Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions.They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute cour...Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions.They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute course contingent upon the site of damage.The main types include amyotrophic lateral sclerosis,progressive muscular atrophy,primary lateral sclerosis,and progressive bulbar palsy,the pathological processes of which are largely identical,with the main disparity lying in the location of the lesions.Amyotrophic lateral sclerosis is the representative condition in this group of diseases,while other types are its variants.Hence,this article mainly focuses on the advancements and challenges in drug research for amyotrophic lateral sclerosis but also briefly addresses several other important degenerative motor neuron diseases.Although the precise pathogenesis remains elusive,recent advancements have shed light on various theories,including gene mutation,excitatory amino acid toxicity,autoimmunology,and neurotrophic factors.The US Food and Drug Administration has approved four drugs for use in delaying the progression of amyotrophic lateral sclerosis:riluzole,edaravone,AMX0035,and tofersen,with the latter being the most recent to receive approval.However,following several phaseⅢtrials that failed to yield favorable outcomes,AMX0035 has been voluntarily withdrawn from both the US and Canadian markets.This article presents a comprehensive summary of drug trials primarily completed between January 1,2023,and June 30,2024,based on data sourced from clinicaltrials.gov.Among these trials,five are currently in phaseⅠ,seventeen are in phaseⅡ,and eleven are undergoing phaseⅢevaluation.Notably,24 clinical trials are now investigating potential disease-modifying therapy drugs,accounting for the majority of the drugs included in this review.Some promising drugs being investigated in preclinical studies,such as ATH-1105,are included in our analysis,and another review in frontiers in gene therapy and immunotherapy has demonstrated their therapeutic potential for motor neuron diseases.This article was written to be an overview of research trends and treatment prospects related to motor neuron disease drugs,with the aim of highlighting the latest potentialities for clinical therapy.展开更多
Use of immunomodulating agents to prevent the progression of autoimmuneβ-cell damage leading to type 1 diabetes mellitus(T1DM)is an interesting area for research.These include non-specific anti-inflammatory agents,im...Use of immunomodulating agents to prevent the progression of autoimmuneβ-cell damage leading to type 1 diabetes mellitus(T1DM)is an interesting area for research.These include non-specific anti-inflammatory agents,immunologic vaccination and anti-inflammatory agents targeting specific immune cells or cytokines.Teplizumab is an anti-CD3-molecule that binds to and leads to the disappearance of the CD3/TCR complex and rendering the T cell anergic to its target antigen.Preclinical and clinical trials have demonstrated its efficacy in reducing the decline in serum C-peptide levels and the need for insulin therapy if used early in the disease process of T1DM.The benefits have been apparent as early as six months to as long as seven years after therapy.It has recently been approved by the Food and Drug Administration to delay the onset of clinical(stage 3)type 1 diabetes in children above 8 years of age.In their recent metaanalysis published in the World Journal of Diabetes,Ma et al found that those in the teplizumab treatment group have a greater likelihood of reduction in insulin use,change in C-peptide response,and better glycemic control compared to the control group with a good safety profile.However,all the included randomized control trials have been conducted in high-income countries.High cost of therapy and unknown utility of the molecule in stage 3 disease limit its widespread use.展开更多
Amyotrophic lateral sclerosis（ALS）is a progressively fatal neuromuscular disorder classically characterized by loss of upper and lower motor neurons from the cortex to the spinal cord Diagnosed patients have a media...Amyotrophic lateral sclerosis（ALS）is a progressively fatal neuromuscular disorder classically characterized by loss of upper and lower motor neurons from the cortex to the spinal cord Diagnosed patients have a median survival of about 3 years and death usually results from eventual respiratory failure.展开更多
