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In Oregon pertussis outbreak, unvaccinated children were affected earlier
were, according to Steve G. Robison, MPH, and Juventila Liko, MD, MPH, from the Immunization Program, Oregon Health Authority, Portland.
A total of 351 pertussis cases in children aged 2 months to 10 years were reported in Portland and the upper Willamette Valley from Jan. 1 to Nov. 1, 2012. Children who were unvaccinated accounted for 76 (22%) of the reported cases, and children who were poorly vaccinated accounted for 50 of the 275 (18%) cases in vaccinated children.
“Children who are not immunized represent a dynamic risk of spreading disease in an outbreak and have an impact that is greater than simply lessening overall community immunity levels. Diseases such as pertussis may spread across areas through the choice of parents to not immunize or to limit immunizations. Once locally present, pertussis will spread to the unimmunized and vulnerable, who in turn through the weight of exposure, may then ignite a wider outbreak in vaccinated populations,” the investigators noted.
Find the full study in the Journal of Pediatrics (doi: 10.1016/j.jpeds.2016.12.047).
were, according to Steve G. Robison, MPH, and Juventila Liko, MD, MPH, from the Immunization Program, Oregon Health Authority, Portland.
A total of 351 pertussis cases in children aged 2 months to 10 years were reported in Portland and the upper Willamette Valley from Jan. 1 to Nov. 1, 2012. Children who were unvaccinated accounted for 76 (22%) of the reported cases, and children who were poorly vaccinated accounted for 50 of the 275 (18%) cases in vaccinated children.
“Children who are not immunized represent a dynamic risk of spreading disease in an outbreak and have an impact that is greater than simply lessening overall community immunity levels. Diseases such as pertussis may spread across areas through the choice of parents to not immunize or to limit immunizations. Once locally present, pertussis will spread to the unimmunized and vulnerable, who in turn through the weight of exposure, may then ignite a wider outbreak in vaccinated populations,” the investigators noted.
Find the full study in the Journal of Pediatrics (doi: 10.1016/j.jpeds.2016.12.047).
were, according to Steve G. Robison, MPH, and Juventila Liko, MD, MPH, from the Immunization Program, Oregon Health Authority, Portland.
A total of 351 pertussis cases in children aged 2 months to 10 years were reported in Portland and the upper Willamette Valley from Jan. 1 to Nov. 1, 2012. Children who were unvaccinated accounted for 76 (22%) of the reported cases, and children who were poorly vaccinated accounted for 50 of the 275 (18%) cases in vaccinated children.
“Children who are not immunized represent a dynamic risk of spreading disease in an outbreak and have an impact that is greater than simply lessening overall community immunity levels. Diseases such as pertussis may spread across areas through the choice of parents to not immunize or to limit immunizations. Once locally present, pertussis will spread to the unimmunized and vulnerable, who in turn through the weight of exposure, may then ignite a wider outbreak in vaccinated populations,” the investigators noted.
Find the full study in the Journal of Pediatrics (doi: 10.1016/j.jpeds.2016.12.047).
FROM THE JOURNAL OF PEDIATRICS
Mid-life cardiovascular risk factors set stage for later-life dementia
HOUSTON – Cardiovascular risk factors present in middle age may presage dementia in later years, a subanalysis of a 25-year atherosclerosis study has determined.
Diabetes conferred the greatest dementia risk, nearly doubling the chance of dementia, Rebecca Gottesman, MD, PhD, said at the International Stroke Conference, sponsored by the American Heart Association.
“In fact, the risk associated with diabetes nears the increased risk associated with having an APOE4 [apolipoprotein E epsilon 4] allele,” said Dr. Gottesman of Johns Hopkins University, Baltimore.
Her subanalysis of the biracial ARIC-NCS (Atherosclerosis Risk in Communities Neurocognitive Study) also identified some racial differences in risk, with blacks being more vulnerable to the risk imposed by diabetes, and whites more vulnerable to the hypertension-associated risk.
The ARIC study, sponsored by the National Heart, Lung, and Blood Institute, is a prospective epidemiologic study conducted in four U.S. communities. ARIC is designed to investigate the causes of atherosclerosis and its clinical outcomes, and variation in cardiovascular risk factors, medical care, and disease by race, gender, location, and date. To date, the ARIC project has published over 800 articles in peer-reviewed journals. A total of 15,792 participants received an extensive examination, including medical, social, and demographic data. These participants were reexamined every 3 years with the first screen occurring in 1987-1989. Follow-up occurs yearly by telephone to maintain contact with participants and to assess the health status of the cohort.
ARIC-NCS comprises about 10,000 of these subjects. Of these, 6,471 completed the fifth visit, which occurred during 2011-2013. They have undergone cognitive, neurologic, and brain imaging assessments to diagnose mild cognitive impairment or dementia and assign an etiology for the cognitive disorder. Last year, investigators published the study’s primary findings: Nearly 30% had a diagnosis of either dementia or mild cognitive impairment.
Dr. Gottesman sought to determine the extent to which these subjects’ baseline cardiovascular risk factors influenced their chances of cognitive decline or dementia. She assessed risk for the entire cohort, and then for black and white subjects separately.
Dementia was present in 1,516 cases (23%). In the total cohort, dementia was – not surprisingly – significantly associated with increasing age. Subjects aged 50-54 years had twice the risk for dementia when compared with younger subjects, while those aged 60-66 years had eight times greater risk. Black race conferred a 30% increased risk, compared with white race (hazard ratio, 1.3). Education of less than a high school degree was associated with a 40% increased risk. Having at least one copy of the APOE4 allele doubled the risk.
Diabetes was second only to genetic status, increasing the risk by 80%.
Dr. Gottesman then divided the cohort by race and reexamined these risk factors separately. She found some significant differences in the way these factors affected risk in white and black subjects.
Age exerted a greater influence on dementia risks in whites than it did in blacks. The risk was about doubled in both groups for people aged 50-54 years. But at age 55-59 years, it was significantly higher in whites than in blacks (HR, 4.37 vs. 3.53). The risk differential was even greater between whites and blacks aged 60-66 years (HR, 9.5 vs. 6.2).
Blacks with low education were more vulnerable to dementia than were whites (HR, 1.6 vs. 1.29). APOE4 status (at least one allele) more than doubled the risk of dementia for whites (HR, 2.23) but was not as strong in blacks (HR, 1.61).
Obesity was riskier for whites, increasing the risk of dementia by 22%, but it had no influence on risk among blacks. Current smoking increased the risk for whites by 62% but was not a significant risk factor for blacks. Prehypertension also affected whites more, increasing the risk by 35%, compared with a nonsignificant 17% for blacks. Full-blown hypertension increased the risk of dementia similarly in both groups (37% and 36%, respectively).
Diabetes increased the risk of dementia more in blacks than it did in whites (85% vs. 69%).
“We don’t have a clear explanation of these disparities in dementia risk with regard to race,” Dr. Gottesman said. “It could be, though, that even if a risk factor has the same relationship with dementia in both groups, if it is more prevalent in one group, that may somewhat account for this larger population attributable risk.”
She had no financial disclosures.
On Twitter @alz_gal
HOUSTON – Cardiovascular risk factors present in middle age may presage dementia in later years, a subanalysis of a 25-year atherosclerosis study has determined.
Diabetes conferred the greatest dementia risk, nearly doubling the chance of dementia, Rebecca Gottesman, MD, PhD, said at the International Stroke Conference, sponsored by the American Heart Association.
“In fact, the risk associated with diabetes nears the increased risk associated with having an APOE4 [apolipoprotein E epsilon 4] allele,” said Dr. Gottesman of Johns Hopkins University, Baltimore.
Her subanalysis of the biracial ARIC-NCS (Atherosclerosis Risk in Communities Neurocognitive Study) also identified some racial differences in risk, with blacks being more vulnerable to the risk imposed by diabetes, and whites more vulnerable to the hypertension-associated risk.
The ARIC study, sponsored by the National Heart, Lung, and Blood Institute, is a prospective epidemiologic study conducted in four U.S. communities. ARIC is designed to investigate the causes of atherosclerosis and its clinical outcomes, and variation in cardiovascular risk factors, medical care, and disease by race, gender, location, and date. To date, the ARIC project has published over 800 articles in peer-reviewed journals. A total of 15,792 participants received an extensive examination, including medical, social, and demographic data. These participants were reexamined every 3 years with the first screen occurring in 1987-1989. Follow-up occurs yearly by telephone to maintain contact with participants and to assess the health status of the cohort.
ARIC-NCS comprises about 10,000 of these subjects. Of these, 6,471 completed the fifth visit, which occurred during 2011-2013. They have undergone cognitive, neurologic, and brain imaging assessments to diagnose mild cognitive impairment or dementia and assign an etiology for the cognitive disorder. Last year, investigators published the study’s primary findings: Nearly 30% had a diagnosis of either dementia or mild cognitive impairment.
Dr. Gottesman sought to determine the extent to which these subjects’ baseline cardiovascular risk factors influenced their chances of cognitive decline or dementia. She assessed risk for the entire cohort, and then for black and white subjects separately.
Dementia was present in 1,516 cases (23%). In the total cohort, dementia was – not surprisingly – significantly associated with increasing age. Subjects aged 50-54 years had twice the risk for dementia when compared with younger subjects, while those aged 60-66 years had eight times greater risk. Black race conferred a 30% increased risk, compared with white race (hazard ratio, 1.3). Education of less than a high school degree was associated with a 40% increased risk. Having at least one copy of the APOE4 allele doubled the risk.
Diabetes was second only to genetic status, increasing the risk by 80%.
Dr. Gottesman then divided the cohort by race and reexamined these risk factors separately. She found some significant differences in the way these factors affected risk in white and black subjects.
Age exerted a greater influence on dementia risks in whites than it did in blacks. The risk was about doubled in both groups for people aged 50-54 years. But at age 55-59 years, it was significantly higher in whites than in blacks (HR, 4.37 vs. 3.53). The risk differential was even greater between whites and blacks aged 60-66 years (HR, 9.5 vs. 6.2).
Blacks with low education were more vulnerable to dementia than were whites (HR, 1.6 vs. 1.29). APOE4 status (at least one allele) more than doubled the risk of dementia for whites (HR, 2.23) but was not as strong in blacks (HR, 1.61).
Obesity was riskier for whites, increasing the risk of dementia by 22%, but it had no influence on risk among blacks. Current smoking increased the risk for whites by 62% but was not a significant risk factor for blacks. Prehypertension also affected whites more, increasing the risk by 35%, compared with a nonsignificant 17% for blacks. Full-blown hypertension increased the risk of dementia similarly in both groups (37% and 36%, respectively).
Diabetes increased the risk of dementia more in blacks than it did in whites (85% vs. 69%).
“We don’t have a clear explanation of these disparities in dementia risk with regard to race,” Dr. Gottesman said. “It could be, though, that even if a risk factor has the same relationship with dementia in both groups, if it is more prevalent in one group, that may somewhat account for this larger population attributable risk.”
She had no financial disclosures.
On Twitter @alz_gal
HOUSTON – Cardiovascular risk factors present in middle age may presage dementia in later years, a subanalysis of a 25-year atherosclerosis study has determined.
Diabetes conferred the greatest dementia risk, nearly doubling the chance of dementia, Rebecca Gottesman, MD, PhD, said at the International Stroke Conference, sponsored by the American Heart Association.
“In fact, the risk associated with diabetes nears the increased risk associated with having an APOE4 [apolipoprotein E epsilon 4] allele,” said Dr. Gottesman of Johns Hopkins University, Baltimore.
