAV

System organ damage

AAV can result in systemic organ damage and failure, with the kidney and lung as major targets^1-3

AAV can result in damage to vital organs such as the lungs, kidneys, nervous system, gastrointestinal system, skin, eyes and heart.^3,4 Both GPA and MPA show a lot of clinical commonality, whereas EGPA is distinctly different.²

As many as 23% (n=11/48) of PR3- and MPO-ANCA positive patients who require RRT at the time of diagnosis die within 6 months and 29% (n=14/48) do not regain renal function.^5* In patients with renal involvement at diagnosis, ESRD occurs in 13% (n=9/72) of PR3- and MPO-ANCA positive patients within 3 years of diagnosis. Compared with a short prodromal phase, patients with a long prodromal phase (>22 weeks between first AAV symptoms and diagnosis) are more likely to have proteinuria present at 6 months and are at double the risk of 3-year ESRD, which underlines the importance of early diagnosis in order to improve renal outcomes.^6†

A. ENT²

Frequency

GPA: 50–95%; MPA: 2–30%; EGPA: 20–80%

Manifestations

GPA: Crusting rhinitis, destructive sinusitis, saddle-nose deformity, nasal septum deformity, otitis media
MPA: Not specific, not destructive, not granulomatous
EGPA: Allergic rhinitis, non-destructive sinus polyposis

B. Lungs²

Frequency

GPA: 60–80%; MPA: 60–80%; EGPA: 50%

Manifestations

GPA: Lung plain and/or excavated nodules, alveolar haemorrhage, bronchial and/or subglottic stenosis
MPA: Alveolar haemorrhage
EGPA: Transient patchy infiltrates and eosinophil pleural effusion, but rarely nodules

C. Skin²

Frequency

GPA: 10–50%; MPA: 35–60%; EGPA: 50–70%

Manifestations

GPA and MPA: Purpura
EGPA: Purpura, pseudourticarial rash

D. Kidneys²

Frequency

GPA: 60–80%; MPA: 80%; EGPA: 20%

Manifestations

GPA, MPA and EGPA: Pauci-immune necrotising extra-capillary glomerulonephritis

GPA and MPA patients accumulate organ damage from a combination of vasculitis activity and glucocorticoid-related AEs^7–9

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.^7,8‡§ 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). Patients initially experience early increased damage following diagnosis (n=270), with 81.5% (n=220/270) of patients experiencing ≥1 item in the VDI at 6 months compared to 24.4% (n=66/270) of patients at baseline, with renal (proteinuria and GFR <50 mL/minute) and cardiovascular (hypertension) damage the most frequent. Severe damage, a VDI score ≥5, increases over time and at long-term follow-up 33.7% (n=91/270) of patients had severe damage. Hypertension was the most commonly reported item at long-term follow-up. At baseline, 4.8% (n=13/270) of patients had hypertension. Within 6 months, this rose to 17.0% (n=46/270) and at long-term follow-up 41.5% (n=112/270) of patients had hypertension (p<0.01 ).^8§

High levels of long-term vasculitis damage were independently associated with increased cumulative glucocorticoid use (p=0.016).^9§

This serious morbidity is accompanied by a significantly increased long-term 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.^8–10§**

At a mean of 7 years post diagnosis in patients with GPA or MPA…^8§

References & footnotes

Footnotes

^*AAV patients with (n=212; mean age: 58 years; PR3-ANCA positive: n=138; MPO-ANCA positive: n=65; ANCA negative: n=9) and without (n=61; mean age: 52 years) renal involvement (active urinary sediment, proteinuria, impaired renal function or biopsy) diagnosed and treated with AAV at a single centre in the Netherlands between January 1990 and December 2007 who were followed until death, loss to follow-up or December 2010.⁵
^†Retrospective data collected from patients (n=72; mean age: 64 years) with a clinical AAV diagnosis (Chapel Hill disease deﬁnitions and PR3-/MPO-ANCA positive) and renal involvement at diagnosis (rise in serum creatinine >30% and/or erythrocyturia [≥10 red blood cells per high-power ﬁeld and/or red blood cell casts]) in a single-centre cohort (Northwest Clinics, Netherlands) between 1 February 2005 and 1 February 2015.⁶
^‡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.⁷
^§Patients (n=735 recruited; mean age: 57.6 years) with newly diagnosed GPA (55%) or MPA (45%; 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: 53%; MPA: 48%; 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%; MPA: 45%; mean age: 56.8 years; mean follow-up: 7.1 years) and VDI + glucocorticoid data from 296/535 patients (GPA: 56%; MPA: 44%: mean age: 56.6 years).^8,9
^**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 United Kingdom (The Health Improvement Network) between 1992 and 2013. Mortality data were obtained from the 2003–13 cohort.¹⁰

