Antibodies to Full-Length Agrin Protein in Chinese Patients With Myasthenia Gravis.

This study aimed to establish a cell-based assay (CBA) for the detection of agrin antibodies (Agrin-Ab) to explore the clinical features of agrin antibody-positive Chinese patients with myasthenia gravis (Agrin-MG). We developed a CBA based on the human full-length agrin protein expressed in HEK293T cells for the reliable and efficient detection of Agrin-Ab. Clinical data and serum samples were collected from 1948 MG patients in 26 provinces in China. The demographic and clinical features of Agrin-MG patients were compared with those of other MG patient subsets. Eighteen Agrin-MG cases were identified from 1948 MG patients. Nine patients were Agrin-Ab positive, and nine were AChR-Ab and Agrin-Ab double-positive (Agrin/AChR-MG). Eleven (61.11%) patients were males older than 40 years of age. The initial symptom in 13 (81.25%) cases was ocular weakness. Occasionally, the initial symptom was limb-girdle weakness (two cases) or bulbar muscle weakness (one case). Agrin-MG patients demonstrated slight improvement following treatment with either acetylcholinesterase inhibitor or prednisone; however, the combination of the two drugs could effectively relieve MG symptoms. In China, Agrin-MG demonstrated seropositivity rates of 0.92%. These patients were commonly middle-aged or elderly men. The patients usually presented weakness in the ocular, bulbar, and limb muscles, which may be combined with thymoma. These patients have more severe diseases, although the combination of pyridostigmine and prednisone was usually effective in relieving symptoms.

Population Pharmacokinetic Analysis of Tacrolimus in Adult Chinese Patients with Myasthenia Gravis: A Prospective Study.

BACKGROUND AND OBJECTIVES: Tacrolimus is a widely used immunosuppressive agent with narrow therapeutic window. Nowadays, tacrolimus has gained acceptance as a therapeutic option in myasthenia gravis (MG) treament, however, little is known about its pharmacokinetic characteristics in MG population. In this study, we aimed to investigate the population pharmacokinetic (PopPK) of tacrolimus in patients with MG and to develop model-informed dosing regimens. METHODS: Trough concentrations of tacrolimus (267 measurements) and cytochrome P450 (CYP) genotypes were determined in 97 Chinese adults. The non-linear mixed-effects model was used for PopPK modeling. Monte Carlo simulations based on the established model were employed to design dosing regimens. RESULTS: The PopPK model was described using a one-compartment model with first-order absorption and elimination. The mean apparent clearance (CL/F) of tacrolimus was 17.1 L/h, with a between-subject variability of 20.1%. Covariate screening of demographic characteristics, blood test results, co-medications, and CYP3A5*3 or CYP3A4*1G polymorphisms showed that the CYP3A5*3 genotype and co-administration of a Wuzhi capsule significantly affected tacrolimus CL/F. CONCLUSIONS: For patients with the CYP3A5*3*3 allele, the required tacrolimus dose for 75% of subjects to achieve target trough concentrations of 4.8-15 ng/mL was 2 mg every 12 h (q12h). For patients with the CYP3A5*1*1 allele, the required dose was 2 mg tacrolimus q12h with a Wuzhi capsule, and for patients with the CYP3A5*1*3 allele, the required dose was 3 mg of tacrolimus q12h or 4 mg q24h co-administered with a Wuzhi capsule. This model could be employed to optimize individualized therapies for patients with MG.

Paediatric myasthenia gravis: Prognostic factors for drug free remission.

