Plasma Exchange and Glucocorticoids for Treatment of Anti-Neutrophil Cytoplasm Antibody (ANCA) - Associated Vasculitis

Granulomatosis with polyangiitis (Wegener's) (WG) and microscopic polyangiitis (MPA) are
syndromes of primary systemic vasculitis associated with anti-neutrophil cytoplasm antibodies
(ANCA). Together, these syndromes are grouped as ANCA-associated systemic vasculitis (AAV).

Plasma exchange, a method of rapidly removing potentially pathogenic ANCA and other mediators
of inflammation and coagulation, has shown promise as an adjunctive therapy in AAV to improve
early disease control and improve rates of renal recovery in severe disease. Glucocorticoids
(steroids) are a standard of care in the treatment of AAV. High doses of glucocorticoids
early in disease, although reduce disease activity due to their anti-inflammatory and
immunosuppressive properties, also increase the risk of infection, particularly in the
elderly and in the presence of uremia. There is no randomized trial data to guide
glucocorticoids dosing.

Patients with severe new or relapsing AAV and pulmonary hemorrhage and/or renal disease will
be eligible for this trial.

Subjects participating in this study will be randomized to receive one of the following
groups;

1. Plasma exchange - 7 exchanges and, either standard or low-dose glucocorticoids or

2. No plasma exchange and, either standard or low-dose glucocorticoids

All studies will receive standard remission-induction therapy with either cyclophosphamide or
rituximab.

Inclusion Criteria:

• New or previous clinical diagnosis of granulomatosis with polyangiitis or microscopic
polyangiitis consistent with the Chapel-Hill consensus definitions

AND

• Positive test for proteinase 3-ANCA or myeloperoxidase-ANCA

AND

- Severe vasculitis defined by at least one of the following:

1. Renal involvement with both:

- Renal biopsy demonstrating focal necrotizing glomerulonephritis or active
urine sediment characterized by glomerular haematuria or red cell casts and
proteinuria

AND

- eGFR <50 ml/min/1.73 m2

2. Pulmonary hemorrhage due to active vasculitis defined by:

- A compatible chest x-ray or CT scan (diffuse pulmonary infiltrates)

AND

- The absence of an alternative explanation for all pulmonary infiltrates
(e.g. volume overload or pulmonary infection)

AND

3. At least one of the following:

- Evidence of alveolar hemorrhage on bronchoscopic examination or increasingly
bloody returns with bronchoalveolar lavage

- Observed hemoptysis

- Unexplained anemia (<10 g/dL) or documented drop in hemoglobin >1 g/dL)

- Increased diffusing capacity of carbon dioxide

- Provision of informed consent by patient or a surrogate decision maker

Exclusion Criteria:

- A diagnosis of vasculitis other than granulomatosis with polyangiitis or microscopic
polyangiitis

- Positive anti-glomerular basement membrane antibody test or renal biopsy demonstrating
linear glomerular immunoglobulin deposition

- Receipt of dialysis for >21 days immediately prior to randomization or prior renal
transplant

- Age <15 years

- Pregnancy

- Inability or unwillingness to comply with birth control/abstinence

- Treatment with >1 IV dose of cyclophosphamide and/or >14 days of oral cyclophosphamide
and/or >14 days of prednisone/prednisolone (>30 mg/day) and/or >1 dose of rituximab
within the 28 days immediately prior to randomization

- A comorbidity that, in the opinion of the investigator, precludes the use of
cyclophosphamide, glucocorticoids, or plasma exchange or absolutely mandates the use
of plasma exchange