Objective Modified upper abdominal cluster transplantation ( MCT) ,which was inspired by classical cluster transplant technique,has been proven more effective and feasible in the treatment of patients with end stage l...Objective Modified upper abdominal cluster transplantation ( MCT) ,which was inspired by classical cluster transplant technique,has been proven more effective and feasible in the treatment of patients with end stage liver diseases associated with insulin - dependent展开更多
Multiple sclerosis （MS） is a chronic and devastating autoimmune demyelinating disease of the central nervous system. With the increased understanding of the pathophysiology of this disease in the past two decades, m...Multiple sclerosis （MS） is a chronic and devastating autoimmune demyelinating disease of the central nervous system. With the increased understanding of the pathophysiology of this disease in the past two decades, many disease-modifying therapies that primarily target adaptive immunity have been shown to prevent exacerbations and new lesions in patients with relapsing-remitting MS. However, these therapies only have limited efficacy on the progression of disability. Increasing evidence has pointed to innate immunity, axonal damage and neuronal loss as important contributors to disease progression. Remyelination of denuded axons is considered an effective way to protect neurons from damage and to restore neuronal function. The identification of several key molecules and pathways controlling the differentiation of oligodendrocyte progenitor cells and myelination has yielded clues for the development of drug candidates that directly target remyelination and neuroprotection. The long-term efficacy of this strategy remains to be evaluated in clinical trials. Here, we provide an overview of current and emerging therapeutic concepts, with a focus on the opportunities and challenges for the remyelination approach to the treatment of MS.展开更多
Huntington＇s disease （HD） is an autosomal-dominant neurodegenerative disease characterized by the selec- tive loss of neurons in the striatum and cortex, leading to progressive motor dysfunction, cognitive decline ...Huntington＇s disease （HD） is an autosomal-dominant neurodegenerative disease characterized by the selec- tive loss of neurons in the striatum and cortex, leading to progressive motor dysfunction, cognitive decline and behavioral symptoms. HD is caused by a trinucleotide （CAG） repeat expansion in the gene encoding for huntingtin. Several studies have suggested that inflammation is an important feature of HD and it is already observed in the early stages of the disease. Recently, new molecules presenting anti-inflammatory and/or immunomodulatory have been investigated for HD. The objective of this review is to discuss the data obtained so far on the immune-based therapeutic strategies for HD.展开更多
AIM To evaluate the outcomes in biological treatment and quality of life of psoriatic patients with chronic hepatitis C(CHC)treated with new Direct-Acting Antiviral agents(DAAs)compared to pegylated interferon-2αplus...AIM To evaluate the outcomes in biological treatment and quality of life of psoriatic patients with chronic hepatitis C(CHC)treated with new Direct-Acting Antiviral agents(DAAs)compared to pegylated interferon-2αplus ribavirin(P/R)therapy.METHODS This is a retrospective study involving psoriatic patients in biological therapy who underwent anti-hepatitis C virus(HCV)treatment at the Department of Dermatology Galeazzi Orthopaedic Institute Milan,Italy from January 2010 to November 2017.The patients were divided into two groups:patients that underwent therapy with DAAs and patients that underwent HCV treatment with P/R.Patients were assessed by a dermatologist for psoriasis symptoms,collecting Psoriasis Area Severity Index(PASI)scores and the Dermatology Quality of Life Index(DLQI).PASI and DLQI scores were evaluated 24 wk after the end of HCV treatment and were assumed as an outcome of the progression of psoriasis.Switching to a different b DMARD was considered as an inadequate response to biological therapy.The dropout of HCV therapy and sustained virological response(SVR)were considered as outcomes of HCV therapy.RESULTS Fifty-nine psoriatic patients in biological therapy underwent antiviral therapy for CHC.Of this,27 patients were treated with DAAs and 32 with P/R.After 24 wk post treatment,the DLQI and the PASI scores were significantly lower(P<0.001 and P<0.005,respectively)in the DAAs group compared with P/R group.None of the patients in the DAAs group(0/27)compared to 8 patients of the P/R group(8/32)needed a shift in biological treatment.CONCLUSION DAAs seem to be more effective and safe than P/R in HCV-positive psoriatic patients on biological treatment.Fewer dermatological adverse events may be due to interferon-free therapy.展开更多
