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他克莫司治疗儿童重症肌无力的疗效研究
李久伟, 方方, 任晓暾, 张炜华, 杨欣英, 任长红, 巩帅, 吕俊兰, 王晓慧, 王旭, 吴沪生, 丁昌红
中国当代儿科杂志 ›› 2020, Vol. 22 ›› Issue (9) : 964-969.
PDF(1338 KB)
PDF(1338 KB)
他克莫司治疗儿童重症肌无力的疗效研究
Clinical effect of tacrolimus in the treatment of myasthenia gravis in children
目的 评价他克莫司治疗儿童重症肌无力（MG）的疗效及安全性。方法 采用他克莫司治疗28例MG儿童，运用重症肌无力日常生活（MG-ADL）量表于治疗1、3、6、9、12个月时评估他克莫司的疗效及安全性。结果 他克莫司治疗1、3、6、9、12个月时的MG-ADL绝对评分与基线水平相比均降低（P < 0.05），且呈逐渐降低趋势。他克莫司治疗1、3、6、9、12个月时的有效率分别为59%、81%、84%、88%、88%。他克莫司治疗6、9、12、18个月时累计停用泼尼松4、13、14、15例。所有患儿治疗期间均未出现病情反复。主要不良反应/事件有无症状血镁降低（5例）；尿潜血阳性（1例），后自行转为阴性；均未因不良反应/事件停药。1例患儿因反复呕吐自行停药。根据CYP3A5基因型分为慢代谢组（慢代谢型，n=19）、非慢代谢组（快代谢型+中间型，n=9），慢代谢组患儿他克莫司剂量低于非慢代谢组（P < 0.05），非慢代谢组他克莫司血药谷浓度低于慢代谢组（P < 0.05），慢代谢组有效率高于非慢代谢组（P < 0.05）。结论 他克莫司治疗儿童MG疗效显著、安全性好，是需要免疫抑制剂治疗的MG患儿的良好选择。CYP3A5基因型对他克莫司使用剂量有一定的指导意义。
Objective To evaluate the efficacy and safety of tacrolimus in the treatment of children with myasthenia gravis (MG). Methods A total of 28 children with MG were treated with tacrolimus. MG-Activities of Daily Living (MG-ADL) scale was used to assess clinical outcome and safety after 1, 3, 6, 9, and 12 months of treatment. Results After tacrolimus treatment, the MG-ADL score at 1, 3, 6, 9 and 12 months was lower than that at baseline (P < 0.05), and the MG-ADL score showed a gradually decreasing trend. The response rates to tacrolimus treatment at 1, 3, 6, 9, and 12 months were 59%, 81%, 84%, 88%, and 88% respectively. At 6, 9, 12, and 18 months of treatment, 4, 13, 14, and 15 children respectively were withdrawn from prednisone. No recurrence was observed during treatment. Major adverse reactions/events were asymptomatic reduction in blood magnesium in 5 children and positive urine occult blood in 1 child, which turned negative without special treatment, and tacrolimus was not stopped due to such adverse reactions/events. One child was withdrawn from tacrolimus due to recurrent vomiting. According to CYP3A5 genotypes, all of the patients were divided into two groups:slow metabolic type (n=19) and non-slow metabolic type (fast metabolic type + intermediate type; n=9). The non-slow metabolism group received a higher dose of tacrolimus, but had a lower trough concentration of tacrolimus than the slow metabolism group (P < 0.05). The slow metabolism group had a higher response rates to tacrolimus treatment than the non-slow metabolism group (P < 0.05). Conclusions Tacrolimus appears to be effective and safe in the treatment of children with MG and is thus an option for immunosuppressive therapy. CYP3A5 genotyping has a certain guiding significance for determining the dosage of tacrolimus.
重症肌无力 / 免疫抑制剂 / 他克莫司 / CYP3A5 / 儿童
Myasthenia gravis / Immunosuppressant / Tacrolimus / CYP3A5 / Child
[1] Peragallo JH. Pediatric myasthenia gravis[J]. Semin Pediatr Neurol, 2017, 24(2):116-121.
[2] Liew WK, Kang PB. Update on juvenile myasthenia gravis[J]. Curr Opin Pediatr, 2013, 25(6):694-700.
[3] Gui M, Luo X, Lin J, et al. Long-term outcome of 424 childhood-onset myasthenia gravis patients[J]. J Neurol, 2015, 262(4):823-830.
[4] Ahn SW, Joo IS, Kim BJ, et al. A multicenter prospective observational study on the safety and efficacy of tacrolimus in patients with myasthenia gravis[J]. J Neurol Sci, 2017, 379:271-275.
[5] Zhao CB, Zhang X, Zhang H, et al. Clinical efficacy and immunological impact of tacrolimus in Chinese patients with generalized myasthenia gravis[J]. Int Immunopharmacol, 2011, 11(4):519-524.