Abbreviations

AAV, ANCA-associated vasculitis; AE, adverse event; ANCA, anti-neutrophil cytoplasmic antibody; CI, confidence interval; EGPA, eosinophilic granulomatosis with polyangiitis; ENT, ear, nose and throat; ESRD, end-stage renal disease; EUVAS, European Vasculitis Study Group; GFR, glomerular filtration rate; GI, gastrointestinal; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; MPO, myeloperoxidase; PR3, proteinase 3; RRT, renal replacement therapy; RCT, randomised controlled trial; VDI, Vasculitis Damage Index

References

Hutton HL, et al. Semin Nephrol 2017;37(5):418–35.
Pagnoux C. Eur J Rheumatol 2016;3(3):122–33.
Kitching A, et al. Nat Rev Dis Primers 2020;6(1):71.
Al-Hussain T, et al. Adv Anat Pathol 2017;24(4):226–34.
De Joode AAE, et al. Clin J Am Soc Nephrol 2013;8(10):1709–17.
Houben E, et al. BMC Nephrol 2017;18(1):378.
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 (Oxford) 2015;54(3):471–81.
Wallace ZS, et al. Semin Arthritis Rheum 2016;45(4):483–9.

Additional

DE-FCM-2100195

GCC-AVA-2500012 | Date of preparation: October 2025

Introduction to AAV

Mortality & morbidity

AAV leads to an increased risk of mortality, especially in the first year after diagnosis^1,2*

In the first year after a GPA or MPA diagnosis (n=524), the mortality rate is 10.7% (n=56)^1*

Of these patients: Half (50%) of mortality in the first year is due to treatment-related infection¹

In clinical trial settings, the cumulative survival rate at 2 and 5 years in patients with newly diagnosed GPA and MPA is 85% and 78%, respectively.^3†

Population-based data suggest that the long-term mortality rate in patients with AAV has improved considerably over the past two decades, but is still not as good as matched controls.^2‡

In a study following individuals for a median 5.2 years, the mortality rate in incident GPA or MPA patients receiving current treatment was 2.6 times higher than an age- and sex-matched general population (p<0.0001).^3†

References & footnotes

Footnotes

*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=535; median age: 61 years) with newly diagnosed GPA (53%) or MPA (47%; adapted 1994 Chapel Hill disease definitions, clinical presentation, and positive ANCA serology and/or histology) recruited into four EUVAS RCTs in 70 general and university hospitals in 15 countries between 1995 and 2002 with a median 5.16 years of follow-up for all patients. A control cohort was matched for age, sex, year and country.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 United Kingdom (The Health Improvement Network) between 1992 and 2013, and divided into two cohorts based on the year of diagnosis (1992–2002 and 2003–2013).²

Abbreviations

AAV, ANCA-associated vasculitis; ANCA, anti-neutrophil cytoplasmic antibody; EUVAS, European Vasculitis Study Group; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; RCT, randomised controlled trial

References

Little MA, et al. Ann Rheum Dis 2010;69(6):1036−43.
Wallace ZS, et al. Semin Arthritis Rheum 2016;45(4):483–9.
Flossmann O, et al. Ann Rheum Dis 2011;70(3):488–94.

