Tailoring Maintenance Therapy to Cluster of Differentiation 5 Positive (CD5+) Regulatory B Cell Recovery in ANCA Vasculitis
Tailoring Maintenance Therapy to Cluster of Differentiation 5 Positive (CD5+) Regulatory B Cell Recovery in ANCA Vasculitis
ANCA vasculitis is a pauci-immune systemic small vessel vasculitis. The anti-neutrophilic
 cytoplasmic antibodies (ANCA) are pathogenic and cause disease by activating neutrophils
 which damage blood vessels. CD means "cluster of differentiation" . CD5 is a type I
 transmembrane protein found on T cells, thymocytes, and some B cells. CD20 is a type III
 transmembrane protein found on B cells. The investigators previously detected an association
 between recovery of Interleukin 10 (IL-10)-secreting CD20+ and CD5+ regulatory B cells after
 immunotherapy (with rituximab and corticosteroids) and decreased risk of subsequent relapse
 in patients with ANCA-vasculitis. The investigators hypothesize that patients with complete
 reconstitution of a functional regulatory B cell repertoire after induction therapy are at
 low risk of relapse and may be monitored conservatively without further immunotherapy. The
 investigators will test this hypothesis through a proof of concept randomized controlled
 study. Patients with normalization of CD5+ regulatory B cells will be randomized to
 maintenance therapy with rituximab vs. close observation without immunosuppression. Patients
 whose peripheral CD5+ regulatory B cells remain low after induction therapy (who are at
 higher risk of relapse), will receive maintenance immunosuppression with rituximab. Patients
 needing or randomized to maintenance therapy who are unable to receive rituximab will receive
 azathioprine or mycophenolate mofetil, two standard alternative medications for maintenance
 immunosuppression.
The goal of this study is to test the hypothesis that, in ANCA vasculitis, use of CD5+ B
 cells at the time of B cell reconstitution in the peripheral blood can be used to stratify
 patients between those with low % CD5+ B cells at greater risk of relapse who would need
 maintenance immunosuppression and those with normalized CD5+ B cells who would be at lower
 risk and relapse, and therefore may not need maintenance immunosuppression. The latter group
 will be randomized to either maintenance immunosuppression vs close clinical observation
 without maintenance immunosuppression. This study is not designed to evaluate the efficacy of
 new therapies in ANCA vasculitis. The treatment regimen used in the proposed study are
 routinely used in the treatment of patients with ANCA vasculitis and considered
 standard-of-care.
Inclusion Criteria:

 -  Patients 18-85 years old.

 -  ANCA Glomerulonephritis (GN) or vasculitis per Chapel Hill Consensus Criteria, with
 documented current or previously positive Myeloperoxidase (MPO)- or Proteinase 3
 (PR3)-ANCA by ELISA test. Patients with biopsy-proven, pauci-immune crescentic
 glomerulonephritis are eligible if they have a positive ANCA test by immunofluorescent
 microscopy (IIFM).

 -  Patients must be in complete remission for at least 1 month and after AT LEAST 3
 MONTHS of induction of therapy with corticosteroids and rituximab (either 1000 mg IV x
 2 or 375 mg/m2 IV x 4) OR corticosteroids and cyclophosphamide (monthly IV or daily
 oral doses). They must be on no more than 5 mg daily of oral prednisone or equivalent.
 Complete remission is defined as a BVAS score = 0.

 -  Patients may be ANCA negative or positive at randomization.

 Exclusion Criteria:

 -  Patients who have had ≥ 2 relapses (defined as recurrence of any signs or symptoms
 attributable to active vasculitis) previously as patients with multiple prior relapses
 may be at higher risk of future relapse and require maintenance therapy

 -  Patients with persistent low-grade disease activity ("grumbling" disease defined as
 BVAS > 0 and ≤ 3)

 -  Patients with active systemic infections or deep space infections within the 3 months
 prior to screening.

 -  Patients participating in another clinical trial mandating maintenance therapy

 -  Patients with drug-induced ANCA vasculitis (e.g. levamisole-adulterated cocaine)

 -  Active tuberculosis, human immunodeficiency virus (HIV), hepatitis C virus or
 hepatitis B virus infections

 -  For women of child-bearing potential, pregnancy, breastfeeding, unwillingness or
 inability to comply with effective contraception

 -  Inability to come to scheduled visits