曾意茹?李小晶?侯池?梁惠慈?陳文雄?吳汶霖
【摘要】目的 探討嗎替麥考酚酯(MMF)治療兒童神經(jīng)系統(tǒng)自身免疫性疾病的療效及安全性。方法 收集并分析12例被診斷為神經(jīng)系統(tǒng)自身免疫性疾病且使用MMF治療的患兒的臨床資料、輔助檢查結(jié)果、治療及預(yù)后的資料。結(jié)果 12例的診斷分別為神經(jīng)系統(tǒng)炎性脫髓鞘病8例,其中髓鞘少突膠質(zhì)細(xì)胞糖蛋白(MOG) IgG相關(guān)疾病5例、水通道蛋白-4(AQP4)抗體陽性的視神經(jīng)脊髓炎譜系疾?。∟MOSD) 1例、多發(fā)性硬化(MS) 1例、慢性炎性脫髓鞘性多發(fā)性神經(jīng)根神經(jīng)病(CIDP)1例,自身免疫性腦炎(AE,抗體陰性)2例,免疫性小腦共濟(jì)失調(diào)1例,眼陣攣肌陣攣綜合征(OMS)1例。MMF起始劑量為0.25 g/d,維持劑量為0.25 ~ 0.5 g/d。每1 ~ 3個(gè)月定期隨診,根據(jù)臨床癥狀和檢驗(yàn)結(jié)果調(diào)整MMF的劑量。使用MMF前共復(fù)發(fā)39次,用藥后8例患兒無復(fù)發(fā),分別為MOG IgG相關(guān)疾病3例、AE 2例、MS 1例、CIDP 1例、免疫性小腦共濟(jì)失調(diào)1例。4例患兒復(fù)發(fā),分別為MOG IgG相關(guān)疾病2例、AQP4 IgG NMOSD 1例、OMS 1例。MMF治療后年平均復(fù)發(fā)率較治療前下降(中位數(shù)1.92次/年 vs. 0.00 次/年, P = 0.034)。MMF治療前、后的改良Rankin評分比較差異有統(tǒng)計(jì)學(xué)意義(中位數(shù)3.00分 vs. 1.00分,P = 0.002)。治療過程中2例患兒出現(xiàn)嚴(yán)重不良反應(yīng),分別為結(jié)核潛伏感染和重癥肺炎,個(gè)別患兒僅表現(xiàn)為輕度胃腸反應(yīng),給予對癥治療后癥狀消失。結(jié)論 MMF或可降低兒童神經(jīng)系統(tǒng)炎性脫髓鞘病及AE的復(fù)發(fā)率以及改善神經(jīng)功能障礙,MMF治療仍有復(fù)發(fā)的OMS患兒需啟動其他免疫治療,MMF治療有可能會出現(xiàn)嚴(yán)重不良反應(yīng)。
【關(guān)鍵詞】嗎替麥考酚酯;兒童;自身免疫性神經(jīng)疾病;復(fù)發(fā)
Efficacy and safety of mycophenolate mofetil in treatment of pediatric immune-mediated disease of the nervous system Zeng Yiru, Li Xiaojing, Hou Chi, Liang Huici, Chen Wenxiong, Wu Wenlin. Department of Neurology, Guangzhou Women and Childrens Medical Center, Guangzhou 510623, China
Corresponding author, Li Xiaojing, E-mail: lixiaojingfy@ 163. com
【Abstract】Objective To evaluate the efficacy and safety of mycophenolate mofetil (MMF) in the treatment of pediatric immune-mediated disease of the nervous system. Methods Clinical data, auxiliary examination results, treatment and clinical prognosis of 12 children diagnosed with immune-mediated disease of the nervous system were collected and retrospectively analyzed. Results Among 12 children, 8 cases were diagnosed with