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Mendelian randomization and colocalization analysis reveal novel drug targets for myasthenia gravis.Human Genomics Apr 2024Myasthenia gravis (MG) is a complex autoimmune disease affecting the neuromuscular junction with limited drug options, but the field of MG treatment recently benefits...
OBJECTIVE
Myasthenia gravis (MG) is a complex autoimmune disease affecting the neuromuscular junction with limited drug options, but the field of MG treatment recently benefits from novel biological agents. We performed a drug-targeted Mendelian randomization (MR) study to identify novel therapeutic targets of MG.
METHODS
Cis-expression quantitative loci (cis-eQTL), which proxy expression levels for 2176 druggable genes, were used for MR analysis. Causal relationships between genes and disease, identified by eQTL MR analysis, were verified by comprehensive sensitivity, colocalization, and protein quantitative loci (pQTL) MR analyses. The protein-protein interaction (PPI) analysis was also performed to extend targets, followed by enzyme-linked immunosorbent assay (ELISA) to explore the serum level of drug targets in MG patients. A phenome-wide MR analysis was then performed to assess side effects with a clinical trial review assessing druggability.
RESULTS
The eQTL MR analysis has identified eight potential targets for MG, one for early-onset MG and seven for late-onset MG. Further colocalization analyses indicated that CD226, CDC42BPB, PRSS36, and TNFSF12 possess evidence for colocalization with MG or late-onset MG. pQTL MR analyses identified the causal relations of TNFSF12 and CD226 with MG and late-onset MG. Furthermore, PPI analysis has revealed the protein interaction between TNFSF12-TNFSF13(APRIL) and TNFSF12-TNFSF13B(BLyS). Elevated TNFSF13 serum level of MG patients was also identified by ELISA experiments. This study has ultimately proposed three promising therapeutic targets (TNFSF12, TNFSF13, TNFSF13B) of MG.
CONCLUSIONS
Three drug targets associated with the BLyS/APRIL pathway have been identified. Multiple biological agents, including telitacicept and belimumab, are promising for MG therapy.
Topics: Humans; Myasthenia Gravis; Mendelian Randomization Analysis; Quantitative Trait Loci; Protein Interaction Maps; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide
PubMed: 38659056
DOI: 10.1186/s40246-024-00607-7 -
Journal of Medical Case Reports Sep 2023Myasthenia gravis is an autoimmune condition affecting the neuromuscular junction and causing muscle weakness along with fatigue (myasthenia). When the clinical...
BACKGROUND
Myasthenia gravis is an autoimmune condition affecting the neuromuscular junction and causing muscle weakness along with fatigue (myasthenia). When the clinical manifestations of myasthenia gravis are isolated to the eye muscles, only causing weak eye movements, it is referred to as ocular myasthenia gravis, which can mimic a 1 and ½ syndrome.
CASE PRESENTATION
An African-American female in her fifties with past medical history of hypertension presented to our outpatient clinic with complaints of blurred vision for two weeks. Her symptoms were associated with facial discomfort and a generalized headache. On physical examination upon her initial presentation, there was demonstratable swelling of the left upper eyelid with drooping. Her extraocular movements revealed defects with the abduction and adduction of the right eye, and the left eye would not adduct, although the outward movement was normal. The left eye failed to lift/elevate completely when looking upwards, a pseudo 1 and ½ syndrome. A positive Cogan lid twitch was also noticed. Imaging of the brain and orbit ruled out central causes. Diagnosis of ocular myasthenia gravis was made in accordance with positive anti-acetylcholine receptor antibodies. With 120 mg pyridostigmine oral dose, the patient experienced improvement subjectively and objectively, and the patient was discharged on oral pyridostigmine and prednisone. Six months later, with prednisone having been tapered off, the patient developed a myasthenic crisis and was treated with plasmapheresis and intravenous immunoglobulins. After recovering from the myasthenic crisis, efgartigimod infusions were instituted, which helped our patient restore normal life.
