Efficacy and Safety of Teriflunomide in Chinese Patients with Relapsing Forms of Multiple Sclerosis: A Subgroup Analysis of the Phase 3 TOWER Study.

BACKGROUND: Disease-modifying therapy is the standard treatment for patients with multiple sclerosis (MS) in remission. The primary objective of the current analysis was to assess the efficacy and safety of two teriflunomide doses (7 mg and 14 mg) in the subgroup of Chinese patients with relapsing MS included in the TOWER study. METHODS: TOWER was a multicenter, multinational, randomized, double-blind, parallel-group (three groups), placebo-controlled study. This subgroup analysis includes 148 Chinese patients randomized to receive either teriflunomide 7 mg (n = 51), teriflunomide 14 mg (n = 43), or placebo (n = 54). RESULTS: Of the 148 patients in the intent-to-treat population, adjusted annualized relapse rates were 0.63 (95% confidence interval [CI]: 0.44, 0.92) in the placebo group, 0.48 (95% CI: 0.33, 0.70) in the teriflunomide 7 mg group, and 0.18 (95% CI: 0.09, 0.36) in the teriflunomide 14 mg group; this corresponded to a significant relative risk reduction in the teriflunomide 14 mg group versus placebo (-71.2%, P = 0.0012). Teriflunomide 14 mg also tended to reduce 12-week confirmed disability worsening by 68.1% compared with placebo (hazard ratio: 0.319, P = 0.1194). There were no differences across all treatment groups in the proportion of patients with treatment-emergent adverse events (TEAEs; 72.2% in the placebo group, 74.5% in the teriflunomide 7 mg group, and 69.8% in the teriflunomide 14 mg group); corresponding proportions for serious adverse events were 11.1%, 3.9%, and 11.6%, respectively. The most frequently reported TEAEs with teriflunomide versus placebo were neutropenia, increased alanine aminotransferase, and hair thinning. CONCLUSIONS: Teriflunomide was as effective and safe in the Chinese subpopulation as it was in the overall population of patients in the TOWER trial. Teriflunomide has the potential to meet unmet medical needs for MS patients in China. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00751881; https://clinicaltrials.gov/ct2/show/NCT00751881?term=NCT00751881&rank=1.

Pathological Findings in Myasthenia Gravis Patients with Thymic Hyperplasia and Thymoma.

Thymectomy is routinely carried out in patients with myasthenia gravis (MG) and thymomas. However, there is still a dispute as to whether MG patients with thymic hyperplasia should undergo thymectomy. We aimed to investigate the pathological findings in the thymus in patients with co-existing MG and thymic hyperplasia or thymomas treated with thymectomy, as well as effects of immunosuppression. Thirty-three patients with MG were selected and grouped accordingly: patients with no thymic abnormalities, patients with thymic hyperplasia, and patients with thymomas. All patients were treated with methylprednisolone alongside immunosuppression. A separate cohort of 24 MG patients with thymic hyperplasia or thymomas and treated with thymectomy were selected. As controls, 5 patients with thymomas or thymic carcinoma without MG were selected. Expression of CD5, extracellular regulated protein kinases1/2 mitogen activated protein kinase (ERK1/2MAPKs) and CD95 ligand (FasL) in the thymus was examined. Methylprednisolone and immunosuppressive therapy are highly effective in MG patients with normal thymus tissue and MG patients with thymic hyperplasia compared to MG patients with thymomas alone. CD5 expression was highest in MG patients with thymic hyperplasia, correlating with expression of ERK1/2MAPKs. FasL expression was similar across all groups. Thymomas may be distinguished from thymic hyperplasia by expression of CD5 and ERK1/2MAPKs. Thymectomy is the preferred treatment for MG patients with thymomas but may not be necessary in MG patients with thymic hyperplasia who are treated with immunosuppressive therapy.

[Association of glucocorticoid receptor gene polymorphism with myasthenia gravis].

OBJECTIVE: To investigate the association of two glucocorticoid receptor (GR) polymorphisms (BclI, ER22/23EK) with Myasthenia Gravis (MG). METHODS: The genotypes of GR in 61 MG patients (MGG) and 57 age and gender-matched healthy controls (HCG) were determined by polymerase chain reaction and nucleotide sequence determination. RESULTS: The frequencies of three genotypes (GG, CG, CC) in BclIwere 3.3%, 34.4%, 62.3% in MGG and 3.5%, 38.6%, 57.9%in HCG respectively. The difference in the distribution of genotypes between MGG and HCG was statistically insignificant (P = 0.887). The frequencies of G and C allele were 20.5% vs 79.5 %in MGG, and 22.8% vs 77.2% in HCG. The difference in the distribution of alleles between MGG and HCG was statistically insignificant (P = 0.968). The genotype frequencies in two groups were both in Hardy-Weinberg equilibrium (P > 0.05). The genotypes of ER22/23EK in MGG and HCG were all GG and no mutation was detected. CONCLUSION: BclI and ER22/23EK polymorphisms of GR have no definite relationship with the risk of MG.

[The expression and clinical implications of glucocorticoid receptor isoforms in peripheral blood mononuclear cells in myasthenia gravis].