Background:Clinical remission is the treatment target in rheumatoid arthritis(RA).This study aimed to investigate clinical remission and related factors in a large cohort of patients with RA.Methods:This study compose...Background:Clinical remission is the treatment target in rheumatoid arthritis(RA).This study aimed to investigate clinical remission and related factors in a large cohort of patients with RA.Methods:This study composed of 342 patients with RA.Data were collected by face-to-face interview of 1049 patients with RA who visited the Department of Rheumatology of three teaching hospitals from September 2015 to May 2016.The patients with RA were clinically assessed by rheumatologists and a four-page questionnaire was completed on site.Subsequently,patients fulfilled remission criteria were further analyzed.The practicability of different definitions of remission of RA was rated by a panel of rheumatologists.Sustained intensive disease modifying anti-rheumatic drug(DMARD)treatment was defined as a combination treatment with two or more DMARDs for at least 6 months.Results:In this cohort of 342 patients with RA,the proportions of patients achieving remission were 38.0%,29.5%,24.9%,21.1%,19.0%,18.1%,and 17.0%,based on criteria of disease activity score in 28 joints(DAS28)using CRP(DAS28-CRP),DAS28 using ESR(DAS28-ESR),routine assessment of patient index data 3(RAPID-3),Boolean,simplified disease activity index(SDAI),clinical disease activity index,and the newly described clinical deep remission(CliDR),respectively.Boolean and CliDR are the best in practicability scored by rheumatologists(7.5 and 8.0,respectively).Compared with the non-sustained intensive group,sustained intensive treatment with DMARDs yielded higher remission rates of 25.6%,23.8%,and 21.3%in patients with RA based on Boolean(χ^2=3.937,P=0.047),SDAI(χ^2=4.666,P=0.031),and CliDR criteria(χ^2=4.297,P=0.038).The most commonly prescribed conventional synthesized DMARDs(csDMARDs)in patients with RA was leflunomide,followed by methotrexate,and hydroxychloroquine.Compared with the non-remission group,patients achieving remission had a longer median duration of DMARDs(45.0[22.8–72.3]months,Z=-2.295,P=0.022).Conclusions:The findings in this study indicated that clinical deep remission is achievable in patients with RA.Sustained intensive DMARD treatment is needed to achieve a better outcome in RA.展开更多
A 30-year-old female patient with coexisting ankylosing spondylitis and rheumatoid arthritis was diagnosed and treated. The human leukocyte antigen （HLA）-B27 is a predisposing factor of ankylosing spondylitis and HL...A 30-year-old female patient with coexisting ankylosing spondylitis and rheumatoid arthritis was diagnosed and treated. The human leukocyte antigen （HLA）-B27 is a predisposing factor of ankylosing spondylitis and HLA-DR4 is a predisposing factor of rheumatoid arthritis. This patient was HLA-B27 and HLA-DR4 positive, and ankylosing spondylitis manifested before rheumatoid arthritis. After disease modifying anti-rheumatic drugs successfully arrested ankylosing spondylitis activity the patient conceived and delivered a healthy baby. One year later, she developed peripheral polyarthritis and was diagnosed with rheumatoid arthritis. We hypothesized that pregnancy may be one of the environmental factors that can activate rheumatoid arthritis, and that disease modifying anti-rheumatic drugs play an important role in keeping the disease under control.展开更多
Background:Disease modifying therapies(DMTs)are urgently needed for neurodegenerative diseases(NDD)such as Alzheimer’s disease(AD)and many other disorders characterized by protein aggregation and neurodegeneration.De...Background:Disease modifying therapies(DMTs)are urgently needed for neurodegenerative diseases(NDD)such as Alzheimer’s disease(AD)and many other disorders characterized by protein aggregation and neurodegeneration.Despite advances in understanding the neurobiology of NDD,there are no approved DMTs.Discussion:Defining disease-modification is critical to drug-development programs.A DMT is an intervention that produces an enduring change in the trajectory of clinical decline of an NDD by impacting the disease processes leading to nerve cell death.A DMT is neuroprotective,and neuroprotection will result in disease modification.Disease modification can be demonstrated in clinical trials by a drug-placebo difference in clinical outcomes supported by a drug-placebo difference on biomarkers reflective of the fundamental pathophysiology of the NDD.Alternatively,disease modification can be supported by findings on a staggered start or delayed withdrawal clinical trial design.Collecting multiple biomarkers is necessary to support a comprehensive view of disease modification.Conclusion:Disease modification is established by demonstrating an enduring change in the clinical trajectory of an NDD based on intervention in the fundamental pathophysiology of the disease leading to nerve cell death.Supporting data are collected in clinical trials.Effectively defining a DMT will assist in NDD drug development programs.展开更多
