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Eritoran fails to improve mortality in severe sepsis
Eritoran, a highly active and specific lipopolysaccharide inhibitor, failed to improve 1-month or 1-year mortality in an international phase III clinical trial of nearly 2,000 patients with severe sepsis, according to a report published March 19 in JAMA.
Eritoran had appeared very promising in preclinical, phase I, and phase II trials, blocking cytokine responses, terminating lipopolysaccharide-associated inflammatory events, and ultimately reducing patient mortality. "Despite these promising early results, no evidence of significant benefit was observed with eritoran in this large phase III trial," said Dr. Steven M. Opal of the division of infectious diseases at Memorial Hospital of Rhode Island, Pawtucket, and his associates.
"Eritoran joins a long list of other experimental sepsis treatments that do not improve outcomes in clinical trials in these critically ill patients," they noted.
Eritoran is a synthetic analog of lipid A and a potent, specific antagonist against lipopolysaccharide activity, which drives the inflammatory response. In this 5-year double-blind study conducted at 197 ICUs throughout North America, Europe, South American, Africa, Asia, and Australia, 1,984 patients with severe sepsis or septic shock were randomly assigned to receive either intravenous eritoran (1,322 subjects) or matching placebo (662 subjects) and followed at 1 month, 3 months, 6 months, and 1 year.
The pathogens that most commonly caused sepsis in this study were Escherichia coli (22%), Staphylococcus aureus (12%), and Streptococcus pneumoniae (11%). The lung was the site of infection in approximately half of the patients in each group.
The incidence of bloodstream infection was similar between the two groups, affecting 38% of the eritoran group and 40% of the placebo group.
Both groups of patients received comparable supportive care, appropriate antimicrobial therapy, and timely infection control.
The primary outcome measure was 28-day mortality in these patients who were at high risk of dying. This rate was not significantly different between the group that received active drug (28%) and the group that received placebo (27%). Similarly, all-cause mortality at 1 year was comparable between the two groups, at 44% and 43%, respectively, the investigators said (JAMA 2013;309:1154-62).
In several subgroup analyses, eritoran also showed no beneficial effect on patient mortality. The rates were similar regardless of baseline APACHE score, baseline SOFA score, the presence or absence of septic shock, the site of the primary infection, or whether the infection was gram-negative or gram-positive.
"Our results ... call into question the role of an endotoxin-blocking agent in halting the inflammatory progression and organ dysfunction once sepsis is already underway," Dr. Opal and his associates said.
This study was supported by Eisai, developer of eritoran. Dr. Opal and his associates reported ties to numerous industry sources.
Eritoran, a highly active and specific lipopolysaccharide inhibitor, failed to improve 1-month or 1-year mortality in an international phase III clinical trial of nearly 2,000 patients with severe sepsis, according to a report published March 19 in JAMA.
Eritoran had appeared very promising in preclinical, phase I, and phase II trials, blocking cytokine responses, terminating lipopolysaccharide-associated inflammatory events, and ultimately reducing patient mortality. "Despite these promising early results, no evidence of significant benefit was observed with eritoran in this large phase III trial," said Dr. Steven M. Opal of the division of infectious diseases at Memorial Hospital of Rhode Island, Pawtucket, and his associates.
"Eritoran joins a long list of other experimental sepsis treatments that do not improve outcomes in clinical trials in these critically ill patients," they noted.
Eritoran is a synthetic analog of lipid A and a potent, specific antagonist against lipopolysaccharide activity, which drives the inflammatory response. In this 5-year double-blind study conducted at 197 ICUs throughout North America, Europe, South American, Africa, Asia, and Australia, 1,984 patients with severe sepsis or septic shock were randomly assigned to receive either intravenous eritoran (1,322 subjects) or matching placebo (662 subjects) and followed at 1 month, 3 months, 6 months, and 1 year.
The pathogens that most commonly caused sepsis in this study were Escherichia coli (22%), Staphylococcus aureus (12%), and Streptococcus pneumoniae (11%). The lung was the site of infection in approximately half of the patients in each group.
The incidence of bloodstream infection was similar between the two groups, affecting 38% of the eritoran group and 40% of the placebo group.
Both groups of patients received comparable supportive care, appropriate antimicrobial therapy, and timely infection control.
The primary outcome measure was 28-day mortality in these patients who were at high risk of dying. This rate was not significantly different between the group that received active drug (28%) and the group that received placebo (27%). Similarly, all-cause mortality at 1 year was comparable between the two groups, at 44% and 43%, respectively, the investigators said (JAMA 2013;309:1154-62).
In several subgroup analyses, eritoran also showed no beneficial effect on patient mortality. The rates were similar regardless of baseline APACHE score, baseline SOFA score, the presence or absence of septic shock, the site of the primary infection, or whether the infection was gram-negative or gram-positive.
"Our results ... call into question the role of an endotoxin-blocking agent in halting the inflammatory progression and organ dysfunction once sepsis is already underway," Dr. Opal and his associates said.
This study was supported by Eisai, developer of eritoran. Dr. Opal and his associates reported ties to numerous industry sources.
Eritoran, a highly active and specific lipopolysaccharide inhibitor, failed to improve 1-month or 1-year mortality in an international phase III clinical trial of nearly 2,000 patients with severe sepsis, according to a report published March 19 in JAMA.
Eritoran had appeared very promising in preclinical, phase I, and phase II trials, blocking cytokine responses, terminating lipopolysaccharide-associated inflammatory events, and ultimately reducing patient mortality. "Despite these promising early results, no evidence of significant benefit was observed with eritoran in this large phase III trial," said Dr. Steven M. Opal of the division of infectious diseases at Memorial Hospital of Rhode Island, Pawtucket, and his associates.
"Eritoran joins a long list of other experimental sepsis treatments that do not improve outcomes in clinical trials in these critically ill patients," they noted.
Eritoran is a synthetic analog of lipid A and a potent, specific antagonist against lipopolysaccharide activity, which drives the inflammatory response. In this 5-year double-blind study conducted at 197 ICUs throughout North America, Europe, South American, Africa, Asia, and Australia, 1,984 patients with severe sepsis or septic shock were randomly assigned to receive either intravenous eritoran (1,322 subjects) or matching placebo (662 subjects) and followed at 1 month, 3 months, 6 months, and 1 year.
The pathogens that most commonly caused sepsis in this study were Escherichia coli (22%), Staphylococcus aureus (12%), and Streptococcus pneumoniae (11%). The lung was the site of infection in approximately half of the patients in each group.
The incidence of bloodstream infection was similar between the two groups, affecting 38% of the eritoran group and 40% of the placebo group.
Both groups of patients received comparable supportive care, appropriate antimicrobial therapy, and timely infection control.
The primary outcome measure was 28-day mortality in these patients who were at high risk of dying. This rate was not significantly different between the group that received active drug (28%) and the group that received placebo (27%). Similarly, all-cause mortality at 1 year was comparable between the two groups, at 44% and 43%, respectively, the investigators said (JAMA 2013;309:1154-62).
In several subgroup analyses, eritoran also showed no beneficial effect on patient mortality. The rates were similar regardless of baseline APACHE score, baseline SOFA score, the presence or absence of septic shock, the site of the primary infection, or whether the infection was gram-negative or gram-positive.
"Our results ... call into question the role of an endotoxin-blocking agent in halting the inflammatory progression and organ dysfunction once sepsis is already underway," Dr. Opal and his associates said.
This study was supported by Eisai, developer of eritoran. Dr. Opal and his associates reported ties to numerous industry sources.
FROM JAMA
Major Finding: 28-day mortality was not significantly different between 1,322 patients given eritoran (28%) and 662 given a matching placebo (27%).
Data Source: A 5-year international phase III clinical trial comparing intravenous eritoran to placebo in 1,984 patients with severe sepsis treated at 197 ICUs.
Disclosures: This study was supported by Eisai, developer of eritoran. Dr. Opal and his associates reported ties to numerous industry sources.
Cortisol breakdown impaired during critical illness
The breakdown and clearance of cortisol are impaired during critical illness, which may account in part for the abnormally high blood levels of cortisol often observed in ICU patients, according to a report published online March 19 in the New England Journal of Medicine.
Hypercortisolemia often accompanies critical illness, but until now it usually has been attributed to increased cortisol production driven by stress-induced activation of the hypothalamic-pituitary-adrenal axis. However, some researchers posited that another possible contributor to hypercortisolemia in this setting might be suppression of the removal of cortisol.
"We hypothesized that cortisol metabolism is reduced during critical illness, contributing to sustained hypercortisolemia with enhanced negative-feedback inhibition of corticotropin," said Dr. Eva Boonen of the clinical division and laboratory of intensive care medicine, Catholic University of Leuven (Belgium), and her associates.
To test their hypothesis, the investigators studied 158 consecutive adults treated for critical illness in a single ICU and 64 demographically matched but not critically ill control subjects. They measured five aspects of cortisol metabolism: daily corticotropin and cortisol levels; plasma cortisol levels reflecting the clearance, metabolism, and production of cortisol during an infusion of deuterium-labeled tracers; plasma clearance of a therapeutic 100-mg IV bolus of hydrocortisone; urinary levels of cortisol metabolites; and levels of major cortisol-metabolizing enzymes in liver and adipose tissue.
Their findings demonstrated that "elevated cortisol levels in critically ill patients were only partially explained by an increase of 83% in cortisol production, as compared with controls." In addition, impaired breakdown and clearance of cortisol contributed to hypercortisolemia, the investigators reported. They found a reduction of more than 50% in cortisol clearance after administration of the 100 mg of hydrocortisone (N. Engl. J. Med. 2013 March 19 [doi: 10.1056/NEJMoa1214969]).
The clinical implications of these study results are important because the findings markedly change "our understanding of the stress response. Reduced inactivation of cortisol may be important not only to increase circulating levels but also to potentiate cortisol levels and activity within the vital tissues that express inactivating enzymes.
"More pragmatically, the data suggest that ‘stress doses’ of hydrocortisone, which are advocated to replace cortisol production in critically ill patients who are presumed to have adrenal failure, are at least 3 times too high," Dr. Boonen and her colleagues said.
The data also suggest that "a low cortisol response to corticotropin stimulation does not necessarily reflect adrenal failure, since cortisol production in critically ill patients is not subnormal, and the suppressed clearance maintains hypercortisolemia. Our results may therefore help to explain why studies investigating the effect of the daily administration of 200 mg of hydrocortisone in patients with sepsis ... have had conflicting results," they added.
This study was supported by the Belgian Fund for Scientific Research, the British Heart Foundation, the Flemish government\'s Methusalem Program, and the European Research Council. No relevant conflicts of interest were reported.
This study "provides a convincing explanation for some of the elevation in plasma cortisol levels observed in critically ill patients," said Dr. Celso E. Gomez-Sanchez.
In addition to the substantial decrease in cortisol breakdown documented by Dr. Boonen and colleagues, there are other changes in cortisol hemostasis that occur during critical illness and contribute to the failure of adrenal function. These include adrenal stimulation by cytokines, the suppression of corticotropin, "and probably adrenal endothelial dysfunction," he said.
Dr. Sanchez is in the endocrine section at G.V. Montgomery Veterans Administration Medical Center and the University of Mississippi Medical Center, both in Jackson. He reported no relevant conflicts of interest. These remarks were taken from his editorial comment accompanying Dr. Boonen’s report (N. Engl. J. Med. 2013 March 19 [doi: 10.1056/NEJMe1302305]).
This study "provides a convincing explanation for some of the elevation in plasma cortisol levels observed in critically ill patients," said Dr. Celso E. Gomez-Sanchez.
In addition to the substantial decrease in cortisol breakdown documented by Dr. Boonen and colleagues, there are other changes in cortisol hemostasis that occur during critical illness and contribute to the failure of adrenal function. These include adrenal stimulation by cytokines, the suppression of corticotropin, "and probably adrenal endothelial dysfunction," he said.
Dr. Sanchez is in the endocrine section at G.V. Montgomery Veterans Administration Medical Center and the University of Mississippi Medical Center, both in Jackson. He reported no relevant conflicts of interest. These remarks were taken from his editorial comment accompanying Dr. Boonen’s report (N. Engl. J. Med. 2013 March 19 [doi: 10.1056/NEJMe1302305]).
This study "provides a convincing explanation for some of the elevation in plasma cortisol levels observed in critically ill patients," said Dr. Celso E. Gomez-Sanchez.
In addition to the substantial decrease in cortisol breakdown documented by Dr. Boonen and colleagues, there are other changes in cortisol hemostasis that occur during critical illness and contribute to the failure of adrenal function. These include adrenal stimulation by cytokines, the suppression of corticotropin, "and probably adrenal endothelial dysfunction," he said.
Dr. Sanchez is in the endocrine section at G.V. Montgomery Veterans Administration Medical Center and the University of Mississippi Medical Center, both in Jackson. He reported no relevant conflicts of interest. These remarks were taken from his editorial comment accompanying Dr. Boonen’s report (N. Engl. J. Med. 2013 March 19 [doi: 10.1056/NEJMe1302305]).
The breakdown and clearance of cortisol are impaired during critical illness, which may account in part for the abnormally high blood levels of cortisol often observed in ICU patients, according to a report published online March 19 in the New England Journal of Medicine.
Hypercortisolemia often accompanies critical illness, but until now it usually has been attributed to increased cortisol production driven by stress-induced activation of the hypothalamic-pituitary-adrenal axis. However, some researchers posited that another possible contributor to hypercortisolemia in this setting might be suppression of the removal of cortisol.
"We hypothesized that cortisol metabolism is reduced during critical illness, contributing to sustained hypercortisolemia with enhanced negative-feedback inhibition of corticotropin," said Dr. Eva Boonen of the clinical division and laboratory of intensive care medicine, Catholic University of Leuven (Belgium), and her associates.
To test their hypothesis, the investigators studied 158 consecutive adults treated for critical illness in a single ICU and 64 demographically matched but not critically ill control subjects. They measured five aspects of cortisol metabolism: daily corticotropin and cortisol levels; plasma cortisol levels reflecting the clearance, metabolism, and production of cortisol during an infusion of deuterium-labeled tracers; plasma clearance of a therapeutic 100-mg IV bolus of hydrocortisone; urinary levels of cortisol metabolites; and levels of major cortisol-metabolizing enzymes in liver and adipose tissue.
Their findings demonstrated that "elevated cortisol levels in critically ill patients were only partially explained by an increase of 83% in cortisol production, as compared with controls." In addition, impaired breakdown and clearance of cortisol contributed to hypercortisolemia, the investigators reported. They found a reduction of more than 50% in cortisol clearance after administration of the 100 mg of hydrocortisone (N. Engl. J. Med. 2013 March 19 [doi: 10.1056/NEJMoa1214969]).
The clinical implications of these study results are important because the findings markedly change "our understanding of the stress response. Reduced inactivation of cortisol may be important not only to increase circulating levels but also to potentiate cortisol levels and activity within the vital tissues that express inactivating enzymes.
"More pragmatically, the data suggest that ‘stress doses’ of hydrocortisone, which are advocated to replace cortisol production in critically ill patients who are presumed to have adrenal failure, are at least 3 times too high," Dr. Boonen and her colleagues said.
