User login
Assessing the Status of Personal Protective Equipment
The National Institute of Occupational Safety and Health (NIOSH) has been gathering information about storage conditions and inventory for personal protective equipment (PPE) in federal, state, municipal, county, and hospital system stockpiles. Maintaining the stockpiles for public health emergencies, such as infectious disease outbreaks, is a “significant cost and time investment,” NIOSH says. That investment includes restocking and leasing or purchasing environmentally controlled storage space.
NIOSH asked for comments on how facilities monitor respirator and gown deterioration, how they rotate PPE, and the degree to which environmental controls are implemented and maintained. Even when resources exist to store PPE per the manufacturer’s recommendations, NIOHS says, “the influence of long-term storage time alone or PPE performance has been questioned.”
The period for comment is closed. Survey responses will be used to inform a research study in which N95 respirators and high-protection–level surgical gowns are sampled from stockpiles nationwide and tested against established performance standards. The study will assess the potential to extend manufacturer-recommended shelf life and the effect of “common, albeit sometimes non-ideal, stockpile conditions” on the protections provided by respirators and surgical gowns.
The information collected will be added to the PPE database, available at https://wwwn.cdc.gov/ppeinfo.
The National Institute of Occupational Safety and Health (NIOSH) has been gathering information about storage conditions and inventory for personal protective equipment (PPE) in federal, state, municipal, county, and hospital system stockpiles. Maintaining the stockpiles for public health emergencies, such as infectious disease outbreaks, is a “significant cost and time investment,” NIOSH says. That investment includes restocking and leasing or purchasing environmentally controlled storage space.
NIOSH asked for comments on how facilities monitor respirator and gown deterioration, how they rotate PPE, and the degree to which environmental controls are implemented and maintained. Even when resources exist to store PPE per the manufacturer’s recommendations, NIOHS says, “the influence of long-term storage time alone or PPE performance has been questioned.”
The period for comment is closed. Survey responses will be used to inform a research study in which N95 respirators and high-protection–level surgical gowns are sampled from stockpiles nationwide and tested against established performance standards. The study will assess the potential to extend manufacturer-recommended shelf life and the effect of “common, albeit sometimes non-ideal, stockpile conditions” on the protections provided by respirators and surgical gowns.
The information collected will be added to the PPE database, available at https://wwwn.cdc.gov/ppeinfo.
The National Institute of Occupational Safety and Health (NIOSH) has been gathering information about storage conditions and inventory for personal protective equipment (PPE) in federal, state, municipal, county, and hospital system stockpiles. Maintaining the stockpiles for public health emergencies, such as infectious disease outbreaks, is a “significant cost and time investment,” NIOSH says. That investment includes restocking and leasing or purchasing environmentally controlled storage space.
NIOSH asked for comments on how facilities monitor respirator and gown deterioration, how they rotate PPE, and the degree to which environmental controls are implemented and maintained. Even when resources exist to store PPE per the manufacturer’s recommendations, NIOHS says, “the influence of long-term storage time alone or PPE performance has been questioned.”
The period for comment is closed. Survey responses will be used to inform a research study in which N95 respirators and high-protection–level surgical gowns are sampled from stockpiles nationwide and tested against established performance standards. The study will assess the potential to extend manufacturer-recommended shelf life and the effect of “common, albeit sometimes non-ideal, stockpile conditions” on the protections provided by respirators and surgical gowns.
The information collected will be added to the PPE database, available at https://wwwn.cdc.gov/ppeinfo.
Compound could treat lymphoma, myeloma
A nucleoside analog has shown potential for treating primary effusion lymphoma (PEL) and multiple myeloma (MM), according to researchers.
The compound, 6-ethylthioinosine (6-ETI), killed both PEL and MM cells in vitro.
6-ETI also reduced tumor burden and prolonged survival in mouse models of MM and PEL.
Ethel Cesarman, MD, PhD, of Weill Cornell Medicine in New York, New York, and her colleagues conducted this research and disclosed their results in the Journal of Clinical Investigation.
The researchers identified 6-ETI via high-throughput screening, and they initially tested the compound in PEL cell lines. 6-ETI induced necrosis, apoptosis, and autophagy in these cells.
In a xenograft model of PEL, mice treated with 6-ETI experienced “striking and immediate regression of the implanted xenograft within 3 days of treatment,” according to the researchers.
In addition, mice that received 6-ETI had significantly longer progression-free and overall survival than control mice (P<0.0001 for both), and the researchers said there were no obvious toxicities from the treatment.
Looking into the mechanism of 6-ETI, the researchers found that adenosine kinase (ADK) is required to phosphorylate and activate the compound, and PEL cells have high levels of ADK.
Because PEL cells closely resemble plasma cells, the researchers theorized that MM might produce high levels of ADK as well. Experiments in MM cells proved this theory correct.
So the researchers tested 6-ETI in MM cell lines and samples from MM patients. The compound induced apoptosis and autophagy, and it activated a DNA damage response in MM cells.
In a mouse model of MM, 6-ETI treatment significantly reduced tumor burden but did not result in weight loss. And treated mice had significantly longer overall survival than control mice (P<0.005).
Dr Cesarman and her colleagues are now trying to better understand how 6-ETI works and determine what other cancers expressing high levels of ADK might respond to the drug.
“This compound could provide a much-needed approach to treat people with some forms of plasma malignancies as well as other cancers that express ADK,” Dr Cesarman said. 
A nucleoside analog has shown potential for treating primary effusion lymphoma (PEL) and multiple myeloma (MM), according to researchers.
The compound, 6-ethylthioinosine (6-ETI), killed both PEL and MM cells in vitro.
6-ETI also reduced tumor burden and prolonged survival in mouse models of MM and PEL.
Ethel Cesarman, MD, PhD, of Weill Cornell Medicine in New York, New York, and her colleagues conducted this research and disclosed their results in the Journal of Clinical Investigation.
The researchers identified 6-ETI via high-throughput screening, and they initially tested the compound in PEL cell lines. 6-ETI induced necrosis, apoptosis, and autophagy in these cells.
In a xenograft model of PEL, mice treated with 6-ETI experienced “striking and immediate regression of the implanted xenograft within 3 days of treatment,” according to the researchers.
In addition, mice that received 6-ETI had significantly longer progression-free and overall survival than control mice (P<0.0001 for both), and the researchers said there were no obvious toxicities from the treatment.
Looking into the mechanism of 6-ETI, the researchers found that adenosine kinase (ADK) is required to phosphorylate and activate the compound, and PEL cells have high levels of ADK.
Because PEL cells closely resemble plasma cells, the researchers theorized that MM might produce high levels of ADK as well. Experiments in MM cells proved this theory correct.
So the researchers tested 6-ETI in MM cell lines and samples from MM patients. The compound induced apoptosis and autophagy, and it activated a DNA damage response in MM cells.
In a mouse model of MM, 6-ETI treatment significantly reduced tumor burden but did not result in weight loss. And treated mice had significantly longer overall survival than control mice (P<0.005).
Dr Cesarman and her colleagues are now trying to better understand how 6-ETI works and determine what other cancers expressing high levels of ADK might respond to the drug.
“This compound could provide a much-needed approach to treat people with some forms of plasma malignancies as well as other cancers that express ADK,” Dr Cesarman said.
A nucleoside analog has shown potential for treating primary effusion lymphoma (PEL) and multiple myeloma (MM), according to researchers.
The compound, 6-ethylthioinosine (6-ETI), killed both PEL and MM cells in vitro.
6-ETI also reduced tumor burden and prolonged survival in mouse models of MM and PEL.
Ethel Cesarman, MD, PhD, of Weill Cornell Medicine in New York, New York, and her colleagues conducted this research and disclosed their results in the Journal of Clinical Investigation.
The researchers identified 6-ETI via high-throughput screening, and they initially tested the compound in PEL cell lines. 6-ETI induced necrosis, apoptosis, and autophagy in these cells.
In a xenograft model of PEL, mice treated with 6-ETI experienced “striking and immediate regression of the implanted xenograft within 3 days of treatment,” according to the researchers.
In addition, mice that received 6-ETI had significantly longer progression-free and overall survival than control mice (P<0.0001 for both), and the researchers said there were no obvious toxicities from the treatment.
Looking into the mechanism of 6-ETI, the researchers found that adenosine kinase (ADK) is required to phosphorylate and activate the compound, and PEL cells have high levels of ADK.
Because PEL cells closely resemble plasma cells, the researchers theorized that MM might produce high levels of ADK as well. Experiments in MM cells proved this theory correct.
So the researchers tested 6-ETI in MM cell lines and samples from MM patients. The compound induced apoptosis and autophagy, and it activated a DNA damage response in MM cells.
In a mouse model of MM, 6-ETI treatment significantly reduced tumor burden but did not result in weight loss. And treated mice had significantly longer overall survival than control mice (P<0.005).
Dr Cesarman and her colleagues are now trying to better understand how 6-ETI works and determine what other cancers expressing high levels of ADK might respond to the drug.
“This compound could provide a much-needed approach to treat people with some forms of plasma malignancies as well as other cancers that express ADK,” Dr Cesarman said.
Drug receives rare pediatric disease designation for SCD
The US Food and Drug Administration (FDA) has granted rare pediatric disease designation to IMR-687, a product intended to treat sickle cell disease (SCD).
IMR-687 is the first SCD candidate to be designated as a drug for a rare pediatric disease, and this designation builds upon the FDA’s earlier granting of orphan designation for IMR-687.
IMR-687 is a selective inhibitor of phosphodiesterase-9 (PDE9i) in blood cells. It was specifically designed to address the underlying pathology of SCD.