Background:Chronic antibiotic-refractory pouchitis(CARP)is a complication of ileal pouch-anal anastomosis(IPAA),which poses a therapeutic challenge.Vedolizumab,a gut-selective monoclonal antibody to the a4b7 of integr...Background:Chronic antibiotic-refractory pouchitis(CARP)is a complication of ileal pouch-anal anastomosis(IPAA),which poses a therapeutic challenge.Vedolizumab,a gut-selective monoclonal antibody to the a4b7 of integrin,has been used in such patients,but data on its efficacy are limited.Our aim was to assess the efficacy and safety of vedolizumab as induction therapy in CARP patients.Methods:In this single-center,historic cohort,patients with CARP who received vedolizumab between January 2015 to June 2017 were identified and analysed.Patients were included if they had active pouchitis with a total of modified pouch disease activity index(mPDAI)score5 or if unavailable clinician diagnosis of active pouchitis.Pre-treatment and at 3-month posttherapy pouchoscopy and clinical visits were used to calculate mPDAI.Results:A total of 19 patients were included in the study.The mean age was 26.7612.8 years,with 10(53%)males.Nine(47%)patients had been treated with anti-tumor necrosis factor(TNF)agents before colectomy and 10(53%)had anti-TNFs after colectomy and IPAA.Six(32%)patients had improvement in the mPDAI symptom subscores(P=0.031)and 14(74%)had improvement in both endoscopic and total mPDAI scores with a median change of-2 units(both P=0.031).Adverse events were noted only in two(11%)patients and four(21%)required surgery for CARP.Conclusions:Our study suggests that vedolizumab has efficacy and can be safely used for CARP patients.Larger studies with a higher number of patients are required to confirm these findings.展开更多
基金supported by the National Key Research and Development Program of China,No.2022YFC2703101(to YC)the National Natural Science Fundation of China,No.82371422(to YC)+1 种基金the National Innovation and Entrepreneurship Training Program for College Students,No.202310611408(to XW)the 1·3·5 Project for Disciplines of Excellence Clinical Research Fund,West China Hospital,Sichuan University,No.2023HXFH032(to YC)。
文摘Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions.They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute course contingent upon the site of damage.The main types include amyotrophic lateral sclerosis,progressive muscular atrophy,primary lateral sclerosis,and progressive bulbar palsy,the pathological processes of which are largely identical,with the main disparity lying in the location of the lesions.Amyotrophic lateral sclerosis is the representative condition in this group of diseases,while other types are its variants.Hence,this article mainly focuses on the advancements and challenges in drug research for amyotrophic lateral sclerosis but also briefly addresses several other important degenerative motor neuron diseases.Although the precise pathogenesis remains elusive,recent advancements have shed light on various theories,including gene mutation,excitatory amino acid toxicity,autoimmunology,and neurotrophic factors.The US Food and Drug Administration has approved four drugs for use in delaying the progression of amyotrophic lateral sclerosis:riluzole,edaravone,AMX0035,and tofersen,with the latter being the most recent to receive approval.However,following several phaseⅢtrials that failed to yield favorable outcomes,AMX0035 has been voluntarily withdrawn from both the US and Canadian markets.This article presents a comprehensive summary of drug trials primarily completed between January 1,2023,and June 30,2024,based on data sourced from clinicaltrials.gov.Among these trials,five are currently in phaseⅠ,seventeen are in phaseⅡ,and eleven are undergoing phaseⅢevaluation.Notably,24 clinical trials are now investigating potential disease-modifying therapy drugs,accounting for the majority of the drugs included in this review.Some promising drugs being investigated in preclinical studies,such as ATH-1105,are included in our analysis,and another review in frontiers in gene therapy and immunotherapy has demonstrated their therapeutic potential for motor neuron diseases.This article was written to be an overview of research trends and treatment prospects related to motor neuron disease drugs,with the aim of highlighting the latest potentialities for clinical therapy.
