RÉSUMÉ
BACKGROUND AND OBJECTIVES: To investigate intrathymic B lymphopoiesis in patients with myasthenia gravis (MG) and explore thymus pathology associated with clinical impact. METHODS: Thymic lymphocytes from 15 young patients without MG, 22 adult patients without MG, 14 patients with MG without thymoma, and 11 patients with MG with thymoma were subjected to flow cytometry analysis of T follicular helper (Tfh), naive B, memory B, plasmablasts, CD19+B220high thymic B cells, B-cell activating factor receptor, and C-X-C chemokine receptor 5 (CXCR5). Peripheral blood mononuclear cells of 16 healthy subjects and 21 untreated patients with MG were also analyzed. Immunologic values were compared, and correlations between relevant values and clinical parameters were evaluated. RESULTS: The frequencies of circulating and intrathymic plasmablasts were significantly higher in patients with MG than controls. On the other hand, the frequency of CD19+B220high thymic B cells was not increased in MG thymus. We observed a significant increase in CXCR5 expression on plasmablasts in MG thymus and an increased frequency of intrathymic plasmablasts that was correlated with preoperative disease activity. The frequency of intrathymic Tfh cells was significantly lower in patients who received immunosuppressive (IS) therapy than those without IS therapy. However, there was no significant difference in the frequency of intrathymic plasmablasts irrespective of IS therapy. DISCUSSION: Our findings confirmed a correlation between increased frequency of intrathymic plasmablasts and disease activity before thymectomy. We postulate that activated intrathymic plasmablasts endow pathogenic capacity in MG.
Sujet(s)
Lymphocytes B , Agranulocytes , Lymphopoïèse , Myasthénie , Cellules souches , Lymphocytes T , Thymome , Tumeurs du thymus , Adolescent , Adulte , Sujet âgé , Lymphocytes B/immunologie , Enfant , Enfant d'âge préscolaire , Femelle , Humains , Agranulocytes/immunologie , Mâle , Adulte d'âge moyen , Myasthénie/sang , Myasthénie/immunologie , Myasthénie/physiopathologie , Cellules souches/immunologie , Lymphocytes T/immunologie , Thymectomie , Thymome/sang , Thymome/immunologie , Thymome/physiopathologie , Tumeurs du thymus/sang , Tumeurs du thymus/immunologie , Tumeurs du thymus/physiopathologie , Jeune adulteRÉSUMÉ
Myasthenia gravis (MG) is an autoimmune disease with autoantibodies against the mainly nicotinic acetylcholine receptor (AChR). High mobility group box1 (HMGB1) acts as a danger signal and drives the pathogenesis of autoimmune-mediated diseases. However, the role of HMGB1 in the pathogenesis of MG is not fully understood. Therefore, in this study, we analyzed serum levels of HMGB1 and immunohistochemical HMGB1 staining of muscle tissues in the passive transfer MG model to investigate the role of HMGB1 in MG. As a result, serum HMGB1 levels tended to be higher and the quantitative score of muscle pathology showed greater HMGB1 deposition (P = 0.02) along with sparser AChR staining and more severe inflammation in the passive transfer MG rats (n = 6) than those in control rats (n = 6). These findings indicate that HMGB1 is an important mediator and biomarker for inflammation in the pathogenesis of MG and can be a therapeutic target in MG.