inflammatory demyelinating disease including myelin oligodendrocyte-glycoprotein (MOG-IgG)-associated disease (n = 5), aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (NMOSD-AQP4) (n = 1), multiple sclerosis (MS) (n = 1), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) (n = 1);two children were diagnosed with autoimmune encephalitis (AE, negative antibody), one child was diagnosed with autoimmune cerebellar ataxia and one child of oculomotor myoclonus syndrome (OMS). The initial dose of MMF was 0.25 g/d and the maintenance dose was ranged from 0.25 to 0.5 g/d. All children were followed up every 1-3 months. The dose of MMF was adjusted according to clinical symptoms and examination results. Before MMF treatment, all patients developed 39 times of episode, whereas 8 children had no episode after MMF treatment including 3 cases of MOG-IgG-associated disease, 2 cases of AE, 1 case of MS, 1 case of CIDP and 1 case of autoimmune cerebellar ataxia. Four patients recurred including 2 cases of MOG-IgG-associated disease, 1 case of NMOSD-AQP4 and 1 case of OMS. The median annual recurrence rate after MMF treatment was 0.00, significantly lower than 1.92 times/year before MMF treatment (P = 0.034). The median modified Rankin score significantly differed before and after MMF treatment (3.00 vs. 1.00, P = 0.002). During MMF treatment, 2 children experienced severe adverse events including latent tuberculosis infection and severe pneumonia. Two patients developed mild gastrointestinal symptoms, which were alleviated after symptomatic treatment. Conclusions MMF probably could reduce the recurrence of pediatric inflammatory demyelinating disease and AE and mitigate neurological dysfunction. Immunotherapy should be considered for OMS children with recurrence after MMF treatment. However, MMF treatment might induce severe adverse events.