CONCLUSION
Our patient who presented with "blurred vision" was discovered to have binocular diplopia due to significant dysconjugate eye movements. After diligently ruling out central etiologies, we concluded that her presentation was due to a peripheral etiology. Her serologies and her presentation helped confirm a diagnosis of ocular myasthenia gravis. Also, as in most cases, our patient also progressed to develop generalized myasthenia gravis while on pyridostigmine. Efgartigimod infusions instituted after our patient recovered from a myasthenic crisis have helped her restore a normal life.
Topics: Female; Humans; Diplopia; Pyridostigmine Bromide; Prednisone; Vision Disorders; Myasthenia Gravis; Muscle Weakness
PubMed: 37679826
DOI: 10.1186/s13256-023-04089-4 -
Neurologia Sep 2021
Review
Topics: Humans; Lupus Erythematosus, Systemic; Myasthenia Gravis
PubMed: 34175261
DOI: 10.1016/j.nrleng.2020.08.017 -
Muscle & Nerve Jan 2023Within the last 5 years, the US Food and Drug Administration (FDA) has approved complement and neonatal Fc receptor (FcRN) inhibitors for treatment of generalized...
Within the last 5 years, the US Food and Drug Administration (FDA) has approved complement and neonatal Fc receptor (FcRN) inhibitors for treatment of generalized myasthenia gravis, and several other therapies are in late-stage clinical trials or under regulatory review. However, questions about which patients are most likely to benefit from which therapies, and the relative effectiveness of these very expensive drugs, has resulted in uncertainty around the place that they should occupy in the existing therapeutic armamentarium. MGNet (a Rare Diseases Clinical Research Consortium funded by the National Institute of Neurological Diseases and Stroke) held two meetings during the 14th International Conference of the Myasthenia Gravis Foundation of America to discuss the most critical needs for clinical trial readiness and biomarker development in the context of therapy development for myasthenia gravis. Herein we provide a summary of these discussions, but not a consensus opinion, and offer a series of recommendations to guide focused research in the most critical areas. We welcome ongoing discussion through comments on this work.
Topics: United States; Infant, Newborn; Humans; Myasthenia Gravis; Longitudinal Studies
PubMed: 36321730
DOI: 10.1002/mus.27742 -
Cureus Jul 2023Pembrolizumab is a monoclonal antibody frequently used as immunotherapy for lung cell carcinoma that has been reported to cause hypothyroidism and myasthenia gravis...
Pembrolizumab is a monoclonal antibody frequently used as immunotherapy for lung cell carcinoma that has been reported to cause hypothyroidism and myasthenia gravis among other, unwanted side effects. Here, we present an interesting case of a 77-year-old male previously diagnosed with lung adenocarcinoma managed with pembrolizumab. Initially, he was admitted after a mechanical fall sustaining a facial laceration and subacute fracture in the nasal bone. However, during the workup, thyroid-stimulating hormone (TSH) was found to be elevated, which was attributed to the history of pembrolizumab usage.
PubMed: 37457610
DOI: 10.7759/cureus.41889 -
Frontiers in Immunology 2021Myasthenia gravis (MG) is an autoimmune disease primarily mediated by acetylcholine receptor antibodies (AChR-Ab), cellular immune dependence, and complement system... (Review)
Review
Myasthenia gravis (MG) is an autoimmune disease primarily mediated by acetylcholine receptor antibodies (AChR-Ab), cellular immune dependence, and complement system involvement. Since the AChR on the postsynaptic membrane is destroyed by an immune attack, sufficient endplate potential cannot be generated, resulting in the development of a synaptic transmission disorder at the neuromuscular junction and in muscle weakness. The role of the complement system in MG has been demonstrated in animal models and clinical tests, and it has been determined that complement inhibition in patients with MG can prevent disease induction and reverse its progression. Eculizumab is a humanized monoclonal antibody that inhibits the cleavage of complement protein C5 and prevents autoimmune damage; additionally, it has received subsequent approval by the Federal Drug Administration of the United States for MG treatment. However, various concerns regarding the use of eculizumab persist. In this review, we have discussed the treatment time, cost effectiveness, long-term efficacy, and tolerability of eculizumab for MG treatment. We have also summarized historical information and have presented perspectives on this new therapeutic modality.
