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Therapeutic Advances in Neurological... 2023Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes (CMS) represent an etiologically heterogeneous group of (very) rare... (Review)
Review
Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes (CMS) represent an etiologically heterogeneous group of (very) rare chronic diseases. MG and LEMS have an autoimmune-mediated etiology, while CMS are genetic disorders. A (strain dependent) muscle weakness due to neuromuscular transmission disorder is a common feature. Generalized MG requires increasingly differentiated therapeutic strategies that consider the enormous therapeutic developments of recent years. To include the newest therapy recommendations, a comprehensive update of the available German-language guideline 'Diagnostics and therapy of myasthenic syndromes' has been published by the German Neurological society with the aid of an interdisciplinary expert panel. This paper is an adapted translation of the updated and partly newly developed treatment guideline. It defines the rapid achievement of complete disease control in myasthenic patients as a central treatment goal. The use of standard therapies, as well as modern immunotherapeutics, is subject to a staged regimen that takes into account autoantibody status and disease activity. With the advent of modern, fast-acting immunomodulators, disease activity assessment has become pivotal and requires evaluation of the clinical course, including severity and required therapies. Applying MG-specific scores and classifications such as Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Foundation of America allows differentiation between mild/moderate and (highly) active (including refractory) disease. Therapy decisions must consider age, thymic pathology, antibody status, and disease activity. Glucocorticosteroids and the classical immunosuppressants (primarily azathioprine) are the basic immunotherapeutics to treat mild/moderate to (highly) active generalized MG/young MG and ocular MG. Thymectomy is indicated as a treatment for thymoma-associated MG and generalized MG with acetylcholine receptor antibody (AChR-Ab)-positive status. In (highly) active generalized MG, complement inhibitors (currently eculizumab and ravulizumab) or neonatal Fc receptor modulators (currently efgartigimod) are recommended for AChR-Ab-positive status and rituximab for muscle-specific receptor tyrosine kinase (MuSK)-Ab-positive status. Specific treatment for myasthenic crises requires plasmapheresis, immunoadsorption, or IVIG. Specific aspects of ocular, juvenile, and congenital myasthenia are highlighted. The guideline will be further developed based on new study results for other immunomodulators and biomarkers that aid the accurate measurement of disease activity.
PubMed: 38152089
DOI: 10.1177/17562864231213240 -
Journal of Neurology Jul 2023Myasthenia gravis (MG) is characterized by muscle weakness caused by autoantibodies that bind to the postsynaptic membrane at the neuromuscular junction and impair... (Review)
Review
Myasthenia gravis (MG) is characterized by muscle weakness caused by autoantibodies that bind to the postsynaptic membrane at the neuromuscular junction and impair acetylcholine receptor function. Weakness of respiratory muscles represents the most severe MG manifestation, and 10-15% of all patients experience an MG crisis with the need of mechanical ventilatory support at least once in their life. MG patients with respiratory muscle weakness need active immunosuppressive drug treatment long term, and they need regular specialist follow-up. Comorbidities affecting respiratory function need attention and optimal treatment. Respiratory tract infections can lead to MG exacerbations and precipitate an MG crisis. Intravenous immunoglobulin and plasma exchange are the core treatments for severe MG exacerbations. High-dose corticosteroids, complement inhibitors, and FcRn blockers represent fast-acting treatments that are effective in most MG patients. Neonatal myasthenia is a transient condition with muscle weakness in the newborn caused by mother's muscle antibodies. In rare cases, treatment of respiratory muscle weakness in the baby is required.