【Key words】Mycophenolate mofetil;Child;Immune-mediated disease of the nervous system;
Recurrence
嗎替麥考酚酯(MMF)是一種免疫抑制劑,在上世紀(jì)90年代中期首次被用于預(yù)防移植抗排斥反應(yīng)。MMF在體內(nèi)迅速被吸收轉(zhuǎn)化為麥考酚酸(MPA), MPA可選擇性抑制次黃嘌呤核苷酸脫氫酶,影響DNA復(fù)制,從而干擾T、B淋巴細(xì)胞增殖,而體細(xì)胞可通過補(bǔ)救途徑繼續(xù)合成DNA,因此對正常的體細(xì)胞無影響[1]。文獻(xiàn)報(bào)道,MPA可以抑制細(xì)胞因子分泌,抑制B細(xì)胞激活、分化,減少漿細(xì)胞數(shù)量[2-3]。目前MMF被廣泛應(yīng)用于自身免疫性神經(jīng)疾病中,尤其是復(fù)發(fā)性炎性脫髓鞘疾病,且療效確切,但在兒童神經(jīng)系統(tǒng)自身免疫性疾病中的應(yīng)用報(bào)道較少[4-8]。我們發(fā)現(xiàn)既往未有MMF治療兒童神經(jīng)系統(tǒng)自身免疫性疾病的相關(guān)報(bào)道,遂對12例使用MMF治療的患兒的臨床特征、治療、預(yù)后和不良反應(yīng)進(jìn)行了總結(jié)分析,探討MMF治療兒童自身免疫性神經(jīng)疾病的療效及安全性。
對象與方法
一、研究對象
納入我科2013年10月1日至2020年4月1日使用MMF治療的復(fù)發(fā)性神經(jīng)系統(tǒng)自身免疫性疾病患兒為研究對象。納入標(biāo)準(zhǔn):①起病年齡 < 18歲。②復(fù)發(fā)病例,臨床復(fù)發(fā)定義為病情穩(wěn)定2個(gè)月后,出現(xiàn)新的神經(jīng)系統(tǒng)功能缺損癥狀,持續(xù) ≥ 24 h,伴或不伴影像學(xué)新病灶[9-10]。③中樞神經(jīng)系統(tǒng)脫髓鞘病的診斷符合國際兒童多發(fā)性硬化(MS)研究組對兒童MS和免疫介導(dǎo)的中樞神經(jīng)系統(tǒng)脫髓鞘疾病的診斷標(biāo)準(zhǔn)[11]。慢性炎癥性脫髓鞘性多發(fā)性神經(jīng)根神經(jīng)?。–IPD)的診斷符合2010年歐洲神經(jīng)病學(xué)聯(lián)盟和周圍神經(jīng)病學(xué)會關(guān)于CIPD的管理指南的診斷標(biāo)準(zhǔn)[12]。免疫性小腦共濟(jì)失調(diào)和眼陣攣肌陣攣綜合征(OMS)的診斷符合2019年免疫介導(dǎo)小腦共濟(jì)失調(diào)指南的診斷標(biāo)準(zhǔn)[13]。抗體陰性的自身免疫性腦炎(AE)符合Graus等(2016年)提出的診斷標(biāo)準(zhǔn)[11-14]。排除標(biāo)準(zhǔn):①有神經(jīng)系統(tǒng)遺傳代謝性疾病、顱內(nèi)感染、中毒、退行性疾病、外傷、腫瘤者。②合并結(jié)核等嚴(yán)重的潛在感染。本研究經(jīng)我院倫理委員會批準(zhǔn)(穗婦兒倫審批第2019052419364384號),患兒監(jiān)護(hù)人均簽署知情同意書。
二、研究方法
收集并分析12例被診斷為神經(jīng)系統(tǒng)自身免疫性疾病并使用MMF治療的患兒的臨床資料、輔助檢查結(jié)果、治療及預(yù)后的資料。MMF治療的有效性以年平均復(fù)發(fā)率(ARR,ARR = 復(fù)發(fā)次數(shù)/
年數(shù))、改良Rankin評分(mRS)為評價(jià)指標(biāo)。mRS評分用于評估患兒首次發(fā)病及末次隨訪時(shí)的臨床神經(jīng)功能缺陷程度[4]。比較患兒治療前、后的實(shí)驗(yàn)室檢查等結(jié)果。采用不良反應(yīng)常見術(shù)語標(biāo)準(zhǔn)(CTCAE)對患兒不良反應(yīng)進(jìn)行分級,統(tǒng)計(jì)不良反應(yīng)的發(fā)生情況。
三、統(tǒng)計(jì)學(xué)處理