In preclinical studies, IMR-687 demonstrated the ability to increase fetal globin. This prevented the polymerization of sickled hemoglobin and reduced red blood cell sickling, leukocytosis, and the occlusion of blood vessels.
Researchers presented these results at the 2016 ASH Annual Meeting.
Imara Inc., the company developing IMR-687, is conducting a phase 1a trial of the product in healthy volunteers.
If the trial has a positive outcome (results are expected this summer), Imara will initiate a phase 2a study in adults with SCD later this year. The company expects to initiate a phase 2 study in pediatric patients in 2018.
About rare pediatric disease designation
Rare pediatric disease designation is granted to drugs that show promise to treat orphan diseases affecting fewer than 200,000 patients in the US, primarily patients age 18 or younger.
The designation provides incentives to advance the development of drugs for rare disease, including access to the FDA’s expedited review and approval programs.
Under the FDA’s Rare Pediatric Disease Priority Review Voucher Program, a sponsor with rare pediatric disease designation who receives an approval of a new drug application is eligible for a voucher that can be redeemed to obtain priority review for any subsequent marketing application.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted rare pediatric disease designation to IMR-687, a product intended to treat sickle cell disease (SCD).
IMR-687 is the first SCD candidate to be designated as a drug for a rare pediatric disease, and this designation builds upon the FDA’s earlier granting of orphan designation for IMR-687.
IMR-687 is a selective inhibitor of phosphodiesterase-9 (PDE9i) in blood cells. It was specifically designed to address the underlying pathology of SCD.
In preclinical studies, IMR-687 demonstrated the ability to increase fetal globin. This prevented the polymerization of sickled hemoglobin and reduced red blood cell sickling, leukocytosis, and the occlusion of blood vessels.
Researchers presented these results at the 2016 ASH Annual Meeting.
Imara Inc., the company developing IMR-687, is conducting a phase 1a trial of the product in healthy volunteers.
If the trial has a positive outcome (results are expected this summer), Imara will initiate a phase 2a study in adults with SCD later this year. The company expects to initiate a phase 2 study in pediatric patients in 2018.
About rare pediatric disease designation
Rare pediatric disease designation is granted to drugs that show promise to treat orphan diseases affecting fewer than 200,000 patients in the US, primarily patients age 18 or younger.
The designation provides incentives to advance the development of drugs for rare disease, including access to the FDA’s expedited review and approval programs.
Under the FDA’s Rare Pediatric Disease Priority Review Voucher Program, a sponsor with rare pediatric disease designation who receives an approval of a new drug application is eligible for a voucher that can be redeemed to obtain priority review for any subsequent marketing application.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted rare pediatric disease designation to IMR-687, a product intended to treat sickle cell disease (SCD).
IMR-687 is the first SCD candidate to be designated as a drug for a rare pediatric disease, and this designation builds upon the FDA’s earlier granting of orphan designation for IMR-687.
IMR-687 is a selective inhibitor of phosphodiesterase-9 (PDE9i) in blood cells. It was specifically designed to address the underlying pathology of SCD.
In preclinical studies, IMR-687 demonstrated the ability to increase fetal globin. This prevented the polymerization of sickled hemoglobin and reduced red blood cell sickling, leukocytosis, and the occlusion of blood vessels.
Researchers presented these results at the 2016 ASH Annual Meeting.
Imara Inc., the company developing IMR-687, is conducting a phase 1a trial of the product in healthy volunteers.
If the trial has a positive outcome (results are expected this summer), Imara will initiate a phase 2a study in adults with SCD later this year. The company expects to initiate a phase 2 study in pediatric patients in 2018.
About rare pediatric disease designation
Rare pediatric disease designation is granted to drugs that show promise to treat orphan diseases affecting fewer than 200,000 patients in the US, primarily patients age 18 or younger.
The designation provides incentives to advance the development of drugs for rare disease, including access to the FDA’s expedited review and approval programs.
Under the FDA’s Rare Pediatric Disease Priority Review Voucher Program, a sponsor with rare pediatric disease designation who receives an approval of a new drug application is eligible for a voucher that can be redeemed to obtain priority review for any subsequent marketing application.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
Gene therapy granted fast track status for hemophilia A
The US Food and Drug Administration (FDA) has granted fast track designation to SB-525, a gene therapy intended for use in patients with hemophilia A.
SB-525 is designed to provide continuous therapeutic expression of factor VIII protein.
SB-525 uses a recombinant adeno-associated virus (AAV) to deliver a human factor VIII complementary DNA construct and synthetic liver-specific promoter to the nucleus of liver cells.
The therapy is being developed by Sangamo Therapeutics, Inc.
In research presented at the 2016 ASH Annual Meeting (abstract 1173), SB-525 induced the expression of human factor VIII in mice and non-human primates (NHPs). SB-525 also corrected the bleeding defect in a mouse model of hemophilia A.
Dosing studies in NHPs demonstrated a robust and reproducible dose response curve, according to researchers. In these animals, mean human factor VIII levels ranged from 5% of normal at the lowest dose to 230% at the highest (AAV doses in the 6 x 1011 – 6 x 1012 vgs/kg range).
The researchers said the peak circulating human factor VIII levels in these experiments exceeded levels previously reported in NHPs. And this could significantly reduce the dose required to achieve therapeutically relevant levels in human subjects.
Sangamo is planning to open a phase 1/2 trial of SB-525 in adults with hemophilia A by the end of the second quarter of 2017. Data from this study are expected in late 2017 or early 2018.
In addition to the fast track designation, SB-525 has orphan drug designation from the FDA.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologic license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted fast track designation to SB-525, a gene therapy intended for use in patients with hemophilia A.
SB-525 is designed to provide continuous therapeutic expression of factor VIII protein.
SB-525 uses a recombinant adeno-associated virus (AAV) to deliver a human factor VIII complementary DNA construct and synthetic liver-specific promoter to the nucleus of liver cells.
The therapy is being developed by Sangamo Therapeutics, Inc.
In research presented at the 2016 ASH Annual Meeting (abstract 1173), SB-525 induced the expression of human factor VIII in mice and non-human primates (NHPs). SB-525 also corrected the bleeding defect in a mouse model of hemophilia A.
Dosing studies in NHPs demonstrated a robust and reproducible dose response curve, according to researchers. In these animals, mean human factor VIII levels ranged from 5% of normal at the lowest dose to 230% at the highest (AAV doses in the 6 x 1011 – 6 x 1012 vgs/kg range).
The researchers said the peak circulating human factor VIII levels in these experiments exceeded levels previously reported in NHPs. And this could significantly reduce the dose required to achieve therapeutically relevant levels in human subjects.
Sangamo is planning to open a phase 1/2 trial of SB-525 in adults with hemophilia A by the end of the second quarter of 2017. Data from this study are expected in late 2017 or early 2018.
In addition to the fast track designation, SB-525 has orphan drug designation from the FDA.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologic license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted fast track designation to SB-525, a gene therapy intended for use in patients with hemophilia A.
SB-525 is designed to provide continuous therapeutic expression of factor VIII protein.
SB-525 uses a recombinant adeno-associated virus (AAV) to deliver a human factor VIII complementary DNA construct and synthetic liver-specific promoter to the nucleus of liver cells.
The therapy is being developed by Sangamo Therapeutics, Inc.
In research presented at the 2016 ASH Annual Meeting (abstract 1173), SB-525 induced the expression of human factor VIII in mice and non-human primates (NHPs). SB-525 also corrected the bleeding defect in a mouse model of hemophilia A.
Dosing studies in NHPs demonstrated a robust and reproducible dose response curve, according to researchers. In these animals, mean human factor VIII levels ranged from 5% of normal at the lowest dose to 230% at the highest (AAV doses in the 6 x 1011 – 6 x 1012 vgs/kg range).
The researchers said the peak circulating human factor VIII levels in these experiments exceeded levels previously reported in NHPs. And this could significantly reduce the dose required to achieve therapeutically relevant levels in human subjects.
Sangamo is planning to open a phase 1/2 trial of SB-525 in adults with hemophilia A by the end of the second quarter of 2017. Data from this study are expected in late 2017 or early 2018.
In addition to the fast track designation, SB-525 has orphan drug designation from the FDA.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologic license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
Asthma step-up therapy in children improves outcomes
SAN FRANCISCO – Stepping up pharmacotherapy in children with poorly controlled asthma resulted in fewer asthma-related emergency department (ED) visits and inpatient stays than maintaining current medication therapy, a study found.
Perhaps surprisingly, however, the patients with the worst outcomes were those who were told only to improve their medication adherence, said Dane Snyder, MD, a physician at Nationwide Children’s Hospital who is also in the department of pediatrics at Ohio State University, Columbus.
Asthma affects nearly 1 in 10 children, and national guidelines recommend step-up asthma pharmacotherapy in patients with poorly controlled asthma. The researchers assessed the impact of step-up therapy on inpatient care, and emergency and urgent care visits for children with poor asthma control in the Nationwide Children’s Hospital Primary Care Network in Columbus, Ohio. More than 10,000 asthma patients are treated at the 12 clinics in the network, and the study was part of a quality improvement initiative starting in July 2015.
Between August and October 2015, researchers used documentation in a standard asthma note to identify 908 patients aged 2-18 years who had poor asthma control based on their Asthma Control Test (ACT) score and history. Of these patients, 463 with a mean ACT score of 15.8 were assigned to step-up pharmacotherapy, while 445 with a mean ACT of 16.2 were not. The two groups also were similar in their use of unscheduled health care utilization in the 12 months before the study period.
Over the next 12 months, 1.3% of patients receiving step-up therapy had inpatient stays, compared with 4% in the other group, translating to a 68% lower risk of admission with step-up therapy (relative risk, 0.316; P = .01). Those receiving step-up therapy also were 37% less likely to visit the ED for asthma, with 7.1% of ED visits for those with step-up therapy and 11.2% of visits for those without it (RR, 0.634; P = .032). Visits to urgent care, however, showed no significant difference between those receiving step-up therapy (10.8%) and those who had not (10.3%).
