RESUMO
OBJECTIVE: To investigate the association between changes in anti-acetylcholine receptor antibody (AChR Ab) levels induced by immunosuppressive treatment and myasthenia gravis (MG) prognosis at 1-year post-treatment in patients with MG. METHODS: We included 53 consecutive AChR Ab-positive patients with MG whose AChR Ab levels were remeasured within 100 days of initiating immunosuppressive treatment (median remeasuring time post-treatment: 71 (55-84) days). The AChR Ab level reduction rate (RR-AChRAb, %/day) adjusted for the time between treatment initiation, and AChR Ab level remeasurement was calculated as follows: (pretreatment-post-treatment AChR Ab level)/pretreatment AChR Ab level/days between therapy initiation and AChR Ab level remeasurement ×100. Participants were divided into two groups based on the cut-off value of RR-AChR Ab, determined using receiver operating characteristic analyses for achieving minimal manifestation (MM) or better status at 1-year postimmunosuppressive treatment. The Myasthenia Gravis Foundation of America postintervention status and MG activity of daily living (MG-ADL) score at 1-year post-treatment were compared between the two groups. RESULTS: The RR-AChRAb cut-off value was 0.64%/day. The high RR-AChRAb group had a higher ratio of MM or better status (90% vs 65%, p=0.03) and lower MG-ADL score (median; 1 vs 2, p=0.04) than the low RR-AChRAb group. Kaplan-Meier analyses showed the early MM achievement in the high RR-AChRAb group (p=0.002, log-rank test). CONCLUSIONS: High RR-AChRAb is associated with a favourable outcome at 1-year post-treatment. AChR Ab remeasurement within 100 days of therapy may be useful for predicting AChR Ab-positive MG outcomes at 1-year post-treatment.
Assuntos
Autoanticorpos/sangue , Imunossupressores/uso terapêutico , Miastenia Gravis/imunologia , Receptores Colinérgicos/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/sangue , Miastenia Gravis/tratamento farmacológico , Prognóstico , Adulto JovemRESUMO
OBJECTIVE: Myasthenia gravis (MG) is an autoimmune disease mostly caused by autoantibodies against acetylcholine receptor associated with thymus abnormalities. Thymectomy has been proven to be an efficacious treatment for patients with MG, but postoperative myasthenic crisis often occurs and is a major complication. We aimed to develop and validate a simple scoring system based on clinical characteristics in the preoperative status to predict the risk of postoperative myasthenic crisis. METHODS: We studied 393 patients with MG who underwent thymectomy at 6 tertiary centers in Japan (275 patients for derivation and 118 for validation). Clinical characteristics, such as gender, age at onset and operation, body mass index, disease duration, MG subtype, severity, symptoms, preoperative therapy, operative data, and laboratory data, were reviewed retrospectively. A multivariate logistic regression with LASSO penalties was used to determine the factors associated with postoperative myasthenic crisis, and a score was assigned. Finally, the predictive score was evaluated using bootstrapping technique in the derivation and validation groups. RESULTS: Multivariate logistic regression identified 3 clinical factors for predicting postoperative myasthenic crisis risk: (1) vital capacity < 80%, (2) disease duration < 3 months, and (3) bulbar symptoms immediately before thymectomy. The postoperative myasthenic crisis predictive score, ranging from 0 to 6 points, had areas under the curve of 0.84 (0.66-0.96) in the derivation group and 0.80 (0.62-0.95) in the validation group. INTERPRETATION: A simple scoring system based on 3 preoperative clinical characteristics can predict the possibility of postoperative myasthenic crisis. Ann Neurol 2017;82:841-849.
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Miastenia Gravis/diagnóstico , Complicações Pós-Operatórias/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/cirurgia , Estudos Retrospectivos , Fatores de Risco , Timectomia/efeitos adversosRESUMO
OBJECTIVE: High mobility group box 1 (HMGB1) functions as an inflammatory mediator and is implicated in the pathogenesis of various autoimmune diseases. Our primary aim is to determine whether HMGB1 is involved in the pathogenesis of myasthenia gravis (MG). METHODS: Serum HMGB1 levels of 60 patients with anti-acetylcholine receptor (AChR) antibody-positive MG without immunosuppressive treatment and of 10 patients with anti-muscle-specific receptor tyrosine kinase (MuSK) antibody-positive MG were compared with those in 40 controls. We also investigated the potential correlation between serum HMGB1 levels and the clinical variables in patients with MG. RESULTS: Serum HMGB1 levels in patients with anti-AChR antibody-positive MG were higher than those in controls (7.80 ± 7.47 vs 4.13 ± 2.55 ng/mL, p=0.004) and were decreased after treatment (p=0.051). Although not significant, patients with anti-MuSK antibody-positive MG showed higher serum HMGB1 levels than the controls (p=0.178). There were correlations between serum HMGB1 levels and phenotypes of anti-AChR antibody-positive MG: patients with generalised MG showed higher HMGB1 levels than those of patients with ocular MG (p=0.059) and controls (p=0.002); patients with thymoma showed higher HMGB1 levels than those without thymoma (p=0.094) and controls (p=0.001). CONCLUSIONS: Serum HMGB1 is elevated in patients with MG and may play a key role in the inflammation of the neuromuscular junction.