采用SPSS 22.0進(jìn)行統(tǒng)計(jì)分析。正態(tài)分布的計(jì)量資料采用描述,治療前后各項(xiàng)指標(biāo)比較采用配對t檢驗(yàn);非正態(tài)分布數(shù)據(jù)采用中位數(shù)(四分位數(shù)間距)描述,治療前后各項(xiàng)指標(biāo)比較采用符號秩和檢驗(yàn);計(jì)數(shù)資料用頻數(shù)表示。P < 0.05 (雙尾)為差異有統(tǒng)計(jì)學(xué)意義。
結(jié)果
一、納入患兒的臨床特點(diǎn)
本研究共納入12例患兒,均來自中國華南地區(qū),男∶女為2∶1,起病年齡為(5.5±2.7)歲。12例中神經(jīng)系統(tǒng)炎性脫髓鞘病8例:髓鞘少突膠質(zhì)細(xì)胞糖蛋白(MOG)IgG相關(guān)疾病5例[4例為MOG IgG相關(guān)的多相性播散性腦脊髓炎(MEDM)、1例為MOG IgG相關(guān)的復(fù)發(fā)性視神經(jīng)炎],水通道蛋白-4(AQP4)抗體陽性的視神經(jīng)脊髓炎譜系疾病(NMOSD) 1例,MS 1例,CIDP 1例。其余4例為AE(抗體陰性)2例、免疫性小腦共濟(jì)失調(diào)1例、OMS 1例?;純旱呐R床表現(xiàn)見表1。
二、納入患兒的治療方法
1.急性期治療方案
靜脈滴注人Ig(IVIG),復(fù)發(fā)急性期給予2 g/kg,總量分3 ~ 5 d滴注。靜脈滴注甲潑尼龍(IVMP)沖擊治療,10 ~ 15 mg/(kg·d),共3 d,之后階梯式減量。
2. 維持治療
MMF使用適應(yīng)證:①一線免疫治療效果不佳;②復(fù)發(fā)≥2次。對于在腎上腺皮質(zhì)激素(激素)口服減停過程中復(fù)發(fā)的患兒,在急性期病情穩(wěn)定后給予MMF口服維持治療,起始劑量為0.25 g/d,維持劑量為0.25 ~ 0.5 g/d。每1 ~ 3個(gè)月定期隨診,根據(jù)臨床癥狀和檢驗(yàn)結(jié)果調(diào)整MMF的劑量。
三、納入患兒的病程
12例患兒首次發(fā)病至末次隨訪的時(shí)間為(41.7±16.8)個(gè)月,均接受過IVIG和IVMP治療。12例患兒使用MMF前共復(fù)發(fā)39次,觀察時(shí)間為(24.0±19.9)個(gè)月;使用MMF后共有4例復(fù)發(fā),其中3例停用MMF,2例后續(xù)使用利妥昔單抗治療,2例再次予IVIG和IVMP沖擊治療后病情緩解。其余8例患兒在接受MMF治療后隨訪(26.5±9.0)個(gè)月,均暫無復(fù)發(fā)。
四、納入患兒MMF治療前、后的實(shí)驗(yàn)室檢查結(jié)果
7例患兒MMF治療前后行外周血CD19+ B淋巴細(xì)胞測定,治療后較治療前有下降趨勢,但差異無統(tǒng)計(jì)學(xué)意義(P = 0.384)。7例患兒MMF治療前后行外周血CD4+ T淋巴細(xì)胞測定,治療后較治療前下降(P = 0.045)。7例患兒MMF治療前后行外周血CD8+ T淋巴細(xì)胞測定,治療后較治療前有下降趨勢,但差異無統(tǒng)計(jì)學(xué)意義(P = 0.054)。8例患兒MMF治療前后行血清IgG測定,治療后與治療前比較差異無統(tǒng)計(jì)學(xué)意義(P = 0.395),見表2。
五、MMF治療的安全性
入組的12例患兒中有2例出現(xiàn)嚴(yán)重不良反應(yīng),包括1例重癥肺炎,予停用MMF,行呼吸機(jī)輔助通氣治療(CTCAE 4級);1例合并結(jié)核潛伏感染,停用MMF,采用3HR方案(異煙肼加利福平,1次/日,共3個(gè)月)抗結(jié)核治療(CTCAE 3級)。2例患兒有一過性輕度胃腸道反應(yīng)(CTCAE 1級),其余患兒未出現(xiàn)明顯不良反應(yīng)。
六、MMF治療前、后的復(fù)發(fā)情況及有效性
12例患兒治療前mRS為3.00(1.75)分,治療后為1.00(1.00)分,治療后較治療前降低(Z = -3.108,P = 0.002)。
12例患兒MMF治療前ARR為1.92(1.72)次/年。MMF治療后4例患兒在隨訪過程中出現(xiàn)復(fù)發(fā),12例患兒MMF治療后的ARR為0.00(0.70)次/年,治療前、后比較差異有統(tǒng)計(jì)學(xué)意義(Z = -2.118,P = 0.034)。12例患兒的臨床表現(xiàn)、診斷、復(fù)發(fā)、預(yù)后等情況見表1。