The data also suggest that "a low cortisol response to corticotropin stimulation does not necessarily reflect adrenal failure, since cortisol production in critically ill patients is not subnormal, and the suppressed clearance maintains hypercortisolemia. Our results may therefore help to explain why studies investigating the effect of the daily administration of 200 mg of hydrocortisone in patients with sepsis ... have had conflicting results," they added.
This study was supported by the Belgian Fund for Scientific Research, the British Heart Foundation, the Flemish government\'s Methusalem Program, and the European Research Council. No relevant conflicts of interest were reported.
The breakdown and clearance of cortisol are impaired during critical illness, which may account in part for the abnormally high blood levels of cortisol often observed in ICU patients, according to a report published online March 19 in the New England Journal of Medicine.
Hypercortisolemia often accompanies critical illness, but until now it usually has been attributed to increased cortisol production driven by stress-induced activation of the hypothalamic-pituitary-adrenal axis. However, some researchers posited that another possible contributor to hypercortisolemia in this setting might be suppression of the removal of cortisol.
"We hypothesized that cortisol metabolism is reduced during critical illness, contributing to sustained hypercortisolemia with enhanced negative-feedback inhibition of corticotropin," said Dr. Eva Boonen of the clinical division and laboratory of intensive care medicine, Catholic University of Leuven (Belgium), and her associates.
To test their hypothesis, the investigators studied 158 consecutive adults treated for critical illness in a single ICU and 64 demographically matched but not critically ill control subjects. They measured five aspects of cortisol metabolism: daily corticotropin and cortisol levels; plasma cortisol levels reflecting the clearance, metabolism, and production of cortisol during an infusion of deuterium-labeled tracers; plasma clearance of a therapeutic 100-mg IV bolus of hydrocortisone; urinary levels of cortisol metabolites; and levels of major cortisol-metabolizing enzymes in liver and adipose tissue.
Their findings demonstrated that "elevated cortisol levels in critically ill patients were only partially explained by an increase of 83% in cortisol production, as compared with controls." In addition, impaired breakdown and clearance of cortisol contributed to hypercortisolemia, the investigators reported. They found a reduction of more than 50% in cortisol clearance after administration of the 100 mg of hydrocortisone (N. Engl. J. Med. 2013 March 19 [doi: 10.1056/NEJMoa1214969]).
The clinical implications of these study results are important because the findings markedly change "our understanding of the stress response. Reduced inactivation of cortisol may be important not only to increase circulating levels but also to potentiate cortisol levels and activity within the vital tissues that express inactivating enzymes.
"More pragmatically, the data suggest that ‘stress doses’ of hydrocortisone, which are advocated to replace cortisol production in critically ill patients who are presumed to have adrenal failure, are at least 3 times too high," Dr. Boonen and her colleagues said.
The data also suggest that "a low cortisol response to corticotropin stimulation does not necessarily reflect adrenal failure, since cortisol production in critically ill patients is not subnormal, and the suppressed clearance maintains hypercortisolemia. Our results may therefore help to explain why studies investigating the effect of the daily administration of 200 mg of hydrocortisone in patients with sepsis ... have had conflicting results," they added.
This study was supported by the Belgian Fund for Scientific Research, the British Heart Foundation, the Flemish government\'s Methusalem Program, and the European Research Council. No relevant conflicts of interest were reported.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Major finding: Elevated cortisol levels in critically ill patients are only partly explained by increased cortisol production; they also are due to impaired breakdown and clearance of cortisol.
Data source: An analysis of cortisol metabolism in 158 ICU patients and 64 demographically matched but not critically ill control subjects.
Disclosures: This study was supported by the Belgian Fund for Scientific Research, the British Heart Foundation, the Flemish government’s Methusalem Program, and the European Research Council. No relevant conflicts of interest were reported.
Hypertension, genetics interact to increase brain amyloid deposition
Patients with uncontrolled hypertension showed greater deposition of beta-amyloid on florbetapir PET imaging of the brain than did those without hypertension or those whose hypertension was controlled with medication in a cross-sectional study of healthy, cognitively normal, middle-aged and older adults with at least one apolipoprotein E epsilon-4 allele.
This finding indicates that uncontrolled hypertension may increase the risk for Alzheimer’s disease beyond that conferred by having one or more copies of the high-risk apolipoprotein E epsilon-4 (apo E–epsilon-4) allele in adults who are cognitively normal. It also raises the question of whether such patients may be able to attenuate their Alzheimer’s risk through proper control of blood pressure, Karen M. Rodrigue, Ph.D., of the Center for Vital Longevity, University of Texas School of Behavioral and Brain Sciences, Dallas, and her associates reported March 18 in JAMA Neurology.
"We may be able to prevent, or at least slow, pathological aging in some individuals through lifestyle modification or pharmacologic intervention," the researchers wrote.
Dr. Rodrigue and her colleagues examined both the individual and the combined impact of apo E–epsilon-4 carriage and hypertension on beta-amyloid deposition in a subgroup of 118 subjects aged 47-89 years who were participating in a brain-imaging study. This subgroup involved well-educated middle-age and older adults who performed normally on a battery of cognitive tests, showed no abnormalities on neurological and psychiatric testing, and were free of vascular disease on clinical examination.
The subjects’ blood pressure was measured on seven separate occasions during the study, and apo E–status was determined from DNA analysis of venous blood samples. All the study subjects also underwent MRI and PET scanning of the brain.
A total of 18.6% of the study subjects had one apo E–epsilon-4 and another 4.2% had two apo E–epsilon-4 alleles.
Fifty-four of the study subjects had physician-diagnosed hypertension for which they took medication (mean age, 74 years), including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, potassium-sparing diuretics, alpha-blockers, or a combination of these drugs. Another 15 subjects reported no diagnosis of hypertension (mean age, 73 years) but consistently showed blood pressure elevations exceeding stage 1 criteria for the disorder. The 49 normotensive individuals ranged in age from 47 to 88 years.
Study subjects who carried at least one apo E–epsilon-4 allele and had uncontrolled hypertension showed the greatest levels of beta-amyloid deposition on brain scans, compared with subjects who had only one of those risk factors and subjects who had neither of those risk factors, the investigators said (JAMA Neurol. 2013 March 18 [doi:10.1001/jamaneurol.2013.1342]).
Study subjects whose hypertension was controlled by medication showed "significantly less amyloid burden than the unmedicated group" and only a slightly higher amyloid burden than did the subjects who had no hypertension.
"Our study demonstrates that hypertension, a prevalent vascular risk factor in aging populations, interacts with apo E–epsilon-4 genotype to increase amyloid deposition in cognitively healthy middle-age and older adults," Dr. Rodrigue and her associates noted.
It also highlights the complex interactions that vascular and genetic risk factors exert on the aging brain, and suggests that the two types of risk factors may act synergistically in inducing cognitive decline.
The investigators cautioned that their findings "should not be overinterpreted" because the study design was cross-sectional rather than prospective, and the study population was exceptionally healthy rather than representative of the general population. "Future studies with larger sample sizes that examine additional factors, such as duration of hypertension treatment, are needed to support these findings," they said.
This study was funded by the National Institutes of Health, the Alzheimer’s Association, and the National Institute on Aging. Dr. Rodrigue reported no financial conflicts of interest, but one of her associates reported ties to Avid Radiopharmaceuticals, which supplied the radiotracer florbetapir (Amyvid) used in this study and is supporting a longitudinal component of the study.
Patients with uncontrolled hypertension showed greater deposition of beta-amyloid on florbetapir PET imaging of the brain than did those without hypertension or those whose hypertension was controlled with medication in a cross-sectional study of healthy, cognitively normal, middle-aged and older adults with at least one apolipoprotein E epsilon-4 allele.
This finding indicates that uncontrolled hypertension may increase the risk for Alzheimer’s disease beyond that conferred by having one or more copies of the high-risk apolipoprotein E epsilon-4 (apo E–epsilon-4) allele in adults who are cognitively normal. It also raises the question of whether such patients may be able to attenuate their Alzheimer’s risk through proper control of blood pressure, Karen M. Rodrigue, Ph.D., of the Center for Vital Longevity, University of Texas School of Behavioral and Brain Sciences, Dallas, and her associates reported March 18 in JAMA Neurology.
"We may be able to prevent, or at least slow, pathological aging in some individuals through lifestyle modification or pharmacologic intervention," the researchers wrote.
Dr. Rodrigue and her colleagues examined both the individual and the combined impact of apo E–epsilon-4 carriage and hypertension on beta-amyloid deposition in a subgroup of 118 subjects aged 47-89 years who were participating in a brain-imaging study. This subgroup involved well-educated middle-age and older adults who performed normally on a battery of cognitive tests, showed no abnormalities on neurological and psychiatric testing, and were free of vascular disease on clinical examination.
The subjects’ blood pressure was measured on seven separate occasions during the study, and apo E–status was determined from DNA analysis of venous blood samples. All the study subjects also underwent MRI and PET scanning of the brain.
A total of 18.6% of the study subjects had one apo E–epsilon-4 and another 4.2% had two apo E–epsilon-4 alleles.
Fifty-four of the study subjects had physician-diagnosed hypertension for which they took medication (mean age, 74 years), including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, potassium-sparing diuretics, alpha-blockers, or a combination of these drugs. Another 15 subjects reported no diagnosis of hypertension (mean age, 73 years) but consistently showed blood pressure elevations exceeding stage 1 criteria for the disorder. The 49 normotensive individuals ranged in age from 47 to 88 years.
Study subjects who carried at least one apo E–epsilon-4 allele and had uncontrolled hypertension showed the greatest levels of beta-amyloid deposition on brain scans, compared with subjects who had only one of those risk factors and subjects who had neither of those risk factors, the investigators said (JAMA Neurol. 2013 March 18 [doi:10.1001/jamaneurol.2013.1342]).
Study subjects whose hypertension was controlled by medication showed "significantly less amyloid burden than the unmedicated group" and only a slightly higher amyloid burden than did the subjects who had no hypertension.
"Our study demonstrates that hypertension, a prevalent vascular risk factor in aging populations, interacts with apo E–epsilon-4 genotype to increase amyloid deposition in cognitively healthy middle-age and older adults," Dr. Rodrigue and her associates noted.
It also highlights the complex interactions that vascular and genetic risk factors exert on the aging brain, and suggests that the two types of risk factors may act synergistically in inducing cognitive decline.
The investigators cautioned that their findings "should not be overinterpreted" because the study design was cross-sectional rather than prospective, and the study population was exceptionally healthy rather than representative of the general population. "Future studies with larger sample sizes that examine additional factors, such as duration of hypertension treatment, are needed to support these findings," they said.
This study was funded by the National Institutes of Health, the Alzheimer’s Association, and the National Institute on Aging. Dr. Rodrigue reported no financial conflicts of interest, but one of her associates reported ties to Avid Radiopharmaceuticals, which supplied the radiotracer florbetapir (Amyvid) used in this study and is supporting a longitudinal component of the study.
Patients with uncontrolled hypertension showed greater deposition of beta-amyloid on florbetapir PET imaging of the brain than did those without hypertension or those whose hypertension was controlled with medication in a cross-sectional study of healthy, cognitively normal, middle-aged and older adults with at least one apolipoprotein E epsilon-4 allele.
This finding indicates that uncontrolled hypertension may increase the risk for Alzheimer’s disease beyond that conferred by having one or more copies of the high-risk apolipoprotein E epsilon-4 (apo E–epsilon-4) allele in adults who are cognitively normal. It also raises the question of whether such patients may be able to attenuate their Alzheimer’s risk through proper control of blood pressure, Karen M. Rodrigue, Ph.D., of the Center for Vital Longevity, University of Texas School of Behavioral and Brain Sciences, Dallas, and her associates reported March 18 in JAMA Neurology.
"We may be able to prevent, or at least slow, pathological aging in some individuals through lifestyle modification or pharmacologic intervention," the researchers wrote.
Dr. Rodrigue and her colleagues examined both the individual and the combined impact of apo E–epsilon-4 carriage and hypertension on beta-amyloid deposition in a subgroup of 118 subjects aged 47-89 years who were participating in a brain-imaging study. This subgroup involved well-educated middle-age and older adults who performed normally on a battery of cognitive tests, showed no abnormalities on neurological and psychiatric testing, and were free of vascular disease on clinical examination.
The subjects’ blood pressure was measured on seven separate occasions during the study, and apo E–status was determined from DNA analysis of venous blood samples. All the study subjects also underwent MRI and PET scanning of the brain.
A total of 18.6% of the study subjects had one apo E–epsilon-4 and another 4.2% had two apo E–epsilon-4 alleles.
Fifty-four of the study subjects had physician-diagnosed hypertension for which they took medication (mean age, 74 years), including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, potassium-sparing diuretics, alpha-blockers, or a combination of these drugs. Another 15 subjects reported no diagnosis of hypertension (mean age, 73 years) but consistently showed blood pressure elevations exceeding stage 1 criteria for the disorder. The 49 normotensive individuals ranged in age from 47 to 88 years.
Study subjects who carried at least one apo E–epsilon-4 allele and had uncontrolled hypertension showed the greatest levels of beta-amyloid deposition on brain scans, compared with subjects who had only one of those risk factors and subjects who had neither of those risk factors, the investigators said (JAMA Neurol. 2013 March 18 [doi:10.1001/jamaneurol.2013.1342]).
Study subjects whose hypertension was controlled by medication showed "significantly less amyloid burden than the unmedicated group" and only a slightly higher amyloid burden than did the subjects who had no hypertension.
"Our study demonstrates that hypertension, a prevalent vascular risk factor in aging populations, interacts with apo E–epsilon-4 genotype to increase amyloid deposition in cognitively healthy middle-age and older adults," Dr. Rodrigue and her associates noted.
It also highlights the complex interactions that vascular and genetic risk factors exert on the aging brain, and suggests that the two types of risk factors may act synergistically in inducing cognitive decline.
The investigators cautioned that their findings "should not be overinterpreted" because the study design was cross-sectional rather than prospective, and the study population was exceptionally healthy rather than representative of the general population. "Future studies with larger sample sizes that examine additional factors, such as duration of hypertension treatment, are needed to support these findings," they said.
This study was funded by the National Institutes of Health, the Alzheimer’s Association, and the National Institute on Aging. Dr. Rodrigue reported no financial conflicts of interest, but one of her associates reported ties to Avid Radiopharmaceuticals, which supplied the radiotracer florbetapir (Amyvid) used in this study and is supporting a longitudinal component of the study.
FROM JAMA NEUROLOGY
Major Finding: Healthy middle-age and older adults who had at least one apo E–epsilon-4 allele and uncontrolled hypertension had significantly higher levels of brain beta-amyloid deposition than did subjects who had at least one apo E–epsilon-4 allele and controlled hypertension and subjects who had neither risk factor.
Data Source: A cross-sectional study of PET brain imaging in 118 cognitively normal adults aged 47-89 years, of whom 54 had controlled and 15 had uncontrolled hypertension.
Disclosures: This study was funded by the National Institutes of Health, the Alzheimer’s Association, and the National Institute on Aging. Dr. Rodrigue reported no financial conflicts of interest, but one of her associates reported ties to Avid Radiopharmaceuticals, which supplied the radiotracer florbetapir (Amyvid) used in this study and is supporting a longitudinal component of the study.
Use of vena cava filters varies enormously by hospital
The use of vena cava filters for acute venous thromboembolism varies enormously across hospitals, according to a study published online March 18 in JAMA Internal Medicine.