[6] Wang L, Zhang S, Xi J, et al. Efficacy and safety of tacrolimus for myasthenia gravis:a systematic review and meta-analysis[J]. J Neurol, 2017, 264(11):2191-2200.
[7] Tao X, Wang W, Jing F, et al. Long-term efficacy and side effects of low-dose tacrolimus for the treatment of myasthenia gravis[J]. Neurol Sci, 2017, 38(2):325-330.
[8] Ponseti JM, Azem J, Fort JM, et al. Long-term results of tacrolimus in cyclosporine- and prednisone-dependent myasthenia gravis[J]. Neurology, 2005, 64(9):1641-1643.
[9] Cruz JL, Wolff ML, Vanderman AJ, et al. The emerging role of tacrolimus in myasthenia gravis[J]. Ther Adv Neurol Disord, 2015, 8(2):92-103.
[10] 王维治, 刘卫彬. 重症肌无力管理国际共识(2016)解读[J]. 中华神经科杂志, 2017, 50(2):83-87.
[11] Nishikawa N, Nagai M, Tsujii T, et al. Treatment of myasthenia gravis in patients with elderly onset at advanced age[J]. Jpn Clin Med, 2015, 6:9-13.
[12] Mori T, Mori K, Suzue M, et al. Effective treatment of a 13-year-old boy with steroid-dependent ocular myasthenia gravis using tacrolimus[J]. Brain Dev, 2013, 35(5):445-448.
[13] Kakisaka Y, Haginoya K, Yokoyama H, et al. Successful treatment of a 2-year-old girl with intractable myasthenia gravis using tacrolimus[J]. Brain Dev, 2006, 28(8):534-536.
[14] Liu C, Gui M, Cao Y, et al, et al. Tacrolimus improves symptoms of children with myasthenia gravis refractory to prednisone[J]. Pediatr Neurol, 2017, 77:42-47.
[15] 中华医学会神经病学分会神经免疫学组, 中国免疫学会神经免疫学分会. 中国重症肌无力诊断和治疗指南2015[J]. 中华神经科杂志, 2015, 48(11):934-940.
[16] Chen P, Feng H, Deng J, et al. Leflunomide treatment in corticosteroid-dependent myasthenia gravis:an open-label pilot study[J]. J Neurol, 2016, 263(1):83-88.
[17] Rowin J, Meriggioli MN, Tüzün E, et al. Etanercept treatment in corticosteroid-dependent myasthenia gravis[J]. Neurology, 2004, 63(12):2390-2392.
[18] Kanai T, Uzawa A, Kawaguchi N, et al. Adequate tacrolimus concentration for myasthenia gravis treatment[J]. Eur J Neurol, 2017, 24(2):270-275.
[19] Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis:executive summary[J]. Neurology, 2016, 87(4):419-425.
[20] Pasternak AL, Zhang L, Hertz DL. CYP3A pharmacogenetic association with tacrolimus pharmacokinetics differs based on route of drug administration[J]. Pharmacogenomics, 2018, 19(6):563-576.
[21] Wolfe GI, Herbelin L, Nations SP, et al. Myasthenia gravis activities of daily living profile[J]. Neurology, 1999, 52(7):1487-1489.
[22] 王秀云, 许贤豪, 孙宏, 等. 重症肌无力病人的临床绝对评分法和相对评分法[J]. 中华神经科杂志, 1997, 30(2):87-90.
[23] MacMillan D. FK506 binding proteins:cellular regulators of intracellular Ca2+ signalling[J]. Eur J Pharmacol, 2013, 700(1-3):181-193.
[24] Kim YH, Shin HY, Kim SM. Long-term safety and efficacy of tacrolimus in myasthenia gravis[J]. Yonsei Med J, 2019, 60(7):633-639.
[25] Takeuchi H, Iwamoto H, Nakamura Y, et al. Synergistic effects of calcineurin inhibitors and steroids on steroid sensitivity of peripheral blood mononuclear cells[J]. Cell Med, 2015, 7(2):51-57.
[26] Gilhus NE. Myasthenia gravis[J]. N Engl J Med, 2016, 375(26):2570-2581.
[27] 陈玉萍, 王卫, 王中魁, 等. 他克莫司治疗重症肌无力疗效及安全性评价[J]. 中华内科杂志, 2013, 52(7):567-569.
[28] Chen D, Hou S, Zhao M, et al. Dose optimization of tacrolimus with therapeutic drug monitoring and CYP3A5 polymorphism in patients with myasthenia gravis[J]. Eur J Neurol, 2018, 25(8):1049-e80.
[29] Uslu Gökceo?lu A, Comak E, Dogan CS, et al. Magnesium excretion and hypomagnesemia in pediatric renal transplant recipients[J]. Ren Fail, 2014, 36(7):1056-1059.
