Batoclimab vs Placebo for Generalized Myasthenia Gravis: A Randomized Clinical Trial.

Importance: Myasthenia gravis (MG) is caused by autoantibodies that disrupt the neuromuscular junction. The neonatal fragment crystallizable receptor (FcRn) antagonists, efgartigimod and rozanolixizumab, reduce immunoglobulin G (IgG) level in the circulation and alleviate symptoms in patients with generalized MG. Objective: To examine the efficacy and safety profile of batoclimab, a monoclonal IgG1 antibody, in patients with generalized MG. Design, Setting, and Participants: This was a multicenter randomized clinical trial conducted from September 15, 2021, to June 29, 2022, at 27 centers in China. Adult patients 18 years or older with generalized MG were screened, and those who were antibody positive were enrolled. Intervention: Eligible patients received batoclimab or matching placebo in addition to standard of care. Each treatment cycle consisted of 6 weekly subcutaneous injections of batoclimab, 680 mg, or matching placebo followed by 4 weeks of observation. A second treatment cycle was conducted in patients who required continuing treatment. Main Outcome and Measure: The primary outcome was sustained improvement, as defined by a 3-point or greater reduction in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score from baseline for 4 or more consecutive weeks in the first cycle in individuals who were positive for acetylcholine receptor or muscle-specific kinase antibodies. Results: A total of 178 adult patients with generalized MG were screened, 132 were randomly assigned, 131 tested positive for antibodies, and 1 tested negative for antibodies. A total of 132 patients (mean [SE] age, 43.8 [13.6] years; 88 women [67.2%]) were enrolled. The rate of sustained MG-ADL improvement in the first cycle in antibody-positive patients was 31.3% (20 of 64) in the placebo group vs 58.2% (39 of 67) in the batoclimab group (odds ratio, 3.45; 95% CI, 1.62-7.35; P = .001). The MG-ADL score diverged between the 2 groups as early as week 2. The mean (SE) maximum difference in MG-ADL score reduction occurred 1 week after the last dose (day 43, 1.7 [0.3] in the placebo group vs 3.6 [0.3] in the batoclimab group; group difference, -1.9; 95% CI, -2.8 to -1.0; nominal P < .001). The rates of treatment-related and severe treatment-emergent adverse events in patients were 36.9% (24 of 65) and 7.7% (5 of 65) in the placebo group vs 70.1% (47 of 67) and 3.0% (2 of 67) in the batoclimab group, respectively. Conclusions and Relevance: Batoclimab increased the rate of sustained MG-ADL improvement and was well tolerated in adult patients with generalized MG. Clinical effects and the extent of IgG reduction were similar to those previously reported for efgartigimod and rozanolixizumab. Future studies of large sample size are needed to further understand the safety profile of batoclimab. Trial Registration: ClinicalTrials.gov Identifier: NCT05039190.

Rs1800629 polymorphism in TNF-alpha is associated with the susceptibility and initial short-term glucocorticoids efficacy in myasthenia gravis patients.

Tumor necrosis factor-alpha (TNF-α) is a potent pro-inflammatory agent involved in various autoimmune and inflammatory diseases including myasthenia gravis (MG). In this study, we enrolled 409 adult MG patients and 487 healthy individuals to investigate the association between TNF-α polymorphism and MG. We found the rs1800629 A allele frequency was significantly higher in the MG group than in the control group. Subgroup analysis revealed that the A allele frequencies were significantly higher in the early-onset subgroup, non-thymoma subgroup, ocular-onset subgroup, and mild severity subgroup than in the control group. To minimize the interactions between clinical features, we used a comprehensive classification and found that the rs1800629 A allele frequency was significantly higher in the non-thymoma AChR-Ab negative subgroup than in the control group. In the analysis of initial short-term glucocorticoids (GC) efficacy in the treatment-naive patients, the rs1800629 A allele frequency was significantly higher in the unresponsive subgroup than in the responsive group and the control group. Logistic regression demonstrated the rs1800629 genotypes in the dominant model and disease duration prior to GC treatment independently contributed to initial short-term GC efficacy. In conclusion, our study revealed that in Chinese adult MG patients, rs1800629 polymorphism in TNF-α was associated with the susceptibility of MG and might indicate the initial short-term GC efficacy.