文摘Use of immunomodulating agents to prevent the progression of autoimmuneβ-cell damage leading to type 1 diabetes mellitus(T1DM)is an interesting area for research.These include non-specific anti-inflammatory agents,immunologic vaccination and anti-inflammatory agents targeting specific immune cells or cytokines.Teplizumab is an anti-CD3-molecule that binds to and leads to the disappearance of the CD3/TCR complex and rendering the T cell anergic to its target antigen.Preclinical and clinical trials have demonstrated its efficacy in reducing the decline in serum C-peptide levels and the need for insulin therapy if used early in the disease process of T1DM.The benefits have been apparent as early as six months to as long as seven years after therapy.It has recently been approved by the Food and Drug Administration to delay the onset of clinical(stage 3)type 1 diabetes in children above 8 years of age.In their recent metaanalysis published in the World Journal of Diabetes,Ma et al found that those in the teplizumab treatment group have a greater likelihood of reduction in insulin use,change in C-peptide response,and better glycemic control compared to the control group with a good safety profile.However,all the included randomized control trials have been conducted in high-income countries.High cost of therapy and unknown utility of the molecule in stage 3 disease limit its widespread use.
基金supported by the NUS Graduate School for Integrative Sciences and Engineering
文摘Amyotrophic lateral sclerosis（ALS）is a progressively fatal neuromuscular disorder classically characterized by loss of upper and lower motor neurons from the cortex to the spinal cord Diagnosed patients have a median survival of about 3 years and death usually results from eventual respiratory failure.
文摘Objective Modified upper abdominal cluster transplantation ( MCT) ,which was inspired by classical cluster transplant technique,has been proven more effective and feasible in the treatment of patients with end stage liver diseases associated with insulin - dependent
文摘Multiple sclerosis （MS） is a chronic and devastating autoimmune demyelinating disease of the central nervous system. With the increased understanding of the pathophysiology of this disease in the past two decades, many disease-modifying therapies that primarily target adaptive immunity have been shown to prevent exacerbations and new lesions in patients with relapsing-remitting MS. However, these therapies only have limited efficacy on the progression of disability. Increasing evidence has pointed to innate immunity, axonal damage and neuronal loss as important contributors to disease progression. Remyelination of denuded axons is considered an effective way to protect neurons from damage and to restore neuronal function. The identification of several key molecules and pathways controlling the differentiation of oligodendrocyte progenitor cells and myelination has yielded clues for the development of drug candidates that directly target remyelination and neuroprotection. The long-term efficacy of this strategy remains to be evaluated in clinical trials. Here, we provide an overview of current and emerging therapeutic concepts, with a focus on the opportunities and challenges for the remyelination approach to the treatment of MS.
文摘Huntington＇s disease （HD） is an autosomal-dominant neurodegenerative disease characterized by the selec- tive loss of neurons in the striatum and cortex, leading to progressive motor dysfunction, cognitive decline and behavioral symptoms. HD is caused by a trinucleotide （CAG） repeat expansion in the gene encoding for huntingtin. Several studies have suggested that inflammation is an important feature of HD and it is already observed in the early stages of the disease. Recently, new molecules presenting anti-inflammatory and/or immunomodulatory have been investigated for HD. The objective of this review is to discuss the data obtained so far on the immune-based therapeutic strategies for HD.