Her subanalysis of the biracial ARIC-NCS (Atherosclerosis Risk in Communities Neurocognitive Study) also identified some racial differences in risk, with blacks being more vulnerable to the risk imposed by diabetes, and whites more vulnerable to the hypertension-associated risk.
The ARIC study, sponsored by the National Heart, Lung, and Blood Institute, is a prospective epidemiologic study conducted in four U.S. communities. ARIC is designed to investigate the causes of atherosclerosis and its clinical outcomes, and variation in cardiovascular risk factors, medical care, and disease by race, gender, location, and date. To date, the ARIC project has published over 800 articles in peer-reviewed journals. A total of 15,792 participants received an extensive examination, including medical, social, and demographic data. These participants were reexamined every 3 years with the first screen occurring in 1987-1989. Follow-up occurs yearly by telephone to maintain contact with participants and to assess the health status of the cohort.
ARIC-NCS comprises about 10,000 of these subjects. Of these, 6,471 completed the fifth visit, which occurred during 2011-2013. They have undergone cognitive, neurologic, and brain imaging assessments to diagnose mild cognitive impairment or dementia and assign an etiology for the cognitive disorder. Last year, investigators published the study’s primary findings: Nearly 30% had a diagnosis of either dementia or mild cognitive impairment.
Dr. Gottesman sought to determine the extent to which these subjects’ baseline cardiovascular risk factors influenced their chances of cognitive decline or dementia. She assessed risk for the entire cohort, and then for black and white subjects separately.
Dementia was present in 1,516 cases (23%). In the total cohort, dementia was – not surprisingly – significantly associated with increasing age. Subjects aged 50-54 years had twice the risk for dementia when compared with younger subjects, while those aged 60-66 years had eight times greater risk. Black race conferred a 30% increased risk, compared with white race (hazard ratio, 1.3). Education of less than a high school degree was associated with a 40% increased risk. Having at least one copy of the APOE4 allele doubled the risk.
Diabetes was second only to genetic status, increasing the risk by 80%.
Dr. Gottesman then divided the cohort by race and reexamined these risk factors separately. She found some significant differences in the way these factors affected risk in white and black subjects.
Age exerted a greater influence on dementia risks in whites than it did in blacks. The risk was about doubled in both groups for people aged 50-54 years. But at age 55-59 years, it was significantly higher in whites than in blacks (HR, 4.37 vs. 3.53). The risk differential was even greater between whites and blacks aged 60-66 years (HR, 9.5 vs. 6.2).
Blacks with low education were more vulnerable to dementia than were whites (HR, 1.6 vs. 1.29). APOE4 status (at least one allele) more than doubled the risk of dementia for whites (HR, 2.23) but was not as strong in blacks (HR, 1.61).
Obesity was riskier for whites, increasing the risk of dementia by 22%, but it had no influence on risk among blacks. Current smoking increased the risk for whites by 62% but was not a significant risk factor for blacks. Prehypertension also affected whites more, increasing the risk by 35%, compared with a nonsignificant 17% for blacks. Full-blown hypertension increased the risk of dementia similarly in both groups (37% and 36%, respectively).
Diabetes increased the risk of dementia more in blacks than it did in whites (85% vs. 69%).
“We don’t have a clear explanation of these disparities in dementia risk with regard to race,” Dr. Gottesman said. “It could be, though, that even if a risk factor has the same relationship with dementia in both groups, if it is more prevalent in one group, that may somewhat account for this larger population attributable risk.”
She had no financial disclosures.
On Twitter @alz_gal
AT THE INTERNATIONAL STROKE CONFERENCE
Key clinical point:
Major finding: Smoking and hypertension increased the risk of dementia by 40% each; diabetes, by 80%.
Data source: The Atherosclerosis Risk in Communities Neurocognitive Study study comprised more than 6,000 people.
Disclosures: Dr. Gottesman had no financial disclosures.
Stable response in sickle cell disease patient treated with gene therapy
A teenage boy with sickle cell disease has been successfully treated with a therapy that uses a viral vector to insert functional genes into blood-producing stem cells.
The patient’s positive response to the intervention was first reported in 2015, and his clinical remission was reported in late 2016 at the American Society of Hematology’s annual meeting.
The new report, published online March 1 in the New England Journal of Medicine, contains the first detailed description of the case (2017;376:848-55).
Treatment consisted of LentiGlobin BB305, an engineered lentiviral vector–mediated addition of an antisickling human beta-globin gene (HbAT87Q ) into the patient’s hematopoietic stem cells. The technology was developed by bluebird bio, which partially funded the study and helped design its protocol.
The investigators, led by Marina Cavazzana, MD, PhD, of Necker Children’s Hospital, Assistance Publique–Hôpitaux de Paris, collected blood-producing stem cells from the patient’s bone marrow. The cells were transduced ex vivo using LentiGlobin BB305.
After the patient underwent 4 days of myeloablation and a 2-day washout period, the transduced stem cells were infused at 5.6x106 CD34+ cells per kilogram. The patient continued receiving red blood cell transfusions until at least 30% healthy hemoglobin with the signature of the introduced gene could be detected.
Neutrophil engraftment occurred at 38 days after transplantation, and platelet engraftment, at 3 months. Red cell transfusions were discontinued at 3 months.
The patient saw vector-bearing healthy cells in the blood increase during the first 3 months after transplantation, the investigators reported, and the cells continue to be produced at stable levels through month 15, which suggests “engraftment of transduced stem cells that were capable of long-term repopulation,” the investigators wrote.
Also at 15 months after transplantation, the patient had 48% HbAT87Q, while 30% healthy hemoglobin is considered sufficient to see clinical improvement in SCD patients.
The patient has not experienced sickle cell disease–related clinical events or hospitalization since transplantation, Dr. Cavazzana and her colleagues reported, noting all his medications, including pain medication, have been stopped.
Most adverse events seen in the study were associated with busulfan, the drug used in myeloablation, and no adverse events were associated with the gene therapy itself.
These results, the investigators concluded, provide proof of concept for lentiviral vectors in delivering this gene therapy for SCD. This approach, they said, “may help to guide the design of future clinical trials of gene therapy for sickle cell disease.” One important advantage for lentiviral vectors over retroviral vectors is that the former appear less likely to generate cancer-causing mutations; the engineered vector used in this study is self-inactivating.
Two more SCD patients have since been enrolled in the same study.
In a press statement accompanying the March 1 publication, the makers of the gene therapy said these results had prompted them to modify protocols in an ongoing U.S-based study of the same therapy in SCD, in the hope of achieving outcomes similar to those seen in France.
The study was funded by bluebird bio and grants from Assistance Publique–Hôpitaux de Paris and INSERM. Of the 27 authors, 9 disclosed being stockholders of bluebird, receiving fees, holding patents on technologies used in the study, or being employees. One reported financial relationships with other firms, and 17, including the corresponding author, reported no commercial conflicts of interest.
A teenage boy with sickle cell disease has been successfully treated with a therapy that uses a viral vector to insert functional genes into blood-producing stem cells.
The patient’s positive response to the intervention was first reported in 2015, and his clinical remission was reported in late 2016 at the American Society of Hematology’s annual meeting.
The new report, published online March 1 in the New England Journal of Medicine, contains the first detailed description of the case (2017;376:848-55).
Treatment consisted of LentiGlobin BB305, an engineered lentiviral vector–mediated addition of an antisickling human beta-globin gene (HbAT87Q ) into the patient’s hematopoietic stem cells. The technology was developed by bluebird bio, which partially funded the study and helped design its protocol.
The investigators, led by Marina Cavazzana, MD, PhD, of Necker Children’s Hospital, Assistance Publique–Hôpitaux de Paris, collected blood-producing stem cells from the patient’s bone marrow. The cells were transduced ex vivo using LentiGlobin BB305.
After the patient underwent 4 days of myeloablation and a 2-day washout period, the transduced stem cells were infused at 5.6x106 CD34+ cells per kilogram. The patient continued receiving red blood cell transfusions until at least 30% healthy hemoglobin with the signature of the introduced gene could be detected.
Neutrophil engraftment occurred at 38 days after transplantation, and platelet engraftment, at 3 months. Red cell transfusions were discontinued at 3 months.
The patient saw vector-bearing healthy cells in the blood increase during the first 3 months after transplantation, the investigators reported, and the cells continue to be produced at stable levels through month 15, which suggests “engraftment of transduced stem cells that were capable of long-term repopulation,” the investigators wrote.
Also at 15 months after transplantation, the patient had 48% HbAT87Q, while 30% healthy hemoglobin is considered sufficient to see clinical improvement in SCD patients.
The patient has not experienced sickle cell disease–related clinical events or hospitalization since transplantation, Dr. Cavazzana and her colleagues reported, noting all his medications, including pain medication, have been stopped.
Most adverse events seen in the study were associated with busulfan, the drug used in myeloablation, and no adverse events were associated with the gene therapy itself.
These results, the investigators concluded, provide proof of concept for lentiviral vectors in delivering this gene therapy for SCD. This approach, they said, “may help to guide the design of future clinical trials of gene therapy for sickle cell disease.” One important advantage for lentiviral vectors over retroviral vectors is that the former appear less likely to generate cancer-causing mutations; the engineered vector used in this study is self-inactivating.
Two more SCD patients have since been enrolled in the same study.
In a press statement accompanying the March 1 publication, the makers of the gene therapy said these results had prompted them to modify protocols in an ongoing U.S-based study of the same therapy in SCD, in the hope of achieving outcomes similar to those seen in France.
The study was funded by bluebird bio and grants from Assistance Publique–Hôpitaux de Paris and INSERM. Of the 27 authors, 9 disclosed being stockholders of bluebird, receiving fees, holding patents on technologies used in the study, or being employees. One reported financial relationships with other firms, and 17, including the corresponding author, reported no commercial conflicts of interest.
A teenage boy with sickle cell disease has been successfully treated with a therapy that uses a viral vector to insert functional genes into blood-producing stem cells.
The patient’s positive response to the intervention was first reported in 2015, and his clinical remission was reported in late 2016 at the American Society of Hematology’s annual meeting.
The new report, published online March 1 in the New England Journal of Medicine, contains the first detailed description of the case (2017;376:848-55).
Treatment consisted of LentiGlobin BB305, an engineered lentiviral vector–mediated addition of an antisickling human beta-globin gene (HbAT87Q ) into the patient’s hematopoietic stem cells. The technology was developed by bluebird bio, which partially funded the study and helped design its protocol.
The investigators, led by Marina Cavazzana, MD, PhD, of Necker Children’s Hospital, Assistance Publique–Hôpitaux de Paris, collected blood-producing stem cells from the patient’s bone marrow. The cells were transduced ex vivo using LentiGlobin BB305.
After the patient underwent 4 days of myeloablation and a 2-day washout period, the transduced stem cells were infused at 5.6x106 CD34+ cells per kilogram. The patient continued receiving red blood cell transfusions until at least 30% healthy hemoglobin with the signature of the introduced gene could be detected.
Neutrophil engraftment occurred at 38 days after transplantation, and platelet engraftment, at 3 months. Red cell transfusions were discontinued at 3 months.
The patient saw vector-bearing healthy cells in the blood increase during the first 3 months after transplantation, the investigators reported, and the cells continue to be produced at stable levels through month 15, which suggests “engraftment of transduced stem cells that were capable of long-term repopulation,” the investigators wrote.
Also at 15 months after transplantation, the patient had 48% HbAT87Q, while 30% healthy hemoglobin is considered sufficient to see clinical improvement in SCD patients.