Topics: Animals; Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Combined Modality Therapy; Complement Inactivating Agents; Complement System Proteins; Disease Management; Disease Susceptibility; Drug Development; Humans; Myasthenia Gravis; Treatment Outcome
PubMed: 34456922
DOI: 10.3389/fimmu.2021.715036 -
Brain Communications 2022Myasthenia gravis is an autoimmune disease affecting neuromuscular transmission and causing skeletal muscle weakness. Additionally, systemic inflammation, cognitive...
Myasthenia gravis is an autoimmune disease affecting neuromuscular transmission and causing skeletal muscle weakness. Additionally, systemic inflammation, cognitive deficits and autonomic dysfunction have been described. However, little is known about myasthenia gravis-related reorganization of the brain. In this study, we thus investigated the structural and functional brain changes in myasthenia gravis patients. Eleven myasthenia gravis patients (age: 70.64 ± 9.27; 11 males) were compared to age-, sex- and education-matched healthy controls (age: 70.18 ± 8.98; 11 males). Most of the patients ( = 10, 0.91%) received cholinesterase inhibitors. Structural brain changes were determined by applying voxel-based morphometry using high-resolution T-weighted sequences. Functional brain changes were assessed with a neuropsychological test battery (including attention, memory and executive functions), a spatial orientation task and brain-derived neurotrophic factor blood levels. Myasthenia gravis patients showed significant grey matter volume reductions in the cingulate gyrus, in the inferior parietal lobe and in the fusiform gyrus. Furthermore, myasthenia gravis patients showed significantly lower performance in executive functions, working memory (Spatial Span, = 0.034, = 1.466), verbal episodic memory ( = 0.003, = 1.468) and somatosensory-related spatial orientation (Triangle Completion Test, = 0.003, = 1.200). Additionally, serum brain-derived neurotrophic factor levels were significantly higher in myasthenia gravis patients (= 0.001, = 2.040). Our results indicate that myasthenia gravis is associated with structural and functional brain alterations. Especially the grey matter volume changes in the cingulate gyrus and the inferior parietal lobe could be associated with cognitive deficits in memory and executive functions. Furthermore, deficits in somatosensory-related spatial orientation could be associated with the lower volumes in the inferior parietal lobe. Future research is needed to replicate these findings independently in a larger sample and to investigate the underlying mechanisms in more detail.
PubMed: 35198977
DOI: 10.1093/braincomms/fcac018 -
Acta Neurologica Scandinavica Sep 2021To describe presenting symptoms, clinical outcomes, and therapeutic management of concurrent Coronavirus disease 2019 (COVID-19) infections in patients with a...
OBJECTIVE
To describe presenting symptoms, clinical outcomes, and therapeutic management of concurrent Coronavirus disease 2019 (COVID-19) infections in patients with a pre-existing myasthenia gravis (MG).
METHODS
We conducted a retrospective study in patients with preexisting MG presenting with concurrent COVID-19 between September 21st and November 4th, 2020 when attending the emergency department or routine neurology consultation at the National Institute Mongi Ben Hamida of Neurology of Tunis, Tunisia.
RESULTS
Five patients were identified. The Myasthenia Gravis Foundation of America scores (MGFA) prior to COVID-19 infection were class I in one patient, class II (IIa, IIb) in two patients, and class IIIb in one patient. Four patients had mild to moderate courses of COVID-19 infection. One patient presented a critical infection with acute respiratory disease syndrome (ARDS) requiring mechanical ventilation. Two of them also demonstrated signs of MG exacerbation requiring the use of intravenous immunoglobulin in one case. We maintained immunosuppressant therapy to MG in all our patients. All our patients received Azithromycin (AZM) as a part of specific drug treatment of COVID-19 infection. Outcome was favorable in 4 patients and rapidly fatal evolution was observed in the patient with ADRS.
DISCUSSIONS AND CONCLUSION
The results from our study suggest that prior MG activity could partially influence the subsequent clinical outcomes. It emerged also that ongoing long-term immunosuppressive immunotherapy to MG should be maintained during the COVID-19 pandemic and that AZM can be used safely in MG patients and concurrent COVID-19 infection.
