【作者】 王莉；

【导师】 张锐；

【作者基本信息】 郑州大学 ， 神经病学（专业学位）， 2022， 硕士

【摘要】 背景及目的视神经脊髓炎谱系疾病(neuromyelitis optica spectrum disorder,NMOSD)是一种同时或相继累及视神经和脊髓的炎症性脱髓鞘性自身免疫性疾病,其与自身免疫病和非特异性自身抗体共存的报道逐渐增多。这一现象的机制尚不清楚,其临床过程与单纯NMOSD患者相比是否有显著或者特征性的差异尚无定论,自身抗体阳性和自身免疫病发展二者之间的关系有待进一步研究。既往相关研究较少,且对组间发病年龄、残疾状态评分、影像学表现、部分实验室指标和临床预后等方面存在不一致甚至是矛盾的结论。研究合并或不合并自身免疫病及伴有和不伴有自身抗体阳性的NMOSD患者人口学特征、临床表现、影像学表现、血清学及脑脊液检查、以及复发和预后的不同,探索其临床规律,可加深神经内科和风湿免疫科医师对这一临床现象的了解,并对未来的合理诊疗、疾病复发预测模型的建立和病理机制的探索提供依据。方法收集2019年6月到2021年6月就诊于郑州大学第一附属医院并确诊为NMOSD患者的临床资料包括性别、发病年龄、病程、首发表现、诱因、临床表现、合并其他自身免疫病种类、发现自身免疫病时间,极值和随访残疾扩展状态量表(expanded disability status scale,EDSS)评分和复发情况,血清学指标包括白细胞计数、中性粒细胞计数、单核细胞计数、血小板计数、血红蛋白浓度、血脂、糖化血红蛋白、血钾、甲状腺功能以及抗核抗体谱,脑脊液相关指标包括脑脊液白细胞计数、淋巴细胞百分比、单核细胞百分比、蛋白定量和电泳数据,影像学表现及AQP4抗体状态,并在2022年3月份完成随访登记工作。自身免疫病类型由风湿科医师按照相应的临床指南进行判断,所有资料统一记录在EXCEL数据表格中,按照研究目的进行分组,以SPSS29.0专业计算软件为基础,用Kolmogorov·Smimov方法检验数据正态性,定义P>0.05为正态分布数据,反之为非正态分布数据。对正态分布数据采用平均值和方差进行描述(Mean±SD),反之使用中位数Midian(P25-P75)进行描述。正态分布数据进行两个独立样本t检验,非正态分布数据进行Mann·Whitney U分析,定性资料运用卡方检验或Fisher确切概率法进行分析,以P<0.05为差异具有统计学意义。本研究经郑州大学第一附属医院医学伦理委员会批准(2021-KY-0822-002)。结果确诊的398例患者中共纳入294例患者,男56例,女238例,平均年龄42.35±15.43岁。其中单纯NMOSD患者197例(男49例,女148例),合并其他自身免疫病患者97例(男7例,女90例)。265例进行其他自身抗体检测的患者中合并其他自身抗体阳性患者164例(男15例,女149例)。有32.99%的NMOSD患者合并其他自身免疫病,以干燥综合征、自身免疫性甲状腺炎和系统性红斑狼疮最常见;61.89%的NMOSD患者伴有非特异性自身抗体阳性,以抗Ro52、抗SSA和抗甲状腺抗体最为常见。1.与未合并自身免疫疾病的NMOSD(单纯组)对比,合并自身免疫疾病的NMOSD(合并组)性别比例有明显差异(P<0.001),女性患NMOSD更容易合并自身免疫疾病;合并组AQP4-IgG 阳性率高于单纯组,差异具有统计学意义(P=0.005);合并组患者更易出现大脑受累,差异具有统计学意义(P=0.038),合并组患者脊髓受累节段数大于单纯组患者,差异具有统计学意义(P=0.043);与单纯组相比,合并组具有广泛的血液系统损害,合并组在外周血白细胞计数、中性粒细胞计数、淋巴细胞计数、PLR、血红蛋白浓度指标均低于单纯组,差异具有统计学意义(P<0.05);而两组在血清免疫球蛋白水平存在差异,未合并自身免疫病NMOSD组血清免疫球蛋白IgG水平低于合并自身免疫病组,差异具有统计学意义(P=0.006)。2.与不伴有其他自身抗体阳性的NMOSD患者(阴性组)相比,伴有其他自身抗体阳性的NMOSD患者(阳性组)性别比例有明显差异(P<0.001),女性患NMOSD更容易合并自身免疫疾病;阳性组AQP4-IgG 阳性率高于阴性组,差异具有统计学意义(P=0.001);阳性组患者脊髓受累节段数大于阴性组患者,差异具有统计学意义(P=0.027);随访EDSS 阳性组高于阴性组,差异具有统计学意义(p=0.029);两组在外周血白细胞计数、中性粒细胞计数、淋巴细胞计数、单核细胞计数、PLR、血红蛋白浓度方面存在显著差异(P<0.05),阴性组上述几个指标均大于阳性组;而两组在血清免疫球蛋白水平、IgG商值、脑脊液生成指数、24小时鞘内合成率存在显著差异(P<0.05),自身抗体阳性组在这些指标均高于阴性组。3.合并自身免疫病或伴有其他自身抗体阳性的NMOSD患者临床表现、极值EDSS评分、复发次数和残疾类型与单纯NMOSD患者相比无显著差异(P>0.05),而自身免疫病的临床症状严重程度相对较轻。结论NMOSD患者自身抗体阳性率和自身免疫病患病率较高,合并自身免疫病及伴有自身抗体阳性的NMOSD患者具有更严重的机体免疫状态,存在血液系统受损和更长的脊髓受累节段;非特异性自身抗体的存在应该引起重视,其可能反映了更严重的血脑屏障破坏和不良预后。更多还原