Altered gut microbiota and metabolites in untreated myasthenia gravis patients.

Objective: The homeostasis of the immune system is influenced by the gut microbiota. Previous studies have reported dysbiosis in the gut microbiota of myasthenia gravis (MG) patients. To investigate potential alterations in gut microbiota and metabolites in newly diagnosed and untreated MG patients, we conducted a case-control study. Methods: Fecal samples were collected from 11 newly diagnosed and untreated MG patients as well as 11 age-and sex-matched healthy controls. These samples underwent analysis for gut microbiota using 16S ribosomal RNA (rRNA) gene sequencing, while fecal metabolome was analyzed using liquid chromatography-electrospray tandem mass spectrometry system (LC-ESI-MS/MS). Results: The microbial community richness (observed species) and diversity (Shannon and Simpson indices) were significantly lower in the MG group compared to the control group. Microbiota composition analysis revealed significant differences between the MG and control groups at phylum, family, and genus levels. Linear discriminant analysis effect size (LEfSe) analysis showed a substantial decrease in abundance of the genus Faecalibacterium within the MG group. Fecal metabolome analysis identified three up-regulated metabolites involved in amino acid metabolism (taurine, creatinine, L-carnitine), one up-regulated metabolite involved in lipid metabolism (oleic acid), with correlation analysis indicating a positive association between Faecalibacterium abundance and creatinine levels. Conclusion: Our findings suggest that dysbiosis already exists in newly diagnosed and untreated MG patients, implying that dysbiosis within the gut microbiota may be an initiating factor contributing to MG pathogenesis. Furthermore, F. prausnitzii may hold promise as a probiotic for treating MG.

Safety of inactivated SARS-CoV-2 vaccines in myasthenia gravis: A survey-based study.

Background: Vaccination remains the most effective measure to prevent SARS-CoV-2 infection and worse outcomes. However, many myasthenia gravis (MG) patients are hesitant to receive vaccine due to fear of worsening. Methods: MG patients were consecutively enrolled in two MG centers in North China. The "worsening" after vaccination was self-reported by MG patients, and severity was measured with a single simple question. The general characteristics and disease status immediately prior to the first dose were compared between the worsening and non-worsening groups. Independent factors associated with worsening were explored with multivariate regression analysis. Results: One hundred and seven patients were included. Eleven patients (10.3%) reported worsening after vaccination, including eight patients with mild or moderate worsening and three patients with severe worsening. Only one of them (0.9%) needed an escalation of immunosuppressive treatments. There were significant differences between the worsening and non-worsening groups in terms of Myasthenia Gravis Foundation of America classes immediately before the first dose and intervals since the last aggravation. Precipitating factors might contribute to the worsening in some patients. Logistic regression revealed that only interval since the last aggravation ≤6 months was associated with worsening after SARS-CoV-2 vaccination (P = 0.01, OR = 8.62, 95% CI: 1.93-38.46). Conclusion: SARS-CoV-2 vaccines (an overwhelming majority were inactivated vaccines) were found safe in milder Chinese MG patients who finished two doses. Worsening after vaccination was more frequently seen in patients who were presumed as potentially unstable (intervals since last aggravation ≤6 months). However, mild worsening did occur in patients who were presumed to be stable. Precipitating factors should still be sought and treated for better outcome.

Minimal Manifestation Status Indicates a Stable State in Myasthenia Gravis: A Quantitative Study.

