吗替麦考酚酯治疗抗富亮氨酸胶质瘤失活蛋白1脑炎的临床与免疫参数观察

Clinical and immunological analysis of mycophenolate mofetil treatment in anti-leucine-rich glioma-inactivated 1 encephalitis

目的分析单中心自身免疫性脑炎队列中接受吗替麦考酚酯（MMF）治疗达到1年的抗富亮氨酸胶质瘤失活蛋白1（LGll）脑炎病例，对其疗效、相关免疫参数和安全性进行评估。方法选择2014年6月至2017年8月在北京协和医院神经科诊治并接受MMF治疗的抗LGll脑炎病例15例。根据北京协和医院《脑炎与副肿瘤综合征登记项目》流程对抗LGll脑炎患者进行评估及随访，每2个月评估改良Rankin量表（mRS）评分，并对血清IgG水平、外周血CD．。阳性B细胞、CD。阳性T细胞和CD。阳性T细胞计数等免疫参数进行评估。采用SPSSV20软件对以上数据进行分析。采用Graphpad Prism6．0软件进行统计绘图。对MMF剂量采用足量诱导期（1．5～3．0g／d）与减量维持期（0．75-2．00g／d）的方案。结果15例患者MMF治疗超过1年，其中13例患者治疗后mRS评分较治疗前好转（mRS评分降低≥1分）。全部患者在随访中均达到良好的神经功能状态（mRS评分≤2分，含复发病例3例）；其中治疗后无症状者9例（9／15，mRS评分=0分）。治疗前中位mRS评分为2（1，3）分，治疗后中位mRS评分为0（0，1）分，差异具有统计学意义（Z=-3．115，P=0．002）。外周血CD19阳性B细胞数治疗前中位数（四分位数）值为320（227，628）×10^6／L[正常值（160～350）×10^6／L]，在MMF治疗过程中，CD19阳性B细胞数呈逐步下降的趋势，至观察终点（12个月）达到最低值[152（105，223）×10^6／L]，较治疗前减低（Z=-2．028，P=0．043）。CD4阳性T细胞数治疗后[1055（802，1072）×10^6／L]与治疗前[1136（736，1432）×10^6／L]比较差异无统计学意义。CD。阳性T细胞数治疗后[568（393，743）×10^6／L]与治疗前[627（413，784）×10^6／L]比较差异无统计学意义。血清IgG治疗前[9．07（6．70，11．32）g／L]与治疗后[8．35（6．63，10．69）g／L]比较差异无统计学意义。在6个月时IgG达到最低值[7．04（5．62，9．74）g／L]（正常值7～17g／L）。3例（3／15）复发，予以增加MMF剂量并联合一线免疫治疗；复发时CD19阳性B细胞数升高。结论MMF联合一线免疫治疗对抗LGll脑炎效果良好。MMF的足量诱导期与减量维持期方案具有可行性。外周血CD19阳性B淋巴细胞数的动态变化可作为MMF治疗个体化的参考依据。

Objective To evaluate the efficacy and safety of mycophenolate mofetil （MMF） in anti- leucine-rich glioma-inaetivated 1 （ LGI1 ） encephalitis by analyzing the clinical and immunologic data of patients treated with MMF in this prospective cohort of anti-LGI1 encephalitis. Methods Patients treated with MMF for more than one year in Peking Union Medical College Hospital were included in this study.MMF was given at a dosage of 1.5 - 3.0 g/d in the induction period （ two to four months） and 0. 75 - 2.00 g/d in the maintenance period. All the patients were followed up regularly. Modified Rankin Scale （mRS） score evaluation, serum IgG and peripheral CDig-positive B cells, CD4-positive T cells and CDs-positive T ceils testing were performed every two months. Results Fifteen patients were included in this study who received first-line immunotherapy combined with MMF. No other second-fine therapy including rituximab was used. Thirteen patients responded well to MMF combined with first-line immunotherapy （a decrease in mRS score of more than 1 ）. All 15 patients had a good outcome （ i. e. , a mRS score of 0 - 2） , including nine patients without residual symptoms （a mRS score of 0）. After 12 months of MMF treatment, CDl9-positive B cells were significantly decreased （median 320 （227, 628） × 10^6/L vs 152 （105, 223） × 10^6/L; Z= -2.028,P=0.043）, while serum IgG （9.07 （6.70, 11.32） g/Lvs 8.35 （6.63, 10.69） g/L, P= 0. 144））, CD4positive T cells （1 136 （736, 1 432） ×10^6/Lvs 1 055 （802, 1 072） × 10^6/L, P =0. 866） and CDs-positive T ceils （627 （413, 784）×10^6/L vs 568 （393, 743） × 10^6/L, P=0.735） were not significantly changed. Three patients relapsed and were treated with additional cycle of first-line immunotherapy and increased dosage of MMF （ induction dosage） resulting in remission. CDi9-positive B cells were tested to be increased during the patients＇ relapse. No serious adverse event was noted in all these patients. Conclusions MMF is safe and effective as a long-term immunotherapy in patients with anti-LGI1 encephalitis. MMF can be used as an add-on therapy to first-line immunotherapy for autoimmune encephalitis. CD19-positive B cell count should be monitored and used as a parameter to individualize dosage of MMF.