RESUMO
Skeletal muscle weakness is a leading cause of mobility disability in the elderly (sarcopenia), as a complication of acute or chronic illness (cachexia), and due to inherited or acquired muscle diseases (muscular dystrophies, myositides, etc.). As of now, there are no approved drugs that can reliably increase muscle strength and function. However, with our understanding of the regulation of myocyte signaling and homeostasis evolving rapidly, experimental treatments are now entering the clinic. We review the current status of clinical research in pharmacological therapies for muscle disorders.
Assuntos
Debilidade Muscular/tratamento farmacológico , Debilidade Muscular/fisiopatologia , Músculo Esquelético/fisiopatologia , HumanosRESUMO
Myasthenia gravis (MG) is an autoimmune disorder caused by target-specific pathogenic antibodies directed toward postsynaptic neuromuscular junction (NMJ) proteins, most commonly the skeletal muscle nicotinic acetylcholine receptor (AChR). In MG, high-affinity anti-AChR Abs binding to the NMJ lead to loss of functional AChRs, culminating in neuromuscular transmission failure and myasthenic symptoms. Intravenous immune globulin (IVIg) has broad therapeutic application in the treatment of a range of autoimmune diseases, including MG, although its mechanism of action is not clear. Recently, the anti-inflammatory and anti-autoimmune activities of IVIg have been attributed to the IgG Fc domains. Soluble immune aggregates bearing intact Fc fragments have been shown to be effective treatment for a number of autoimmune disorders in mice, and fully recombinant multimeric Fc molecules have been shown to be effective in treating collagen-induced arthritis, murine immune thrombocytopenic purpura, and experimental inflammatory neuritis. In this study, a murine model of MG (EAMG) was used to study the effectiveness of this novel recombinant polyvalent IgG2a Fc (M045) in treating established myasthenia, with a direct comparison to treatment with IVIg. M045 treatment had profound effects on the clinical course of EAMG, accompanied by down-modulation of pathogenic antibody responses. These effects were associated with reduced B cell activation and T cell proliferative responses to AChR, an expansion in the population of FoxP3(+) regulatory T cells, and enhanced production of suppressive cytokines, such as IL-10. Treatment was at least as effective as IVIg in suppressing EAMG, even at doses 25-30 fold lower. Multimeric Fc molecules offer the advantages of being recombinant, homogenous, available in unlimited quantity, free of risk from infection and effective at significantly reduced protein loads, and may represent a viable therapeutic alternative to polyclonal IVIg.
Assuntos
Linfócitos B/efeitos dos fármacos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Imunoterapia/métodos , Miastenia Gravis Autoimune Experimental/terapia , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Autoanticorpos/sangue , Linfócitos B/imunologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Humanos , Imunidade Humoral/efeitos dos fármacos , Fragmentos Fc das Imunoglobulinas/genética , Imunoglobulina G/genética , Imunoglobulinas Intravenosas/administração & dosagem , Interleucina-10/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Miastenia Gravis Autoimune Experimental/imunologia , Receptores Colinérgicos/imunologia , Proteínas Recombinantes/genética , Linfócitos T Reguladores/imunologiaRESUMO
BACKGROUND: Increased morbidity in many patients with myasthenia gravis (MG) on long-term immunosuppression highlights the need for improved treatments. The aim of this study is to investigate the safety and efficacy of iscalimab (CFZ533), a fully human anti-CD40 monoclonal antibody, in patients with moderate-to-severe MG receiving standard-of-care (SoC) therapies. METHODS: In this double-blind, placebo-controlled phase 2 study, symptomatic patients (n = 44) despite SoC were randomized 1:1 to receive intravenous iscalimab (10 mg/kg; n = 22) or placebo (n = 22) every 4 weeks for 6 doses in total. Patients were followed up for 6 months after the last dose. The total duration of the study was 52 weeks. RESULTS: In total, 34 of 44 patients (77.3 %) completed the study. The primary endpoint, Quantitative MG score, did not change significantly between baseline and week 25 for iscalimab (median [90 % CI], -4.07 [-5.67, -2.47]) versus placebo (-2.93 [-4.53, -1.33]); however, non-thymectomized patients (n = 29) showed more favorable results (iscalimab, -4.35 [-6.07, -2.64] vs placebo, -2.26 [-4.16, -0.36]). A statistically significant difference between iscalimab and placebo groups was observed in MG Composite score (adjusted mean change: -4.19 [-6.67, -1.72]; p = 0.007) at week 13, and MG-Activities of Daily Living score (-1.93 [-3.24, -0.62]; p = 0.018) at week 21. Adverse events were comparable between the iscalimab (91 %) and placebo (96 %) groups. CONCLUSION: Iscalimab showed favorable safety and improvements compared with placebo in non-thymectomized patients with moderate-to-severe MG. It did not show any protective effect in patients with moderate-to-severe MG.