Topics: Adult; COVID-19; Female; Humans; Male; Middle Aged; Myasthenia Gravis; Retrospective Studies; SARS-CoV-2; Tunisia
PubMed: 33914898
DOI: 10.1111/ane.13440 -
Journal of Cardiothoracic Surgery Dec 2022The study's goal was to investigate the percentage of anxiety and depression in Chinese thymoma patients before surgery, and also the factors that influence it.
BACKGROUND
The study's goal was to investigate the percentage of anxiety and depression in Chinese thymoma patients before surgery, and also the factors that influence it.
METHODS
The study included patients who had an anterior mediastinal mass discovered by chest CT and were scheduled for video-assisted thoracoscopic surgery. The mental health rating scales were completed by all patients before surgery. Patients were divided into two groups based on the Hospital Anxiety and Depression Scale (HADS): anxiety/depression and non-anxiety/depression. The association between thymoma clinical factors and the HADS score was studied statistically.
RESULTS
The study comprised eighty patients with thymoma. Before the operation, 22.5% (18/80) of the patients had anxiety and/or depression. The resigned coping style characteristics, along with myasthenia gravis (MG), were associated with preoperative anxiety and depression. The greater the score of the resigned dimension, the greater the risk of anxiety and depression, based on the results of logical regression analysis. Thymoma patients with myasthenia gravis have a higher risk of anxiety and depression.
CONCLUSION
Patients with myasthenia gravis and resigned coping style were found to have higher anxiety and depression before surgery for Chinese thymoma patients.
Topics: Humans; Thymoma; Thymectomy; Depression; Thymus Neoplasms; Myasthenia Gravis; Thoracic Surgery, Video-Assisted
PubMed: 36527139
DOI: 10.1186/s13019-022-02081-5 -
European Radiology Jul 2024It is uncertain whether modern iodine-based or gadolinium-based contrast media (CM) administration can lead to increased symptoms in patients with myasthenia gravis. (Review)
Review
OBJECTIVES
It is uncertain whether modern iodine-based or gadolinium-based contrast media (CM) administration can lead to increased symptoms in patients with myasthenia gravis.
METHODS
A systematic search in Medline was conducted for studies describing the symptomatology of myasthenia gravis patients before and after receiving intravenous (IV) CM and having a matched control group of myasthenia gravis patients who did not receive IV CM.
RESULTS
Three retrospective studies were selected with a total of 374 myasthenia gravis patients who received iodine-based CM and a total of 313 myasthenia gravis patients who underwent unenhanced CT and served as controls. Pooling of the data from the three retrospective studies showed that in 23 of 374 patients, increased symptoms after iodine-based CM administration were described (6.1%). Increased symptomatology also occurred in 11 of 313 patients after unenhanced CT (3.5%). When looking more deeply into the data of the three studies, conflicting results were found, as two articles did not find any relationship between CM and myasthenia gravis symptoms. The remaining study only found a significant increase in symptomatology within 1 day after CT scanning: seven patients (6.3%) in the contrast-enhanced CT group and one patient (0.6%) in the unenhanced CT group (p = 0.01).
CONCLUSIONS
There is limited evidence on the relationship between CM and myasthenia gravis symptoms. In the vast majority of myasthenia gravis patients, CM are safe. Probably, in less than 5% of the patients, iodine-based CM administration may lead to increased severity of the symptoms within the first 24 h after administration.
CLINICAL RELEVANCE STATEMENT
Be aware that intravenous administration of iodine-based contrast media can lead to an increase of symptoms in patients with myasthenia gravis within the first 24 h. This can probably happen in less than 5% of the patients.
KEY POINTS
• It is unclear whether modern contrast media can lead to increased symptoms in myasthenia gravis patients after intravenous administration. • There seems to be a small risk of increased myasthenia gravis symptoms within 24 h after intravenous administration of iodine-based contrast media, probably in less than 5% of the administrations. • Gadolinium-based contrast media are safe for patients with myasthenia gravis.
Topics: Myasthenia Gravis; Humans; Contrast Media; Tomography, X-Ray Computed; Gadolinium; Practice Guidelines as Topic; Europe; Iodine
PubMed: 38092951
DOI: 10.1007/s00330-023-10463-z