Assuntos
Proteína HMGB1/biossíntese , Proteína HMGB1/genética , Miastenia Gravis/genética , Miastenia Gravis/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/análise , Feminino , Humanos , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/patologia , Receptores Proteína Tirosina Quinases/imunologia , Receptores Colinérgicos/imunologia , Regulação para Cima/genética , Adulto JovemRESUMO
OBJECTIVE: Myasthenia gravis (MG) is an antibody-mediated inflammatory disease affecting post-synaptic membranes of neuromuscular junctions, and objective biomarkers of MG disease activity are lacking. Pentraxin 3 (PTX3) is an acute-phase inflammatory glycoprotein in the same family as C-reactive protein that is associated with disease activity in several autoimmune disorders. Thus, we investigated whether circulating PTX3 is a useful biomarker of MG activity. METHODS: Serum PTX3 was measured in 40 patients with MG who were positive for anti-acetylcholine receptor antibody, and in 30 healthy and disease controls, using a commercial enzyme-linked immunosorbent assay kit. In patients with MG, the correlation of serum PTX3 levels with disease severity scales at serum sampling, including MG Foundation of America (MGFA) classification, MG activity of daily living (MG-ADL) score, and quantitative MG (QMG) score, were investigated. RESULTS: Although there was no significant difference in serum PTX3 between the MG and control groups (mean, 3346 pg/mL in MG group vs. 2870 pg/mL in control group, P = 0.56), serum PTX3 moderately correlated with all disease severity scores (MGFA classification: Spearman's ρ = 0.53, P = 0.0004; MG-ADL score: Spearman's ρ = 0.45, P = 0.004; QMG score: Spearman's ρ = 0.50, P = 0.004). CONCLUSION: Our results suggest that circulating PTX3 may reflect the extent of neuromuscular junction damage and might be involved in the pathogenesis of MG.
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Proteína C-Reativa , Miastenia Gravis , Componente Amiloide P Sérico , Biomarcadores , Proteína C-Reativa/metabolismo , Humanos , Componente Amiloide P Sérico/metabolismo , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: This study aimed to investigate the timing of meeting the criteria for a status of "minimal manifestation (MM) or better" and the factors that influenced whether "MM or better status" or "MM or better status with an oral prednisolone (PSL) dose of 5 mg/day or less (5-mg MM)" was met in patients with acetylcholine receptor (AChR) antibody-positive generalized myasthenia gravis (MG). METHODS: We performed a retrospective study in 93 patients with AChR antibody-positive generalized MG who were followed for 3 years after the start of immunotherapy. We reviewed clinical data, such as MG-related symptoms, the MG activities of daily living profile (MGADL) score, immunotherapy including the dose of PSL, and achievement of the status of MM or better at baseline and 3, 6, 12, 24, and 36 months after treatment. RESULTS: An MM or better status was achieved in 60% of the patients 3 months and in 90% of the patients 2 years after initiating immunotherapy. At 2 years, 60% of the patients had achieved the treatment goal, which was an "5-mg MM". More frequent plasmapheresis and higher dose of PSL within 3 months after immunotherapy initiation were associated with difficulty in achieving the 5-mg MM status at 2 years. CONCLUSION: Approximately 60% of the MG patients achieved the treatment goal within 2 years after treatment. PSL dose and the cumulative number of plasmapheresis procedures at 3 months after immunotherapy initiation may help identify treatment-resistant patients with MG.
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Atividades Cotidianas , Miastenia Gravis , Autoanticorpos , Humanos , Miastenia Gravis/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Complement-dependent disruption of motor endplate is detected in anti-acetylcholine receptor (AChR) antibody-positive myasthenia gravis (MG). We measured serum AChR α1 subunit protein levels, which may be associated with neuromuscular damage, in 55 patients with MG (47 were seropositive and 8 were negative) and in 20 controls. Serum AChR α1 subunit protein concentrations were higher in patients with anti-AChR antibody-positive MG than those in controls (P = .04), were negatively correlated with MG activities of daily living score (P = .01), and tended to be higher in ocular MG than in generalized MG. AChR α1 subunit protein elevation may be related to seropositive MG pathogenesis, especially in the ocular type.
