Efficacy And Safety Of Reduced Rituximab In The Treatment Of Neuromyelitis Optica Spectrum Disorders Under B Cell Monitoring

Research Background:Neuromyelitis optica(NMO)is an inflammatory demyelinating disease of the central nervous system,mainly involving the optic nerve and spinal cord.It is an autoimmune disease characterized by abnormal humoral immune regulation.The location of the lesion is roughly identical with that of highly expressed AQP4.There is a group of demyelinating diseases which can not meet the diagnostic criteria of NMO.They have similar pathogenesis and clinical manifestations with NMO.Some cases eventually evolve into NMO.Wingerchuk et al.proposed the concept of Neuromyelitis Optica Spectrum Disorders(NMOSD)in 2007.NMOSD patients generally have severe symptoms,high recurrence rate,high disability rate and poor prognosis.Recurrence and cumulative damage of the disease can often lead to permanent blindness and paralysis.As the progression of disability in NMOSD is directly related to the severity of the attack,once NMOSD is diagnosed,preventive treatment strategies for recurrence must be implemented.Rituximab,as a monoclonal antibody against CD20 on the surface of B cells,can deplete B cells,effectively improve NMOSD symptoms,reduce recurrence and slow down the progress of neurological dysfunction.RTX is recommended as a first-line drug in the guideline of NMOSD diagnosis and treatment,but the use of RTX at home and abroad is not uniform.Most of the foreign countries adopt high-dose B-cell-derived tumor clearance schemes.Blind copying of foreign schemes is unreasonable due to different race,physical condition and economic conditions.In this study,patients with NMOSD were treated with reduced rituximab regimen under B cell monitoring(intravenous drip,100mg on the first day and 500mg on the next day).The control group was treated with azathioprine and cyclophosphamide,respectively.The aim was to analyze and compare the efficacy and safety of reduced rituximab in the treatment of NMOSD patients.In the aspect of mechanism research,it has been shown that B-cell mediated humoral immunity plays an important role in the pathogenesis of NMOSD.At the same time,B-cell antigen presentation and regulatory B-cell effect also mediate the pathogenesis of NMOSD.Recent studies have shown that costimulatory molecules play an important role in many autoimmune diseases.Among them,the costimulatory molecules ICOS/ICOSL and PD-1/PD-L1,which are closely related to B cell activation and function regulation,have become the research hotspots of autoimmune injury.However,the roles and mechanisms of ICOS/ICOSL and PD-1/PD-L1 pathways in the pathological process of NMOSD are still at the initial stage.The relationship between the expression of these molecules and the evolution of the disease after B cell clearance is worth exploring.Objective:To observe the efficacy and safety of reduced rituximab regimen in patients with optic neuromyelitis lineage disease under B cell monitoring,and to explore the possible mechanisms from the perspective of costimulatory molecules.Methods:This study included 35 patients with NMOSD who were followed up regularly from 2016.12 to 2018.12 in the Department of Neurology,First Affiliated Hospital of Suzhou University.They were treated with high-dose hormone shock therapy in the acute stage of onset.According to the different immunosuppressive agents used after the remission stage,they were divided into three groups:1.Rituximab group(RTX group)in remission.Phase ? was treated with rituximab(intravenous drip,100mg on the first day+ 500mg on the next day).Peripheral blood B lymphocyte subsets,CD4+T cell surface ICOS and PD-1,monocyte surface ICOSL and PD-L1 were regularly reviewed.When total B lymphocyte was greater than or equal to 3%or memory B lymphocyte was greater than or equal to 0.5%,the Administration was repeated once.2.The azathioprine group(AZA group)was treated with azathioprine at remission stage(using method:oral,dosage of 2-3 mg/kg/d).3.Cyclophosphamide group(CTX group)was treated with cyclophosphamide in remission period(use method:intravenous drip,single dose of cyclophosphamide 500-1000mg/m2,once 4 weeks,cumulative dose not exceeding 10-15g).Each group was observed from 12 to 24 months.The differences of Expanded Disability Status Scale(EDSS),Annualized Relapse Rate(ARR),adverse drug reactions and other indicators of the three groups before and after treatment were counted,and the data before and after treatment were analyzed.To evaluate the efficacy and safety of the three treatment regimens.Results:There were 35 patients included in this study,including 14 in RTX group,12 in AZA group and 9 in CTX group.1.EDSS scores of three groups decreased significantly before and after treatment,with statistical significance(P<0.01).Compared with the EDSS scores before and after treatment in three groups,the EDSS scores in RTX group were significantly lower than those before and after AZA treatment,with statistical significance(P<0.05).2.The non-recurrence rates of RTX group,AZA group and CTX group were 78.6%,58.5%and 77.8%,respectively,but the annual recurrence rates of the three groups were compared by non-parametric test,and the difference was not statistically significant(P>0.05).3.Compared with AZA group and CTX group,the proportion of hormone-independent patients in RTX group was significantly higher than that in AZA group and CTX group(P<0.05).4.The total incidence of adverse events in RTX group,AZA group and CTX group were 21.4%,41.7%and 77.8%respectively.The difference between RTX group and CTX group was statistically significant(P<0.05).5.RTX can rapidly deplete peripheral blood total B lymphocyte and memory B lymphocyte.In the RTX group,the costimulatory molecules(ICOS,PD-1)on CD4+T cell subsets in peripheral blood and the costimulatory molecules(ICOSL,PD-L1)on CD14+monocytes were down-regulated in the acute phase.Statistical significance(P<0.05).Conclusion:1.B-cell monitoring under reduced rituximab regimen in the treatment of NMOSD reduced EDSS levels compared with azathioprine,the incidence of adverse events was lower than cyclophosphamide,overall safe and effective.2.Co-stimulatory molecules(ICOS,PD-1)on peripheral blood CD4+T cell subsets and costimulatory molecules on CD 14+monocytes(ICOSL,PD-L1)were down-regulated in the acute phase during remission,which may be a biomarker for monitoring the progress and efficacy of rituximab in the treatment of optic neuromyelitis lineage diseases.