SEATTLE – A regimen of twice-daily doses of extended-release arbaclofen appears to reduce spasticity effectively in patients with multiple sclerosis (MS), according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. The regimen is well tolerated.

Spasticity is common in MS, and the traditional treatment is oral baclofen, a GABA_B receptor agonist. Therapeutic doses of baclofen may cause side effects that decrease adherence, however. Arbaclofen is a more active R-enantiomer of baclofen, which is a racemic mixture. Arbaclofen extended-release (ER) tablets enable twice-daily administration, which reduces dosing frequency and may decrease the rate of adverse events.

Daniel Kantor, MD, a faculty member at Florida Atlantic University in Boca Raton, and colleagues conducted a multicenter, double-blind, parallel-group study to compare the efficacy and safety of arbaclofen ER with those of placebo and baclofen in patients with MS-related spasticity. They randomized adults in North America and Eastern Europe in equal groups to arbaclofen ER (20 mg b.i.d.), baclofen (20 mg q.i.d.), or placebo. The dose was titrated over 2 weeks, and participants subsequently entered a 12-week maintenance phase. The study’s two primary endpoints were the mean change in Total Numeric-Transformed Modified Ashworth Scale for the most affected limb (TNmAS-MAL) and Clinician Global Impression of Change (CGIC) from baseline through the maintenance period.

Dr. Kantor and colleagues randomized 341 patients in their study. Of this population, 57.5% had relapsing-remitting MS, 38.4% had secondary progressive MS, 2.6% had primary progressive MS, and 0.9% had progressive relapsing MS. Thirteen patients from one site were excluded from analysis after study completion when an audit found irregularities. The mean baseline TNmAS-MAL score was 7.93 in the arbaclofen ER group, 7.75 in the baclofen group, and 7.55 in the placebo group. At the end of the maintenance period, the mean decrease in TNmAS-MAL score was larger with arbaclofen ER than with placebo (least-squares mean [LSMean] −2.90 vs. −1.95). In addition, CGIC was significantly improved for arbaclofen ER, compared with placebo (LSMean 1.00 vs. 0.52).

Furthermore, the change in MS Spasticity Scale (MSSS-88) was greater in the arbaclofen ER group than in the placebo group (−30.1 vs. −16.7). Results on the TNmAS, CGIC, and MSSS-88 did not significantly differ between arbaclofen ER and baclofen. Drowsiness and dizziness were less common in the arbaclofen ER group than in the baclofen group. A total of 63 (57.3%) patients receiving arbaclofen ER, 82 (72.6%) receiving baclofen, and 59 (50.0%) receiving placebo reported treatment-emergent adverse events. The most common adverse events were somnolence, asthenia, and muscle weakness.

The study did not have funding support. Dr. Kantor reported having received consulting fees from AbbVie, Actelion, Bayer, Biogen, Celgene, EMD Serono, Genentech/Roche, Mylan, Novartis, Osmotica, and Sanofi Genzyme.

egreb@mdedge.com

SEATTLE – A regimen of twice-daily doses of extended-release arbaclofen appears to reduce spasticity effectively in patients with multiple sclerosis (MS), according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. The regimen is well tolerated.

Spasticity is common in MS, and the traditional treatment is oral baclofen, a GABA_B receptor agonist. Therapeutic doses of baclofen may cause side effects that decrease adherence, however. Arbaclofen is a more active R-enantiomer of baclofen, which is a racemic mixture. Arbaclofen extended-release (ER) tablets enable twice-daily administration, which reduces dosing frequency and may decrease the rate of adverse events.

Daniel Kantor, MD, a faculty member at Florida Atlantic University in Boca Raton, and colleagues conducted a multicenter, double-blind, parallel-group study to compare the efficacy and safety of arbaclofen ER with those of placebo and baclofen in patients with MS-related spasticity. They randomized adults in North America and Eastern Europe in equal groups to arbaclofen ER (20 mg b.i.d.), baclofen (20 mg q.i.d.), or placebo. The dose was titrated over 2 weeks, and participants subsequently entered a 12-week maintenance phase. The study’s two primary endpoints were the mean change in Total Numeric-Transformed Modified Ashworth Scale for the most affected limb (TNmAS-MAL) and Clinician Global Impression of Change (CGIC) from baseline through the maintenance period.