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Autoanticorpos/sangue , Miastenia Gravis/sangue , Miastenia Gravis/diagnóstico , Receptores Nicotínicos/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Initial worsening of symptoms after the start of corticosteroid administration is a major concern in the treatment of myasthenia gravis (MG). However, the risk factors or specific patient backgrounds related to this issue have not been fully understood. We aimed to determine the risk factors and developed a scoring system for predicting initial worsening in generalized MG. METHODS: We enrolled 62 generalized MG patients with anti-acetylcholine receptor antibody. Initial worsening was defined as an increment of three points in the Quantitative MG score within 2â¯weeks after the start of steroid treatment. A multivariate logistic regression model was used to determine the risk factors, and predictive scores were assigned. Bootstrap resampling was applied to evaluate the risk score model's internal validity. RESULTS: Steroid-induced initial worsening occurred in 26% of MG patients and was correlated with thymoma-associated or early-onset MG (pâ¯=â¯0.018), initial prednisolone doses ≥40â¯mg/day (pâ¯=â¯0.029), and upper limb weakness (pâ¯=â¯0.039). Stepwise multivariate logistic regression identified these three clinical factors for predicting initial worsening in MG. A predictive score of 0-3 points had a bootstrapping area under the curve of 0.770 (0.625-0.878). CONCLUSIONS: Our scoring system based on three clinical characteristics can predict the likelihood of steroid-induced initial worsening in MG.
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Administração Oral , Corticosteroides/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Miastenia Gravis , Corticosteroides/efeitos adversos , Adulto , Idoso , Anti-Inflamatórios/efeitos adversos , Autoanticorpos/sangue , Avaliação da Deficiência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/sangue , Miastenia Gravis/induzido quimicamente , Miastenia Gravis/tratamento farmacológico , Valor Preditivo dos Testes , Receptores Colinérgicos/imunologia , Fatores de RiscoRESUMO
High-dose intravenous methylprednisolone (IVMP) is often used as a treatment for generalized myasthenia gravis (MG); however, little is reported about the efficacy of IVMP in ocular MG. We evaluated the efficacy and safety of IVMP therapy and compared results with those of conventional oral prednisolone (PSL) treatment in ocular MG. We retrospectively studied 18 patients with ocular MG. Clinical course and safety during 6â¯months in 10 patients who were treated with IVMP were compared with those of 8 who were treated with PSL. IVMP (1000â¯mg/day) was administered one to three times within 6â¯months, whereas oral PSL was administered at the dose of 5-10â¯mg/day. The score for MG activities of daily living profile (MGADL) was assessed at baseline and at 1, 3, and 6â¯months after treatment. Patients who received IVMP showed faster improvements than those receiving PSL; the median changes in the ocular scores on the MGADL was -2 versus 0 at 1â¯month (pâ¯=â¯0.03), -3 versus -1 at 3â¯months (pâ¯=â¯0.07), and -3 versus -2 (pâ¯=â¯0.86) at 6â¯months. No patient in either group developed initial worsening of symptoms or generalized weakness. In conclusion, IVMP results in more rapid improvement than oral PSL therapy and can be a treatment option for ocular MG.
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Anti-Inflamatórios/uso terapêutico , Metilprednisolona/uso terapêutico , Miastenia Gravis/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios/administração & dosagem , Feminino , Humanos , Masculino , Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Most patients with myasthenia gravis (MG) have elevated levels of autoantibodies against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction, which leads to muscle weakness. We developed a fusion protein, AChR-Fc, as a novel therapeutic biomolecule for patients with MG and examined its efficacy. AChR-Fc was expressed by Chinese hamster ovary cells and purified. We examined the neutralizing activity and cellular cytotoxicity of AChR-Fc using anti-AChR antibody-producing hybridoma cells and serum samples from 16 patients with MG. The effects of AChR-Fc in vivo were also examined using rat MG models. AChR-Fc bound to anti-AChR antibodies and exhibited cytotoxicity against patient-derived antibody-producing B cells. Additionally, a dose-dependent improvement in the clinical signs of disease was observed in a rat MG model. AChR-Fc can diminish signs of MG by neutralizing anti-AChR antibodies and enhancing cytotoxicity against autoantibody-producing B cells. Thus, AChR-Fc can be a novel therapeutic biomolecule for patients with MG.
