幼年型皮肌炎特异性抗体研究进展

幼年型皮肌炎（juvenile dermatomyositis，JDM）是以近端肌无力和皮疹为主要临床表现的自身免疫疾病，亦可累及多系统、多脏器。肌炎特异性抗体（myositis-specific autoantibodies，MSA）与JDM患者的并发症及预后高度相关。抗Mi-2抗体阳性患者预后较好，临床症状典型；抗MDA5抗体阳性患者多伴发弥漫性间质性肺疾病及皮肤溃疡，肌炎症状轻；抗NXP2抗体阳性患者易合并钙质沉着，该抗体与胃肠出血及穿孔相关；抗TIF1-γ抗体阳性患者有弥漫、顽固的皮损表现；抗SAE抗体在儿童中检出率较低，相关报道较少。该文综述了5种MSA亚型JDM患者的临床表型特点，为JDM患儿的临床治疗和随访管理提供依据。     

幼年型皮肌炎常见肌炎抗体与临床表型的关联分析

背景 目前成人和儿童皮肌炎的肌炎抗体谱与临床表型谱的分析受单纯与复合抗体、是否已治疗等混杂因素影响。目的 探讨幼年型皮肌炎(JDM)肌炎特异性抗体(MSA)与临床表型的相关性。设计 病例系列报告。方法 JDM诊断参照Bohan/Peter标准或2017年EULAR/ACR标准。纳入复旦大学附属儿科医院(我院)风湿科2011年开始建立的JDM随访系统中2017年3月至2020年4月行欧蒙免疫印迹法检测16种肌炎抗体的连续病例。从我院HIS系统中和风湿科JDM随访系统中采集来我院就诊时的临床数据:发病年龄,诊断时病程,随访病程,体温,皮肤、骨和关节、肺、肝、肾表现,实验室检查,MAS,重叠SLE,儿童肌力(CMAS)评分。主要结局指标 单纯和复合抗-MDA5抗体患儿临床表型特点。结果 符合本文纳入标准的103例JDM进入分析,男54例(52.4%),诊断JDM后未经治疗前行特异性抗体谱检测60例。初诊时CMAS评分中位数为33(23.0,44.7)。主要临床表现:发热、皮肤溃疡、皮肤钙化、关节痛或关节炎、间质性肺炎、合并重症肺炎、吞咽困难、血尿和IgA肾病、合并巨噬细胞活化综合征。103例JDM患儿中,肌炎抗体阳性68例(66.0%),其中MSA阳性64例,肌炎相关性抗体(MAA)阳性24例,MSA+MAA阳性20例。抗-MDA5抗体组、抗-NXP2抗体组、抗-TIF-1γ抗体组及抗体全阴性组4组间发病年龄和初诊时病程比较差异有统计学意义。抗-TIF-1γ抗体组发病年龄更小,初诊时病程更长。抗-MDA5抗体组更易发生皮肤溃疡、关节炎/关节痛,更多合并间质性肺炎和发热。4组间CMAS评分、ALT、AST、LDH、α-羟丁酸脱氢酶(HBDH)、CK、Fer差异有统计学意义,抗-NXP2抗体组CMAS评分最低,CK、LDH和HBDH最高,抗-MDA5抗体组ALT、AST最高、CK最低,Fer最高;抗-TIF-1γ抗体组ALT、AST、LDH、Fer最低;抗体全阴性组ALT、AST、CK、LDH、HBDH未显示有意义的特点。初治单纯抗-MDA5组(n=9)HBDH、Fer基本正常,初治复合抗-MDA5组(n=10)HBDH、Fer显著增高。结论 抗-MDA5、抗-NXP2和抗-TIF-1γ抗体阳性JDM患儿呈现了足以鉴别的临床表型和实验室检查结果,未治疗情况下单纯与复合抗-MDA5抗体阳性JDM患儿HBDH和Fer有明显的鉴别意义,抗体全阴性患儿临床表型和实验室结果无明显特征。     