The patient has not experienced sickle cell disease–related clinical events or hospitalization since transplantation, Dr. Cavazzana and her colleagues reported, noting all his medications, including pain medication, have been stopped.
Most adverse events seen in the study were associated with busulfan, the drug used in myeloablation, and no adverse events were associated with the gene therapy itself.
These results, the investigators concluded, provide proof of concept for lentiviral vectors in delivering this gene therapy for SCD. This approach, they said, “may help to guide the design of future clinical trials of gene therapy for sickle cell disease.” One important advantage for lentiviral vectors over retroviral vectors is that the former appear less likely to generate cancer-causing mutations; the engineered vector used in this study is self-inactivating.
Two more SCD patients have since been enrolled in the same study.
In a press statement accompanying the March 1 publication, the makers of the gene therapy said these results had prompted them to modify protocols in an ongoing U.S-based study of the same therapy in SCD, in the hope of achieving outcomes similar to those seen in France.
The study was funded by bluebird bio and grants from Assistance Publique–Hôpitaux de Paris and INSERM. Of the 27 authors, 9 disclosed being stockholders of bluebird, receiving fees, holding patents on technologies used in the study, or being employees. One reported financial relationships with other firms, and 17, including the corresponding author, reported no commercial conflicts of interest.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Using gene therapy in blood-producing stem cells led to clinical remission and durable healthy hemoglobin production in a teenage boy with sickle cell disease.
Major finding: At 15 months post treatment, the patient’s level of therapeutic antisickling beta-globin was 50%, suggesting engraftment and ongoing healthy cell production.
Data source: The first case report from a phase I/II open label trial in France, enrolling three patients with sickle cell disease.
Disclosures: The study was funded by bluebird bio, maker of the technology, and grants from Assistance Publique–Hôpitaux de Paris and INSERM. One-third of coauthors disclosed financial relationships with the sponsor.
Nemolizumab improves pruritus in atopic dermatitis
Monthly subcutaneous injections of nemolizumab, a humanized monoclonal antibody that inhibits interleukin-31 signaling, significantly improved pruritus associated with atopic dermatitis (AD) in a small, 3-month phase II trial. The results were published online March 2 in the New England Journal of Medicine.
“Although this trial has limitations, most notably the small number of patients and short duration, it provides evidence supporting the role of interleukin-31 in the pathobiologic mechanism of atopic dermatitis,” said Thomas Ruzicka, MD, of the department of dermatology and allergology, Ludwig Maximilian University, Munich, and his associates.
Pruritus aggravates atopic dermatitis and has been linked to loss of sleep, depression, aggressiveness, body disfiguration, and suicidal thoughts. Existing treatments, including emollients, topical glucocorticoids, calcineurin inhibitors, and oral antihistamines, have limited efficacy and can cause adverse effects when used long term, the investigators noted.
They assessed nemolizumab in a manufacturer-funded multiple-dose trial involving 264 adults in the United States, Europe, and Japan who had refractory moderate to severe atopic dermatitis, inadequately controlled with topical treatments. Study participants were randomly assigned in a double blind fashion to receive 12 weeks of 0.1 mg/kg nemolizumab (53 patients), 0.5 mg/kg nemolizumab (54 patients), 2.0 mg/kg nemolizumab (52 patients), or placebo (53 control subjects) every 4 weeks. Another 52 participants were given 2.0 mg/kg nemolizumab every 8 weeks in an exploratory analysis. All the study participants were permitted to use emollients and localized treatments, and some were permitted by the investigators to use a potent topical glucocorticoid as rescue therapy after week 4.
A total of 216 patients (82%) completed the trial.
The primary efficacy endpoint was the percentage improvement at week 12 in scores on a pruritus visual analogue scale, which patients recorded electronically every day. These scores improved significantly in a dose-dependent manner for active treatment, compared with placebo. Pruritus declined by 43.7% with the 0.1 mg/kg dose (P =.002), 59.8% with the 0.5 mg/kg dose (P less than .001), and 63.1% with the 2.0 mg/kg dose (P less than .001), compared with 20.9% with placebo.
Nemolizumab also bested placebo in several secondary endpoints including scores on a verbal rating of pruritus, the Eczema Area and Severity Index, and the static Investigator’s Global Assessment, the investigators said (N Engl J Med 2017;376:826-35. doi: 10.1056/NEJMoa1606490).
The study population was too small to allow the investigators to draw conclusions regarding adverse events, even before a relatively high number of participants dropped out. However, patients who received active treatment had a higher rate of dermatitis exacerbations and peripheral edema than did those who received placebo.
The group given 0.5 mg/kg nemolizumab every month showed the greatest treatment benefit and the best benefit-to-risk profile, Dr. Ruzicka and his associates said.
This trial was funded by Chugai Pharmaceutical, which also participated in the study design, data collection and analysis, and preparation of the manuscript. Dr. Ruzicka reported receiving research grants and personal fees from Chugai and honoraria from Astellas; his associates reported ties to numerous industry sources.
In addition to the benefits cited by Ruzicka et al., nemolizumab appeared to work quickly, reducing pruritus by nearly 30% within the first week, compared with a slight placebo effect.
Data from larger and longer-term studies, as well as pediatric trials, are needed to fully understand how nemolizumab and other new agents should be incorporated into the management of AD.
It will be important to assess how quickly disease flares occur when these agents are stopped, and whether the concomitant use of other treatments may enhance their effectiveness or induce longer remissions.
Lynda C. Schneider, MD, is in the division of immunology at Boston Children’s Hospital. She disclosed having received grant support from Astellas, personal fees from Anacor Pharmaceuticals, and other support from the National Eczema Association outside the submitted work. Dr. Schneider made these remarks in an editorial accompanying the study (N Engl J Med. 2017 March 2. doi:10.1056/NEJMe1616072).
In addition to the benefits cited by Ruzicka et al., nemolizumab appeared to work quickly, reducing pruritus by nearly 30% within the first week, compared with a slight placebo effect.
Data from larger and longer-term studies, as well as pediatric trials, are needed to fully understand how nemolizumab and other new agents should be incorporated into the management of AD.
It will be important to assess how quickly disease flares occur when these agents are stopped, and whether the concomitant use of other treatments may enhance their effectiveness or induce longer remissions.
Lynda C. Schneider, MD, is in the division of immunology at Boston Children’s Hospital. She disclosed having received grant support from Astellas, personal fees from Anacor Pharmaceuticals, and other support from the National Eczema Association outside the submitted work. Dr. Schneider made these remarks in an editorial accompanying the study (N Engl J Med. 2017 March 2. doi:10.1056/NEJMe1616072).
In addition to the benefits cited by Ruzicka et al., nemolizumab appeared to work quickly, reducing pruritus by nearly 30% within the first week, compared with a slight placebo effect.
Data from larger and longer-term studies, as well as pediatric trials, are needed to fully understand how nemolizumab and other new agents should be incorporated into the management of AD.
It will be important to assess how quickly disease flares occur when these agents are stopped, and whether the concomitant use of other treatments may enhance their effectiveness or induce longer remissions.
Lynda C. Schneider, MD, is in the division of immunology at Boston Children’s Hospital. She disclosed having received grant support from Astellas, personal fees from Anacor Pharmaceuticals, and other support from the National Eczema Association outside the submitted work. Dr. Schneider made these remarks in an editorial accompanying the study (N Engl J Med. 2017 March 2. doi:10.1056/NEJMe1616072).
Monthly subcutaneous injections of nemolizumab, a humanized monoclonal antibody that inhibits interleukin-31 signaling, significantly improved pruritus associated with atopic dermatitis (AD) in a small, 3-month phase II trial. The results were published online March 2 in the New England Journal of Medicine.
“Although this trial has limitations, most notably the small number of patients and short duration, it provides evidence supporting the role of interleukin-31 in the pathobiologic mechanism of atopic dermatitis,” said Thomas Ruzicka, MD, of the department of dermatology and allergology, Ludwig Maximilian University, Munich, and his associates.
Pruritus aggravates atopic dermatitis and has been linked to loss of sleep, depression, aggressiveness, body disfiguration, and suicidal thoughts. Existing treatments, including emollients, topical glucocorticoids, calcineurin inhibitors, and oral antihistamines, have limited efficacy and can cause adverse effects when used long term, the investigators noted.
They assessed nemolizumab in a manufacturer-funded multiple-dose trial involving 264 adults in the United States, Europe, and Japan who had refractory moderate to severe atopic dermatitis, inadequately controlled with topical treatments. Study participants were randomly assigned in a double blind fashion to receive 12 weeks of 0.1 mg/kg nemolizumab (53 patients), 0.5 mg/kg nemolizumab (54 patients), 2.0 mg/kg nemolizumab (52 patients), or placebo (53 control subjects) every 4 weeks. Another 52 participants were given 2.0 mg/kg nemolizumab every 8 weeks in an exploratory analysis. All the study participants were permitted to use emollients and localized treatments, and some were permitted by the investigators to use a potent topical glucocorticoid as rescue therapy after week 4.
A total of 216 patients (82%) completed the trial.
The primary efficacy endpoint was the percentage improvement at week 12 in scores on a pruritus visual analogue scale, which patients recorded electronically every day. These scores improved significantly in a dose-dependent manner for active treatment, compared with placebo. Pruritus declined by 43.7% with the 0.1 mg/kg dose (P =.002), 59.8% with the 0.5 mg/kg dose (P less than .001), and 63.1% with the 2.0 mg/kg dose (P less than .001), compared with 20.9% with placebo.
Nemolizumab also bested placebo in several secondary endpoints including scores on a verbal rating of pruritus, the Eczema Area and Severity Index, and the static Investigator’s Global Assessment, the investigators said (N Engl J Med 2017;376:826-35. doi: 10.1056/NEJMoa1606490).
The study population was too small to allow the investigators to draw conclusions regarding adverse events, even before a relatively high number of participants dropped out. However, patients who received active treatment had a higher rate of dermatitis exacerbations and peripheral edema than did those who received placebo.
The group given 0.5 mg/kg nemolizumab every month showed the greatest treatment benefit and the best benefit-to-risk profile, Dr. Ruzicka and his associates said.
This trial was funded by Chugai Pharmaceutical, which also participated in the study design, data collection and analysis, and preparation of the manuscript. Dr. Ruzicka reported receiving research grants and personal fees from Chugai and honoraria from Astellas; his associates reported ties to numerous industry sources.
Monthly subcutaneous injections of nemolizumab, a humanized monoclonal antibody that inhibits interleukin-31 signaling, significantly improved pruritus associated with atopic dermatitis (AD) in a small, 3-month phase II trial. The results were published online March 2 in the New England Journal of Medicine.
“Although this trial has limitations, most notably the small number of patients and short duration, it provides evidence supporting the role of interleukin-31 in the pathobiologic mechanism of atopic dermatitis,” said Thomas Ruzicka, MD, of the department of dermatology and allergology, Ludwig Maximilian University, Munich, and his associates.
Pruritus aggravates atopic dermatitis and has been linked to loss of sleep, depression, aggressiveness, body disfiguration, and suicidal thoughts. Existing treatments, including emollients, topical glucocorticoids, calcineurin inhibitors, and oral antihistamines, have limited efficacy and can cause adverse effects when used long term, the investigators noted.