In a study involving all 263 nonfederal hospitals in California, the frequency of the use of vena cava filters in acute venous thromboembolism (VTE) showed "an exceptionally wide range" – from 0% to nearly 40% of all VTE hospitalizations, depending on the hospital, said Dr. Richard H. White of the University of California, Davis, and his associates.
Many factors that could potentially account for this striking variation were examined, but none of them exerted any meaningful effect on the frequency of filter use. Patient factors such as race, insurance status, and number of comorbidities; hospital factors such as funding source and for-profit status; and miscellaneous factors such as geographic proximity all had no significant influence on the use of these medical devices.
Together these findings "suggest that use of vena cava filters is based substantially on the local hospital culture and practice patterns," the investigators said. "The enthusiasm of specific physician-leaders within each hospital who advocate for or against the use of vena cava filters probably plays a central role in explaining the variation in [their] use across hospitals."
Dr. White and his colleagues assessed differences in the use of vena cava filters because the subject has not been carefully studied to date. There is still great uncertainty about the relative benefits vs. risks with the devices, which have not been shown to improve patient survival and have been linked to high rates of lower-extremity thrombosis and other serious complications.
The researchers focused their retrospective observational study on patients hospitalized in California for acute VTE between 2006 and 2011, and excluded all such cases that were associated with major trauma "because of the high rate of elective prophylactic vena cava filter use in this population."
Overall, there were 130,643 hospitalizations for acute VTE during the study period. A vena cava filter was placed in approximately 14% of these hospitalizations in 2006, a rate that rose to more than 16% in 2009 but dropped back down again to 15% in 2010.
The frequency of filter use varied from 0% of VTE cases at some hospitals to as high as 38.96% of VTE cases at other hospitals. There was wide variation even between hospitals in the same geographic regions, the investigators said (JAMA Intern. Med. 2013 March 18 [doi:10.1001/jamainternmed.2013.2352]).
When the data were analyzed according to the expected average use of vena cava filters, it was found that 109 hospitals used the devices significantly more often than expected, while 59 used them significantly less frequently than expected. That left only 95 hospitals, one-third of the entire sample, using the filters as frequently as expected.
Significant clinical predictors of filter use included acute bleeding at the time of admission (odds ratio, 3.4); major operation after admission for VTE (OR, 3.4); the presence of metastatic cancer (OR, 1.7); and extreme severity of illness vs. mild illness (OR, 2.5).
The researchers also performed an analysis that controlled for these factors that might influence the decision to use a vena cava filter, as well as the number of chronic comorbidities, and the occurrence of acute pulmonary embolism as opposed to deep vein thrombosis alone.
"Even after adjusting for these variables, the effect of which hospital a patient was in represented a significant source of the variation. Specifically, in a hierarchical model that included clinical risk factors alone, 18.49% of the residual variation in vena cava filter use could be attributed to between-hospital variation," they noted.
Small and rural hospitals were less likely to use vena cava filters, which was not surprising and likely reflects the "paucity of trained interventional radiologists or vascular surgeons" at such hospitals, the investigators added.
This study was supported by the Hibbard E. Williams Endowment at the University of California, Davis. No financial conflicts of interest were reported.
The evidence for the effectiveness of the vena cava filter is scant, but the evidence for its harm is not, said Dr. Vinay Prasad and his colleagues.
Placement of the device has been associated with hematoma, pneumothorax, and air embolism, while later complications include an increased risk of DVT, occlusion of the device, fracture of the device with embolization of the debris, device migration, and perforation. "We need either the FDA [Food and Drug Administration] to require current filter manufacturers to perform efficacy studies of their devices as a condition for remaining on the market, or a large federally funded study to determine if this expensive device leads to greater benefit than harm," they said.
Meanwhile, informed consent forms should be altered to ensure that patients understand "there is evidence of harm without evidence of benefit" for vena cava filters, the investigators added.
Dr. Prasad is at the National Cancer Institute. He and his colleagues reported having no conflicts of interest. These remarks were taken from their editorial comment accompanying Dr. White’s report (JAMA Intern. Med. 2013 March 18 [doi:10.1001/jamainternmed.2013.2725]).
The evidence for the effectiveness of the vena cava filter is scant, but the evidence for its harm is not, said Dr. Vinay Prasad and his colleagues.
Placement of the device has been associated with hematoma, pneumothorax, and air embolism, while later complications include an increased risk of DVT, occlusion of the device, fracture of the device with embolization of the debris, device migration, and perforation. "We need either the FDA [Food and Drug Administration] to require current filter manufacturers to perform efficacy studies of their devices as a condition for remaining on the market, or a large federally funded study to determine if this expensive device leads to greater benefit than harm," they said.
Meanwhile, informed consent forms should be altered to ensure that patients understand "there is evidence of harm without evidence of benefit" for vena cava filters, the investigators added.
Dr. Prasad is at the National Cancer Institute. He and his colleagues reported having no conflicts of interest. These remarks were taken from their editorial comment accompanying Dr. White’s report (JAMA Intern. Med. 2013 March 18 [doi:10.1001/jamainternmed.2013.2725]).
The evidence for the effectiveness of the vena cava filter is scant, but the evidence for its harm is not, said Dr. Vinay Prasad and his colleagues.
Placement of the device has been associated with hematoma, pneumothorax, and air embolism, while later complications include an increased risk of DVT, occlusion of the device, fracture of the device with embolization of the debris, device migration, and perforation. "We need either the FDA [Food and Drug Administration] to require current filter manufacturers to perform efficacy studies of their devices as a condition for remaining on the market, or a large federally funded study to determine if this expensive device leads to greater benefit than harm," they said.
Meanwhile, informed consent forms should be altered to ensure that patients understand "there is evidence of harm without evidence of benefit" for vena cava filters, the investigators added.
Dr. Prasad is at the National Cancer Institute. He and his colleagues reported having no conflicts of interest. These remarks were taken from their editorial comment accompanying Dr. White’s report (JAMA Intern. Med. 2013 March 18 [doi:10.1001/jamainternmed.2013.2725]).
The use of vena cava filters for acute venous thromboembolism varies enormously across hospitals, according to a study published online March 18 in JAMA Internal Medicine.
In a study involving all 263 nonfederal hospitals in California, the frequency of the use of vena cava filters in acute venous thromboembolism (VTE) showed "an exceptionally wide range" – from 0% to nearly 40% of all VTE hospitalizations, depending on the hospital, said Dr. Richard H. White of the University of California, Davis, and his associates.
Many factors that could potentially account for this striking variation were examined, but none of them exerted any meaningful effect on the frequency of filter use. Patient factors such as race, insurance status, and number of comorbidities; hospital factors such as funding source and for-profit status; and miscellaneous factors such as geographic proximity all had no significant influence on the use of these medical devices.
Together these findings "suggest that use of vena cava filters is based substantially on the local hospital culture and practice patterns," the investigators said. "The enthusiasm of specific physician-leaders within each hospital who advocate for or against the use of vena cava filters probably plays a central role in explaining the variation in [their] use across hospitals."
Dr. White and his colleagues assessed differences in the use of vena cava filters because the subject has not been carefully studied to date. There is still great uncertainty about the relative benefits vs. risks with the devices, which have not been shown to improve patient survival and have been linked to high rates of lower-extremity thrombosis and other serious complications.
The researchers focused their retrospective observational study on patients hospitalized in California for acute VTE between 2006 and 2011, and excluded all such cases that were associated with major trauma "because of the high rate of elective prophylactic vena cava filter use in this population."
Overall, there were 130,643 hospitalizations for acute VTE during the study period. A vena cava filter was placed in approximately 14% of these hospitalizations in 2006, a rate that rose to more than 16% in 2009 but dropped back down again to 15% in 2010.
The frequency of filter use varied from 0% of VTE cases at some hospitals to as high as 38.96% of VTE cases at other hospitals. There was wide variation even between hospitals in the same geographic regions, the investigators said (JAMA Intern. Med. 2013 March 18 [doi:10.1001/jamainternmed.2013.2352]).
When the data were analyzed according to the expected average use of vena cava filters, it was found that 109 hospitals used the devices significantly more often than expected, while 59 used them significantly less frequently than expected. That left only 95 hospitals, one-third of the entire sample, using the filters as frequently as expected.
Significant clinical predictors of filter use included acute bleeding at the time of admission (odds ratio, 3.4); major operation after admission for VTE (OR, 3.4); the presence of metastatic cancer (OR, 1.7); and extreme severity of illness vs. mild illness (OR, 2.5).
The researchers also performed an analysis that controlled for these factors that might influence the decision to use a vena cava filter, as well as the number of chronic comorbidities, and the occurrence of acute pulmonary embolism as opposed to deep vein thrombosis alone.
"Even after adjusting for these variables, the effect of which hospital a patient was in represented a significant source of the variation. Specifically, in a hierarchical model that included clinical risk factors alone, 18.49% of the residual variation in vena cava filter use could be attributed to between-hospital variation," they noted.
Small and rural hospitals were less likely to use vena cava filters, which was not surprising and likely reflects the "paucity of trained interventional radiologists or vascular surgeons" at such hospitals, the investigators added.
This study was supported by the Hibbard E. Williams Endowment at the University of California, Davis. No financial conflicts of interest were reported.
The use of vena cava filters for acute venous thromboembolism varies enormously across hospitals, according to a study published online March 18 in JAMA Internal Medicine.
In a study involving all 263 nonfederal hospitals in California, the frequency of the use of vena cava filters in acute venous thromboembolism (VTE) showed "an exceptionally wide range" – from 0% to nearly 40% of all VTE hospitalizations, depending on the hospital, said Dr. Richard H. White of the University of California, Davis, and his associates.
Many factors that could potentially account for this striking variation were examined, but none of them exerted any meaningful effect on the frequency of filter use. Patient factors such as race, insurance status, and number of comorbidities; hospital factors such as funding source and for-profit status; and miscellaneous factors such as geographic proximity all had no significant influence on the use of these medical devices.
Together these findings "suggest that use of vena cava filters is based substantially on the local hospital culture and practice patterns," the investigators said. "The enthusiasm of specific physician-leaders within each hospital who advocate for or against the use of vena cava filters probably plays a central role in explaining the variation in [their] use across hospitals."
Dr. White and his colleagues assessed differences in the use of vena cava filters because the subject has not been carefully studied to date. There is still great uncertainty about the relative benefits vs. risks with the devices, which have not been shown to improve patient survival and have been linked to high rates of lower-extremity thrombosis and other serious complications.
The researchers focused their retrospective observational study on patients hospitalized in California for acute VTE between 2006 and 2011, and excluded all such cases that were associated with major trauma "because of the high rate of elective prophylactic vena cava filter use in this population."
Overall, there were 130,643 hospitalizations for acute VTE during the study period. A vena cava filter was placed in approximately 14% of these hospitalizations in 2006, a rate that rose to more than 16% in 2009 but dropped back down again to 15% in 2010.
The frequency of filter use varied from 0% of VTE cases at some hospitals to as high as 38.96% of VTE cases at other hospitals. There was wide variation even between hospitals in the same geographic regions, the investigators said (JAMA Intern. Med. 2013 March 18 [doi:10.1001/jamainternmed.2013.2352]).
When the data were analyzed according to the expected average use of vena cava filters, it was found that 109 hospitals used the devices significantly more often than expected, while 59 used them significantly less frequently than expected. That left only 95 hospitals, one-third of the entire sample, using the filters as frequently as expected.
Significant clinical predictors of filter use included acute bleeding at the time of admission (odds ratio, 3.4); major operation after admission for VTE (OR, 3.4); the presence of metastatic cancer (OR, 1.7); and extreme severity of illness vs. mild illness (OR, 2.5).
The researchers also performed an analysis that controlled for these factors that might influence the decision to use a vena cava filter, as well as the number of chronic comorbidities, and the occurrence of acute pulmonary embolism as opposed to deep vein thrombosis alone.
"Even after adjusting for these variables, the effect of which hospital a patient was in represented a significant source of the variation. Specifically, in a hierarchical model that included clinical risk factors alone, 18.49% of the residual variation in vena cava filter use could be attributed to between-hospital variation," they noted.
Small and rural hospitals were less likely to use vena cava filters, which was not surprising and likely reflects the "paucity of trained interventional radiologists or vascular surgeons" at such hospitals, the investigators added.
This study was supported by the Hibbard E. Williams Endowment at the University of California, Davis. No financial conflicts of interest were reported.
FROM JAMA INTERNAL MEDICINE
Major Finding: The frequency of vena cava filter use varied from 0% of VTE cases at some hospitals to 38.96% of VTE cases at other hospitals.
Data Source: A retrospective observational study involving 130,643 cases of acute VTE treated at 263 California hospitals in 2006-2011.
Disclosures: This study was supported by the Hibbard E. Williams Endowment at the University of California, Davis. No financial conflicts of interest were reported.
Pregnancies after vasculitis diagnosis are at risk
The risks of pregnancy loss and of preterm birth were higher in women who had vasculitis before they conceived than in women who were diagnosed as having vasculitis after conception in a retrospective cohort study.
Women who conceived before receiving a diagnosis of vasculitis had a rate of pregnancy loss similar to the general population, whereas women who conceived after they had received a diagnosis of vasculitis had a significantly higher rate of pregnancy loss, reported Dr. Megan E. B. Clowse of the division of rheumatology and immunology at Duke University, Durham, N.C., and her associates in the Vasculitis Clinical Research Consortium.
The investigators examined pregnancy outcomes among women with vasculitis, as well as the outcomes of pregnancies fathered by men with the disease, because so little is known about the subject. Such pregnancies were rare until recent improvements in treatments helped patients survive longer and lead fuller lives.
"Our goal was to identify pregnancies that occurred within a large cohort of women and men with vasculitis and assess whether such pregnancies were at greater risk for adverse outcomes and whether vasculitis activity increased during pregnancy," the researchers wrote.
They invited patients listed in a registry of rare diseases to complete an anonymous questionnaire regarding their reproductive health. A total of 329 women (who had 496 pregnancies) and 107 men (who fathered 156 pregnancies) were included in the analysis (Arthritis Care Res. 2013 Feb. 11 [doi:10.1002/acr.21983]).
Among the women, 140 had granulomatosis with polyangiitis, 22 had microscopic polyangiitis, 59 had Churg-Strauss syndrome, 18 had polyarteritis nodosa, 43 had Behcet’s disease, and 46 had Takayasu’s arteritis. The mean age at diagnosis was 39.7 years (range, 10-78 years). The mean age at the time of the study was 47 years.
The rate of pregnancy loss was significantly higher among the women who had vasculitis when they conceived (33.8%) than it was among women who conceived before they were diagnosed as having vasculitis (22.4%), giving a relative risk of 1.77 (CI 1.02-3.09; P = .04). This 22.4% rate of pregnancy loss is comparable with that reported in the general population (15%-20%), while the rate found in women who already had vasculitis was significantly higher than that in the general population, Dr. Clowse and her associates said.
Similarly, the rate of preterm birth was significantly higher in pregnancies that occurred after a diagnosis of vasculitis (23.3%) than in pregnancies that occurred before a diagnosis of vasculitis (11.4%), giving a relative risk of 2.35 (CI 1.07-5.16; P =.03).
However, the researchers said, it is important to note that the maternal age at conception was approximately 5 years older for women who became pregnant after they had vasculitis, which could have influenced the increased morbidity in this group.
