Therapeutic drug monitoring(TDM)was one of most sought-after objective tools to determine therapeutic efficiency of different biologics and its role in the management of patients with inflammatory bowel disease(IBD)wa...Therapeutic drug monitoring(TDM)was one of most sought-after objective tools to determine therapeutic efficiency of different biologics and its role in the management of patients with inflammatory bowel disease(IBD)was regarded with great anticipation.But implementation of the TDM in clinical practice was challenged by several factors including uncertainty of the optimal cut-off values,assay variable sensitivity in detecting drug levels and antibodies and,most importantly,individual pharmacokinetics.While reactive TDM was embraced in clinical practice as a useful tool in assessing lack of response to therapy,the utility of proactive TDM in managing IBD therapy is still challenged by the lack of consistency between evidence.Described here,there are four groups of IBD patients for whom proactive TDM has the potential to greatly impact their therapeutic outcomes:Patients with perianal Crohn’s disease,patients with severe ulcerative colitis,pregnant women with IBD and children.As the future of IBD management moves towards personalizing treatment,TDM will be an important decision node in a machine learning based algorithm predicting the best strategy to maximize treatment results while minimizing the loss of response to therapy.展开更多
BACKGROUND The existence of genetic anticipation has been long disputed in inflammatory bowel disease(IBD)in the absence of the explanatory mechanism.AIM To determine whether it was predictive of genetic anticipation,...BACKGROUND The existence of genetic anticipation has been long disputed in inflammatory bowel disease(IBD)in the absence of the explanatory mechanism.AIM To determine whether it was predictive of genetic anticipation,we evaluated telomere length in IBD.We hypothesized that multiplex IBD families exhibit a genetic defect impacting telomere maintenance mechanisms.METHODS We studied three IBD families with multiple affected members in three successive generations.We determined telomere length(TL)in lymphocytes and granulocytes from peripheral blood of the affected members using flow cytometry and fluorescence in-situ hybridization(flow FISH).We also performed whole exome sequencing in the blood of all available family members and used PhenoDB to identify potential candidate gene variants with recessive or dominant modes of inheritance.RESULTS Out of twenty-four patients of European descent selected to participate in the study,eleven patients,eight parent-child pairs affected by IBD,were included in the genetic anticipation analysis.Median difference in age at diagnosis between two successive generations was 16.5 years,with earlier age at onset in the younger generations.In most of the affected members,the disease harbored similar gastrointestinal and extraintestinal involvement but was more aggressive among the younger generations.TL was not associated with earlier age at onset or more severe disease in members of successive generations affected by IBD.NOD2 gene mutations were present in the Crohn’s disease patients of one family.However,no gene variants were identified as potential candidates for inheritance.CONCLUSION Telomere shortening appears unlikely to be involved in mechanisms of possible genetic anticipation in IBD.Further studies using a larger sample size are required to confirm or refute our findings.展开更多
文摘Therapeutic drug monitoring(TDM)was one of most sought-after objective tools to determine therapeutic efficiency of different biologics and its role in the management of patients with inflammatory bowel disease(IBD)was regarded with great anticipation.But implementation of the TDM in clinical practice was challenged by several factors including uncertainty of the optimal cut-off values,assay variable sensitivity in detecting drug levels and antibodies and,most importantly,individual pharmacokinetics.While reactive TDM was embraced in clinical practice as a useful tool in assessing lack of response to therapy,the utility of proactive TDM in managing IBD therapy is still challenged by the lack of consistency between evidence.Described here,there are four groups of IBD patients for whom proactive TDM has the potential to greatly impact their therapeutic outcomes:Patients with perianal Crohn’s disease,patients with severe ulcerative colitis,pregnant women with IBD and children.As the future of IBD management moves towards personalizing treatment,TDM will be an important decision node in a machine learning based algorithm predicting the best strategy to maximize treatment results while minimizing the loss of response to therapy.
基金The authors thank Professor Mary Armanios for assistance with telomere analysis. Theauthors would like to dedicate this paper in memoriam to Dr. Theodore M. Bayless, agreat mentor and a believer in genetic anticipation in inflammatory bowel disease.
文摘BACKGROUND The existence of genetic anticipation has been long disputed in inflammatory bowel disease(IBD)in the absence of the explanatory mechanism.AIM To determine whether it was predictive of genetic anticipation,we evaluated telomere length in IBD.We hypothesized that multiplex IBD families exhibit a genetic defect impacting telomere maintenance mechanisms.METHODS We studied three IBD families with multiple affected members in three successive generations.We determined telomere length(TL)in lymphocytes and granulocytes from peripheral blood of the affected members using flow cytometry and fluorescence in-situ hybridization(flow FISH).We also performed whole exome sequencing in the blood of all available family members and used PhenoDB to identify potential candidate gene variants with recessive or dominant modes of inheritance.RESULTS Out of twenty-four patients of European descent selected to participate in the study,eleven patients,eight parent-child pairs affected by IBD,were included in the genetic anticipation analysis.Median difference in age at diagnosis between two successive generations was 16.5 years,with earlier age at onset in the younger generations.In most of the affected members,the disease harbored similar gastrointestinal and extraintestinal involvement but was more aggressive among the younger generations.TL was not associated with earlier age at onset or more severe disease in members of successive generations affected by IBD.NOD2 gene mutations were present in the Crohn’s disease patients of one family.However,no gene variants were identified as potential candidates for inheritance.CONCLUSION Telomere shortening appears unlikely to be involved in mechanisms of possible genetic anticipation in IBD.Further studies using a larger sample size are required to confirm or refute our findings.