Assuntos
Atividades Cotidianas , Miastenia Gravis , Humanos , Resultado do Tratamento , Anticorpos Monoclonais/efeitos adversos , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/induzido quimicamente , Método Duplo-CegoRESUMO
Previous studies have reported alterations in numbers or function of regulatory T (Treg) cells in myasthenia gravis (MG) patients, but published results have been inconsistent, likely due to the isolation of heterogenous "Treg" populations. In this study, we used surface CD4, CD25(high), and CD127(low/-) expression to isolate a relatively pure population of Tregs, and established that there was no alteration in the relative numbers of Tregs within the peripheral T cell pool in MG patients. In vitro proliferation assays, however, demonstrated that Treg-mediated suppression of responder T (Tresp) cells was impaired in MG patients and was associated with a reduced expression of FOXP3 in isolated Tregs. Suppression of both polyclonal and AChR-activated Tresp cells from MG patients could be restored using Tregs isolated from healthy controls, indicating that the defect in immune regulation in MG is primarily localized to isolated Treg cells, and revealing a potential novel therapeutic target.
Assuntos
Miastenia Gravis/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Células Apresentadoras de Antígenos/imunologia , Antígenos CD4/metabolismo , Estudos de Casos e Controles , Separação Celular , Citocinas/biossíntese , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Humanos , Técnicas In Vitro , Interleucina-10/biossíntese , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/genética , Miastenia Gravis/metabolismo , Receptores Colinérgicos/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo , Adulto JovemRESUMO
INTRODUCTION: In this study we describe a patient with a prolonged myasthenic crisis refractory to conventional immunomodulatory therapy who was treated with GM-CSF (granulocyte macrophage colony-stimulating factor, sargramostim). METHODS: T-regulatory cell (Treg) suppressive function and Foxp3 expression were evaluated before and after treatment with GM-CSF. RESULTS: Treatment with GM-CSF was associated with clinical improvement, expansion in the circulating numbers of Foxp3(+) cells, increase in Foxp3 expression levels in Tregs, early improvement in Treg suppressive capacity for AChR-α-induced T-cell proliferation, and subsequent enhancement in Treg suppression of polyclonal T-cell proliferation. CONCLUSION: Although definitive conclusions cannot be drawn from a single case, the correlation with similar findings in GM-CSF-treated animals with experimental autoimmune myasthenia gravis suggests further exploration of the effects of GM-CSF in myasthenia gravis should be studied in a clinical trial setting.