They assessed nemolizumab in a manufacturer-funded multiple-dose trial involving 264 adults in the United States, Europe, and Japan who had refractory moderate to severe atopic dermatitis, inadequately controlled with topical treatments. Study participants were randomly assigned in a double blind fashion to receive 12 weeks of 0.1 mg/kg nemolizumab (53 patients), 0.5 mg/kg nemolizumab (54 patients), 2.0 mg/kg nemolizumab (52 patients), or placebo (53 control subjects) every 4 weeks. Another 52 participants were given 2.0 mg/kg nemolizumab every 8 weeks in an exploratory analysis. All the study participants were permitted to use emollients and localized treatments, and some were permitted by the investigators to use a potent topical glucocorticoid as rescue therapy after week 4.
A total of 216 patients (82%) completed the trial.
The primary efficacy endpoint was the percentage improvement at week 12 in scores on a pruritus visual analogue scale, which patients recorded electronically every day. These scores improved significantly in a dose-dependent manner for active treatment, compared with placebo. Pruritus declined by 43.7% with the 0.1 mg/kg dose (P =.002), 59.8% with the 0.5 mg/kg dose (P less than .001), and 63.1% with the 2.0 mg/kg dose (P less than .001), compared with 20.9% with placebo.
Nemolizumab also bested placebo in several secondary endpoints including scores on a verbal rating of pruritus, the Eczema Area and Severity Index, and the static Investigator’s Global Assessment, the investigators said (N Engl J Med 2017;376:826-35. doi: 10.1056/NEJMoa1606490).
The study population was too small to allow the investigators to draw conclusions regarding adverse events, even before a relatively high number of participants dropped out. However, patients who received active treatment had a higher rate of dermatitis exacerbations and peripheral edema than did those who received placebo.
The group given 0.5 mg/kg nemolizumab every month showed the greatest treatment benefit and the best benefit-to-risk profile, Dr. Ruzicka and his associates said.
This trial was funded by Chugai Pharmaceutical, which also participated in the study design, data collection and analysis, and preparation of the manuscript. Dr. Ruzicka reported receiving research grants and personal fees from Chugai and honoraria from Astellas; his associates reported ties to numerous industry sources.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Monthly nemolizumab injections significantly improved pruritus in adults with moderate to severe atopic dermatitis.
Major finding: Pruritus declined by 43.7% with the 0.1-mg/kg dose, 59.8% with the 0.5-mg/kg dose, and 63.1% with the 2.0-mg/kg dose, compared with 20.9% with placebo.
Data source: A manufacturer-funded international randomized double-blind placebo-controlled phase II trial of 216 adults with moderate to severe AD treated for 12 weeks.
Disclosures: This trial was funded by Chugai Pharmaceutical, which also participated in the study design, data collection and analysis, and preparation of the manuscript. Dr. Ruzicka reported receiving research grants and personal fees from Chugai and honoraria from Astellas; his associates reported ties to numerous industry sources.
Blinatumomab superior to chemotherapy for refractory ALL
Blinatumomab proved superior to standard chemotherapy for relapsed or refractory acute lymphoblastic leukemia (ALL), based on results of an international phase III trial reported online March 2 in the New England Journal of Medicine.
The trial was halted early when an interim analysis revealed the clear benefit with blinatumomab, Hagop Kantarjian, MD, chair of the department of leukemia, University of Texas MD Anderson Cancer Center, Houston, and his associates wrote.
The manufacturer-sponsored open-label study included 376 adults with Ph-negative B-cell precursor ALL that was either refractory to primary induction therapy or to salvage with intensive combination chemotherapy, first relapse with the first remission lasting less than 12 months, second or greater relapse, or relapse at any time after allogeneic stem cell transplantation.
Study participants were randomly assigned to receive either blinatumomab (267 patients) or the investigator’s choice of one of four protocol-defined regimens of standard chemotherapy (109 patients) and were followed at 101 medical centers in 21 countries for a median of 11 months.
For each 6-week cycle of blinatumomab therapy, patients received treatment for 4 weeks (9 mcg blinatumomab per day during week 1 of induction cycle one and 28 mcg/day thereafter, by continuous infusion) and then no treatment for 2 weeks.
Maintenance treatment with blinatumomab was given as a 4-week continuous infusion every 12 weeks.
At the interim analysis – when 75% of the total number of planned deaths for the final analysis had occurred – the monitoring committee recommended that the trial be stopped early because of the benefit observed with blinatumomab therapy. Median overall survival was significantly longer with blinatumomab (7.7 months) than with chemotherapy (4 months), with a hazard ratio for death of 0.71. The estimated survival at 6 months was 54% with blinatumomab and 39% with chemotherapy.
Remission rates also favored blinatumomab: Rates of complete remission with full hematologic recovery were 34% vs. 16% and rates of complete remission with full, partial, or incomplete hematologic recovery were 44% vs. 25%.
In addition, the median duration of remission was 7.3 months with blinatumomab and 4.6 months with chemotherapy. And 6-month estimates of event-free survival were 31% vs. 12%. These survival and remission benefits were consistent across all subgroups of patients and persisted in several sensitivity analyses, the investigators said (N Engl J Med. 2017 Mar 2. doi: 10.1056/nejmOA1609783).
A total of 24% of the patients in the blinatumomab group and 24% of the patients in the chemotherapy group underwent allogeneic stem cell transplantation, with comparable outcomes and death rates.
Serious adverse events occurred in 62% of patients receiving blinatumomab and in 45% of those receiving chemotherapy, including fatal adverse events in 19% and 17%, respectively. The fatal events were considered to be related to treatment in 3% of the blinatumomab group and in 7% of the chemotherapy group. Rates of treatment discontinuation from an adverse event were 12% and 8%, respectively.
Patient-reported health status and quality of life improved with blinatumomab but worsened with chemotherapy.
“Given the previous exposure of these patients to myelosuppressive and immunosuppressive treatments, the activity of an immune-based therapy such as blinatumomab, which depends on functioning T cells for its activity, provides encouragement that responses may be further enhanced and made durable with additional immune activation strategies,” Dr. Kantarjian and his associates noted.
Dr. Kantarjian reported receiving research support from Amgen, Pfizer, Bristol-Myers Squibb, Novartis, and ARIAD; his associates reported ties to numerous industry sources.
Blinatumomab proved superior to standard chemotherapy for relapsed or refractory acute lymphoblastic leukemia (ALL), based on results of an international phase III trial reported online March 2 in the New England Journal of Medicine.
The trial was halted early when an interim analysis revealed the clear benefit with blinatumomab, Hagop Kantarjian, MD, chair of the department of leukemia, University of Texas MD Anderson Cancer Center, Houston, and his associates wrote.
The manufacturer-sponsored open-label study included 376 adults with Ph-negative B-cell precursor ALL that was either refractory to primary induction therapy or to salvage with intensive combination chemotherapy, first relapse with the first remission lasting less than 12 months, second or greater relapse, or relapse at any time after allogeneic stem cell transplantation.
Study participants were randomly assigned to receive either blinatumomab (267 patients) or the investigator’s choice of one of four protocol-defined regimens of standard chemotherapy (109 patients) and were followed at 101 medical centers in 21 countries for a median of 11 months.
For each 6-week cycle of blinatumomab therapy, patients received treatment for 4 weeks (9 mcg blinatumomab per day during week 1 of induction cycle one and 28 mcg/day thereafter, by continuous infusion) and then no treatment for 2 weeks.
Maintenance treatment with blinatumomab was given as a 4-week continuous infusion every 12 weeks.
At the interim analysis – when 75% of the total number of planned deaths for the final analysis had occurred – the monitoring committee recommended that the trial be stopped early because of the benefit observed with blinatumomab therapy. Median overall survival was significantly longer with blinatumomab (7.7 months) than with chemotherapy (4 months), with a hazard ratio for death of 0.71. The estimated survival at 6 months was 54% with blinatumomab and 39% with chemotherapy.
Remission rates also favored blinatumomab: Rates of complete remission with full hematologic recovery were 34% vs. 16% and rates of complete remission with full, partial, or incomplete hematologic recovery were 44% vs. 25%.
In addition, the median duration of remission was 7.3 months with blinatumomab and 4.6 months with chemotherapy. And 6-month estimates of event-free survival were 31% vs. 12%. These survival and remission benefits were consistent across all subgroups of patients and persisted in several sensitivity analyses, the investigators said (N Engl J Med. 2017 Mar 2. doi: 10.1056/nejmOA1609783).
A total of 24% of the patients in the blinatumomab group and 24% of the patients in the chemotherapy group underwent allogeneic stem cell transplantation, with comparable outcomes and death rates.
Serious adverse events occurred in 62% of patients receiving blinatumomab and in 45% of those receiving chemotherapy, including fatal adverse events in 19% and 17%, respectively. The fatal events were considered to be related to treatment in 3% of the blinatumomab group and in 7% of the chemotherapy group. Rates of treatment discontinuation from an adverse event were 12% and 8%, respectively.
Patient-reported health status and quality of life improved with blinatumomab but worsened with chemotherapy.
“Given the previous exposure of these patients to myelosuppressive and immunosuppressive treatments, the activity of an immune-based therapy such as blinatumomab, which depends on functioning T cells for its activity, provides encouragement that responses may be further enhanced and made durable with additional immune activation strategies,” Dr. Kantarjian and his associates noted.
Dr. Kantarjian reported receiving research support from Amgen, Pfizer, Bristol-Myers Squibb, Novartis, and ARIAD; his associates reported ties to numerous industry sources.
Blinatumomab proved superior to standard chemotherapy for relapsed or refractory acute lymphoblastic leukemia (ALL), based on results of an international phase III trial reported online March 2 in the New England Journal of Medicine.
The trial was halted early when an interim analysis revealed the clear benefit with blinatumomab, Hagop Kantarjian, MD, chair of the department of leukemia, University of Texas MD Anderson Cancer Center, Houston, and his associates wrote.
The manufacturer-sponsored open-label study included 376 adults with Ph-negative B-cell precursor ALL that was either refractory to primary induction therapy or to salvage with intensive combination chemotherapy, first relapse with the first remission lasting less than 12 months, second or greater relapse, or relapse at any time after allogeneic stem cell transplantation.
Study participants were randomly assigned to receive either blinatumomab (267 patients) or the investigator’s choice of one of four protocol-defined regimens of standard chemotherapy (109 patients) and were followed at 101 medical centers in 21 countries for a median of 11 months.
For each 6-week cycle of blinatumomab therapy, patients received treatment for 4 weeks (9 mcg blinatumomab per day during week 1 of induction cycle one and 28 mcg/day thereafter, by continuous infusion) and then no treatment for 2 weeks.
Maintenance treatment with blinatumomab was given as a 4-week continuous infusion every 12 weeks.
At the interim analysis – when 75% of the total number of planned deaths for the final analysis had occurred – the monitoring committee recommended that the trial be stopped early because of the benefit observed with blinatumomab therapy. Median overall survival was significantly longer with blinatumomab (7.7 months) than with chemotherapy (4 months), with a hazard ratio for death of 0.71. The estimated survival at 6 months was 54% with blinatumomab and 39% with chemotherapy.
Remission rates also favored blinatumomab: Rates of complete remission with full hematologic recovery were 34% vs. 16% and rates of complete remission with full, partial, or incomplete hematologic recovery were 44% vs. 25%.
In addition, the median duration of remission was 7.3 months with blinatumomab and 4.6 months with chemotherapy. And 6-month estimates of event-free survival were 31% vs. 12%. These survival and remission benefits were consistent across all subgroups of patients and persisted in several sensitivity analyses, the investigators said (N Engl J Med. 2017 Mar 2. doi: 10.1056/nejmOA1609783).
A total of 24% of the patients in the blinatumomab group and 24% of the patients in the chemotherapy group underwent allogeneic stem cell transplantation, with comparable outcomes and death rates.