Introduction: Minimal manifestation (MM) or better was recommended as the treatment goal for myasthenia gravis (MG). The sustainability of this status has not been described quantitatively in patients who had attained or are close to it. Methods: Patients who were with no or slight impact on daily living were recruited and followed at baseline and 3, 6, and 12 months. The included patients were classified into 3 post-intervention status (PIS) categories: remission (R), MM, and slight impact (SI). The proportion of patients belonging to real-time (not considering the intervals between assessments) and sustained (considering the intervals between assessments) PIS categories was compared at each follow-up. A sensitivity analysis (SA) cohort was established by including patients with PIS categories in all four follow-ups. The QMGS, MG-ADL, and MG-QOL15 scores in patients belonging to each PIS category at each follow-up were compared. The sustainability of the R/MM status was examined and correlated with real-time R/MM status at follow-ups. Results: At baseline, 376 patients could be classified, including 55 as R (14.2%), 209 as MM (54.0%), and 112 as SI (28.9%). In the whole cohort, 68.8-89.7%, 71-76.7% and 19.8-77.1% of the patients classified into real-time R, MM, and SI categories remained unchanged in each follow-up compared with the previous follow-up. The proportion of patients belonging to each real-time or sustained R/MM status at the three follow-ups was 89.7-92.1 or 60.8-67. In the SA cohort, at least 86.4% of the baseline R/MM patients remained in R/MM status till 12 months. There were no differences in keeping real-time R/MM status at 6 or 12 months between patients with and without sustained R/MM status at 3 and 6 months. There were differences in the QMGS, MG-ADL, and MG-QOL15 scores among patients belonging to each real-time category at baseline and follow-ups, ranking as R < MM < SI. The same trend was observed in patients belonging to each sustained PIS category with smaller scores than the same items of real-time categories. Conclusion: The sustainability of the R/MM status was confirmed. The R/MM status indicated a stable state of MG. The QMGS, MG-ADL, and MG-QOL15 scores may provide a quantitative reference for these PIS.

Optimization of the cut-offs in acetylcholine receptor antibodies and diagnostic performance in myasthenia gravis patients.

OBJECTIVE: This study aims to establish an optimization procedure to define the cut-offs of quantitative assays for acetylcholine receptor antibody (AChRAb), evaluate their diagnostic performance in myasthenia gravis (MG), and explore the association with clinical features. METHODS: Samples from a representative cohort of 77 MG patients, 80 healthy controls (HC) and 80 other autoimmune diseases (OAD) patients were tested using competitive inhibition ELISA and RIA. Raw values (OD and cpm) and processed values (inhibition rate, binding rate and concentration) were used to define the cut-offs with statistical methods, a rough method, and receiver operating characteristic (ROC) curve. Optimal cut-offs were selected by comparing false positive rates in HC and OAD individuals. The diagnostic performance was evaluated in whole MG cohort and subgroups. Agreement between ELISA and RIA for AChRAb positivity were examined with Kappa test and McNemar test. Clinical association with AChRAb was explored by comparison among subgroups and with Spearman rank correlation. RESULTS: The optimal cut-offs for AChRAb positivity were determined as OD ≤ 1.79 for ELISA and cpm ≥ 1234.12 for RIA, which derived from statistical method and performed better than those derived from ROC curves. The sensitivity and specificity were 74.03%, 100% for ELISA, and 74.03%, 99.37% for RIA. There was good agreement between ELISA and RIA for AChRAb positivity in whole cohort and subgroups (weighted к ≥ 0.71, p < 0.01; McNemar test, p > 0.05). Levels of AChRAb were different in MG subgroups (p < 0.01). Correlation between Quantitative Myasthenia Gravis scores and AChRAb levels was moderate for ELISA and RIA (rs = -0.60 and 0.57, p < 0.01). CONCLUSION: The raw testing values of ELISA and RIA were found as optimal quantitative measures of AChRAb levels. There are good agreements on diagnostic performance between two assays. Quantitative values are more informative than positivity in association with clinical features.

Criteria for Treatment Response in Myasthenia Gravis: Comparison Between Absolute Change and Improvement Percentage in Severity Scores.

