江 璐 唐韓云 閔 月 李曉忠

蘇州大學(xué)附屬兒童醫(yī)院（江蘇蘇州 215000）

兒童寡肌病性皮肌炎合并肺間質(zhì)病變2例報(bào)告

江 璐 唐韓云 閔 月 李曉忠

蘇州大學(xué)附屬兒童醫(yī)院（江蘇蘇州 215000）

目的探討托珠單抗對(duì)兒童寡肌病性皮肌炎合并肺間質(zhì)病變的療效。方法回顧分析2例寡肌病性皮肌炎合并肺間質(zhì)病變患兒的臨床特點(diǎn)及治療與預(yù)后，并復(fù)習(xí)相關(guān)文獻(xiàn)。結(jié)果男女各1例，女性患兒10歲11個(gè)月、男性患兒8歲5個(gè)月，起病時(shí)均有氣促，但無(wú)肌肉損害的臨床表現(xiàn)；均有典型皮疹，但肌力及肌張力正常。實(shí)驗(yàn)室檢查以血清鐵蛋白、乳酸脫氫酶、谷氨酸氨基轉(zhuǎn)移酶及天冬氨酸氨基轉(zhuǎn)移酶升高為主，肌酸肌酶除首次入院時(shí)稍高，復(fù)查始終在正常范圍。高分辨CT示肺間質(zhì)病變。臨床診斷為寡肌病性皮肌炎合并肺間質(zhì)病變。女性患兒經(jīng)大劑量激素、環(huán)磷酰胺、環(huán)孢素、吡菲尼酮及丙種球蛋白等治療無(wú)效死亡。男性患兒在常規(guī)激素治療的基礎(chǔ)上，加用托珠單抗（240 mg/次，2次），病情穩(wěn)定，隨訪復(fù)查各指標(biāo)均在正常范圍內(nèi)。結(jié)論兒童寡肌病性皮肌炎臨床表現(xiàn)以及實(shí)驗(yàn)室檢查結(jié)果不典型，死亡發(fā)生率高。聯(lián)合托珠單抗治療有效。

皮肌炎； 寡肌病性； 肺間質(zhì)病變； 托珠單抗

兒童寡肌病性皮肌炎（hypomyopathic dermatomyositis，HDM）是少見(jiàn)的自身免疫性疾病，合并肺間質(zhì)病變（interstitial lung disease，ILD）死亡率高?，F(xiàn)報(bào)告2例兒童HDM并發(fā)肺間質(zhì)病變病例，并回顧相關(guān)文獻(xiàn)，以期加深對(duì)此病的認(rèn)識(shí)。

