| Part oneLong-term Efficacy of Tacrolimus in Myasthenia Gravis Patients Objective To evaluate the efficacy and safety of low-dose tacrolimus in patients with myasthenia gravis （MG）.Methods Experimengts followed-up was conducted on 97 MG patients,who received low-dose tacrolimus from February 2011 to April 2015 at 309th Hospital of PLA for 8-60 months. We evaluated by the MG activities of daily living （MG-ADL）scores,and adverse effects of tacrolimus.Results1.At the end of follow-up,6 patients were complete stable remission, 17 patients were pharmacological remission,26 patients were minimal manifestation status,32 patients were improved,2 patients were unchanged, 1 patient was worse, 10 patients were exacerbation ,and 3 patients were death .2.The MG activities of daily living score was 6.91 零3.54,4.03±2.92,2.45±2.76,1.42±1.64,0.90±1.19,0.89±1.18,at discharge,the half,first,second,third and fourth year in follow-up, and the difference was statistically significant.3.MG-ADL score of thymic and non-thymic patients in the half,first,second,third and fourth year in follow-up was 6.67 ± 4.30 VS8.00 ± 3.08,4.33 ± 4.47VS3.67 ±3.28,2.22±2.28 VS1.78± 2.33,1.22 ±1.79 VS0.89± 1.05,0.67 ±0.71 VS1.33 ±1.41,0.44± 0.73 VS 1.33 ± 1.41,but the difference was not statistically significan.4.MG-ADL score of thymoma and non-thymoma patients in the half,first,second,third and fourth year in follow-up was 8.00±6.56 VS7.20±3.21,7.33±6.51 VS3.33±2.97,3.00 ± 3.46 VS1.80 ± 2.04,2.00 ±2.65 VS0.87± 1.13,100± 1.0 VS1.00 ±1.20,1.00 ± 1.0 VS0.87 ± 1.25 but the difference was not statistically significan.5.The dose of tacrolimus of fast metabolic pattern and slow metabolic pattern patients at discharge,the half,first,second year was 3.07 ± 0.26VS3.29 ± 0.47、2.87 ±0.52VS3.14±0.66、2.40±0.91VS2.57± 1.02、1.90±1.29VS2.36± 1.17,The dose of tacrolimus of slow metabolic pattern were lower than fast metabolic pattern patients , but the difference was not statistically significan.6.Side effects : Seven patients experienced elevated blood glucose.Two patients developed neoplasms.Gastrointestinal symptoms were reported by three patients.Mild increases in aminotransferases were observed in three patients.Three patients suffered from bone marrow suppression.Two patients suffered from skin rashes and erythema.Kidney damage was observed in one patient.One patient suffered from tooth mobility,another patient from muscle soreness,and another required treatment discontinuation for chronic headache.Conclusion Low dose tacrolimus in the treatment of MG can significantly improve the symptoms, and there are some side effect .Tacrolimus immunotherapy is a valid option for themanagement of MG,and can be gradually reduced in dose once symptoms are improved until complete withdrawal is achieved.Part twoThe Role of Follicular Regulatory T cells and Follicular Helper T cells in Pathogenesis of Myasthenia Gravis Objective To investigate the effect of Thl cells,Th2 cells,Th17 cells,Regulatory cells （Treg cells）,follicular regulatory T cells （Tfr cells） and follicular T helper cells（Tfh cells） and related cytokines in the pathogenesis of MG.Methods The venous blood of 47 MG patients and 23 healthy control groups were collected, and the clinical data was collected in detail . The frequency of Th1,Th2,Th17,Treg,Tfh and Tfr cells in peripheral blood mononuclear cells （PBMCs）were determined by flow cytometry. The levels of serum IL-2,IL-6,IL-10 and IL-21 were detected by ELISA. The differences of the percentage in each subgroup and the cytokine concentrations were compared between the MG and the healthy control group. The relationship between the subgroups and the cytokine concentration was compared with the clinical features and the severity of the disease. The differences of the percentage in each subgroup and the cytokine concentrations were compared between before and after treatment. The differences of changes of the percentage of Th17,Treg,Tfh and Tfr in the three treatments of tacrolimus,glucocorticoid and pyridostigmine bromide were compared. In addition,the correlation between the percentage of subgroup and the absolute score of MG was analyzed.Results1.The levels of serum IL-2,IL-6 and IL-10 of MG group were higher than those in healthy control group,and the percentage of Thl cells in MG group was higher than that in healthy control group,The percentage of Th2 cells was lower than that of healthy control group ,but the difference was not statistically significan.The levels of serum IL-21 in MG group was higher than that in healthy control group. The percentage of Treg and Tfr cells in MG group was lower than that in healthy control group,Tfr/Tfh ratio was lower than that in healthy control group,the percentage of Th17,Tfh cells was higher than that of healthy control group,Th17/Treg ratio was higher than that in healthy control group,and the difference was statistically significant.2.Compared with the generalized MG （GMG） group,the ocular MG （OMG） group showed lower levels of serum IL-2 and IL-6,lower percentages of Th2 cells and higher levels of serum IL-10,higher percentages of Thl cells ,but the difference was not statistically significan. Compared with the GMG group,the OMG group showed lower levels of serum IL-21,lower percentages of Th17 cells,Tfh cells ,Thl7/Treg ratio and higher percentages of Treg cells,Tfr cells,Tfr/Tfh ratio and the difference was statistically significant. The difference of of serum IL-2,IL-6,IL-10,IL-21 and the percentages of Thl,Th2,Th17,Treg,Tfh,Tfr and Th17/Treg,Tfr/Tfh ratio in thymoma,thymic hyperplasia,thymus normal group was not statistically significant.The difference of of serum IL-2,IL-6,IL-10,IL-21 and the percentages of Thl,Th2,Th17,Treg,Tfh,Tfr and Th17/Treg,Tfr/Tfh ratio in early-onset myasthenia gravis group and Late onset of myasthenia gravis group was not statistically significant.3.MG patients showed higher levels of serum IL-2,IL-10 lower levels of serum IL-6 and higher percentages of Thl cells and lower percentages of Th2 cells after receiving treatment,but the difference was not statistically significant. MG patients showed lower levels of serum IL-21 and higher percentages of Treg cells,Tfr cells and lower percentages of Th17 cells ,Tfh cells after receiving treatment,and the difference was statistically significant. The differences of changes of the percentage of Th17,Treg,Tfh and Tfr in the three treatments of tacrolimus,glucocorticoid and pyridostigmine bromide was not statistically significant.4.The percentage of Treg,Tfr cells and Tfr/Tfh ratio was negatively correlated with MG absolute score,The percentage of Tfh,Th17 cells and Th17/Treg ratio was postive correlated with MG absolute score. The percentage of Tfr cells was negatively correlated with the level of Tfh cells,the percentage of Treg cells was negatively correlated with the level of Th17 cells.Conclusion1.Th1 and Th2 cells were not directly associated with the onset and treatment outcome of MG.2.Th17,Treg,Tfr and Tfh cells were associated with the onset,disease severity and treatment outcome of MG,but was not related to age and thymus.3.Tfr cells and Treg cells have negative immune regulation effects in the pathogenesis of myasthenia gravis... |
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