Background: The absolute change in the severity score between the baseline and pre-specified time frame (absolute criterion) was recommended as a criterion for myasthenia gravis (MG) treatment response. But heterogeneity of disease severity might dilute major changes in individual patients. The rationality of relative criterion (improvement percentage) had not been evaluated in treatment response in patients with MG. Objectives: To investigate the consistency between an absolute criterion and a relative criterion in the evaluation of treatment response in patients with MG. Methods: We retrospectively analyzed the treatment response to a 3-month standardized treatment protocol with only glucocorticoid in 257 MG patients native to immunological treatments. With the commonly used absolute criterion, cut-offs of relative criteria were generated with the receiver operating characteristic (ROC) curve in the whole cohort and in patients with different degrees of baseline severity stratified by pre-treatment quantitative myasthenia gravis score (QMGS). The consistency between absolute and relative criteria was examined with Cohen's Kappa test and Venn diagrams. Results: The absolute and relative criteria had an overall substantial consistency (Kappa value, 0.639, p < 0.001) in the cohort. The Kappa values were substantial to almost perfect in mild and moderate groups and moderate in severe groups between the absolute and relative criteria (all p ≤ 0.001). More patients were classified as responsive with an absolute criterion while as unresponsive with a relative criterion in the moderate and severe groups. Conclusions: The overall consistency between absolute and relative criteria was substantial in the whole cohort. The inconsistency between the two criteria was mainly from the moderate or severe patients at the baseline.

Vitamin D Receptor Polymorphism and Myasthenia Gravis in Chinese Han Population.

Myasthenia gravis (MG) is an autoimmune disease in which antibodies bind to acetylcholine receptors (AChR) or other functional molecules in the postsynaptic membrane at the neuromuscular junction. Vitamin D (VD) has a number of pluripotent effects, which include immune-regulation and bone metabolism. The immunomodulatory actions of 1,25(OH)2D3 are mediated by its binding to a vitamin D receptor (VDR). In the study, we undertook a case-control study to explore the association between VDR gene polymorphism and the susceptibility and severity of MG patients. Four hundred and eighty MG patients and 487 healthy controls were included and gene polymorphisms of VDR were determined with improved multiplex ligation detection reaction technique and SNPscanTM technique. MG patients were classified into subgroups by essential clinical features and by a comprehensive classification. The frequencies of alleles and genotypes were compared between the MG group and the control group, between each MG subgroup and the control group, and between each pair of MG subgroups. There were no significant differences in frequencies of alleles and genotypes between MG patients and healthy controls, between MG subgroups and healthy controls, or between each pair of MG subgroups in the analysis of subgroups classified by essential clinical features (onset age, gender, thymoma, AChRAb positivity, onset involvement) and the maximal severity (modified Oosterhuis score). In the analysis of subgroups with a comprehensive classification, the frequencies of alleles and genotypes in rs731236 showed significant differences between adult non-thymoma AChRAb negative MG subgroup and the control group, as well as the adult non-thymoma AChRAb positive MG group. In the Chinese Han population, rs731236 was found to be possibly associated with adult non-thymoma AChRAb negative MG patients, although this needs further confirmation.

Complement C3 polymorphism is associated with the susceptibility of myasthenia gravis in Chinese adult patients.

Complement component 3 (C3) had been proved to be involved in the pathogenesis and exacerbation of both myasthenia gravis (MG) patients and experimental autoimmune myasthenia gravis (EAMG) models. We evaluated the underlying association between five SNPs (rs344555, rs7951, rs3745568, rs366510 and rs163913) in C3 gene and Chinese adult MG patients. Our study consisted of 409 adult MG patients and 487 healthy controls. Subgroups were classified by gender, onset age, thymoma, anti-AChR antibody, onset muscle involvement (ocular/generalized) and severity (Oosterhuis score at the maximal severity during the initial two years after the onset of MG). We found significant differences in allele frequencies between MG and the control group, between various MG subgroups and the control group in rs344555 and rs3745568. There were significant differences in genotype frequencies between MG group and the control group, between MG subgroups and the control group under the codominant and additive inheritance models in rs344555 and rs3745568. No association was found between the frequencies of these SNPs and the severity of MG. We also used a comprehensive classification which was close to the clinical scenario to minimize the interaction among clinical features. In rs344555, the T allele frequency in thymoma (-) AChR-Ab (+) subgroup was significantly higher than that in the control group. Our results indicated that rs344555 was associated with the susceptibility of Chinese adult MG patients; rs3745568 was probably associated with the susceptibility of Chinese adult MG patients. No association was found between the frequencies of these SNPs and the severity of MG.

