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 terifluno...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 (7mg and 14mg)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 7mg (n =51), teriflunomide 14mg (n=43),or placebo (n=54). Results:Of the 148patients 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 7mg group,and 0.18(95%CI:0.09,0.36)in the terifltmomide 14mg group;this corresponded to a significant relative risk reduction in the teriflunomide 14mg group versus placebo (-71.2%,P =0.0012).Terifiunomide 14mg 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 7mg group,and 69.8% in the teriflunomide 14mg 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.展开更多
Background： Th9 cells are a newly discovered CD4＋ T helper cell subtype, characterized by high interleukin （IL）-9 secretion. Growing evidences suggest that Th9 cells are involved in the pathogenic mechanism of mul...Background： Th9 cells are a newly discovered CD4＋ T helper cell subtype, characterized by high interleukin （IL）-9 secretion. Growing evidences suggest that Th9 cells are involved in the pathogenic mechanism of multiple sclerosis （MS）. Mast cells are multifunctional innate imnmne cells, which are perhaps best known for their role as dominant effector cells in allergies and asthma. Several lines of evidence point to an important role lbr mast cells in MS and its animal models. Simultaneously, there is dynamic ＂＇cross-talk＂ between Th9 and mast cells. The aim of the present study was to examine the IL-9-mast cell axis in experimental autoimmune encephalomyelitis （EAE） and deternaine its interaction alter neutralizing anti-lL-9 antibody treatment. Methods： Female C57BL/6 mice were randomly divided into three groups （#1 = 5 in each group）： mice with myelin oligodendrocyte glycoprotein （MOG）-induced EAE （EAE group）, EAE mice treated with anti-lL-9 antibody （anti-lL-9 Abs group）, and EAE mice treated with IgG isotype control （lgG group）. EAE clinical score was evaluated. Mast cells from central nervous system （CNS） were detected by flow cytometry. The production of chemokine recruiting mast cells in the CNS was explored by reverse transcription-polymerase chain reaction （RT-PCR）. In mice with MOG-induced EAE, the expression of IL-9 receptor （IL-9R） complexes in CNS and spleen mast cells was also explored by RT-PCR, and then was repeating validated by immunocytochemistry. In vitro, spleen cells from EAE mice were cultured with anti-lL-9 antibody, and quantity of mast cells was counted by flow cytoinetry alter co-culture. Results： Compared with IgG group, IL-9 blockade delayed clinical disease onset and ameliorated EAE severity （t = -2.217, P- 0.031 ）, accompany with mast cells infiltration decreases （day 5： t = -8.005, P 〈 0.001; day 15： t = -11.857, P 〈 0.001; day 20： t- 5.243, P = 0.001 ） in anti-lL-9 Abs group. The messenger RNA expressions of C-C motif chemokine ligand 5 （t = -5.932, P = 0.003） and vascular cell adhesion molecule-I （t = -4.029, P 0.004） were significantly decreased alter 1L-9 neutralization in anti-lL-9 Abs group, compared with lgG group. In MOG-induced EAE, the 1L-9R complexes were expressed in CNS and spleen mast cells. 1#7 vitro, splenocyles cultured with anti-lL-9 antibody showed significantly lower levels of mast cells in a dose-dependent manner, compared with splenocytes cultured with anti-mouse lgG （5 μg/ml： t = -0.894, P = 0.397; 10 p-g/ml： t = -3.348, P - 0.019：20 μg/ml： I - -7.639, P 〈 0.001 ）.Conclusions： This study revealed that 1L-9 neutralization reduced mast cell infiltration in CNS and ameliorated EAE, which might be relate to the interaction between IL-9 and mast cells.展开更多
Chronic inflammatory demyelinating polyradiculoneuropathy, or chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune-mediated inflammatory disorder at the peripheral nervous system, in which th...Chronic inflammatory demyelinating polyradiculoneuropathy, or chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune-mediated inflammatory disorder at the peripheral nervous system, in which the progression is chronic and also remission relapse. In most cases, it is also associated with cerebrospinal fluid (CSF) protein-cell separation. Electrophysiologically, the peripheral nerve conduction velocity decreases, blocks and characterized as discrete abnormal waveform. Pathologically, there is also multifocal demyelination of myelinated fibers, nerve endometrial edema, inflammatory cell infiltration, etc.展开更多
文摘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 (7mg and 14mg)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 7mg (n =51), teriflunomide 14mg (n=43),or placebo (n=54). Results:Of the 148patients 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 7mg group,and 0.18(95%CI:0.09,0.36)in the terifltmomide 14mg group;this corresponded to a significant relative risk reduction in the teriflunomide 14mg group versus placebo (-71.2%,P =0.0012).Terifiunomide 14mg 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 7mg group,and 69.8% in the teriflunomide 14mg 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.