1 臨床資料

例1，女，10歲11個(gè)月，因“發(fā)現(xiàn)面部紅斑1個(gè)月”入院。入院體格檢查：神志清，顏面部紫紅水腫、色素性融合性紅斑疹，雙手指關(guān)節(jié)、肘部可見(jiàn)紫紅色鱗屑性丘疹（Gottron征），肌力Ⅴ級(jí)、肌張力正常，心、肺、腹未見(jiàn)異常。實(shí)驗(yàn)室檢查：谷氨酸氨基轉(zhuǎn)移酶（ALT）448.3 U/L、天冬氨酸氨基轉(zhuǎn)移酶（AST）629.9 U/L、肌酸激酶（CK）229.2 U/L、乳酸脫氫酶（LDH）697 U/ L；血清鐵蛋白（SF）1 142.5 ng/mL；肌酸激酶同工酶（CK-MB）正常；抗核抗體陰性，抗增殖細(xì)胞核抗原（PCNA）可疑，抗Ro-52陽(yáng)性，抗干燥綜合征相關(guān)抗原A（SSA）可疑，其余均為陰性。骨髓穿刺示輕度感染表現(xiàn)。肺高分辨CT（HRCT）示兩肺多發(fā)斑片、條索狀高密度影，部分呈間質(zhì)性改變。肺功能檢查示限制性通氣功能障礙。膝關(guān)節(jié)磁共振成像（MRI）示雙側(cè)股骨后方軟組織少許條狀短時(shí)間反轉(zhuǎn)恢復(fù)（short time inversion recovery，STIR）序列高信號(hào)。肌電圖可見(jiàn)數(shù)處正銳波及纖顫波出現(xiàn)，運(yùn)動(dòng)單位電位時(shí)限明顯縮短，提示為肌源性損害。根據(jù)患兒典型皮疹但無(wú)肌肉損害的臨床表現(xiàn)，入院時(shí)CK輕度增高，結(jié)合肌電圖、MRI及肺HRCT，診斷為HDM合并ILD。入院后予環(huán)磷酰胺8～12 mg/(kg·d)，丙種球蛋白1 g/(kg·d)×2 d，甲基潑尼松龍2 mg/(kg·d)及護(hù)肝等治療，1周后復(fù)查SF、ALT、AST、LDH較前降低，CK正常。第3周復(fù)查肺HRCT示兩肺多發(fā)斑片狀、條索狀高密度影較前無(wú)明顯緩解，予甲基潑尼松龍15～30 mg/(kg·d)沖擊治療3 d，后改潑尼松口服。第4周患兒氣促加重，肺部聞及濕啰音，第2次給予丙種球蛋白支持及抗感染治療，同時(shí)口服環(huán)孢素、吡非尼酮、乙酰半胱氨酸等治療，療效欠佳。第5周患兒突發(fā)呼吸困難，肺HRCT示兩側(cè)胸膜腔、縱隔、頸部皮下氣腫，胸片示左側(cè)胸腔積液，復(fù)查SF、ALT及AST較前升高，行胸腔閉式引流排氣排液，兩周后復(fù)查胸部HRCT示縱隔、肺間質(zhì)、 頸胸部皮下氣腫，左側(cè)病灶較前進(jìn)展，右側(cè)病灶同前， 左肺膨脹不全，左側(cè)少量氣胸可疑。第7周行皮下氣腫切開(kāi)排氣，繼續(xù)口服潑尼松、環(huán)孢素、吡菲尼酮，間斷鼻導(dǎo)管低流量吸氧等治療。第12周患兒病情無(wú)改善，家屬要求自動(dòng)出院。出院1周后電話回訪，患兒死亡。