After comparing these findings, the researchers went back and manually reviewed all 463 charts of the group who received step-up therapy to determine whether the children actually did receive a step up in therapy. Nearly a quarter (23%) of the children in the intervention group simply resumed taking their previously prescribed mediation, and 8% took allergy medication. The remaining 69% had step-up therapy.
The researchers then reanalyzed the data among those who truly had step-up pharmacotherapy, those who did not, and those who resumed taking their prior medication. The difference in inpatient admissions remained the same because none of the children who had resumed medication were admitted.
ED visits showed a more gradual distribution: 7.3% of those receiving step-up therapy, 8.4% of those who resumed taking their medication, and 11% of those with no intervention went to the ED. But these differences did not reach statistical significance.
Similarly, the differences among the three groups in urgent care visits was not statistically significant, but 15% of those who resumed taking prior medication had urgent care visits, compared with 10.3% of those with step-up therapy and 9.2% of those in the control group.
Those findings suggest that “stepping up pharmacotherapy, even in the face of controller nonadherence, can improve outcomes,” Dr. Snyder told his colleagues.
“While challenging, management changes in a large primary care network are possible,” Dr. Snyder said. He also emphasized that manually auditing bulk data, as they did with the 463 records, can be important in assessing outcomes of quality improvement measures.
The research did not use external funding, and Dr. Snyder had no disclosures.
SAN FRANCISCO – Stepping up pharmacotherapy in children with poorly controlled asthma resulted in fewer asthma-related emergency department (ED) visits and inpatient stays than maintaining current medication therapy, a study found.
Perhaps surprisingly, however, the patients with the worst outcomes were those who were told only to improve their medication adherence, said Dane Snyder, MD, a physician at Nationwide Children’s Hospital who is also in the department of pediatrics at Ohio State University, Columbus.
Asthma affects nearly 1 in 10 children, and national guidelines recommend step-up asthma pharmacotherapy in patients with poorly controlled asthma. The researchers assessed the impact of step-up therapy on inpatient care, and emergency and urgent care visits for children with poor asthma control in the Nationwide Children’s Hospital Primary Care Network in Columbus, Ohio. More than 10,000 asthma patients are treated at the 12 clinics in the network, and the study was part of a quality improvement initiative starting in July 2015.
Between August and October 2015, researchers used documentation in a standard asthma note to identify 908 patients aged 2-18 years who had poor asthma control based on their Asthma Control Test (ACT) score and history. Of these patients, 463 with a mean ACT score of 15.8 were assigned to step-up pharmacotherapy, while 445 with a mean ACT of 16.2 were not. The two groups also were similar in their use of unscheduled health care utilization in the 12 months before the study period.
Over the next 12 months, 1.3% of patients receiving step-up therapy had inpatient stays, compared with 4% in the other group, translating to a 68% lower risk of admission with step-up therapy (relative risk, 0.316; P = .01). Those receiving step-up therapy also were 37% less likely to visit the ED for asthma, with 7.1% of ED visits for those with step-up therapy and 11.2% of visits for those without it (RR, 0.634; P = .032). Visits to urgent care, however, showed no significant difference between those receiving step-up therapy (10.8%) and those who had not (10.3%).
After comparing these findings, the researchers went back and manually reviewed all 463 charts of the group who received step-up therapy to determine whether the children actually did receive a step up in therapy. Nearly a quarter (23%) of the children in the intervention group simply resumed taking their previously prescribed mediation, and 8% took allergy medication. The remaining 69% had step-up therapy.
The researchers then reanalyzed the data among those who truly had step-up pharmacotherapy, those who did not, and those who resumed taking their prior medication. The difference in inpatient admissions remained the same because none of the children who had resumed medication were admitted.
ED visits showed a more gradual distribution: 7.3% of those receiving step-up therapy, 8.4% of those who resumed taking their medication, and 11% of those with no intervention went to the ED. But these differences did not reach statistical significance.
Similarly, the differences among the three groups in urgent care visits was not statistically significant, but 15% of those who resumed taking prior medication had urgent care visits, compared with 10.3% of those with step-up therapy and 9.2% of those in the control group.
Those findings suggest that “stepping up pharmacotherapy, even in the face of controller nonadherence, can improve outcomes,” Dr. Snyder told his colleagues.
“While challenging, management changes in a large primary care network are possible,” Dr. Snyder said. He also emphasized that manually auditing bulk data, as they did with the 463 records, can be important in assessing outcomes of quality improvement measures.
The research did not use external funding, and Dr. Snyder had no disclosures.
SAN FRANCISCO – Stepping up pharmacotherapy in children with poorly controlled asthma resulted in fewer asthma-related emergency department (ED) visits and inpatient stays than maintaining current medication therapy, a study found.
Perhaps surprisingly, however, the patients with the worst outcomes were those who were told only to improve their medication adherence, said Dane Snyder, MD, a physician at Nationwide Children’s Hospital who is also in the department of pediatrics at Ohio State University, Columbus.
Asthma affects nearly 1 in 10 children, and national guidelines recommend step-up asthma pharmacotherapy in patients with poorly controlled asthma. The researchers assessed the impact of step-up therapy on inpatient care, and emergency and urgent care visits for children with poor asthma control in the Nationwide Children’s Hospital Primary Care Network in Columbus, Ohio. More than 10,000 asthma patients are treated at the 12 clinics in the network, and the study was part of a quality improvement initiative starting in July 2015.
Between August and October 2015, researchers used documentation in a standard asthma note to identify 908 patients aged 2-18 years who had poor asthma control based on their Asthma Control Test (ACT) score and history. Of these patients, 463 with a mean ACT score of 15.8 were assigned to step-up pharmacotherapy, while 445 with a mean ACT of 16.2 were not. The two groups also were similar in their use of unscheduled health care utilization in the 12 months before the study period.
Over the next 12 months, 1.3% of patients receiving step-up therapy had inpatient stays, compared with 4% in the other group, translating to a 68% lower risk of admission with step-up therapy (relative risk, 0.316; P = .01). Those receiving step-up therapy also were 37% less likely to visit the ED for asthma, with 7.1% of ED visits for those with step-up therapy and 11.2% of visits for those without it (RR, 0.634; P = .032). Visits to urgent care, however, showed no significant difference between those receiving step-up therapy (10.8%) and those who had not (10.3%).
After comparing these findings, the researchers went back and manually reviewed all 463 charts of the group who received step-up therapy to determine whether the children actually did receive a step up in therapy. Nearly a quarter (23%) of the children in the intervention group simply resumed taking their previously prescribed mediation, and 8% took allergy medication. The remaining 69% had step-up therapy.
The researchers then reanalyzed the data among those who truly had step-up pharmacotherapy, those who did not, and those who resumed taking their prior medication. The difference in inpatient admissions remained the same because none of the children who had resumed medication were admitted.
ED visits showed a more gradual distribution: 7.3% of those receiving step-up therapy, 8.4% of those who resumed taking their medication, and 11% of those with no intervention went to the ED. But these differences did not reach statistical significance.
Similarly, the differences among the three groups in urgent care visits was not statistically significant, but 15% of those who resumed taking prior medication had urgent care visits, compared with 10.3% of those with step-up therapy and 9.2% of those in the control group.
Those findings suggest that “stepping up pharmacotherapy, even in the face of controller nonadherence, can improve outcomes,” Dr. Snyder told his colleagues.
“While challenging, management changes in a large primary care network are possible,” Dr. Snyder said. He also emphasized that manually auditing bulk data, as they did with the 463 records, can be important in assessing outcomes of quality improvement measures.
The research did not use external funding, and Dr. Snyder had no disclosures.
AT PAS 2017
Key clinical point:
Major finding: Children with poorly controlled asthma receiving step-up pharmacotherapy had a 68% lower risk of inpatient admission and 37% lower risk of emergency department visits for asthma (P less than .05).
Data source: The findings are based on a nonrandomized trial of 903 children, aged 2-18 years, tracked for 12 months in the Nationwide Children’s Hospital Primary Care Network in Columbus, Ohio.
Disclosures: The research did not use external funding, and Dr. Snyder had no disclosures.
Double the dose of antihypertensive meds?
A 50-year-old man returns for follow-up of hypertension. He is currently taking 20 mg of lisinopril. His blood pressure readings over the past month are 150/96, 155/98, 160/94, and 162/96. His renal function is normal, and he has been taking his lisinopril regularly.
What do you recommend?
A. Increase his lisinopril to 20 mg twice a day.
B. Switch to valsartan.
C. Add amlodipine.
But is there much benefit in doubling the dose of antihypertensive medications?
H.J. Gomez and colleagues studied the dose response of lisinopril in essential hypertension.2 Patients received very-low-dose (1.25 mg or 5 mg), moderate-dose (20 mg), or high-dose (80 mg) lisinopril. The difference in blood pressure reduction between 20 mg and 80 mg was modest (5 mm/3 mm less in those receiving 80 mg, compared with 20 mg). There was no clinical effect at 1.25 mg of lisinopril, but a relatively flat dose response above 20 mg.
A similar finding was reported by J.R. Benz and colleagues in regard to escalating doses of valsartan.3 The study looked at blood pressure in response to valsartan at doses of 80 mg and 160 mg, and in combination with hydrochlorothiazide. The difference in blood pressure between valsartan 160 mg and 80 mg was 3 mm/0.8 mm. The difference in blood pressure between patients taking 80 mg of valsartan and 25 mg hydrochlorothiazide, compared with those taking 80 mg of valsartan, was 12/6.