文摘Background： Th9 cells are a newly discovered CD4＋ T helper cell subtype, characterized by high interleukin （IL）-9 secretion. Growing evidences suggest that Th9 cells are involved in the pathogenic mechanism of multiple sclerosis （MS）. Mast cells are multifunctional innate imnmne cells, which are perhaps best known for their role as dominant effector cells in allergies and asthma. Several lines of evidence point to an important role lbr mast cells in MS and its animal models. Simultaneously, there is dynamic ＂＇cross-talk＂ between Th9 and mast cells. The aim of the present study was to examine the IL-9-mast cell axis in experimental autoimmune encephalomyelitis （EAE） and deternaine its interaction alter neutralizing anti-lL-9 antibody treatment. Methods： Female C57BL/6 mice were randomly divided into three groups （#1 = 5 in each group）： mice with myelin oligodendrocyte glycoprotein （MOG）-induced EAE （EAE group）, EAE mice treated with anti-lL-9 antibody （anti-lL-9 Abs group）, and EAE mice treated with IgG isotype control （lgG group）. EAE clinical score was evaluated. Mast cells from central nervous system （CNS） were detected by flow cytometry. The production of chemokine recruiting mast cells in the CNS was explored by reverse transcription-polymerase chain reaction （RT-PCR）. In mice with MOG-induced EAE, the expression of IL-9 receptor （IL-9R） complexes in CNS and spleen mast cells was also explored by RT-PCR, and then was repeating validated by immunocytochemistry. In vitro, spleen cells from EAE mice were cultured with anti-lL-9 antibody, and quantity of mast cells was counted by flow cytoinetry alter co-culture. Results： Compared with IgG group, IL-9 blockade delayed clinical disease onset and ameliorated EAE severity （t = -2.217, P- 0.031 ）, accompany with mast cells infiltration decreases （day 5： t = -8.005, P 〈 0.001; day 15： t = -11.857, P 〈 0.001; day 20： t- 5.243, P = 0.001 ） in anti-lL-9 Abs group. The messenger RNA expressions of C-C motif chemokine ligand 5 （t = -5.932, P = 0.003） and vascular cell adhesion molecule-I （t = -4.029, P 0.004） were significantly decreased alter 1L-9 neutralization in anti-lL-9 Abs group, compared with lgG group. In MOG-induced EAE, the 1L-9R complexes were expressed in CNS and spleen mast cells. 1#7 vitro, splenocyles cultured with anti-lL-9 antibody showed significantly lower levels of mast cells in a dose-dependent manner, compared with splenocytes cultured with anti-mouse lgG （5 μg/ml： t = -0.894, P = 0.397; 10 p-g/ml： t = -3.348, P - 0.019：20 μg/ml： I - -7.639, P 〈 0.001 ）.Conclusions： This study revealed that 1L-9 neutralization reduced mast cell infiltration in CNS and ameliorated EAE, which might be relate to the interaction between IL-9 and mast cells.
文摘Chronic inflammatory demyelinating polyradiculoneuropathy, or chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune-mediated inflammatory disorder at the peripheral nervous system, in which the progression is chronic and also remission relapse. In most cases, it is also associated with cerebrospinal fluid (CSF) protein-cell separation. Electrophysiologically, the peripheral nerve conduction velocity decreases, blocks and characterized as discrete abnormal waveform. Pathologically, there is also multifocal demyelination of myelinated fibers, nerve endometrial edema, inflammatory cell infiltration, etc.