Topics: Infant, Newborn; Humans; Myasthenia Gravis; Neuromuscular Junction; Neuromuscular Diseases; Muscle Weakness; Respiratory Tract Diseases
PubMed: 37101094
DOI: 10.1007/s00415-023-11733-y -
Frontiers in Neurology 2023Myasthenia gravis (MG) is a chronic autoimmune disease mediated by antibodies against post-synaptic proteins of the neuromuscular junction. Up to 10%-30% of patients are... (Review)
Review
Myasthenia gravis (MG) is a chronic autoimmune disease mediated by antibodies against post-synaptic proteins of the neuromuscular junction. Up to 10%-30% of patients are refractory to conventional treatments. For these patients, rituximab has been used off-label in the recent decades. Rituximab is a monoclonal antibody against the CD20 protein that leads to B cell depletion and to the synthesis of new antibody-secreting plasma cells. Although rituximab was created to treat B-cell lymphoma, its use has widely increased to treat autoimmune diseases. In MG, the benefit of rituximab treatment in MuSK-positive patients seems clear, but a high variability in the results of observational studies and even clinical trials has been reported for AChR-positive patients. Moreover, few evidence has been reported in seronegative MG and juvenile MG and some questions about regimen of administration or monitoring strategies, remains open. In this review, we intend to revise the available literature on this topic and resume the current evidence of effectiveness of Rituximab in MG, with special attention to results on every MG subtype, as well as the administration protocols, monitoring strategies and safety profile of the drug.
PubMed: 37849836
DOI: 10.3389/fneur.2023.1275533 -
Neural Regeneration Research Aug 2023Myasthenia gravis is an acquired, humoral immunity-mediated autoimmune disease characterized by the production of autoantibodies that impair synaptic transmission at the... (Review)
Review
Myasthenia gravis is an acquired, humoral immunity-mediated autoimmune disease characterized by the production of autoantibodies that impair synaptic transmission at the neuromuscular junction. The intervention-mediated clearance of immunoglobulin G (IgG) was shown to be effective in controlling the progression of the disease. The neonatal Fc receptor (FcRn) plays a key role in prolonging the serum half-life of IgG. Antagonizing FcRn to prevent its binding to IgG can accelerate the catabolism of the latter, resulting in decreased levels of IgG, including pathogenic autoantibodies, thereby achieving a therapeutic effect. In this review, we detail the substantial research progress, both basic and clinical, relating to the use of FcRn inhibitors in the treatment of myasthenia gravis.
PubMed: 36751773
DOI: 10.4103/1673-5374.363824 -
Journal of Neurology Aug 2023Ravulizumab demonstrated efficacy and an acceptable safety profile versus placebo in the randomized controlled period (RCP) of the phase 3 CHAMPION MG trial in patients...
Long-term efficacy and safety of ravulizumab in adults with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis: results from the phase 3 CHAMPION MG open-label extension.
INTRODUCTION
Ravulizumab demonstrated efficacy and an acceptable safety profile versus placebo in the randomized controlled period (RCP) of the phase 3 CHAMPION MG trial in patients with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis. We report an interim analysis of the ongoing open-label extension (OLE) designed to evaluate long-term treatment effects.
METHODS
Following completion of the 26-week RCP, patients could enter the OLE; patients who received ravulizumab in the RCP continued the drug; patients who previously received placebo switched to ravulizumab. Patients receive body-weight-based maintenance dosing of ravulizumab every 8 weeks. Efficacy endpoints up to 60 weeks included Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores, with least-squares (LS) mean change and 95% confidence intervals (95% CI) reported.
RESULTS
Long-term efficacy and safety in the OLE were analyzed in 161 and 169 patients, respectively. Improvements in all scores were maintained through 60 weeks in patients who received ravulizumab during the RCP; LS mean change from RCP baseline in MG-ADL score was - 4.0 (95% CI: - 4.8, - 3.1; p < 0.0001). Rapid (within 2 weeks) and sustained improvements occurred in patients previously receiving placebo; LS mean change in MG-ADL score from OLE baseline to Week 60 was - 1.7 (95% CI: - 2.7, - 0.8; p = 0.0007). Similar trends were seen in QMG scores. Ravulizumab treatment was associated with a decreased rate of clinical deterioration events compared with placebo. Ravulizumab was well tolerated; no meningococcal infections were reported.
CONCLUSION
Findings support the sustained efficacy and long-term safety of ravulizumab, administered every 8 weeks, in adults with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis.