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Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Miastenia Gravis/tratamento farmacológico , Linfócitos T Reguladores/efeitos dos fármacos , Idoso , Proliferação de Células/efeitos dos fármacos , Fatores de Transcrição Forkhead/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Masculino , Miastenia Gravis/imunologia , Miastenia Gravis/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Resultado do TratamentoRESUMO
The recommendations for clinical research standards published in 2000 by a task force of the Medical Scientific Advisory Board (MSAB) of the Myasthenia Gravis Foundation of America (MGFA) were largely successful in introducing greater uniformity in the recording and reporting of MG clinical trials. Recognizing that changes in clinical trial design and implementation may increase the likelihood that new therapies are developed for MG, the MGFA MSAB Task Force here presents updated recommendations for the design and implementation of clinical trials in MG, including (a) the use of a quantitative measure, such as the MG-Composite, that is weighted for clinical significance and incorporates patient reported outcomes; (b) consideration of nontrial strategies; and (c) development of biomarkers that support mechanistic studies of pharmacotherapies. The hope is that these updated task force recommendations will expedite the development and acceptance of more effective and less noxious therapies for MG.
Assuntos
Ensaios Clínicos como Assunto/normas , Miastenia Gravis/terapia , Projetos de Pesquisa/normas , Comitês Consultivos , Biomarcadores , Humanos , Avaliação de Resultados em Cuidados de Saúde , Sociedades Médicas , Estados UnidosRESUMO
Mutations in LMNA cause a variety of diseases affecting striated muscle including autosomal Emery-Dreifuss muscular dystrophy (EDMD), LMNA-associated congenital muscular dystrophy (L-CMD), and limb-girdle muscular dystrophy type 1B (LGMD1B). Here, we describe novel and recurrent LMNA mutations identified in 50 patients from the United States and Canada, which is the first report of the distribution of LMNA mutations from a large cohort outside Europe. This augments the number of LMNA mutations known to cause EDMD by 16.5%, equating to an increase of 5.9% in the total known LMNA mutations. Eight patients presented with either p.R249W/Q or p.E358K mutations and an early onset EDMD phenotype: two mutations recently associated with L-CMD. Importantly, 15 mutations are novel and include eight missense mutations (p.R189P, p.F206L, p.S268P, p.S295P, p.E361K, p.G449D, p.L454P, and p.W467R), three splice site mutations (c.IVS4 + 1G>A, c.IVS6 - 2A>G, and c.IVS8 + 1G>A), one duplication/in frame insertion (p.R190dup), one deletion (p.Q355del), and two silent mutations (p.R119R and p.K270K). Analysis of 4 of our lamin A mutations showed that some caused nuclear deformations and lamin B redistribution in a mutation specific manner. Together, this study significantly augments the number of EDMD patients on the database and describes 15 novel mutations that underlie EDMD, which will contribute to establishing genotype-phenotype correlations.
Assuntos
Análise Mutacional de DNA , Lamina Tipo A/genética , Distrofia Muscular de Emery-Dreifuss/genética , Sequência de Aminoácidos , Animais , Canadá , Linhagem Celular , Humanos , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Alinhamento de Sequência , Estados UnidosRESUMO
Every year, influenza virus infection causes significant mortality and morbidity in human populations. Although egg-based inactivated viral vaccines are available, their effectiveness depends on the correct prediction of the circulating viral strains and is limited by the time constraint of the manufacturing process. Recombinant subunit vaccines are easier to manufacture with a relatively short lead time but are limited in their efficacy partly because the purified recombinant membrane proteins in the soluble form most likely do not retain their native membrane-bound structure. Nanodisc (ND) particles are soluble, stable, and reproducibly prepared discoid shaped nanoscale structures that contain a discrete lipid bilayer bound by two amphipathic scaffold proteins. Because ND particles permit the functional reconstitution of membrane/envelope proteins, we incorporated recombinant hemagglutinin (HA) from influenza virus strain A/New Caledonia/20/99 (H1N1) into NDs and investigated their potential to elicit an immune response to HA and confer immunity to influenza virus challenge relative to the commercial vaccines Fluzone and FluMist. HA-ND vaccination induced a robust anti-HA antibody response consisting of predominantly the immunoglobulin G1 (IgG1) subclass and a high hemagglutination inhibition titer. Intranasal immunization with HA-ND induced an anti-HA IgA response in nasal passages. HA-ND vaccination conferred protection that was comparable to that of Fluzone and FluMist against challenge with influenza virus strain A/Puerto Rico/8/1934 (H1N1).
Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/administração & dosagem , Imunidade Humoral , Vacinas contra Influenza/imunologia , Nanopartículas/uso terapêutico , Infecções por Orthomyxoviridae/prevenção & controle , Animais , Anticorpos Antivirais/biossíntese , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/uso terapêutico , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Proteínas de Membrana/uso terapêutico , Camundongos , Nanopartículas/química , Infecções por Orthomyxoviridae/imunologia , Fosfolipídeos/uso terapêuticoRESUMO
Emery-Dreifuss muscular dystrophy (EDMD) is a neuromuscular disorder exhibiting a cardiomyopathy with cardiac conduction defects. X-linked EDMD arises from mutations in the EMD gene, which encodes for a nuclear membrane protein termed emerin. In this study, we describe novel and recurrent EMD mutations identified in 18 probands and three carriers from a cohort of 255 North American patients referred for EDMD genetic mutation analysis. Eight of these mutations are novel including six frameshift mutations (p.D9GfsX24, p.F39SfsX17, p.R45KfsX16, p.F190YfsX19, p.R203PfsX34 and p.R204PfsX7) and two non-sense mutations (p.S143X, p.W200X). Our data augment the number of EMD mutations by 13.8%, equating to an increase of 5.2% in the total known EMD mutations and to an increase of 6.0% in the number of different mutations. Analysis of the exon distribution of mutations within the EMD gene, suggests a nonrandom distribution, with exon 2 as a hot spot. This phenomenon may be due to its high GC content, which at 60% is the most GC-rich exon in the EMD gene.
Assuntos
Éxons/genética , Proteínas de Membrana/genética , Distrofia Muscular de Emery-Dreifuss/genética , Mutação , Proteínas Nucleares/genética , Adolescente , Adulto , Criança , Pré-Escolar , Códon sem Sentido , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Mutação da Fase de Leitura , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutagênese Insercional , Mutação de Sentido Incorreto , Deleção de Sequência , Adulto JovemRESUMO
Importance: This ongoing study assesses long-term safety and durability of response in infants with spinal muscular atrophy (SMA) type 1 after dosing with onasemnogene abeparvovec gene replacement therapy. Objective: The primary objective of this ongoing study is to assess safety. The secondary objective is to determine whether developmental milestones achieved in the START phase 1 clinical trial were maintained and new milestones gained. Design, Setting, and Participants: This study is an ongoing, observational, follow-up study for continuous safety monitoring for 15 years in patients from the START phase I study (conducted May 5, 2014, through December 15, 2017) at Nationwide Children's Hospital in Columbus, Ohio. Participants were symptomatic infants with SMA type 1 and 2 copies of SMN2 previously treated with an intravenous dose of onasemnogene abeparvovec (low dose, 6.7 × 1013 vg/kg; or therapeutic dose, 1.1 × 1014 vg/kg) in START. Thirteen of 15 original START patients are included in this analysis; 2 patients' families declined follow-up participation. Data were analyzed from September 21, 2017, to June 11, 2020. Exposures: Median time since dosing of 5.2 (range, 4.6-6.2) years; 5.9 (range, 5.8-6.2) years in the low-dose cohort and 4.8 (range, 4.6-5.6) years in the therapeutic-dose cohort. Main Outcomes and Measures: The primary outcome measure was the incidence of serious adverse events (SAEs). Results: At data cutoff on June 11, 2020, 13 patients treated in START were enrolled in this study (median age, 38.9 [range, 25.4-48.0] months; 7 females; low-dose cohort, n = 3; and therapeutic-dose cohort, n = 10). Serious adverse events occurred in 8 patients (62%), none of which resulted in study discontinuation or death. The most frequently reported SAEs were acute respiratory failure (n = 4 [31%]), pneumonia (n = 4 [31%]), dehydration (n = 3 [23%]), respiratory distress (n = 2 [15%]), and bronchiolitis (n = 2 [15%]). All 10 patients in the therapeutic-dose cohort remained alive and without the need for permanent ventilation. Prior to baseline, 4 patients (40%) in the therapeutic-dose cohort required noninvasive ventilatory support, and 6 patients (60%) did not require regular ventilatory support, which did not change in long-term follow-up. All 10 patients treated with the therapeutic dose maintained previously acquired motor milestones. Two patients attained the new milestone of "standing with assistance" without the use of nusinersen. Conclusions and Relevance: The findings of this ongoing clinical follow-up of patients with SMA type 1 treated with onasemnogene abeparvovec supports the long-term favorable safety profile up to 6 years of age and provides evidence for sustained clinical durability of the therapeutic dose. Trial Registration: ClinicalTrials.gov Identifier: NCT03421977.