圖1 例2患兒肺部HRCT

例2，男，8歲5個(gè)月，因“發(fā)熱，眶周水腫皮疹伴關(guān)節(jié)腫2周”第一次入院。入院體格檢查：眶周水腫伴顏面色素性融合性紅斑疹，指關(guān)節(jié)見(jiàn)Gottron征，伴雙手指及膝關(guān)節(jié)腫脹，無(wú)疼痛，無(wú)明顯活動(dòng)受限，肌力Ⅴ級(jí)，肌張力正常，心、肺、腹未見(jiàn)異常。入院時(shí)查高敏C反應(yīng)蛋白（CRP）77.06 mg/L、CK 233.1 U/L、ALT正常、AST 75.1 U/L、LDH 811 U/L，SF 461.5 ng/mL，自身抗體篩查均陰性。骨髓穿刺示呈感染表現(xiàn)。左腿腘窩皮膚活檢病理示真皮小血管周圍散在單個(gè)核細(xì)胞浸潤(rùn)，提示真皮小血管周圍炎，免疫熒光標(biāo)記檢查未見(jiàn)明顯陽(yáng)性熒光沉積。上肢MRI示左側(cè)尺橈骨、左肩皮下、雙側(cè)股骨內(nèi)側(cè)脂肪層短時(shí)間反轉(zhuǎn)恢復(fù)序列（STIR）信號(hào)不均勻。肺HRCT示肺紋理增生。肌電圖及肺功能未做。根據(jù)患兒典型皮疹，肌力、肌張力正常，實(shí)驗(yàn)室檢查以SF、LDH升高為主，CK入院時(shí)稍高，結(jié)合皮膚活檢結(jié)果診斷為HDM。予常規(guī)抗炎抗免疫藥物治療后，病情穩(wěn)定后出院。5個(gè)月后，患兒因發(fā)熱、氣促再次入院，入院時(shí)精神差，顏面部及指關(guān)節(jié)皮疹較前消褪，皮膚粗糙，肌力及肌張力正常。實(shí)驗(yàn)室檢查：CRP 53.63 mg/L；SF>1 650 ng/mL，AST 116.8 U/ L，LDH 1 131.5 U/L；CK、CK-MB、肌鈣蛋白均正常，肌紅蛋白稍低。肺HRCT示兩肺散在小結(jié)節(jié)、條索影，兩側(cè)胸膜增厚（圖1A），提示ILD 。臨床診斷為HDM合并ILD。入院后予甲基潑尼松龍2 mg/(kg· d)、丙種球蛋白1 g/(kg·d)×2 d以及抗感染、護(hù)肝治療，并口服羥氯喹、嗎替麥考酚酯、他克莫司、乙酰半胱氨酸，后激素改甲基潑尼松龍片口服?；純喊l(fā)熱、氣急等癥狀緩解，復(fù)查SF> 1 650 ng/mL，考慮疾病仍處于活動(dòng)狀態(tài)，加用托珠單抗240 mg，3天后復(fù)查SF 800.6 ng/ mL，病情穩(wěn)定后出院。兩周后，患兒入院行第2次托珠單抗治療，復(fù)查SF 179.8 ng/mL、肝功能正常，肺HRCT較前好轉(zhuǎn)明顯（圖1B），無(wú)不適出院。現(xiàn)患兒定期門診隨訪，SF等各項(xiàng)指標(biāo)均在正常范圍內(nèi)，病情得到較好地控制。

2 討論

幼年特發(fā)性炎性肌?。?juvenile idiopathic inflammatory myopathies，JIIM）是一類以骨骼肌慢性炎癥、皮疹及其他系統(tǒng)表現(xiàn)為特征的全身性自身免疫性疾病[1]。根據(jù)臨床特點(diǎn)[2]分為幼年皮肌炎（juvenile dermatomyositis，JDM）、幼年多發(fā)性肌炎（juvenile polymyositis，JPM）以及寡肌病性皮肌炎（hypomyopathic dermatomyositis，HDM）和無(wú)肌病性皮肌炎（amyopathic dermatomyositis，ADM）。Sontheimer[3]提出，臨床無(wú)肌病性皮肌炎（clinically amyopathic dermatomyositis，CADM）是ADM和HDM的總稱。本組2例患兒都有典型皮肌炎皮疹，但肌力、肌張力均正常，實(shí)驗(yàn)室檢查指標(biāo)以SF、LDH、ALT及AST升高為主，CK除首次入院時(shí)稍高，復(fù)查始終在正常范圍，此外例1患兒肌電圖結(jié)果、例2患兒皮膚活檢結(jié)果也都支持CADM診斷。有文獻(xiàn)報(bào)道，CADM和DM患者的皮膚病理學(xué)結(jié)果相同，與兩者相關(guān)的系統(tǒng)性疾病包括惡性腫瘤和肺部疾病[4]。

由血清學(xué)結(jié)果發(fā)現(xiàn)，在肌炎特異性自身抗體（myositis-specific-autoantibodies，MSAs）中，抗p155/140抗體、抗MJ抗體與JDM相關(guān)，前者與光敏性皮疹有關(guān)，后者與肌肉、關(guān)節(jié)病變有關(guān)[5]；抗Jo-1抗體與肺間質(zhì)病變、關(guān)節(jié)炎、發(fā)熱以及雷諾現(xiàn)象密切相關(guān)[5]；抗Mi-2抗體與JDM以及典型皮疹特征相關(guān)；在CADM合并急進(jìn)性ILD患者中，抗CADM-140抗體/抗MAD5抗體陽(yáng)性率高[6,7]。而肌炎相關(guān)自身抗體（myositisassociated-autoantibodies，MAAs）如抗U1RNP、抗Ro、抗PM-Scl及抗Ku抗體在15%的JIIM患者中發(fā)現(xiàn)[8]，在其他自身免疫疾病患者中也能檢測(cè)到。