幼年皮肌炎120例临床特点及治疗随访分析

目的 研究幼年皮肌炎(JDM)的临床特征、治疗效果以及转归.方法 回顾性分析2003年12月-2011年3月在北京儿童医院住院JDM患儿120例,分析其起病情况、临床表现、实验室检查及辅助检查、治疗方法、随访和预后.结果 120例患儿男55例,女65例;发病年龄1～14岁,平均年龄7岁.患儿均有典型的皮损及不同程度的肌肉症状,83例(69%)患儿有内脏受累,最常受累系统为呼吸系统(48%).所有患儿肌酶增高,肌电图均表现为肌源性损害.120例患儿均采用糖皮质激素治疗,均在早期加用甲氨蝶呤,有肺损害及重症患儿加用环孢素或环磷酰胺.早期治疗效果及远期预后均较好,120例在急性期死亡7例,死于肺部受累并感染致呼吸衰竭5例,并巨噬细胞活化综合征2例.结论 JDM是一种少见疾病,以肌无力和皮肤损害为突出表现,其皮损具有特征性,各脏器功能评估对诊断和判断疾病严重性非常有益;糖皮质激素联合免疫抑制剂治疗JDM安全有效,且预后较好.     

抗黑色素瘤分化相关基因蛋白5抗体阳性幼年皮肌炎11例的临床特点

目的:分析抗黑色素瘤分化相关基因蛋白5(MDA5)抗体阳性幼年皮肌炎(JDM)患儿的临床特点。方法:回顾性分析2016年1月至2019年1月于首都儿科研究所附属儿童医院风湿免疫科住院的11例抗MDA5抗体阳性JDM患儿的临床资料,分析其临床特点,总结治疗经验。结果:11例抗MDA5抗体阳性JDM患儿中,男2例,女9例;...     

幼年皮肌炎46例临床特征及治疗随访分析

目的研究幼年皮肌炎(JDM)的临床特征、实验室及辅助检查、治疗用药和疗效以及远期预后,使该病能早期诊断及时治疗。方法回顾性分析了2003—2007年北京儿童医院住院JDM患儿46例,分析其临床表现、实验室及影像学检查、治疗用药及远期随访结果和预后。结果46例患儿中女20例,男26例,女比男为1∶1.3;年龄1~14岁,平均年龄7岁。临床表现主要为皮疹及肌无力,93%的患儿有高春征,100%的患儿有颜面部紫红色皮疹,89%的患儿有甲床毛细血管异常;所有的患儿均有不同程度的肌无力,严重者需要呼吸机辅助呼吸。46%的患儿有内脏受累,其中大部分(71%)为2个以上系统受累,最常受累系统为呼吸系统(37%),其次是消化系统(33%)、心血管系统(26%)及神经系统(11%)。实验室检查100%的患儿有肌酶增高,其中CK最具特异性。所有的患儿肌电图均表现为肌源性损害。治疗用药,除应用糖皮质激素外,均在早期加用甲氨蝶呤,有肺损害及重症患儿加用环孢素A。早期治疗效果及远期预后均较好,46例患儿在急性期死亡2例,死因为肺部受累合并感染致呼吸衰竭,远期并发症少见。结论JDM是一类预后相对较好的自身免疫性疾病,关键在于早期诊断和积极治疗,认识JDM的特征性表现有助于早期诊断。     

儿童风湿病国际相关诊治指南系列解读之三——特发性炎症性肌病新分类标准和幼年皮肌炎诊断要点更新

作为特发性炎症性肌病(ⅡM)和幼年ⅡM(JⅡM)类别之一的幼年皮肌炎(JDM)是一种罕见、可危及生命的全身性自身免疫疾病,代表了儿童期主要的肌病类型,JDM、JⅡM不仅影响肌肉和皮肤,其他系统器官(肺、心脏和肠道)也可受累,但有可能被低估。最新机制研究和大型合作研究网络极大促进了JDM、ⅡM及其亚型的识别、标准化评估和治疗进展。也定义了一些免疫风险因素和JDM、ⅡM病因机制的潜在途径。在新标准中,应用标准化评估、肌炎相关性和肌炎特异性抗体细分亚组和疾病的严重度,显示了这些因素的价值。这些亮点深入验证后,将有助于疾病活动和损害评估的标准化,促进精准治疗制定。这是儿科风湿病医生需要关注的方面。     