Serious adverse events occurred in 62% of patients receiving blinatumomab and in 45% of those receiving chemotherapy, including fatal adverse events in 19% and 17%, respectively. The fatal events were considered to be related to treatment in 3% of the blinatumomab group and in 7% of the chemotherapy group. Rates of treatment discontinuation from an adverse event were 12% and 8%, respectively.
Patient-reported health status and quality of life improved with blinatumomab but worsened with chemotherapy.
“Given the previous exposure of these patients to myelosuppressive and immunosuppressive treatments, the activity of an immune-based therapy such as blinatumomab, which depends on functioning T cells for its activity, provides encouragement that responses may be further enhanced and made durable with additional immune activation strategies,” Dr. Kantarjian and his associates noted.
Dr. Kantarjian reported receiving research support from Amgen, Pfizer, Bristol-Myers Squibb, Novartis, and ARIAD; his associates reported ties to numerous industry sources.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Blinatumomab proved superior to standard chemotherapy for relapsed or refractory ALL in a phase III trial.
Major finding: Median overall survival with blinatumomab (7.7 months) was significantly longer than with chemotherapy (4.0 months), and rates of complete remission with full hematologic recovery were 34% vs 16%, respectively.
Data source: A manufacturer-sponsored international randomized open-label phase-3 trial involving 376 adults followed for 11 months.
Disclosures: This trial was funded by Amgen, which also participated in the study design, data analysis, and report writing. Dr. Kantarjian reported receiving research support from Amgen, Pfizer, Bristol-Myers Squibb, Novartis, and ARIAD; his associates reported ties to numerous industry sources.
Tissue, peripheral eosinophilia correlate with UC activity, severity
Evidence linking tissue and peripheral eosinophilia with ulcerative colitis (UC) activity and severity was found in a retrospective chart review of pediatric UC cases.
Further, the review found both types of eosinophilia linked with the need for step-up therapy or corticosteroid therapy in the first year following UC diagnosis.
Sara Morgenstern, MD, of Tel Aviv University, and her coauthors reviewed all pediatric UC cases diagnosed between ages 0 and 17 years at the Schneider Children’s Hospital of Israel, Petah Tikva, between 1990 and 2015. Of 96 children diagnosed with UC by colonoscopy and followed for a median of 13 years, 31 had severe eosinophilia at the time of diagnosis, compared with 40 who had mild eosinophilia, and 25 who had a normal tissue eosinophil count. After remission, 77 had a normal eosinophilia and 19 had mild eosinophilia.
“At diagnosis, at follow-up with histologic activity and at follow-up with histologic remission, peripheral eosinophilia was demonstrated in 27%, 30% and 8%, respectively,” Dr. Morgenstern and her coauthors wrote. In the control group, 5% had peripheral eosinophilia, a significant difference (Dig Liver Dis. 2017 Feb;49[2]:170-4).
Disease activity and severity, as measured using the Pediatric UC Activity Index score, correlated significantly with tissue and blood eosinophil counts at diagnosis (P = .02 and P = .01, respectively). Disease activity and severity also correlated significantly with corticosteroid therapy, immunomodulatory therapy, and biologic therapy during the first year following diagnosis (P = .018, .04, and .05 for tissue eosinophilia; P = .013, .01, and .04 for peripheral eosinophilia, respectively).
“These findings may suggest that both tissue and peripheral eosinophilia may serve as a diagnostic marker for disease activity, severity, and short-term outcomes also in the pediatric population,” they wrote.
Dr. Morgenstern and her coauthors had no relevant financial disclosures.
Evidence linking tissue and peripheral eosinophilia with ulcerative colitis (UC) activity and severity was found in a retrospective chart review of pediatric UC cases.
Further, the review found both types of eosinophilia linked with the need for step-up therapy or corticosteroid therapy in the first year following UC diagnosis.
Sara Morgenstern, MD, of Tel Aviv University, and her coauthors reviewed all pediatric UC cases diagnosed between ages 0 and 17 years at the Schneider Children’s Hospital of Israel, Petah Tikva, between 1990 and 2015. Of 96 children diagnosed with UC by colonoscopy and followed for a median of 13 years, 31 had severe eosinophilia at the time of diagnosis, compared with 40 who had mild eosinophilia, and 25 who had a normal tissue eosinophil count. After remission, 77 had a normal eosinophilia and 19 had mild eosinophilia.
“At diagnosis, at follow-up with histologic activity and at follow-up with histologic remission, peripheral eosinophilia was demonstrated in 27%, 30% and 8%, respectively,” Dr. Morgenstern and her coauthors wrote. In the control group, 5% had peripheral eosinophilia, a significant difference (Dig Liver Dis. 2017 Feb;49[2]:170-4).
Disease activity and severity, as measured using the Pediatric UC Activity Index score, correlated significantly with tissue and blood eosinophil counts at diagnosis (P = .02 and P = .01, respectively). Disease activity and severity also correlated significantly with corticosteroid therapy, immunomodulatory therapy, and biologic therapy during the first year following diagnosis (P = .018, .04, and .05 for tissue eosinophilia; P = .013, .01, and .04 for peripheral eosinophilia, respectively).
“These findings may suggest that both tissue and peripheral eosinophilia may serve as a diagnostic marker for disease activity, severity, and short-term outcomes also in the pediatric population,” they wrote.
Dr. Morgenstern and her coauthors had no relevant financial disclosures.
Evidence linking tissue and peripheral eosinophilia with ulcerative colitis (UC) activity and severity was found in a retrospective chart review of pediatric UC cases.
Further, the review found both types of eosinophilia linked with the need for step-up therapy or corticosteroid therapy in the first year following UC diagnosis.
Sara Morgenstern, MD, of Tel Aviv University, and her coauthors reviewed all pediatric UC cases diagnosed between ages 0 and 17 years at the Schneider Children’s Hospital of Israel, Petah Tikva, between 1990 and 2015. Of 96 children diagnosed with UC by colonoscopy and followed for a median of 13 years, 31 had severe eosinophilia at the time of diagnosis, compared with 40 who had mild eosinophilia, and 25 who had a normal tissue eosinophil count. After remission, 77 had a normal eosinophilia and 19 had mild eosinophilia.
“At diagnosis, at follow-up with histologic activity and at follow-up with histologic remission, peripheral eosinophilia was demonstrated in 27%, 30% and 8%, respectively,” Dr. Morgenstern and her coauthors wrote. In the control group, 5% had peripheral eosinophilia, a significant difference (Dig Liver Dis. 2017 Feb;49[2]:170-4).
Disease activity and severity, as measured using the Pediatric UC Activity Index score, correlated significantly with tissue and blood eosinophil counts at diagnosis (P = .02 and P = .01, respectively). Disease activity and severity also correlated significantly with corticosteroid therapy, immunomodulatory therapy, and biologic therapy during the first year following diagnosis (P = .018, .04, and .05 for tissue eosinophilia; P = .013, .01, and .04 for peripheral eosinophilia, respectively).
“These findings may suggest that both tissue and peripheral eosinophilia may serve as a diagnostic marker for disease activity, severity, and short-term outcomes also in the pediatric population,” they wrote.
Dr. Morgenstern and her coauthors had no relevant financial disclosures.
FROM DIGESTIVE AND LIVER DISEASE
Key clinical point:
Major finding: At diagnosis, at follow-up with histologic activity, and at follow-up with histologic remission, peripheral eosinophilia was demonstrated in 27%, 30%, and 8%, respectively.
Data source: Ninety-six children diagnosed with UC by colonoscopy.
Disclosures: Dr. Morgenstern and her coauthors had no relevant financial disclosures.
Vaccine + chemo induce robust T-cell responses in late-stage cervical cancer
ORLANDO – In patients with advanced cervical cancer, combining chemotherapy with a vaccine against human papillomavirus (HPV) type 16 resulted in a robust, T-cell–mediated immune response and long duration survival for a large proportion of patients, reported investigators from the Netherlands.
Patients with advanced, HPV16-positive cervical cancer who were treated with standard chemotherapy and vaccinated with HPV16 synthetic long peptides (HPV16-SLP) had substantially increased T-cell responses, and these responses correlated with survival, said Marij Welters, PhD, from Leiden (the Netherlands) University Medical Center.
Data from this study provide “a strong rationale to conduct a randomized phase II trial in which a combination with checkpoint inhibitors might be attractive,” she added.
Combination required
Although therapeutic vaccination with HPV16-SLP has been shown to evoke T-cell–mediated shrinkage of HPV16-induced cervical neoplasia, the investigators found in a previous study that vaccination did not result in either tumor regression or prolonged progression-free survival of patients with advanced or recurrent HPV16-induced cervical cancer.
In the phase I trial reported here, the investigators explored whether combination HPV16-SLP with chemotherapy could potentiate T-cell responses.
In a second study, Welters et al. also showed that vaccination with HPV16-SLP after the second round of chemotherapy, when myeloid cells were at their nadir, resulted in robust T-cell responses in both mice and humans.
In the phase I trial reported here, the authors reported on the feasibility and efficacy of the technique in a larger cohort of patients with late-stage, HPV16-positive cervical cancer.
The investigators enrolled cohorts of 12 patients each and delivered one HPV16-SLP vaccine dose 2 weeks after the second, third, and fourth cycles of a total of six chemotherapy cycles with carboplatin and paclitaxel. The vaccine was test dosed at levels of 20, 40, 100, and 300 mcg/peptide, with or without 1 mcg/kg of pegylated interferon-alpha at each peptide dose level. The peptides covered the length of the HPV16 E6 and E7 proteins.
“Upon vaccination, we see a very strong T-cell response induced by the vaccine,” Dr. Welters said.
They also tested general immune responses to various microbial antigens and saw no significant differences in responses among the various dose cohorts.
Early response data was available for a total of 59 patients, 35 of whom received the vaccine/chemotherapy combination as first-line therapy and 24 of whom received it in the second line.
Two of the first-line patients had a complete response, as did one patient who received the combination as second-line therapy. Respective rates of partial responses were 22 and 5, stable disease was seen in 9 and 13 patients, and disease progression in 2 and 5 patients.
The overall response rate for patients treated in the first line was 69%, and the combined overall response and stable-disease rates were 94%. Among patients treated in the second line, the respective rates were 25% and 79%.
Median overall survival (OS) from the time of the first chemotherapy dose was 16.8 months among the first-line patients vs. 7.9 months among second-line patients (P = .0110)
At the data cutoff, median OS had not been reached for the two highest peptide dose levels (100 and 300 mcg).
The investigators also found that OS was independent of general immune status among the patients, suggesting that the benefit was derived specifically from induced T-cell responses.
‘Provocative and promising’
Invited discussant Heather McArthur, MD, MPH, from Cedars-Sinai Medical Center, Los Angeles, called the finding “provocative and promising.”
“So, it doesn’t matter if your immune system is suppressed overall. It’s the quality of players on the field and the focus and specificity of those players that matter, and that’s what they were able to demonstrate, which I think is incredibly powerful,” she said.
She noted, however, that although safety was listed as a study endpoint, Dr. Welters did not provide data on toxicities.
The trial was supported by the Dutch Cancer Society and ISA Pharmaceuticals BV. Dr. Welters reported no conflicts of interest. Dr. McArthur has previously disclosed participation in advisory boards for Celgene, Merck, Spectrum Pharmaceuticals, OBI Pharma, Peregrine Pharmaceuticals, and Syndax Pharmaceuticals, and research support from Bristol-Myers Squibb, MedImmune/AstraZeneca, Eli Lilly, ZIOPHARM Oncology, and Merck.