CADM患者較DM患者易合并ILD[9]。ILD 是影響預(yù)后的重要因素，也是引起死亡的首位原因，合并快速進(jìn)展型ILD的患者有60%在2個(gè)月內(nèi)死亡[10]。肺HRCT的檢查結(jié)果與開(kāi)胸肺活檢的組織學(xué)基本一致[11]，肺HRCT診斷的特異性高達(dá)90%[12]。CRP及SF水平與外周血白介素6（IL-6）水平呈正相關(guān)，且與疾病活動(dòng)性評(píng)估指標(biāo)的一般情況及肺部表現(xiàn)相關(guān)[13]。Gono等[14]報(bào)道，并發(fā)急性或亞急性間質(zhì)性肺病的患者有著非常高的SF水平，與無(wú)間質(zhì)性肺病的患者相比有顯著性差異。因此肺HRCT及SF對(duì)診斷及監(jiān)測(cè)病情有重要的臨床價(jià)值。

治療上，主要采用激素和免疫抑制劑，對(duì)于危重癥患兒可予大劑量激素沖擊聯(lián)合丙種球蛋白支持治療，但當(dāng)合并ILD時(shí)，激素沖擊治療療效欠佳，有加重感染的可能。例2患兒急性發(fā)作被控制后，因SF一直較高，使用托珠單抗將SF水平降低，后期隨訪中各指標(biāo)均在正常范圍內(nèi)。托珠單抗作為IL-6受體拮抗劑是一種新型生物制劑。有文獻(xiàn)報(bào)道，IL-6在DM及PM患者中均升高，且在DM患者中更高[15]。DM患者局部炎癥部位的組織可檢測(cè)到升高的IL-6 mRNA，當(dāng)疾病活動(dòng)時(shí)IL-6也在這些部位聚集[16,17]，經(jīng)托珠單抗治療后，DM患者的血清IL-6下降，較PM患者明顯[15]。 Hiroyuki等[18]認(rèn)為，可以用IL-6和IL-18水平來(lái)預(yù)測(cè)JDM相關(guān)性嗜血細(xì)胞綜合征（JDM-associated macrophage activation syndrome，JDM-MAS）和ILD的疾病活動(dòng)性。國(guó)外有報(bào)道稱，托珠單抗治療PM小鼠[19]和治療成人難治性PM[20]有效。Masahiro等[21]也報(bào)道過(guò)1例應(yīng)用托珠單抗治療重疊綜合征患兒，認(rèn)為托珠單抗對(duì)難治性DM有效。目前托珠單抗已經(jīng)進(jìn)入我國(guó)市場(chǎng)，但治療HDM屬于超說(shuō)明書(shū)用藥。通過(guò)分析這2例病例，認(rèn)為也許可以通過(guò)托珠單抗聯(lián)合常規(guī)抗炎抗免疫藥物來(lái)治療此類患兒，但由于其長(zhǎng)期的臨床療效和不良反應(yīng)有待進(jìn)一步觀察，未來(lái)需要設(shè)計(jì)更多合理的臨床對(duì)照試驗(yàn)來(lái)加以驗(yàn)證。

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(本文編輯：鄒 強(qiáng))

《臨床兒科雜志》啟用科技期刊學(xué)術(shù)不端文獻(xiàn)檢測(cè)系統(tǒng)