討論
目前對于MMF、利妥昔單抗或每月IVIG治療作為預(yù)防MOG抗體相關(guān)脫髓鞘疾病的復(fù)發(fā)均有報(bào)道,但哪種治療方案療效更佳暫無統(tǒng)一意見[5, 15-16]。本研究納入5例MOG IgG陽性的炎性脫髓鞘病患兒,經(jīng)MMF治療后其mRS和ARR較治療前低,與之前的研究結(jié)果一致,提示MMF作為MOG抗體相關(guān)脫髓鞘疾病的免疫抑制維持治療可能有助于患者神經(jīng)功能的恢復(fù)及降低復(fù)發(fā)率[5, 15-16]。
本研究中的1例AQP4 IgG NMOSD患兒經(jīng)MMF治療后的mRS較治療前低,但ARR無明顯改善。MMF是成人AQP4 IgG NMOSD序貫免疫抑制治療的一線藥物,有研究顯示MMF可降低AQP4 IgG NMOSD患者復(fù)發(fā)率和改善神經(jīng)功能狀態(tài)[17]。但本研究中的患兒治療前后ARR下降不明顯,可能與以下原因有關(guān):①病例數(shù)過少;②治療后隨訪時(shí)間尚短;③MMF用量不足,本例患兒MMF用量為5 mg/(kg·d),相對其他研究劑量偏低[18-19]。
兒童MS以復(fù)發(fā)緩解型為主,較成人患者復(fù)發(fā)率高,復(fù)發(fā)時(shí)病情更嚴(yán)重,預(yù)后也更差[20-22]。復(fù)發(fā)緩解型MS的治療包括急性期治療和疾病修飾治療(DMT)。本研究中的1例MS患兒MMF治療前ARR為0.47次/年,治療后隨訪31個(gè)月無復(fù)發(fā),提示MMF或可降低兒童MS的復(fù)發(fā)率。另外MMF為口服用藥,有更好的接受度。我們認(rèn)為MMF或可作為兒童DMT的選擇。
MMF治療周圍神經(jīng)脫髓鞘病鮮有報(bào)道,本研究中1例CIPD患兒在使用MMF后病情得到長期緩解,提示MMF對于中樞神經(jīng)和周圍神經(jīng)炎性脫髓鞘疾病可能有良好的療效。
MMF主要用于復(fù)發(fā)或一線免疫治療不佳的AE患者[23]。本研究2例AE患兒分別在第3次和第4次復(fù)發(fā)后采用MMF治療,分別治療25個(gè)月和29個(gè)月,均無復(fù)發(fā),mRS也均較治療前低,結(jié)果與其他同類研究相似[4, 18]。
目前治療OMS多采用激素、ACTH、Ig和血漿置換,但治療后復(fù)發(fā)率可達(dá)50%。本研究中的1例OMS患兒在起病6個(gè)月時(shí)加用MMF治療,但在用藥2個(gè)月內(nèi)出現(xiàn)2次復(fù)發(fā),其后采用利妥昔單抗聯(lián)合每1 ~ 3個(gè)月輸注IVIG治療,目前隨訪13個(gè)月無復(fù)發(fā)。與既往報(bào)道中對于多次復(fù)發(fā)的OMS患者選擇單用利妥昔單抗或與其他免疫抑制劑(如Ig)聯(lián)用可改善臨床癥狀以及減少復(fù)發(fā)相似[24]。
本研究中有2例患兒因出現(xiàn)較嚴(yán)重感染而停用MMF。MMF可通過抑制T、B淋巴細(xì)胞增殖和細(xì)胞因子的產(chǎn)生達(dá)到免疫抑制作用,但也可增加感染的風(fēng)險(xiǎn)[2-3]。我們發(fā)現(xiàn)經(jīng)MMF治療后患兒的CD4+ T淋巴細(xì)胞水平較治療前降低,這提示在以后的研究中既應(yīng)考慮MMF治療的效果,也應(yīng)根據(jù)疾病的免疫致病機(jī)制動態(tài)監(jiān)測相關(guān)的免疫指標(biāo),從而選擇適合的MMF劑量和療程,在達(dá)到抑制免疫的同時(shí)又能降低感染的風(fēng)險(xiǎn)。綜上所述,MMF或可降低兒童神經(jīng)系統(tǒng)炎性脫髓鞘病及AE的復(fù)發(fā)率以及改善神經(jīng)功能障礙,MMF治療仍有復(fù)發(fā)的OMS患兒需啟動其他免疫治療,MMF治療有可能會出現(xiàn)嚴(yán)重不良反應(yīng),但發(fā)生率較低,仍較為安全。
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(收稿日期:2020-06-30)
(本文編輯:洪悅民)