In a meta-analysis of 354 randomized trials of fixed-dose blood pressure medications, M.R. Law and colleagues found that cutting the doses in half only reduced effectiveness of lowering BP by 20%.4 The average reduction in systolic BP was 9.1 mm Hg, and reduction in diastolic BP was 5.5mm Hg – which only was reduced to 7.1 mm Hg/4.4 mm Hg when the doses of medications were cut in half. Side effects attributed to beta-blockers, calcium channel blockers, and diuretics were very dose related, whereas the side effects attributed to ACE inhibitors were not.
In another meta-analysis comparing monotherapy vs. combination therapy for lowering blood pressure, adding another drug lowered blood pressure fivefold more than doubling the dose of the initial antihypertensive drug.5
I think the right answer in this case would be to add amlodipine instead of doubling the dose of lisinopril or switching to valsartan as a single agent. The data are striking on how little effect there is in increasing antihypertensive medication doses. Adding another antihypertensive medication should be the standard practice when the first medication started does not achieve the desired goal.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].
References
1. JAMA. 2003 May 21;289(19):2560-72.
2. Br J Clin Pharm. 1989;28:415-20.
3. J Hum Hypertens. 1998 Dec;12(12):861-6.
4. BMJ. 2003 Jun 28;326(7404):1427.
5. Am J Med. 2009 Mar;122(3):290-300.
A 50-year-old man returns for follow-up of hypertension. He is currently taking 20 mg of lisinopril. His blood pressure readings over the past month are 150/96, 155/98, 160/94, and 162/96. His renal function is normal, and he has been taking his lisinopril regularly.
What do you recommend?
A. Increase his lisinopril to 20 mg twice a day.
B. Switch to valsartan.
C. Add amlodipine.
But is there much benefit in doubling the dose of antihypertensive medications?
H.J. Gomez and colleagues studied the dose response of lisinopril in essential hypertension.2 Patients received very-low-dose (1.25 mg or 5 mg), moderate-dose (20 mg), or high-dose (80 mg) lisinopril. The difference in blood pressure reduction between 20 mg and 80 mg was modest (5 mm/3 mm less in those receiving 80 mg, compared with 20 mg). There was no clinical effect at 1.25 mg of lisinopril, but a relatively flat dose response above 20 mg.
A similar finding was reported by J.R. Benz and colleagues in regard to escalating doses of valsartan.3 The study looked at blood pressure in response to valsartan at doses of 80 mg and 160 mg, and in combination with hydrochlorothiazide. The difference in blood pressure between valsartan 160 mg and 80 mg was 3 mm/0.8 mm. The difference in blood pressure between patients taking 80 mg of valsartan and 25 mg hydrochlorothiazide, compared with those taking 80 mg of valsartan, was 12/6.
In a meta-analysis of 354 randomized trials of fixed-dose blood pressure medications, M.R. Law and colleagues found that cutting the doses in half only reduced effectiveness of lowering BP by 20%.4 The average reduction in systolic BP was 9.1 mm Hg, and reduction in diastolic BP was 5.5mm Hg – which only was reduced to 7.1 mm Hg/4.4 mm Hg when the doses of medications were cut in half. Side effects attributed to beta-blockers, calcium channel blockers, and diuretics were very dose related, whereas the side effects attributed to ACE inhibitors were not.
In another meta-analysis comparing monotherapy vs. combination therapy for lowering blood pressure, adding another drug lowered blood pressure fivefold more than doubling the dose of the initial antihypertensive drug.5
I think the right answer in this case would be to add amlodipine instead of doubling the dose of lisinopril or switching to valsartan as a single agent. The data are striking on how little effect there is in increasing antihypertensive medication doses. Adding another antihypertensive medication should be the standard practice when the first medication started does not achieve the desired goal.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].
References
1. JAMA. 2003 May 21;289(19):2560-72.
2. Br J Clin Pharm. 1989;28:415-20.
3. J Hum Hypertens. 1998 Dec;12(12):861-6.
4. BMJ. 2003 Jun 28;326(7404):1427.
5. Am J Med. 2009 Mar;122(3):290-300.
A 50-year-old man returns for follow-up of hypertension. He is currently taking 20 mg of lisinopril. His blood pressure readings over the past month are 150/96, 155/98, 160/94, and 162/96. His renal function is normal, and he has been taking his lisinopril regularly.
What do you recommend?
A. Increase his lisinopril to 20 mg twice a day.
B. Switch to valsartan.
C. Add amlodipine.
But is there much benefit in doubling the dose of antihypertensive medications?
H.J. Gomez and colleagues studied the dose response of lisinopril in essential hypertension.2 Patients received very-low-dose (1.25 mg or 5 mg), moderate-dose (20 mg), or high-dose (80 mg) lisinopril. The difference in blood pressure reduction between 20 mg and 80 mg was modest (5 mm/3 mm less in those receiving 80 mg, compared with 20 mg). There was no clinical effect at 1.25 mg of lisinopril, but a relatively flat dose response above 20 mg.
A similar finding was reported by J.R. Benz and colleagues in regard to escalating doses of valsartan.3 The study looked at blood pressure in response to valsartan at doses of 80 mg and 160 mg, and in combination with hydrochlorothiazide. The difference in blood pressure between valsartan 160 mg and 80 mg was 3 mm/0.8 mm. The difference in blood pressure between patients taking 80 mg of valsartan and 25 mg hydrochlorothiazide, compared with those taking 80 mg of valsartan, was 12/6.
In a meta-analysis of 354 randomized trials of fixed-dose blood pressure medications, M.R. Law and colleagues found that cutting the doses in half only reduced effectiveness of lowering BP by 20%.4 The average reduction in systolic BP was 9.1 mm Hg, and reduction in diastolic BP was 5.5mm Hg – which only was reduced to 7.1 mm Hg/4.4 mm Hg when the doses of medications were cut in half. Side effects attributed to beta-blockers, calcium channel blockers, and diuretics were very dose related, whereas the side effects attributed to ACE inhibitors were not.
In another meta-analysis comparing monotherapy vs. combination therapy for lowering blood pressure, adding another drug lowered blood pressure fivefold more than doubling the dose of the initial antihypertensive drug.5
I think the right answer in this case would be to add amlodipine instead of doubling the dose of lisinopril or switching to valsartan as a single agent. The data are striking on how little effect there is in increasing antihypertensive medication doses. Adding another antihypertensive medication should be the standard practice when the first medication started does not achieve the desired goal.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].
References
1. JAMA. 2003 May 21;289(19):2560-72.
2. Br J Clin Pharm. 1989;28:415-20.
3. J Hum Hypertens. 1998 Dec;12(12):861-6.
4. BMJ. 2003 Jun 28;326(7404):1427.
5. Am J Med. 2009 Mar;122(3):290-300.
JAK-1 inhibitor upadacitinib advances to phase III for refractory Crohn’s
CHICAGO – An investigational inhibitor of the Janus-1 kinase receptor induced clinical and endoscopic remission at several doses in patients with long-standing, treatment-resistant Crohn’s disease.
The two highest doses of upadacitinib (ABT-494; AbbVie) also allowed about 30% of patients to rapidly withdraw systemic steroids and stay in remission during the 16-week dose-finding induction trial, William J. Sandborn, MD, said at the annual Digestive Disease Week®.
“This rapid steroid tapering was a unique feature of the trial,” said Dr. Sandborn of the University of California, San Diego. “Usually during induction trials, steroids are held fixed at 20 mg-30 mg throughout the trial and then withdrawn to maintenance levels.”
The preplanned analysis used a unique composite outcome of 7-day stool frequency and abdominal pain. At the time of trial design, the scale had only been validated in patients with mild-moderate Crohn’s, so the investigators used the validated stool frequency cutpoint of 1.5 per day as a measure of clinical remission.
That was not an appropriate target for this unique study group, Dr. Sandborn said.
“CELEST was the most refractory patient population ever recruited into a Crohn’s disease clinical trial. If we could do this over now, we would use a cutpoint of less than 3 instead of 1.5 or less. This is a really tough clinical endpoint” that probably isn’t a realistic clinical goal for patients in this category. “There’s no way we would do it this way today. A number of studies since then now suggest that the right cutpoint for remission in these patients would be about 3 per day.”
CELEST enrolled 220 patients who were randomized to five treatment arms comprising 30-35 patients each: placebo; twice daily upadacitinib at 3 mg, 6 mg, 12 mg, and 24 mg (24 mg BID); and 24 mg once daily (24 mg OD). The study lasted 16 weeks and was followed by 36 weeks of blinded extension treatment. Dr. Sandborn reported the 16-week induction phase data.
The patients had moderate to severe Crohn’s disease, with a mean baseline Crohn’s Disease Activity Index (CDAI) score of about 300 and a Simple Endoscopic Score-Crohns disease (SES-CD) of about 15. About 95% had already failed at least one anti–tumor necrosis factor (TNF) drug. Half had failed at least two.
The coprimary endpoints were the proportion of patients who achieved clinical remission (stool frequency of 1.5 or less per day and abdominal pain of 1 or lower) at week 16 and endoscopic remission at weeks 12 or 16. Secondary endpoints included CDAI response, clinical response (at least a 30% reduction from baseline in stool frequency or abdominal pain), and endoscopic response.
In the primary analysis, the rate of endoscopic remission was significant (P less than .05) in both the 24-mg BID and the 24-mg OD groups. However, clinical remission with the original stool frequency cutpoint of 1.5/day or less wasn’t significantly different from placebo in any group. Dr. Sandborn did point out a 27% rate of clinical remission in those taking 12 mg, which had a P value of less than 0.1, relative to placebo.
Among the secondary endpoints, remission as measured by the CDAI score (less than 150) occurred in 39% of those taking 12 mg – the only significant response in that category.