Dr. Kantor and colleagues randomized 341 patients in their study. Of this population, 57.5% had relapsing-remitting MS, 38.4% had secondary progressive MS, 2.6% had primary progressive MS, and 0.9% had progressive relapsing MS. Thirteen patients from one site were excluded from analysis after study completion when an audit found irregularities. The mean baseline TNmAS-MAL score was 7.93 in the arbaclofen ER group, 7.75 in the baclofen group, and 7.55 in the placebo group. At the end of the maintenance period, the mean decrease in TNmAS-MAL score was larger with arbaclofen ER than with placebo (least-squares mean [LSMean] −2.90 vs. −1.95). In addition, CGIC was significantly improved for arbaclofen ER, compared with placebo (LSMean 1.00 vs. 0.52).

Furthermore, the change in MS Spasticity Scale (MSSS-88) was greater in the arbaclofen ER group than in the placebo group (−30.1 vs. −16.7). Results on the TNmAS, CGIC, and MSSS-88 did not significantly differ between arbaclofen ER and baclofen. Drowsiness and dizziness were less common in the arbaclofen ER group than in the baclofen group. A total of 63 (57.3%) patients receiving arbaclofen ER, 82 (72.6%) receiving baclofen, and 59 (50.0%) receiving placebo reported treatment-emergent adverse events. The most common adverse events were somnolence, asthenia, and muscle weakness.

The study did not have funding support. Dr. Kantor reported having received consulting fees from AbbVie, Actelion, Bayer, Biogen, Celgene, EMD Serono, Genentech/Roche, Mylan, Novartis, Osmotica, and Sanofi Genzyme.

egreb@mdedge.com

SEATTLE – A regimen of twice-daily doses of extended-release arbaclofen appears to reduce spasticity effectively in patients with multiple sclerosis (MS), according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. The regimen is well tolerated.

Spasticity is common in MS, and the traditional treatment is oral baclofen, a GABA_B receptor agonist. Therapeutic doses of baclofen may cause side effects that decrease adherence, however. Arbaclofen is a more active R-enantiomer of baclofen, which is a racemic mixture. Arbaclofen extended-release (ER) tablets enable twice-daily administration, which reduces dosing frequency and may decrease the rate of adverse events.

Daniel Kantor, MD, a faculty member at Florida Atlantic University in Boca Raton, and colleagues conducted a multicenter, double-blind, parallel-group study to compare the efficacy and safety of arbaclofen ER with those of placebo and baclofen in patients with MS-related spasticity. They randomized adults in North America and Eastern Europe in equal groups to arbaclofen ER (20 mg b.i.d.), baclofen (20 mg q.i.d.), or placebo. The dose was titrated over 2 weeks, and participants subsequently entered a 12-week maintenance phase. The study’s two primary endpoints were the mean change in Total Numeric-Transformed Modified Ashworth Scale for the most affected limb (TNmAS-MAL) and Clinician Global Impression of Change (CGIC) from baseline through the maintenance period.

Dr. Kantor and colleagues randomized 341 patients in their study. Of this population, 57.5% had relapsing-remitting MS, 38.4% had secondary progressive MS, 2.6% had primary progressive MS, and 0.9% had progressive relapsing MS. Thirteen patients from one site were excluded from analysis after study completion when an audit found irregularities. The mean baseline TNmAS-MAL score was 7.93 in the arbaclofen ER group, 7.75 in the baclofen group, and 7.55 in the placebo group. At the end of the maintenance period, the mean decrease in TNmAS-MAL score was larger with arbaclofen ER than with placebo (least-squares mean [LSMean] −2.90 vs. −1.95). In addition, CGIC was significantly improved for arbaclofen ER, compared with placebo (LSMean 1.00 vs. 0.52).