GCC-AVA-2500012 | Date of preparation: October 2025

Introduction to AAV

Referral, diagnosis & follow-up

AAV patients often experience a complex pathway of patient referral and diagnosis^1*

EULAR recommendations state that patients should have access to education focusing on the impact of AAV and its prognosis, key warning symptoms and treatment (including treatment-related complications). AAV requires multidisciplinary management by centres with, or with ready access to, specific vasculitis expertise.²

Most patients are referred by other physicians¹

Many patients have renal disease at presentation, but general non-specific referral symptoms predominate¹

Renal disease: 64%
Fatigue: 58%
Fever: 54%
Weight loss: 53%
Joint pain: 47%

16% of patients have had their referral symptoms for over 3 months before receiving an AAV diagnosis¹

Comorbidities at diagnosis are common (65% of patients)¹

Hypertension: 45%
Type 2 diabetes: 16%
COPD/asthma: 15%
Coronary arterial disease: 10%
Arthritis: 9%
Osteoporosis: 7%
BMI > 35: 6%
Cardiac failure: 6%

The relative rarity and non-specific presentation of AAV can lead to a delay in disease diagnosis of more than 6 months in one-third of patients.³

Diagnosis of AAV and differentiation into the GPA, MPA or EGPA subtype depends on the patient’s clinical symptom constellation, the results of imaging studies and laboratory investigation.^3,4

Due to the linkage of anti-PR3 with GPA and anti-MPO with MPA, ANCA testing is critical for diagnosis.^3–7

Up to 20% of GPA and MPA patients and over 60% of EGPA patients are ANCA negative⁴
A positive ANCA test result can be found in other conditions, e.g. autoimmune hepatitis, ulcerative colitis, infection with hepatitis C virus or HIV, or infectious endocarditis, without associated vasculitis⁴

An organ biopsy, usually renal, is often performed to confirm the diagnosis.^3,4

Referral

Diagnosis

Follow-up

Find out more about AAV patients‘ journey

References & footnotes

Footnotes

^*Retrospective study reviewing 929 incident AAV patients (GPA: 54%; MPA: 46%; mean age: 57 years; male: 53.7%) in France, Germany, Italy and the United Kingdom (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.¹

Abbreviations

AAV, ANCA-associated vasculitis; ANCA, anti-neutrophil cytoplasmic antibody; BMI, body mass index; COPD, chronic obstructive pulmonary disease; EGPA, eosinophilic granulomatosis with polyangiitis; ENT, ear, nose and throat; EULAR, European Alliance of Associations for Rheumatology; GP, general practitioner; GPA, granulomatosis with polyangiitis; HIV, human immunodeficiency virus; ICU, intensive care unit; MPA, microscopic polyangiitis; MPO, myeloperoxidase; PR3, proteinase 3

References

Rutherford PA, et al. J Am Soc Nephrol 2018;29:839(Abstract SA-PO403).
Hellmich B, et al. Ann Rheum Dis 2023;0:1–18.
Yates M, Watts R. Clin Med (Lond) 2017;17(1):60–4.
Pagnoux C. Eur J Rheumatol 2016;3(3):122–33.
Al-Hussain T, et al. Adv Anat Pathol 2017;24(4):226–34.
Chen M, et al. Medicine (Baltimore) 2008;87(4):203–9.
Lionaki S, et al. Arthritis Rheum 2012;64(10):3452–62.

GCC-AVA-2500012 | Date of preparation: October 2025

Additional resources

GCC-AVA-2500012 | Date of preparation: October 2025

AAV treatment

Treatment pathway

A framework of practice for the treatment and management of AAV patients

AAV is a chronic condition with a relapsing course that needs long-term immunosuppressive therapy^1–4

EULAR recommendations state that AAV patients should be offered best care which must be based on shared decision-making between the patient and the physician, considering efficacy, safety and costs⁵

Diagram adapted from Hellmich B, et al. Ann Rheum Dis 2023. Always refer to the product SmPC for approved indications before prescribing.

References & footnotes

Footnotes

^*As part of a strategy to substantially reduce exposure to GCs.
^†Rituximab preferred in relapsing disease.
^‡In patients with serum creatinine >300 μmol/L due to active glomerulonephritis.
^§If remission not achieved, consult an expert centre; if remission achieved, proceed to maintenance phase.
^**Stop avacopan after duration of treatment of 6–12 months (there are no data on use of avacopan beyond 1 year, so longer-term use cannot be recommended); in ADVOCATE, remission sustained until Week 52 (the second primary endpoint) was reached at a higher rate in the avacopan (65.7%) than GC (54.9%) treatment groups, suggesting that avacopan may have efficacy for maintenance of remission.
^††Longer duration of treatment should be balanced against patient preferences and risks of continuing immunosuppression.