托法替布治疗合并间质性肺病的难治性幼年型皮肌炎一例并文献复习

目的总结托法替布治疗难治性幼年型皮肌炎(JDM)的经验。方法分析2021年3月中国医科大学附属盛京医院小儿肾脏风湿免疫科收治的1例确诊合并间质性肺病(ILD)的难治性JDM患儿的病史特点、托法替布治疗过程、辅助检查等资料, 以评价其疗效。结果患儿, 男, 12岁, 持续周身皮疹, 戈特隆征阳性, 四肢近端进行性肌无力, 病程超过6个月, 伴心肌酶、转氨酶、血沉、肌红蛋白、涎液化糖链抗原6(KL-6)显著升高, 抗PL-7肌炎抗体阳性, 肌电图提示四肢肌源性损害, 影像学显示双肺胸膜下间质性炎症改变, 确诊为合并ILD的JDM。予患儿糖皮质激素联合环孢素及环磷酰胺治疗5月余, KL-6仍持续高值, 肺部间质性渗出无好转, 且血沉复升, 免疫性高炎症未控制, 诊断为难治性JDM合并ILD, 遂予托法替布治疗, 停用免疫抑制剂, 效果显著, 免疫性炎症指标下降, 肺部间质渗出较前好转, 泼尼松逐渐减量。随访9月余病情稳定, 四肢肌力Ⅳ级, 肌肉酶学、免疫学炎症指标正常, 且未见不良反应。结论托法替布为合并ILD的难治性JDM的治疗提供了新的临床选择, 在传统的激素及免疫抑制剂疗效不佳时, 尽...     

儿童自身免疫性溶血性贫血治疗选择

儿童自身免疫性溶血性贫血是一种较少见的获得性自身免疫性疾病。准确的分型及病因诊断,是其诊断及治疗依据。目前儿童自身免疫性溶血性贫血主要采用经验性治疗,糖皮质激素为温抗体型一线药物。对于反复及难治患者,近年来利妥昔单抗等二线治疗在儿童中报道增加,取得一定疗效。本文就儿童自身免疫性溶血性贫血诊疗方法的选择进行总结,供临床医师参考。     

严重胃肠道受累的幼年皮肌炎4例病例系列报告

目的 探讨幼年皮肌炎(JDM)合并严重胃肠道受累患儿的临床特点、诊断与治疗。方法 回顾性分析4例合并严重胃肠道受累及肠穿孔JDM患儿的临床资料及诊治经过,并行文献复习。结果 4例患儿(P1～P4),男1例,女3例,起病年龄1岁8个月至5岁,发现胃肠道症状于JDM确诊后4～10个月,胃肠道受累的首发症状均为腹痛。P1先后十二指肠及横结肠穿孔,P2十二指肠穿孔合并肝动脉破裂,P3肠穿孔部位不详,P4肠壁增厚;4例均为抗NXP2抗体强阳性,均使用大剂量甲基泼尼松龙、环磷酰胺、IVIG冲击治疗,P1行穿孔造瘘术后治疗2年完全缓解,在修补造瘘口后猝死;P2术后死于感染及十二指肠瘘;P3死于弥漫腹壁出血;P4自体干细胞移植术后完全缓解。检索PubMed数据库共检索到12例JDM合并胃肠道穿孔患儿,发生在JDM确诊后2个月至9年,穿孔时首发症状为腹痛,可伴有呕吐及发热;十二指肠穿孔8例,结肠穿孔3例,空肠穿孔1例,胃幽门部穿孔1例,食管颈部穿孔1例,1例不详;其中5例患儿多部位或多次穿孔。11例行外科手术;9例好转,3例死亡,其中1例死于反复肠穿孔,1例死于术后ARDS,1例死因不详。结论 难治性JDM长期不缓解可合并消化道穿孔,其消化道首发症状为腹痛;常见肠穿孔部位为十二指肠腹膜后;发生严重胃肠道受累的JDM常见肌炎特异性抗体为抗NXP2抗体;肠穿孔一旦发生病死率高,尤其是十二指肠穿孔并无有效的术式;对于难治性JDM自体干细胞移植可能是改善预后的有效措施。     