Furthermore, the change in MS Spasticity Scale (MSSS-88) was greater in the arbaclofen ER group than in the placebo group (−30.1 vs. −16.7). Results on the TNmAS, CGIC, and MSSS-88 did not significantly differ between arbaclofen ER and baclofen. Drowsiness and dizziness were less common in the arbaclofen ER group than in the baclofen group. A total of 63 (57.3%) patients receiving arbaclofen ER, 82 (72.6%) receiving baclofen, and 59 (50.0%) receiving placebo reported treatment-emergent adverse events. The most common adverse events were somnolence, asthenia, and muscle weakness.

The study did not have funding support. Dr. Kantor reported having received consulting fees from AbbVie, Actelion, Bayer, Biogen, Celgene, EMD Serono, Genentech/Roche, Mylan, Novartis, Osmotica, and Sanofi Genzyme.

egreb@mdedge.com

Almost 30 years ago a young woman made an appointment to see me. I had just started my internal medicine practice and almost all the patients who saw me were new to me. I assumed she was establishing care with me. Her first words to me were “Hello Dr. Paauw, I would like to interview you to see if you will be a good fit as my doctor.” We talked for the 40-minute appointment time. I asked her about her health, her life, and what she wanted out of both. We shared with each other that we both were parents of young children. When the appointment was over, she said she would really like for me to be her doctor. She told me that the main thing she appreciated about me was that I listened, and that her previous physician never sat down at her appointments and often had his hand on the door handle for much of the visit. Physicians and patients both agree that compassionate care is essential for good patient care, yet about half of patients and 60% of doctors believe it is lacking in our medical system.¹

Remember the golden first minutes

When you step in the room and greet the patient, make sure the first few minutes are about connecting with a new patient or reconnecting with a patient who has visited your office in the past. I often start by asking the patient to give me an update on how they are doing. This lets me know what is important to them. I do not touch the computer until after this initial check-in.

Use the computer as a bond to strengthen your patient relationship

Many studies have shown patients find the computer gets between the doctor and patient. It is especially problematic if it breaks eye contact with the patient. People are less likely to share scary, sensitive, or embarrassing information if someone is looking at a computer and typing. As you look up tests, radiology reports, or consultant notes, let the patient in on what you are doing. Explain why you are searching in the record, and if it helps make an important point, show your findings to the patient. Offer to print out results, so they have something to carry with them.

Explain what you are looking for and what you find on the physical exam

Being a patient is scary. We all want reassurance that our fears are not true. When you find normal findings on exam, share those with the patient. Hearing “your heart sounds good, your pulses are strong” really helps patients. Explaining what we are doing when we examine is also helpful. Explain why you are feeling for lymph nodes in the neck, why we percuss the abdomen. Patients are often fascinated by getting a window into how we are thinking. I usually have medical students with me, which offers another avenue to explaining the how and why behind the exam. In asking and explaining to students, the patient is also taught why we do what we do.

Make sure that we cover what they are afraid of, not just what their symptom is

Patients come in not just to get symptom relief but to rest their mind from their fears of what it could be. I find it helpful to ask the patient what they think is the cause of the problem, or if they are worried about any specific diagnosis. With certain symptoms this is particularly important (for example, headaches, fatigue, or abdominal pain).

None of these suggestions are easy to do in busy, time-pressured clinic visits. I have found though that when patients feel cared about, listened to and can have their fears addressed they value our advice more, and less time is needed to negotiate the plan, as it has been developed together.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at fpnews@mdedge.com.

Reference

Lown BA et al. Health Aff (Millwood). 2011 Sep;30(9):1772-8.

Almost 30 years ago a young woman made an appointment to see me. I had just started my internal medicine practice and almost all the patients who saw me were new to me. I assumed she was establishing care with me. Her first words to me were “Hello Dr. Paauw, I would like to interview you to see if you will be a good fit as my doctor.” We talked for the 40-minute appointment time. I asked her about her health, her life, and what she wanted out of both. We shared with each other that we both were parents of young children. When the appointment was over, she said she would really like for me to be her doctor. She told me that the main thing she appreciated about me was that I listened, and that her previous physician never sat down at her appointments and often had his hand on the door handle for much of the visit. Physicians and patients both agree that compassionate care is essential for good patient care, yet about half of patients and 60% of doctors believe it is lacking in our medical system.¹

Remember the golden first minutes

When you step in the room and greet the patient, make sure the first few minutes are about connecting with a new patient or reconnecting with a patient who has visited your office in the past. I often start by asking the patient to give me an update on how they are doing. This lets me know what is important to them. I do not touch the computer until after this initial check-in.