Abbreviations

EULAR, European Alliance of Associations for Rheumatology; GC, glucocorticoid; RPGN, rapidly progressive glomerulonephritis.

References

Yates M, Watts R. ANCA-associated vasculitis. Clin Med (Lond) 2017;17(1):60–4.
Ntatsaki E, et al. Rheumatology (Oxford) 2014;53(12):2306–9.
Yates M, et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis 2016;75(9):1583–94.
Rutherford PA, et al. Real world experience in ANCA-associated vasculitis (AAV) – a complex pathway of patient referral, diagnosis and management. J Am Soc Nephrol 2018;29:839(Abstract SA-PO403).
Hellmich B, et al. EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update. Ann Rheum Dis 2023;0:1–18.

GCC-AVA-2500012 | Date of preparation: October 2025

AAV treatment

Treatment pathway

A framework of practice for the treatment and management of AAV patients

AAV is a chronic condition with a relapsing course that needs long-term immunosuppressive therapy^1–4

Diagram adapted from Hellmich B, et al. Ann Rheum Dis 2023. Always refer to the product SmPC for approved indications before prescribing.

References & footnotes

Footnotes

Abbreviations

EULAR, European Alliance of Associations for Rheumatology; GC, glucocorticoid; RPGN, rapidly progressive glomerulonephritis.

References

Yates M, Watts R. ANCA-associated vasculitis. Clin Med (Lond) 2017;17(1):60–4.
Ntatsaki E, et al. Rheumatology (Oxford) 2014;53(12):2306–9.
Yates M, et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis 2016;75(9):1583–94.
Rutherford PA, et al. Real world experience in ANCA-associated vasculitis (AAV) – a complex pathway of patient referral, diagnosis and management. J Am Soc Nephrol 2018;29:839(Abstract SA-PO403).
Hellmich B, et al. EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update. Ann Rheum Dis 2023;0:1–18.

GCC-AVA-2500012 | Date of preparation: October 2025

AAV treatment

The balance of treatment

Treatment must balance controlling vasculitis with minimising treatment-related damage^1–4

At the time of AAV diagnosis or relapse, the major concerns around treatment involve controlling vasculitis activity and minimising the acute adverse effects from therapy.^1,2 Later when remission is achieved, cumulative organ damage, often related to long-term low dose glucocorticoids, and patient experience are more important.^1–4

The EULAR Guidelines now state that patients should be periodically screened for treatment-related adverse effects and co-morbidities. They recommend prophylaxis and life-style advice to reduce treatment-related complications and other co-morbidities.⁵

Treatment-related AEs are the leading cause of acute mortality⁶

In the first year after a GPA or MPA diagnosis, 56 of 524 patients died. A total of 59% (n=33/56) of these deaths were as a result of treatment-related AEs.^6*

A systematic literature review of glucocorticoid-related AEs in AAV clinical studies published between 1 January 2007 and 30 January 2018 identified mortality (33%) as the glucocorticoid-related serious AE with the highest frequency observed during early induction treatment. Other common glucocorticoid-related serious AEs experienced by patients include infections (20%), musculoskeletal (17%) and renal disorders (15%).^7†

References & footnotes

Footnotes

^*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.⁶
^†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 CPMMP/ICH/377/95) which threaten life or function.⁷

Abbreviations

AAV, ANCA-associated vasculitis; AE, adverse event; ANCA, anti-neutrophil cytoplasmic antibody; EULAR, European Alliance of Associations for Rheumatology; EUVAS, European Vasculitis Study Group; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; RCT, randomised controlled trial.