ORLANDO – In patients with advanced cervical cancer, combining chemotherapy with a vaccine against human papillomavirus (HPV) type 16 resulted in a robust, T-cell–mediated immune response and long duration survival for a large proportion of patients, reported investigators from the Netherlands.
Patients with advanced, HPV16-positive cervical cancer who were treated with standard chemotherapy and vaccinated with HPV16 synthetic long peptides (HPV16-SLP) had substantially increased T-cell responses, and these responses correlated with survival, said Marij Welters, PhD, from Leiden (the Netherlands) University Medical Center.
Data from this study provide “a strong rationale to conduct a randomized phase II trial in which a combination with checkpoint inhibitors might be attractive,” she added.
Combination required
Although therapeutic vaccination with HPV16-SLP has been shown to evoke T-cell–mediated shrinkage of HPV16-induced cervical neoplasia, the investigators found in a previous study that vaccination did not result in either tumor regression or prolonged progression-free survival of patients with advanced or recurrent HPV16-induced cervical cancer.
In the phase I trial reported here, the investigators explored whether combination HPV16-SLP with chemotherapy could potentiate T-cell responses.
In a second study, Welters et al. also showed that vaccination with HPV16-SLP after the second round of chemotherapy, when myeloid cells were at their nadir, resulted in robust T-cell responses in both mice and humans.
In the phase I trial reported here, the authors reported on the feasibility and efficacy of the technique in a larger cohort of patients with late-stage, HPV16-positive cervical cancer.
The investigators enrolled cohorts of 12 patients each and delivered one HPV16-SLP vaccine dose 2 weeks after the second, third, and fourth cycles of a total of six chemotherapy cycles with carboplatin and paclitaxel. The vaccine was test dosed at levels of 20, 40, 100, and 300 mcg/peptide, with or without 1 mcg/kg of pegylated interferon-alpha at each peptide dose level. The peptides covered the length of the HPV16 E6 and E7 proteins.
“Upon vaccination, we see a very strong T-cell response induced by the vaccine,” Dr. Welters said.
They also tested general immune responses to various microbial antigens and saw no significant differences in responses among the various dose cohorts.
Early response data was available for a total of 59 patients, 35 of whom received the vaccine/chemotherapy combination as first-line therapy and 24 of whom received it in the second line.
Two of the first-line patients had a complete response, as did one patient who received the combination as second-line therapy. Respective rates of partial responses were 22 and 5, stable disease was seen in 9 and 13 patients, and disease progression in 2 and 5 patients.
The overall response rate for patients treated in the first line was 69%, and the combined overall response and stable-disease rates were 94%. Among patients treated in the second line, the respective rates were 25% and 79%.
Median overall survival (OS) from the time of the first chemotherapy dose was 16.8 months among the first-line patients vs. 7.9 months among second-line patients (P = .0110)
At the data cutoff, median OS had not been reached for the two highest peptide dose levels (100 and 300 mcg).
The investigators also found that OS was independent of general immune status among the patients, suggesting that the benefit was derived specifically from induced T-cell responses.
‘Provocative and promising’
Invited discussant Heather McArthur, MD, MPH, from Cedars-Sinai Medical Center, Los Angeles, called the finding “provocative and promising.”
“So, it doesn’t matter if your immune system is suppressed overall. It’s the quality of players on the field and the focus and specificity of those players that matter, and that’s what they were able to demonstrate, which I think is incredibly powerful,” she said.
She noted, however, that although safety was listed as a study endpoint, Dr. Welters did not provide data on toxicities.
The trial was supported by the Dutch Cancer Society and ISA Pharmaceuticals BV. Dr. Welters reported no conflicts of interest. Dr. McArthur has previously disclosed participation in advisory boards for Celgene, Merck, Spectrum Pharmaceuticals, OBI Pharma, Peregrine Pharmaceuticals, and Syndax Pharmaceuticals, and research support from Bristol-Myers Squibb, MedImmune/AstraZeneca, Eli Lilly, ZIOPHARM Oncology, and Merck.
ORLANDO – In patients with advanced cervical cancer, combining chemotherapy with a vaccine against human papillomavirus (HPV) type 16 resulted in a robust, T-cell–mediated immune response and long duration survival for a large proportion of patients, reported investigators from the Netherlands.
Patients with advanced, HPV16-positive cervical cancer who were treated with standard chemotherapy and vaccinated with HPV16 synthetic long peptides (HPV16-SLP) had substantially increased T-cell responses, and these responses correlated with survival, said Marij Welters, PhD, from Leiden (the Netherlands) University Medical Center.
Data from this study provide “a strong rationale to conduct a randomized phase II trial in which a combination with checkpoint inhibitors might be attractive,” she added.
Combination required
Although therapeutic vaccination with HPV16-SLP has been shown to evoke T-cell–mediated shrinkage of HPV16-induced cervical neoplasia, the investigators found in a previous study that vaccination did not result in either tumor regression or prolonged progression-free survival of patients with advanced or recurrent HPV16-induced cervical cancer.
In the phase I trial reported here, the investigators explored whether combination HPV16-SLP with chemotherapy could potentiate T-cell responses.
In a second study, Welters et al. also showed that vaccination with HPV16-SLP after the second round of chemotherapy, when myeloid cells were at their nadir, resulted in robust T-cell responses in both mice and humans.
In the phase I trial reported here, the authors reported on the feasibility and efficacy of the technique in a larger cohort of patients with late-stage, HPV16-positive cervical cancer.
The investigators enrolled cohorts of 12 patients each and delivered one HPV16-SLP vaccine dose 2 weeks after the second, third, and fourth cycles of a total of six chemotherapy cycles with carboplatin and paclitaxel. The vaccine was test dosed at levels of 20, 40, 100, and 300 mcg/peptide, with or without 1 mcg/kg of pegylated interferon-alpha at each peptide dose level. The peptides covered the length of the HPV16 E6 and E7 proteins.
“Upon vaccination, we see a very strong T-cell response induced by the vaccine,” Dr. Welters said.
They also tested general immune responses to various microbial antigens and saw no significant differences in responses among the various dose cohorts.
Early response data was available for a total of 59 patients, 35 of whom received the vaccine/chemotherapy combination as first-line therapy and 24 of whom received it in the second line.
Two of the first-line patients had a complete response, as did one patient who received the combination as second-line therapy. Respective rates of partial responses were 22 and 5, stable disease was seen in 9 and 13 patients, and disease progression in 2 and 5 patients.
The overall response rate for patients treated in the first line was 69%, and the combined overall response and stable-disease rates were 94%. Among patients treated in the second line, the respective rates were 25% and 79%.
Median overall survival (OS) from the time of the first chemotherapy dose was 16.8 months among the first-line patients vs. 7.9 months among second-line patients (P = .0110)
At the data cutoff, median OS had not been reached for the two highest peptide dose levels (100 and 300 mcg).
The investigators also found that OS was independent of general immune status among the patients, suggesting that the benefit was derived specifically from induced T-cell responses.
‘Provocative and promising’
Invited discussant Heather McArthur, MD, MPH, from Cedars-Sinai Medical Center, Los Angeles, called the finding “provocative and promising.”
“So, it doesn’t matter if your immune system is suppressed overall. It’s the quality of players on the field and the focus and specificity of those players that matter, and that’s what they were able to demonstrate, which I think is incredibly powerful,” she said.
She noted, however, that although safety was listed as a study endpoint, Dr. Welters did not provide data on toxicities.
The trial was supported by the Dutch Cancer Society and ISA Pharmaceuticals BV. Dr. Welters reported no conflicts of interest. Dr. McArthur has previously disclosed participation in advisory boards for Celgene, Merck, Spectrum Pharmaceuticals, OBI Pharma, Peregrine Pharmaceuticals, and Syndax Pharmaceuticals, and research support from Bristol-Myers Squibb, MedImmune/AstraZeneca, Eli Lilly, ZIOPHARM Oncology, and Merck.
AT THE CLINICAL IMMUNO-ONCOLOGY SYMPOSIUM
Key clinical point: An HPV16 peptide vaccine, combined with chemotherapy, induced immune response in patients with advanced cervical cancer.
Major finding: The overall response rate for chemotherapy-naive patients treated with the combination of chemotherapy and an HPV16 synthetic long peptide vaccine was 69%.
Data source: Phase I dose-finding trial with response data on 59 patients with advanced cervical cancer.
Disclosures: The trial was supported by the Dutch Cancer Society and ISA Pharmaceuticals BV. Dr. Welters reported no conflicts of interest. Dr. McArthur has previously disclosed participation in advisory boards for Celgene, Merck, Spectrum Pharmaceuticals, OBI Pharma, Peregrine Pharmaceuticals, and Syndax Pharmaceuticals and research support from Bristol-Myers Squibb, MedImmune/AstraZeneca, Eli Lilly, ZIOPHARM Oncology, and Merck.
Electrical stimulation skin patch shows promise in easing migraine pain
A wireless skin patch using electrical stimulation at an intensity lower than pain threshold reduced migraine pain when compared against sham stimulation in a trial of 71 adults with episodic migraine. The findings were published online March 1 in Neurology.
“Our rationale is activation of pain inhibitory centers, via the conditioned pain modulation effect; remote noxious stimuli can exert a generalized analgesic effect,” wrote David Yarnitsky, MD, of the Rambam Healthcare Campus and Technion Faculty of Medicine, Haifa, Israel, and his colleagues.
The devices were randomized to give a nonpainful sham stimulation at a very low frequency (controls) or a nonpainful active stimulation at one of four levels (active treatment). Patients were asked to place the wireless patch on the arm of their choice, regardless of the location of migraine pain, and activate the device for 20 minutes as soon as possible after a migraine attack began. They were instructed to use their smartphones to adjust the stimulation as appropriate during the treatment time. The stimulations were active programs at 80-120 Hz with pulse widths of 200, 150, 100, and 50 microseconds. The sham stimulation was a 0.1-Hz frequency with 45-microsecond pulses.
Overall, 64% of patients at the top three stimuli levels reduced their pain level by at least half 2 hours after the treatment, compared with 26% of patients using the sham stimulation. Average reductions were 46% for the 200-microsecond stimulus, 48% for 150, and 39% for 100.
In addition, 58% of the patients in the 200-microsecond group with moderate to severe pain at baseline reported reductions to mild or no pain, compared with 24% of sham patients.
Treatment with stimulation within 20 minutes of migraine onset was the most helpful, resulting in a 47% pain reduction, compared with a 25% reduction with delayed treatment, the researchers noted.
No patients reported side effects or adverse events related to the device.
The investigators said that complete 20-minute treatments were obtained for 70% of each of the top three stimuli levels, for 58% of treatments at 50-microsecond pulse widths, and for just 28% of placebo treatments. This low rate of completion of placebo stimuli may be the result of a loss of blinding for some of the sham activations, the investigators acknowledged, but they argued that “it is likely that this fact did not lead to falsely improved results; on the contrary, had those incomplete stimuli periods been completed, it is most likely that sham effectiveness results would have been lower than currently reported, making the results even more distinct.”
The study was funded by Theranica, and Dr. Yarnitsky disclosed serving on the company’s medical advisory board.
A wireless skin patch using electrical stimulation at an intensity lower than pain threshold reduced migraine pain when compared against sham stimulation in a trial of 71 adults with episodic migraine. The findings were published online March 1 in Neurology.
“Our rationale is activation of pain inhibitory centers, via the conditioned pain modulation effect; remote noxious stimuli can exert a generalized analgesic effect,” wrote David Yarnitsky, MD, of the Rambam Healthcare Campus and Technion Faculty of Medicine, Haifa, Israel, and his colleagues.