Our aim was to identify clinical outcomes, serological features and possible prognostic indicators of paediatric myasthenia gravis (MG). We collected 74 MG patients with disease onset before the age of 16 years (73% pre-pubertal onset defined as ≤10 years), seen regularly at two UK specialist centres, over a period of 11 years. The cohort was multi-ethnic, with a high number of non-Caucasians (52%). Ocular presentation was seen in 38 (51%) and only 8 (21%) of these generalised. Fifty-two (70%) patients had antibodies to the acetylcholine receptor (AChR) measured by radioimmunoprecipitation, 10 (14%) had antibodies only to clustered AChRs detected by a cell based assay, 3 (4%) had muscle-specific kinase and one (1%) low-density lipoprotein receptor-related protein 4 antibody. Only 8 (11%) had no detectable antibodies. Seventeen patients attained drug free remission (Kaplan Meyer survival curve estimates 25% by 7 years). Several factors were associated with a higher likelihood of free remission: onset age ≤10 years, Asian and Caucasian races, lack of AChR antibodies on RIA, and normal repetitive nerve stimulation at diagnosis. However, in a multifactorial regression analysis, the antibody status was the only significant predictor for drug free remission, with 60% of patients with antibodies only to clustered AChR achieving this outcome. Complete drug free remission is not uncommon in paediatric MG and several factors appear to influence this outcome with antibody status being the most important. These factors can be easily evaluated at diagnosis, and may help to determine whose patients are likely to require more intensive treatments.

Effect of ethnic origin and gender on the clinical manifestations of myasthenia gravis among the Jewish population in Israel.

Reports on patients with myasthenia gravis (MG) of different ethnic origins demonstrated differences in weakness distribution and serological results. We studied MG characteristics in a cohort of Ashkenazi (ASH) and non-Ashkenazi (NASH) Jewish origin according to their ethnic origins and gender. The frequency of age of MG onset was distributed in a bi-modal fashion in the female patients and increased gradually over time, with a peak around 70years of age in the male patients. Ocular MG was more frequent in males and ASH patients. Unlike previous reports, our male patients had a higher proportion of positive serum anti-acetyl choline receptor (AChR) than female patients, with no ethnic-based differences in the rates of anti-AChR or anti-muscle specific kinase. Comorbidity with another autoimmune disease was more frequent among female patients with late-onset MG and NASH patients (mainly Israel-born). Male MG patients tended to have more malignant comorbidities than female MG patients. These results demonstrate the effect of ethnicity on clinical aspects of MG within the Jewish population in Israel, and reveal novel effects of gender-associated comorbidities in patients with MG.

Prevalence and clinical aspects of immigrants with myasthenia gravis in northern Europe.

INTRODUCTION: Multiethnic studies can provide etiological clues toward the genetic and environmental influence of a disease. The aim of this study was to determine prevalence and clinical features of myasthenia gravis (MG) in immigrants compared with native patients in 2 population-based cohorts. METHODS: This cross-sectional study included 843 MG patients (375 from Norway and 468 from the Netherlands). Ethnic background was defined by questionnaires. RESULTS: Among the participating MG patients, 163 of 843 (19.3%) were first or second generation immigrants, mainly from Europe, Asia, and South America. No marked prevalence differences were found between immigrants and native ethnic groups. MG with muscle specific kinase antibodies and MG with thymoma were more frequent in Asian MG immigrants compared with other ethnic groups (8% vs. 0-4%; P < 0.001 and 21% vs. 6-10%; P < 0.001), respectively. CONCLUSIONS: Our findings indicate that Asian immigrant MG patients carry genetic factors or environmental/lifestyle factors which contribute to their specific phenotype, even after migration. Muscle Nerve 55: 819-827, 2017.

The HLA-B*4601-DRB1*0901 haplotype is positively correlated with juvenile ocular myasthenia gravis in a southern Chinese Han population.

Myasthenia gravis (MG) is a sporadic disorder that has been increasingly linked to inherited genetic factors. Previous studies have demonstrated that human leukocyte antigen (HLA) plays an important role in the pathogenesis of MG. We determined the genotypes of the HLA-A, B, and DRB1 alleles in 257 southern Chinese Han MG patients using polymerase chain reaction sequence-based typing (PCR-SBT). The allele frequencies in the MG patients were compared to 292 healthy controls using the case-control method. HLA-A*0207, HLA-B*4601, HLA-DRB1*0403, HLA-DRB1*0901, and HLA-DRB1*1602 were more frequent in juvenile ocular MG patients than controls. HLA-DRB1*0701 was significantly reduced in the juvenile ocular MG group compared with controls. HLA-A*0207-B*4601, HLA-B*4601-DRB1*0403, HLA-B*4601-DRB1*0901, and HLA-B*4601-DRB1*1602 were found to be in strong linkage disequilibrium in juvenile ocular MG patients. Within the MG patients, there was a strong positive association between HLA-B*4601-DRB1*0901 and juvenile ocular MG patients, and the value of odds ratios (OR) decreased as the disease became more severe and the age of onset increased. We believe this could be the main heredity phenotype in juvenile ocular MG patients from southern China and may be a clinical marker to predict the severity of the disease.