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Linfócitos B/imunologia , Miastenia Gravis/imunologia , Receptores Nicotínicos/imunologia , Proteínas Recombinantes de Fusão/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Autoanticorpos/metabolismo , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Cricetinae , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Receptores Nicotínicos/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Vacinação , Adulto JovemRESUMO
Myasthenia gravis (MG) is an autoimmunological inflammatory disorder of the neuromuscular junction. Inflammation could be a key player for understanding the pathogenesis of MG. We measured the serum levels of 24 inflammatory cytokines in 43 patients with anti-acetylcholine receptor antibody-positive MG and 25 healthy controls. In patients with MG, serum levels of a proliferation-inducing ligand (APRIL), IL-19, IL-20, IL-28A and IL-35 were significantly increased as compared with controls (p < 0.05). Among them, IL-20, IL-28A and IL-35 were significantly decreased after treatment (p < 0.05). In clinical subtype analyses, APRIL and IL-20 were increased in patients with late-onset MG and IL-28A levels were increased in patients with thymoma-associated MG compared with healthy controls (p < 0.01). The results of the present study demonstrate both anti-inflammatory and inflammatory cytokines are upregulated in MG, reflecting the importance of cytokine-mediated inflammation and its regulation in MG pathophysiology.
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Citocinas/sangue , Miastenia Gravis/imunologia , Adulto , Idoso , Anticorpos/sangue , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica , Humanos , Interleucinas/sangue , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/sangue , Receptores Colinérgicos/imunologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangueRESUMO
BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder presumed to be associated with genetic susceptibility. This study aims to determine whether HLA is associated with MG in Japanese patients. METHODS: We included 58 MG patients with anti-acetylcholine receptor antibody (AChR+MG) and 14 MG patients with muscle-specific receptor tyrosine kinase (MuSK+MG) and determined HLA-A, B, DRB1 and -DQB1 alleles using polymerase chain reaction with sequence-specific oligonucleotide and primers. AChR+MG was classified into the three subgroups: early-onset MG (EOMG; n=11), late-onset MG (LOMG; n=20), and thymoma-associated MG (n=27). Healthy volunteers (n=100) served as controls. RESULTS: A significant positive association was observed between MuSK+MG with the DRB1*14 [57.1%, MuSK+MG vs. 18.0%, healthy controls (HC); odds ratio (OR): 6.1] and DQB1*05 [78.6%, MuSK+MG vs. 30.0%, HC; odds ratio (OR): 8.5]. We found a negative association between LOMG and DQB1*04 [5.0%, LOMG vs. 37.0%, HC; OR: 0.09]. There was no association between other MG subgroups and HLA alleles. CONCLUSION: HLA-DRB1*14 and DQB1*05 were associated with MuSK+MG, therefore these alleles may play important roles in developing MuSK+MG across the races.
Assuntos
Povo Asiático/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Miastenia Gravis/genética , Receptores Proteína Tirosina Quinases/genética , Receptores Colinérgicos/genética , Adulto , Idoso , Autoanticorpos/genética , Feminino , Estudos de Associação Genética/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/diagnóstico , Miastenia Gravis/epidemiologia , Estudos Retrospectivos , Adulto JovemRESUMO
The differential susceptibility of skeletal muscle by myasthenia gravis (MG) is not well understood. We utilized RNA expression profiling of extraocular muscle (EOM), diaphragm (DIA), and extensor digitorum (EDL) of rats with experimental autoimmune MG (EAMG) to evaluate the hypothesis that muscles respond differentially to injury produced by EAMG. EAMG was induced in female Lewis rats by immunization with acetylcholine receptor purified from the electric organ of the Torpedo. Six weeks later after rats had developed weakness and serum antibodies directed against the AChR, animals underwent euthanasia and RNA profiling performed on DIA, EDL, and EOM. Profiling results were validated by qPCR. Across the three muscles between the experiment and control groups, 359 probes (1.16%) with greater than 2-fold changes in expression in 7 of 9 series pairwise comparisons from 31,090 probes were identified with approximately two-thirds being increased. The three muscles shared 16 genes with increased expression and 6 reduced expression. Functional annotation demonstrated that these common expression changes fell predominantly into categories of metabolism, stress response, and signaling. Evaluation of specific gene function indicated that EAMG led to a change to oxidative metabolism. Genes related to muscle regeneration and suppression of immune response were activated. Evidence of a differential immune response among muscles was not evident. Each muscle had a distinct RNA profile but with commonality in gene categories expressed that are focused on muscle repair, moderation of inflammation, and oxidative metabolism.
