Long-term effect of intravenous immunoglobulin on anti-MuSK antibody-positive myasthenia gravis

Anti-muscle-specific receptor tyrosine kinase (MuSK) antibody-positive myasthenia gravis (MG) patients show various responses to conventional immunosuppressive treatment and some patients are resistant to these therapies. We report a 50-year-old Japanese man with anti-MuSK antibody-positive MG, who showed no or poor response to various therapies, including plasmapheresis, corticosteroid, and tacrolimus. The patient was then treated with intravenous immunoglobulin (IVIG), and showed a good response that persisted over 20 months. The outcome of this case suggests that IVIG treatment may be an effective therapeutic option for anti-MuSK antibody-positive MG, with a potentially long-term effect.     

Intravenous immunoglobulin in the preparation of thymectomy for myasthenia gravis

OBJECTIVES: A clinical trial including six patients was conducted to assess the effect of intravenous immunoglobulin (IVIg) in the preparation of thymectomy for patients with myasthenia gravis (MG). MATERIAL AND METHODS: Six consecutive patients of type IIB MG treated with IVIg at a dose 0.4 g/kg daily for 5 days before thymectomy were enrolled in this study. RESULTS: All patients responded positively to this treatment. Improvement began to occur 1-9 days after starting the injection (mean 3.33 days), and reached a maximum in 3-19 days (mean 6.50 days). Thymectomy was performed 9-13 days (mean 11.20 days) after starting the injection in five of the six patients with uneventful post-operative courses. CONCLUSION: IVIg might be an alternative to plasmapheresis (PE) in the prethymectomy preparation of MG patients, and thymectomy should be performed within 2 weeks after IVIg treatment to minimize the perioperative complications. Controlled trial vs PE enrolling more patients is needed to assess the significance of the IVIg in the preparation of thymectomy for patients of MG.     

Randomized,controlled trial of intravenous immunoglobulin in myasthenia gravis

We initiated a randomized, double-blinded, placebo-controlled trial of intravenous immunoglobulin (IVIG) treatment in myasthenia gravis (MG). Patients received IVIG 2 gm/kg at induction and 1 gm/kg after 3 weeks vs. 5% albumin placebo. The primary efficacy measurement was the change in the quantitative MG Score (QMG) at day 42. Fifteen patients were enrolled (6 to IVIG; 9 to placebo) before the study was terminated because of insufficient IVIG inventories. At day 42, there was no significant difference in primary or secondary outcome measurements between the two groups. In a subsequent 6-week open-label study of IVIG, positive trends were observed.     

静脉注射免疫球蛋白与血浆置换治疗重症肌无力的meta分析

目的系统评价静脉注射免疫球蛋白(IVIg)与血浆置换(PLEX)治疗重症肌无力(MG)的有效性和安全性。方法计算机检索Cochrane图书馆、Pubmed、Embase、CNKI及万方数据库,系统收集国内外有关这两种方式治疗MG的相关文献。按系统评价的方法,由2名研究员独立对文献进行质量评价和资料提取后,采用Rev Man 5.2软件进行Meta分析。结果共纳入9篇文献,合计2132例MG患者。Meta分析结果显示,IVIG与PLEX治疗MG的有效性无明显差异[OR=0.94,95%CI(0.57,1.32),P=0.79];IVIg与PLEX的治疗相关不良反应发生率也无明显差异[OR=0.91,95%CI(-0.37,2.21),P=0.83]。结论 IVIG与PLEX对MG的治疗效果以及治疗相关的不良反应发生率均无明显差异,因此,临床上可根据具体情况选择合适的治疗方式。     

静脉注射人免疫球蛋白治疗全身型重症肌无力的短期疗效观察

目的观察静脉注射人免疫球蛋白(intravenous immunoglobulin, IVIg)治疗全身型重症肌无力(myasthenia gravis, MG)的短期临床疗效、安全性。方法纳入2016年1月至2019年9月期间北京医院就诊的58例Osserman分型Ⅱb及以上的全身型MG患者。收集患者一般信息、入院诊断、治疗用药情况,采用许氏绝对与相对评分法(the absolute and relative score of MG,ARS-MG)评估患者IVIg治疗前及治疗后7、14 d临床症状的改善情况,并比较不同年龄(<60岁和≥60岁)、病程(≤1年和>1年)以及有无构音障碍、咀嚼障碍、呼吸困难者间IVIg疗效的差异。结果 58例MG患者IVIg治疗后第7天许氏评分较治疗前降低[(17.21±10.52)分比(23.22±10.45)分,P<0.01]。IVIg治疗7 d时其总有效率为48.28%(n=58),治疗后14 d其总有效率为59.46%(n=37)。不同年龄、病程以及有无构音障碍、咀嚼障碍、呼吸困难者间IVIg疗效比较无统计学差异(均P>0...     