FOXP3 -3279 and IVS9+459 polymorphisms are associated with genetic susceptibility to myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disorder in which CD4(+)CD25(+) FOXP3(+)regulatory T cells (Tregs) are thought to play important roles in driving the ongoing autoimmune response. Although it is known that single-nucleotide polymorphisms (SNPs) in the fork head/winged-helix transcription factor 3 (FOXP3) gene contribute to some autoimmune diseases, information about the role of this gene in MG is limited. We therefore evaluated the association between FOXP3 gene SNPs and susceptibility to MG in a Han Chinese population. In a hospital-based, case-control study, two SNPs in the FOXP3 gene (-3279 and IVS9+459) were investigated in 118 MG and 124 healthy controls, and their relationship with the four parameters of gender, onset age, thymus pathology, and clinical classification of MG were performed with a stratified analysis. We found that the frequency of the FOXP3 IVS9+459 G allele was significantly lower in MG patients than in healthy controls (P=0.041), while the frequency of the FOXP3 -3279 polymorphisms was not significantly different between the two groups. Our results suggest that FOXP3 IVS9+459 polymorphisms appear to have an effect on the risk of MG in a Han Chinese population, and the G allele may be a genetic protective factor to MG.

Genetics of myasthenia gravis: a case-control association study in the Hellenic population.

Myasthenia gravis (MG) is an heterogeneous autoimmune disease characterized by the production of autoantibodies against proteins of the postsynaptic membrane, in the neuromuscular junction. The contribution of genetic factors to MG susceptibility has been evaluated through family and twin studies however, the precise genetic background of the disease remains elusive. We conducted a case-control association study in 101 unrelated MG patients of Hellenic origin and 101 healthy volunteers in order to assess the involvement of common genetic variants in susceptibility to MG. We focused on three candidate genes which have been clearly associated with several autoimmune diseases, aiming to investigate their potential implication in MG pathogenesis. These are interferon regulatory factor 5 (IRF-5), TNFα-induced protein 3 (TNFAIP3), also known as A20, and interleukin-10 (IL-10), key molecules in the regulation of immune function. A statistical trend of association (P = 0.068) between IL-10 promoter single nucleotide polymorphisms (SNPs) and the subgroups of early and late-onset MG patients was revealed. No statistically significant differences were observed in the rest of the variants examined. As far as we are aware, this is the first worldwide attempt to address the possible association between IRF-5 and TNFAIP3 common genetic variants and the genetic basis of MG.

HLA-DQA1*03:02/DQB1*03:03:02 is strongly associated with susceptibility to childhood-onset ocular myasthenia gravis in Southern Han Chinese.

OBJECTIVE: Our aim was to investigate the correlation between onset age, clinical features and HLA-DQA1/DQB1 genetic variability in myasthenia gravis (MG) patients in Southern Han Chinese. METHODS: 205 MG patients and 100 controls were genotyped for HLA-DQA1 and -DQB1 using sequence-based typing (SBT) and analyzed for haplotype frequencies. Anti-acetylcholine receptor (AChR) autoantibodies were measured in all, and muscle-specific tyrosine kinase (MuSK) antibodies were tested in AChR antibody negative patients. RESULTS: HLA-DQA1/DQB1 haplotypes showed association only with childhood-onset MG. Haplotype DQA1*03:02/DQB1*03:03:02 (DQ9) was positively associated with the childhood-onset MG, while haplotype DQA1*02:01/DQB1*02:02 and DQA1*05:01:01/DQB1*02:01:01 (DQ2) were negatively associated with this group. Childhood-onset ocular MG patients had an extremely high phenotype frequency of DQ9 haplotype (90.1% of patients, 34.0% of controls, p≤0.0001, OR=17.8). CONCLUSIONS: The childhood-onset ocular MG in Southern Han Chinese may present a particular subgroup of distinct genetic background. Its correlation to the HLA haplotype DQA1*03:02/DQB1*03:03:02 might explain the phenotypic difference of MG between Han Chinese and Caucasians.