Sujet(s)
Protéine HMGB1/métabolisme , Muscles squelettiques/métabolisme , Myasthénie auto-immune expérimentale/métabolisme , Animaux , Femelle , Protéine HMGB1/sang , Myasthénie auto-immune expérimentale/sang , RatsRÉSUMÉ
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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Activités de la vie quotidienne , Myasthénie , Autoanticorps , Humains , Myasthénie/traitement médicamenteux , Pronostic , Études rétrospectives , Résultat thérapeutiqueRÉSUMÉ
Introduction: Propofol infusion syndrome (PRIS) is rare but a potentially lethal adverse event. The pathophysiologic mechanism is still unknown. Patient concerns: A 22-year-old man was admitted for the treatment of Guillain-Barré syndrome. On day six, he required mechanical ventilation due to progressive muscle weakness; propofol (3.5 mg/kg/hour) was administered for five days for sedation. On day 13, he had hypotension with abnormal electrocardiogram findings, acute kidney injury, hyperkalemia and severe rhabdomyolysis. Diagnosis and interventions: The patient was transferred to our intensive care unit (ICU) on suspicion of PRIS. Administration of noradrenaline and renal replacement therapy and fasciotomy for compartment syndrome of lower legs due to PRIS-rhabdomyolysis were performed. Outcomes: The patient gradually recovered and was discharged from the ICU on day 30. On day 37, he had repeated sinus bradycardia with pericardial effusion in echocardiography. Cardiac 18F-FDG PET on day 67 demonstrated heterogeneous 18F-FDG uptake in the left ventricle. Electron microscopic investigation of endomyocardial biopsy on day 75 revealed mitochondrial myelinization of the cristae, which indicated mitochondrial damage of cardiomyocytes. He was discharged without cardiac abnormality on day 192. Conclusions: Mitochondrial damage in both morphological and functional aspects was observed in the present case. Sustained mitochondrial damage may be a therapeutic target beyond the initial therapy of discontinuing propofol administration.
RÉSUMÉ
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.
Sujet(s)
Autoanticorps/sang , Myasthénie/sang , Myasthénie/diagnostic , Récepteurs nicotiniques/sang , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Marqueurs biologiques/sang , Femelle , Humains , Mâle , Adulte d'âge moyen , Jeune adulteRÉSUMÉ
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.
Sujet(s)
Anti-inflammatoires/usage thérapeutique , Méthylprednisolone/usage thérapeutique , Myasthénie/traitement médicamenteux , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Anti-inflammatoires/administration et posologie , Femelle , Humains , Mâle , Méthylprednisolone/administration et posologie , Adulte d'âge moyen , Études rétrospectives , Résultat thérapeutiqueRÉSUMÉ
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.
Sujet(s)
Administration par voie orale , Hormones corticosurrénaliennes/administration et posologie , Anti-inflammatoires/administration et posologie , Myasthénie , Hormones corticosurrénaliennes/effets indésirables , Adulte , Sujet âgé , Anti-inflammatoires/effets indésirables , Autoanticorps/sang , Évaluation de l'invalidité , Femelle , Humains , Mâle , Adulte d'âge moyen , Myasthénie/sang , Myasthénie/induit chimiquement , Myasthénie/traitement médicamenteux , Valeur prédictive des tests , Récepteurs cholinergiques/immunologie , Facteurs de risqueRÉSUMÉ
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.
Sujet(s)
Myasthénie/diagnostic , Complications postopératoires/diagnostic , Femelle , Humains , Mâle , Adulte d'âge moyen , Myasthénie/chirurgie , Études rétrospectives , Facteurs de risque , Thymectomie/effets indésirablesRÉSUMÉ
OBJECTIVES: To clarify the social disadvantages associated with myasthenia gravis (MG) and examine associations with its disease and treatment. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: We evaluated 917 consecutive cases of established MG seen at 13 neurological centres in Japan over a short duration. OUTCOME MEASURES: All patients completed a questionnaire on social disadvantages resulting from MG and its treatment and a 15-item MG-specific quality of life scale at study entry. Clinical severity at the worst condition was graded according to the MG Foundation of America classification, and that at the current condition was determined according to the quantitative MG score and MG composite. Maximum dose and duration of dose ≥20â mg/day of oral prednisolone during the disease course were obtained from the patients' medical records. Achievement of the treatment target (minimal manifestation status with prednisolone at ≤5â mg/day) was determined at 1, 2 and 4â years after starting treatment and at study entry. RESULTS: We found that 27.2% of the patients had experienced unemployment, 4.1% had been unwillingly transferred and 35.9% had experienced a decrease in income, 47.1% of whom reported that the decrease was ≥50% of their previous total income. In addition, 49.0% of the patients reported feeling reduced social positivity. Factors promoting social disadvantages were severity of illness, dose and duration of prednisolone, long-term treatment, and a depressive state and change in appearance after treatment with oral steroids. Early achievement of the treatment target was a major inhibiting factor. CONCLUSIONS: Patients with MG often experience unemployment, unwilling job transfers and a decrease in income. In addition, many patients report feeling reduced social positivity. To inhibit the social disadvantages associated with MG and its treatment, greater focus needs to be placed on helping patients with MG resume a normal lifestyle as soon as possible by achieving the treatment target.