學(xué)術(shù)不端行為是指違反學(xué)術(shù)規(guī)范、學(xué)術(shù)道德的行為，國(guó)際上一般用來(lái)指捏造數(shù)據(jù)（fabrication）、篡改數(shù)據(jù)（falsi fi cation）和剽竊（plagiarism）3種行為。為了提高來(lái)稿質(zhì)量，防止抄襲、偽造、剽竊、一稿多投等學(xué)術(shù)不端行為的發(fā)生，本刊已啟用“科技期刊學(xué)術(shù)不端文獻(xiàn)檢測(cè)系統(tǒng)”，對(duì)檢測(cè)出有嚴(yán)重不端行為的稿件，編輯部將一律退稿。

該系統(tǒng)由中國(guó)知識(shí)資源總庫(kù)所收錄的數(shù)千萬(wàn)條中文文獻(xiàn)、數(shù)百萬(wàn)條英文文獻(xiàn)支持。系統(tǒng)將檢測(cè)的文章與數(shù)據(jù)庫(kù)內(nèi)的文獻(xiàn)進(jìn)行比對(duì)，不僅可以檢測(cè)文獻(xiàn)總的文字復(fù)制比例，還可詳細(xì)列出檢測(cè)文獻(xiàn)中每一段雷同文字的詳細(xì)出處，并準(zhǔn)確定位每一段文字的具體位置，能夠給出一個(gè)完整的比對(duì)報(bào)告。因此，希望廣大作者在撰寫(xiě)論文時(shí)，一定要本著實(shí)事求是的科學(xué)精神，自覺(jué)抵制學(xué)術(shù)不端行為，引用他人的研究成果務(wù)必標(biāo)引參考文獻(xiàn)。本刊希望借助此工具，與廣大專家、讀者、作者一起，共同遏制學(xué)術(shù)不端之風(fēng)，構(gòu)建公平公正的學(xué)術(shù)交流平臺(tái)，營(yíng)造健康的學(xué)術(shù)環(huán)境。

Childhood hypomyopathic dermatomyositis combined with interstitial lung disease: two cases report

JIANG Lu, TANG Hanyun, MIN Yue, LI Xiaozhong
(Department of Nephrology and Rheumatology, Children’s Hospital of Soochow University, Suzhou 215000, Jiangsu, China)

ObjectiveTo discusses the effectiveness of tocilizumab in the treatment of hypomyopathic dermatomysositis (HDM) combined with interstitial lung disease (ILD) in children.MethodsThe clinical characteristic, treatment, and prognosis of HDM combined with ILD were analyzed in 2 patients. The related literatures were reviewed.ResultsBoth ten-year-old girl and 8-year-old boy had shortness of breath after activities, but had no clinical manifestations of muscle damage; both of them had typical rash, but had nornal muscle strength and muscular tension. Laboratory tests showed the elevation of serum ferritin, lactate dehydrogenase, glutamate aminotransferase, and aspartate aminotransferase. Creatine kinase slightly increased in the initial test, and then was in the normal range in the following tests. The high resolution computed tomography showed that pulmonary interstitial lesions. HDM combined ILD was diagnosed clinically. The girl died after treatment with high-dose hormones, cyclophosphamide, cyclosporine, pirfenidone, and gamma globulin failed. The boy was stabled after conventional hormone treatment plus tocilizumab (240 mg twice). His laboratory indicators were in the normal range in the follow-up.ConclusionsThe clinical manifestations and laboratory indicators aren't typical in childhood HDM. The mortality is high. Combined with tocilizumab treatment is effective in one case.

dermatomyositis; hypomyopathic; interstitiallung lung disease; tocilizumab

10.3969/j.issn.1000-3606.2017.06.013

2016-11-28)

國(guó)家自然科學(xué)基金資助項(xiàng)目（No.81370787）；江蘇省臨床醫(yī)學(xué)科技專項(xiàng)——新型臨床診療技術(shù)攻關(guān)（No.SBL2014030237）

李曉忠 電子信箱：xiaozhonglicn@yeah.net