Associations of BAFF rs2893321 polymorphisms with myasthenia gravis susceptibility.
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ABSTRACT:
SUBMITTER: Deng H
PROVIDER: S-EPMC6822419 | biostudies-literature | 2019 Oct
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe pathogenesis of extraocular muscle (EOM) weakness in myasthenia gravis might involve a mechanism specific to the EOM. The aim of this study was to investigate characteristics of the EOM related to its susceptibility to myasthenia gravis.MethodsFemale F344 rats and female Sprague-Dawley rats were assigned to experimental and control groups. The experimental group received injection with Ringer solution containing monoclonal antibody against the acetylcholine receptor (AChR), mAb35 (0.25 mg/kg), to induce experimental autoimmune myasthenia gravis, and the control group received injection with Ringer solution alone. Three muscles were analyzed: EOM, diaphragm, and tibialis anterior. Tissues were examined by light microscopy, fluorescence histochemistry, and transmission electron microscopy. Western blot analysis was used to assess marker expression and ELISA analysis was used to quantify creatine kinase levels. Microarray assay was conducted to detect differentially expressed genes.ResultsIn the experimental group, the EOM showed a simpler neuromuscular junction (NMJ) structure compared to the other muscles; the NMJ had fewer synaptic folds, showed a lesser amount of AChR, and the endplate was wider compared to the other muscles. Results of microarray assay showed differential expression of 54 genes in the EOM between the experimental and control groups.ConclusionVarious EOM characteristics appear to be related to the increased susceptibility of the EOM and the mechanism of EOM weakness in myasthenia gravis.
| S-EPMC3568149 | biostudies-literature
Project description:OBJECTIVE: To identify novel genetic loci that predispose to early-onset myasthenia gravis (EOMG) applying a two-stage association study, exploration, and replication strategy. METHODS: Thirty-four loci and one confirmation loci, human leukocyte antigen (HLA)-DRA, were selected as candidate genes by team members of groups involved in different research aspects of MG. In the exploration step, these candidate genes were genotyped in 384 EOMG and 384 matched controls and significant difference in allele frequency were found in eight genes. In the replication step, eight candidate genes and one confirmation loci were genotyped in 1177 EOMG patients and 814 controls, from nine European centres. RESULTS: ALLELE FREQUENCY DIFFERENCES WERE FOUND IN FOUR NOVEL LOCI: CD86, AKAP12, VAV1, B-cell activating factor (BAFF), and tumor necrosis factor-alpha (TNF-?), and these differences were consistent in all nine cohorts. Haplotype trend test supported the differences in allele frequencies between cases and controls. In addition, allele frequency difference in female versus male patients at HLA-DRA and TNF-? loci were observed. INTERPRETATION: The genetic associations to EOMG outside the HLA complex are novel and of interest as VAV1 is a key signal transducer essential for T- and B-cell activation, and BAFF is a cytokine that plays important roles in the proliferation and differentiation of B-cells. Moreover, we noted striking epistasis between the predisposing VAV1 and BAFF haplotypes; they conferred a greater risk in combination than alone. These, and CD86, share the same signaling pathway, namely nuclear factor-kappaB (NF?B), thus implicating dysregulation of proinflammatory signaling in predisposition to EOMG.
| S-EPMC4184684 | biostudies-literature
Project description:Background Myasthenia gravis (MG) is an autoimmune disorder with fluctuating muscle weakness, divided into generalized and localized (ocular) forms. Maternal antibodies to acetylcholine receptors cross the placenta and may cause transient neonatal myasthenia gravis (TNMG). We present a case of seronegative maternal ocular MG and delayed TNMG. Case A 29-year-old G3P1011 underwent cesarean birth of a male infant who developed oxygen desaturation requiring supplemental oxygen on day of life (DOL) 3. Based on the clinical course and after exclusion of other diagnoses, the infant was diagnosed with TNMG. Infant's condition improved spontaneously and he was weaned off supplemental oxygen and discharged home on DOL 12. Conclusion Infants born to mothers with seronegative localized (ocular) MG are also susceptible to TNMG which may be late in onset.