References

Yates M, et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis 2016;75(9):1583–94.
Robson JC, et al. Patient perceptions of glucocorticoids in anti-neutrophil cytoplasmic antibody-associated vasculitis. Rheumatol Int 2018;38(4):675–82.
Yates M, Watts R. ANCA-associated vasculitis. Clin Med (Lond) 2017;17(1):60–4.
Robson J, et al. Glucocorticoid treatment and damage in the anti-neutrophil cytoplasm antibody-associated vasculitides: long-term data from the European Vasculitis Study Group trials. Rheumatology (Oxford) 2015;54(3):471–81.
Hellmich B, et al. EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update. Ann Rheum Dis 2023;0:1–18.
Little MA, et al. Early mortality in systemic vasculitis: relative contribution of adverse events and active vasculitis. 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. J Am Soc Nephrol 2018;29:840(2. Abstract SA-PO405).

GCC-AVA-2500012 | Date of preparation: October 2025

AAV treatment

Latest clinical data in AAV

ADVOCATE

2021

Avacopan-based regimen is superior at sustaining remission at Week 52 compared to a GC-based regimen¹

At Week 26, avacopan-based regimen demonstrated non-inferiority in achieving clinical remission vs a GC-based regimen (p<0.001)
At Week 52, avacopan-based regimen demonstrated superiority at sustaining clinical remission vs a GC-based regimen (p=0.007)
Incidences of serious adverse events were similar in avacopan-based regimen and GC-based regimen groups (37.3% vs 39%, respectively)

Read the summary

Link to publication

PEXIVAS

2020

Reducing the GC dose in severe AAV patients did not significantly impact the primary outcome of death or ESRD, but did reduce the rate of infection (HR=0.69)²

Risk of death or ESRD with reduced GC dose was non-inferior to standard GC dose
Reduced-dose regimen decreased the risk of serious infections (0.69; 95% CI, 0.52 to 0.93) without increasing the risk of other adverse events
The continued use of a standard-dose GC regimen, even in patients with severe AAV should be re-evaluated
Use of PLEX in this patient population provided no added benefit

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Link to publication

MAINRITSAN 3

2020

Extended maintenance therapy leads to better clinical outcomes³

Relapse rates were reduced in patients receiving long-term RTX
treatment compared to standard maintenance therapy
With standard maintenance therapy, relapse rates remain high. At month 28, 25% of patients experienced a relapse.
There was no difference in the incidence of AEs with long-term treatment

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RITAZAREM

2019

Preliminary results show that a reduced GC dose can be effective for reinducing remission in AAV, and RTX was superior to AZA at maintaining remission^4,5

Remission induction with a reduced GC dose should be considered clinically, as it was as effective as a typical GC dose regimen
Initial findings show RTX to be superior to AZA in reducing relapses
Relapses still occurred in both treatment groups. By 24 months, 13% of the RTX patients and 38% of the AZA patients experienced a relapse.

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MAINRITSAN 2

2018

Tailored and fixed-schedule RTX regimens are equally as effective at maintaining remission, but relapses still occur⁶

Relapse rates were similar with tailored and fixed-schedule RTX treatment
The tailored regimen demonstrated that remission maintenance can be achieved with fewer RTX infusions
Further research is required to establish reliable laboratory tests that can predict the appearance of relapse

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MAINRITSAN 1

2014

RTX is more effective than AZA for maintenance of remission, but GC use and relapse remain common^7-10

RTX was shown to be a more effective maintenance therapy than AZA for newly diagnosed AAV patients
Minor and major relapses occurred throughout the maintenance phase of treatment. By Month 28, 17% of patients suffered a major relapse, increasing to 38% by Month 60.
GC use remained common amongst all patients throughout the 60-month follow-up period

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RAVE

2010

RTX was found to be non-inferior to daily CYC for the induction and maintenance of remission, but remission rates remain variable^11–13

Patient achievement and maintenance of full remission remains variable with current therapies
1 in 3 patients fail to achieve remission at 6 months without use of GCs, and 1 in 2 fail to sustain remission at 12 months
Non-severe relapse is an under-recognised clinical problem; these patients suffer subsequent relapses resulting in high GC exposure

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Link to publication

References & footnotes

Abbreviations

AAV, ANCA-associated vasculitis; AE, adverse event; ANCA, anti-neutrophil cytoplasmic antibody; AZA, azathioprine; CYC, cyclophosphamide; ESRD, end-stage renal disease; GC, glucocorticoid; HR, hazard ratio; PLEX, plasma exchange; RTX, rituximab