CA-antibody: an immunological marker of thymic neoplasia in myasthenia gravis?

We have examined sera from 141 patients with myasthenia gravis and 11 non-myasthenia gravis patients with thymoma for antibodies to a citric acid extract of skeletal muscle (CA-antibodies). Sera were obtained from 5 different centers. The thymus histology was defined in each case. Sera from 56/66 patients (85%) with thymoma contained CA-antibodies, while such antibodies were only detected in 6/75 (8%) of the non-thymoma patients. None of the patients with thymus hyperplasia had CA-antibodies. One MG patient who developed MG after a bone-marrow transplantation, also developed CA-antibodies. The remaining 5 CA positive non-thymoma MG patients were all greater than 65 years and had thymic atrophy. Two of them had myasthenia gravis and polymyalgia rheumatica. In 2 thymoma patients with non-detectable levels of CA-antibodies before thymectomy, such antibodies were demonstrated in high titres after the operation. In 2 other sera from thymoma patients, the titres of CA-antibodies fell to less than 32 after thymectomy. There were 3 sera with CA-antibodies among 11 sera from non-MG patients with thymic tumours.     

Efficacy and tolerability of subcutaneously administered immunoglobulin in myasthenia gravis: A systematic review

Subcutaneous immunoglobulin (SCIg) is an emerging therapeutic alternative in the management of myasthenia gravis (MG) due to its potential efficacy, safety, cost effectiveness and ease of administration. At present, there are no systematic reviews that summarized the effects of SCIg in patients with MG. The objective of this study is to determine the efficacy and safety of SCIg in the treatment of adult patients with myasthenia gravis. Relevant records were identified from August 2018 to January 2019 systematic search. Five relevant articles with a total of 34 patients with MG were included in this review. Data on functional disability score and adverse events were obtained. Based on the included uncontrolled studies, the functional disability scores of adult MG patients after SCIg administration showed consistent improvement. Headache and local site injection reactions were the most common adverse events reported. The evidence from limited uncontrolled studies gathered in this review showed that SCIg may improve functional disability in patients with MG. Local and mild adverse events were reported with its administration, but no systemic and serious adverse events were noted.     

Experimental myasthenia gravis: Isolation and quantitative assay of anti-acetylcholine receptor antibody protein concentration in sera of rabbits immunized with Narke acetylcholine receptor

Antibody to acetylcholine receptor from Narke electroplax japonica was isolated from serum of rabbits with experimental autoimmune myasthenia gravis by affinity chromatography on a column of torpedo AChR-agarose conjugates. Sixty-three to eight hundred and ninety-six micrograms of antibody protein were obtained per milliliter myasthenic serum. Serum concentrations of antibody protein correlated with the intensity of the disease and were in exact proportion to the antibody titers of the same samples measured by double immunoprecipitant method. This study showed that anti-AChR antibody played a major role in experimental autoimmune myasthenia gravis and provided the first direct, quantitative evidence that the titers measured by Lindstrom's method could be quite a reliable index of antibody protein concentration in the serum of experimental myasthenia gravis subjects.     

电视胸腔镜和胸骨正中切口入路胸腺扩大切除手术治疗重症肌无力的对照研究

目的比较电视胸腔镜(video-assisted thoracoscopic surgery,VATS)与胸骨正中切口入路胸腺扩大切除治疗重症肌无力(myasthenia gravis,MG)的疗效和手术特点。方法回顾性分析2009-01至2015-12期间北京医院胸外科实施胸腺扩大切除手术治疗的MG患者680例,根据手术入路的不同,分为电视胸腔镜经右侧胸腔入路(胸腔镜组;348例)和胸骨正中切口入路(胸骨切口组,332例),比较两组患者的临床资料及疗效。结果胸腔镜胸腔入路组手术持续时间长于胸骨切口组〔(135.34±30.55)min vs.(115.25±28.50)min,t=3.421,P=0.001〕,术中出血量〔(85.34±28.12)mL vs.(158.35±25.64)mL,t=5.364,P=0.009)〕、术后引流量〔(238.24±68.48)mL vs.(476.38±85.56)mL,t=3.250,P=0.003)〕、术后ICU监护时间〔(2.36±1.20)d vs.(3.44±2.36)d,t=1.128,P=0.001〕和平均住院时间〔(7.45±2.47)d vs.(10.23±3.65)d,t=2.725,P=0.015〕均明显少于胸骨切口入路组,但两组患者的肌无力危象发生率(8.52%vs.10.64%,χ~2=0.504,P=0.458)和术后总有效率(85.60%vs.83.05%,χ~2=0.596,P=0.746)差异无统计学意义。结论电视胸腔镜下胸腺扩大切除手术治疗MG的安全性和有效率较高,手术创伤小,并发症少,术后恢复迅速,是治疗重症肌无力最重要的手术方式之一。     