RESUMO
Thymectomy is an effective treatment for myasthenia gravis (MG). However, there is limited data on its effectiveness in non-thymomatous late-onset MG (LOMG). The aim of this study was to analyze the effects of thymectomy in LOMG. We retrospectively reviewed the 2-year post-thymectomy prognosis in 39 consecutive patients with non-thymomatous, anti-acetylcholine receptor antibody positive, and generalized LOMG (age at onset ≥ 50 years). The MG foundation of America (MGFA) classification, MGFA post-intervention status, dosage of prednisolone and pyridostigmine, and anti-acetylcholine receptor antibody titers were evaluated. Among the 39 LOMG patients, thymic hyperplasia was seen in 5 (12.8%). MGFA classification and prednisolone dosage before thymectomy were similar between the LOMG with thymic hyperplasia group (n = 5) and the LOMG with involuted thymus group (n = 34). Two years after thymectomy, the LOMG patients with thymic hyperplasia showed higher proportion of remission (60 vs. 26%) and received lower prednisolone dosage compared to patients with involuted thymus (0.8 vs. 4.0 mg/day). Notably, the proportion of patients with minimal manifestation or better status with receiving ≤ 5 mg/day prednisolone was much higher in the thymic hyperplasia group than in the involuted thymus group (100 vs. 62%). In conclusion, thymectomy could have beneficial effects in generalized LOMG, particularly in patients with thymic hyperplasia.
Assuntos
Miastenia Gravis/cirurgia , Timectomia/métodos , Resultado do Tratamento , Idade de Início , Idoso , Autoanticorpos/sangue , Inibidores da Colinesterase/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/sangue , Miastenia Gravis/tratamento farmacológico , Prednisolona/uso terapêutico , Brometo de Piridostigmina/uso terapêutico , Receptores Colinérgicos/imunologia , Timo/anormalidades , Timo/efeitos dos fármacos , Timo/cirurgia , Tomógrafos ComputadorizadosRESUMO
Extracellular peroxiredoxin 5 (PRX5) is known to be an inflammatory mediator. The serum PRX5 levels of 40 patients with anti-acetylcholine receptor antibody-positive MG and those of 40 controls were measured. PRX5 levels in patients with MG were higher than those in the controls (P=0.045). Thymoma-associated MG patients showed higher PRX5 levels than late-onset MG patients and controls (P<0.05). There were significant associations between the serum PRX5 levels and high mobility group box 1 levels. PRX5 elevation in MG could be related to the neuromuscular junction breakdown and plays a pivotal role in the pathogenic inflammation of MG.
Assuntos
Miastenia Gravis/sangue , Miastenia Gravis/fisiopatologia , Peroxirredoxinas/sangue , Regulação para Cima/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Feminino , Proteína HMGB1/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/imunologia , Doenças Neurodegenerativas/sangue , Receptores Colinérgicos/imunologia , Estatística como Assunto , Estatísticas não Paramétricas , Adulto JovemRESUMO
Helicobacter cinaedi, a gram-negative spiral bacillus that inhabits the intestinal tracts of rodents and primates, is associated with gastroenteritis in humans. H. cinaedi infection has been commonly reported in immunocompromised individuals such as human immunodeficiency virus-infected patients, but rarely in immunocompetent individuals. Prior contact with animals has attracted attention as a possible source of H. cinaedi infection. We report a case of meningitis in an immunocompetent 34-year-old woman who had daily contact with a kitten for a month. She developed acute headaches, fevers, and chills. Neurological examination revealed neck stiffness and her cerebrospinal fluid (CSF) exhibited polymorphonuclear pleocytosis and a decreased concentration of glucose. Blood and CSF cultures were negative; however, the pathogen responsible for her condition was identified as H. cinaedi by polymerase chain reaction in CSF. This is the first adult case of meningitis caused by H. cinaedi. Thus, this bacillus should be considered a possible causative agent of bacterial meningitis in healthy adults.
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Infecções por Helicobacter/diagnóstico , Helicobacter , Meningites Bacterianas/diagnóstico , Adulto , Feminino , Infecções por Helicobacter/complicações , Humanos , Meningites Bacterianas/complicaçõesRESUMO
Although immunosuppressive effects of antiepileptic drug are well known, serious complications of antiepileptic drug are rare. We report a case of hypogammaglobulinemia associated with aplasia of B lymphocytes after carbamazepine treatment. Despite repeated intravenous immunoglobulin replacement therapy, this condition persisted for more than three months. The present case suggested that routine monitoring of the blood cell count and serum levels of immunoglobulin are important in patients treated with carbamazepine, and a lymphocyte subpopulation study is valuable in cases of hypogammaglobulinemia.