Maintenance of ANCA Vasculitis Remission by Intermittent Rituximab Dosing
Maintenance of ANCA Vasculitis Remission by Intermittent Rituximab Dosing
The purpose of this study is to determine the best management strategy to maintain remission
 in patients with ANCA vasculitis who have been treated with rituximab induced B cell
 depletion for at least two years. This study will compare intermittent B Cell depletion upon
 B cell return or intermittent B cell depletion upon serologic relapse.
Anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis is a systemic autoimmune disease
 characterized by small vessel inflammation caused by pathogenic autoantibodies directed
 against proteinase 3 (PR3) or myeloperoxidase (MPO). Immunosuppressive therapy can result in
 remission; however, many patients relapse, which results in additional injury.

 Rituximab, a humanized murine monoclonal antibody directed against CD20 located on the
 surface of B-lymphocytes (B cells), is effective in depleting B cells. The RAVE and RITUXVAS
 trials have shown efficacy of rituximab with steroids for induction of remission in ANCA
 vasculitis, similar to cyclophosphamide and steroids. Rituximab is now FDA-approved for
 induction of remission therapy in ANCA vasculitis. The utility of anti-B-cell therapy for
 early induction of remission in ANCA vasculitis is not surprising given that ANCA are
 pathogenic in vitro and in vivo. It is clear that remission in many patients is not sustained
 with a single induction course of rituximab, and relapses often occur after B cell
 re-population suggesting that scheduled, serial dosing of rituximab could result in sustained
 remissions.

 Despite yielding promising outcomes, rituximab is also associated with a number of adverse
 events including infectious complications and late onset of neutropenia5, 15. Furthermore,
 the complications of continuous B cell depletion for extended durations are unknown. One of
 the major goals in the field is to utilize prolonged B cell depletion only in the
 subpopulation of patients where the risk of disease relapse outweighs the risk of
 treatment-related adverse events.

 A rise in ANCA titers and reconstitution of B cells are promising biomarkers of impending
 disease relapse following treatment with rituximab4-6

 A prospective and longitudinal clinical trial is needed to determine the ideal treatment
 strategy for long-term maintenance of remission. We propose to compare intermittent rituximab
 dosing based on B cell return and a serologic ANCA flare

 The study design is an open-label, single center, randomized and two-arm controlled trial to
 evaluate the optimal maintenance of remission strategy that provides the best relapse-free
 survival in patients with ANCA vasculitis as determined by relapse-free remission at 18, 24
 and 36 months from enrollment. The investigators are looking to enroll and randomize 200
 subjects with ANCA vasculitis on rituximab-induced continuous B cell depletion for a minimum
 of two years to one of two arms as follows:

 1. Intermittent B cell depletion with rituximab re-dosing upon B cell return: Subjects will
 not receive their regularly-scheduled every-six-month dose of rituximab and will instead
 receive rituximab 1000 mg IV x 2 doses (spaced 2-3 weeks apart) once peripheral B cells
 return ( ≥ 10 B cells/mm3). This cycle will then re-start. Subjects will be seen in
 clinic every three months.

 2. Hold continuous dosing with rituximab with re-dosing upon a significant ANCA titer
 increase: For MPO, a significant increase will be defined as a 5-fold rise in ANCA titer
 and a level greater than 4 times the cutoff value for the assay. For PR3, a significant
 rise will be defined as a 4-fold rise in ANCA titer to a level at least twofold above
 the cutoff for the assay. Subjects will not receive regularly scheduled every six-month
 doses of rituximab and will instead be monitored every three months. Subjects who
 sustain a significant increase in ANCA titer will receive rituximab 1000mg IV x 2 doses,
 ~2-3 weeks apart. If the ANCA titer remains two-fold above baseline and above a
 specified threshold (the cutoff value of the assay for PR3 and 4 times the cutoff value
 for MPO) , subjects will continue to receive rituximab 1000mg IV every 6 months for a
 maximum of 2 doses, at which time a new baseline ANCA titer will be established and the
 cycle will re-start.
Inclusion Criteria:

 1. All patients must be able and willing to give written informed consent and comply with
 the requirements of the study protocol.

 2. Diagnosis: ANCA vasculitis as defined by a positive MPO- and/or PR3-ANCA test together
 with clinical features characteristic of ANCA-positive diseases as detailed in the
 2012 Chapel Hill Consensus Conference Definitions(18).

 3. eGFR ≥ 30 cc/min/1.73m2

 4. Age: 18-82 years old

 5. Treated with rituximab-induced continuous B cell depletion and in remission (defined
 by a modified BVAS-WG=0 AND a prednisone dose of ≤ 7.5 mg) for at least 24 months.

 6. CD20 (B cells) undetectable at time of enrollment/randomization

 7. Urine Hcg negative for women of child bearing potential and not planning to become
 pregnant for at least 12 months from enrollment and at least 12 months after any study
 related rituximab dose

 8. Judged to be otherwise healthy by the Investigator, based on medical history and
 physical examination (no known active disease process for which life expectancy is
 less than 36 months)

 Exclusion Criteria:

 1. Secondary Disease: disease suspected to be induced by levamisole-adulterated cocaine

 2. All transplanted patients

 3. Treatment: additional immunosuppressive agents other than rituximab and/or total daily
 prednisone dose ≥ 7.5 milligrams

 4. Hypogammaglobulinemia: IgG level < 250 mg/dL

 5. Terminal cancer or other primary illness with life expectancy of less than 36 months

 6. Active anti-GBM disease and other known autoimmune disease for which the need for
 additional immunosuppression is likely

 7. Pregnancy or breastfeeding