The association of HLA-DQA1*0401 and DQB1*0604 with thymomatous myasthenia gravis in northern Chinese patients.

Genetic analyses indicate that HLA complex genes can be involved in susceptibility to autoimmune myasthenia gravis (MG). Various HLA alleles serve as genetic elements that either predispose to or protect against MG. This study investigates the probable relationship between HLA-DQ allele polymorphisms and MG cases in northern China. The HLA-DQA1 and DQB1 alleles were determined by polymerase chain reaction/sequence-specific primers (PCR-SSP) in 84 MG patients, and the results were compared to 293 healthy controls. Our findings indicate that DQ A1*0401(P=0.008, OR: 2.5, 95%CI: 1.24-3.07) and B1*0301(P=0.000, OR: 2.29, 95%CI: 1.48-3.54) were the most frequent allele; the frequencies of DQA1*0103(P=0.000, OR:0.24, 95%CI 0.13-0.49) and DQB1*0601(P=0.001, OR:0.40, 95%CI 0.22-0.50) were significantly decreased in MG patients compared with healthy controls. Patients with thymomatous MG were positively associated with DQA1 *0401(P=0.011, OR:4.57, 95% CI 1.40-14.90) and DQB1 *0604 (P=0.001, OR:4.01, 95% CI 1.65-9.73) as compared to MG patients without thymoma. Different genetic mechanisms may exist between MG patients with thymoma and those without thymoma. The HLA-DQ associations in MG subgroups suggest that disease heterogeneity may be influenced by different genes or alleles.

PTPN22 and myasthenia gravis: replication in an Italian population and meta-analysis of literature data.

Polymorphisms in PTPN22 are associated with many autoimmune diseases; while rs2476601 is supposed to play a major role, other experimental data suggest that rs2488457 may be even more important. Results in myasthenia gravis are controversial. In 356 Italian myasthenic patients and 439 controls genotyped for both polymorphisms, we found that rs2476601 was not associated with myasthenia, presence of autoantibodies, thymus pathology, sex or onset age unlike previous studies on other European populations (confirmed by the present meta-analysis). On the other hand, while rs2488457 was not associated with myasthenia or thymus pathology, we found a correlation of rs2488457 with low autoantibody titers and a trend of association with a less severe disease. Both polymorphisms were in tight linkage disequilibrium in controls, not in patients. Our results suggest that SNPs in this gene different from rs2476601, and/or epigenetic interactions, could play a greater role.

Neuromyelitis optica spectrum disorders in patients with myasthenia gravis: ten new aquaporin-4 antibody positive cases and a review of the literature.

BACKGROUND: Neuromyelitis optica (NMO, Devic syndrome) and myasthenia gravis (MG) are rare antibody-mediated autoimmune disorders. Concurrent incidence has been reported in only few patients, mostly non-Caucasians. OBJECTIVE: To report on ten Caucasian patients with NMO spectrum disorders (NMOSD) and MG and to provide a comprehensive review of the literature. METHOD: Retrospective study. RESULTS: In total, 26 patients (m:f = 1:12; Caucasian in 12) with MG (generalized in 17) and NMOSD (NMO in 21, longitudinally extensive transverse myelitis in five) were identified from the authors' own files (n = 10) and the previous literature (n = 16). MG preceded NMOSD in 24/25 cases (96%). AQP4-Ab were tested in 20 patients and were positive in 17 (85%). Twenty out of 25 patients (80%) had been treated with thymectomy or thymic irradiation, which preceded NMOSD in all cases (median latency, 12 years; range, 0.3-32). At last follow-up, complete remission of MG was reported in 15/22 (68%), and MG was well controlled with pyridostigmine in three. Co-existing autoimmune disorders or autoimmune antibodies were reported in 17 patients. CONCLUSION: Our study demonstrates that i) AQP4-Ab-positive NMOSD are more commonly associated with MG in Caucasians than previously thought; ii) MG precedes NMOSD in most cases, often by more than a decade; iii) NMOSD almost exclusively occur in females with juvenile or early-onset MG; and iv) MG frequently takes an unusually mild course in patients with NMOSD. A history of thymectomy could be a possible risk factor for the later development of NMOSD. We recommend testing for AQP4-Ab in MG patients presenting with atypical motor or optic symptoms.