Thymus and myasthenia gravis: antigen processing in the human thymus and the consequences for the generation of autoreactive T cells

Peptides displayed by antigen presenting cells in the thymus shape the T cell repertoire. We investigated the antigen processing machinery of the MHC class II presentation pathway and describe the differential expression of lysosomal proteases in compartments of the thymus and the peripheral lymphoid tissue. Overexpression of certain proteases found in the thymus and thymoma associated with myasthenia gravis is likely to affect tolerance induction and may promote the generation autoreactive CD4+ T helper cells.     

Peroneal nerve repetitive nerve stimulation test: Its value in diagnosis of myasthenia gravis and Lambert–Eaton myasthenic syndrome

We have developed a repetitive nerve stimulation (RNS) technique for the peroneal nerve. Normal limits for the decremental responses for the anterior tibialis and extensor digitorum brevis muscles are 6–21% at the low rate of stimulation and 44–70% at the high rate of stimulation. These values exceed the normal limits for other commonly tested muscles. This may be due to the lower safety factor for neuromuscular transmission for the anterior tibialis and extensor digitorum brevis muscles. We present 4 cases in which the peroneal nerve RNS test was crucial for the diagnosis of the limb-girdle form of MG or LEMS. Thus, we conclude that, in a small number of patients with neuromuscular transmission disorders, the peroneal nerve RNS test is needed for confirmation of disease. © 1995 John Wiley & Sons, Inc.     

Protective effect of scFv-DAF fusion protein on the complement attack to acetylcholine receptor: a possible option for treatment of myasthenia gravis

Introduction: Autoantibody‐induced complement activation, which causes disruption of the postsynaptic membrane, is recognized as a key pathogenic factor in myasthenia gravis (MG). Therefore, specific targeting of complement inhibitors to the site of complement activation is a potential therapeutic strategy for treatment of MG. Methods: We assessed expression of single‐chain antibody fragment–decay accelerating factor (scFv‐DAF), comprising a single‐chain fragment scFv1956 based on the rat complement inhibitor DAF in prokaryotic systems, and studied its inhibitory effect on complement deposition in vitro. Results: The recombinant conjugate scFv‐DAF completely retained the wild‐type binding activity of scFv1956 to AChR and inhibited complement activation of DAF in vitro. Conclusions: We found that scFv‐DAF could bind specifically to TE671 cells, and it is significantly more potent at inhibiting complement deposition than the untargeted parent molecule DAF. scFv‐DAF may be a candidate for in vivo protection of the AChR in MG. Muscle Nerve, 2012     

Inhibition of IL‐6 overproduction by steroid treatment before transsternal thymectomy for myasthenia gravis: does it help stabilize perioperative condition?

Overproduction of interleukin (IL)-6 plays an important role in the pathophysiology of myasthenia gravis (MG), and thymectomy can cause myasthenic crisis because of surgically induced overproduction of IL-6. Preoperative steroid therapy is beneficial in preventing MG crisis during the perioperative period. The purpose of this study was to clarify the effect of preoperative steroid therapy on proinflammatory mediators during the perioperative period of transsternal thymectomy for MG. The study group comprised 20 consecutive MG patients undergoing transsternal thymectomy during the period March 2002 through March 2004. Seventeen of these patients received dose-escalated steroid therapy before thymectomy (steroid treatment group) and three did not (non-steroid treatment group). Serum concentrations of C-reactive protein (CRP) and IL-6 were determined during the perioperative period; clinical outcomes were reviewed, and the results were compared between the two groups. Peak serum IL-6 and CRP concentrations were significantly lower in the steroid treatment group than in the non-steroid treatment group. Amongst perioperative variables subjected to multiple regression analysis, preoperative steroid treatment were found to be the most significant independent predictor of inhibited IL-6 production on postoperative day 1. No postoperative respiratory failure occurred in the steroid treatment group, but it did occur in the non-steroid treatment group. Preoperative steroid therapy can ameliorate IL-6 overproduction and may help stabilize the patient's postoperative condition.     