Use the computer as a bond to strengthen your patient relationship

Many studies have shown patients find the computer gets between the doctor and patient. It is especially problematic if it breaks eye contact with the patient. People are less likely to share scary, sensitive, or embarrassing information if someone is looking at a computer and typing. As you look up tests, radiology reports, or consultant notes, let the patient in on what you are doing. Explain why you are searching in the record, and if it helps make an important point, show your findings to the patient. Offer to print out results, so they have something to carry with them.

Explain what you are looking for and what you find on the physical exam

Being a patient is scary. We all want reassurance that our fears are not true. When you find normal findings on exam, share those with the patient. Hearing “your heart sounds good, your pulses are strong” really helps patients. Explaining what we are doing when we examine is also helpful. Explain why you are feeling for lymph nodes in the neck, why we percuss the abdomen. Patients are often fascinated by getting a window into how we are thinking. I usually have medical students with me, which offers another avenue to explaining the how and why behind the exam. In asking and explaining to students, the patient is also taught why we do what we do.

Make sure that we cover what they are afraid of, not just what their symptom is

Patients come in not just to get symptom relief but to rest their mind from their fears of what it could be. I find it helpful to ask the patient what they think is the cause of the problem, or if they are worried about any specific diagnosis. With certain symptoms this is particularly important (for example, headaches, fatigue, or abdominal pain).

None of these suggestions are easy to do in busy, time-pressured clinic visits. I have found though that when patients feel cared about, listened to and can have their fears addressed they value our advice more, and less time is needed to negotiate the plan, as it has been developed together.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at fpnews@mdedge.com.

Reference

Lown BA et al. Health Aff (Millwood). 2011 Sep;30(9):1772-8.

Almost 30 years ago a young woman made an appointment to see me. I had just started my internal medicine practice and almost all the patients who saw me were new to me. I assumed she was establishing care with me. Her first words to me were “Hello Dr. Paauw, I would like to interview you to see if you will be a good fit as my doctor.” We talked for the 40-minute appointment time. I asked her about her health, her life, and what she wanted out of both. We shared with each other that we both were parents of young children. When the appointment was over, she said she would really like for me to be her doctor. She told me that the main thing she appreciated about me was that I listened, and that her previous physician never sat down at her appointments and often had his hand on the door handle for much of the visit. Physicians and patients both agree that compassionate care is essential for good patient care, yet about half of patients and 60% of doctors believe it is lacking in our medical system.¹

Remember the golden first minutes

When you step in the room and greet the patient, make sure the first few minutes are about connecting with a new patient or reconnecting with a patient who has visited your office in the past. I often start by asking the patient to give me an update on how they are doing. This lets me know what is important to them. I do not touch the computer until after this initial check-in.

Use the computer as a bond to strengthen your patient relationship

Many studies have shown patients find the computer gets between the doctor and patient. It is especially problematic if it breaks eye contact with the patient. People are less likely to share scary, sensitive, or embarrassing information if someone is looking at a computer and typing. As you look up tests, radiology reports, or consultant notes, let the patient in on what you are doing. Explain why you are searching in the record, and if it helps make an important point, show your findings to the patient. Offer to print out results, so they have something to carry with them.

Explain what you are looking for and what you find on the physical exam

Being a patient is scary. We all want reassurance that our fears are not true. When you find normal findings on exam, share those with the patient. Hearing “your heart sounds good, your pulses are strong” really helps patients. Explaining what we are doing when we examine is also helpful. Explain why you are feeling for lymph nodes in the neck, why we percuss the abdomen. Patients are often fascinated by getting a window into how we are thinking. I usually have medical students with me, which offers another avenue to explaining the how and why behind the exam. In asking and explaining to students, the patient is also taught why we do what we do.