严重胃肠道受累的幼年皮肌炎4例病例系列报告

目的 探讨幼年皮肌炎(JDM)合并严重胃肠道受累患儿的临床特点、诊断与治疗。方法 回顾性分析4例合并严重胃肠道受累及肠穿孔JDM患儿的临床资料及诊治经过,并行文献复习。结果 4例患儿(P1～P4),男1例,女3例,起病年龄1岁8个月至5岁,发现胃肠道症状于JDM确诊后4～10个月,胃肠道受累的首发症状均为腹痛。P1先后十二指肠及横结肠穿孔,P2十二指肠穿孔合并肝动脉破裂,P3肠穿孔部位不详,P4肠壁增厚;4例均为抗NXP2抗体强阳性,均使用大剂量甲基泼尼松龙、环磷酰胺、IVIG冲击治疗,P1行穿孔造瘘术后治疗2年完全缓解,在修补造瘘口后猝死;P2术后死于感染及十二指肠瘘;P3死于弥漫腹壁出血;P4自体干细胞移植术后完全缓解。检索PubMed数据库共检索到12例JDM合并胃肠道穿孔患儿,发生在JDM确诊后2个月至9年,穿孔时首发症状为腹痛,可伴有呕吐及发热;十二指肠穿孔8例,结肠穿孔3例,空肠穿孔1例,胃幽门部穿孔1例,食管颈部穿孔1例,1例不详;其中5例患儿多部位或多次穿孔。11例行外科手术;9例好转,3例死亡,其中1例死于反复肠穿孔,1例死于术后ARDS,1例死因不详。结论 难治性JDM长期不缓解可合并消化道穿孔,其消化道首发症状为腹痛;常见肠穿孔部位为十二指肠腹膜后;发生严重胃肠道受累的JDM常见肌炎特异性抗体为抗NXP2抗体;肠穿孔一旦发生病死率高,尤其是十二指肠穿孔并无有效的术式;对于难治性JDM自体干细胞移植可能是改善预后的有效措施。     

Allergic factors associated with the development of asthma and the influence of cetirizine in a double-blind, randomised, placebo-controlled trial: First results of ETA®

There is a common progression known as the allergic march from atopic dermatitis to allergic asthma. Cetirizine has several antiallergic properties that suggest a potential effect on the development of airway inflammation and asthma in infants with atopic dermatitis. Methods. Over a two year period, 817 infants aged one to two years who suffered from atopic dermatitis and with a history of atopic disease in a parent or sibling were included in the ETAC^® (Early Treatment of the Atopic Child) trial, a multi-country, double-blind, randomised, placebo-controlled trial. The infants were treated for 18 months with either cetirizine (0.25mg/ kg b.i.d.) or placebo. The number of infants who developed asthma was compared between the two groups. Clinical and biological assessments including analysis of total and specific IgE antibodies were performed. Results. In the placebo group, the relative risk (RR) for developing asthma was elevated in patients with a raised level of total IgE (≥ 30 kU/I) or specific IgE (≥ 0.35 kUA/I) for grass pollen, house dust mite or cat dander (RR between 1.4 and 1.7). Compared to placebo, cetirizine significantly reduced the incidence of asthma for patients sensitised to grass pollen (RR = 0.5) or to house dust mite (RR = 0.6). However, in the population that included all infants with normal and elevated total or specific IgE (intention-to-treat - ITT), there was no difference between the numbers of infants developing asthma while receiving cetirizine or placebo. The adverse events profile was similar in the two treatment groups. Discussion. Raised total IgE level and raised specific IgE levels to grass pollen, house dust mite or cat dander were predictive of subsequent asthma. Cetirizine halved the number of patients developing asthma in the subgroups sensitised to grass pollen or house dust mite (i.e. 20% of the study population). In view of the proven safety of the drug, we propose this treatment as a primary pharmacological intervention strategy to prevent the development of asthma in specifically sensitised infants with atopic dermatitis.     