Genetic variations in catechol-O-methyltransferase gene are associated with levodopa response variability in Chinese patients with Parkinson's disease.

Catechol-O-methyltransferase (COMT) is one of the main enzymes in dopamine metabolism and is reported to be associated with susceptibility to Parkinson's disease (PD) and pharmacotherapy. However, researchers mostly focus on the most common polymorphism, rs4680. In this case-control study, we investigated the association of SNPs other than rs4680 with the levodopa (L-dopa) response and other clinical features in Chinese PD patients. Eleven single nucleotide polymorphisms (SNPs) in the COMT gene were genotyped, and clinical data were collected. Patients with the TT genotype of rs165728 or rs174699 had larger daily levodopa equivalent doses (LEDs) than the patients with CC and CT genotypes under the dominant model (p = 0.01421 for rs165728 and p = 0.02302 for rs174699). Under the dominant model, the patients with GG at rs4680 G > A had a lower occurrence of dyskinesia than those with AA and AG (p = 0.0196). Patients with CC at rs4633 had a lower occurrence of dyskinesia than those with TT and TC (p = 0.0429) under the dominant model. The frequencies of the rs174675 T and rs933271 C alleles were higher in PD patients than in the controls (p < 0.05). Our primary results showed the possible association of SNPs other than the most common functional rs4680 in COMT with interindividual variance in the L-dopa daily dose and susceptibility to dyskinesia in Chinese patients, although this was an exploratory study based on a small sample size. Larger and more randomized samples are necessary for further investigation.

A Chinese case of fragile X-associated tremor/ataxia syndrome (FXTAS) with orthostatic tremor:case report and literature review on tremor in FXTAS.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset, X-linked genetic, neurodegenerative disorder caused by a "premutation (PM)" in the fragile X mental retardation 1 (FMR1) gene. Here we report a case of FXTAS from mainland of China who presented with rare orthostatic tremor. A review of tremor of FXTAS in the literature is also included. CASE PRESENTATION: A 67-year-old right-handed farmer started with tremor of both legs 8 years ago which was present while standing but absent when sitting or lying and progressed with unsteady gait one and a half years ago. The brain MRI showed high intensity signal in the bilateral middle cerebellar peduncles (MCP) in T2-weighted and fluid-attenuated inversion recovery (FLAIR) images and gene test for premutation for FMR1 was positive with 101 CGG repeats. The patient met the the diagnosis of definite FXTAS. Clonazepam and topiramate were administered to control tremor. We reviewed the literature and identified 64 cases with detailed clinical and genetic information. Orthostatic tremor associated with FXTAS is very rare. We found 85.2% patients reported tremor,42.6% with intention tremor,36.1% with kinetic tremor,32.8% with rest tremor and 29.5% with posture tremor. 37.7% of patients who have tremor showed at least two types of tremor. There were 6 patients with isolated rest tremor. There was 2 patient with voice tremor and 6 with head tremor. We also found that 74.6% FXTAS patients had family history of FMR1 gene associated diseases including Fragile X syndrome (FXS), FXTAS or fragile X-associated primary ovarian insufficiency (FXPOI). CONCLUSIONS: Adding our data to the available literature suggests that orthostatic tremor could be a rare initial manifestation of FXTAS and the review will increasing our understanding the phenotype of tremor in FXTAS. Family history of FMR1 gene associated diseases might be an important clue to the diagnosis.

Association between CTLA-4 gene polymorphism and myasthenia gravis in a Chinese cohort.