Make sure that we cover what they are afraid of, not just what their symptom is

Patients come in not just to get symptom relief but to rest their mind from their fears of what it could be. I find it helpful to ask the patient what they think is the cause of the problem, or if they are worried about any specific diagnosis. With certain symptoms this is particularly important (for example, headaches, fatigue, or abdominal pain).

None of these suggestions are easy to do in busy, time-pressured clinic visits. I have found though that when patients feel cared about, listened to and can have their fears addressed they value our advice more, and less time is needed to negotiate the plan, as it has been developed together.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at fpnews@mdedge.com.

Reference

Lown BA et al. Health Aff (Millwood). 2011 Sep;30(9):1772-8.

Louisiana has joined a handful of other states in passing a so-called fetal heartbeat bill that would ban abortions as early as 6 weeks, about the time a heartbeat is usually detectable.

The legislation, which does not include an exception for rape or incest cases, passed by a 79-23 vote on May 29 in the Louisiana House. The bill does allow exceptions if the woman’s life is in danger, if the pregnancy poses risk of serious impairment to a woman’s body, of if the pregnancy is deemed medically futile. Democratic Gov. John Bel Edwards said he plans to sign the measure when it hits his desk.

“In 2015, I ran for governor as a pro-life candidate after serving as a pro-life legislator for 8 years,” Gov. Edwards said in a May 29 statement. “As governor, I have been true to my word and my beliefs on this issue. As I prepare to sign this bill, I call on the overwhelming bipartisan majority of legislators who voted for it to join me in continuing to build a better Louisiana that cares for the least among us and provides more opportunity for everyone.”

Six other states have enacted similar abortion bans: Alabama, Georgia, Kentucky, Mississippi, Missouri, and Ohio. While most of the laws bar abortions after a heartbeat is detected, Alabama’s measure prohibits abortion at every pregnancy stage and penalizes physicians with a Class A felony for performing an abortion and a Class C felony for attempting to perform an abortion. Alabama Gov. Kay Ivey (R) signed the bill into law on May 15.

A number of lawsuits have been filed against the bans, including a May 24 legal challenge against Alabama’s law by Planned Parenthood Federation of America and the American Civil Liberties Union (ACLU), and a May 15 legal challenge against Ohio’s law by the ACLU and Planned Parenthood of Greater Ohio.

The U.S. Supreme Court on May 28 upheld part of an Indiana law that requires burial or cremation of fetal remains after an abortion, but the justices declined to address the measure’s prohibition on abortions sought because of race, sex, or disability of the fetus.

Court analysts say it’s only a matter of time before the Supreme Court takes up one of the abortion ban cases, most likely the legal challenge against Alabama’s law. Abortion critics have been encouraged by the Supreme Court appointment of right-leaning Justice Brett M. Kavanaugh, and hope the Alabama measure will drive the Supreme Court to reconsider its central holding in Roe v. Wade, court watchers said.

agallegos@mdedge.com

Louisiana has joined a handful of other states in passing a so-called fetal heartbeat bill that would ban abortions as early as 6 weeks, about the time a heartbeat is usually detectable.

The legislation, which does not include an exception for rape or incest cases, passed by a 79-23 vote on May 29 in the Louisiana House. The bill does allow exceptions if the woman’s life is in danger, if the pregnancy poses risk of serious impairment to a woman’s body, of if the pregnancy is deemed medically futile. Democratic Gov. John Bel Edwards said he plans to sign the measure when it hits his desk.

“In 2015, I ran for governor as a pro-life candidate after serving as a pro-life legislator for 8 years,” Gov. Edwards said in a May 29 statement. “As governor, I have been true to my word and my beliefs on this issue. As I prepare to sign this bill, I call on the overwhelming bipartisan majority of legislators who voted for it to join me in continuing to build a better Louisiana that cares for the least among us and provides more opportunity for everyone.”

