Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare multisystem autoimmune disease, characterised by necrotising pauci-immune small-vessel vasculitis. This systemic disease can lead to significant organ damage and primarily affects the kidneys, lungs, ears, nose and throat, and musculoskeletal systems.
The latest consensus guidelines from the European Alliance of Associations for Rheumatology (EULAR) and the Kidney Disease: Improving Global Outcomes (KDIGO) provide new insights and updates on managing AAV. This article explores these guidelines, highlighting the latest recommendations and advancements in treatment.
Understanding AAV
AAV comprises three clinico-pathological syndromes: Granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). The estimated overall annual incidence of AAV is 13-to-20 cases/million, with a prevalence of 300-to-421 cases/million. AAV poses significant clinical challenges due to its multisystem involvement.
In Ireland, the RITA-Ireland Vasculitis RIV registry and biobank is managed in collaboration with the Irish national vasculitis patient organisation, Vasculitis Ireland Awareness.
The aim of this registry is to collate clinical data and bio-samples from patients with vasculitis across Ireland. To date, 1,021 patients with various forms of vasculitis have been recruited across eight nephrology, rheumatology, and immunology centres, facilitating extensive research in this field.
Updated EULAR principles
The EULAR taskforce conducted a systematic literature review and consulted 20 experts from 16 countries. The updated recommendations set out definitions of various disease activity states in AAV, allowing for continuity across clinical trials. EULAR outlined four overarching principles for managing AAV:
1. Shared decision-making: Patients should be offered the best care based on shared decision-making between the patient and the physician, considering efficacy, safety, and costs.
Communication between physicians and patients is crucial to ensure engagement with the treatment plan and prevent end-organ damage due to uncontrolled inflammation. Health and lifestyle factors such as employment, fertility, and vaccination status should be considered.
2. Patient education: Patients should have access to education focusing on the impact of AAV, its prognosis, key warning symptoms, and treatment (including treatment-related complications). Vasculitis Ireland Awareness provides useful information for patients and their families. (www.vasculitis-ia.org)
3. Screening for adverse effects: Patients should be periodically screened for treatment-related adverse effects and comorbidities. Prophylaxis and lifestyle advice should be provided to reduce complications. Patients with AAV have increased cardiovascular risk and higher rates of diabetes and hypertension.
4. Multidisciplinary management: The diagnosis and treatment of AAV can be challenging and expert knowledge is invaluable. Due to the systemic nature of AAV, treatment frequently involves collaboration between specialities.
Dublin Vasculitis and Allergy Group (DVAG), led by Prof Mark Little and Dr Patrick Mitchell, meet monthly, bringing together experts to discuss challenging cases with interdisciplinary input.
The European Reference Network for Rare Immunodeficiency, Autoinflammatory, and Autoimmune Diseases (ERN-RITA) national centres of excellence in Ireland comprise of seven specialist centres for vasculitis, fostering collaboration and excellence in patient care across the country. (www.tcd.ie/medicine/thkc/european-reference-network—rita-ireland/)
Diagnosis and treatment initiation
EULAR and KDIGO emphasise the importance of initiating treatment immediately in patients with clinical signs of AAV and positive ANCA serology, prior to confirming the diagnosis with a kidney biopsy. This approach prevents delays that could lead to rapid disease progression and organ damage.
Serology: For patients with signs and symptoms of AAV, PR3 and MPO antibody testing should be performed as the first step. ANCA serotype is emerging as the preferred subclassification for AAV, with patients diagnosed with PR3-ANCA or MPO-ANCA. Genetic similarities have been seen within these subgroups suggesting that this classification is meaningful.
ANCA positivity can be seen in other autoimmune diseases and infections and may also be drug induced. Importantly, ANCA negativity does not exclude the diagnosis of AAV. Anti-glomerular basement membrane (GBM) antibodies should also be tested in patients with pulmonary renal syndrome as dual positivity (anti-GBM/AAV overlap) can be seen, and plasma exchange (PLEX) may be beneficial in these patients.
Induction treatment
Tailored treatment choices: For induction, the combination of glucocorticoids with either rituximab or cyclophosphamide remains standard. Patient-specific factors are considered when choosing between rituximab and cyclophosphamide.
Rituximab is the treatment of choice for children, premenopausal women, as well as those with relapsing disease or PR3-ANCA positivity. When considering rituximab dosing, there is no difference in patient outcomes between patients prescribed 375mg/m2 per week for four weeks (as seen in RAVE trial) and 1g in weeks zero and two.
On the other hand, cyclophosphamide may be considered in patients with severe renal impairment or diffuse alveolar haemorrhage. The recent PEXIVAS trial did not identify a difference between rituximab and cyclophosphamide when considering renal impairment or diffuse alveolar haemorrhage, however, the study was not powered to examine this outcome.