References

Jayne D, et al. Avacopan for the Treatment of ANCA-Associated Vasculitis. N Engl J Med 2021;384(7):599–609.
Walsh M, et al. Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis. N Engl J Med 2020:382(7):622–31.
Charles P, et al. Long-Term Rituximab Use to Maintain Remission of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Randomized Trial. Ann Intern Med 2020;173(30):179–87.
Smith RM, et al. Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis. Ann Rheum Dis 2020;79(9):1243–96
Smith RM, et al. A Randomized Controlled Trial of Rituximab (RTX) vs. Azathioprine (AZA) After Induction of Remission with RTX for Patients with ANCA-Associated Vasculitis (AAV) and Relapsing Disease. J Am Soc Nephrol 2019:30.
Charles P, et al. Comparison of individually tailored versus fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2). Ann Rheum Dis 2020;173(30):1143–9.
Guillevin L, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med 2014;371(19):1771–80.
Terrier B, et al. Long-term efficacy of remission-maintenance regimens for ANCA-associated vasculitides. Ann Rheum Dis 2018;77(8):1150–6.
Terrier B, et al. Long-term efficacy of remission-maintenance regimens for ANCA-associated vasculitides. Ann Rheum Dis 2018;77(8): 1150–6. [Supplementary appendix].
Guillevin L, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med 2014;371(19):1771–80. [Supplementary appendix].
Stone JH, et al. Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis. N Engl J Med 2010;363(3):221–32.
Specks U, et al. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N Engl J Med 2013;369(5):417–27.
Miloslavsky EM, et al. Outcomes of nonsevere relapses in antineutrophil cytoplasmic antibody-associated vasculitis treated with glucocorticoids. Arthritis Rheum 2015;67(6):1629–36.

GCC-AVA-2500012 | Date of preparation: October 2025

AAV treatment

Real-world experience

Many patients do not achieve or sustain full remission^1*

Patient response to remission induction therapy is variable. After 12 months of therapy (n=929), 59% of GPA (granulomatosis with polyangiitis, previously called Wegener’s) and MPA (microscopic polyangiitis) patients achieve full remission, and >50% of patients continue glucocorticoid use.¹More patients need to achieve and sustain remission without prolonged glucocorticoid use.

Response to induction therapy is variable and many patients do not achieve a full response, even at 12 months¹

>50% of patients continue to use glucocorticoids 12 months after starting induction therapy¹

AEs remain an issue for new and relapsing patients^1,2

Over the first 12 months of treatment in patients with GPA or MPA, AEs are common.^1,2 At this time, glucocorticoid dose is typically highest, as current treatment guidelines recommend the use of glucocorticoids for remission induction.^1-3 The majority of patients continue to use glucocorticoids 12 months after starting remission induction.^1,2

New patients (n=929)^1†

Month 1

Month 3

Month 6

Month 12

Relapsing patients (n=268)^2†

Month 1

Month 3

Month 6

Month 12

References & footnotes

Footnotes

^*Retrospective clinical audit of healthcare records from 929 incident AAV patients (GPA: 54%; MPA: 46%; mean age: 57 years; male: 54%) in France, Germany, Italy and the United Kingdom (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.¹
^†Retrospective study reviewing 929 incident AAV patients (GPA: 54%; MPA: 46%; mean age: 57 years; male: 54%) and 268 relapsing AAV patients (GPA: 54%; MPA:46%; mean age: 58 years; male: 60%) from France, Germany, Italy and the United Kingdom (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.^1,2

Abbreviations

AAV, ANCA-associated vasculitis; AE, adverse event; ANCA, anti-neutrophil cytoplasmic antibody; CYC, cyclophosphamide; GC, glucocorticoid; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; RTX, rituximab

References

Rutherford P, et al. Arthritis Rheumatol 2018;70(Suppl 10):Abstract 2724.
Rutherford PA, et al. J Am Soc Nephrol 2018;29:839(Abstract SA-PO402).
Yates M, et al. Ann Rheum Dis 2016;75(9):1583–94.