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孤独症谱系障碍(autistic-spectrum disorders,ASDs)近年来患病率逐年攀升至1%左右,其症状往往伴随终生,成为严重威胁儿童健康和发展的神经发育性疾患;注意缺陷多动障碍(attention deficit hyperactivity disorder,ADHD)是儿童期最常见的精神障碍,国内报道患病率为4.13%～5.83%,其症状可延续至青少年期,甚至到成年期[1]。这两类精神障碍在成年期的临床表现、共患病、治疗策略和预后与儿童期有哪些不同呢?本文通过回顾相     

Infiltrations of Epstein-Barr virus-carrying cells in granular lymphocyte-proliferative disorders corresponding to chronic active Epstein-Barr virus infection

A 21-year-old man with granular lymphocyte-proliferative disorders (GLPD) associated with chronic active Epstein-Barr virus (EBV) infection is described. Chromosomal analyses revealed several clonal abnormalities and two of them were mainly repetitious. High copy numbers of monoclonal EBV genome were also detected in the proliferative large granular lymphocytes (LGLs), indicating the monoclonal expansion of EBV-infected LGLs. The patient had an indolent course for several years, and there was no evidence of infiltrations of his bone marrow until the end stage. At autopsy, microscopic studies revealed marked infiltrations of LGL in the liver and spleen, and the infiltrating cells were NK-cell immunophenotype. The infiltrated LGLs showed latency I.     

LUTEINIZING HORMONE RECEPTOR MUTATIONS IN DISORDERS OF SEXUAL DEVELOPMENT AND CANCER

Human male sexual development is regulated by chorionic gonadotropin (CG) and luteinizing hormone (LH). Aberrant sexual development caused by both activating and inactivating mutations of the human luteinizing hormone receptor (LHR) have been described. All known activating mutations of the LHR are missense mutations caused by single base substitution. The most common activating mutation is the replacement of Asp-578 by Gly due to the substitution of A by G at nucleotide position 1733. All activating mutations are present in exon 11 which encodes the transmembrane domain of the receptor. Constitutive activity of the LHR causes LH releasing hormone-independent precocious puberty in boys and the autosomal dominant disorder familial male-limited precocious puberty (FMPP). Both germline and somatic activating mutations of the LHR have been found in patients with testicular tumors. Activating mutations have no effect on females. The molecular genetics of the inactivating mutations of the LHR are more variable and include single base substitution, partial gene deletion, and insertion. These mutations are not localized and are present in both the extracellular and transmembrane domain of the receptor. Inactivation of the LHR gives rise to the autosomal recessive disorder Leydig cell hypoplasia (LCH) and male hypogonadism or male pseudohermaphroditism. Severity of the clinical phenotype in LCH patients correlates with the amount of residual activity of the mutated receptor. Females are less affected by inactivating mutation of the LHR. Symptoms caused by homozygous inactivating mutation of the LHR include polycystic ovaries and primary amenorrhea.     

EXCITING NEW TREATMENT APPROACHES FOR PATHYPHYSIOLOGIC MECHANISMS OF SICKLE CELL DISEASE

During the past several decades, our understanding of the complex pathophysiology of vasoocclusion associated with sickle cell disease has improved greatly. Interaction of genes, hemoglobin molecules, red cell membrane and metabolic changes, cell-cell interactions and cell-plasma interactions, red cell adhesion to vascular endothelium, activation of coagulation, and vascular reactivity play a role in vaso occlusion. Penicillin prophylaxis of pneumococcal infections and appropriate use of blood transfusions and other supportive measures improved survival of sickle cell patients. Hydroxyurea made a major impact on sickle cell therapy when it was shown to decrease acute painful episodes, acute chest syndrome, and the need for blood transfusion in adults. Significant experience in the use of hydroxyurea has been accumulated in older children. The benefits and risks of hydroxyurea for younger children and long-term risks in all patients will be evaluated in future investigations. Other promising therapies include butyrate compounds, clotrimazole, magnesium supplementation, poloxamer 188, antiadhesion agents, anticoagulant approaches, and nitric oxide. Hemopoietic transplantation remains the only curative therapy. However, several transgenic mouse models are available for studies of gene therapy or other treatment approaches on biochemical, cellular, and pathologic effects of mutant genes.     