Characteristics of myasthenia gravis according to onset-age: Japanese nationwide survey.

OBJECTIVE: To clarify the prevalence and clinical characteristics of myasthenia gravis (MG) in Japan. METHODS: We performed a nationwide epidemiological survey of MG in Japan. The clinical features were compared among five groups of patients, divided according to onset age. A generalized additive model (GAM) was used to assess the linearity of these relationships. RESULTS: A total of 8542 patients were reported, and detailed data were analyzed for 3141 patients. The estimated number of MG patients in Japan was 15,100, giving a prevalence of 11.8 per 100,000. Elderly-onset MG (≥ 65 years) accounted for 7.3% in 1987 (adjusted for population in 2005), but this had increased to 16.8% in 2006. Infantile-onset MG (0-4 years) accounted for 10.1% in 1987, and was still as high as 7.0% in 2006. The rate of ocular MG was highest (80.6%) in infantile-onset and lowest (26.4%) in early-onset disease, but the rate rose again in the late-onset group. GAM analysis of the ocular form showed a U-shaped curve, with a dip in the 20s. Anti-acetylcholine receptor antibodies were positive in only 50% of infantile-onset, but nearly 90% of elderly-onset patients. GAM analyses assessing the concurrence of thymoma and hyperplasia both showed reversed U-shapes, with peaks in the 50s and 20s-40s, respectively. CONCLUSIONS: Persistent high incidence of infantile-onset disease and clinical heterogeneity according to onset age are characteristic features of MG in Japan.

MuSK-antibody-positive myasthenia gravis in a South Asian population.

BACKGROUND: MuSK-antibody-positive myasthenia gravis (MuSK-MG) is diagnosed in 0-40% of cases with generalized seronegative MG in different populations. The presence of anti-MuSK antibodies defines a distinct clinico-immuno-pathological subtype of MG. We analysed for the first time the serology and clinical characteristics of MuSK-MG in a South Asian population. METHODS: 113 patients with MG attending Neurology Units in three state hospitals in the district of Colombo, Sri Lanka were studied. AChR antibodies were tested in all patients whilst MuSK antibodies were tested in patients seronegative for AChR antibodies. Sera from patients with other neurological diseases (OND) concurrently attending the same hospitals were obtained as controls. RESULTS: Four of 19 AChRAb-negative generalised MG patients (21%) were positive for MuSKAbs. Two were women and in 3, disease onset was before the age of 30 years. Although 3 of 4 had ocular-bulbar involvement at presentation, none had facial or bulbar muscle wasting. Two of the 4 patients (50%) had developed myasthenic crisis and had required ventilation. A good treatment outcome appears to be related to early commencement of immunosuppressive medication. None of the patients with ocular MG or OND were positive for either AChR or MuSK antibodies. CONCLUSIONS: MuSK-MG is seen in about a fifth of generalised seronegative MG patients in Sri Lanka. The clinical characteristics are consistent with features described in Caucasian MuSK-MG patients.

Association of HLA-A in autoimmune myasthenia gravis with thymoma.

We investigated an association of the HLA-A locus in 78 French Caucasian patients with autoimmune myasthenia gravis (MG) and thymic epithelial tumours. The largest effect was a protection associated with HLA-A02 in MG patients with a B2 type thymoma (OR=0.323, 95% CI: 0.113-0.756, P=0.00041). The frequency of HLA-A25 was also increased in the whole group of patients (OR=3.62, 95% CI: 1.62-7.08, P=0.0041). Our findings emphasise the interest of the histological classification in the genetic study of thymomas.