Most (59%) of the women who had vasculitis when they conceived reported no change in their disease activity during pregnancy, and another 23% reported an improvement in vasculitis activity during pregnancy. Only 18% of women who had vasculitis when they conceived reported increased symptoms during pregnancy. Increased disease activity did not have a statistically significant effect on pregnancy loss or preterm delivery.
Exposure to cyclophosphamide or prednisone did not appear to affect pregnancy outcomes. However, the numbers of pregnancies among women taking these medications was small.
Among the men, 61 had granulomatosis with polyangitis, 8 had microscopic polyangiitis, 24 had Churg-Strauss syndrome, 9 had polyarteritis nodosa, 4 had Behcet’s disease, and 1 had Takayasu’s arteritis. The average age at diagnosis was 54.6 years (range, 23-86 years)
Six men fathered 18 pregnancies after they had been diagnosed as having vasculitis, and 48 men fathered 138 pregnancies before they were diagnosed as having vasculitis. The rate of pregnancy loss was 41.2% for fathers with vasculitis and 23.0% for fathers who did not yet have a diagnosis of vasculitis, a difference that did not reach statistical significance.
One man treated with cyclophosphamide fathered two pregnancies within a few years that resulted in live births without complications. However, two other men who had received cyclophosphamide at least 10 years before fathering a pregnancy reported a total of seven pregnancy losses (including one with anencephaly) and four live births.
This study was limited in that it relied on retrospective self-report for diagnosis and was not powered to ascertain the role of confounding factors such as maternal age at the time of conception, prior pregnancy complications, and tobacco use. It also may have been biased because patients who had pregnancy difficulties may have been more likely than those who did not to complete a long questionnaire on that topic.
In addition, the number of men in the cohort was low, and a high proportion of them reported multiple pregnancy losses. It remains unclear whether this reflects a true increase in pregnancy loss rate for fathers with vasculitis or "simply reflects the greater interest that these particular men might have in responding to such a survey," Dr. Clowse and her colleagues said.
This study was supported by the Vasculitis Foundation and the Vasculitis Clinical Research Consortium, which receives support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Center for Research Resources, and the Office of Rare Diseases Research. No financial conflicts of interest were reported.
The risks of pregnancy loss and of preterm birth were higher in women who had vasculitis before they conceived than in women who were diagnosed as having vasculitis after conception in a retrospective cohort study.
Women who conceived before receiving a diagnosis of vasculitis had a rate of pregnancy loss similar to the general population, whereas women who conceived after they had received a diagnosis of vasculitis had a significantly higher rate of pregnancy loss, reported Dr. Megan E. B. Clowse of the division of rheumatology and immunology at Duke University, Durham, N.C., and her associates in the Vasculitis Clinical Research Consortium.
The investigators examined pregnancy outcomes among women with vasculitis, as well as the outcomes of pregnancies fathered by men with the disease, because so little is known about the subject. Such pregnancies were rare until recent improvements in treatments helped patients survive longer and lead fuller lives.
"Our goal was to identify pregnancies that occurred within a large cohort of women and men with vasculitis and assess whether such pregnancies were at greater risk for adverse outcomes and whether vasculitis activity increased during pregnancy," the researchers wrote.
They invited patients listed in a registry of rare diseases to complete an anonymous questionnaire regarding their reproductive health. A total of 329 women (who had 496 pregnancies) and 107 men (who fathered 156 pregnancies) were included in the analysis (Arthritis Care Res. 2013 Feb. 11 [doi:10.1002/acr.21983]).
Among the women, 140 had granulomatosis with polyangiitis, 22 had microscopic polyangiitis, 59 had Churg-Strauss syndrome, 18 had polyarteritis nodosa, 43 had Behcet’s disease, and 46 had Takayasu’s arteritis. The mean age at diagnosis was 39.7 years (range, 10-78 years). The mean age at the time of the study was 47 years.
The rate of pregnancy loss was significantly higher among the women who had vasculitis when they conceived (33.8%) than it was among women who conceived before they were diagnosed as having vasculitis (22.4%), giving a relative risk of 1.77 (CI 1.02-3.09; P = .04). This 22.4% rate of pregnancy loss is comparable with that reported in the general population (15%-20%), while the rate found in women who already had vasculitis was significantly higher than that in the general population, Dr. Clowse and her associates said.
Similarly, the rate of preterm birth was significantly higher in pregnancies that occurred after a diagnosis of vasculitis (23.3%) than in pregnancies that occurred before a diagnosis of vasculitis (11.4%), giving a relative risk of 2.35 (CI 1.07-5.16; P =.03).
However, the researchers said, it is important to note that the maternal age at conception was approximately 5 years older for women who became pregnant after they had vasculitis, which could have influenced the increased morbidity in this group.
Most (59%) of the women who had vasculitis when they conceived reported no change in their disease activity during pregnancy, and another 23% reported an improvement in vasculitis activity during pregnancy. Only 18% of women who had vasculitis when they conceived reported increased symptoms during pregnancy. Increased disease activity did not have a statistically significant effect on pregnancy loss or preterm delivery.
Exposure to cyclophosphamide or prednisone did not appear to affect pregnancy outcomes. However, the numbers of pregnancies among women taking these medications was small.
Among the men, 61 had granulomatosis with polyangitis, 8 had microscopic polyangiitis, 24 had Churg-Strauss syndrome, 9 had polyarteritis nodosa, 4 had Behcet’s disease, and 1 had Takayasu’s arteritis. The average age at diagnosis was 54.6 years (range, 23-86 years)
Six men fathered 18 pregnancies after they had been diagnosed as having vasculitis, and 48 men fathered 138 pregnancies before they were diagnosed as having vasculitis. The rate of pregnancy loss was 41.2% for fathers with vasculitis and 23.0% for fathers who did not yet have a diagnosis of vasculitis, a difference that did not reach statistical significance.
One man treated with cyclophosphamide fathered two pregnancies within a few years that resulted in live births without complications. However, two other men who had received cyclophosphamide at least 10 years before fathering a pregnancy reported a total of seven pregnancy losses (including one with anencephaly) and four live births.
This study was limited in that it relied on retrospective self-report for diagnosis and was not powered to ascertain the role of confounding factors such as maternal age at the time of conception, prior pregnancy complications, and tobacco use. It also may have been biased because patients who had pregnancy difficulties may have been more likely than those who did not to complete a long questionnaire on that topic.
In addition, the number of men in the cohort was low, and a high proportion of them reported multiple pregnancy losses. It remains unclear whether this reflects a true increase in pregnancy loss rate for fathers with vasculitis or "simply reflects the greater interest that these particular men might have in responding to such a survey," Dr. Clowse and her colleagues said.
This study was supported by the Vasculitis Foundation and the Vasculitis Clinical Research Consortium, which receives support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Center for Research Resources, and the Office of Rare Diseases Research. No financial conflicts of interest were reported.
The risks of pregnancy loss and of preterm birth were higher in women who had vasculitis before they conceived than in women who were diagnosed as having vasculitis after conception in a retrospective cohort study.
Women who conceived before receiving a diagnosis of vasculitis had a rate of pregnancy loss similar to the general population, whereas women who conceived after they had received a diagnosis of vasculitis had a significantly higher rate of pregnancy loss, reported Dr. Megan E. B. Clowse of the division of rheumatology and immunology at Duke University, Durham, N.C., and her associates in the Vasculitis Clinical Research Consortium.
The investigators examined pregnancy outcomes among women with vasculitis, as well as the outcomes of pregnancies fathered by men with the disease, because so little is known about the subject. Such pregnancies were rare until recent improvements in treatments helped patients survive longer and lead fuller lives.
"Our goal was to identify pregnancies that occurred within a large cohort of women and men with vasculitis and assess whether such pregnancies were at greater risk for adverse outcomes and whether vasculitis activity increased during pregnancy," the researchers wrote.
They invited patients listed in a registry of rare diseases to complete an anonymous questionnaire regarding their reproductive health. A total of 329 women (who had 496 pregnancies) and 107 men (who fathered 156 pregnancies) were included in the analysis (Arthritis Care Res. 2013 Feb. 11 [doi:10.1002/acr.21983]).
Among the women, 140 had granulomatosis with polyangiitis, 22 had microscopic polyangiitis, 59 had Churg-Strauss syndrome, 18 had polyarteritis nodosa, 43 had Behcet’s disease, and 46 had Takayasu’s arteritis. The mean age at diagnosis was 39.7 years (range, 10-78 years). The mean age at the time of the study was 47 years.
The rate of pregnancy loss was significantly higher among the women who had vasculitis when they conceived (33.8%) than it was among women who conceived before they were diagnosed as having vasculitis (22.4%), giving a relative risk of 1.77 (CI 1.02-3.09; P = .04). This 22.4% rate of pregnancy loss is comparable with that reported in the general population (15%-20%), while the rate found in women who already had vasculitis was significantly higher than that in the general population, Dr. Clowse and her associates said.
Similarly, the rate of preterm birth was significantly higher in pregnancies that occurred after a diagnosis of vasculitis (23.3%) than in pregnancies that occurred before a diagnosis of vasculitis (11.4%), giving a relative risk of 2.35 (CI 1.07-5.16; P =.03).
However, the researchers said, it is important to note that the maternal age at conception was approximately 5 years older for women who became pregnant after they had vasculitis, which could have influenced the increased morbidity in this group.
Most (59%) of the women who had vasculitis when they conceived reported no change in their disease activity during pregnancy, and another 23% reported an improvement in vasculitis activity during pregnancy. Only 18% of women who had vasculitis when they conceived reported increased symptoms during pregnancy. Increased disease activity did not have a statistically significant effect on pregnancy loss or preterm delivery.
Exposure to cyclophosphamide or prednisone did not appear to affect pregnancy outcomes. However, the numbers of pregnancies among women taking these medications was small.
Among the men, 61 had granulomatosis with polyangitis, 8 had microscopic polyangiitis, 24 had Churg-Strauss syndrome, 9 had polyarteritis nodosa, 4 had Behcet’s disease, and 1 had Takayasu’s arteritis. The average age at diagnosis was 54.6 years (range, 23-86 years)
Six men fathered 18 pregnancies after they had been diagnosed as having vasculitis, and 48 men fathered 138 pregnancies before they were diagnosed as having vasculitis. The rate of pregnancy loss was 41.2% for fathers with vasculitis and 23.0% for fathers who did not yet have a diagnosis of vasculitis, a difference that did not reach statistical significance.
One man treated with cyclophosphamide fathered two pregnancies within a few years that resulted in live births without complications. However, two other men who had received cyclophosphamide at least 10 years before fathering a pregnancy reported a total of seven pregnancy losses (including one with anencephaly) and four live births.
This study was limited in that it relied on retrospective self-report for diagnosis and was not powered to ascertain the role of confounding factors such as maternal age at the time of conception, prior pregnancy complications, and tobacco use. It also may have been biased because patients who had pregnancy difficulties may have been more likely than those who did not to complete a long questionnaire on that topic.
In addition, the number of men in the cohort was low, and a high proportion of them reported multiple pregnancy losses. It remains unclear whether this reflects a true increase in pregnancy loss rate for fathers with vasculitis or "simply reflects the greater interest that these particular men might have in responding to such a survey," Dr. Clowse and her colleagues said.
This study was supported by the Vasculitis Foundation and the Vasculitis Clinical Research Consortium, which receives support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Center for Research Resources, and the Office of Rare Diseases Research. No financial conflicts of interest were reported.
FROM ARTHRITIS CARE AND RESEARCH
Major Finding: The rate of pregnancy loss was significantly higher among women who had vasculitis when they conceived (33.8%) than it was among women who conceived before they were diagnosed with vasculitis (22.4%).
Data Source: A cohort study involving 329 women with vasculitis who had 496 pregnancies and 107 men with vasculitis who fathered 156 pregnancies.
Disclosures: This study was supported by the Vasculitis Foundation and the Vasculitis Clinical Research Consortium, which receives support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Center for Research Resources, and the Office of Rare Diseases Research. No financial conflicts of interest were reported.
Older women with primary biliary cirrhosis responders to UDCA
The age and sex of the patient at the onset of primary biliary cirrhosis predict the severity of disease and the likelihood of response to treatment with ursodeoxycholic acid, Dr. Marco Carbone and his associates reported in Gastroenterology.
In what they described as the first study large enough to permit examination of meaningful numbers of patient subgroups, the researchers found that among women, older age at diagnosis correlated with a better chance of responding to UDCA and with a less severe disease phenotype. These findings are reassuring because women with primary biliary cirrhosis outnumber men by approximately 10 to 1, and most are older than 50 years at disease onset.
Source: American Gastroenterological Association
But the other side of the coin is that the minority of patients who do present at an earlier age, or are men, are more likely to have a severe disease phenotype and less likely to respond to therapy.
"Collectively our findings highlight that primary biliary cirrhosis is not a uniform disease with uniform risks and impact, but one with high- and low-risk patients," said Dr. Carbone of the department of hepatology, Cambridge (England) University Hospitals National Health Service Foundation Trust, and his associates (doi:10.1053/j.gastro.2012.12.005).
The researchers analyzed data from the United Kingdom–Primary Biliary Cirrhosis cohort, an ongoing national genetic study of the disease that enrolled patients from every hospital in the country during a recent 3-year period. This patient population represents 25% of all primary biliary cirrhosis patients in the United Kingdom.
Dr. Carbone and his colleagues assessed the records of 2,353 participants in the UK-PBC, including a subgroup of 1,379 who supplied extra detailed clinical information. The cohort included 221 men.
More than 80% of the study subjects were managed outside of specialist liver transplant centers. These patients were just as likely as were those managed at specialty centers to be offered therapy with UDCA.
Women who presented at age 50 or older were significantly more likely than were younger women or men to have less severe disease and to respond to UDCA. In particular, women aged 70 and older at presentation had a greater than 90% chance of responding.
One possible explanation for this finding is that hormones, particularly high estrogen levels, may raise resistance to treatment. "There certainly are plausible biologic mechanisms for such an endocrine effect, as female sex hormones modulate immune regulation and biliary epithelial cell turnover. Furthermore, case reports show that tamoxifen, an antiestrogen, improves liver biochemistry in primary biliary cirrhosis," the investigators said.
This finding suggests that a clinical trial of antiestrogens as adjunctive therapy should be considered for high-risk patients who don’t respond to UDCA, they noted.
Men typically presented at an older age but with more severe disease, as evidenced by their reduced platelet counts and higher frequency of splenomegaly.
"This is likely to represent delayed diagnosis resulting from the misperception that primary biliary cirrhosis is ‘a female disease,’ with the presence of features such as elevated [liver enzymes] being falsely ascribed to conditions or etiologies that are common in the male population, such as increased alcohol consumption," Dr. Carbone and his associates said.
Men were just as likely as were women to be offered UDCA therapy, but were significantly less likely to respond adequately.
Autonomic symptoms were more marked among women than men. In a substudy in which male subjects were matched with female subjects, the difference in autonomic symptoms closely correlated with differences in fatigue severity, "raising the obvious question as to whether reduction in autonomic dysfunction might reduce fatigue," the investigators said.
One possible reason that men have fewer autonomic symptoms may be that they tend to have higher underlying blood pressure than women, they added.
Overall, it appears that most patients with primary biliary cirrhosis present at an older age, have few symptoms, and respond well to UDCA – a "benign picture" that should guide planning and delivery of care.