Bibliometric data: a disaster for many non-American biomedical journals

Bibliometric data published by the Institute of Scientific Information in Philadelphia (ISI), and which was previously discussed in Acta Paediatrica , has increasingly been used despite all the relevant and severe criticism that has been raised against this method of evaluating individual research results and grading scientific journals. It is obvious that the present trend regarding the use of bibliometric data as a basis for priorities and funding of research and for the promotion of individual scientists favours American-oriented research projects at the expense of those that are based on concepts of predominantly European relevance.

Conclusion: For the future of non-American research, it is important that no single super-power, i.e. the USA, should dominate scientific priorities. The condition for efficient European competition is that European Centres with high levels of competence for creative research and training of scientists from all over the world are established. In addition, it is important that the results of European research are published in prestigious European journals, as was the situation before World War II.     

Personality profiles and heart rate variability (vagal tone) in children with recurrent abdominal pain

The aim of the study was to explore psychological factors and autonomic activity in children with recurrent abdominal pain and to compare them with those in a control group of healthy children. The Personality Inventory for Children was used for assessment of developmental, emotional and psychosocial factors in 25 children with recurrent abdominal pain (age, 7-15 y). Parasympathetic and sympathetic functions in these children and in 23 healthy control subjects (age, 7-13 y) were also investigated, non-invasively using a computerized polygraph. Vagal tone (parasympathetic function) was indexed by calculation of respiratory sinus arrhythmia in beats/min. Skin conductance (sympathetic function) was recorded by the constant current method. On the Personality Inventory for Children, 16 patients had high scores on somatic concern. Several patients had scores in the clinical range for depression, withdrawal and anxiety, but the mean scores for these personality profile scales were well within the normal range of healthy children. Interestingly, there was a spike on the L (Lie)-scale for most of the patients and 15 patients had scores above or close to the clinical cut-off value. As compared with the scores in healthy children, vagal tone and sympathetic tone were normal. Conclusion: Many children with recurrent abdominal pain have scores in the clinical range for depression, withdrawal, anxiety and L-scale indicating coping problems, denial and a trend towards somatic concern that may contribute to the evolution of abdominal pain. Autonomic nerve activity was not disturbed in these children.     

Understanding infant formula

The World Health organisation recommends breast feeding infants for the first six months of life. When this breast feeding does not occur either through parental choice or medical need, infant formulas will be required. There is a bewildering array of formulas on the UK market for many different requirements. When faced with an unsettled infant many parents (and healthcare professionals) will experiment with the infant formula available and then attend the paediatric clinic looking for help and advice. It is therefore essential that paediatricians understand what milks are available and what the key differences between different products are. This review attempts to provide a simple guide through many of the formulations currently available in the UK; and offers advice for the dietary management of the child with extra calorie requirements, infants with cow's milk protein allergy, gastro oesophageal reflux disease, apparent unresolved hunger and infantile colic. Whatever the underlying condition, there is likely to be an infant formula that is suitable in this generation of ever expanding formulations.     

Overcoming surfactant inhibition with polymers

Inhibition of the function of pulmonary surfactant in the alveolar space is an important element of the pathophysiology of many lung diseases, including meconium aspiration syndrome, pneumonia and acute respiratory distress syndrome. The known mechanisms by which surfactant dysfunction occurs are (a) competitive inhibition of phospholipid entry into the surface monolayer (e.g. by plasma proteins), and (b) infiltration and destabilization of the surface film by extraneous lipids (e.g. meconium-derived free fatty acids). Recent data suggest that addition of non-ionic polymers such as dextran and polyethylene glycol to surfactant mixtures may significantly improve resistance to inhibition. Polymers have been found to neutralize the effects of several different inhibitors, and can produce near-complete restoration of surfactant function. The anti-inhibitory properties of polymers, and their possible role as an adjunct to surfactant therapy, deserve further exploration.