Myasthenia gravis: presentation and outcome in 104 patients managed in a single institution.

BACKGROUND AND OBJECTIVES: Few studies have attempted to delineate the clinical profile of myasthenia gravis (MG) among people of Arab ancestry. Therefore, we sought to clarify the clinical profile, the outcome of treatment and the role of thymectomy in non-thymomatous MG in Saudi Arabia. PATIENTS AND METHODS: We retrospectively studied 104 patients followed over a mean period of 7.2 years (range, 1 to 22 years) at the King Khaled University Hospital, Riyadh, Saudi Arabia. Disease outcomes were compared among thymectomized and non-thymectomized patients according to the post-intervention status criteria of the Myasthenia Gravis Foundation of America (MGFA). RESULTS: Age of onset was 22.5+/-9.3 years (meanA+/-SD) in females and 28.2+/-15.9 years in males, with peaks in the second and third decades among females and the third and fourth decades among males. At diagnosis, a majority of patients had moderate generalized weakness, equivalent to MGFA class III severity. After medical treatment with or without thymectomy, 9.6% of all patients had achieved complete stable remission, 3.8% had pharmacological remission, 27.9% had minimal manifestations, 23.1% were improved, 20.2% were unchanged and 15.4% were worse. Only thymectomized patients without a thymoma achieved remission, a significant benefit over those who had no thymectomy (P=.02). CONCLUSION: MG presents at a younger age among Saudi Arabs compared to other racial groups. Thymectomy conferred significant benefits towards achievement of remission.

Myasthenia gravis in South Africans: racial differences in clinical manifestations.

We present data on the phenotypic variation in myasthenia gravis of 205 subjects from a multi-racial South African cohort. Consecutive subjects seen more than twice from 1996 to 2006, were included. Documented observational data included a myasthenia gravis and extra-ocular eye muscle score. Results showed Black subjects were more likely than Whites to develop treatment-resistant complete ophthalmoplegia and ptosis (18% vs. 2%; p=0.041). Of the 14 patients with this phenotype, 13 had generalised disease and positive AChR antibodies. Despite similar sized cohorts, White subjects were more likely than Blacks to develop generalised myasthenia poorly responsive to therapy (p=0.005). There were no significant racial differences in the time between diagnosis to initiation of therapy, or the performance and timing of thymectomy. The racial variation in some phenotypic features of myasthenia gravis and outcome to therapy, highlights the need to study biological factors in different subgroups to develop a more rational approach to immuno-suppressive therapy.

Clinical and serological study of myasthenia gravis in HuBei Province, China.

BACKGROUND: Ocular and childhood myasthenia gravis (MG) cases seem relatively more common in Oriental than in Caucasian populations, but there have been no comprehensive serological studies on patients from mainland China. METHODS: 391 unselected patients with MG attending Tongji Hospital in WuHan (the largest hospital in the province of HuBei, China) were studied during a 15-month period; most had already received treatment for their condition. RESULTS: The male to female ratio was 0.8. 50% of the patients were children (<15 years), and age at onset showed a single peak at between 5 and 10 years of age. 64% of the children and 66% of the adults were positive for acetylcholine receptor (AChR) antibodies but the antibody titres were lower than in similar Caucasian studies, although this was partly due to the high incidence of ocular MG. Of the 43 patients with generalised MG without AChR antibodies, only 1 had muscle-specific kinase antibodies (2.5%) and 2 had voltage-gated calcium channel antibodies indicating probable Lambert-Eaton myasthenic syndrome. 75% of the children, compared with only 28% of the adults, had ocular MG. Thymoma was evident by MRI in 1.5% of children and in 20% of adults. Despite most patients having received prednisone, very few had obtained full clinical remission. CONCLUSION: This study emphasises the frequency of early childhood onset with ocular symptoms and shows that many of these patients have AChR antibodies. By contrast, patients presenting in later age seem to be very uncommon in comparison with recent studies in Caucasian populations.