The rate of endoscopic response (at least a 50% improvement in endoscopic findings) was 21% in the 6-mg group and 25% in the 24-mg OD group (P less than 0.05) and in about 30% of the 12-mg and 24-mg BID group (P less than 0.01).
When the clinical remission analysis employed the revised stool frequency cutpoint of less than 2.8/day, clinical remission rates improved somewhat. Almost 40% of those taking 24-mg BID achieved clinical remission (P less than 0.01), and 30% of those taking 6 mg achieved clinical remission, but the significance was marginal (P less than 0.1).
Steroid-free remission rates were significantly better than placebo in the 18-mg group (39%) and the 15-mg group (33%), both with a P value less than 0.05.
Dr. Sandborn also showed dramatic changes in C-reactive protein and fecal calprotectin. These dropped precipitously in all active groups by week 2, in a dose-respondent manner, and stayed well-suppressed in the two highest-dose groups. In the placebo groups, C-reactive protein rose over the 16 weeks, and fecal calprotectin remained unchanged from baseline.
The drug was reasonably well-tolerated and safe. About 80% of each dosing group reported at least one adverse event. The 12-mg dose appeared particularly troublesome, with 25% stopping because of an adverse event. By comparison, the discontinuation rate was 8% in the 24-mg BID group and 14% in the 24-mg OD group.
Serious adverse events were consistent with what is known about the JAK1-inhibitor safety profile, Dr. Sandborn said. There were nine serious infections, including Escherichia coli bacteremia, subcutaneous abscess, and sepsis (3-mg group); anorectal abscess, urinary tract infection, and sepsis (12-mg group); sepsis (24 mg BID); and peritonitis and sepsis (24 mg QD). There was one nonmelanoma skin cancer, which Dr. Sandborn said was probably pre-existing but not recognized at baseline. Three cases of herpes zoster occurred, all in the 24-mg BID group.
One patient experienced a gastrointestinal perforation, which sometimes occurs in Crohn’s disease. Two patients experienced a myocardial infarction, a number “too small to understand fully,” Dr. Sandborn said.
The drug will move forward into phase III trials, but the final dose hasn’t been decided on.
Dr. Sandborn has received consulting fees from AbbVie, which is developing the drug and sponsored CELEST.
[email protected]
On Twitter @alz_gal
CHICAGO – An investigational inhibitor of the Janus-1 kinase receptor induced clinical and endoscopic remission at several doses in patients with long-standing, treatment-resistant Crohn’s disease.
The two highest doses of upadacitinib (ABT-494; AbbVie) also allowed about 30% of patients to rapidly withdraw systemic steroids and stay in remission during the 16-week dose-finding induction trial, William J. Sandborn, MD, said at the annual Digestive Disease Week®.
“This rapid steroid tapering was a unique feature of the trial,” said Dr. Sandborn of the University of California, San Diego. “Usually during induction trials, steroids are held fixed at 20 mg-30 mg throughout the trial and then withdrawn to maintenance levels.”
The preplanned analysis used a unique composite outcome of 7-day stool frequency and abdominal pain. At the time of trial design, the scale had only been validated in patients with mild-moderate Crohn’s, so the investigators used the validated stool frequency cutpoint of 1.5 per day as a measure of clinical remission.
That was not an appropriate target for this unique study group, Dr. Sandborn said.
“CELEST was the most refractory patient population ever recruited into a Crohn’s disease clinical trial. If we could do this over now, we would use a cutpoint of less than 3 instead of 1.5 or less. This is a really tough clinical endpoint” that probably isn’t a realistic clinical goal for patients in this category. “There’s no way we would do it this way today. A number of studies since then now suggest that the right cutpoint for remission in these patients would be about 3 per day.”
CELEST enrolled 220 patients who were randomized to five treatment arms comprising 30-35 patients each: placebo; twice daily upadacitinib at 3 mg, 6 mg, 12 mg, and 24 mg (24 mg BID); and 24 mg once daily (24 mg OD). The study lasted 16 weeks and was followed by 36 weeks of blinded extension treatment. Dr. Sandborn reported the 16-week induction phase data.
The patients had moderate to severe Crohn’s disease, with a mean baseline Crohn’s Disease Activity Index (CDAI) score of about 300 and a Simple Endoscopic Score-Crohns disease (SES-CD) of about 15. About 95% had already failed at least one anti–tumor necrosis factor (TNF) drug. Half had failed at least two.
The coprimary endpoints were the proportion of patients who achieved clinical remission (stool frequency of 1.5 or less per day and abdominal pain of 1 or lower) at week 16 and endoscopic remission at weeks 12 or 16. Secondary endpoints included CDAI response, clinical response (at least a 30% reduction from baseline in stool frequency or abdominal pain), and endoscopic response.
In the primary analysis, the rate of endoscopic remission was significant (P less than .05) in both the 24-mg BID and the 24-mg OD groups. However, clinical remission with the original stool frequency cutpoint of 1.5/day or less wasn’t significantly different from placebo in any group. Dr. Sandborn did point out a 27% rate of clinical remission in those taking 12 mg, which had a P value of less than 0.1, relative to placebo.
Among the secondary endpoints, remission as measured by the CDAI score (less than 150) occurred in 39% of those taking 12 mg – the only significant response in that category.
The rate of endoscopic response (at least a 50% improvement in endoscopic findings) was 21% in the 6-mg group and 25% in the 24-mg OD group (P less than 0.05) and in about 30% of the 12-mg and 24-mg BID group (P less than 0.01).
When the clinical remission analysis employed the revised stool frequency cutpoint of less than 2.8/day, clinical remission rates improved somewhat. Almost 40% of those taking 24-mg BID achieved clinical remission (P less than 0.01), and 30% of those taking 6 mg achieved clinical remission, but the significance was marginal (P less than 0.1).
Steroid-free remission rates were significantly better than placebo in the 18-mg group (39%) and the 15-mg group (33%), both with a P value less than 0.05.
Dr. Sandborn also showed dramatic changes in C-reactive protein and fecal calprotectin. These dropped precipitously in all active groups by week 2, in a dose-respondent manner, and stayed well-suppressed in the two highest-dose groups. In the placebo groups, C-reactive protein rose over the 16 weeks, and fecal calprotectin remained unchanged from baseline.
The drug was reasonably well-tolerated and safe. About 80% of each dosing group reported at least one adverse event. The 12-mg dose appeared particularly troublesome, with 25% stopping because of an adverse event. By comparison, the discontinuation rate was 8% in the 24-mg BID group and 14% in the 24-mg OD group.
Serious adverse events were consistent with what is known about the JAK1-inhibitor safety profile, Dr. Sandborn said. There were nine serious infections, including Escherichia coli bacteremia, subcutaneous abscess, and sepsis (3-mg group); anorectal abscess, urinary tract infection, and sepsis (12-mg group); sepsis (24 mg BID); and peritonitis and sepsis (24 mg QD). There was one nonmelanoma skin cancer, which Dr. Sandborn said was probably pre-existing but not recognized at baseline. Three cases of herpes zoster occurred, all in the 24-mg BID group.
One patient experienced a gastrointestinal perforation, which sometimes occurs in Crohn’s disease. Two patients experienced a myocardial infarction, a number “too small to understand fully,” Dr. Sandborn said.
The drug will move forward into phase III trials, but the final dose hasn’t been decided on.
Dr. Sandborn has received consulting fees from AbbVie, which is developing the drug and sponsored CELEST.
[email protected]
On Twitter @alz_gal
CHICAGO – An investigational inhibitor of the Janus-1 kinase receptor induced clinical and endoscopic remission at several doses in patients with long-standing, treatment-resistant Crohn’s disease.
The two highest doses of upadacitinib (ABT-494; AbbVie) also allowed about 30% of patients to rapidly withdraw systemic steroids and stay in remission during the 16-week dose-finding induction trial, William J. Sandborn, MD, said at the annual Digestive Disease Week®.
“This rapid steroid tapering was a unique feature of the trial,” said Dr. Sandborn of the University of California, San Diego. “Usually during induction trials, steroids are held fixed at 20 mg-30 mg throughout the trial and then withdrawn to maintenance levels.”
The preplanned analysis used a unique composite outcome of 7-day stool frequency and abdominal pain. At the time of trial design, the scale had only been validated in patients with mild-moderate Crohn’s, so the investigators used the validated stool frequency cutpoint of 1.5 per day as a measure of clinical remission.
That was not an appropriate target for this unique study group, Dr. Sandborn said.
“CELEST was the most refractory patient population ever recruited into a Crohn’s disease clinical trial. If we could do this over now, we would use a cutpoint of less than 3 instead of 1.5 or less. This is a really tough clinical endpoint” that probably isn’t a realistic clinical goal for patients in this category. “There’s no way we would do it this way today. A number of studies since then now suggest that the right cutpoint for remission in these patients would be about 3 per day.”
CELEST enrolled 220 patients who were randomized to five treatment arms comprising 30-35 patients each: placebo; twice daily upadacitinib at 3 mg, 6 mg, 12 mg, and 24 mg (24 mg BID); and 24 mg once daily (24 mg OD). The study lasted 16 weeks and was followed by 36 weeks of blinded extension treatment. Dr. Sandborn reported the 16-week induction phase data.
The patients had moderate to severe Crohn’s disease, with a mean baseline Crohn’s Disease Activity Index (CDAI) score of about 300 and a Simple Endoscopic Score-Crohns disease (SES-CD) of about 15. About 95% had already failed at least one anti–tumor necrosis factor (TNF) drug. Half had failed at least two.