The devices were randomized to give a nonpainful sham stimulation at a very low frequency (controls) or a nonpainful active stimulation at one of four levels (active treatment). Patients were asked to place the wireless patch on the arm of their choice, regardless of the location of migraine pain, and activate the device for 20 minutes as soon as possible after a migraine attack began. They were instructed to use their smartphones to adjust the stimulation as appropriate during the treatment time. The stimulations were active programs at 80-120 Hz with pulse widths of 200, 150, 100, and 50 microseconds. The sham stimulation was a 0.1-Hz frequency with 45-microsecond pulses.
Overall, 64% of patients at the top three stimuli levels reduced their pain level by at least half 2 hours after the treatment, compared with 26% of patients using the sham stimulation. Average reductions were 46% for the 200-microsecond stimulus, 48% for 150, and 39% for 100.
In addition, 58% of the patients in the 200-microsecond group with moderate to severe pain at baseline reported reductions to mild or no pain, compared with 24% of sham patients.
Treatment with stimulation within 20 minutes of migraine onset was the most helpful, resulting in a 47% pain reduction, compared with a 25% reduction with delayed treatment, the researchers noted.
No patients reported side effects or adverse events related to the device.
The investigators said that complete 20-minute treatments were obtained for 70% of each of the top three stimuli levels, for 58% of treatments at 50-microsecond pulse widths, and for just 28% of placebo treatments. This low rate of completion of placebo stimuli may be the result of a loss of blinding for some of the sham activations, the investigators acknowledged, but they argued that “it is likely that this fact did not lead to falsely improved results; on the contrary, had those incomplete stimuli periods been completed, it is most likely that sham effectiveness results would have been lower than currently reported, making the results even more distinct.”
The study was funded by Theranica, and Dr. Yarnitsky disclosed serving on the company’s medical advisory board.
A wireless skin patch using electrical stimulation at an intensity lower than pain threshold reduced migraine pain when compared against sham stimulation in a trial of 71 adults with episodic migraine. The findings were published online March 1 in Neurology.
“Our rationale is activation of pain inhibitory centers, via the conditioned pain modulation effect; remote noxious stimuli can exert a generalized analgesic effect,” wrote David Yarnitsky, MD, of the Rambam Healthcare Campus and Technion Faculty of Medicine, Haifa, Israel, and his colleagues.
The devices were randomized to give a nonpainful sham stimulation at a very low frequency (controls) or a nonpainful active stimulation at one of four levels (active treatment). Patients were asked to place the wireless patch on the arm of their choice, regardless of the location of migraine pain, and activate the device for 20 minutes as soon as possible after a migraine attack began. They were instructed to use their smartphones to adjust the stimulation as appropriate during the treatment time. The stimulations were active programs at 80-120 Hz with pulse widths of 200, 150, 100, and 50 microseconds. The sham stimulation was a 0.1-Hz frequency with 45-microsecond pulses.
Overall, 64% of patients at the top three stimuli levels reduced their pain level by at least half 2 hours after the treatment, compared with 26% of patients using the sham stimulation. Average reductions were 46% for the 200-microsecond stimulus, 48% for 150, and 39% for 100.
In addition, 58% of the patients in the 200-microsecond group with moderate to severe pain at baseline reported reductions to mild or no pain, compared with 24% of sham patients.
Treatment with stimulation within 20 minutes of migraine onset was the most helpful, resulting in a 47% pain reduction, compared with a 25% reduction with delayed treatment, the researchers noted.
No patients reported side effects or adverse events related to the device.
The investigators said that complete 20-minute treatments were obtained for 70% of each of the top three stimuli levels, for 58% of treatments at 50-microsecond pulse widths, and for just 28% of placebo treatments. This low rate of completion of placebo stimuli may be the result of a loss of blinding for some of the sham activations, the investigators acknowledged, but they argued that “it is likely that this fact did not lead to falsely improved results; on the contrary, had those incomplete stimuli periods been completed, it is most likely that sham effectiveness results would have been lower than currently reported, making the results even more distinct.”
The study was funded by Theranica, and Dr. Yarnitsky disclosed serving on the company’s medical advisory board.
FROM NEUROLOGY
Key clinical point:
Major finding: A total of 64% of migraine patients experienced a 50% pain reduction when treated with a skin patch that delivered wireless, painless electrical stimulation, compared with 26% of patients who received sham treatment.
Data source: A prospective, double-blind, randomized, crossover, sham-controlled study including 71 adults and 299 episodes of migraine.
Disclosures: The study was funded by Theranica, and lead author Dr. Yarnitsky disclosed serving on the company’s medical advisory board.
Herbal/dietary supplements linked to liver injury requiring transplant
Herbal or dietary supplements are the fourth most common cause of drug-induced acute hepatic necrosis requiring liver transplantation in the United States, according to a study of liver transplant registry data.
Researchers analyzed registry data for 2,408 adults who underwent urgent liver transplantation for acute hepatic necrosis between 2003 and 2015, 625 of whom were recorded as having drug-induced liver injury. Of these, 21 cases were reportedly due to herbal or dietary supplements, all of which occurred after 2007. Eight cases were attributed to Lipolyze, Hydroxycut, testosterone, and OxyElite Pro, a muscle-building and weight-loss dietary supplement containing a blend of plant-derived extracts. The remaining cases did not list a specific product (Transplantation Proc 2017;49[2]:322-5).
“The potential hepatotoxicity of these HDS [herbal/dietary supplement] agents can result in the need for liver transplantation for irreversible liver failure,” wrote Dr. Linda L. Wong of the University of Hawaii and coauthors, citing two cases in Hawaii where patients needed liver transplant after taking OxyElite Pro.
They also referred to other case reports and case series of liver transplantation occurring in individuals who had taken the supplements usnic acid, Herbalife, Hydroxycut, linoleic acid, black cohosh, Chinese herbs, kava kava, skullcap, ma huang, or bai fang herb. “The benefits of the current regulatory oversight of medications breaks down when patients misuse non-FDA [Food and Drug Administration] approved herbal/dietary supplements (HDS) or ‘natural remedies’ with their inherent unknown side effects, interactions, and complications,” they wrote.
The mean age of individuals for which an herbal/dietary supplement was thought to be the cause of the hepatotoxicity was 36.8 years, 14 of the 21 were female, and the mean waiting time for liver transplantation was 4.7 days. One of the 21 patients died.
Overall, the most common drug associated with drug-induced liver injury was acetaminophen (300 cases), followed by antituberculosis medications (30), and antibiotics (30).
The authors suggested the true figure for HDS-induced liver transplantation may be underestimated, pointing to the fact that in this study, a further 154 cases were recorded as drug-induced injury but no drug was listed.
“Transplant centers and physicians may have difficulty identifying the exact inciting agent because patients do not typically report HDS when queried about medication use,” the authors wrote.
Given this, they recommended that transplant professionals specifically ask potential transplant recipients about their use of HDS, and request a detailed list of these along with the time course of use. They noted that family members and friends may not be privy to this information, and the patients themselves may not be in a position to answer because of decompensation with encephalopathy.
“It is critical to obtain this information as early as possible in the evaluation of the potential liver transplant recipient with an unknown etiology of liver disease or who presents with acute hepatic decompensation,” they wrote.
They also called for transplant professionals to report any information about confirmed HDS use in their patients to the FDA.
“It is imperative that transplant professionals inform the FDA of these dangerous compounds, with the ultimate intent of enforcing regulatory oversight,” they wrote. “This adherence to strict reporting will in turn translate to a reduction in the need for liver transplantation from HDS use.”
No conflicts of interest were declared.
Herbal or dietary supplements are the fourth most common cause of drug-induced acute hepatic necrosis requiring liver transplantation in the United States, according to a study of liver transplant registry data.
Researchers analyzed registry data for 2,408 adults who underwent urgent liver transplantation for acute hepatic necrosis between 2003 and 2015, 625 of whom were recorded as having drug-induced liver injury. Of these, 21 cases were reportedly due to herbal or dietary supplements, all of which occurred after 2007. Eight cases were attributed to Lipolyze, Hydroxycut, testosterone, and OxyElite Pro, a muscle-building and weight-loss dietary supplement containing a blend of plant-derived extracts. The remaining cases did not list a specific product (Transplantation Proc 2017;49[2]:322-5).
“The potential hepatotoxicity of these HDS [herbal/dietary supplement] agents can result in the need for liver transplantation for irreversible liver failure,” wrote Dr. Linda L. Wong of the University of Hawaii and coauthors, citing two cases in Hawaii where patients needed liver transplant after taking OxyElite Pro.
They also referred to other case reports and case series of liver transplantation occurring in individuals who had taken the supplements usnic acid, Herbalife, Hydroxycut, linoleic acid, black cohosh, Chinese herbs, kava kava, skullcap, ma huang, or bai fang herb. “The benefits of the current regulatory oversight of medications breaks down when patients misuse non-FDA [Food and Drug Administration] approved herbal/dietary supplements (HDS) or ‘natural remedies’ with their inherent unknown side effects, interactions, and complications,” they wrote.
The mean age of individuals for which an herbal/dietary supplement was thought to be the cause of the hepatotoxicity was 36.8 years, 14 of the 21 were female, and the mean waiting time for liver transplantation was 4.7 days. One of the 21 patients died.
Overall, the most common drug associated with drug-induced liver injury was acetaminophen (300 cases), followed by antituberculosis medications (30), and antibiotics (30).
The authors suggested the true figure for HDS-induced liver transplantation may be underestimated, pointing to the fact that in this study, a further 154 cases were recorded as drug-induced injury but no drug was listed.
“Transplant centers and physicians may have difficulty identifying the exact inciting agent because patients do not typically report HDS when queried about medication use,” the authors wrote.
Given this, they recommended that transplant professionals specifically ask potential transplant recipients about their use of HDS, and request a detailed list of these along with the time course of use. They noted that family members and friends may not be privy to this information, and the patients themselves may not be in a position to answer because of decompensation with encephalopathy.
“It is critical to obtain this information as early as possible in the evaluation of the potential liver transplant recipient with an unknown etiology of liver disease or who presents with acute hepatic decompensation,” they wrote.
They also called for transplant professionals to report any information about confirmed HDS use in their patients to the FDA.
“It is imperative that transplant professionals inform the FDA of these dangerous compounds, with the ultimate intent of enforcing regulatory oversight,” they wrote. “This adherence to strict reporting will in turn translate to a reduction in the need for liver transplantation from HDS use.”
No conflicts of interest were declared.
Herbal or dietary supplements are the fourth most common cause of drug-induced acute hepatic necrosis requiring liver transplantation in the United States, according to a study of liver transplant registry data.
Researchers analyzed registry data for 2,408 adults who underwent urgent liver transplantation for acute hepatic necrosis between 2003 and 2015, 625 of whom were recorded as having drug-induced liver injury. Of these, 21 cases were reportedly due to herbal or dietary supplements, all of which occurred after 2007. Eight cases were attributed to Lipolyze, Hydroxycut, testosterone, and OxyElite Pro, a muscle-building and weight-loss dietary supplement containing a blend of plant-derived extracts. The remaining cases did not list a specific product (Transplantation Proc 2017;49[2]:322-5).
“The potential hepatotoxicity of these HDS [herbal/dietary supplement] agents can result in the need for liver transplantation for irreversible liver failure,” wrote Dr. Linda L. Wong of the University of Hawaii and coauthors, citing two cases in Hawaii where patients needed liver transplant after taking OxyElite Pro.
