What therapy suppresses the autoimmune response to Proteinase 3 (PR3)?

From the Guidelines

Therapy for suppressing the autoimmune response to proteinase 3 (PR3) should prioritize rituximab for maintenance therapy, particularly for patients with known relapsing disease, PR3-AAV, and azathioprine allergy, due to its advantage over azathioprine in preventing relapses and improving health-related quality of life, as shown in the MAINRITSAN study 1. The standard treatment regimen for PR3-AAV typically involves induction therapy with cyclophosphamide or rituximab combined with high-dose corticosteroids to achieve remission.

• Induction therapy with rituximab (375 mg/m² weekly for 4 weeks or 1000 mg on days 1 and 15) is recommended for patients with relapsing disease or those concerned about fertility 1.
• Maintenance therapy with rituximab is preferred over azathioprine due to its effectiveness in preventing relapses and improving health-related quality of life, as demonstrated by the MAINRITSAN study, which showed significant improvements in Health Assessment Questionnaire (HAQ) scores for patients treated with rituximab compared to azathioprine 1.
• The duration of maintenance therapy should be individualized, but it is generally recommended to continue therapy for 24-48 months following induction of remission, with longer durations considered for relapsing patients or those with an increased risk of relapse 1.
• Regular monitoring of complete blood counts, liver and kidney function, and ANCA titers is essential during treatment to assess response and detect potential toxicities early.
• The choice of maintenance therapy should be guided by the patient's risk of relapse, with rituximab preferred for patients with a high risk of relapse, such as those with PR3-AAV or a history of relapsing disease 1.

From the FDA Drug Label

The mechanisms whereby azathioprine affects autoimmune diseases are not known. Azathioprine is immunosuppressive, delayed hypersensitivity and cellular cytotoxicity tests being suppressed to a greater degree than are antibody responses For example, the severity of adjuvant arthritis is reduced by azathiopine. The drug suppresses hypersensitivities of the cellmediated type and causes variable alterations in antibody production Suppression of T-cell effects, including ablation of T-cell suppression, is dependent on the temporal relationship to antigenic stimulus or engraftment.

Therapy suppressing the autoimmune response to PR3 is not directly mentioned in the provided drug labels. However, based on the information provided, azathioprine can suppress autoimmune responses, but its effect on PR3 is not specified.

• Azathioprine has been shown to suppress disease manifestations as well as underlying pathology in animal models of autoimmune disease.
• The exact mechanism of azathioprine in autoimmune diseases is unknown, but it is considered immunosuppressive.
• Mycophenolate mofetil is also an immunosuppressive drug, but its effect on PR3 is not mentioned in the provided drug label. 2 3

From the Research

Therapy Suppressing the Autoimmune Response to PR3

• The study 4 investigated the efficacy and safety of rituximab induction therapy in patients with granulomatosis with polyangiitis (GPA), which is associated with an autoimmune response to proteinase 3 (PR3).
• The results showed that rituximab is an effective remission-inducing agent in GPA, and the addition of a conventional maintenance agent to rituximab and glucocorticoids decreased the incidence of relapse without increasing adverse events.
• Another study 5 compared the efficacy and safety of rituximab, mycophenolate, methotrexate, and cyclophosphamide versus azathioprine as maintenance therapy in antineutrophil cytoplasmic antibody-associated vasculitis (AAV), which also involves an autoimmune response to PR3.
• The study found that rituximab demonstrated lower relapse rates than mycophenolate, and had the highest probability of being the best relapse-lowering therapy, followed by cyclophosphamide, methotrexate, azathioprine, and mycophenolate.
• However, there is no direct evidence from the provided studies on the specific therapy suppressing the autoimmune response to PR3, but rituximab has shown effectiveness in treating GPA and AAV, which are related to PR3.

Mechanism of Action

• Rituximab is a monoclonal antibody that targets CD20-positive B cells, which play a key role in the autoimmune response to PR3.
• By depleting B cells, rituximab can reduce the production of autoantibodies against PR3, thereby suppressing the autoimmune response.
• The exact mechanism of action of rituximab in GPA and AAV is not fully understood, but it is thought to involve the depletion of autoreactive B cells and the reduction of inflammatory cytokines.

Clinical Implications

• The use of rituximab as a therapy for suppressing the autoimmune response to PR3 may be effective in treating GPA and AAV.
• However, further studies are needed to confirm the efficacy and safety of rituximab in these conditions, and to determine the optimal dosage and treatment regimen.
• Additionally, the use of rituximab in combination with other immunosuppressive agents, such as mycophenolate or methotrexate, may be effective in reducing the risk of relapse and improving treatment outcomes.