Assuntos
Produtos Biológicos/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Seguimentos , Terapia Genética/métodos , Humanos , Masculino , Resultado do TratamentoRESUMO
Acquired myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction in which patients experience fluctuating skeletal muscle weakness that often affects selected muscle groups preferentially. The target of the autoimmune attack in most cases is the skeletal muscle acetylcholine receptor (AChR), but in others, non-AChR components of the neuromuscular junction, such as the muscle-specific receptor tyrosine kinase, are targeted. The pathophysiological result is muscle endplate dysfunction and consequent fatigable muscle weakness. Clinical presentations vary substantially, both for anti-AChR positive and negative MG, and accurate diagnosis and selection of effective treatment depends on recognition of less typical as well as classic disease phenotypes. Accumulating evidence suggests that clinical MG subgroups might respond differently to treatment. In this Review, we provide current information about the epidemiology, immunopathogenesis, clinical presentations, diagnosis, and treatment of MG, including emerging therapeutic strategies.
Assuntos
Miastenia Gravis , Corticosteroides/uso terapêutico , Fatores Etários , Idade de Início , Inibidores da Colinesterase/uso terapêutico , Feminino , Humanos , Imunossupressores/uso terapêutico , Imunoterapia , Masculino , Miastenia Gravis/diagnóstico , Miastenia Gravis/epidemiologia , Miastenia Gravis/fisiopatologia , Miastenia Gravis/terapia , Neuroimunomodulação/fisiologia , Junção Neuromuscular/fisiopatologia , Receptores Proteína Tirosina Quinases/imunologia , Receptores Colinérgicos/imunologia , Fatores Sexuais , TimectomiaRESUMO
Objective: To determine the prevalence and clinical features of anti-HMGCR myopathy among patients with presumed limb-girdle muscular dystrophy (LGMD) in whom genetic testing has failed to elucidate causative mutations. Methods: Patients with presumed LGMD and unrevealing genetic testing were selected based on a few clinico-pathologic features and tested for anti-HMGCR autoantibodies (n = 11). These clinico-pathologic features are peak creatine kinase (CK) greater than 1,000 IU/L and at least 3 of the following features: (1) limb-girdle pattern of weakness, (2) selective involvement of posterior thigh on clinical examination or muscle imaging, (3) dystrophic changes on muscle biopsy, and (4) no family history of muscular dystrophy. Results: Six patients tested positive for anti-HMGCR autoantibodies. In 4, there was a presymptomatic phase, lasting as long as 10 years, characterized by elevated CK levels without weakness. Muscle biopsies revealed variable degrees of a dystrophic pathology without prominent inflammation. In an independent cohort of patients with anti-HMGCR myopathy, 17 of 51 (â¼33%) patients were initially presumed to have a form of LGMD based on clinico-pathologic features but were ultimately found to have anti-HMGCR myopathy. Most of these patients responded favorably to immunomodulatory therapies, evidenced by reduction of CK levels and improved strength. Conclusions: Anti-HMGCR myopathy can resemble LGMD. Diagnosis of patients with a LGMD-like presentation of anti-HMGCR myopathy is critical because these patients may respond favorably to immunotherapy, especially those with shorter disease duration.