【Abstract】 Background and ObjectiveNeuromyelitis optica spectrum disorder(NMOSD)is an inflammatory demyelinating autoimmune disease involving both the optic nerve and spinal cord,either simultaneously or sequentially,and its coexistence with autoimmune diseases and non-organ-specific auto-antibodies is increasingly reported.The mechanisms of the coexistence of these autoimmune diseases and autoantibodies with NMOSD are unknown,and whether the corresponding clinical course differs from that of patients with NMOSD alone is inconclusive,and the relationship between auto-antibody positivity and autoimmune disease development needs to be further investigated.Previous relevant studies are scarce and there are inconsistent or even contradictory findings regarding age of onset,disability status score,imaging manifestations,some laboratory indicators and clinical prognosis between groups.The study of demographic characteristics,clinical manifestations,imaging manifestations,serological and cerebrospinal fluid examinations,and differences in recurrence and prognosis of NMOSD patients with or without autoimmune diseases and auto-antibodies can help to explore the clinical patterns and deepen neurologists and rheumatologists’s understanding of this clinical phenomenon.What’s more,the study may provide a basis for future rational diagnosis and treatment,the establishment of predictive models for disease recurrence,and the exploration of pathological mechanisms.MethodClinical information including gender,age at onset,duration of disease,first presentation,triggers,clinical manifestations,types of other autoimmune diseases combined,EDSS scores at peak and follow-up,and number of relapses were collected from June 2019 to June 2021 for all patients seen at the First Affiliated Hospital of Zhengzhou University and diagnosed with NMOSD.And serological indicators including white blood cell count,neutrophil count,monocyte count,platelet count,hemoglobin concentration,lipid level,glycosylated hemoglobin level,potassium level,thyroid functions and antinuclear antibody profile;CSF indicators included leukocyte count,lymphocyte percentage,monocyte percentage,protein quantification and CSF electrophoresis datas,imaging performances and AQP4 antibody status.EDSS scores were assessed by two neurologists and autoimmune disease diagnoses were judged by rheumatologists according to clinical guidelines.All data were recorded uniformly in an EXCEL data sheet,grouped according to the study purpose,and analyzed based on SPSS 29.0 professional computing software.Kolmogorov Smirnov method was used to test the normality of data.P>0.05 was defined as normal distribution data.Mean and variance were used to describe the normal distribution data(mean±SD),while median(P25-P75)was used to describe the normal distribution data.Two independent samples t-test was used for normal distribution data,Mann Whimey U analysis was used for non-normal distribution data,and chi-square test or Fisher exact probability method was used for qualitative data analysis.This study was approved by the First Affiliated Hospital of Zhengzhou University Medical Ethics Committee(2021-KY-0822-002).Results294 patients were included in the 398 patients diagnosed,including 197 patients with NMOSD alone(49 males and 148 females)and 97 patients with other autoimmune diseases(7 males and 90 females).164 patients(15 males and 149 females)were detected non-organ-specific auto-antibodies positive in the 268 patients who were tested.32.99%of NMOSD patients were combined with other autoimmune diseases,with Sjogren syndrome,autoimmune thyroiditis and systemic lupus erythematosus being the most frequent;and 61.89%of NMOSD patients were non-specific auto-antibodies positive,with anti-Ro52,anti-SSA and anti-thyroid antibodies being the most frequent.1.Compared with NMOSD without autoimmune disease(simple group),the difference of gender ratio of NMOSD with autoimmune disease(combined group)was statistically significant(P<0.001),and women with NMOSD were more likely to have combined autoimmune disease;the rate of AQP4-IgG positivity was higher in the combined group than in the simple group,and the difference was statistically significant(P=0.005);patients in the combined group were more likely to have brain involvement,and the difference was statistically significant(P=0.038);the combined group had longer spinal cord involved segments compared with the simple group with statistically significant differences(P=0.043);the combined group had extensive hematologic damage,and the peripheral blood leukocyte count,neutrophil count,lymphocyte count,PLR,and hemoglobin concentration indicators were all lower in the combined group than in the simple group,the difference was statistically significant(P<0.05);and the serum immunoglobulin IgG level of the simple group was lower than that of the combined group,and the difference was statistically significant(P<0.05).2.Compared with NMOSD patients without other auto-antibodies(negative group),there was a significant difference in the gender ratio of NMOSD patients with other auto-antibodies(positive group)(P<0.05),and women with NMOSD were more likely to have combined autoimmune diseases;the rate of AQP4-IgG positivity in the positive group was higher than that in the negative group,and the difference was statistically significant(P=0.001);the positive group had longer spinal cord involved segments compared with the negative group with statistically significant difference(P=0.029);there were significant differences in peripheral blood leukocyte count,neutrophil count,lymphocyte count,monocyte count,PLR,and hemoglobin concentration between the two groups(P<0.05),and the negative group had higher levels of these indicators than the positive group;while the two groups had significant differences in serum immunoglobulin level,IgG quotient,cerebrospinal fluid production index,and 24-hour intrathecal synthesis rate(P<0.05),and the levels of these indexes were higher in the positive group than in the negative group.3.There were no significant differences in clinical manifestations,extreme EDSS scores,number of relapses and type of disabilities in NMOSD patients with autoimmune disease or with other auto-antibody compared with pure NMOSD patients(P>0.05),while the severity of clinical symptoms of autoimmune disease was relatively mild.ConclusionNMOSD patients with autoimmune disease or auto-antibodies have more severe immune status,and are more likely to have hematologic compromise and longer segments of spinal cord involvement.The presence of autoantibodies may predict a poor prognosis.更多还原