Defining Immune Tolerance in ANCA-associated Vasculitis (AAV)
Defining Immune Tolerance in ANCA-associated Vasculitis (AAV)
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.
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 immunotherapy medicines may be correctly changed and safely withdrawn in some people.
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.