Assuntos
Hidroximetilglutaril-CoA Redutases/imunologia , Doenças Musculares/diagnóstico , Doenças Musculares/imunologia , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/imunologia , Adolescente , Adulto , Autoanticorpos/imunologia , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/epidemiologia , Distrofia Muscular do Cíngulo dos Membros/epidemiologiaRESUMO
We had previously observed that treatment utilizing granulocyte-macrophage colony-stimulating factor (GM-CSF) had profound effects on the induction of experimental autoimmune myasthenia gravis (EAMG), a well-characterized antibody-mediated autoimmune disease. In this study, we show that EAMG induced by repeated immunizations with acetylcholine receptor (AChR) protein in C57BL6 mice is effectively suppressed by GM-CSF treatment administered at a stage of chronic, well-established disease. In addition, this amelioration of clinical disease is accompanied by down-modulation of both autoreactive T cell, and pathogenic autoantibody responses, a mobilization of DCs with a tolerogenic phenotype, and an expansion of regulatory T cells (Tregs) that potently suppress AChR-stimulated T cell proliferation in vitro. These observations suggest that the mobilization of antigen-specific Tregs in vivo using pharmacologic agents, like GM-CSF, can modulate ongoing anti-AChR immune responses capable of suppressing antibody-mediated autoimmunity.
Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Miastenia Gravis Autoimune Experimental/imunologia , Animais , Anticorpos/sangue , Anticorpos/imunologia , Especificidade de Anticorpos , Divisão Celular , Doença Crônica , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Miastenia Gravis Autoimune Experimental/sangue , Miastenia Gravis Autoimune Experimental/tratamento farmacológico , Receptores Colinérgicos/imunologia , Linfócitos T Reguladores/fisiologiaRESUMO
Current treatments for myasthenia gravis (MG) rely upon the administration of immunosuppressive agents which result in global, nonspecific attenuation of the immune response. An alternative approach would be to attempt to design therapies that specifically dampen autoreactivity without affecting general immunity. Recently, dendritic cells (DCs) have been shown to possess potent capabilities to tolerize T cells in an antigen-specific manner. We have observed that the selective activation of particular subsets of DCs utilizing granulocyte-macrophage colony-stimulating factor (GM-CSF) had profound effects on the induction of experimental autoimmune myasthenia gravis (EAMG). Specifically, treatment with GM-CSF effectively suppressed the induction of EAMG and down-modulated anti-AChR T cell and pathogenic antibody responses. These effects were associated with the activation of tolerogenic DCs, the enhanced production of suppressive cytokines, such as IL-10, and the mobilization of CD4(+)CD25(+) and FoxP3(+) regulatory T cells (Tregs). We have further shown that GM-CSF effectively ameliorates clinical disease severity in mice with active, ongoing EAMG. Based on these observations, we hypothesize that the selective activation of particular DC subsets in vivo using pharmacologic agents, like GM-CSF, can suppress ongoing anti-AChR immune responses by mobilizing antigen-specific Tregs capable of suppressing autoimmune MG.