OBJECTIVE: To evaluate the expression of glucocorticoid receptor (GR) alpha and GRbeta in peripheral blood mononuclear cells (PBMC) from patients of myasthenia gravis (MG). To investigate the relationship between the expression level of GR and glucocorticoid (GC) therapeutic effects to MG patients. METHODS: The clinical score was recorded and used to assessing the therapeutic effects. Then the expression level of GRalpha and GRbeta in PBMC by immunocytochemistry was measured. We analysed the relationship of the therapeutic effects with expression level of GR. RESULTS: The scores of GRalpha positive PBMC score were same in healthy-control group, GC sensitive group, and GC dependent group. But GRalpha positive PBMC score in GC resistance group was decreased compared with the others (P < 0.01). The scores of GRbeta positive PBMC score were same in healthy-control group, GC sensitive group, and GC resistant group. But GRbeta positive PBMC score in GC dependent group was increased compared with the others (P < 0.01). CONCLUSIONS: The expression of GRalpha in GC resistant group are decreased, and the expression of GRbeta in GC dependence group is increased. The expression level of GRalpha or GRbeta is associated with the effect of GC in treatment of MG.

[Neuropsychiatric symptoms in dementia and elderly people in the community: results from the Beijing Dementia Cooperative Study].

OBJECTIVE: To determine the prevalence of neuropsychiatric symptoms in dementia and normal elderly people living in the Chinese community of Beijing. METHODS: A cross-sectional study derived from the Beijing Dementia Cooperative Study was carried out a population survey was carried out on a total of 1540 participants aged 65 years and older living in Beijing city and rural areas. All the individuals and 373 demented elderly people completed a series of neuropsychological examination and the Neuropsychiatric Inventory (NPI). RESULTS: Among the dementia participants, 49.33% had exhibited neuropsychiatric symptoms (35.66% rated as clinically significant), in which 80.4% reported 2 or more disturbances, with depression (23.86%), apathy (21.72%) and anxiety (20.38%) being most common. Of the 1540 normal individuals, 18.25% of them exhibited neuropsychiatric symptoms (6.49% rated as clinically significant), in which 53% reported 2 or more disturbances, with sleepless (10%), depression (8.9%) and anxiety (6.97%) being the most common. CONCLUSION: To our knowledge, this was the first multi-center study on neuropsychiatric disturbances in dementia and cognitive normal elderly people. Neuropsychiatric symptoms occurred mainly in persons with dementia and of clinical severity. Though the neuropsychiatric disturbances reported in cognitive normal individuals were lower and less serious compared to dementia, they should not be neglected. These finding suggested that a screening programme focusing on identifying these symptoms should be included in the physician's diagnostic tools for dementia.

[Study on the mechanism of Alzheimer disease-related gene presenilin-1].

OBJECTIVE: To study the pathogenic mechanism of Alzheimer disease-related gene presenilin-1 (PS-1) mutation causing AD. METHODS: Four neural cells, including SY5Y cell, transgenic cells harboring PS-1 mutation, wild-type PS-1 and lipofectin were measured for neuronal Ca(2+) homeostasis and cell apoptosis. Intracellular calcium antagonist and antioxidant, such as Ginaton and nimodipine, were used in cultured neural cell and neuronal Ca(2+) level and cell apoptosis were examined. RESULTS: Elevation of intracellular calcium level and cell apoptosis induced by amyloid beta-peptide (Abeta) were enhanced in PS-1 mutation cell, as compared with others cells (P < 0.01). Intracellular calcium antagonist and antioxidant could inhibit apoptosis and decrease intracellular calcium level for PS-1 mutation (P > 0.05). There was significant correlation between the percentage of apoptosis and intracellular calcium level for PS-1 mutation. CONCLUSIONS: The pathogenic mechanism of PS-1 gene mutation causing AD was PS-1 mutation enhancing apoptosis by intracellular calcium overload. Intracellular calcium blocker and antioxidant could decrease intracellular calcium overload and inhibit apoptosis.

[The characteristics of enhanced gadolinium DTPA brain magnetic resonance images in 298 multiple sclerosis patients].

OBJECTIVE: To investigate the characteristics of enhanced brain magnetic resonance imaging (MRI) with gadolinium-DTPA (GD) in patients with multiple sclerosis (MS). METHODS: Brain enhanced MRI were studied in 186 patients with clinically definite multiple sclerosis. 298 MRI enhanced lesions were followed every 4 weeks and the study lasted 3 months to 2 years. RESULTS: Of the 298 enhanced MRI lesions 207 (69.5%) lasted less than 4 weeks, 251 (84.2%) 8 weeks, and 272 (91.3%) 12 weeks. There were 3 lesions lasting more than 2 years. Round, oval, ring form, arcuate, spotty, or irregular MRI GD enhanced lesions were found in our MS data. CONCLUSIONS: Most of the MRI GD enhanced lesions disappear in 4 weeks. Very few can last more than 2 years. So it is necessary to perform the GD enhanced MRI in 4 weeks for studying MS intracranial GD enhanced lesions. The DA enhanced MRI lesions in MS may be round, oval, ring form, arcuate, spotty or irregular.

[Phrenic radix conduction time in inflammatory demyelinating polyneuropathy patients].

OBJECTIVE: To investigate the features and application of phrenic radix conduction time (PRCT) in inflammatory demyelinating polyneuropathy (IDP) patients. METHODS: Distal motor latency (DML) was recorded by stimulating phrenic nerve electrically and phrenic nerve root magnetically in 20 IDP patients with surface electrodes at intercostal space. The difference of the two DML was calculated and compared with those recorded previously from 61 sides in 31 healthy control subjects. RESULTS: PRCT of the IDP patients was longer than that of the controls, and it correlated with the severity of clinical dyspnea. The abnormal rate of PRCT was higher than the incidence of clinical dyspnea. CONCLUSIONS: PRCT could reflect the functional status of the spinal roots related to respiration in IDP patients at an electrophysiological level. It correlates well with the degree of clinical dyspnea. Its detection is helpful to find out the subclinical dyspnea in IDP patients.