Presynaptic changes of neuromuscular transmission in mice induced by passive transfer of plasma with anti-presynaptic membrane receptor antibodies from a patient with myasthenia gravis

Electrophysiological studies were conducted in three groups of mice to determine the possible involvement of the antibodies to presynaptic membrane receptor (PsmR), a beta-bungarotoxin (beta-BuTX) binding protein, in the pathogenesis of myasthenia gravis (MG). Mice were untreated (untreated group, n = 8) or were injected (i.p.) with blood plasma from a MG patient, which contained antibodies to PsmR, at a dose of 1 ml per day for more than 2 months (MG plasma group, n = 12) or with plasma from healthy subjects (normal plasma group, n = 10). Prior to plasma injection, cyclophosphamide was given at 300 mg/kg (i.p.) to all three groups. About three weeks after plasma injection, most mice of the MG plasma group became less mobile in comparison with those of the two control groups. Electrophysiological recording showed three main changes in the MG plasma group: (1) the increase in the frequency of miniature endplate potentials (mEPPs) induced by Krebs solution with high K+ concentration (17.5 mM) was significantly lowered, which was confirmed in mice injected with IgG (50 mg per day) from this patient for two days; (2) the quantal content of EPP was decreased; and (3) the decrement in the amplitude of a train EPP (50 Hz) was quickened. Our results suggest that this experimental model is different from that of Lambert-Eaton myasthenic syndrome and that antibodies to PsmR may also be involved in the pathogenesis of MG.     

Immunohistological studies of the thymus in myasthenia gravis : Correlation with clinical state and thymocyte culture responses

In frozen sections of thymus from 9 out of 12 myasthenia gravis patients, the medulla contained follicles of B lymphocytes with germinal centres showing the same immunofluorescence staining pattern as is seen normally in reactive lymphoid tissues. Only 1 similar follicle was seen in 9 normal thymus samples. There was a positive association between the extent of germinal centres, plasma anti-acetylcholine receptor (AChR) titre, and spontaneous anti-AChR production by thymocytes in vitro. These thymic changes were not universally found, and are thus probably not central to the initiation of myasthenia.Between the follicles, in 9 cases, there was an apparent increase in interdigitating cells with closely associated ‘inducer’ (OKT₄⁺)T lymphocytes. Thymic antigen presenting cells — either here or in the germinal centres — could be involved in breaking self-tolerance, or in perpetuating the autoimmune response, and it may be their removal that is therapeutic.     

Zn-binding globulin in human fetal brain and liver: a marker for passive blood/CSF transfer of protein

The presence of Zn-binding globulin (ZnbG) during human fetal development was studied in cerebrospinal fluid (CSF) and plasma with immunodiffusion methods and in brain, CSF, plasma and liver using immunocytochemical methods. At the earliest stages examined with immuno-cytochemistry (5–6 weeks gestation) no staining for ZnbG was visible in liver, plasma, CSF or brain. However, the primitive mesenchyme exhibited a prominent staining reaction. In late embryonic and early fetal stages, staining for the protein was most prominent in the spinal cord, brain stem and diencephalon and in the choroid plexuses and marginal and subplate zones in the telencephalon. At the cellular level, synaptic strata and territories were most strongly stained. The distribution of ZnbG in the early developing central nervous system suggests that this protein may be involved in the initial establishment of CNS circuitry. Embryonic brain was positive for ZnbG well before the protein could be detected in CSF, plasma or liver. The early occurrence of ZnbG in brain tissue prior to its presence in liver or plasma also suggests that the protein is synthesized in early fetal brain. At the time when CSF first became positive (17 weeks gestation), the brain staining had largely disappeared. ZnbG in plasma increased throughout gestation to reach 2.6 ± 0.4 mg/100 ml at term and subsequently increased to an adult value of 6.8 ± 1.5 mg/100 ml. The CSF to plasma ratio did not change significantly during development and was low (1–2%) at all fetal ages examined when compared with other plasma proteins; this is consistent with passive transfer between the two compartments both in the fetus and in the adult.