CLINICALTRIALS
gov identifier: NCT03920293; EudraCT: 2018-003243-39.
Topics: Adult; Humans; Activities of Daily Living; Autoantibodies; Myasthenia Gravis; Receptors, Cholinergic; Treatment Outcome
PubMed: 37103755
DOI: 10.1007/s00415-023-11699-x -
Cureus Dec 2023Myasthenia gravis (MG), a rare disease, is the most common neuromuscular junction problem. It's the quintessential autoimmune disease with ocular, bulbar, respiratory,... (Review)
Review
Myasthenia gravis (MG), a rare disease, is the most common neuromuscular junction problem. It's the quintessential autoimmune disease with ocular, bulbar, respiratory, axial, and limb muscles exhibiting a typical fatigable weakening due to the development of antibodies against the acetylcholine receptor (AChR). Infections, stress, surgeries, thymus gland anomalies, and pharmaceutical side effects can also cause it. Ocular symptoms are initially experienced by most of the sufferers. The majority of the sufferers will go through at least one episode of symptom exacerbation during their illness. The immune system in MG interferes with nerve-muscle communication, causing muscles to become weak and tired quickly. The actual cause is not yet known, but a problem in the thymus gland may be the cause. In a person suffering from this disease, the size of the thymus becomes larger than normal, which is also called thymic hyperplasia. It is more common for women to have early-onset MG (EOMG) than for males to have late-onset MG (LOMG). Merely clinical evidence, encompassing the patients' medical history and physical indications of fluctuating muscle weakness in a specific region, is utilized to diagnose MG. Complementary diagnostic procedures and lab techniques aid in confirming the synaptic dysfunction and characterizing its kind and degree. Early diagnosis and the availability of effective treatments have reduced the burden of severe impairment and high mortality previously associated with MG. Current immunomodulation-based therapies come with side effects brought on by persistent immune suppression. Improved knowledge of this relatively uncommon but curable condition is required among primary carers. The objective of this review is to provide information about MG and to help people recognize its symptoms and start treatment without panic so that the progression of this disease can be stopped and complications can be avoided.
PubMed: 38186498
DOI: 10.7759/cureus.50017 -
RMD Open Nov 2023Autoimmune disorders occur when immune cells go wrong and attack the body's own tissues. Currently, autoimmune disorders are largely treated by broad immunosuppressive... (Review)
Review
Autoimmune disorders occur when immune cells go wrong and attack the body's own tissues. Currently, autoimmune disorders are largely treated by broad immunosuppressive agents and blocking antibodies, which can manage the diseases but often are not curative. Thus, there is an urgent need for advanced therapies for patients suffering from severe and refractory autoimmune diseases, and researchers have considered cell therapy as potentially curative approach for several decades. In the wake of its success in cancer therapy, adoptive transfer of engineered T cells modified with chimeric antigen receptors (CAR) for target recognition could now become a therapeutic option for some autoimmune diseases. Here, we review the ongoing developments with CAR T cells in the field of autoimmune disorders. We will cover first clinical results of applying anti-CD19 and anti-B cell maturation antigen CAR T cells for B cell elimination in systemic lupus erythematosus, refractory antisynthetase syndrome and myasthenia gravis, respectively. Furthermore, in preclinical models, researchers have also developed chimeric autoantibody receptor T cells that can eliminate individual B cell clones producing specific autoantibodies, and regulatory CAR T cells that do not eliminate autoreactive immune cells but dampen their wrong activation. Finally, we will address safety and manufacturing aspects for CAR T cells and discuss mRNA technologies and automation concepts for ensuring the future availability of safe and efficient CAR T cell products.
Topics: Humans; Immunotherapy, Adoptive; T-Lymphocytes; Receptors, Chimeric Antigen; Autoimmune Diseases
PubMed: 37996128
DOI: 10.1136/rmdopen-2022-002907 -
Arthritis Research & Therapy Aug 2023In addition to decreasing the level of cholesterol, proprotein convertase subtilis kexin 9 (PCSK9) inhibitor has pleiotropic effects, including immune regulation....