Abnormal CTLA-4 expression is involved in the development of myasthenia gravis (MG), and serum CTLA-4 levels are positively correlated with serum anti-AChR antibody concentration, which might be related with the severity of MG. Polymorphism in CTLA-4 gene is associated with various autoimmune disorders. We investigated the association of polymorphism in CTLA-4 gene with the clinical variables and severity of MG. The frequencies of alleles and genotypes were compared between 480 MG patients and 487 healthy controls, as well as among subgroups of MG patients. The frequency of rs733618*C allele is significantly higher in MG group and several subgroups than in control group. Genotype is not found as independent factor for essential clinical variables of MG. The frequency of rs231775*A allele is significantly lower in ocular onset subgroup than in control group, and the frequencies of rs231775*A allele and rs3087243*A allele are significantly lower in ocular onset subgroup than in generalized onset subgroup. Genotypes of the two SNPs are found as independent factors for ocular onset. The frequency of rs231775*A allele is significantly lower in mild subgroup than that in control group. Genotype is not found as independent factor for mild severity. A haplotype containing rs733618*C, rs231775*G and rs3087243*G is identified to increase the general risk of MG by 1.278-fold and ocular onset MG subgroup by 1.362-fold. There is association of rs733618 with the general susceptibility of MG, and association of rs231775 and rs3087243 with the susceptibility of ocular onset MG, but no association with the severity of MG.

Retraction Note to: Juvenile-onset myasthenia gravis: autoantibody status, clinical characteristics and genetic polymorphisms.

The Joint Editors-in-Chief have retracted this article [1] at the request of the University of Bergen and the Norwegian Board of Health Supervision.

IL-4Rα Polymorphism Is Associated With Myasthenia Gravis in Chinese Han Population.

Interleukin-4 (IL-4) is a potent growth and differentiation factor for B cells which play a vital role in the pathogenesis of myasthenia gravis (MG). IL-4 exerts its function by binding to three types of IL-4 receptor (IL-4R) complexes. IL-4Rα is the key component of the IL-4R complex. We hypothesize that polymorphism of IL-4Rα gene may be associated with the susceptibility and severity of MG. A Chinese cohort of 480 MG patients and 487 healthy controls were recruited. Polymorphisms of IL-4Rα gene were determined with SNPscan™ methods and compared between MG and control groups, as well as among MG subgroups. Rs2107356 and rs1805010 were found to be associated with adult thymoma associated MG, and rs1801275 was found to be associated with adult non-thymoma AChR-Ab positive MG. We did not found association between IL-4Rα polymorphism and the severity of MG. Genetic variations of IL-4Rα were found associated with the susceptibility of MG in Chinese Han population.

Juvenile-onset myasthenia gravis: autoantibody status, clinical characteristics and genetic polymorphisms.

Myasthenia gravis (MG) is an autoimmune disorder mediated by antibodies against proteins at the neuromuscular junction. Juvenile-onset MG (JMG) has been reported to have special characteristics. It is still unclear whether there are any pathogenic and genetic differences between juvenile and adult MG. In this study, we evaluated the clinical characteristics, autoantibody status (antibodies against AChR, MuSK, LRP4, titin and RyR) and genetic susceptibility (CHRNA1, CTLA4 and AIRE) in 114 Chinese JMG patients, and compared with 207 young adult MG patients (onset age 18-40 years). JMG patients were classified into two subgroups: the very early onset group (<8 years) and puberty onset group (8-18 years). The very early onset MG patients had a higher proportion of ocular MG and thymus hyperplasia, compared with puberty onset MG and young adult MG (P < 0.05). AChR antibodies were found in majority of JMG patients and were associated with more severe disease (P < 0.05), while other antibodies were rare in JMG. Moreover, the very early onset MG had a more prominent genetic predisposition than puberty and adult MG, affecting the susceptible genes CHRNA1 and CTLA4. JMG has the same pathogenic background as adult MG, but has typical clinical features and a prominent genetic predisposition in very early onset patients (<8 years). Specific therapeutic considerations are needed.