文摘AIM To evaluate the outcomes in biological treatment and quality of life of psoriatic patients with chronic hepatitis C(CHC)treated with new Direct-Acting Antiviral agents(DAAs)compared to pegylated interferon-2αplus ribavirin(P/R)therapy.METHODS This is a retrospective study involving psoriatic patients in biological therapy who underwent anti-hepatitis C virus(HCV)treatment at the Department of Dermatology Galeazzi Orthopaedic Institute Milan,Italy from January 2010 to November 2017.The patients were divided into two groups:patients that underwent therapy with DAAs and patients that underwent HCV treatment with P/R.Patients were assessed by a dermatologist for psoriasis symptoms,collecting Psoriasis Area Severity Index(PASI)scores and the Dermatology Quality of Life Index(DLQI).PASI and DLQI scores were evaluated 24 wk after the end of HCV treatment and were assumed as an outcome of the progression of psoriasis.Switching to a different b DMARD was considered as an inadequate response to biological therapy.The dropout of HCV therapy and sustained virological response(SVR)were considered as outcomes of HCV therapy.RESULTS Fifty-nine psoriatic patients in biological therapy underwent antiviral therapy for CHC.Of this,27 patients were treated with DAAs and 32 with P/R.After 24 wk post treatment,the DLQI and the PASI scores were significantly lower(P<0.001 and P<0.005,respectively)in the DAAs group compared with P/R group.None of the patients in the DAAs group(0/27)compared to 8 patients of the P/R group(8/32)needed a shift in biological treatment.CONCLUSION DAAs seem to be more effective and safe than P/R in HCV-positive psoriatic patients on biological treatment.Fewer dermatological adverse events may be due to interferon-free therapy.
基金the grants from the National Natural Science Foundation of China(No.31530020 and No.81401329)Beijing Sci-Tech Program(No.Z171100000417007).
文摘Background:Clinical remission is the treatment target in rheumatoid arthritis(RA).This study aimed to investigate clinical remission and related factors in a large cohort of patients with RA.Methods:This study composed of 342 patients with RA.Data were collected by face-to-face interview of 1049 patients with RA who visited the Department of Rheumatology of three teaching hospitals from September 2015 to May 2016.The patients with RA were clinically assessed by rheumatologists and a four-page questionnaire was completed on site.Subsequently,patients fulfilled remission criteria were further analyzed.The practicability of different definitions of remission of RA was rated by a panel of rheumatologists.Sustained intensive disease modifying anti-rheumatic drug(DMARD)treatment was defined as a combination treatment with two or more DMARDs for at least 6 months.Results:In this cohort of 342 patients with RA,the proportions of patients achieving remission were 38.0%,29.5%,24.9%,21.1%,19.0%,18.1%,and 17.0%,based on criteria of disease activity score in 28 joints(DAS28)using CRP(DAS28-CRP),DAS28 using ESR(DAS28-ESR),routine assessment of patient index data 3(RAPID-3),Boolean,simplified disease activity index(SDAI),clinical disease activity index,and the newly described clinical deep remission(CliDR),respectively.Boolean and CliDR are the best in practicability scored by rheumatologists(7.5 and 8.0,respectively).Compared with the non-sustained intensive group,sustained intensive treatment with DMARDs yielded higher remission rates of 25.6%,23.8%,and 21.3%in patients with RA based on Boolean(χ^2=3.937,P=0.047),SDAI(χ^2=4.666,P=0.031),and CliDR criteria(χ^2=4.297,P=0.038).The most commonly prescribed conventional synthesized DMARDs(csDMARDs)in patients with RA was leflunomide,followed by methotrexate,and hydroxychloroquine.Compared with the non-remission group,patients achieving remission had a longer median duration of DMARDs(45.0[22.8–72.3]months,Z=-2.295,P=0.022).Conclusions:The findings in this study indicated that clinical deep remission is achievable in patients with RA.Sustained intensive DMARD treatment is needed to achieve a better outcome in RA.