The coprimary endpoints were the proportion of patients who achieved clinical remission (stool frequency of 1.5 or less per day and abdominal pain of 1 or lower) at week 16 and endoscopic remission at weeks 12 or 16. Secondary endpoints included CDAI response, clinical response (at least a 30% reduction from baseline in stool frequency or abdominal pain), and endoscopic response.
In the primary analysis, the rate of endoscopic remission was significant (P less than .05) in both the 24-mg BID and the 24-mg OD groups. However, clinical remission with the original stool frequency cutpoint of 1.5/day or less wasn’t significantly different from placebo in any group. Dr. Sandborn did point out a 27% rate of clinical remission in those taking 12 mg, which had a P value of less than 0.1, relative to placebo.
Among the secondary endpoints, remission as measured by the CDAI score (less than 150) occurred in 39% of those taking 12 mg – the only significant response in that category.
The rate of endoscopic response (at least a 50% improvement in endoscopic findings) was 21% in the 6-mg group and 25% in the 24-mg OD group (P less than 0.05) and in about 30% of the 12-mg and 24-mg BID group (P less than 0.01).
When the clinical remission analysis employed the revised stool frequency cutpoint of less than 2.8/day, clinical remission rates improved somewhat. Almost 40% of those taking 24-mg BID achieved clinical remission (P less than 0.01), and 30% of those taking 6 mg achieved clinical remission, but the significance was marginal (P less than 0.1).
Steroid-free remission rates were significantly better than placebo in the 18-mg group (39%) and the 15-mg group (33%), both with a P value less than 0.05.
Dr. Sandborn also showed dramatic changes in C-reactive protein and fecal calprotectin. These dropped precipitously in all active groups by week 2, in a dose-respondent manner, and stayed well-suppressed in the two highest-dose groups. In the placebo groups, C-reactive protein rose over the 16 weeks, and fecal calprotectin remained unchanged from baseline.
The drug was reasonably well-tolerated and safe. About 80% of each dosing group reported at least one adverse event. The 12-mg dose appeared particularly troublesome, with 25% stopping because of an adverse event. By comparison, the discontinuation rate was 8% in the 24-mg BID group and 14% in the 24-mg OD group.
Serious adverse events were consistent with what is known about the JAK1-inhibitor safety profile, Dr. Sandborn said. There were nine serious infections, including Escherichia coli bacteremia, subcutaneous abscess, and sepsis (3-mg group); anorectal abscess, urinary tract infection, and sepsis (12-mg group); sepsis (24 mg BID); and peritonitis and sepsis (24 mg QD). There was one nonmelanoma skin cancer, which Dr. Sandborn said was probably pre-existing but not recognized at baseline. Three cases of herpes zoster occurred, all in the 24-mg BID group.
One patient experienced a gastrointestinal perforation, which sometimes occurs in Crohn’s disease. Two patients experienced a myocardial infarction, a number “too small to understand fully,” Dr. Sandborn said.
The drug will move forward into phase III trials, but the final dose hasn’t been decided on.
Dr. Sandborn has received consulting fees from AbbVie, which is developing the drug and sponsored CELEST.
[email protected]
On Twitter @alz_gal
AT DDW
Key clinical point:
Major finding: Several doses achieved statistically significant effects in endoscopic and clinical response. About 30% of patients taking a higher dose achieved steroid-free remission.
Data source: The phase II dose-ranging study comprised 220 patients.
Disclosures: AbbVie is developing the drug and sponsored the study. Dr. Sandborn is a consultant for the company.
Debunking Acne Myths: Should Patients With Oily Skin Use a Moisturizer?
Myth: Moisturizers Make Acne Worse in Patients With Oily Skin
Excessive sebum production can lead to oily skin that appears greasy and shiny, which contributes to the development of acne on the face. Acne patients with oily skin may be deterred from using moisturizers out of fear that their condition will worsen, yet therapeutic moisturizers have been shown to maintain hydration and overall integrity of the stratum corneum.
In a study of patient experiences with oily skin, 68% (n=37) of participants said their skin felt unclean, dirty, or grimy. Some participants noted a feeling of having clogged pores or an additional layer of skin, and others reported that their skin felt oily or greasy to the touch. The study also reported that participants with oily skin felt self-conscious, which impacted their daily life. These domains also are affected by having acne.
In the same study, 18% (n=10) of participants reported washing their face 6 to 15 times per day, 50% (n=27) washed their face 3 to 5 times per day, and 42% (n=23) washed their face 1 to 2 times per day. Instead of applying heavy moisturizers, acne patients with oily skin may feel the need to constantly wash their face. Gentle face washing is recommended to help improve and prevent acne, but patients who wash their face excessively are at risk for skin barrier impairment and development of dry skin.
Acne patients can use noncomedogenic moisturizers to prevent and alleviate skin irritation and soothe the skin by slowing the evaporation of water. Many moisturizers on the market claim to be suitable for acne treatment and may independently contribute to improving the signs and symptoms of acne. It is important for dermatologists to direct patients with oily skin to oil-free moisturizers containing ingredients such as dimethicone, which is known to reduce transepidermal water loss without a greasy feel and contains both occlusive and emollient properties. Dimethicone is suitable for use in patients with acne and sensitive skin and is noncomedogenic and hypoallergenic. Many oil-free moisturizers also contain certain metals and botanical extracts, such as aloe vera and witch hazel, that are known to have anti-inflammatory and skin-soothing properties. Some liquid face cleansers also moisturize, which may be all that is needed in patients with oily skin.
It also is important to inform patients with oily skin that common acne treatments such as benzoyl peroxide, retinoids, salicylic acid, and oral isotretinoin commonly cause dry skin or irritation, leading to barrier disruption in the stratum corneum and subsequently causing increased transepidermal water loss and inflammation. Concomitant use of noncomedogenic moisturizers can enhance treatment efficacy, alleviate dryness, and improve skin comfort in acne patients who are taking these medications.
Expert Commentary
An often forgotten element of acne vulgaris is that it is in fact a disease of barrier dysfunction and disruption. As mentioned above, many of the medications used to treat this chronic inflammatory disease are either directly cytotoxic to keratinocytes (benzoyl peroxide) or alter the thickness and composition of the stratum corneum (retinoids), impairing its protective functions. The inflammatory cascade associated with acne itself can impair the barrier, synergizing with the array of aforementioned medications. Both etiological factors disrupt an often overlooked yet crucial component of the skin barrier, the cutaneous microbiota. The altered landscape, or petri dish if you will, unhinges the balance between the >500 species of organisms living in harmony on the skin, decreasing bacterial diversity and facilitating the overgrowth of specific organisms, here specifically certain types of Propionibacterium acnes, which contribute to the ongoing inflammatory cascade. If that's not enough, sebum, which is certainly in excess in acne, contributes very little to barrier function and skin hydration but can be used to cause a different form of disruption by P acnes, which when converted into short-chain fatty acids can impair cutaneous immune tolerance ultimately creating, you guessed it, more inflammation (thank Dr. Rich Gallo for tying this all together). All in all, the barrier is a mess, highlighting the need for barrier repair with a moisturizer to restore the "balance" on every level: Repair and replace the stratum corneum, restore the tools for the right bacteria to grow (water, carbs, lipids, etc). Moisturizers are a must in acne!
—Adam Friedman, MD (Washington, DC)
Arbuckle R, Atkinson MJ, Clark M, et al. Patient experiences with oily skin: the qualitative development of content for two new patient reported outcome questionnaires [published online October 16, 2008]. Health Qual Life Outcomes. 2008;6:80.
Bikowski J. The use of therapeutic moisturizers in various dermatologic disorders. Cutis. 2001;68(suppl 5):3-11.
Chularojanamontri L, Tuchinda P, Kulthanan K, et al. Moisturizers for acne: what are their constituents? J Clin Aesthet Dermatol. 2014;7:36-44.
Goodman G. Cleansing and moisturizing in acne patients. Am J Clin Dermatol. 2009;10(suppl 1):1-6.
Isoda K, Seki T, Inoue Y, et al. Efficacy of the combined use of a facial cleanser and moisturizers for the care of mild acne patients with sensitive skin [published online December 6, 2014]. J Dermatol. 2015;42:181-188.
Myth: Moisturizers Make Acne Worse in Patients With Oily Skin
Excessive sebum production can lead to oily skin that appears greasy and shiny, which contributes to the development of acne on the face. Acne patients with oily skin may be deterred from using moisturizers out of fear that their condition will worsen, yet therapeutic moisturizers have been shown to maintain hydration and overall integrity of the stratum corneum.
In a study of patient experiences with oily skin, 68% (n=37) of participants said their skin felt unclean, dirty, or grimy. Some participants noted a feeling of having clogged pores or an additional layer of skin, and others reported that their skin felt oily or greasy to the touch. The study also reported that participants with oily skin felt self-conscious, which impacted their daily life. These domains also are affected by having acne.
In the same study, 18% (n=10) of participants reported washing their face 6 to 15 times per day, 50% (n=27) washed their face 3 to 5 times per day, and 42% (n=23) washed their face 1 to 2 times per day. Instead of applying heavy moisturizers, acne patients with oily skin may feel the need to constantly wash their face. Gentle face washing is recommended to help improve and prevent acne, but patients who wash their face excessively are at risk for skin barrier impairment and development of dry skin.
Acne patients can use noncomedogenic moisturizers to prevent and alleviate skin irritation and soothe the skin by slowing the evaporation of water. Many moisturizers on the market claim to be suitable for acne treatment and may independently contribute to improving the signs and symptoms of acne. It is important for dermatologists to direct patients with oily skin to oil-free moisturizers containing ingredients such as dimethicone, which is known to reduce transepidermal water loss without a greasy feel and contains both occlusive and emollient properties. Dimethicone is suitable for use in patients with acne and sensitive skin and is noncomedogenic and hypoallergenic. Many oil-free moisturizers also contain certain metals and botanical extracts, such as aloe vera and witch hazel, that are known to have anti-inflammatory and skin-soothing properties. Some liquid face cleansers also moisturize, which may be all that is needed in patients with oily skin.