Rs3761389 polymorphism in autoimmune regulator (AIRE) gene is associated with susceptibility of myasthenia gravis in Chinese patients.

Polymorphism in autoimmune regulator (AIRE) gene is associated with various autoimmune disorders. Abnormal AIRE expression is associated with the development of myasthenia gravis (MG). We investigated the association of polymorphism in AIRE gene and the clinical features and severity of MG. The frequencies of alleles and genotypes were compared between 480MG patients and 487 healthy controls, as well as among subgroups of MG patients. The frequencies of rs3761389G allele in MG group (OR=1.213, CI 95% 1.014-1.451, p=0.035) and in mild (Oosterhuis score 0-2) subgroup (OR=1.393, CI 95% 1.110-1.751, p=0.004) were significantly higher than those in the control group. There were significant differences in the frequencies of rs3761389 genotypes (OR=1.20, CI 95% 1.00-1.43, p=0.046, log-additive model) and mild subgroup (OR=1.32, CI 95% 1.03-1.69, p=0.0058, log-additive model) compared with the control group. A Logistic regression analysis did not identify rs3761389 genotype as an independent risk factor to predict the severity of MG. This study provides the necessary preliminary data on the association with rs3761389 in AIRE gene with the susceptibility of MG, but not with the severity of MG.

Gene Polymorphisms for Both Auto-antigen and Immune-Modulating Proteins Are Associated with the Susceptibility of Autoimmune Myasthenia Gravis.

Myasthenia gravis (MG) is an antibody-mediated autoimmune disease against antigens at the neuromuscular junction. Both genetic and environmental factors contribute to the susceptibility of MG. We undertook a case-control study to explore the contribution of genes of the auto-antigen and immune-modulating proteins in the pathogenesis of MG. We enrolled 389 adult MG patients and 487 healthy controls. Eighteen SNPs were selected from genes of cholinergic receptor nicotinic alpha 1 (CHRNA1), autoimmune regulator (AIRE), cytotoxic T lymphocyte-associated protein 4 (CTLA-4), protein tyrosine phosphatase nonreceptor type 22 (PTPN22), and interleukin-10 (IL-10). Rs16862847 and rs2229957 in CHRNA1, rs3761389 in AIRE, and rs733618 in CTLA-4 were significantly associated with MG, with the highest association in SNPs of CHRNA1. Carrier of rs16862847 G allele was found to be an independent risk factor in predicting high-level acetylcholine receptor (AChR) antibodies (P = 0.003, OR = 10.296). Genetic interaction analysis revealed a synergistic effect of CHRNA1 (rs16862847), AIRE (rs3761389), and CTLA-4 (rs733618) in the susceptibility of MG (P < 0.0001, OR = 1.95). These findings highlight the role of auto-antigen gene (CHRNA1) in the autoimmune reactions against AChR and reveal synergistic contribution of genes of both auto-antigen and immune-regulating proteins (AIRE and CTLA-4) in the pathogenesis of MG.

Association study between IL-17A and IL-17F gene polymorphism and myasthenia gravis in Chinese patients.

Alleles of IL-17A and IL-17F genes were reported to be associated with many inflammatory and autoimmune disorders in Asian patients. Serum level and mRNA of IL-17A in peripheral blood mononuclear cells were reported to be significantly higher in MG patients than in healthy controls. In experimental autoimmune myasthenia gravis (EAMG) animals, IL-17 may have effects on the severity of MG. This study investigated the association between four SNPs of IL-17A and IL-17F gene (rs8193036, rs2275913 and rs3748067 in IL-17A; rs763780 in IL-17F) and MG in Chinese patients. The allele frequencies were compared between 480 MG patients and 487 healthy controls, between each MG subgroup and the control group, and between each pairs of MG subgroups. Subgroups were specified by clinical features (onset age, gender, thymoma, AChRAb and muscle involvement at onset) and maximal severity during the follow-up. No associations were found between the four SNPs of IL-17A and IL-17F gene and MG in Chinese patients.