GCC-AVA-2500012 | Date of preparation: October 2025

Disease mechanism

AAV pathogenesis

The interaction between the activated alternative complement pathway, neutrophils and C5a is associated with vasculitis damage in AAV.¹

The development of AAV is a complex and multifactorial autoimmune process^2,3

The initial causes of AAV are currently unclear.³ Predisposing factors such as microbial infection, genetic influence, environmental agents and specific drugs are all fundamental to the development of AAV.^2,3

Exposure to silica, pesticides, fumes, construction materials, hydrocarbon (cleaning agents, paint, diesel), drugs (propylthiouracil, hydralazine, D-penicillamine, cefotaxime, minocycline, anti-TNF agents, phenytoin) and certain psychoactive agents may all cause AAV.^2,3

Stage 1

Stage 2

ANCA involvement

Loss of immune tolerance to ANCA antigens and development of ANCA by plasma cells²

ANCAs are most commonly directed against the neutrophil lysosomal enzymes PR3 and MPO in GPA and MPA, respectively^2-6

Neutrophils are primed

Neutrophils are primed by inflammatory cytokines (TNF-α, IL-1 and IL-18) produced in response to an infection or another event, with genetic predisposition also relevant^3,7,8

ANCA antigens presented

Primed neutrophils present ANCA antigens (e.g. MPO and PR3) at their cell surface that bind to ANCA, resulting in neutrophil activation^2,3,7,8

Inflammation mediators released

Activated neutrophils adhere to and penetrate the blood vessel wall, and release mediators of inflammation and cell injury, e.g. NETS^2,3,7

Alternative complement pathway activated

Activated neutrophils also release factors such as properdin that have an autocrine role in activating the alternative complement pathway, leading to the generation of C5a^2,7

Binding of C5a to C5aR1

Binding of C5a to C5aR1 amplifies ANCA-induced inflammation and vascular damage⁷

Necrotising vasculitis

This process leads to necrotising vasculitis in small blood vessels⁷

Chronic inflammation

Over a few days, acute inflammation and necrosis are replaced by chronic inflammation and scarring⁷

References & footnotes

Abbreviations

AAV, ANCA-associated vasculitis; ANCA, anti-neutrophil cytoplasmic antibody; C5a, complement 5a; GPA, granulomatosis with polyangiitis; IL, interleukin; MPA, microscopic polyangiitis; MPO, myeloperoxidase; NETS, neutrophil extracellular traps; PR3, proteinase 3; R, receptor; TNF, tumour necrosis factor

References

Bekker P, et al. Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study. PLoS One 2016;11(10):e0164646.
Hutton HL, et al. ANCA-Associated Vasculitis: Pathogenesis, Models, and Preclinical Testing. Semin Nephrol 2017;37(5):418–35.
Al-Hussain T, et al. Pathophysiology of ANCA-associated Vasculitis. Adv Anat Pathol 2017;24(4):226–34.
Chen M, et al. Antineutrophil cytoplasmic autoantibody-associated vasculitis in older patients. Medicine (Baltimore) 2008;87(4):203–9.
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 2012;64(10):3452–62.
Pagnoux C. Updates in ANCA-associated vasculitis. Eur J Rheumatol 2016;3(3):122–33.
Jennette JC, Nachman PH. ANCA Glomerulonephritis and Vasculitis. Clin J Am Soc Nephrol 2017;12(10):1680–91.
von Borstel A, et al. Cellular immune regulation in the pathogenesis of ANCA-associated vasculitides. Autoimmun Rev 2018;17(4):413–21.

GCC-AVA-2500012 | Date of preparation: October 2025

Disease mechanism

AAV pathogenesis

The interaction between the activated alternative complement pathway, neutrophils and C5a is associated with vasculitis damage in AAV.¹

The development of AAV is a complex and multifactorial autoimmune process^2,3

Stage 1

Stage 2

ANCA involvement

Loss of immune tolerance to ANCA antigens and development of ANCA by plasma cells²

ANCAs are most commonly directed against the neutrophil lysosomal enzymes PR3 and MPO in GPA and MPA, respectively^2-6

Neutrophils are primed

Neutrophils are primed by inflammatory cytokines (TNF-α, IL-1 and IL-18) produced in response to an infection or another event, with genetic predisposition also relevant^3,7,8

ANCA antigens presented

Primed neutrophils present ANCA antigens (e.g. MPO and PR3) at their cell surface that bind to ANCA, resulting in neutrophil activation^2,3,7,8

