Defining Immune Tolerance in ANCA-associated Vasculitis (AAV)

Terminated

Brief Summary: The goal of the study is to find biological markers (certain proteins or cellular markers found in a blood test) that will inform doctors which patients diagnosed with ANCA-associated vasculitis (AAV) are most likely to be able to stop their medications suppressing their immune systems and remain in remission.

Detailed Description: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are small vessel vasculitides that typically follow a chronic course and are associated with serious illness and death.Three clinical conditions are recognized: microscopic polyangiitis (MPA); granulomatosis with polyangiitis (Wegener's, GPA); and eosinophilic granulomatosis with polyangiitis (EPA, formerly Churg Strauss Syndrome). Though these conditions have different clinical features, they can have overlapping immunological characteristics.

The precise cause of AAV is not understood, but there are clear genetic associations which, in the context of predisposing environmental factors, such as infections, may lead to development of disease. There are no diagnostic criteria for AAV, but there are validated classification criteria and disease definitions.

There is a need to find biological markers that define immunological tolerance so that immunotherapy medicines may be correctly changed and safely withdrawn in some people.

Recruitment & Eligibility

Inclusion Criteria

Tolerant AAV participants:

Age 18 years or older
Diagnosis of granulomatosis with polyangiitis (Wegener's, GPA) or microscopic polyangiitis (MPA) according to the definitions of the Chapel Hill Consensus Conference (CHCC)
History of being myeloperoxidase (MPO)-ANCA positive during a disease flare
In clinical remission with Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) = 0 and off all immunosuppression for ≥ 2 years
Negative MPO-ANCA and proteinase 3 (PR3)-ANCA by ELISA at screening
For women of child-bearing potential, a negative urine or serum pregnancy test at the time of screening
Ability to sign and understand informed consent
Willingness to comply with study procedures.

Non-Tolerant AAV participants:

Age 18 years or older
Diagnosis of granulomatosis with polyangiitis (Wegener's), GPA or microscopic polyangiitis (MPA) according to the definitions of the CHCC
History of being MPO-ANCA positive during a disease flare
Within the past 5 years, must have had a disease exacerbation, defined as an increase in the BVAS/WG score and re-institution of immunosuppressive therapy after therapy had been reduced or completely discontinued
In clinical remission with BVAS/WG = 0 and on minimal maintenance therapy for ≥3 months prior to the screening visit. Minimal maintenance therapy is defined as:
- Low-dose glucocorticoids (≤10 mg of prednisone or prednisolone daily) and/or:
  - Azathioprine ≤ 150mg daily or
  - Mycophenolate mofetil (MMF) ≤ 1 gram daily or mycophenolate sodium ≤ 720 mg daily.
Positive MPO-ANCA by ELISA on at least 2 occasions within the last 52 weeks, the most recent result being within 8 weeks of visit -1
For women of child-bearing potential, a negative urine or serum pregnancy test at the time of screening
Ability to sign and understand informed consent
Willingness to comply with study procedures.

Healthy Controls:

Healthy participant age ≥18 years
For women of child-bearing potential, a negative urine or serum pregnancy test at the time of screening
Ability to sign and understand informed consent
Willingness to comply with study procedures.

Exclusion Criteria

Tolerant AAV Participants:

Use of systemic intravenous (IV) or oral glucocorticoids for ˃ 1 month for any non-vasculitis indication within 8 weeks of the screening visit
Any prior treatment with rituximab
Presence of known chronic viral infections or autoimmune diseases
History of malignancy, excluding non-melanomatous skin cancers or cervical cancer carcinoma in situ within 5 years of the screening visit.

Non-Tolerant AAV participants:

Use of IV pulse glucocorticoids (methylprednisolone or other) or cyclophosphamide within the year prior to the screening visit
Use of IV or oral glucocorticoids for > 1 month for any non- vasculitis indication within 8 weeks of screening visit
Any prior treatment with rituximab
Maintenance therapy with methotrexate within 3 months of the screening visit
Presence of known chronic viral infections or other autoimmune diseases
History of malignancy, excluding non-melanoma skin cancers or cervical cancer carcinoma in situ within 5 years of the screening visit.

Healthy Controls:

Use of IV or oral glucocorticoids for > 1 month for any non-vasculitis indication within 8 weeks of the screening visit
Presence of known chronic viral infections or other autoimmune diseases
History of malignancy, excluding non-melanoma skin cancers or cervical cancer carcinoma in situ within 5 years of the screening visit.

AAV Participants Discontinuing Immunosuppression:

Any prior treatment with rituximab
Maintenance therapy with methotrexate within 3 months of the screening visit
Presence of known chronic viral infections or other autoimmune diseases
History of malignancy, excluding non-melanoma skin cancers or cervical cancer carcinoma in situ, within 5 years of the screening visit.

Arm && Interventions

Group	Intervention	Description
Non-Tolerant AAV	Venipuncture for blood sample collection	Non-Tolerant participants with ANCA-associated vasculitis (AAV)
Tolerant AAV	Venipuncture for blood sample collection	Tolerant participants with AAV
Healthy Controls	Venipuncture for blood sample collection	Healthy participants that fulfill eligibility criteria -similar in age to Tolerant and Non-Tolerant AAV participants.
AAV Discontinuing Immunosuppression	Venipuncture for blood sample collection	Participants have been in clinical remission and on minimal maintenance therapy for at least 2 years prior to screening. Their primary physicians have planned to discontinue immunosuppression medication in the next year after screening.

Primary Outcome Measures

Name	Time	Method
Tolerance Biomarker Identification	Difference from baseline to week 26	Identification of biomarkers associated with clinical tolerance in patients with ANCA-associated vasculitis by comparative immunophenotyping of individual leukocyte subsets from tolerant and non-tolerant patients with AAV. Due to early study termination, data was not available to evaluate this endpoint.

Secondary Outcome Measures

Name	Time	Method
Tolerance Signature Stability	Baseline to Week 26	Measurement of the stability of a tolerance immune signature in patients with AAV over time. Due to early study termination, data was not available to evaluate this endpoint.
Tolerance Signature Versus Clinical Status	Baseline to Week 26	Correlation of possible changes in the tolerance signature with changes in clinical status. Due to early study termination, data was not available to evaluate this endpoint.
Immunosuppression Associated Signature	Baseline to 8 Weeks Post-Immunosuppression Withdrawal	Definition of an immune signature associated with maintenance immunosuppression. Due to early study termination, data was not available to evaluate this endpoint.

Locations (3): University College London, Centre for Nephrology
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London, England, United Kingdom
Addenbrooke's Hospital
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Cambridge, England, United Kingdom
Hammersmith Hospital
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London, England, United Kingdom