Assuntos
Autoimunidade/imunologia , Miastenia Gravis Autoimune Experimental/imunologia , Animais , Células Dendríticas/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Tolerância Imunológica/imunologiaRESUMO
BACKGROUND: Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor gene. Patients with this disease have low concentrations of insulin-like growth factor-1 (IGF-1), and studies of overexpression and administration of IGF-1 showed benefit in a transgenic model; thus the IGF-1 pathway presents as a potential treatment target. We assessed safety, tolerability, and preliminary efficacy of BVS857, an IGF-1 mimetic, in patients with spinal and bulbar muscular atrophy. METHODS: In this randomised, double-blind, placebo-controlled trial, we recruited patients from neuromuscular centres in Denmark (Copenhagen), Germany (Ulm), Italy (Padova), and three sites within the USA (Bethesda, MD; Irvine, CA; and Columbus, OH). Eligible patients were 18 years or older with a confirmed genetic diagnosis of spinal and bulbar muscular atrophy, were ambulatory, had symptomatic weakness, and had serum IGF-1 concentrations of 170 ng/mL or lower. Patients were randomly assigned (2:1) to study drug or placebo by a number scheme. Patients, investigators, and study personnel were masked to treatment assignment. After a safety and tolerability assessment with eight patients, BVS857 was administered once a week (0·06 mg/kg intravenously) for 12 weeks. Primary outcome measures were safety, tolerability, and the effects of BVS857 on thigh muscle volume (TMV) measured by MRI. The ratio of TMV at day 85 to baseline was analysed with ANCOVA per protocol. Secondary outcomes of muscle strength and function were measured with the Adult Myopathy Assessment Tool, lean body mass through dual energy x-ray absorptiometry, and BVS857 pharmacokinetics. This trial was registered with ClinicalTrials.gov, NCT02024932. FINDINGS: 31 patients were assessed for eligibility, 27 of whom were randomly assigned to either BVS857 treatment (n=18) or placebo (n=9), and 24 were included in the preliminary efficacy analysis (BVS857 group, n=15; placebo group, n=9). BVS857 was generally safe with no serious adverse events. No significant differences were found in adverse events between the BVS857 and placebo groups. Immunogenicity was detected in 13 (72%) of 18 patients in the BVS857 group, including crossreacting antibodies with neutralising capacity to endogenous IGF-1 in five patients. TMV decreased from baseline to day 85 in the placebo group (-3·4% [-110 cm3]) but not in the BVS857 group (0% [2 cm3]). A significant difference in change in TMV was observed in the BVS857 group versus the placebo group (geometric-mean ratio 1·04 [90% CI 1·01-1·07]; p=0·02). There were no differences between groups in measures of muscle strength and function. INTERPRETATION: TMV remained stable in patients with spinal and bulbar muscular atrophy after being given BVS857 for 12 weeks. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Additional studies might be needed to assess the efficacy of activating the IGF-1 pathway in this disease. FUNDING: Novartis Pharmaceuticals and the US National Institutes of Health.
Assuntos
Atrofia Bulboespinal Ligada ao X/tratamento farmacológico , Fator de Crescimento Insulin-Like I/uso terapêutico , Atrofia Muscular/tratamento farmacológico , Resultado do Tratamento , Adulto , Idoso , Biomimética , Atrofia Bulboespinal Ligada ao X/complicações , Atrofia Bulboespinal Ligada ao X/diagnóstico por imagem , Estudos de Coortes , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Cooperação Internacional , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Atrofia Muscular/complicações , Atrofia Muscular/diagnóstico por imagemRESUMO
Monoclonal antibodies that target either PD-1 or PD-L1 have recently been approved for treatment of advanced non-small cell lung cancer. These antibodies are immune checkpoint inhibitors which have been shown to exacerbate Myasthenia Gravis (MG) and other autoimmune diseases. While effective in preventing tumor cells from evading immune attack, immune checkpoint inhibitors such as nivolumab, an antibody directed against the programmed cell death protein-1 (PD-1) receptor located on T-cells, may also cause immune dysregulation and could cause or potentiate pre-existing autoimmune conditions. We present a patient with latent ocular MG treated with nivolumab for her stage IV non-small cell lung cancer who developed generalized MG and severe myasthenic crisis. Providers must be aware of the risks inherent to these novel therapies since they can have life-threatening effects.
Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Imunoterapia/efeitos adversos , Miastenia Gravis/imunologia , Nivolumabe/efeitos adversos , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/terapia , Feminino , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/terapia , Miastenia Gravis/complicações , Nivolumabe/uso terapêuticoRESUMO
Components of the complement cascade and circulating immune complexes play important roles in both experimental autoimmune myasthenia gravis and myasthenia gravis in humans. Thus far, no serological factor has been identified to predict the clinical severity of either myasthenia gravis. Upon immunization with acetylcholine receptor, levels of complement factors C1q, C3 and CIC increase with time in sera from C57BL/6 (B6) mice. Both these and plasma samples from myasthenia gravis patients also contain anti-C1q antibodies. The serum levels of anti-C1q antibodies but not C1q, C3 and CIC are significantly correlated with the clinical severity in the experimental myasthenia mice. However, this correlation is not observed in myasthenia gravis patients.
Assuntos
Anticorpos Anti-Idiotípicos/sangue , Complemento C1q/imunologia , Miastenia Gravis Autoimune Experimental/imunologia , Miastenia Gravis/imunologia , Adulto , Animais , Complemento C1/análise , Complemento C1/imunologia , Complemento C1q/análise , Complemento C3/análise , Complemento C3/imunologia , Complexo de Ataque à Membrana do Sistema Complemento/análise , Complexo de Ataque à Membrana do Sistema Complemento/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Debilidade Muscular/fisiopatologia , Miastenia Gravis/sangue , Miastenia Gravis/etiologia , Miastenia Gravis/fisiopatologia , Miastenia Gravis Autoimune Experimental/sangue , Miastenia Gravis Autoimune Experimental/etiologia , Miastenia Gravis Autoimune Experimental/fisiopatologia , Junção Neuromuscular/química , Junção Neuromuscular/patologia , Valor Preditivo dos Testes , Índice de Gravidade de DoençaRESUMO
Myasthenia gravis (MG) is an autoimmune disease associated with the production of autoantibodies against 1) the skeletal muscle acetylcholine receptor; 2) muscle-specific kinase, a receptor tyrosine kinase critical for the maintenance of neuromuscular synapses; 3) low-density lipoprotein receptor-related protein 4, an important molecular binding partner for muscle-specific kinase; and 4) other muscle endplate proteins. In addition to the profile of autoantibodies, MG may be classified according the location of the affected muscles (ocular vs generalized), the age of symptom onset, and the nature of thymic pathology. Immunopathologic events leading to the production of autoantibodies differ in the various disease subtypes. Advances in our knowledge of the immunopathogenesis of the subtypes of MG will allow for directed utilization of the ever-growing repertoire of therapeutic agents that target distinct nodes in the immune pathway relevant to the initiation and maintenance of autoimmune disease. In this review, we examine the pathogenesis of MG subtypes, current treatment options, and emerging new treatments and therapeutic targets.
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Miastenia Gravis/tratamento farmacológico , Linfócitos B/efeitos dos fármacos , Linfócitos B/fisiologia , Inativadores do Complemento/uso terapêutico , Humanos , Miastenia Gravis/imunologia , Miastenia Gravis/terapia , Plasmócitos/efeitos dos fármacos , Plasmócitos/fisiologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/fisiologia , Pesquisa Translacional BiomédicaRESUMO
OBJECTIVES: To review the use of immunoassays in the diagnosis and research of disorders affecting the nervous system. METHODS: Systematic review of the English literature. RESULTS: Immunoassays have demonstrated utility for: (1) the detection of antigen (molecules, genes, gene products, peptides, hormones and drug metabolites) and (2) the detection of an immune response (antigen-antibody complexes and specific and non-specific populations of antibodies) in serum, cerebrospinal fluid, and central nervous system tissue. DISCUSSION: The specificity of the antibody-antigen interaction makes immunoassays an ideal diagnostic and research tool for the investigation of neurological disease. A number of immunoassays are available for this purpose, and the choice of a particular methodology generally depends upon whether one is detecting antigen, antibody or antigen-antibody complexes, and the nature of the biologic sample that is being tested. Ease of testing, sensitivity, specificity and cost are other important considerations.