They also referred to other case reports and case series of liver transplantation occurring in individuals who had taken the supplements usnic acid, Herbalife, Hydroxycut, linoleic acid, black cohosh, Chinese herbs, kava kava, skullcap, ma huang, or bai fang herb. “The benefits of the current regulatory oversight of medications breaks down when patients misuse non-FDA [Food and Drug Administration] approved herbal/dietary supplements (HDS) or ‘natural remedies’ with their inherent unknown side effects, interactions, and complications,” they wrote.
The mean age of individuals for which an herbal/dietary supplement was thought to be the cause of the hepatotoxicity was 36.8 years, 14 of the 21 were female, and the mean waiting time for liver transplantation was 4.7 days. One of the 21 patients died.
Overall, the most common drug associated with drug-induced liver injury was acetaminophen (300 cases), followed by antituberculosis medications (30), and antibiotics (30).
The authors suggested the true figure for HDS-induced liver transplantation may be underestimated, pointing to the fact that in this study, a further 154 cases were recorded as drug-induced injury but no drug was listed.
“Transplant centers and physicians may have difficulty identifying the exact inciting agent because patients do not typically report HDS when queried about medication use,” the authors wrote.
Given this, they recommended that transplant professionals specifically ask potential transplant recipients about their use of HDS, and request a detailed list of these along with the time course of use. They noted that family members and friends may not be privy to this information, and the patients themselves may not be in a position to answer because of decompensation with encephalopathy.
“It is critical to obtain this information as early as possible in the evaluation of the potential liver transplant recipient with an unknown etiology of liver disease or who presents with acute hepatic decompensation,” they wrote.
They also called for transplant professionals to report any information about confirmed HDS use in their patients to the FDA.
“It is imperative that transplant professionals inform the FDA of these dangerous compounds, with the ultimate intent of enforcing regulatory oversight,” they wrote. “This adherence to strict reporting will in turn translate to a reduction in the need for liver transplantation from HDS use.”
No conflicts of interest were declared.
FROM TRANSPLANTATION PROCEEDINGS
Key clinical point: Herbal or dietary supplements are the fourth most common cause of drug-induced acute hepatic necrosis requiring liver transplantation in the United States.
Major finding: Twenty-one cases of liver transplantation linked to the use of herbal or dietary supplements were recorded between 2003 and 2015.
Data source: Analysis of registry data from 2,408 adults who underwent urgent liver transplantation for acute hepatic necrosis.
Disclosures: No conflicts of interest were declared.
Primary prophylaxis of bleeding in portal hypertension safe in cirrhosis with high-risk varices
Primary prophylaxis of bleeding in children with portal hypertension is safe for treatment of cirrhosis associated with high-risk varices, according to Mathieu Duché, MD, of Hôpital Bicêtre in France, and his associates.
In a study from July 1989 to June 2014, researchers examined 1,300 children with various causes of liver disease, based on the presence of palpable splenomegaly and/or ultrasonographic signs of portal hypertension. During the study, a high-risk pattern – including grade 3 esophageal varices, grade 2 varices with red markings and/or gastric varices along the cardia, or gastric varices with or without esophageal varices – was present in 96% of the 246 children who bled spontaneously and in 11% of the 872 children who did not bleed. Of the 246 children who bled spontaneously, 170 children with high-risk varices underwent primary prophylaxis of bleeding with portal surgery, endoscopic banding/sclerotherapy of varices, or interventional radiology.
In 50 children with noncirrhotic causes of portal hypertension and the high risk varices, those with portal vein obstruction underwent portal surgery (Rex bypass or portosystemic shunt) as primary prophylaxis. Endoscopic banding or sclerotherapy was performed instead in younger children or when angiograms did not favor the surgery. One child who had a severe stenosis of the portal trunk underwent successful interventional radiology. After a mean follow-up of 5.5 years after primary prophylaxis, all these patients are alive.
Of the 120 children with cirrhosis with high risk varices, 10 children with well compensated cirrhosis received a portosystemic shunt; thrombosis of the shunt occurred in 1 child who later underwent liver transplantation, and 1 child with a patent shunt developed portosystemic encephalopathy and underwent liver transplantation. No gastrointestinal bleeding was recorded in these 10 children who were alive at the last follow-up.
Of 110 children who underwent endoscopic banding or sclerotherapy, in 76 children there was eradication of varices; there was a relapse of high-risk varices in 20 children, so further endoscopic was needed. In two children who initially underwent endoscopic treatment and achieved eradication of varices, a protein-losing enteropathy and bleeding from ectopic varices, respectively, required subsequent treatment by a surgical portosystemic shunt. Of the 34 children in whom no eradication was obtained with this primary prophylaxis, 3 died and 29 underwent liver transplantation before eradication could be obtained; 1 was lost to follow-up and 1 received a transjugular intrahepatic portosystemic shunt. After a mean follow-up of 5 years, 8 of the 120 children with cirrhosis who underwent primary prophylaxis have died: 4 children died before transplantation, 2 of septic shock unrelated to endoscopic treatment, and 1 of atrioventricular block during variceal injection of aethoxysklerol. Four other children died after transplantation.
It was noted that no esophageal or gastric perforation was observed as a consequence of endoscopic primary prophylaxis in the pre- or posttransplantation period.
“Although no statistical analysis was performed because this was not a controlled study, the results suggest that, compared with liver transplantation performed directly or with care after a spontaneous bleed, primary prophylaxis of bleeding has a fairly good safety record for the management of children with cirrhosis and high-risk varices,” researchers concluded.
Read the full study in the Journal of Hepatology (doi: 10.1016/j.jhep.2016.09.006).
Primary prophylaxis of bleeding in children with portal hypertension is safe for treatment of cirrhosis associated with high-risk varices, according to Mathieu Duché, MD, of Hôpital Bicêtre in France, and his associates.
In a study from July 1989 to June 2014, researchers examined 1,300 children with various causes of liver disease, based on the presence of palpable splenomegaly and/or ultrasonographic signs of portal hypertension. During the study, a high-risk pattern – including grade 3 esophageal varices, grade 2 varices with red markings and/or gastric varices along the cardia, or gastric varices with or without esophageal varices – was present in 96% of the 246 children who bled spontaneously and in 11% of the 872 children who did not bleed. Of the 246 children who bled spontaneously, 170 children with high-risk varices underwent primary prophylaxis of bleeding with portal surgery, endoscopic banding/sclerotherapy of varices, or interventional radiology.
In 50 children with noncirrhotic causes of portal hypertension and the high risk varices, those with portal vein obstruction underwent portal surgery (Rex bypass or portosystemic shunt) as primary prophylaxis. Endoscopic banding or sclerotherapy was performed instead in younger children or when angiograms did not favor the surgery. One child who had a severe stenosis of the portal trunk underwent successful interventional radiology. After a mean follow-up of 5.5 years after primary prophylaxis, all these patients are alive.
Of the 120 children with cirrhosis with high risk varices, 10 children with well compensated cirrhosis received a portosystemic shunt; thrombosis of the shunt occurred in 1 child who later underwent liver transplantation, and 1 child with a patent shunt developed portosystemic encephalopathy and underwent liver transplantation. No gastrointestinal bleeding was recorded in these 10 children who were alive at the last follow-up.
Of 110 children who underwent endoscopic banding or sclerotherapy, in 76 children there was eradication of varices; there was a relapse of high-risk varices in 20 children, so further endoscopic was needed. In two children who initially underwent endoscopic treatment and achieved eradication of varices, a protein-losing enteropathy and bleeding from ectopic varices, respectively, required subsequent treatment by a surgical portosystemic shunt. Of the 34 children in whom no eradication was obtained with this primary prophylaxis, 3 died and 29 underwent liver transplantation before eradication could be obtained; 1 was lost to follow-up and 1 received a transjugular intrahepatic portosystemic shunt. After a mean follow-up of 5 years, 8 of the 120 children with cirrhosis who underwent primary prophylaxis have died: 4 children died before transplantation, 2 of septic shock unrelated to endoscopic treatment, and 1 of atrioventricular block during variceal injection of aethoxysklerol. Four other children died after transplantation.
It was noted that no esophageal or gastric perforation was observed as a consequence of endoscopic primary prophylaxis in the pre- or posttransplantation period.
“Although no statistical analysis was performed because this was not a controlled study, the results suggest that, compared with liver transplantation performed directly or with care after a spontaneous bleed, primary prophylaxis of bleeding has a fairly good safety record for the management of children with cirrhosis and high-risk varices,” researchers concluded.
Read the full study in the Journal of Hepatology (doi: 10.1016/j.jhep.2016.09.006).
Primary prophylaxis of bleeding in children with portal hypertension is safe for treatment of cirrhosis associated with high-risk varices, according to Mathieu Duché, MD, of Hôpital Bicêtre in France, and his associates.
In a study from July 1989 to June 2014, researchers examined 1,300 children with various causes of liver disease, based on the presence of palpable splenomegaly and/or ultrasonographic signs of portal hypertension. During the study, a high-risk pattern – including grade 3 esophageal varices, grade 2 varices with red markings and/or gastric varices along the cardia, or gastric varices with or without esophageal varices – was present in 96% of the 246 children who bled spontaneously and in 11% of the 872 children who did not bleed. Of the 246 children who bled spontaneously, 170 children with high-risk varices underwent primary prophylaxis of bleeding with portal surgery, endoscopic banding/sclerotherapy of varices, or interventional radiology.
In 50 children with noncirrhotic causes of portal hypertension and the high risk varices, those with portal vein obstruction underwent portal surgery (Rex bypass or portosystemic shunt) as primary prophylaxis. Endoscopic banding or sclerotherapy was performed instead in younger children or when angiograms did not favor the surgery. One child who had a severe stenosis of the portal trunk underwent successful interventional radiology. After a mean follow-up of 5.5 years after primary prophylaxis, all these patients are alive.
Of the 120 children with cirrhosis with high risk varices, 10 children with well compensated cirrhosis received a portosystemic shunt; thrombosis of the shunt occurred in 1 child who later underwent liver transplantation, and 1 child with a patent shunt developed portosystemic encephalopathy and underwent liver transplantation. No gastrointestinal bleeding was recorded in these 10 children who were alive at the last follow-up.
Of 110 children who underwent endoscopic banding or sclerotherapy, in 76 children there was eradication of varices; there was a relapse of high-risk varices in 20 children, so further endoscopic was needed. In two children who initially underwent endoscopic treatment and achieved eradication of varices, a protein-losing enteropathy and bleeding from ectopic varices, respectively, required subsequent treatment by a surgical portosystemic shunt. Of the 34 children in whom no eradication was obtained with this primary prophylaxis, 3 died and 29 underwent liver transplantation before eradication could be obtained; 1 was lost to follow-up and 1 received a transjugular intrahepatic portosystemic shunt. After a mean follow-up of 5 years, 8 of the 120 children with cirrhosis who underwent primary prophylaxis have died: 4 children died before transplantation, 2 of septic shock unrelated to endoscopic treatment, and 1 of atrioventricular block during variceal injection of aethoxysklerol. Four other children died after transplantation.
It was noted that no esophageal or gastric perforation was observed as a consequence of endoscopic primary prophylaxis in the pre- or posttransplantation period.
“Although no statistical analysis was performed because this was not a controlled study, the results suggest that, compared with liver transplantation performed directly or with care after a spontaneous bleed, primary prophylaxis of bleeding has a fairly good safety record for the management of children with cirrhosis and high-risk varices,” researchers concluded.
Read the full study in the Journal of Hepatology (doi: 10.1016/j.jhep.2016.09.006).
FROM JOURNAL OF HEPATOLOGY