不同抗体分型的重症肌无力特点分析
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摘要
目的探讨不同抗体分型重症肌无力(myasthenia gravis,MG)患者的临床特点。方法收集114例临床确诊MG患者的临床资料。使用酶联免疫吸附法检测患者血清中的抗乙酰胆碱受体抗体(acetylcholine receptors antibody,AChR Ab)、肌肉特异性激酶抗体(antibody to muscle-specific kinase, MuSK Ab)、抗联接蛋白抗体(titin antibody, Titin Ab)和抗兰尼碱受体抗体(ryanodine receptors antibody, RyR Ab)。根据致病抗体AChR Ab、MuSK Ab的表达情况将患者分为AChR Ab阳性组,MuSK Ab阳性组和双抗体阴性(double serum negative, DSN)组,对3组的临床表现、实验室检查和胸腺病理进行分析;根据疾病严重程度相关抗体Titin Ab和RyR Ab的表达情况,分为Titin Ab阳性组和Titin Ab阴性组,RyR Ab阳性组和RyR Ab阴性组,并比较两种抗体分型的阳性组和阴性组间的临床表现、实验室检查和胸腺病理,以及Titin Ab阳性MG和RyR Ab阳性MG组的受累肌群。结果 AChR Ab(+)组76例(66.7%)、MuSK Ab(+)组9例(7.9%)、DSN组29例(25.4%),三组间甲状腺功能(100.0%vs. 33.3%vs. 58.6%)和自身抗体异常发生率(63.2%vs. 33.3%vs. 37.9%)以及胸腺病理患者比例(胸腺增生/萎缩48.0%vs.33.3%vs. 71.4%,胸腺瘤52.0%vs.66.7%vs.28.6%)差异均有统计学意义(P<0.05);组间两两比较,仅AChR Ab(+)MG甲状腺功能异常率高于MuSK Ab(+)MG及DSN MG组(均P<0.05),余差异均无统计学意义(均P>0.05)。三组间不同临床分型(眼肌型与全身型)患者比例、球部症状和肌无力危象发生率差异均无统计学意义(均P>0.05)。Titin Ab阳性组甲状腺功能异常率高于Titin Ab阴性组(100.0%vs. 33.3%,P<0.05),自身抗体、胸腺病理、球部症状及肌无力危象患者比例差异两组间无统计学意义(均P>0.05)。RyR Ab阳性组胸腺瘤、肌无力危象发生率高于阴性组,自身抗体异常率低于阴性组(分别为66.7%vs. 32.1%、55.3%vs. 21.4%、30.0%vs. 57.1%,均P<0.05);甲状腺功能异常率和球部症状患者比例两组间差异无统计学意义(P>0.05)。Titin Ab(+)MG较RyR Ab (+)MG患者易出现眼外肌在受累(100.0%vs. 60.0%,P<0.05),而RyR Ab (+)MG更易出现球部肌肉(66.7%vs.25.0%,P<0.05)及呼吸肌受累(53.3%vs 20.8%,P<0.05)。结论 AChR Ab、MuSK Ab不同表达情况下,AChR Ab(+)MG易出现甲状腺功能异常,MuSK Ab(+)MG易合并胸腺瘤,而双阴性患者病情温和,胸腺病理多呈良性。RyR Ab(+)MG与Titin Ab(+)MG比较,RyR Ab(+)MG易有球部症状和呼吸肌受累,RyR Ab阳性MG病情更严重。
Objective To explore the characteristics of different phenotypes of myasthenia gravis according to antibodies.Methods The clinical data of 114 MG patients were analyzed.The antibodies in the serum were tested by enzyme linked immunosorbent assay,which were antibody against acetylcholine receptors(AChR Ab),muscle-specific receptor tyrosine kinase(MuSK Ab),Titin Ab and RyR Ab.The patients were divided into three groups according to antibodies involved in the pathogenesis,named AChR Ab(+) MG, MuSK Ab(+) MG and double antibody seronegative(DSN)MG. The clinical features, laboratory findings and thymus histology were analyzed. The 114 MG patients were also divided into groups according to severity related antibodies such as Titin Ab and RyR Ab. They were Titin Ab(+) MG,Titin Ab(-) MG, RyR Ab(+) MG and RyR Ab(-) MG. Comparisons in clinical features,laboratory findings and thymus histology were done between Titin Ab(+) MG and Titin Ab(-) MG subgroups. The same comparisons were done between RyR Ab(+) MG and RyR Ab(-) MG subgroups. The differences of involved muscles were further studied between Titin Ab(+) MG and RyR Ab(+) MG.Results AChR Ab was present in 76 patients, MuSK Ab in 9, the rest(n=29) was in the DSN group. There were significant statistically significant differences in abnormality of thyroid function(100.0% vs. 33.3% vs.58.6%),autoantibodies level(63.2% vs. 33.3% vs. 37.9%)and thymus pathology(hyperplasia/involuted 48.0% vs. 33.3% vs. 71.4%,thymoma 52.0% vs. 66.7% vs.28.6%)among the three groups(P<0.05).In post-hoc analysis,thyroid function was significantly more common in AChR Ab(+) MG than the other two groups.No significant difference was revealed in MG types, bulbar palsy or myasthenia crisis among the three groups.Titin Ab(+) MG patients were more likely with abnormal thyroid functions(100.0% vs. 33.3%) compared with negative ones(P<0.05). No difference was found in autoantibodies level,thymus pathology, bulbar palsy or myasthenia crisis between the two groups.RyR Ab(+) MG was characterized by higher thymoma incidence(66.7% vs.32.1%)and myasthenia crisis(55.3% vs. 21.4%),and less autoantibodies