In contrast, younger patients tend to have a more complex course, with more symptoms that interfere with daily life and a higher risk of treatment failure. "Such patients should be the focus for novel therapy to improve outcomes."
Men have a lower chance of responding to therapy, but fortunately they have a lower symptom burden and their age at disease onset doesn’t affect prognosis.
No financial conflicts were reported.
This large study of primary biliary cirrhosis demonstrates convincingly that PBC is a heterogeneous disease. The finding that the disease appears to be less responsive to UDCA and thus more aggressive in young women and in men is intriguing and clinically relevant. At present, there is no good pathophysiologic explanation for this observation, and it is more likely that this difference is due to diagnostic bias: Because PBC is considered to be a disease of older women it is less likely to be diagnosed in younger women and in men unless it is more active and symptomatic.
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In addition, in mild disease, laboratory values may remain normal until older age, while in aggressive disease with features of secondary autoimmune hepatitis, elevated liver enzymes can be found already early in the disease process. Whether hormonal factors play a role needs further study, and this large patient cohort may help in such an analysis as patients who received contraceptives or hormonal replacements could be compared with patients without hormonal exposure.
What does the study mean for the practicing clinician? The heterogeneity of PBC, the more aggressive course in some patients, and the benefit from additional immunosuppressive therapy require identification of patients at risk. Liver biopsy is the most sensitive test to detect an aggressive course of PBC by showing features of lobular and interface hepatitis, and seems to be indicated particularly in young women, in men, and in insufficient response to initial UDCA treatment.
Ansgar W. Lohse, M.D., is professor of medicine at University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. He has no financial disclosures.
This large study of primary biliary cirrhosis demonstrates convincingly that PBC is a heterogeneous disease. The finding that the disease appears to be less responsive to UDCA and thus more aggressive in young women and in men is intriguing and clinically relevant. At present, there is no good pathophysiologic explanation for this observation, and it is more likely that this difference is due to diagnostic bias: Because PBC is considered to be a disease of older women it is less likely to be diagnosed in younger women and in men unless it is more active and symptomatic.
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In addition, in mild disease, laboratory values may remain normal until older age, while in aggressive disease with features of secondary autoimmune hepatitis, elevated liver enzymes can be found already early in the disease process. Whether hormonal factors play a role needs further study, and this large patient cohort may help in such an analysis as patients who received contraceptives or hormonal replacements could be compared with patients without hormonal exposure.
What does the study mean for the practicing clinician? The heterogeneity of PBC, the more aggressive course in some patients, and the benefit from additional immunosuppressive therapy require identification of patients at risk. Liver biopsy is the most sensitive test to detect an aggressive course of PBC by showing features of lobular and interface hepatitis, and seems to be indicated particularly in young women, in men, and in insufficient response to initial UDCA treatment.
Ansgar W. Lohse, M.D., is professor of medicine at University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. He has no financial disclosures.
This large study of primary biliary cirrhosis demonstrates convincingly that PBC is a heterogeneous disease. The finding that the disease appears to be less responsive to UDCA and thus more aggressive in young women and in men is intriguing and clinically relevant. At present, there is no good pathophysiologic explanation for this observation, and it is more likely that this difference is due to diagnostic bias: Because PBC is considered to be a disease of older women it is less likely to be diagnosed in younger women and in men unless it is more active and symptomatic.
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In addition, in mild disease, laboratory values may remain normal until older age, while in aggressive disease with features of secondary autoimmune hepatitis, elevated liver enzymes can be found already early in the disease process. Whether hormonal factors play a role needs further study, and this large patient cohort may help in such an analysis as patients who received contraceptives or hormonal replacements could be compared with patients without hormonal exposure.
What does the study mean for the practicing clinician? The heterogeneity of PBC, the more aggressive course in some patients, and the benefit from additional immunosuppressive therapy require identification of patients at risk. Liver biopsy is the most sensitive test to detect an aggressive course of PBC by showing features of lobular and interface hepatitis, and seems to be indicated particularly in young women, in men, and in insufficient response to initial UDCA treatment.
Ansgar W. Lohse, M.D., is professor of medicine at University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. He has no financial disclosures.
The age and sex of the patient at the onset of primary biliary cirrhosis predict the severity of disease and the likelihood of response to treatment with ursodeoxycholic acid, Dr. Marco Carbone and his associates reported in Gastroenterology.
In what they described as the first study large enough to permit examination of meaningful numbers of patient subgroups, the researchers found that among women, older age at diagnosis correlated with a better chance of responding to UDCA and with a less severe disease phenotype. These findings are reassuring because women with primary biliary cirrhosis outnumber men by approximately 10 to 1, and most are older than 50 years at disease onset.
Source: American Gastroenterological Association
But the other side of the coin is that the minority of patients who do present at an earlier age, or are men, are more likely to have a severe disease phenotype and less likely to respond to therapy.
"Collectively our findings highlight that primary biliary cirrhosis is not a uniform disease with uniform risks and impact, but one with high- and low-risk patients," said Dr. Carbone of the department of hepatology, Cambridge (England) University Hospitals National Health Service Foundation Trust, and his associates (doi:10.1053/j.gastro.2012.12.005).
The researchers analyzed data from the United Kingdom–Primary Biliary Cirrhosis cohort, an ongoing national genetic study of the disease that enrolled patients from every hospital in the country during a recent 3-year period. This patient population represents 25% of all primary biliary cirrhosis patients in the United Kingdom.
Dr. Carbone and his colleagues assessed the records of 2,353 participants in the UK-PBC, including a subgroup of 1,379 who supplied extra detailed clinical information. The cohort included 221 men.
More than 80% of the study subjects were managed outside of specialist liver transplant centers. These patients were just as likely as were those managed at specialty centers to be offered therapy with UDCA.
Women who presented at age 50 or older were significantly more likely than were younger women or men to have less severe disease and to respond to UDCA. In particular, women aged 70 and older at presentation had a greater than 90% chance of responding.
One possible explanation for this finding is that hormones, particularly high estrogen levels, may raise resistance to treatment. "There certainly are plausible biologic mechanisms for such an endocrine effect, as female sex hormones modulate immune regulation and biliary epithelial cell turnover. Furthermore, case reports show that tamoxifen, an antiestrogen, improves liver biochemistry in primary biliary cirrhosis," the investigators said.
This finding suggests that a clinical trial of antiestrogens as adjunctive therapy should be considered for high-risk patients who don’t respond to UDCA, they noted.
Men typically presented at an older age but with more severe disease, as evidenced by their reduced platelet counts and higher frequency of splenomegaly.
"This is likely to represent delayed diagnosis resulting from the misperception that primary biliary cirrhosis is ‘a female disease,’ with the presence of features such as elevated [liver enzymes] being falsely ascribed to conditions or etiologies that are common in the male population, such as increased alcohol consumption," Dr. Carbone and his associates said.
Men were just as likely as were women to be offered UDCA therapy, but were significantly less likely to respond adequately.
Autonomic symptoms were more marked among women than men. In a substudy in which male subjects were matched with female subjects, the difference in autonomic symptoms closely correlated with differences in fatigue severity, "raising the obvious question as to whether reduction in autonomic dysfunction might reduce fatigue," the investigators said.
One possible reason that men have fewer autonomic symptoms may be that they tend to have higher underlying blood pressure than women, they added.
Overall, it appears that most patients with primary biliary cirrhosis present at an older age, have few symptoms, and respond well to UDCA – a "benign picture" that should guide planning and delivery of care.
In contrast, younger patients tend to have a more complex course, with more symptoms that interfere with daily life and a higher risk of treatment failure. "Such patients should be the focus for novel therapy to improve outcomes."
Men have a lower chance of responding to therapy, but fortunately they have a lower symptom burden and their age at disease onset doesn’t affect prognosis.
No financial conflicts were reported.
The age and sex of the patient at the onset of primary biliary cirrhosis predict the severity of disease and the likelihood of response to treatment with ursodeoxycholic acid, Dr. Marco Carbone and his associates reported in Gastroenterology.
In what they described as the first study large enough to permit examination of meaningful numbers of patient subgroups, the researchers found that among women, older age at diagnosis correlated with a better chance of responding to UDCA and with a less severe disease phenotype. These findings are reassuring because women with primary biliary cirrhosis outnumber men by approximately 10 to 1, and most are older than 50 years at disease onset.
Source: American Gastroenterological Association
But the other side of the coin is that the minority of patients who do present at an earlier age, or are men, are more likely to have a severe disease phenotype and less likely to respond to therapy.
"Collectively our findings highlight that primary biliary cirrhosis is not a uniform disease with uniform risks and impact, but one with high- and low-risk patients," said Dr. Carbone of the department of hepatology, Cambridge (England) University Hospitals National Health Service Foundation Trust, and his associates (doi:10.1053/j.gastro.2012.12.005).
The researchers analyzed data from the United Kingdom–Primary Biliary Cirrhosis cohort, an ongoing national genetic study of the disease that enrolled patients from every hospital in the country during a recent 3-year period. This patient population represents 25% of all primary biliary cirrhosis patients in the United Kingdom.
Dr. Carbone and his colleagues assessed the records of 2,353 participants in the UK-PBC, including a subgroup of 1,379 who supplied extra detailed clinical information. The cohort included 221 men.
More than 80% of the study subjects were managed outside of specialist liver transplant centers. These patients were just as likely as were those managed at specialty centers to be offered therapy with UDCA.
Women who presented at age 50 or older were significantly more likely than were younger women or men to have less severe disease and to respond to UDCA. In particular, women aged 70 and older at presentation had a greater than 90% chance of responding.
One possible explanation for this finding is that hormones, particularly high estrogen levels, may raise resistance to treatment. "There certainly are plausible biologic mechanisms for such an endocrine effect, as female sex hormones modulate immune regulation and biliary epithelial cell turnover. Furthermore, case reports show that tamoxifen, an antiestrogen, improves liver biochemistry in primary biliary cirrhosis," the investigators said.
This finding suggests that a clinical trial of antiestrogens as adjunctive therapy should be considered for high-risk patients who don’t respond to UDCA, they noted.
Men typically presented at an older age but with more severe disease, as evidenced by their reduced platelet counts and higher frequency of splenomegaly.
"This is likely to represent delayed diagnosis resulting from the misperception that primary biliary cirrhosis is ‘a female disease,’ with the presence of features such as elevated [liver enzymes] being falsely ascribed to conditions or etiologies that are common in the male population, such as increased alcohol consumption," Dr. Carbone and his associates said.
Men were just as likely as were women to be offered UDCA therapy, but were significantly less likely to respond adequately.
Autonomic symptoms were more marked among women than men. In a substudy in which male subjects were matched with female subjects, the difference in autonomic symptoms closely correlated with differences in fatigue severity, "raising the obvious question as to whether reduction in autonomic dysfunction might reduce fatigue," the investigators said.
One possible reason that men have fewer autonomic symptoms may be that they tend to have higher underlying blood pressure than women, they added.
Overall, it appears that most patients with primary biliary cirrhosis present at an older age, have few symptoms, and respond well to UDCA – a "benign picture" that should guide planning and delivery of care.
In contrast, younger patients tend to have a more complex course, with more symptoms that interfere with daily life and a higher risk of treatment failure. "Such patients should be the focus for novel therapy to improve outcomes."
Men have a lower chance of responding to therapy, but fortunately they have a lower symptom burden and their age at disease onset doesn’t affect prognosis.
No financial conflicts were reported.
FROM GASTROENTEROLOGY
Major Finding: Women aged 70 and older at presentation for primary biliary cirrhosis had a greater than 90% chance of responding to ursodeoxycholic acid therapy.
Data Source: An observational cross-sectional study describing the phenotype of primary biliary cirrhosis, using data from a UK cohort of 2,353 adults with the autoimmune disease.
Disclosures: No financial conflicts of interest were reported.
Anti-TNF agents vary in ability to cross placenta
Two small studies now add to the very sparse clinical experience with the use of anti-TNF-alpha agents in women who have inflammatory bowel disease and become pregnant, according to separate groups of researchers writing in the March issue of Clinical Gastroenterology and Hepatology.
Both studies confirm that two TNF antagonists do cross the placenta to the fetus at high levels and persist in the infant for months after birth. Discontinuing the drugs during the second trimester lessens but does not eliminate this exposure.
"At this time, we do not know what a safe or harmful level of drug in the newborn is, and what the full consequences of neonatal anti-TNF-alpha exposure to newborn development will be. The risks and benefits of therapy should be individualized, and pediatricians should be cautioned to monitor for potential infections and other abnormalities," said Dr. Uma Mahadevan of the University of California, San Francisco, and her associates (Clin. Gastroenterol. Hepatol. 2012 [doi:10.1016/j.cgh.2012.11.011]).
In their study, Dr. Mahadevan and her colleagues identified 31 pregnant women in their practice or in the Crohn’s Colitis Foundation of America’s Pregnancy IBD and Neonatal Outcomes registry who had Crohn’s disease and were taking infliximab (11 women), adalimumab (10 women), or certolizumab (10 women).
The first two of these anti-TNF-alpha agents are both of the IgG1 subclass and thus should, in theory, cross the placenta at high rates during the third trimester. Certolizumab, a pegylated fragment of an anti-TNF-alpha monoclonal antibody, in theory should not be transported across the placenta. To test these theories, the researchers determined the concentrations of each medication in samples of cord blood, infant serum, and the mother’s plasma taken on the day of birth. None of the infants had birth defects or required neonatal ICU care.
In the infliximab group, the median interval between the last dose of the agent and delivery was 35 days (range, 2-91 days). In every case, cord blood and infant serum samples showed much higher levels of the TNF-alpha antagonist than did maternal plasma samples, at a median ratio of 160:100. The drug persisted in the infants’ circulation for 2-7 months postpartum.
In the adalimumab group, the median interval between the last dose of the agent and delivery was 5.5 weeks. Again, in every case, cord blood and infant serum samples showed much higher levels of the TNF-alpha antagonist than did maternal plasma samples, at a median ratio of 179:100. The drug persisted in the infants’ circulation for at least 11 weeks.
In contrast, no certolizumab was detected in any of the infant samples.
"Based on the results of this study and available safety data, infliximab, adalimumab, and certolizumab can be used through conception and the first and second trimester of pregnancy on schedule. However, the significant placental transfer and subsequent slow postpartum clearance of infliximab and adalimumab raise concerns about their use during the third trimester," Dr. Mahadevan and her associates said.
Such concerns must be balanced against the risk of a flare of IBD, "which has far more consequences to neonatal development," impairing nutritional status of mother and fetus; raising the risk of preterm delivery; and possibly requiring harmful diagnostic testing, medication, and even surgery on the pregnant patient.
Physicians may consider switching patients to certolizumab during pregnancy because of its lack of transfer to the fetus, but "if a pregnant patient is doing well on infliximab or adalimumab, there is no indication, and even a potential risk, of switching ... as the primary goal remains to maintain a quiescent disease state that is critical for a successful pregnancy," they noted.
In the other study, Dr. Zuzana Zelinkova of Erasmus Medical Center, Rotterdam, the Netherlands, and her associates assessed 28 pregnant women who had Crohn’s disease or ulcerative colitis for which they were taking TNF-alpha antagonists.
Of the 17 taking infliximab, 12 had IBD in remission and discontinued the drug at a mean of 23 weeks’ gestation. Three others had perianal fistulas but discontinued early in the second trimester, while two had perianal fistulas and active luminal disease and didn’t discontinue the drug until weeks 30 and 34. None developed IBD relapses.