It also is important to inform patients with oily skin that common acne treatments such as benzoyl peroxide, retinoids, salicylic acid, and oral isotretinoin commonly cause dry skin or irritation, leading to barrier disruption in the stratum corneum and subsequently causing increased transepidermal water loss and inflammation. Concomitant use of noncomedogenic moisturizers can enhance treatment efficacy, alleviate dryness, and improve skin comfort in acne patients who are taking these medications.
Expert Commentary
An often forgotten element of acne vulgaris is that it is in fact a disease of barrier dysfunction and disruption. As mentioned above, many of the medications used to treat this chronic inflammatory disease are either directly cytotoxic to keratinocytes (benzoyl peroxide) or alter the thickness and composition of the stratum corneum (retinoids), impairing its protective functions. The inflammatory cascade associated with acne itself can impair the barrier, synergizing with the array of aforementioned medications. Both etiological factors disrupt an often overlooked yet crucial component of the skin barrier, the cutaneous microbiota. The altered landscape, or petri dish if you will, unhinges the balance between the >500 species of organisms living in harmony on the skin, decreasing bacterial diversity and facilitating the overgrowth of specific organisms, here specifically certain types of Propionibacterium acnes, which contribute to the ongoing inflammatory cascade. If that's not enough, sebum, which is certainly in excess in acne, contributes very little to barrier function and skin hydration but can be used to cause a different form of disruption by P acnes, which when converted into short-chain fatty acids can impair cutaneous immune tolerance ultimately creating, you guessed it, more inflammation (thank Dr. Rich Gallo for tying this all together). All in all, the barrier is a mess, highlighting the need for barrier repair with a moisturizer to restore the "balance" on every level: Repair and replace the stratum corneum, restore the tools for the right bacteria to grow (water, carbs, lipids, etc). Moisturizers are a must in acne!
—Adam Friedman, MD (Washington, DC)
Myth: Moisturizers Make Acne Worse in Patients With Oily Skin
Excessive sebum production can lead to oily skin that appears greasy and shiny, which contributes to the development of acne on the face. Acne patients with oily skin may be deterred from using moisturizers out of fear that their condition will worsen, yet therapeutic moisturizers have been shown to maintain hydration and overall integrity of the stratum corneum.
In a study of patient experiences with oily skin, 68% (n=37) of participants said their skin felt unclean, dirty, or grimy. Some participants noted a feeling of having clogged pores or an additional layer of skin, and others reported that their skin felt oily or greasy to the touch. The study also reported that participants with oily skin felt self-conscious, which impacted their daily life. These domains also are affected by having acne.
In the same study, 18% (n=10) of participants reported washing their face 6 to 15 times per day, 50% (n=27) washed their face 3 to 5 times per day, and 42% (n=23) washed their face 1 to 2 times per day. Instead of applying heavy moisturizers, acne patients with oily skin may feel the need to constantly wash their face. Gentle face washing is recommended to help improve and prevent acne, but patients who wash their face excessively are at risk for skin barrier impairment and development of dry skin.
Acne patients can use noncomedogenic moisturizers to prevent and alleviate skin irritation and soothe the skin by slowing the evaporation of water. Many moisturizers on the market claim to be suitable for acne treatment and may independently contribute to improving the signs and symptoms of acne. It is important for dermatologists to direct patients with oily skin to oil-free moisturizers containing ingredients such as dimethicone, which is known to reduce transepidermal water loss without a greasy feel and contains both occlusive and emollient properties. Dimethicone is suitable for use in patients with acne and sensitive skin and is noncomedogenic and hypoallergenic. Many oil-free moisturizers also contain certain metals and botanical extracts, such as aloe vera and witch hazel, that are known to have anti-inflammatory and skin-soothing properties. Some liquid face cleansers also moisturize, which may be all that is needed in patients with oily skin.
It also is important to inform patients with oily skin that common acne treatments such as benzoyl peroxide, retinoids, salicylic acid, and oral isotretinoin commonly cause dry skin or irritation, leading to barrier disruption in the stratum corneum and subsequently causing increased transepidermal water loss and inflammation. Concomitant use of noncomedogenic moisturizers can enhance treatment efficacy, alleviate dryness, and improve skin comfort in acne patients who are taking these medications.
Expert Commentary
An often forgotten element of acne vulgaris is that it is in fact a disease of barrier dysfunction and disruption. As mentioned above, many of the medications used to treat this chronic inflammatory disease are either directly cytotoxic to keratinocytes (benzoyl peroxide) or alter the thickness and composition of the stratum corneum (retinoids), impairing its protective functions. The inflammatory cascade associated with acne itself can impair the barrier, synergizing with the array of aforementioned medications. Both etiological factors disrupt an often overlooked yet crucial component of the skin barrier, the cutaneous microbiota. The altered landscape, or petri dish if you will, unhinges the balance between the >500 species of organisms living in harmony on the skin, decreasing bacterial diversity and facilitating the overgrowth of specific organisms, here specifically certain types of Propionibacterium acnes, which contribute to the ongoing inflammatory cascade. If that's not enough, sebum, which is certainly in excess in acne, contributes very little to barrier function and skin hydration but can be used to cause a different form of disruption by P acnes, which when converted into short-chain fatty acids can impair cutaneous immune tolerance ultimately creating, you guessed it, more inflammation (thank Dr. Rich Gallo for tying this all together). All in all, the barrier is a mess, highlighting the need for barrier repair with a moisturizer to restore the "balance" on every level: Repair and replace the stratum corneum, restore the tools for the right bacteria to grow (water, carbs, lipids, etc). Moisturizers are a must in acne!
—Adam Friedman, MD (Washington, DC)
Arbuckle R, Atkinson MJ, Clark M, et al. Patient experiences with oily skin: the qualitative development of content for two new patient reported outcome questionnaires [published online October 16, 2008]. Health Qual Life Outcomes. 2008;6:80.
Bikowski J. The use of therapeutic moisturizers in various dermatologic disorders. Cutis. 2001;68(suppl 5):3-11.
Chularojanamontri L, Tuchinda P, Kulthanan K, et al. Moisturizers for acne: what are their constituents? J Clin Aesthet Dermatol. 2014;7:36-44.
Goodman G. Cleansing and moisturizing in acne patients. Am J Clin Dermatol. 2009;10(suppl 1):1-6.
Isoda K, Seki T, Inoue Y, et al. Efficacy of the combined use of a facial cleanser and moisturizers for the care of mild acne patients with sensitive skin [published online December 6, 2014]. J Dermatol. 2015;42:181-188.
Arbuckle R, Atkinson MJ, Clark M, et al. Patient experiences with oily skin: the qualitative development of content for two new patient reported outcome questionnaires [published online October 16, 2008]. Health Qual Life Outcomes. 2008;6:80.
Bikowski J. The use of therapeutic moisturizers in various dermatologic disorders. Cutis. 2001;68(suppl 5):3-11.
Chularojanamontri L, Tuchinda P, Kulthanan K, et al. Moisturizers for acne: what are their constituents? J Clin Aesthet Dermatol. 2014;7:36-44.
Goodman G. Cleansing and moisturizing in acne patients. Am J Clin Dermatol. 2009;10(suppl 1):1-6.
Isoda K, Seki T, Inoue Y, et al. Efficacy of the combined use of a facial cleanser and moisturizers for the care of mild acne patients with sensitive skin [published online December 6, 2014]. J Dermatol. 2015;42:181-188.
Canagliflozin gets boxed warning for amputation
The Food and Drug Administration has added a boxed warning to the label of diabetes drug canagliflozin for the risk of lower limb amputation.
The agency cited data from two clinical trials showing nearly double the risk of leg and foot amputations in patients treated with the canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, compared with placebo, in a recent statement.
The trials, which followed participants for an average of 5.7 and 2.1 years, respectively, showed that lower limb infections, gangrene, diabetic foot ulcers, and ischemia commonly occurred prior to the need for amputation.
The boxed warning advises physicians to consider a patient’s history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers before prescribing canagliflozin and to monitor patients for pain, tenderness, sores, ulcers, or infections on the feet or legs.
Consider discontinuing canagliflozin in these patients, as well as those with symptoms of hypotension, ketoacidosis, elevated serum potassium levels, severe urinary tract infections, hypoglycemia in combination with other prescription diabetes medicines, yeast infections, bone breaks, and increased cholesterol, according to the FDA.
The FDA first issued a safety communication on canagliflozin about a year ago but, at the time, did not advise assessing a patient’s risk for amputation.
Canagliflozin, marketed as Invokana, Invokamet, and Invokamet XR by Janssen Pharmaceuticals, was approved by the FDA in March 2013.
Adverse events involving canagliflozin – or any drug – should be reported to the FDA MedWatch program.
[email protected]
On Twitter @whitneymcknight
The Food and Drug Administration has added a boxed warning to the label of diabetes drug canagliflozin for the risk of lower limb amputation.
The agency cited data from two clinical trials showing nearly double the risk of leg and foot amputations in patients treated with the canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, compared with placebo, in a recent statement.
The trials, which followed participants for an average of 5.7 and 2.1 years, respectively, showed that lower limb infections, gangrene, diabetic foot ulcers, and ischemia commonly occurred prior to the need for amputation.
The boxed warning advises physicians to consider a patient’s history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers before prescribing canagliflozin and to monitor patients for pain, tenderness, sores, ulcers, or infections on the feet or legs.