KDIGO provides guidance on choosing between intravenous (IV) and oral administration of cyclophosphamide. Although outcomes are similar between both, the cumulative dosage of cyclophosphamide is lower with IV cyclophosphamide. However, patients treated with IV pulsed cyclophosphamide may have an increased risk of relapse, as reported in the CYCLOPS study. Cyclophosphamide is preferred in severe presentations of EGPA.
Mycophenolate mofetil (MMF): While the MYCYC trial showed that MMF was non-inferior to cyclophosphamide for remission induction, relapse rates were higher in the PR3 positive subgroup. As a result, the use of MMF for remission induction should be limited to situations where rituximab and cyclophosphamide are not tolerated. In non-organ or life-threatening AAV, methotrexate or MMF can be considered, however, rituximab is preferrable.
| REDUCED-CORTICOSTEROID DOSE IN PEXIVAS TRIAL | |||
|---|---|---|---|
| WEEK | <50kg | 50-75kg | >75kg |
| 1 | 50 | 60 | 75 |
| 2 | 25 | 30 | 40 |
| 3-4 | 20 | 25 | 30 |
| 5-6 | 15 | 20 | 25 |
| 7-8 | 12.5 | 15 | 20 |
| 9-10 | 10 | 12.5 | 15 |
| 11-12 | 7.5 | 10 | 12.5 |
| 13-14 | 6 | 7.5 | 10 |
| 15-16 | 5 | 5 | 7.5 |
| 17-18 | 5 | 5 | 7.5 |
| 19-20 | 5 | 5 | 5 |
| 21-22 | 5 | 5 | 5 |
| 23-52 | 5 | 5 | 5 |
| >52 | Investigators’ local practice | ||
Glucocorticoids: The PEXIVAS trial reduced dose glucocorticoid regimen is advised by both KDIGO and EULAR. In the PEXIVAS trial, the reduced dose prednisolone regime resulted in 40 per cent reduction in oral glucocorticoid exposure in the first six months. It was non-inferior in terms of treatment efficacy and lead to a reduction in serious infections.
The RITAZAREM trial used a further reduced dosing of glucocorticoids with 0.5mg/kg/day and 1.0mg/kg/day in conjunction with rituximab. This trial has produced reassuring data suggesting that 0.5mg/kg/day may be an option for some patients without organ-threatening or life-threatening disease.
As described by EULAR, IV methylprednisolone pulses (1,000-3,000mgs) were used for induction in the RAVE, MEPEX, and PEXIVAS trials. However, there is limited evidence-base for IV methylprednisolone pulses, and considering this, IV pulses should be limited to treatment of severe organ-threatening presentations.
Avacopan: This complement 5a receptor inhibitor is recommended as a glucocorticoid-sparing agent and can be beneficial in patients where reduced exposure to glucocorticoids is a priority, eg, severe osteoporosis. The ADVOCATE trial reported that patients with active glomerulonephritis treated with avacopan had improved recovery of renal function when compared to glucocorticoids.
Avacopan is newly available in Ireland since July 1 2024 for prescription through the high-tech hub. Prescribing is limited to nephrologists, rheumatologists, and immunologists. Further studies are needed to evaluate the role of avacopan beyond one year and for patients presenting with glomerular filtration rate (GFR) <15ml/min/1.73m2.
PLEX: While beneficial in certain circumstance, there is conflicting evidence on the role of PLEX in the literature. The MEPEX trial supported the use of PLEX if serum creatinine is >500µmol/L. Subsequent meta-analysis reported that this evidence was not robust, but suggested there may be benefit with less severe acute kidney injury (AKI).
The PEXIVAS trial found no difference in a compositive end-point of death and end-stage kidney disease (ESKD) at median 2.9 years between the PLEX and no PLEX arm. Further meta-analysis showed that while PLEX may reduce the risk of ESKD at 12 months, it also increases the risk of serious infections.
EULAR and KDIGO concluded that PLEX can be considered in patients with serum creatinine >300µmol/L or rapidly rising creatinine due to active glomerulonephritis. EULAR feel that there is insufficient evidence to make a recommendation for or against PLEX in isolated diffuse alveolar haemorrhage at present.
On the other hand, KDIGO support the use of PLEX in patients with diffuse alveolar haemorrhage who have hypoxaemia. PLEX is recommended by KDIGO and EULAR for patients with anti-GBM/AAV overlap syndrome, though this practice is only supported by low evidence.