All 11 study subjects who were taking adalimumab had quiescent disease in the second trimester and discontinued the drug at a mean gestation of 22 weeks (range, 21-27 weeks). Two of them (18%) developed relapses of IBD.
There were three spontaneous miscarriages during the first trimester, and one child was born with polydactyly.
Levels of TNF-alpha antagonists in cord blood samples were significantly lower in the group who discontinued the drugs early, compared with the group who continued taking them until 10 or fewer weeks before delivery. "We recommend considering the discontinuation of anti-TNF-alpha treatment in patients who have quiescent disease at the beginning of the second trimester," to decrease but not completely eliminate the child’s exposure to these agents, Dr. Zelinkova and her associates said.
Dr. Mahadevan’s study was supported by Abbott (marketer of adalimumab), UCB (marketer of certolizumab), Prometheus Labs, and the Crohn’s Colitis Foundation of America. Dr. Mahadevan and her associates reported ties to Janssen (marketer of infliximab), UCB, and Abbott. Dr. Zelinkova and her associates reported ties to Abbott; Merck, Sharp & Dohme; and Shire.
These two studies firm up our knowledge regarding anti-TNF therapy during pregnancy. They confirm that the IgG1 monoclonal antibodies infliximab and adalimumab have substantial transplacental transfer that increases during the third trimester. Infants born to women who continue these medications during the third trimester will have detectable drug concentrations that persist for 2-7 months.
No serious infectious events occurred in these studies. However, there is a previous report of an infant whose mother took infliximab during the third trimester who was vaccinated with the live organism BCG [Bacille Calmette Guerin] and developed disseminated BCG, which ultimately led to death (J. Am. Acad. Dermatol. 2011;65:870). This case report demonstrates that infants who are born with detectable infliximab or adalimumab levels are at risk for opportunistic infections. In contrast, certolizumab pegol does not cross the placenta.
The studies also show that interruption of infliximab or adalimumab at the end of the second trimester substantially reduces the amount of antibody transferred to the infant and shortens the time required for the infant to clear the antibody. Finally, discontinuation of infliximab and adalimumab during the third trimester appears to be associated with a low risk of relapse.
Altogether, these findings would appear to support the discontinuation of infliximab and adalimumab during the third trimester. Discontinuation of certolizumab pegol is not necessary.
William J. Sandborn, M.D., AGAF, is chief of the division of gastroenterology and director of the UCSD IBD Center in the University of California San Diego Health System. He has consulted for and received research grants from Janssen and consulted for AbbVie (previously Abbott Laboratories) and UCB Pharma.
These two studies firm up our knowledge regarding anti-TNF therapy during pregnancy. They confirm that the IgG1 monoclonal antibodies infliximab and adalimumab have substantial transplacental transfer that increases during the third trimester. Infants born to women who continue these medications during the third trimester will have detectable drug concentrations that persist for 2-7 months.
No serious infectious events occurred in these studies. However, there is a previous report of an infant whose mother took infliximab during the third trimester who was vaccinated with the live organism BCG [Bacille Calmette Guerin] and developed disseminated BCG, which ultimately led to death (J. Am. Acad. Dermatol. 2011;65:870). This case report demonstrates that infants who are born with detectable infliximab or adalimumab levels are at risk for opportunistic infections. In contrast, certolizumab pegol does not cross the placenta.
The studies also show that interruption of infliximab or adalimumab at the end of the second trimester substantially reduces the amount of antibody transferred to the infant and shortens the time required for the infant to clear the antibody. Finally, discontinuation of infliximab and adalimumab during the third trimester appears to be associated with a low risk of relapse.
Altogether, these findings would appear to support the discontinuation of infliximab and adalimumab during the third trimester. Discontinuation of certolizumab pegol is not necessary.
William J. Sandborn, M.D., AGAF, is chief of the division of gastroenterology and director of the UCSD IBD Center in the University of California San Diego Health System. He has consulted for and received research grants from Janssen and consulted for AbbVie (previously Abbott Laboratories) and UCB Pharma.
These two studies firm up our knowledge regarding anti-TNF therapy during pregnancy. They confirm that the IgG1 monoclonal antibodies infliximab and adalimumab have substantial transplacental transfer that increases during the third trimester. Infants born to women who continue these medications during the third trimester will have detectable drug concentrations that persist for 2-7 months.
No serious infectious events occurred in these studies. However, there is a previous report of an infant whose mother took infliximab during the third trimester who was vaccinated with the live organism BCG [Bacille Calmette Guerin] and developed disseminated BCG, which ultimately led to death (J. Am. Acad. Dermatol. 2011;65:870). This case report demonstrates that infants who are born with detectable infliximab or adalimumab levels are at risk for opportunistic infections. In contrast, certolizumab pegol does not cross the placenta.
The studies also show that interruption of infliximab or adalimumab at the end of the second trimester substantially reduces the amount of antibody transferred to the infant and shortens the time required for the infant to clear the antibody. Finally, discontinuation of infliximab and adalimumab during the third trimester appears to be associated with a low risk of relapse.
Altogether, these findings would appear to support the discontinuation of infliximab and adalimumab during the third trimester. Discontinuation of certolizumab pegol is not necessary.
William J. Sandborn, M.D., AGAF, is chief of the division of gastroenterology and director of the UCSD IBD Center in the University of California San Diego Health System. He has consulted for and received research grants from Janssen and consulted for AbbVie (previously Abbott Laboratories) and UCB Pharma.
Two small studies now add to the very sparse clinical experience with the use of anti-TNF-alpha agents in women who have inflammatory bowel disease and become pregnant, according to separate groups of researchers writing in the March issue of Clinical Gastroenterology and Hepatology.
Both studies confirm that two TNF antagonists do cross the placenta to the fetus at high levels and persist in the infant for months after birth. Discontinuing the drugs during the second trimester lessens but does not eliminate this exposure.
"At this time, we do not know what a safe or harmful level of drug in the newborn is, and what the full consequences of neonatal anti-TNF-alpha exposure to newborn development will be. The risks and benefits of therapy should be individualized, and pediatricians should be cautioned to monitor for potential infections and other abnormalities," said Dr. Uma Mahadevan of the University of California, San Francisco, and her associates (Clin. Gastroenterol. Hepatol. 2012 [doi:10.1016/j.cgh.2012.11.011]).
In their study, Dr. Mahadevan and her colleagues identified 31 pregnant women in their practice or in the Crohn’s Colitis Foundation of America’s Pregnancy IBD and Neonatal Outcomes registry who had Crohn’s disease and were taking infliximab (11 women), adalimumab (10 women), or certolizumab (10 women).
The first two of these anti-TNF-alpha agents are both of the IgG1 subclass and thus should, in theory, cross the placenta at high rates during the third trimester. Certolizumab, a pegylated fragment of an anti-TNF-alpha monoclonal antibody, in theory should not be transported across the placenta. To test these theories, the researchers determined the concentrations of each medication in samples of cord blood, infant serum, and the mother’s plasma taken on the day of birth. None of the infants had birth defects or required neonatal ICU care.
In the infliximab group, the median interval between the last dose of the agent and delivery was 35 days (range, 2-91 days). In every case, cord blood and infant serum samples showed much higher levels of the TNF-alpha antagonist than did maternal plasma samples, at a median ratio of 160:100. The drug persisted in the infants’ circulation for 2-7 months postpartum.
In the adalimumab group, the median interval between the last dose of the agent and delivery was 5.5 weeks. Again, in every case, cord blood and infant serum samples showed much higher levels of the TNF-alpha antagonist than did maternal plasma samples, at a median ratio of 179:100. The drug persisted in the infants’ circulation for at least 11 weeks.
In contrast, no certolizumab was detected in any of the infant samples.
"Based on the results of this study and available safety data, infliximab, adalimumab, and certolizumab can be used through conception and the first and second trimester of pregnancy on schedule. However, the significant placental transfer and subsequent slow postpartum clearance of infliximab and adalimumab raise concerns about their use during the third trimester," Dr. Mahadevan and her associates said.
Such concerns must be balanced against the risk of a flare of IBD, "which has far more consequences to neonatal development," impairing nutritional status of mother and fetus; raising the risk of preterm delivery; and possibly requiring harmful diagnostic testing, medication, and even surgery on the pregnant patient.
Physicians may consider switching patients to certolizumab during pregnancy because of its lack of transfer to the fetus, but "if a pregnant patient is doing well on infliximab or adalimumab, there is no indication, and even a potential risk, of switching ... as the primary goal remains to maintain a quiescent disease state that is critical for a successful pregnancy," they noted.
In the other study, Dr. Zuzana Zelinkova of Erasmus Medical Center, Rotterdam, the Netherlands, and her associates assessed 28 pregnant women who had Crohn’s disease or ulcerative colitis for which they were taking TNF-alpha antagonists.
Of the 17 taking infliximab, 12 had IBD in remission and discontinued the drug at a mean of 23 weeks’ gestation. Three others had perianal fistulas but discontinued early in the second trimester, while two had perianal fistulas and active luminal disease and didn’t discontinue the drug until weeks 30 and 34. None developed IBD relapses.
All 11 study subjects who were taking adalimumab had quiescent disease in the second trimester and discontinued the drug at a mean gestation of 22 weeks (range, 21-27 weeks). Two of them (18%) developed relapses of IBD.
There were three spontaneous miscarriages during the first trimester, and one child was born with polydactyly.
Levels of TNF-alpha antagonists in cord blood samples were significantly lower in the group who discontinued the drugs early, compared with the group who continued taking them until 10 or fewer weeks before delivery. "We recommend considering the discontinuation of anti-TNF-alpha treatment in patients who have quiescent disease at the beginning of the second trimester," to decrease but not completely eliminate the child’s exposure to these agents, Dr. Zelinkova and her associates said.
Dr. Mahadevan’s study was supported by Abbott (marketer of adalimumab), UCB (marketer of certolizumab), Prometheus Labs, and the Crohn’s Colitis Foundation of America. Dr. Mahadevan and her associates reported ties to Janssen (marketer of infliximab), UCB, and Abbott. Dr. Zelinkova and her associates reported ties to Abbott; Merck, Sharp & Dohme; and Shire.
Two small studies now add to the very sparse clinical experience with the use of anti-TNF-alpha agents in women who have inflammatory bowel disease and become pregnant, according to separate groups of researchers writing in the March issue of Clinical Gastroenterology and Hepatology.
Both studies confirm that two TNF antagonists do cross the placenta to the fetus at high levels and persist in the infant for months after birth. Discontinuing the drugs during the second trimester lessens but does not eliminate this exposure.
"At this time, we do not know what a safe or harmful level of drug in the newborn is, and what the full consequences of neonatal anti-TNF-alpha exposure to newborn development will be. The risks and benefits of therapy should be individualized, and pediatricians should be cautioned to monitor for potential infections and other abnormalities," said Dr. Uma Mahadevan of the University of California, San Francisco, and her associates (Clin. Gastroenterol. Hepatol. 2012 [doi:10.1016/j.cgh.2012.11.011]).
In their study, Dr. Mahadevan and her colleagues identified 31 pregnant women in their practice or in the Crohn’s Colitis Foundation of America’s Pregnancy IBD and Neonatal Outcomes registry who had Crohn’s disease and were taking infliximab (11 women), adalimumab (10 women), or certolizumab (10 women).
The first two of these anti-TNF-alpha agents are both of the IgG1 subclass and thus should, in theory, cross the placenta at high rates during the third trimester. Certolizumab, a pegylated fragment of an anti-TNF-alpha monoclonal antibody, in theory should not be transported across the placenta. To test these theories, the researchers determined the concentrations of each medication in samples of cord blood, infant serum, and the mother’s plasma taken on the day of birth. None of the infants had birth defects or required neonatal ICU care.
In the infliximab group, the median interval between the last dose of the agent and delivery was 35 days (range, 2-91 days). In every case, cord blood and infant serum samples showed much higher levels of the TNF-alpha antagonist than did maternal plasma samples, at a median ratio of 160:100. The drug persisted in the infants’ circulation for 2-7 months postpartum.
In the adalimumab group, the median interval between the last dose of the agent and delivery was 5.5 weeks. Again, in every case, cord blood and infant serum samples showed much higher levels of the TNF-alpha antagonist than did maternal plasma samples, at a median ratio of 179:100. The drug persisted in the infants’ circulation for at least 11 weeks.
In contrast, no certolizumab was detected in any of the infant samples.
"Based on the results of this study and available safety data, infliximab, adalimumab, and certolizumab can be used through conception and the first and second trimester of pregnancy on schedule. However, the significant placental transfer and subsequent slow postpartum clearance of infliximab and adalimumab raise concerns about their use during the third trimester," Dr. Mahadevan and her associates said.
Such concerns must be balanced against the risk of a flare of IBD, "which has far more consequences to neonatal development," impairing nutritional status of mother and fetus; raising the risk of preterm delivery; and possibly requiring harmful diagnostic testing, medication, and even surgery on the pregnant patient.
Physicians may consider switching patients to certolizumab during pregnancy because of its lack of transfer to the fetus, but "if a pregnant patient is doing well on infliximab or adalimumab, there is no indication, and even a potential risk, of switching ... as the primary goal remains to maintain a quiescent disease state that is critical for a successful pregnancy," they noted.
In the other study, Dr. Zuzana Zelinkova of Erasmus Medical Center, Rotterdam, the Netherlands, and her associates assessed 28 pregnant women who had Crohn’s disease or ulcerative colitis for which they were taking TNF-alpha antagonists.
Of the 17 taking infliximab, 12 had IBD in remission and discontinued the drug at a mean of 23 weeks’ gestation. Three others had perianal fistulas but discontinued early in the second trimester, while two had perianal fistulas and active luminal disease and didn’t discontinue the drug until weeks 30 and 34. None developed IBD relapses.
All 11 study subjects who were taking adalimumab had quiescent disease in the second trimester and discontinued the drug at a mean gestation of 22 weeks (range, 21-27 weeks). Two of them (18%) developed relapses of IBD.
There were three spontaneous miscarriages during the first trimester, and one child was born with polydactyly.
Levels of TNF-alpha antagonists in cord blood samples were significantly lower in the group who discontinued the drugs early, compared with the group who continued taking them until 10 or fewer weeks before delivery. "We recommend considering the discontinuation of anti-TNF-alpha treatment in patients who have quiescent disease at the beginning of the second trimester," to decrease but not completely eliminate the child’s exposure to these agents, Dr. Zelinkova and her associates said.
Dr. Mahadevan’s study was supported by Abbott (marketer of adalimumab), UCB (marketer of certolizumab), Prometheus Labs, and the Crohn’s Colitis Foundation of America. Dr. Mahadevan and her associates reported ties to Janssen (marketer of infliximab), UCB, and Abbott. Dr. Zelinkova and her associates reported ties to Abbott; Merck, Sharp & Dohme; and Shire.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Major Finding: Ratios of infliximab and adalimumab in samples of cord blood and infant serum to maternal plasma occurred at a median of 160:100 and 179:100, respectively, despite discontinuing the drugs a median of 35 days and 5.5 weeks, respectively, before delivery.
Data Source: Two observational studies involving a total of 59 pregnant women in which the levels of anti-TNF-alpha agents were measured in cord blood, infant serum, and maternal plasma on the day of birth.