BACKGROUND
In addition to decreasing the level of cholesterol, proprotein convertase subtilis kexin 9 (PCSK9) inhibitor has pleiotropic effects, including immune regulation. However, the impact of PCSK9 on autoimmune diseases is controversial. Therefore, we used drug target Mendelian randomization (MR) analysis to investigate the effect of PCSK9 inhibitor on different autoimmune diseases.
METHODS
We collected single nucleotide polymorphisms (SNPs) of PCSK9 from published genome-wide association studies statistics and conducted drug target MR analysis to detect the causal relationship between PCSK9 inhibitor and the risk of autoimmune diseases. 3-Hydroxy-3-methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitor, the drug target of statin, was used to compare the effect with that of PCSK9 inhibitor. With the risk of coronary heart disease as a positive control, primary outcomes included the risk of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), myasthenia gravis (MG), multiple sclerosis (MS), asthma, Crohn's disease (CD), ulcerative colitis (UC), and type 1 diabetes (T1D).
RESULTS
PCSK9 inhibitor significantly reduced the risk of SLE (OR [95%CI] = 0.47 [0.30 to 0.76], p = 1.74 × 10) but increased the risk of asthma (OR [95%CI] = 1.15 [1.03 to 1.29], p = 1.68 × 10) and CD (OR [95%CI] = 1.38 [1.05 to 1.83], p = 2.28 × 10). In contrast, HMGCR inhibitor increased the risk of RA (OR [95%CI] = 1.58 [1.19 to 2.11], p = 1.67 × 10), asthma (OR [95%CI] = 1.21 [1.04 to 1.40], p = 1.17 × 10), and CD (OR [95%CI] = 1.60 [1.08 to 2.39], p = 2.04 × 10).
CONCLUSIONS
PCSK9 inhibitor significantly reduced the risk of SLE but increased the risk of asthma and CD. In contrast, HMGCR inhibitor may be a risk factor for RA, asthma, and CD.
Topics: Humans; Arthritis, Rheumatoid; Genome-Wide Association Study; Lupus Erythematosus, Systemic; Mendelian Randomization Analysis; Proprotein Convertase 9; PCSK9 Inhibitors; Asthma
PubMed: 37580807
DOI: 10.1186/s13075-023-03122-7 -
Drugs Sep 2023Rozanolixizumab (rozanolixizumab-noli; RYSTIGGO) is a high affinity humanized immunoglobulin G4 monoclonal antibody directed against human neonatal Fc receptor (FcRn).... (Review)
Review
Rozanolixizumab (rozanolixizumab-noli; RYSTIGGO) is a high affinity humanized immunoglobulin G4 monoclonal antibody directed against human neonatal Fc receptor (FcRn). Administered subcutaneously, it is being developed by UCB Pharma for the treatment of autoimmune diseases and received its first approval on 27 June 2023 in the USA for the treatment of generalized myasthenia gravis (gMG) in adults who are anti-acetylcholine receptor (AChR) or anti-muscle-specific kinase (MuSK) antibody positive. Rozanolixizumab is the first agent to be approved in the USA for both anti-AChR and anti-MuSK antibody-positive gMG. A regulatory assessment of rozanolixizumab for the treatment of gMG is currently underway in the EU and Japan. Clinical development is ongoing for the treatment of leucine-rich glioma-inactivated 1 autoimmune encephalitis, myelin oligodendrocyte glycoprotein (MOG) antibody disease and severe fibromyalgia syndrome. This article summarizes the milestones in the development of rozanolixizumab leading to this first approval for the treatment of gMG in adults who are anti-AChR or anti-MuSK antibody positive.
Topics: Adult; Infant, Newborn; Humans; Antibodies, Monoclonal, Humanized; Encephalitis; Glioma; Myasthenia Gravis
PubMed: 37656420
DOI: 10.1007/s40265-023-01933-1