What are the details of Anti-Neutrophil Cytoplasmic Antibodies (ANCA) related vasculitis?

From the Guidelines

Rituximab is the preferred treatment for ANCA-associated vasculitis, particularly for patients with PR3-ANCA, due to its superior remission rate and lower risk of infectious complications compared to cyclophosphamide, as shown in the RAVE trial 1. The treatment of ANCA-associated vasculitis typically involves induction therapy with high-dose corticosteroids combined with either cyclophosphamide or rituximab.

• The choice of induction therapy depends on the severity of the disease and the presence of specific ANCA subtypes.
• For patients with PR3-ANCA, rituximab has been shown to be more effective than cyclophosphamide in achieving remission, with an odds ratio of 2.11 (95% CI: 1.04-4.30) at 6 months 1.
• In patients with MPO-ANCA, mycophenolate mofetil may be an alternative to cyclophosphamide for non-life-threatening disease, but it is associated with a higher relapse risk in patients with PR3-ANCA 1.
• Glucocorticoids are a major contributor to adverse events, and reducing their dose or using alternative treatments such as avacopan, a C5a receptor antagonist, may improve outcomes and reduce the risk of infections 1. Some key points to consider in the treatment of ANCA-associated vasculitis include:
• The use of Pneumocystis pneumonia prophylaxis with trimethoprim-sulfamethoxazole during immunosuppression.
• Regular monitoring of kidney function, complete blood counts, and inflammatory markers.
• The importance of early diagnosis and aggressive treatment to prevent permanent organ damage and improve long-term outcomes. The pathophysiology of ANCA-associated vasculitis involves ANCA antibodies activating neutrophils, causing them to adhere to vessel walls and release inflammatory mediators that damage blood vessels, particularly in the kidneys, lungs, and upper respiratory tract.
• The 2024 KDIGO clinical practice guideline for the management of ANCA-associated vasculitis provides recommendations for the treatment of this condition, including the use of rituximab and cyclophosphamide as induction therapy, and the importance of reducing glucocorticoid dose and using alternative treatments to minimize adverse events 1.

From the FDA Drug Label

All patients had active disease, with a Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis (BVAS/GPA) greater than or equal to 3, and their disease was severe, with at least one major item on the BVAS/GPA. Ninety-six (49%) of patients had new disease and 101 (51%) of patients had relapsing disease The main outcome measure for both GPA and MPA patients was achievement of complete remission at 6 months defined as a BVAS/GPA of 0, and off glucocorticoid therapy Table 22 Percentage of Patients with GPA/MPA Who Achieved Complete Remission at 6 Months (Intent-to-Treat Population) RITUXAN(n = 99)Cyclophosphamide(n = 98)Treatment Difference(RITUXAN – Cyclophosphamide) Rate64%53%11% 95. 1%* CI(54%, 73%)(43%, 63%)(-3%, 24%)

ANCA-related vasculitis details:

• The study included patients with Granulomatosis with Polyangiitis (GPA) and Microscopic Polyangiitis (MPA), which are forms of ANCA-associated vasculitis.
• Patients had active disease with a BVAS/GPA score of 3 or higher and at least one major item on the BVAS/GPA.
• The main outcome measure was achievement of complete remission at 6 months, defined as a BVAS/GPA score of 0 and off glucocorticoid therapy.
• The study demonstrated non-inferiority of RITUXAN to cyclophosphamide for complete remission at 6 months, with a treatment difference of 11% (2).
• In another study, by month 28, major relapse occurred in 3 patients (5%) in the non-U.S.-licensed rituximab group and 17 patients (29%) in the azathioprine group (2).

From the Research

ANCA-Associated Vasculitis Treatment

• The treatment of ANCA-associated vasculitis (AAV) typically involves the use of immunosuppressive medications, such as cyclophosphamide or rituximab, in combination with glucocorticoids 3, 4, 5, 6.
• Glucocorticoids are effective in inducing remission, but their use is associated with significant toxicity, including increased risk of infections, mood disturbances, and adrenal insufficiency 3, 6, 7.
• Rituximab, an anti-B-cell biological therapy, has been shown to be effective in inducing and maintaining remission in AAV patients, and may be preferred over cyclophosphamide in certain situations, such as in women of childbearing age or in patients with a history of malignancy 4, 6.

Plasma Exchange and Glucocorticoid Regimens

• A randomized trial found that plasma exchange did not reduce the incidence of death or end-stage kidney disease in patients with severe AAV, compared to a control group 3.
• The same trial found that a reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen in terms of death or end-stage kidney disease, and was associated with a lower incidence of serious infections 3.

Glucocorticoid Toxicity Index

• The Glucocorticoid Toxicity Index (GTI) is a tool used to quantify glucocorticoid-associated morbidity, and has been used to assess the toxicity of glucocorticoid treatment in AAV patients 7.
• A retrospective cohort study found that higher cumulative doses of glucocorticoids were associated with worse glucocorticoid-related toxicity, as measured by the GTI score 7.

Future Directions

• Novel strategies that avoid the toxicity associated with currently used agents, such as glucocorticoid-sparing treatments, are being explored as potential alternatives for the management of AAV 6, 7.
• The use of rituximab and other biologic therapies may play a larger role in the treatment of AAV in the future, particularly in patients who are at high risk of glucocorticoid toxicity or who have a history of malignancy 4, 6.