Inflammation mediators released

Activated neutrophils adhere to and penetrate the blood vessel wall, and release mediators of inflammation and cell injury, e.g. NETS^2,3,7

Alternative complement pathway activated

Activated neutrophils also release factors such as properdin that have an autocrine role in activating the alternative complement pathway, leading to the generation of C5a^2,7

Binding of C5a to C5aR1

Binding of C5a to C5aR1 amplifies ANCA-induced inflammation and vascular damage⁷

Necrotising vasculitis

This process leads to necrotising vasculitis in small blood vessels⁷

Chronic inflammation

Over a few days, acute inflammation and necrosis are replaced by chronic inflammation and scarring⁷

References & footnotes

Abbreviations

References

Bekker P, et al. Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study. PLoS One 2016;11(10):e0164646.
Hutton HL, et al. ANCA-Associated Vasculitis: Pathogenesis, Models, and Preclinical Testing. Semin Nephrol 2017;37(5):418–35.
Al-Hussain T, et al. Pathophysiology of ANCA-associated Vasculitis. Adv Anat Pathol 2017;24(4):226–34.
Chen M, et al. Antineutrophil cytoplasmic autoantibody-associated vasculitis in older patients. Medicine (Baltimore) 2008;87(4):203–9.
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 2012;64(10):3452–62.
Pagnoux C. Updates in ANCA-associated vasculitis. Eur J Rheumatol 2016;3(3):122–33.
Jennette JC, Nachman PH. ANCA Glomerulonephritis and Vasculitis. Clin J Am Soc Nephrol 2017;12(10):1680–91.
von Borstel A, et al. Cellular immune regulation in the pathogenesis of ANCA-associated vasculitides. Autoimmun Rev 2018;17(4):413–21.

GCC-AVA-2500012 | Date of preparation: October 2025

Disease mechanism

The importance of complement and neutrophils in AAV activation

C5a plays a major role in the pathogenesis of AAV, amplifying ANCA-induced inflammation and vascular damage¹

Diagram adapted from Bekker P, et al. PLoS One 2016

A. The three pathways of complement activation (classical, lectin and alternative) result in the formation of C3a, C3b, C5a and C5b-9¹.

B. The alternative complement pathway is constantly ticking over through the spontaneous breakdown of C3 to C3b.² It is the dysregulation of this pathway that is relevant in AAV¹.

C. C5 convertase formed during the amplification loop cleaves C5 into C5a and C5b¹.

D. C5b combines with complement components C6, C7, C8 and C9 to form C5b-9, also known as the terminal complement complex or membrane attack complex¹.

E. C5a is the downstream terminal effector molecule in the complement cascade and a potent pro-inflammatory mediator critical in AAV^1,4.

F. C5b-9 is needed for host resistance to encapsulated bacterial infections, such as Neisseria meningitides^1,3.

G. Binding of C5a to C5aR1 results in two key events that act in a vicious cycle to amplify ANCA-induced inflammation and vascular damage:^1,4,5.

Rapid induction of the expression of adhesion molecules on the cell surface that causes leukocyte chemotaxis¹.
Further exposure of ANCA antigens at the neutrophil cell surface facilitates subsequent neutrophil activation⁵.

C5aR1 is also thought to play a role in promoting autoimmunity to ANCA antigens andincreasing ANCA production.⁶

In addition, C5a mediates inflammation by stimulating vascular permeability, neutrophil degranulation, and release of lysosomal proteases and oxidative freeradicals^1,7.

H. C5L2 activation does not play a role in AAV; in other conditions, it has a currently unclear pattern of pro- and anti-inflammatory actions^1,8.

C5a is rapidly degraded by removal of the C-terminal arginine, forming C5a des Arg with approximately 10-fold reduced activity on C5aR1^1,9.

C5a des Arg binds with high affinity to the C5L2 receptor, and is subsequently internalised and degraded^1,10.

References & footnotes

Abbreviations

AAV, ANCA-associated vasculitis; ANCA, anti-neutrophil cytoplasmic antibody; C-terminal, carboxy terminal; MAC, membrane attack complex; R, receptor

References