Consider discontinuing canagliflozin in these patients, as well as those with symptoms of hypotension, ketoacidosis, elevated serum potassium levels, severe urinary tract infections, hypoglycemia in combination with other prescription diabetes medicines, yeast infections, bone breaks, and increased cholesterol, according to the FDA.
The FDA first issued a safety communication on canagliflozin about a year ago but, at the time, did not advise assessing a patient’s risk for amputation.
Canagliflozin, marketed as Invokana, Invokamet, and Invokamet XR by Janssen Pharmaceuticals, was approved by the FDA in March 2013.
Adverse events involving canagliflozin – or any drug – should be reported to the FDA MedWatch program.
[email protected]
On Twitter @whitneymcknight
The Food and Drug Administration has added a boxed warning to the label of diabetes drug canagliflozin for the risk of lower limb amputation.
The agency cited data from two clinical trials showing nearly double the risk of leg and foot amputations in patients treated with the canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, compared with placebo, in a recent statement.
The trials, which followed participants for an average of 5.7 and 2.1 years, respectively, showed that lower limb infections, gangrene, diabetic foot ulcers, and ischemia commonly occurred prior to the need for amputation.
The boxed warning advises physicians to consider a patient’s history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers before prescribing canagliflozin and to monitor patients for pain, tenderness, sores, ulcers, or infections on the feet or legs.
Consider discontinuing canagliflozin in these patients, as well as those with symptoms of hypotension, ketoacidosis, elevated serum potassium levels, severe urinary tract infections, hypoglycemia in combination with other prescription diabetes medicines, yeast infections, bone breaks, and increased cholesterol, according to the FDA.
The FDA first issued a safety communication on canagliflozin about a year ago but, at the time, did not advise assessing a patient’s risk for amputation.
Canagliflozin, marketed as Invokana, Invokamet, and Invokamet XR by Janssen Pharmaceuticals, was approved by the FDA in March 2013.
Adverse events involving canagliflozin – or any drug – should be reported to the FDA MedWatch program.
[email protected]
On Twitter @whitneymcknight
Gray hair
Besides skin wrinkling, volume shifts, and photoaging, graying hair can also be a telltale sign of aging. While it was recently a fashionable trend for younger persons to dye their hair white or gray, graying hair can make a younger person appear older, even in those with naturally premature graying of the hair.
In a study recently published in Genes & Development, researchers at the University of Texas Southwestern Medical Center, Dallas, identified hair shaft progenitors in the matrix that are specific to the hair shaft and not to follicular epithelial cells.1 These hair shaft progenitors express transcription factor KROX20, which expresses stem cell growth factor necessary for hair pigmentation by maintenance of differentiated melanocytes. When KROX20+ is depleted, hair growth is halted and hair turns gray, proving its important role in both hair growth and graying pathways.
Other mechanisms for hair graying include oxidative stress to the hair, at the level of the melanocyte stem cell or at the end-stage of the hair melanocyte, resulting in follicular melanocyte death. With aging and certain genetic mutations (such as that seen in Chediak-Higashi syndrome), reduction of catalase and sometimes downregulation of antioxidant proteins such as BCL-2 and TRP-2 are reduced, resulting in higher reactive oxygen species (ROS) that lead to bulbar melanocyte malfunction and death.
Last year, for the first time, researchers at University College of London identified a gene involved in gray hair, the interferon regulatory factor 4 gene (IRF4).2 The IRF4 gene is involved in regulating production and storage of melanin.
Besides photoprotection and vitamin antioxidants as a preventive measure, therapies that have been developed to target the reduction of ROS in hair have been largely unsatisfactory in treating gray hair. Most people either allow their hair to gray or dye their hair, which can be time consuming and costly and is required on a more frequent basis over time – not to mention the distress related to allergic contact dermatitis caused by some components of some hair dyes, including paraphenylenediamine, which we sometimes see in our profession.
Knowledge of KROX20+, the IRF4 gene, and other pathways involved may be useful in developing novel treatments to prevent or treat graying hair. Information regarding the use of platelet rich plasma (PRP) for hair growth is increasingly being published in the literature. While some physicians purport seeing a reversal in graying with scalp PRP injections, the majority say the results are not universal.
Currently, there are no published studies evaluating the effects of PRP on gray hair. Perhaps providing stem cell factors via injections of PRP or other growth factors may aid not only in hair regrowth but in preserving pigmentation and repigmentation.
Dr. Wesley and Dr. Talakoub are cocontributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Wesley. Write to them at [email protected]. They had no relevant disclosures.
References:
1. Genes Dev. 2017 May 2. doi: 10.1101/gad.298703.117.
2. Nat Commun. 2016 Mar 1;7:10815.
Besides skin wrinkling, volume shifts, and photoaging, graying hair can also be a telltale sign of aging. While it was recently a fashionable trend for younger persons to dye their hair white or gray, graying hair can make a younger person appear older, even in those with naturally premature graying of the hair.
In a study recently published in Genes & Development, researchers at the University of Texas Southwestern Medical Center, Dallas, identified hair shaft progenitors in the matrix that are specific to the hair shaft and not to follicular epithelial cells.1 These hair shaft progenitors express transcription factor KROX20, which expresses stem cell growth factor necessary for hair pigmentation by maintenance of differentiated melanocytes. When KROX20+ is depleted, hair growth is halted and hair turns gray, proving its important role in both hair growth and graying pathways.
Other mechanisms for hair graying include oxidative stress to the hair, at the level of the melanocyte stem cell or at the end-stage of the hair melanocyte, resulting in follicular melanocyte death. With aging and certain genetic mutations (such as that seen in Chediak-Higashi syndrome), reduction of catalase and sometimes downregulation of antioxidant proteins such as BCL-2 and TRP-2 are reduced, resulting in higher reactive oxygen species (ROS) that lead to bulbar melanocyte malfunction and death.
Last year, for the first time, researchers at University College of London identified a gene involved in gray hair, the interferon regulatory factor 4 gene (IRF4).2 The IRF4 gene is involved in regulating production and storage of melanin.
Besides photoprotection and vitamin antioxidants as a preventive measure, therapies that have been developed to target the reduction of ROS in hair have been largely unsatisfactory in treating gray hair. Most people either allow their hair to gray or dye their hair, which can be time consuming and costly and is required on a more frequent basis over time – not to mention the distress related to allergic contact dermatitis caused by some components of some hair dyes, including paraphenylenediamine, which we sometimes see in our profession.
Knowledge of KROX20+, the IRF4 gene, and other pathways involved may be useful in developing novel treatments to prevent or treat graying hair. Information regarding the use of platelet rich plasma (PRP) for hair growth is increasingly being published in the literature. While some physicians purport seeing a reversal in graying with scalp PRP injections, the majority say the results are not universal.
Currently, there are no published studies evaluating the effects of PRP on gray hair. Perhaps providing stem cell factors via injections of PRP or other growth factors may aid not only in hair regrowth but in preserving pigmentation and repigmentation.
Dr. Wesley and Dr. Talakoub are cocontributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Wesley. Write to them at [email protected]. They had no relevant disclosures.
References:
1. Genes Dev. 2017 May 2. doi: 10.1101/gad.298703.117.
2. Nat Commun. 2016 Mar 1;7:10815.
Besides skin wrinkling, volume shifts, and photoaging, graying hair can also be a telltale sign of aging. While it was recently a fashionable trend for younger persons to dye their hair white or gray, graying hair can make a younger person appear older, even in those with naturally premature graying of the hair.
In a study recently published in Genes & Development, researchers at the University of Texas Southwestern Medical Center, Dallas, identified hair shaft progenitors in the matrix that are specific to the hair shaft and not to follicular epithelial cells.1 These hair shaft progenitors express transcription factor KROX20, which expresses stem cell growth factor necessary for hair pigmentation by maintenance of differentiated melanocytes. When KROX20+ is depleted, hair growth is halted and hair turns gray, proving its important role in both hair growth and graying pathways.
Other mechanisms for hair graying include oxidative stress to the hair, at the level of the melanocyte stem cell or at the end-stage of the hair melanocyte, resulting in follicular melanocyte death. With aging and certain genetic mutations (such as that seen in Chediak-Higashi syndrome), reduction of catalase and sometimes downregulation of antioxidant proteins such as BCL-2 and TRP-2 are reduced, resulting in higher reactive oxygen species (ROS) that lead to bulbar melanocyte malfunction and death.
Last year, for the first time, researchers at University College of London identified a gene involved in gray hair, the interferon regulatory factor 4 gene (IRF4).2 The IRF4 gene is involved in regulating production and storage of melanin.
Besides photoprotection and vitamin antioxidants as a preventive measure, therapies that have been developed to target the reduction of ROS in hair have been largely unsatisfactory in treating gray hair. Most people either allow their hair to gray or dye their hair, which can be time consuming and costly and is required on a more frequent basis over time – not to mention the distress related to allergic contact dermatitis caused by some components of some hair dyes, including paraphenylenediamine, which we sometimes see in our profession.
Knowledge of KROX20+, the IRF4 gene, and other pathways involved may be useful in developing novel treatments to prevent or treat graying hair. Information regarding the use of platelet rich plasma (PRP) for hair growth is increasingly being published in the literature. While some physicians purport seeing a reversal in graying with scalp PRP injections, the majority say the results are not universal.
Currently, there are no published studies evaluating the effects of PRP on gray hair. Perhaps providing stem cell factors via injections of PRP or other growth factors may aid not only in hair regrowth but in preserving pigmentation and repigmentation.
Dr. Wesley and Dr. Talakoub are cocontributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Wesley. Write to them at [email protected]. They had no relevant disclosures.
References:
1. Genes Dev. 2017 May 2. doi: 10.1101/gad.298703.117.
2. Nat Commun. 2016 Mar 1;7:10815.