Disclosures: Dr. Mahadevan’s study was supported by Abbott (marketer of adalimumab), UCB (marketer of certolizumab), Prometheus Labs, and the Crohn’s Colitis Foundation of America. Dr. Mahadevan and her associates reported ties to Janssen (marketer of infliximab), UCB, and Abbott. Dr. Zelinkova and her associates reported ties to Abbott; Merck Sharp & Dohme; and Shire.
Intractable vomiting may signal brainstem autoinflammatory disorder
Intractable nausea and vomiting can be the isolated presenting symptom of neuromyelitis optica spectrum disorder, and gastroenterologists as well as internists need to be more aware of this possibility, even though it is rare, Dr. Raffaele Iorio and his colleagues said in the March issue of Clinical Gastroenterology and Hepatology.
Neuromyelitis optica spectrum disorder is a relapsing inflammatory demyelinating disease of the CNS similar to multiple sclerosis, which progresses to optic neuritis and/or longitudinally extensive transverse myelitis. If untreated, it often results in blindness and confinement to a wheelchair. It is especially important to recognize this disorder as early as possible, so that immunosuppressant therapy can be initiated and progression to such devastating outcomes can be averted, said Dr. Iorio, of the department of laboratory medicine and pathology, Mayo Clinic, Rochester, Minn., and his associates.
Source: American Gastroenterological Association
The cause of neuromyelitis optica spectrum disorder is thought to be autoantibodies that target the astrocytic aquaporin-4 (AQP4) water channel, the principal water channel in the central nervous system. The fourth ventricular floor, which contains the chemosensitive nausea and vomiting center (the area postrema), is a particularly AQP4-enriched region of the brain.
For some patients who develop the disorder, intractable nausea and vomiting may be the only presenting symptom. "These patients commonly undergo extensive, but nonrevealing evaluations on presentation to internists and gastroenterologists, who are largely unaware of this emerging neurological entity." Consequently, many patients are subjected to unnecessary gastroscopy, biopsy, x-rays, ultrasound, CTs, and even surgery, the investigators noted.
They previously reported that a retrospective chart review identified 69 patients diagnosed at the Mayo Clinic as having neuromyelitis optica spectrum disorder. Eight of them (12%) presented with intractable nausea and vomiting as the sole initial symptom.
The researchers have since reviewed an additional 70 charts in their database and now report an additional 10 patients (14% of the 70) in whom intractable nausea and vomiting was the only presenting symptom.
Nine of these 10 patients were women. Mean age of symptom onset was 47 years (range, 26-72 years).
Nausea and vomiting were continuous rather than cyclic, and both occurred day and night. Patients did not report headache or other CNS symptoms, but three had intractable hiccups concomitant with their vomiting.
All 10 patients initially presented to a gastroenterologist or internist. Seven required immediate inpatient IV hydration. Treatment with antiemetics "yielded only partial benefit."
Inflammatory markers, including erythrocyte sedimentation rate and C-reactive protein level, were within normal limits.
A total of 6 of the 10 patients underwent extensive GI evaluation, which included abdominal CT, abdominal ultrasound, small bowel x-ray, upper gastroscopy with biopsy, pelvic and liver CT and ultrasound, gastric-emptying studies, and wireless capsule endoscopy.
One patient underwent cholecystectomy when imaging studies detected a "tiny" gallbladder polyp. Her vomiting worsened after the procedure.
A total of 5 of the 10 patients eventually underwent brain MRI. Three of them showed abnormalities in the area postrema, another showed abnormalities in the deep white matter, and the fifth patient showed no abnormalities on this exam. "With timely MRI imaging ... discrete lesions in the area postrema, the AQP4-rich emetic reflex center of the medulla," usually can be visualized, Dr. Iorio and his associates said.
The mean interval between the onset of vomiting and the development of a classic symptom of neuromyelitis optica spectrum disorder was 111 weeks.
When the disorder was finally suspected, testing revealed AQP4-IgG in serum or cerebrospinal fluid samples in all 10 patients.
During a mean follow-up of 57 months, eight patients progressed to classic neuromyelitis optica and two to neuromyelitis optica spectrum disorder.
The typical disease course included the development of optic neuritis followed by paresthesias of the lower limbs that gradually ascended to the torso. Urinary retention, constipation, and weakness of the extremities accompanied by dysesthesias and ataxia soon ensued.
Treatment with plasmapheresis and methylprednisolone generally relieved gait and sensory complaints and improved bladder and bowel function as well as the nausea and vomiting.
This study was supported by the Guthy-Jackson Charitable Foundation, the National Institutes of Health, the Mayo Foundation for Medical Education and Research, and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Iorio reported no financial conflicts of interest. His associates reported holding numerous patents and having ties to Alexion Pharmaceuticals, Novartis, Biogen Idec, Genzyme Corporation, and RSR Ltd.
Intractable nausea and vomiting can be the isolated presenting symptom of neuromyelitis optica spectrum disorder, and gastroenterologists as well as internists need to be more aware of this possibility, even though it is rare, Dr. Raffaele Iorio and his colleagues said in the March issue of Clinical Gastroenterology and Hepatology.
Neuromyelitis optica spectrum disorder is a relapsing inflammatory demyelinating disease of the CNS similar to multiple sclerosis, which progresses to optic neuritis and/or longitudinally extensive transverse myelitis. If untreated, it often results in blindness and confinement to a wheelchair. It is especially important to recognize this disorder as early as possible, so that immunosuppressant therapy can be initiated and progression to such devastating outcomes can be averted, said Dr. Iorio, of the department of laboratory medicine and pathology, Mayo Clinic, Rochester, Minn., and his associates.
Source: American Gastroenterological Association
The cause of neuromyelitis optica spectrum disorder is thought to be autoantibodies that target the astrocytic aquaporin-4 (AQP4) water channel, the principal water channel in the central nervous system. The fourth ventricular floor, which contains the chemosensitive nausea and vomiting center (the area postrema), is a particularly AQP4-enriched region of the brain.
For some patients who develop the disorder, intractable nausea and vomiting may be the only presenting symptom. "These patients commonly undergo extensive, but nonrevealing evaluations on presentation to internists and gastroenterologists, who are largely unaware of this emerging neurological entity." Consequently, many patients are subjected to unnecessary gastroscopy, biopsy, x-rays, ultrasound, CTs, and even surgery, the investigators noted.
They previously reported that a retrospective chart review identified 69 patients diagnosed at the Mayo Clinic as having neuromyelitis optica spectrum disorder. Eight of them (12%) presented with intractable nausea and vomiting as the sole initial symptom.
The researchers have since reviewed an additional 70 charts in their database and now report an additional 10 patients (14% of the 70) in whom intractable nausea and vomiting was the only presenting symptom.
Nine of these 10 patients were women. Mean age of symptom onset was 47 years (range, 26-72 years).
Nausea and vomiting were continuous rather than cyclic, and both occurred day and night. Patients did not report headache or other CNS symptoms, but three had intractable hiccups concomitant with their vomiting.
All 10 patients initially presented to a gastroenterologist or internist. Seven required immediate inpatient IV hydration. Treatment with antiemetics "yielded only partial benefit."
Inflammatory markers, including erythrocyte sedimentation rate and C-reactive protein level, were within normal limits.
A total of 6 of the 10 patients underwent extensive GI evaluation, which included abdominal CT, abdominal ultrasound, small bowel x-ray, upper gastroscopy with biopsy, pelvic and liver CT and ultrasound, gastric-emptying studies, and wireless capsule endoscopy.
One patient underwent cholecystectomy when imaging studies detected a "tiny" gallbladder polyp. Her vomiting worsened after the procedure.
A total of 5 of the 10 patients eventually underwent brain MRI. Three of them showed abnormalities in the area postrema, another showed abnormalities in the deep white matter, and the fifth patient showed no abnormalities on this exam. "With timely MRI imaging ... discrete lesions in the area postrema, the AQP4-rich emetic reflex center of the medulla," usually can be visualized, Dr. Iorio and his associates said.
The mean interval between the onset of vomiting and the development of a classic symptom of neuromyelitis optica spectrum disorder was 111 weeks.
When the disorder was finally suspected, testing revealed AQP4-IgG in serum or cerebrospinal fluid samples in all 10 patients.
During a mean follow-up of 57 months, eight patients progressed to classic neuromyelitis optica and two to neuromyelitis optica spectrum disorder.
The typical disease course included the development of optic neuritis followed by paresthesias of the lower limbs that gradually ascended to the torso. Urinary retention, constipation, and weakness of the extremities accompanied by dysesthesias and ataxia soon ensued.
Treatment with plasmapheresis and methylprednisolone generally relieved gait and sensory complaints and improved bladder and bowel function as well as the nausea and vomiting.
This study was supported by the Guthy-Jackson Charitable Foundation, the National Institutes of Health, the Mayo Foundation for Medical Education and Research, and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Iorio reported no financial conflicts of interest. His associates reported holding numerous patents and having ties to Alexion Pharmaceuticals, Novartis, Biogen Idec, Genzyme Corporation, and RSR Ltd.
Intractable nausea and vomiting can be the isolated presenting symptom of neuromyelitis optica spectrum disorder, and gastroenterologists as well as internists need to be more aware of this possibility, even though it is rare, Dr. Raffaele Iorio and his colleagues said in the March issue of Clinical Gastroenterology and Hepatology.
Neuromyelitis optica spectrum disorder is a relapsing inflammatory demyelinating disease of the CNS similar to multiple sclerosis, which progresses to optic neuritis and/or longitudinally extensive transverse myelitis. If untreated, it often results in blindness and confinement to a wheelchair. It is especially important to recognize this disorder as early as possible, so that immunosuppressant therapy can be initiated and progression to such devastating outcomes can be averted, said Dr. Iorio, of the department of laboratory medicine and pathology, Mayo Clinic, Rochester, Minn., and his associates.
Source: American Gastroenterological Association
The cause of neuromyelitis optica spectrum disorder is thought to be autoantibodies that target the astrocytic aquaporin-4 (AQP4) water channel, the principal water channel in the central nervous system. The fourth ventricular floor, which contains the chemosensitive nausea and vomiting center (the area postrema), is a particularly AQP4-enriched region of the brain.
For some patients who develop the disorder, intractable nausea and vomiting may be the only presenting symptom. "These patients commonly undergo extensive, but nonrevealing evaluations on presentation to internists and gastroenterologists, who are largely unaware of this emerging neurological entity." Consequently, many patients are subjected to unnecessary gastroscopy, biopsy, x-rays, ultrasound, CTs, and even surgery, the investigators noted.
They previously reported that a retrospective chart review identified 69 patients diagnosed at the Mayo Clinic as having neuromyelitis optica spectrum disorder. Eight of them (12%) presented with intractable nausea and vomiting as the sole initial symptom.
The researchers have since reviewed an additional 70 charts in their database and now report an additional 10 patients (14% of the 70) in whom intractable nausea and vomiting was the only presenting symptom.
Nine of these 10 patients were women. Mean age of symptom onset was 47 years (range, 26-72 years).
Nausea and vomiting were continuous rather than cyclic, and both occurred day and night. Patients did not report headache or other CNS symptoms, but three had intractable hiccups concomitant with their vomiting.
All 10 patients initially presented to a gastroenterologist or internist. Seven required immediate inpatient IV hydration. Treatment with antiemetics "yielded only partial benefit."
Inflammatory markers, including erythrocyte sedimentation rate and C-reactive protein level, were within normal limits.
A total of 6 of the 10 patients underwent extensive GI evaluation, which included abdominal CT, abdominal ultrasound, small bowel x-ray, upper gastroscopy with biopsy, pelvic and liver CT and ultrasound, gastric-emptying studies, and wireless capsule endoscopy.
One patient underwent cholecystectomy when imaging studies detected a "tiny" gallbladder polyp. Her vomiting worsened after the procedure.
A total of 5 of the 10 patients eventually underwent brain MRI. Three of them showed abnormalities in the area postrema, another showed abnormalities in the deep white matter, and the fifth patient showed no abnormalities on this exam. "With timely MRI imaging ... discrete lesions in the area postrema, the AQP4-rich emetic reflex center of the medulla," usually can be visualized, Dr. Iorio and his associates said.
The mean interval between the onset of vomiting and the development of a classic symptom of neuromyelitis optica spectrum disorder was 111 weeks.
When the disorder was finally suspected, testing revealed AQP4-IgG in serum or cerebrospinal fluid samples in all 10 patients.
During a mean follow-up of 57 months, eight patients progressed to classic neuromyelitis optica and two to neuromyelitis optica spectrum disorder.
The typical disease course included the development of optic neuritis followed by paresthesias of the lower limbs that gradually ascended to the torso. Urinary retention, constipation, and weakness of the extremities accompanied by dysesthesias and ataxia soon ensued.
Treatment with plasmapheresis and methylprednisolone generally relieved gait and sensory complaints and improved bladder and bowel function as well as the nausea and vomiting.
This study was supported by the Guthy-Jackson Charitable Foundation, the National Institutes of Health, the Mayo Foundation for Medical Education and Research, and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Iorio reported no financial conflicts of interest. His associates reported holding numerous patents and having ties to Alexion Pharmaceuticals, Novartis, Biogen Idec, Genzyme Corporation, and RSR Ltd.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Major Finding: Ten of 70 patients (14%) with neuromyelitis optica spectrum disorder initially presented to gastroenterologists or internists with intractable nausea and vomiting as their only symptom; in the mean of 111 weeks before the CNS cause of these symptoms was identified, they underwent extensive unnecessary GI evaluation including radiographic imaging, gastroscopies, biopsies, and surgery.
Data Source: A single-center retrospective chart review of 70 cases of neuromyelitis optica spectrum disorder.
Disclosures: This study was supported by the Guthy-Jackson Charitable Foundation, the National Institutes of Health, the Mayo Foundation for Medical Education and Research, and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Iorio reported no financial conflicts of interest. His associates reported holding numerous patents and having ties to Alexion Pharmaceuticals, Novartis, Biogen Idec, Genzyme Corp., and RSR Ltd.
Ondansetron not linked to any adverse fetal outcomes
Fetal exposure to ondansetron showed no association with adverse pregnancy outcomes in a nationwide Danish cohort study that included more than 608,000 pregnancies, according to a report published online Feb. 28 in the New England Journal of Medicine.
Ondansetron, an antiemetic often prescribed for nausea and vomiting during pregnancy, was not associated with an increased rate of spontaneous abortion, stillbirth, any major birth defect, preterm delivery, low-birth-weight (LBW) infants, or small-for-gestational-age (SGA) infants, reported Björn Pasternak, M.D., Ph.D., of the department of epidemiology research at Statens Serum Institut, Copenhagen, and his associates.
"Although these results cannot definitively rule out the possibility of adverse effects in association with ondansetron, the results do provide reassurance regarding the use of this agent for nausea and vomiting in pregnancy," the investigators noted.
To date, only two controlled studies have assessed the fetal safety of the drug, which nevertheless is the most frequently prescribed antiemetic in the United States.
Dr. Pasternak and his colleagues used data from Danish national registries to construct a nationwide historical cohort of all pregnancies that resulted in a singleton birth, stillbirth, or any abortive outcome between 2004 and March 31, 2011. (Ondansetron was rarely used during pregnancy before 2004 in Denmark.)