abnormality(30.0% vs.57.1%) compared with RyR Ab(-) MG(P<0.05). No significant difference was discovered in thyroid function, or bulbar palsy between the two groups.Extra-ocular muscles were more frequently involved in Titin Ab(+) MG(100.0% vs. 60.0%), while bulbar(66.7% vs. 25.0%)and respiratory muscle(53.3% vs. 20.8 %) weakness was more common in RyR Ab(+) MG(P<0.05). Conclusions In MG patients with different antibodies, AChR Ab(+) MG is characterized by higher rates of abnormal thyroid functions. MuSK Ab(+) MG is prone to be with thymoma. The DSN group is a milder form of MG, with benign thyroid pathology. Bulbar symptoms and myasthenia crisis were common in RyR Ab(+) MG, which means the course in RyR Ab(+) MG is more severe.
Objective To explore the characteristics of different phenotypes of myasthenia gravis according to antibodies.Methods The clinical data of 114 MG patients were analyzed.The antibodies in the serum were tested by enzyme linked immunosorbent assay,which were antibody against acetylcholine receptors(AChR Ab),muscle-specific receptor tyrosine kinase(MuSK Ab),Titin Ab and RyR Ab.The patients were divided into three groups according to antibodies involved in the pathogenesis,named AChR Ab(+) MG, MuSK Ab(+) MG and double antibody seronegative(DSN)MG. The clinical features, laboratory findings and thymus histology were analyzed. The 114 MG patients were also divided into groups according to severity related antibodies such as Titin Ab and RyR Ab. They were Titin Ab(+) MG,Titin Ab(-) MG, RyR Ab(+) MG and RyR Ab(-) MG. Comparisons in clinical features,laboratory findings and thymus histology were done between Titin Ab(+) MG and Titin Ab(-) MG subgroups. The same comparisons were done between RyR Ab(+) MG and RyR Ab(-) MG subgroups. The differences of involved muscles were further studied between Titin Ab(+) MG and RyR Ab(+) MG.Results AChR Ab was present in 76 patients, MuSK Ab in 9, the rest(n=29) was in the DSN group. There were significant statistically significant differences in abnormality of thyroid function(100.0% vs. 33.3% vs.58.6%),autoantibodies level(63.2% vs. 33.3% vs. 37.9%)and thymus pathology(hyperplasia/involuted 48.0% vs. 33.3% vs. 71.4%,thymoma 52.0% vs. 66.7% vs.28.6%)among the three groups(P<0.05).In post-hoc analysis,thyroid function was significantly more common in AChR Ab(+) MG than the other two groups.No significant difference was revealed in MG types, bulbar palsy or myasthenia crisis among the three groups.Titin Ab(+) MG patients were more likely with abnormal thyroid functions(100.0% vs. 33.3%) compared with negative ones(P<0.05). No difference was found in autoantibodies level,thymus pathology, bulbar palsy or myasthenia crisis between the two groups.RyR Ab(+) MG was characterized by higher thymoma incidence(66.7% vs.32.1%)and myasthenia crisis(55.3% vs. 21.4%),and less autoantibodies abnormality(30.0% vs.57.1%) compared with RyR Ab(-) MG(P<0.05). No significant difference was discovered in thyroid function, or bulbar palsy between the two groups.Extra-ocular muscles were more frequently involved in Titin Ab(+) MG(100.0% vs. 60.0%), while bulbar(66.7% vs. 25.0%)and respiratory muscle(53.3% vs. 20.8 %) weakness was more common in RyR Ab(+) MG(P<0.05). Conclusions In MG patients with different antibodies, AChR Ab(+) MG is characterized by higher rates of abnormal thyroid functions. MuSK Ab(+) MG is prone to be with thymoma. The DSN group is a milder form of MG, with benign thyroid pathology. Bulbar symptoms and myasthenia crisis were common in RyR Ab(+) MG, which means the course in RyR Ab(+) MG is more severe.
