中国儿童型重症肌无力临床异质性的机制及精准治疗方案探讨

Childhood onset Myasthenia gravis (CMG) patients accounted for more than half of the whole myasthenia gravis population in China. Our long-term follow up data disclosed that the children with CMG took different features in clinical presentation, immunologic profiles, and outcomes, from the adults. The outcomes were complete clinical remission (CSR, 20%), remitting-relapsing (55%), partial improvement (6%), generalized conversion (12%) and unimprovement (5%). The refractory children would present severe under-developed liner growth, obesity, and the symptoms of ocular palzy, as well as secondary psychological concerns, which constituted as the big burden for the families, the sufferers, and even the society! It is imperative for the clinicians to solve the status! We planned to select typical CMG cases who displayed good responsiveness, poor responsiveness to oral pyridostigmine alone, or prednisone, or both in combination, and the cases who presented generalized conversion, remitting-relapsing, or the progressiveness pattern, from the database of over 8000 MG patients. The selected children will be studied for the thymic abnormalities, features of peripheral immune cells, polymorphisms of the steroid receptors, coexisted autoimmune diseases, pharmaceutical genotypes, and the characteristics of muscular antigens, in order to generate a precise clinical presentation-immunologic-pharmaceutical pattern to guide the clinical practice. At the same time, some severely refractory children with CMG will be subjected to a new therapeutic strategy to improve their outcome.

与西方国家不同，在中国，儿童期起病的重症肌无力（CMG）占重症肌无力患者群（MG）的一半以上。我们的长期研究发现CMG患者在临床、免疫特征及预后与成人有诸多不同，呈现异质性，临床过程包括完全临床缓解（20%）、缓解复发（55%）、部分改善（8%）、转化为全身型（12%）及无效（5%）。部分难治性患者在长期应用激素后出现严重不良反应，症状改善不良的患者呈现不同程度肌无力症状及神经心理问题，造成严重负担，亟待解决！拟利用我们已建立的8000多例MG患者信息库，将已确诊的AChR-ab阳性的CMG患者分为对吡啶斯的明有效、激素有效、激素无效（或获得性抵抗）、转化为全身型、缓解复发型及无效型等，分析其胸腺改变、外周血免疫细胞特征、激素或药物作用靶点分子特性、合并自身免疫性疾病、药物基因组学及血清－抗原结合特征等，建立临床－免疫特征-治疗模型，并对难治性CMG患者进行新模式单中心队列研究，改善预后。

我们建立了儿童型重症肌无力（CMG）患者的组织库和信息库，通过机器学习的方法建立评估CMG患者全身型转化、缓解、复发、难治性的特点及影响因素的临床预测模型，且模型具有较好的准确率、灵敏度和特异度。此外，通过比较研究不同临床类型的重症肌无力（MG）患者和对照组外周血免疫细胞生物学行为及基因表达等，我们初步发和成型重症肌无力（AMG）相比，CMG患者免疫表型特征存在显著差异；自然杀伤细胞亚群改变参与MG病情演变；HSP90AA1 rs7160651和CYP3A5 rs776746基因位点与难治性显著性相关；CMG患者胸腺中活化的淋巴细胞比例明显高于先心病儿童。长期随访后，我们发现支链氨基酸（BCAAs）有益于改善MG患者的免疫反应；添加他克莫司治疗可明显改善多数激素抵抗的CMG患者症状；且早期胸腺切除术可有效改善全身型CMG患者长期预后。通过以上研究内容及已获取的结果，提示不同临床类型或免疫表型的CMG患者在选择进行靶向治疗中发挥重要作用。