Anti-Rituximab antibody in patients with NMOSDs treated with low dose Rituximab
Graphical abstract
Introduction
Neuromyelitis optica spectrum disorders (NMOSDs) are anti-aquaporin-4 antibody (AQP4-Ab) mediated relapsing neuro-inflammatory diseases, often resulting in paralysis or blindness (Wingerchuk, et al., 2007). Rituximab, a mouse-human chimeric monoclonal antibody specific for the B cell surface antigen CD20, has been used to prevent relapses of NMOSDs in patients and achieved a 70–80% response rate by depleting B cells in many treatment centers (Zéphir et al., 2015, Cree et al., 2005, Kim et al., 2011). In most of reports, the treatment protocol was similar to that used for B cell lymphoma, i.e., 4 weekly doses of 375 mg/m2. Several studies have adopted a lower dose of Rituximab in NMOSDs (Greenberg, et al., 2012), myasthenia gravis (Blum, et al., 2011), systemic lupus erythematosus (SLE) (Looney, et al., 2004), rheumatoid arthritis (RA) (den Broeder, et al., 2017), and autoimmune cytopenia (Provan, et al., 2007). We have previously reported that five patients with NMOSDs benefited from B cell depletion through repeated 100 mg Rituximab treatment in a one-year follow-up study (Yang, et al., 2013). To further evaluate the safety and efficacy of the low dose Rituximab treatment in the current study, we recruited additional patients and observed them for a much longer time.
Another major motivation of this study was to further investigate the immunogenicity of Rituximab, and determine its effect on safety and efficacy. The Anti-Rituximab antibody (ARA) has been described in other disease cohorts, such as pemphigus, primary Sjogren's syndrome, ANCA associated vasculitis, SLE, B cell malignancies and RA (Schmidt et al., 2009, Thurlings et al., 2010, Pijpe et al., 2005, Smith et al., 2006, Albert et al., 2008, Maloney et al., 1997, Edwards et al., 2004). However, there is little information on ARA against the murine composition of Rituximab in NMOSDs. Better understanding and monitoring of the possible immunogenic effects of Rituximab therapy for NMOSDs and their clinical consequences might help to individualize therapy and reduce disease activity.
Section snippets
Subjects and data collection
Nineteen patients fulfilling the diagnostic criteria of NMOSDs were recruited from January 2011 to November 2016 (Wingerchuk, et al., 2015). All study participants received Rituximab (Biogen-Idec, Cambridge, MA, and Genentech, San Francisco, CA) via one 100 mg intravenous infusion per week for 3 continuous weeks. Clinical evaluation was conducted and circulating CD19+ B cells were measured every 12 weeks or at shorter intervals. When the concentration of CD19+ B cells among peripheral blood
Data analysis
Continuous variables were expressed as mean ± standard deviation (SD) and categorical variables were expressed as a percentage. Inter-group differences were compared using Mann-Whitney tests. Intra-group differences were compared using Wilcoxon signed ranks tests. Statistical significance was defined as p < 0.05. Statistical analysis was performed using SPSS 16.0 (SPSS Inc., USA) and visualization of data for figures was carried out using GraphPad Prism Version 5 (San Diego, USA).
Results
Nineteen patients with NMOSDs (16 female and 3 male, 17 with AQP-4-IgG-positive) received Rituximab therapy over a 1–5 year follow-up period. The average onset age of the disease was 34.8 ± 13.7 (range: 16 to 67) years, and mean time from onset to initiation of Rituximab therapy was 3.4 ± 3.4 (range: 0.3 to 12.2) years (Table 1). ARR was reduced markedly after starting low dose Rituximab therapy in the majority (78.9%) of study patients.
Unfortunately, 21.1% patients (4/19) responded poorly to
Discussion
In this study, we performed a retrospective analysis of patients with NMOSDs treated with low dose Rituximab over a 1–5 year follow-up period. Our findings indicated that the majority of patients (78.9%) with NMOSDs were responsive and well-tolerated to low dose Rituximab, in accordance with a previous study using low dose Rituximab for NMOSDs (Greenberg, et al., 2012), and recent meta-analyses of randomized clinical trials studies adopting high dose Rituximab for NMOSDs (Damato et al., 2016,
Conclusion
Repeated low dose Rituximab treatment holds significant therapeutic promise and appeared to be well tolerated for NMOSDs, at least for the majority of patients with profound B cell depletion. Seven out of nineteen (36.9%) patients were ARA positive. The presence of ARA is associated with the requirement for increased frequency of Rituximab reinfusion to maintain treatment response in NMOSDs. In patients with ARA it might be necessary to detect ARA levels and monitor B cell depletion closely, or
Acknowledgements
We thank S. Shi for editorial assistance.
Disclosure of conflicts of interest
The Authors declare that there is no conflict of interest.
Funding
This work was supported by the National Science Foundation of China (grant numbers 81471221, 81571172); Tianjin Research Program of Application Foundation and Advanced Technology (grant number 15JCZDJC35700, 15JCYBJC49800); Youth Incubation Fund of Tianjin Medical University General Hospital (ZYYFY2016004); and the National Key Clinical Specialty Construction Project of China.
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2021, Multiple Sclerosis and Related DisordersCitation Excerpt :Several studies have shown that RTX is more effective in the repeat treatment of neuromyelitis optic (Kim et al., 2011; Pellkofer et al., 2011). Studies by Greenberg and Yang et al have shown that low-dose rituximab is also effective in the treatment of neuromyelitis optic and is more economical and practical (Chay, Donovan, Cummins, Kubler, & Pillans, 2013; Greenberg et al., 2012; Li et al., 2018; Lin et al., 2018; Yang et al., 2013; Zhang et al., 2017). Kim et al found that the efficacy of RTX may be related to the course of disease, and the earlier the treatment, the better (Kim, Kim, Li, Jung, & Kim, 2012).
Impact of Rituximab on relapse rate and disability in an Ecuadorian cohort of patients with neuromyelitis optica spectrum disorders
2021, Multiple Sclerosis and Related DisordersCitation Excerpt :It is clear that the clinical response of RTX will depend on the degree of B cell depletion, however the degree and durability of such depletion is variable among patients (Kim et al., 2019). Some possible explanations for reduced efficacy of RTX include the no expression of CD20 antigen on memory B cells and non-circulating B cells, reduced the half-life of RTX due to the presence of neutralising antibodies and it being a carrier of the FCGR3A-F allele (associated with risk of relapse in patients with NMOSD (Kim et al., 2015; Li et al., 2018; McKeon and Pittock, 2013). The presence of these factors could explain this paradoxical increase in relapses observed in one of our patients.