引文
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[12] Phillips LH 2nd,Torner JC.Epidemiologic evidence for a changing natural history of myasthenia gravis[J]. Neurology, 1996,47(5):1233-1238.
[13] Deymeer F, Gungor-Tuncer O, Yilmaz V, et al. Clinical comparison of anti-MuSK- vs anti-AChR -positive and seronegative myasthenia gravis[J].Neurology,2007,68(8):609-611.
[14] Toth C, McDonald D, Oger J,et al. Acetylcholine receptor antibodies in myasthenia gravis are associated with greater risk of diabetes and thyroid disease [J]. Acta Neurol Scand, 2006,114:124-132.
[15] Nakata R, Motomura M, Masuda T,et al. Thymus histology and concomitant autoimmune diseases in Japanese patients with muscle-specific receptor tyrosine kinase-antibody-positive myasthenia gravis [J]. Eur J Neurol, 2013,20:1272-1276.
[16] Kanazawa M, Shimohata T, Tanaka K, et al. Clinical features of patients with myasthenia gravis associated with autoimmune diseases[J]. Eur J Neurol,2007,14:1403eature
[17] Gilhus NE. Myasthenia and neuromuscular junction [J]. Curr Opin Neurol,2012,25(5):523-529.
[18] Querol L, Illa I.Myasthenia and neuromuscular junction [J]. Curr Opin Neurol, 2013, 26(5):459-465.
[19] Verschuuren JJ, Huijbers MG, Plomp JJ,et al. Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase and low-density lipoprotein receptor-related protein 4[J]. Autoimmun Rev,2013,12(9):918-923.
[20] Gilhus NE, Verschuuren JJ. Myasthenia gravis:subgroup classification and therapeutic strategies[J].Lancet Neurol, 2015,4(10):1023-1036.
[21] Chang T, Leite MI, Senanayake S,et al.Clinical and serological study of myasthenia gravis using both radioimmunoprecipitation and cell-based assays in a South Asian population[J].J Neurol Sci, 2014, 343(1-2):82-87.
[22] Guptill JT, Sanders DB, Evoli A.Anti-MuSK antibody myasthenia gravis:clinical findings and response to treatment in two large cohorts[J]. Muscle Nerve. 2011,44(1):36-40.
[23] Szczudlik P, Szyluk B, Lipowska M,et al.AntiTitin antibody in early- and late-onset myasthenia gravis[J]. Acta Neurol Scand, 2014,130(4):229-233.
[24] Zisimopoulou P, Brenner T, Trakas N,et al. Serological diagnostics in myasthenia gravis based on novel assays and recently identified antigens[J]. Autoimmun Rev, 2013, 12(9):924-930.
[2] Oh SJ.,Morgan MB., Lu L,et al. Different characteristic phenotypes according to antibody in myasthenia Gravis [J].J Clin Neuromuscul Dis. 2012,14(2):57-65.
[3] Baggi F, Andreetta F,Maggi L, et al. Complete stable remission and autoantibody specificity in myasthenia gravis [J].Neurology,2013,80(2):188-195.