| S-EPMC4794443 | biostudies-other
Project description:Myasthenia gravis (MG) is an autoimmune disease affecting the neuromuscular junction, whose clinical hallmark is muscle weakness and early fatigability. Azathioprine (AZA) is commonly used in Myasthenia Gravis therapy. AZA is a purine antagonist, which inhibits the cell cycle in the resting and DNA synthesis phases. It is usually used as an immunosuppressant to block T- and B-cell proliferation. AZA, bioconverted to 6-mercaptopurine by glutathione S-transferase (GST), can be metabolized either through the hypoxanthine phosphoribosyl transferase pathway to active 6-thioguanine nucleotides (6-TGN) or through the thiopurine S-methyltransferase (TPMT) pathway to inactive methyl-thiopurine metabolites. The incorporation of active 6-TGNs into DNA, causing breaks in DNA strands resulting in interference with RNA production and thereby protein synthesis, is responsible for the drug effect. The response to AZA is determined by which metabolic pathway is being favored. While balanced use of both HPRT and TPMT pathways results in responsiveness to AZA, hyperactivity of TPMT skews the balance towards the TPMT pathway and results in unresponsiveness to AZA with no pharmacological effect. In contrast, low TPMT activity skews the balance towards the HPRT pathway, resulting in increasing side-effects due to the accumulation of 6-TGNs. Current treatments for MG therapy are often inadequate because less than 40% of patients achieve complete remission with available drugs. This reflects the lack of drugs acting on target sites for which there is strong evidence of pathogenicity and the inability to identify responder patients. No criteria for responsiveness are available, exposing patients to unpredictable failures and unpredictable side effects. These individuals are at particular risk for adverse drug reaction (ADRs) or therapeutic failure. Genetic profiling with the Affymetrix drug metabolizing enzymes and transports genotyping array offers the ability to determine 1,931 variants and 225 genes involved in drug metabolism and disposition. Accordingly, the study of well-known drug-metabolizing genes can be involved in the specific metabolic pathway of a drug, which is more likely to define genotype-phenotype association and thereby genotype profiles relevant to drug response that can be applied as predictive biomarkers for pharmacological treatment.
2016-05-01 | E-MTAB-4489 | biostudies-arrayexpress
Project description:IntroductionLabor-market participation is potentially very difficult for patients with refractory myasthenia gravis (MG). In this study, employment status and work absences are compared between refractory and nonrefractory MG.MethodsAdults (aged 18-64?years, all diagnosed ?2?years previously) were included if enrolled in the Myasthenia Gravis Foundation of America Patient Registry during July 2013 to February 2018.ResultsSeventy-six patients (9.2%) had refractory and 749 (90.8%) had nonrefractory disease; demographic data did not differ between groups. Relative to the nonrefractory group, the refractory group patients were more than twice as likely to work fewer hours per week (odds ratio [95% confidence interval]: currently employed, 2.777 [1.640-4.704]; employed over previous 6?months, 2.643 [1.595-4.380]), but those employed were not more likely to be absent from work.DiscussionBecause absence from the labor market adversely affects quality of life and personal finances, these findings reaffirm the considerable disease burden associated with refractory MG.
| S-EPMC6900169 | biostudies-literature
Project description:BackgroundThe Quantitative Myasthenia Gravis Score and the Myasthenia Gravis Composite are two commonly used outcome measures in Myasthenia Gravis. So far, their measurement properties have not been compared, so we aimed to study their psychometric properties using the Rasch model.Methods251 patients with stable myasthenia gravis were assessed with both scales, and 211 patients returned for a second assessment. We studied fit to the Rasch model at the first visit, and compared item fit, thresholds, differential item functioning, local dependence, person separation index, and tests for unidimensionality. We also assessed test-retest reliability and estimated the Minimal Detectable Change.ResultsNeither scale fit the Rasch model (X2p < 0.05). The Myasthenia Gravis Composite had lower discrimination properties than the Quantitative Myasthenia Gravis Scale (Person Separation Index: 0.14 and 0.7). There was local dependence in both scales, as well as differential item functioning for ocular and generalized disease. Disordered thresholds were found in 6(60%) items of the Myasthenia Gravis Composite and in 4(31%) of the Quantitative Myasthenia Gravis Score. Both tools had adequate test-retest reliability (ICCs >0.8). The minimally detectable change was 4.9 points for the Myasthenia Gravis Composite and 4.3 points for the Quantitative Myasthenia Gravis Score.ConclusionsNeither scale fulfilled Rasch model expectations. The Quantitative Myasthenia Gravis Score has higher discrimination than the Myasthenia Gravis Composite. Both tools have items with disordered thresholds, differential item functioning and local dependency. There was evidence of multidimensionality in the QMGS. The minimal detectable change values are higher than previous studies on the minimal significant change. These findings might inform future modifications of these tools.
| S-EPMC5240569 | biostudies-literature
Project description:Myasthenia gravis (MG) is the archetypic disorder of both the neuromuscular junction and autoantibody-mediated disease. In most patients, IgG1-dominant antibodies to acetylcholine receptors cause fatigable weakness of skeletal muscles. In the rest, a variable proportion possesses antibodies to muscle-specific tyrosine kinase while the remainder of seronegative MG is being explained through cell-based assays using a receptor-clustering technique and, to a lesser extent, proposed new antigenic targets. The incidence and prevalence of MG are increasing, particularly in the elderly. New treatments are being developed, and results from the randomised controlled trial of thymectomy in non-thymomatous MG, due for release in early 2016, will be of particular clinical value. To help navigate an evidence base of varying quality, practising clinicians may consult new MG guidelines in the fields of pregnancy, ocular and generalised MG (GMG). This review focuses on updates in epidemiology, immunology, therapeutic and clinical aspects of GMG in adults.