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Dépression/épidémiologie , Revenu/statistiques et données numériques , Myasthénie/psychologie , Chômage/statistiques et données numériques , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Études transversales , Femelle , Humains , Japon , Modèles logistiques , Mâle , Adulte d'âge moyen , Analyse multifactorielle , Myasthénie/traitement médicamenteux , Prednisolone/administration et posologie , Échelles d'évaluation en psychiatrie , Qualité de vie , Indice de gravité de la maladie , Soutien social , Enquêtes et questionnaires , Jeune adulteRÉSUMÉ
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.
Sujet(s)
Lymphocytes B/immunologie , Myasthénie/immunologie , Récepteurs nicotiniques/immunologie , Protéines de fusion recombinantes/immunologie , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Animaux , Autoanticorps/métabolisme , Lymphocytes B/métabolisme , Lignée cellulaire tumorale , Cellules cultivées , Cricetinae , Modèles animaux de maladie humaine , Femelle , Humains , Mâle , Adulte d'âge moyen , Rats , Récepteurs nicotiniques/métabolisme , Protéines de fusion recombinantes/métabolisme , Protéines de fusion recombinantes/pharmacologie , Vaccination , Jeune adulteRÉSUMÉ
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.
Sujet(s)
Cytokines/sang , Myasthénie/immunologie , Adulte , Sujet âgé , Anticorps/sang , Études cas-témoins , Femelle , Régulation de l'expression des gènes , Humains , Interleukines/sang , Mâle , Adulte d'âge moyen , Myasthénie/sang , Récepteurs cholinergiques/immunologie , Membre-13 de la superfamille du facteur de nécrose tumorale/sangRÉSUMÉ
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.
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Asiatiques/génétique , Chaines bêta des antigènes HLA-DQ/génétique , Chaines HLA-DRB1/génétique , Myasthénie/génétique , Récepteurs à activité tyrosine kinase/génétique , Récepteurs cholinergiques/génétique , Adulte , Sujet âgé , Autoanticorps/génétique , Femelle , Études d'associations génétiques/méthodes , Humains , Mâle , Adulte d'âge moyen , Myasthénie/diagnostic , Myasthénie/épidémiologie , Études rétrospectives , Jeune adulteRÉSUMÉ
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.
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Myasthénie/sang , Myasthénie/physiopathologie , Peroxirédoxines/sang , Régulation positive/physiologie , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Autoanticorps/sang , Femelle , Protéine HMGB1/sang , Humains , Mâle , Adulte d'âge moyen , Myasthénie/immunologie , Maladies neurodégénératives/sang , Récepteurs cholinergiques/immunologie , Statistiques comme sujet , Statistique non paramétrique , Jeune adulteSujet(s)
Amnésie globale transitoire/anatomopathologie , Amnésie globale transitoire/physiopathologie , Épilepsie/anatomopathologie , Épilepsie/physiopathologie , Hippocampe/anatomopathologie , Hippocampe/physiopathologie , Sujet âgé , Imagerie par résonance magnétique de diffusion , Évolution de la maladie , Électroencéphalographie , Femelle , Études de suivi , HumainsRÉSUMÉ
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.
Sujet(s)
Myasthénie/chirurgie , Thymectomie/méthodes , Résultat thérapeutique , Âge de début , Sujet âgé , Autoanticorps/sang , Anticholinestérasiques/usage thérapeutique , Femelle , Glucocorticoïdes/usage thérapeutique , Humains , Études longitudinales , Mâle , Adulte d'âge moyen , Myasthénie/sang , Myasthénie/traitement médicamenteux , Prednisolone/usage thérapeutique , Bromure de pyridostigmine/usage thérapeutique , Récepteurs cholinergiques/immunologie , Thymus (glande)/malformations , Thymus (glande)/effets des médicaments et des substances chimiques , Thymus (glande)/chirurgie , TomodensitomètreRÉSUMÉ
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.