CNS vasculitis in a patient with MS on daclizumab monotherapy

Abstract

Objective: To report the development of CNS vasculitis in a patient with multiple sclerosis (MS) treated with daclizumab.Methods: This report includes clinical, MRI, immunologic, and pathology data and CSF analysis.Results: After completing a phase II daclizumab monotherapy study with an optimal response as evidenced by significant decrease in MRI disease activity and stable clinical examinations, the patient elected to continue daclizumab therapy outside of NIH study. Daclizumab was discontinued after 21 doses due to the onset of new clinical symptoms and evidence of a vascular pattern of contrast enhancement on brain and spine MRI. Because of continued clinical deterioration, stereotactic brain biopsy was performed, showing small-vessel CNS vasculitis. Treatment was initiated with IV methylprednisolone followed by a regimen of cyclophosphamide. Immunologic studies suggest that unexpected lack of expansion of CD56 bright NK cells and predictable decline in FoxP31 T-regs combined with a transient interruption in daclizumab dosing may have contributed to this serious side effect.Conclusions: Only safety data from larger phase III studies and potentially postmarketing experience will define the exact risk of daclizumab-induced immunopathologies. Nevertheless, our case provides plausible hypothesis and potential biomarker that may be used to screen susceptible patients and implement preventive safety measures during potentially vulnerable periods. Neurology Daclizumab is a humanized monoclonal antibody specific for interleukin (IL)-2Ra receptor (CD25) and has been approved for the prevention of allograft rejection in solid organ transplantation. Multiple phase II studies of daclizumab in multiple sclerosis (MS) have reported significant efficacy in reducing contrast-enhancing lesions (CEL) and clinical disability. [1][2][3][4][5][6] Clinical efficacy of daclizumab treatment in MS has been linked to the expansion of CD56 bright NK cells, 3,6,7 which can regulate adaptive immunity by killing activated autologous T cells. 7 We describe a 42-year-old Caucasian woman (ZAP10) with a 5-year history of relapsing-remitting MS (RRMS) who completed a phase II clinical trial of daclizumab monotherapy in MS. 2METHODS Magnetic resonance images were obtained at the height of the patient's symptoms using described methodology.2 CSF was collected during pretreatment baseline, month 1.5, and month 6.5 on daclizumab therapy on NIH protocol, and during clinical deterioration on daclizumab therapy outside of NIH clinical trial. CSF was spun within 30 minutes of collection and cell-free supernatants were cryopreserved until analysis. CSF supernatants were concentrated (up to 10-fold) by centrifugation through Millipore Amicon Ultra 3 kDa filters and analyzed in multiplex for IL-12p40, CCL19, and interferon-g as described.2 CXCL13 was measured by ELISA (R&D Systems, Minneapolis, MN; Catalogue number DY801).Standard protocol approvals, registrations, and patient consents. The study was approved by the NIH/CNS Institutional Review ...

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“…In addition to what was reported in the Phase II clinical trials, there was a recent case report of a woman who developed CNS vasculitis while on daclizumab therapy 51. The patient had participated in a Phase II trial of daclizumab and elected to continue daclizumab therapy after completion of the trial in an off-label manner.…”

The effects of interleukin-2 on immune response regulation

“…However, treatment with Daclizumab has been shown to inhibit IL-2 mediated STAT5 activation, a fact that is not particularly surprising considering Daclizumab competes with IL-2 for CD25 binding (Goebel et al , 2000). While originally designed to prevent organ rejection in transplant patients, Daclizumab is now FDA approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) (Bielekova et al , 2004, 2006, 2011; Borges et al , 2013; Ohayon et al , 2013). …”