The investigators assessed outcomes in 608,385 pregnancies. Mothers took ondansetron in 1,970 of these pregnancies. The median number of doses dispensed was 30 per pregnancy.
In an initial unadjusted analysis, exposure to ondansetron did not increase the risk of stillbirth, major birth defects, LBW infants, or SGA infants.
The researchers then conducted several propensity-matched analyses for six possible adverse outcomes.
For the 1,233 pregnancies in this analysis in which the mother took ondansetron during the first trimester, 36 infants (2.9%) had a major birth defect. In comparison, 141 of 4,932 infants (also 2.9%) not exposed to the drug had a major birth defect. This study was not powered to assess the risks of individual birth defects.
The rate of preterm birth was 6.2% among women who took ondansetron and 5.2% among women who did not, a difference that was not significant. Similarly, the rates of stillbirth were 0.3% and 0.4%, respectively, also a nonsignificant difference.
The rates of LBW infants were 4.1% with exposure to ondansetron and 3.7% without exposure, also a nonsignificant difference. And the rates of SGA infants were 10.4% and 9.2%, another nonsignificant difference, Dr. Pasternak and his associates reported (New Engl. J. Med. 2013;368:814-23).
These results remained robust in several sensitivity analyses, including one that compared rates of adverse fetal outcomes between women who filled only one prescription for ondansetron and women who filled two or more such prescriptions.
Previously, a case-control study found an increase in the risk of cleft palate with in utero exposure to ondansetron. In this cohort, there were no cases of cleft palate, Dr. Pasternak and his associates said.
This study was funded by the Danish Medical Research Council. No financial conflicts of interest were reported.
Fetal exposure to ondansetron showed no association with adverse pregnancy outcomes in a nationwide Danish cohort study that included more than 608,000 pregnancies, according to a report published online Feb. 28 in the New England Journal of Medicine.
Ondansetron, an antiemetic often prescribed for nausea and vomiting during pregnancy, was not associated with an increased rate of spontaneous abortion, stillbirth, any major birth defect, preterm delivery, low-birth-weight (LBW) infants, or small-for-gestational-age (SGA) infants, reported Björn Pasternak, M.D., Ph.D., of the department of epidemiology research at Statens Serum Institut, Copenhagen, and his associates.
"Although these results cannot definitively rule out the possibility of adverse effects in association with ondansetron, the results do provide reassurance regarding the use of this agent for nausea and vomiting in pregnancy," the investigators noted.
To date, only two controlled studies have assessed the fetal safety of the drug, which nevertheless is the most frequently prescribed antiemetic in the United States.
Dr. Pasternak and his colleagues used data from Danish national registries to construct a nationwide historical cohort of all pregnancies that resulted in a singleton birth, stillbirth, or any abortive outcome between 2004 and March 31, 2011. (Ondansetron was rarely used during pregnancy before 2004 in Denmark.)
The investigators assessed outcomes in 608,385 pregnancies. Mothers took ondansetron in 1,970 of these pregnancies. The median number of doses dispensed was 30 per pregnancy.
In an initial unadjusted analysis, exposure to ondansetron did not increase the risk of stillbirth, major birth defects, LBW infants, or SGA infants.
The researchers then conducted several propensity-matched analyses for six possible adverse outcomes.
For the 1,233 pregnancies in this analysis in which the mother took ondansetron during the first trimester, 36 infants (2.9%) had a major birth defect. In comparison, 141 of 4,932 infants (also 2.9%) not exposed to the drug had a major birth defect. This study was not powered to assess the risks of individual birth defects.
The rate of preterm birth was 6.2% among women who took ondansetron and 5.2% among women who did not, a difference that was not significant. Similarly, the rates of stillbirth were 0.3% and 0.4%, respectively, also a nonsignificant difference.
The rates of LBW infants were 4.1% with exposure to ondansetron and 3.7% without exposure, also a nonsignificant difference. And the rates of SGA infants were 10.4% and 9.2%, another nonsignificant difference, Dr. Pasternak and his associates reported (New Engl. J. Med. 2013;368:814-23).
These results remained robust in several sensitivity analyses, including one that compared rates of adverse fetal outcomes between women who filled only one prescription for ondansetron and women who filled two or more such prescriptions.
Previously, a case-control study found an increase in the risk of cleft palate with in utero exposure to ondansetron. In this cohort, there were no cases of cleft palate, Dr. Pasternak and his associates said.
This study was funded by the Danish Medical Research Council. No financial conflicts of interest were reported.
Fetal exposure to ondansetron showed no association with adverse pregnancy outcomes in a nationwide Danish cohort study that included more than 608,000 pregnancies, according to a report published online Feb. 28 in the New England Journal of Medicine.
Ondansetron, an antiemetic often prescribed for nausea and vomiting during pregnancy, was not associated with an increased rate of spontaneous abortion, stillbirth, any major birth defect, preterm delivery, low-birth-weight (LBW) infants, or small-for-gestational-age (SGA) infants, reported Björn Pasternak, M.D., Ph.D., of the department of epidemiology research at Statens Serum Institut, Copenhagen, and his associates.
"Although these results cannot definitively rule out the possibility of adverse effects in association with ondansetron, the results do provide reassurance regarding the use of this agent for nausea and vomiting in pregnancy," the investigators noted.
To date, only two controlled studies have assessed the fetal safety of the drug, which nevertheless is the most frequently prescribed antiemetic in the United States.
Dr. Pasternak and his colleagues used data from Danish national registries to construct a nationwide historical cohort of all pregnancies that resulted in a singleton birth, stillbirth, or any abortive outcome between 2004 and March 31, 2011. (Ondansetron was rarely used during pregnancy before 2004 in Denmark.)
The investigators assessed outcomes in 608,385 pregnancies. Mothers took ondansetron in 1,970 of these pregnancies. The median number of doses dispensed was 30 per pregnancy.
In an initial unadjusted analysis, exposure to ondansetron did not increase the risk of stillbirth, major birth defects, LBW infants, or SGA infants.
The researchers then conducted several propensity-matched analyses for six possible adverse outcomes.
For the 1,233 pregnancies in this analysis in which the mother took ondansetron during the first trimester, 36 infants (2.9%) had a major birth defect. In comparison, 141 of 4,932 infants (also 2.9%) not exposed to the drug had a major birth defect. This study was not powered to assess the risks of individual birth defects.
The rate of preterm birth was 6.2% among women who took ondansetron and 5.2% among women who did not, a difference that was not significant. Similarly, the rates of stillbirth were 0.3% and 0.4%, respectively, also a nonsignificant difference.
The rates of LBW infants were 4.1% with exposure to ondansetron and 3.7% without exposure, also a nonsignificant difference. And the rates of SGA infants were 10.4% and 9.2%, another nonsignificant difference, Dr. Pasternak and his associates reported (New Engl. J. Med. 2013;368:814-23).
These results remained robust in several sensitivity analyses, including one that compared rates of adverse fetal outcomes between women who filled only one prescription for ondansetron and women who filled two or more such prescriptions.
Previously, a case-control study found an increase in the risk of cleft palate with in utero exposure to ondansetron. In this cohort, there were no cases of cleft palate, Dr. Pasternak and his associates said.
This study was funded by the Danish Medical Research Council. No financial conflicts of interest were reported.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Major finding: For pregnancies exposed to ondansetron, the rate of major birth defects was 2.9% (vs. 2.9% without exposure), that of stillbirth was 0.3% (vs. 0.4%), that of preterm birth was 6.2% (vs. 5.2%), that of LBW infants was 4.1% (vs. 3.7%), and that of SGA infants was 10.4% (vs. 9.2%).
Data source: An historical cohort study of adverse fetal outcomes in 608,385 pregnancies in Denmark during 2004-2011.
Disclosures: This study was funded by the Danish Medical Research Council. No financial conflicts of interest were reported.
Aldo-DHF published: Spironolactone aids LV function but not symptoms
Spironolactone significantly improved left ventricular diastolic function and remodeling in a 1-year study of ambulatory patients who had heart failure with preserved ejection fraction, but that benefit did not translate into improvements in HF symptoms or quality of life, according to a report in the Feb. 27 issue of JAMA.
In the multicenter, double-blind Aldosterone Receptor Blockade in Diastolic HF (Aldo-DHF) clinical trial, 213 men and women aged 50 and older were randomly assigned to receive daily oral spironolactone and 209 to receive a matching placebo for 1 year. Patients on spironolactone had significantly increased LV ejection fraction, decreased LV end-diastolic diameter and LV mass index, and reduced systolic blood pressure, reported Dr. Burkert M. Pieske, professor and head of the department of cardiology at Medical University of Graz, Austria, and his associates.
The drug failed to improve HF symptoms, exercise capacity, depressive symptoms, or quality of life, compared with placebo. "Our study population may have been too young or too healthy, or the treatment period may have been too short, for observing a translation of improved diastolic function into a clinical benefit," the investigators said (JAMA 2013;309:781-91).
These results were presented at the annual meeting of the European Society of Cardiology in Munich last summer, and reported by this newspaper.
Experts reacting to the news at the meeting expressed similar misgivings.
"It was not all good news. Patients had an increase in their potassium level, and even more concerning, they had a reduction in their glomerular filtration rate, an average reduction of about 5 mL/min," commented Dr. Stefan D. Anker, professor of medicine at Charité Medical University in Berlin. In addition, the distance walked on the 6-minute walk test was "slightly decreased with spironolactone. Even though it was a small change of 15 m, it was statistically significant," he noted. On top of all this, "worsening of anemia was seen in patients," he added.
Study discussant Dr. John G.F. Cleland said that although the Aldo-DHF study adds important new information on the progression of diastolic heart failure as seen in the control group, it wasn’t really was a study of diastolic heart failure. Few of the patients were on diuretic drugs, at entry they had fairly normal levels of NT-proBNP, they had mild abnormalities detected by echocardiography, and they exhibited mild deficits in cardiopulmonary exercise testing, said Dr. Cleland, professor of cardiology at the University of Hull, Kingston-upon-Hull, England.
Aldo-DHF was supported by the German-Austrian Heart Failure Study Group and the German Competence Network of Heart Failure. Dr. Edelmann and his associates reported numerous ties to industry sources.
Spironolactone significantly improved left ventricular diastolic function and remodeling in a 1-year study of ambulatory patients who had heart failure with preserved ejection fraction, but that benefit did not translate into improvements in HF symptoms or quality of life, according to a report in the Feb. 27 issue of JAMA.
In the multicenter, double-blind Aldosterone Receptor Blockade in Diastolic HF (Aldo-DHF) clinical trial, 213 men and women aged 50 and older were randomly assigned to receive daily oral spironolactone and 209 to receive a matching placebo for 1 year. Patients on spironolactone had significantly increased LV ejection fraction, decreased LV end-diastolic diameter and LV mass index, and reduced systolic blood pressure, reported Dr. Burkert M. Pieske, professor and head of the department of cardiology at Medical University of Graz, Austria, and his associates.
The drug failed to improve HF symptoms, exercise capacity, depressive symptoms, or quality of life, compared with placebo. "Our study population may have been too young or too healthy, or the treatment period may have been too short, for observing a translation of improved diastolic function into a clinical benefit," the investigators said (JAMA 2013;309:781-91).
These results were presented at the annual meeting of the European Society of Cardiology in Munich last summer, and reported by this newspaper.
Experts reacting to the news at the meeting expressed similar misgivings.
"It was not all good news. Patients had an increase in their potassium level, and even more concerning, they had a reduction in their glomerular filtration rate, an average reduction of about 5 mL/min," commented Dr. Stefan D. Anker, professor of medicine at Charité Medical University in Berlin. In addition, the distance walked on the 6-minute walk test was "slightly decreased with spironolactone. Even though it was a small change of 15 m, it was statistically significant," he noted. On top of all this, "worsening of anemia was seen in patients," he added.
Study discussant Dr. John G.F. Cleland said that although the Aldo-DHF study adds important new information on the progression of diastolic heart failure as seen in the control group, it wasn’t really was a study of diastolic heart failure. Few of the patients were on diuretic drugs, at entry they had fairly normal levels of NT-proBNP, they had mild abnormalities detected by echocardiography, and they exhibited mild deficits in cardiopulmonary exercise testing, said Dr. Cleland, professor of cardiology at the University of Hull, Kingston-upon-Hull, England.
Aldo-DHF was supported by the German-Austrian Heart Failure Study Group and the German Competence Network of Heart Failure. Dr. Edelmann and his associates reported numerous ties to industry sources.
Spironolactone significantly improved left ventricular diastolic function and remodeling in a 1-year study of ambulatory patients who had heart failure with preserved ejection fraction, but that benefit did not translate into improvements in HF symptoms or quality of life, according to a report in the Feb. 27 issue of JAMA.
In the multicenter, double-blind Aldosterone Receptor Blockade in Diastolic HF (Aldo-DHF) clinical trial, 213 men and women aged 50 and older were randomly assigned to receive daily oral spironolactone and 209 to receive a matching placebo for 1 year. Patients on spironolactone had significantly increased LV ejection fraction, decreased LV end-diastolic diameter and LV mass index, and reduced systolic blood pressure, reported Dr. Burkert M. Pieske, professor and head of the department of cardiology at Medical University of Graz, Austria, and his associates.
The drug failed to improve HF symptoms, exercise capacity, depressive symptoms, or quality of life, compared with placebo. "Our study population may have been too young or too healthy, or the treatment period may have been too short, for observing a translation of improved diastolic function into a clinical benefit," the investigators said (JAMA 2013;309:781-91).
These results were presented at the annual meeting of the European Society of Cardiology in Munich last summer, and reported by this newspaper.
Experts reacting to the news at the meeting expressed similar misgivings.
"It was not all good news. Patients had an increase in their potassium level, and even more concerning, they had a reduction in their glomerular filtration rate, an average reduction of about 5 mL/min," commented Dr. Stefan D. Anker, professor of medicine at Charité Medical University in Berlin. In addition, the distance walked on the 6-minute walk test was "slightly decreased with spironolactone. Even though it was a small change of 15 m, it was statistically significant," he noted. On top of all this, "worsening of anemia was seen in patients," he added.
Study discussant Dr. John G.F. Cleland said that although the Aldo-DHF study adds important new information on the progression of diastolic heart failure as seen in the control group, it wasn’t really was a study of diastolic heart failure. Few of the patients were on diuretic drugs, at entry they had fairly normal levels of NT-proBNP, they had mild abnormalities detected by echocardiography, and they exhibited mild deficits in cardiopulmonary exercise testing, said Dr. Cleland, professor of cardiology at the University of Hull, Kingston-upon-Hull, England.
Aldo-DHF was supported by the German-Austrian Heart Failure Study Group and the German Competence Network of Heart Failure. Dr. Edelmann and his associates reported numerous ties to industry sources.
FROM JAMA
Major Finding: Daily spironolactone significantly increased LV ejection fraction, decreased LV end-diastolic volume and LV mass index, and reduced systolic blood pressure, but did not improve HF symptoms, exercise capacity, depressive symptoms, or quality of life.
Data Source: Aldo-DHF, a 1-year multicenter double-blind randomized controlled trial involving 422 patients aged 50 and older who had chronic HF with preserved ejection fraction.
Disclosures: Aldo-DHF was supported by the German-Austrian Heart Failure Study Group and the German Competence Network of Heart Failure. Dr. Edelmann and his associates reported numerous ties to industry sources.