| S-EPMC4826656 | biostudies-other
Project description:The muscle acetylcholine receptor is the major target of the autoimmune response in generalized myasthenia gravis. To investigate the role of the gene encoding the alpha subunit of the receptor (CHRNA), two stable polymorphic d[(GT).(CA)]dinucleotide repeats, designated HB and BB, were characterized within the first intron of CHRNA. The HB*14 allele conferred a relative risk for myasthenia gravis of 2.5 in 81 unrelated patients compared with 100 control subjects. Very significantly, family analysis based on haplotype segregation data indicated that parental haplotypes associated with HB*14 always segregated to the child with myasthenia gravis (P < 0.0002 for the comparison with the transmission of haplotypes not bearing HB*14), whereas their transmission to unaffected siblings was equilibrated. Myasthenia gravis patients also showed a high frequency of microsatellite variants unseen in controls. These findings implicate the CHRNA in susceptibility to myasthenia gravis.
| S-EPMC43849 | biostudies-other
Project description:Background and purposeA major concern with ocular myasthenia gravis (MG) is the potential conversion to generalized MG. This study was conducted to determine if the repetitive nerve stimulation (RNS) test could predict the conversion from ocular to generalized MG.MethodsThe RNS test was conducted in a consistent manner on five muscles in the face and limbs in every patient. Subjects were divided into those who remained as ocular MG (ROMG group) and those who experienced conversion to generalized MG during follow-up (GOMG group).ResultsConversion to generalized MG occurred in 24 (21.4%) of 112 MG patients with ocular onset. The proportion of patients displaying abnormal decreases in responses in the trapezius, abductor digiti minimi, or flexor carpi ulnaris muscles on the RNS test was higher in the GOMG group (p<0.001, p=0.002, and p<0.001, respectively). The Cox proportional-hazards model revealed that an abnormal result on the RNS test was significantly associated with conversion to generalized MG [hazard ratio (HR)=3.13, 95% confidence interval (CI)=1.18-8.32]. Notably, the HR was higher for abnormal results on the RNS test for the limb muscles, at 5.19 (95% CI=2.09-12.90).ConclusionsAn abnormal result on the RNS test, especially in the limb muscles, is an independent predictor of the conversion from ocular to generalized MG. Applying the RNS test to limb muscles could be useful for predicting the conversion to generalized MG in patients with ocular onset.
| S-EPMC8053540 | biostudies-literature
Project description:ImportanceUse of biologic agents in generalized myasthenia gravis is generally limited to therapy-refractory cases; benefit in new-onset disease is unknown.ObjectiveTo assess rituximab in refractory and new-onset generalized myasthenia gravis and rituximab vs conventional immunotherapy in new-onset disease.Design, setting, and participantsA retrospective cohort study with prospectively collected data was conducted on a county-based community sample at Karolinska University Hospital, Stockholm, Sweden. Participants included 72 patients with myasthenia gravis, excluding those displaying muscle-specific tyrosine kinase antibodies, initiating rituximab treatment from January 1, 2010, to December 31, 2018, and patients with new-onset disease initiating conventional immunotherapy from January 1, 2003, to December 31, 2012, with 12 months or more of observation time. The present study was conducted from March 1, 2019, to January 31, 2020.ExposuresTreatment with low-dose rituximab (most often 500 mg every 6 months) or conventional immunosuppressants.Main outcomes and measuresTime to remission (main outcome) as well as use of rescue therapies or additional immunotherapies and time in remission (secondary outcomes).ResultsOf the 72 patients included, 31 patients (43%) were women; mean (SD) age at treatment start was 60 (18) years. Twenty-four patients had received rituximab within 12 months of disease onset and 48 received rituximab at a later time, 34 of whom had therapy-refractory disease. A total of 26 patients (3 [12%] women; mean [SD] age, 68 [11] years at treatment start) received conventional immunosuppressant therapy. Median time to remission was shorter for new-onset vs refractory disease (7 vs 16 months: hazard ratio [HR], 2.53; 95% CI, 1.26-5.07; P = .009 after adjustment for age, sex, and disease severity) and for rituximab vs conventional immunosuppressant therapies (7 vs 11 months: HR, 2.97; 95% CI, 1.43-6.18; P = .004 after adjustment). In addition, fewer rescue therapy episodes during the first 24 months were required (mean [SD], 0.38 [1.10] vs 1.31 [1.59] times; mean difference, -1.26; 95% CI, -1.97 to -0.56; P < .001 after adjustment), and a larger proportion of patients had minimal or no need of additional immunotherapies (70% vs 35%; OR, 5.47; 95% CI, 1.40-21.43; P = .02 after adjustment). Rates of treatment discontinuation due to adverse events were lower with rituximab compared with conventional therapies (3% vs 46%; P < .001 after adjustment).Conclusions and relevanceClinical outcomes with rituximab appeared to be more favorable in new-onset generalized myasthenia gravis, and rituximab also appeared to perform better than conventional immunosuppressant therapy. These findings suggest a relatively greater benefit of rituximab earlier in the disease course. A placebo-controlled randomized trial to corroborate these findings is warranted.
| S-EPMC7199182 | biostudies-literature