The Clinical Observation Of RTX Treating Myasthenia Gravis

Background: Myasthenia gravis(MG)is a rare prototypical autoimmune disorder induced by complement and caused by antibodies(Ab)against postsynaptic membrane proteins.The current treatment of MG includes cholinesterase inhibitor,immunosuppressant,human immunoglobulin,plasma exchange,and thymectomy.However,there are still part of the patients,which we call refractory MG,can not response to the traditionaltreatment of MG ideally or relapse repeatedly after dosage reduction,or havethe tendency of glucocorticoid dependence.In recent years,Rituximab(RTX)has become a new treatmentoption for MG,especially for refractory MG,because of its mild side effect and the gradually recognized efficiency.With the in-depth study of RTX treating MG,it is expected to be a first-line treatment for refractory MG.Till now,there is no consensus about the ideal dose of RTX treating refractory MG.So it is important to explore the efficiency of low-dosage RTX on refractory MG.As we all know,the imbalance of follicular regulatory T cells(Tfh)and follicular regulatory T cells(Tfr)and the expression of Autoimmune regulator gene(Aire)play a significant role in initiation and aggravation of MG.This observation focus on the mechanism of RTX effect on Tfh?Tfr cells and expression of Aire,providing a new potential option for refractory MG treatment.Objective: To investigate the efficacy of RTX(100mg/time)sequential therapy in refractory MG.To observe the changes of circulating Tfh cells(c Tfh),circulating Tfr cells(c Tfr)and B cells and the expression of Aire in refractory MG patients before and after RTX treatment in patients with refractory MG patients and to explore the possible mechanism.Method: 1)17 refractory MG patients in our institution were enrolled from December 2016 to June 2017,including 15 general MG patients and 2 ocular MG patients.Basic clinical data were collected including age,sex,medical history,symptoms before enrolled in the investigation and the clinical assessment such as Classification of Myasthenia Gravis Foundation of America(MGFA),Quantitative MG scoring System(QMGs),the Absolute and Relative Score of MG(ARS-MG),the history of abnormal thymus and thymic operation,result of repeated frequency electrical stimulation(RNES),titer of antibodies and the initial time of the disease.2)MG Patients were treated with low-dose RTX sequential therapy: Human Immunoglobulin for Intravenous Injection(IVIG)was used before RTX if necessary,then 100 mg RTX wes given per week for three consecutive weeks.Patients were followed at 1,3,6 month after treatment and the clinical assessment such as ARS-MG score,QMG score,result of RNES were compared before and after the treatment.3)The peripheral blood were collected with the consent of MG patients.The frequencies of c Tfh,B cells,c Tfr cells and expression of Aire were detected via flow cytometry.Serum level of Ach R antibody were messured using ELISA.Result: 1)B cells were successfully depleted in refractory MG patients with the treatment of 100mg*3weeks RTX within a month.About 11.8% patients need a strengthed treatment to maintain the condition of B cell deleption after 3 months of treatment.There is no more patients needed strengthed treatment after 6 months of RTX treatment.2)The score of ARS-MG and QMGs decreased after RTX treatment.The response rate of RTX within 3 month remains 88.3%,which rise to 94.1% after 6 months of treatment.Patients with bulbar symptoms response to RTX ideally.92.3% of patients achieved symptom remisson within a month and 100% of them achieved symptom alleviated in 3 months after treatment.3)77% of the patients with an abnormal RNES can improve significantly after treatment of RTX within 3 months.And all patients achieved the reduction of prednisone after treatment within 6 months.94.2% patients achieved elevation of symptom with bromobispine or bromobispine and prednisone.52.8% patients can remain stable condition just with bromobispine.4)The incidence of RTX side effect is 24.1%,most of which(84.6%)are mild and transient infusion reactions.Fatigue is the most common adverse effect of after RTX treatment,beside which body ache,head ache,dizzy can also happen after infusion.3 patients present a serious aggrevation of bulbar symptom,which revise within 1 week automatically.3 patients have infection after 3 months of treatment.5)The ratio of c Tfh and the ratio of c Tfh/c Tfr before treatment were significantly higher than those after the treatment(P<0.0001,P=0.0107 respectively).The c Tfr ratio and the expression of Aire in peripheral blood were significantly lower than those after treatment(P=0.0076,P=0.0148,respectively).Conclusions 1)Low dose RTX sequential therapy is efficiency to refractory MG patients as new option for immune suppression treatment.2)Refractory MG patient response to RTX ideally with the revise of RNES and reduction of other immunosuppressant.3)Most of the adverse effect of RTX are transent and mild and can revise with no specific management.The aggrevation of bulbar symptom of patients after infusion should be drawn attention to prevent choking during treatment.4)Despite of the deletion of B cells,the frequency of c Tfh,c Tfr cells,as well as the expression of Aire in peripheral blood changed after RTX treatment with a statistical significance.