Low-dose Of Rituximab In NMOSD:Efficacy,Immunogenicity And Application Timing

Objectives Neuromyelitis Optica Sprectrum Disorders(NMOSD)represent anti-aquaporin-4(AQP4)antibody mediated relapsing central nervous system inflammatory demyelinating disease extending beyond the optic nerves and spinal cord to include the brain areas of high expression of AQP4,including periventricular organs and diencephalons.Rituximab(RTX),a chimeric monoclonal antibody specific for the CD20 B-lymphocyte surface antigen.Increasing studies provided evidence that RTX therapy reduces the frequency of disease relapses and neurological disability in patients with NMOSD.To further evaluate the efficacy of low-dose RTX in NMOSD and perform a subgroup analysis;to evaluate the possible immunogenicity of low-dose RTX in NMOSD and its role in clinical efficacy and safety;to further optimize the initiating or applying timing of low-dose RTX in NMOSD.Methods Twenty-nine patients with NMOSD receiving low-dose RTX treatment were enrolled.The onset age,gender,serum AQP4 antibody,clinical recurrence and other data were collected.The frequency of CD19~+B cells in peripheral blood mononuclear cells were measured and analyzed withflow cytometry.The recurrence frequency and disability EDSS scores status of pre-and post-treatment were compared.Further,the patients with NMOSD were divided into subgroups and analyzed according to onset age,the frequency of episodes before initiating of low-dose RTX and whether accompanying autoimmune disease antibodies.Enzyme linked immunosorbent assay(ELISA)was used to detect the level of anti-human chimeric antibody(HACA)in serum of patients with NMOSD.The patients with NMOSD were analyzed for recurrence frequency,disability status and drug compliance according to whether initiating or applying RTX therapy within 2 years of onset or 2 months of acute attack,further optimizing the initiating or applying timing of low-dose RTX in NMOSD.Results 1.Long-term low-dose RTX therapy can significantly reduce the frequency of recurrence and maintain or significantly reduce the Expanded disability status scale(EDSS)score in patients with NMOSD(p<0.05).2.Regardless of early-onset and late-onset,whether the frequency of episodes before initiating of low-dose RTX more than 1 attack per year or not,and whether accompanying autoimmune disease antibodies or not,the frequency of recurrence was reduced and the EDSS was stable or significantly decreased in patients with NMOSD received low-dose RTX,but there was no significant difference in the degree of recurrence frequency and EDSS between the two subgroups(p>0.05).3.36.9%(7/19)NMOSD patients were HACA positive.After one year of treatment with RTX,the frequency of recurrence exhibited a decreasing trend in the HACA positive group and was obviously reduced in the HACA negative group(p<0.05).However,there was no significant difference in the degree of change in the frequency of recurrence and EDSS between the HACA positive and negative groups(p>0.05).The frequency of RTX reinfusion was higher in patients with HACA(p<0.05),suggesting that the presence of HACA is associated with incomplete B cell depletion and requirement of increasing the frequency of RTX supplemental infusion to maintain low B cell levels.4.Low-dose RTX treatment significantly reduced the frequency of recurrence,and stabilized or significantly reduced the EDSS score(p<0.05)in NMOSD patients who initiated RTX whether within 2 years after onset or not,and whether within 2 months of acute episodes or not.However,the number of recurrent patients and the frequency of recurrence exhibited an increasing trend in NMOSD patients who initiated RTX within 2 months of acute episodes.Further,the frequency of patients who discontinued the treatment regimen resulting from failure to control disease progression was significantly higher in patients initiating RTX treatment whthin 2 months of acute episodes,comparing with those initiating RTX treatment after 2 months of acute episodes(p<0.05).5.The total frequency of recurrence and the frequency of recurrence within 1 year after previous recurrence were significantly higher in NMOSD patients who infused low-dose RTX within 2 months after acute episodes,comparing with those infusing RTX after 2 months of acute episodes(p<0.05).Conclusion 1.Long-term low-dose RTX therapy can effectively prevent disease recurrence and maintain or significantly reduce EDSS score in patients with NMOSD.2.Low-dose RTX therapy can effectively prevent disease recurrence and maintain or significantly reduce EDSS score in patients with NMOSD regardless of early-onset and late-onset,whether the frequency of episodes before initiating of low-dose RTX more than 1 attack per year or not,and whether accompanying autoimmune disease antibodies or not.3.36.9%(7/19)NMOSD patients were HACA positive.The presence of HACA is associated with incomplete B cell depletion and the requirement for increased frequency of RTX reinfusion to maintain treatment response in NMOSDs.In patients with HACA it might be necessary to detect HACA levels and monitor B cell depletion closely,or even attempt other treatments.4.The frequency of patients who discontinued the treatment regimen resulting from failure to control disease progression was significantly higher in patients initiating RTX treatment whthin 2 months of acute episodes,comparing with those initiating RTX treatment after 2 months of acute episodes.It isrecommended to initiate RTX at least 2 months after the acute episode for greater benefits for NMOSD patients.5.The infusion of RTX within 2 months after acute episode might be a potential factor related to the short-term recurrence after last episode in NMOSD patients.It is recommended to infuse RTX at least 2 months after the acute episode.