文摘A 30-year-old female patient with coexisting ankylosing spondylitis and rheumatoid arthritis was diagnosed and treated. The human leukocyte antigen （HLA）-B27 is a predisposing factor of ankylosing spondylitis and HLA-DR4 is a predisposing factor of rheumatoid arthritis. This patient was HLA-B27 and HLA-DR4 positive, and ankylosing spondylitis manifested before rheumatoid arthritis. After disease modifying anti-rheumatic drugs successfully arrested ankylosing spondylitis activity the patient conceived and delivered a healthy baby. One year later, she developed peripheral polyarthritis and was diagnosed with rheumatoid arthritis. We hypothesized that pregnancy may be one of the environmental factors that can activate rheumatoid arthritis, and that disease modifying anti-rheumatic drugs play an important role in keeping the disease under control.
基金JC acknowledges funding from the National Institute of General Medical Sciences(Grant:P20GM109025)and support from Keep Memory Alive.
文摘Background:Disease modifying therapies(DMTs)are urgently needed for neurodegenerative diseases(NDD)such as Alzheimer’s disease(AD)and many other disorders characterized by protein aggregation and neurodegeneration.Despite advances in understanding the neurobiology of NDD,there are no approved DMTs.Discussion:Defining disease-modification is critical to drug-development programs.A DMT is an intervention that produces an enduring change in the trajectory of clinical decline of an NDD by impacting the disease processes leading to nerve cell death.A DMT is neuroprotective,and neuroprotection will result in disease modification.Disease modification can be demonstrated in clinical trials by a drug-placebo difference in clinical outcomes supported by a drug-placebo difference on biomarkers reflective of the fundamental pathophysiology of the NDD.Alternatively,disease modification can be supported by findings on a staggered start or delayed withdrawal clinical trial design.Collecting multiple biomarkers is necessary to support a comprehensive view of disease modification.Conclusion:Disease modification is established by demonstrating an enduring change in the clinical trajectory of an NDD based on intervention in the fundamental pathophysiology of the disease leading to nerve cell death.Supporting data are collected in clinical trials.Effectively defining a DMT will assist in NDD drug development programs.
文摘Background:Chronic antibiotic-refractory pouchitis(CARP)is a complication of ileal pouch-anal anastomosis(IPAA),which poses a therapeutic challenge.Vedolizumab,a gut-selective monoclonal antibody to the a4b7 of integrin,has been used in such patients,but data on its efficacy are limited.Our aim was to assess the efficacy and safety of vedolizumab as induction therapy in CARP patients.Methods:In this single-center,historic cohort,patients with CARP who received vedolizumab between January 2015 to June 2017 were identified and analysed.Patients were included if they had active pouchitis with a total of modified pouch disease activity index(mPDAI)score5 or if unavailable clinician diagnosis of active pouchitis.Pre-treatment and at 3-month posttherapy pouchoscopy and clinical visits were used to calculate mPDAI.Results:A total of 19 patients were included in the study.The mean age was 26.7612.8 years,with 10(53%)males.Nine(47%)patients had been treated with anti-tumor necrosis factor(TNF)agents before colectomy and 10(53%)had anti-TNFs after colectomy and IPAA.Six(32%)patients had improvement in the mPDAI symptom subscores(P=0.031)and 14(74%)had improvement in both endoscopic and total mPDAI scores with a median change of-2 units(both P=0.031).Adverse events were noted only in two(11%)patients and four(21%)required surgery for CARP.Conclusions:Our study suggests that vedolizumab has efficacy and can be safely used for CARP patients.Larger studies with a higher number of patients are required to confirm these findings.