The British Medical Journal (BMJ) issued a rapid recommendation on the role of PLEX in AAV. The panel concluded that for patients with low or low-to-moderate risk of ESKD, immunosuppression alone without PLEX should be offered as the improvement in ESKD with PLEX did not counterbalance the risk of serious infection.
For patients with moderate-to-high or high-risk of developing ESKD, PLEX should be offered with immunosuppression. For patients with pulmonary haemorrhage without renal involvement, the BMJ Rapid Recommendations Panel concluded that immunosuppression alone was preferrable.
The panel made this recommendation based on indirect evidence that PLEX may increase the risk of serious infection and has an uncertain effect on death. Further studies may provide stronger evidence on the role of PLEX.
Sustaining remission with maintenance therapy
Maintaining remission after initial treatment is crucial. A number of treatment options exist:
Rituximab and azathioprine: These are the preferred maintenance therapies for AAV, with rituximab showing particular efficacy in preventing relapses. Considering the improved survival and duration of remission seen in the MAINRITSAN and RITAZAREM trials, EULAR recommend rituximab over azathioprine for maintenance treatment. Azathioprine is preferrable in patients with hypogammaglobulinaemia.
Alternative options: MMF and methotrexate are viable alternatives for patients who cannot tolerate azathioprine, although methotrexate should be avoided in patients with significant renal impairment (GFR <60ml/min/1.73m2).
Duration of treatment: As per KDIGO, maintenance therapy typically lasts between 18 months and four years, tailored to individual patient risk factors and responses. EULAR advise that maintenance therapy should be considered for 24-to-48 months after induction and longer if needed.
The results of the REMAIN study showed fewer relapses in patients treated with azathioprine and glucocorticoids for 48 months versus 24 months (azathioprine/cyclophosphamide induction). In the MAINRITSAN-3 trial, more patients remained relapse-free with 36 months of rituximab versus 18 months. Patients with PR3-ANCA are at higher risk of relapse, as are patients with persistent ANCA positivity. A higher risk of relapse has also been reported in patients with GPA versus MPA.
Other risk factors for relapse include persistent haematuria and B-cell repopulation within 12 months of rituximab. Patients with renal limited vasculitis are at lower risk of relapse. Patients with drug induced vasculitis do not usually require maintenance treatment after remission is achieved and the causative drug is discontinued.
Overall, individual preferences and risk factors should be considered when deciding on duration of maintenance treatment. This question is being addressed by the PARADISE EU trial currently being led by RITA Ireland. (www.paradise-project.eu)
Managing relapses and refractory disease
Relapses are a significant concern in AAV management. Rituximab remains the preferred treatment for reinducing remission in patients with severe relapses, highlighting its role in both initial and long-term management. The RITAZAREM trial has shown that rituximab can restore remission in patients with relapsing AAV.
For refractory disease, a thorough reassessment is required, and alternative diagnoses and treatment options should be considered. KDIGO suggests increasing glucocorticoid doses and switching between rituximab and cyclophosphamide in patients with refractory disease. Referral to centres of expertise is recommended for managing complex cases and a multidisciplinary approach is beneficial.
Embracing novel therapies
The inclusion of avacopan in treatment regimens represents a significant advancement. By targeting the complement pathway, avacopan reduces the dependency on high-dose glucocorticoids, offering a better side-effect profile and improved quality-of-life for patients.
To date, nine patients in Ireland have received avacopan through the Managed Access Programme and ADVOCATE trial. The recently confirmed funding of avacopan and prescribing via the high-tech hub will increase the availability of this medication, providing more individualised treatment options for our patients. Clinical trials have shown the efficacy of avacopan in improving renal outcomes, making it a valuable addition to the AAV treatment landscape.
Looking forward
The continued advancements in understanding and treating AAV highlight the importance of ongoing research and guideline updates. Both EULAR and KDIGO emphasise the need for further investigation into biomarkers for disease activity, optimising immunosuppressive regimens, and evaluating long-term outcomes. These efforts aim to refine treatment protocols and develop new therapies, ultimately enhancing patient care and prognosis.
By integrating these novel recommendations into clinical practice, healthcare providers can navigate the complexities of AAV more effectively. The evolving landscape of AAV management promises a brighter future for those affected by this challenging condition, improving patient outcomes and quality-of-life.
This clinical update provides a comprehensive overview of the latest evidence-based strategies for managing AAV. As research continues to progress, these guidelines will evolve, further shaping the future of AAV treatment and care.
For more details on vasculitis in Ireland visit:
- Vasculitis Ireland Awareness – patient support group at: www.vasculitis-ia.org
- RIV Registry and Biobank at: www.tcd.ie/medicine/thkc/our-research/ritaireland-vasculitis-riv-registry-and-biobank
References available on request
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