[4] Vincent A,Leite MI. Neuromuscular junction autoimmune disease:muscle specific kinase antibodies and treatmentsfor myasthenia gravis[J]. Curr Opin Neurol,2005,18(5):519-25.:519-525.
[5] Oh SJ, Morgan MB, Lu L,et al. Different characteristic phenotypes according to antibody in myasthenia gravis [J].J Clin Neuromuscul Dis,2012,14(2):57-65.
[6] Kostera-Pruszczyk A, Kamińska A, Dutkiewicz M, et al. MuSK(-)positive myasthenia gravis is rare in the Polish population[J]. Eur J Neurol,2008,15(7):720-724.
[7] Romi F, Suzuki S, Suzuki N,et al.Anti-voltage-gated potassium channel Kv1.4 antibodies in myasthenia gravis [J].J Neurol, 2012,259(7):1312-1316.
[8] Suzuki S, Baba A, Kaida K, et al. Cardiac involvements in myasthenia gravis associated with anti(-)Kv1.4 antibodies[J]. Eur J Neurol,2014,21(2):223-330.
[9] Hong Y, Li HF, Skeie GO,et al. Autoantibody profile and clinical characteristics in a cohort of Chinese adult myasthenia gravis patients[J]. J Neuroimmunol,2016,(298):51-57.
[10] 朱慧,高枫,袁云,等.不同重症肌无力患者人群血清抗体检测的临床意义[J].中国神经免疫学和神经病学杂志,2018,25(2):87-92.
[11] 中国免疫学会神经免疫学分会,中华医学会神经病学分会神经免疫学组.重症肌无力诊断和治疗中国专家共识[J].中国神经免疫学和神经病学杂志,2012,19(6):401-408.
[12] Phillips LH 2nd,Torner JC.Epidemiologic evidence for a changing natural history of myasthenia gravis[J]. Neurology, 1996,47(5):1233-1238.
[13] Deymeer F, Gungor-Tuncer O, Yilmaz V, et al. Clinical comparison of anti-MuSK- vs anti-AChR -positive and seronegative myasthenia gravis[J].Neurology,2007,68(8):609-611.
[14] Toth C, McDonald D, Oger J,et al. Acetylcholine receptor antibodies in myasthenia gravis are associated with greater risk of diabetes and thyroid disease [J]. Acta Neurol Scand, 2006,114:124-132.
[15] Nakata R, Motomura M, Masuda T,et al. Thymus histology and concomitant autoimmune diseases in Japanese patients with muscle-specific receptor tyrosine kinase-antibody-positive myasthenia gravis [J]. Eur J Neurol, 2013,20:1272-1276.
[16] Kanazawa M, Shimohata T, Tanaka K, et al. Clinical features of patients with myasthenia gravis associated with autoimmune diseases[J]. Eur J Neurol,2007,14:1403eature
[17] Gilhus NE. Myasthenia and neuromuscular junction [J]. Curr Opin Neurol,2012,25(5):523-529.
[18] Querol L, Illa I.Myasthenia and neuromuscular junction [J]. Curr Opin Neurol, 2013, 26(5):459-465.
[19] Verschuuren JJ, Huijbers MG, Plomp JJ,et al. Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase and low-density lipoprotein receptor-related protein 4[J]. Autoimmun Rev,2013,12(9):918-923.
[20] Gilhus NE, Verschuuren JJ. Myasthenia gravis:subgroup classification and therapeutic strategies[J].Lancet Neurol, 2015,4(10):1023-1036.
[21] Chang T, Leite MI, Senanayake S,et al.Clinical and serological study of myasthenia gravis using both radioimmunoprecipitation and cell-based assays in a South Asian population[J].J Neurol Sci, 2014, 343(1-2):82-87.
[22] Guptill JT, Sanders DB, Evoli A.Anti-MuSK antibody myasthenia gravis:clinical findings and response to treatment in two large cohorts[J]. Muscle Nerve. 2011,44(1):36-40.
[23] Szczudlik P, Szyluk B, Lipowska M,et al.AntiTitin antibody in early- and late-onset myasthenia gravis[J]. Acta Neurol Scand, 2014,130(4):229-233.
[24] Zisimopoulou P, Brenner T, Trakas N,et al. Serological diagnostics in myasthenia gravis based on novel assays and recently identified antigens[J]. Autoimmun Rev, 2013, 12(9):924-930.