Only Follow-Up of Memory B Cells Helps Monitor Rituximab Administration to Patients with Neuromyelitis Optica Spectrum Disorders

Abstract

Introduction: Neuromyelitis optica spectrum disorders (NMOSD) are identified as a spectrum of inflammatory demyelinating disorders involving the brain, spinal cord and optic nerves. These disorders require early diagnosis and highly active immunosuppressive treatment. Rituximab (RTX) has demonstrated efficacy in limiting relapse in NMOSD when using several administration schedules. We questioned if the CD19+ CD27+ memory B cell count was a more reliable marker to monitor RTX administration than the RTX plasma level and CD19+ B cell count.

Methods: We analyzed 125 blood samples from 17 NMOSD patients treated with RTX and also measured the level of anti-aquaporine-4 antibodies (anti-AQP-4 Abs), human anti-chimeric antibodies to the murine fragment of RTX (HACA-RTX Abs), and the RTX concentration.

Results: The mean follow-up time of the cohort was 7.4 (2-16) years. All patients improved with a mean EDSS going from 4 (1-8.5) to 2.7 (1-5.5). The mean interval between RTX infusions was 9.6 months with identification of prolonged responders. Total CD19+ B cell detection with the routine technique did not correlate to re-emergence of CD19+ CD27+ memory B cells. The RTX residual concentration did not correlate with the CD19+ CD27+ memory B cell count or with anti-RTX antibody production.

Conclusion: In contrast to total CD19+ cell, detected with the routine technique, CD19+ CD27+ memory B cells are a reliable marker for biological relapse and allow a decrease in the frequency of infusions.

Keywords: Efficacy; Memory B cells; Neuromyelitis optica spectrum disorder; Rituximab; Safety.

Fig. 1

A typical evolution of memory B cells of a patient (AGS) on follow-up of more than 1 year and the strategy used by the clinical team. a Flow cytometry raw data. The patient had an infusion of rituximab on December 23, 2015. In April 2016 (first row) no B cells were detected. Six months later, on October 2016, B cells represented up to 5.9% of lymphocytes and 1.21% of white blood cells. They were mainly composed of naive B cells (in green). CD27-memory B cells, that is the sum of switched and marginal zone memory B cells (line 3 and 4) represented no more than 0.017% of WBC. No Rituximab was proposed, but monitoring was shortened. In December 2016, while the total B cells increased only slightly, the memory B cells increased and reached 0.039% of white blood cells. In addition the population of CD27 negative memory B cells (fifth line) also increased. Infusion of rituximab was proposed to the patient. Four months later, no B cells were detected. Note that over a course of 1 year only one infusion of rituximab was performed. b The percentage of B cells and the different sub-populations are summarized. Please note that the scale is different for the two charts

Fig. 2

Patient AS and NY had anti-RTX antibodies detected in one sample. Patent AS serum neutralized the RTX activity at 50 ng/ml. Patient NY did not have any