Six other states have enacted similar abortion bans: Alabama, Georgia, Kentucky, Mississippi, Missouri, and Ohio. While most of the laws bar abortions after a heartbeat is detected, Alabama’s measure prohibits abortion at every pregnancy stage and penalizes physicians with a Class A felony for performing an abortion and a Class C felony for attempting to perform an abortion. Alabama Gov. Kay Ivey (R) signed the bill into law on May 15.

A number of lawsuits have been filed against the bans, including a May 24 legal challenge against Alabama’s law by Planned Parenthood Federation of America and the American Civil Liberties Union (ACLU), and a May 15 legal challenge against Ohio’s law by the ACLU and Planned Parenthood of Greater Ohio.

The U.S. Supreme Court on May 28 upheld part of an Indiana law that requires burial or cremation of fetal remains after an abortion, but the justices declined to address the measure’s prohibition on abortions sought because of race, sex, or disability of the fetus.

Court analysts say it’s only a matter of time before the Supreme Court takes up one of the abortion ban cases, most likely the legal challenge against Alabama’s law. Abortion critics have been encouraged by the Supreme Court appointment of right-leaning Justice Brett M. Kavanaugh, and hope the Alabama measure will drive the Supreme Court to reconsider its central holding in Roe v. Wade, court watchers said.

agallegos@mdedge.com

Louisiana has joined a handful of other states in passing a so-called fetal heartbeat bill that would ban abortions as early as 6 weeks, about the time a heartbeat is usually detectable.

The legislation, which does not include an exception for rape or incest cases, passed by a 79-23 vote on May 29 in the Louisiana House. The bill does allow exceptions if the woman’s life is in danger, if the pregnancy poses risk of serious impairment to a woman’s body, of if the pregnancy is deemed medically futile. Democratic Gov. John Bel Edwards said he plans to sign the measure when it hits his desk.

“In 2015, I ran for governor as a pro-life candidate after serving as a pro-life legislator for 8 years,” Gov. Edwards said in a May 29 statement. “As governor, I have been true to my word and my beliefs on this issue. As I prepare to sign this bill, I call on the overwhelming bipartisan majority of legislators who voted for it to join me in continuing to build a better Louisiana that cares for the least among us and provides more opportunity for everyone.”

Six other states have enacted similar abortion bans: Alabama, Georgia, Kentucky, Mississippi, Missouri, and Ohio. While most of the laws bar abortions after a heartbeat is detected, Alabama’s measure prohibits abortion at every pregnancy stage and penalizes physicians with a Class A felony for performing an abortion and a Class C felony for attempting to perform an abortion. Alabama Gov. Kay Ivey (R) signed the bill into law on May 15.

A number of lawsuits have been filed against the bans, including a May 24 legal challenge against Alabama’s law by Planned Parenthood Federation of America and the American Civil Liberties Union (ACLU), and a May 15 legal challenge against Ohio’s law by the ACLU and Planned Parenthood of Greater Ohio.

The U.S. Supreme Court on May 28 upheld part of an Indiana law that requires burial or cremation of fetal remains after an abortion, but the justices declined to address the measure’s prohibition on abortions sought because of race, sex, or disability of the fetus.

Court analysts say it’s only a matter of time before the Supreme Court takes up one of the abortion ban cases, most likely the legal challenge against Alabama’s law. Abortion critics have been encouraged by the Supreme Court appointment of right-leaning Justice Brett M. Kavanaugh, and hope the Alabama measure will drive the Supreme Court to reconsider its central holding in Roe v. Wade, court watchers said.

agallegos@mdedge.com

DALLAS – Children with cystic fibrosis or asthma report sleep interruptions 1 or 2 nights a week caused by their symptoms, but nighttime use of technology may contribute more to sleep problems, according to a new study.

“Routinely addressing sleep concerns, sleep hygiene, and mental health is important in the care of pediatric patients with chronic illness,” concluded Lauren Greenawald, DO, and colleagues at the Alfred I. duPont Hospital for Children in Wilmington, Del. The researchers presented their findings on sleep quality and mental health of children with asthma or cystic fibrosis (CF) at the American Thoracic Society’s international conference.

Dr. Greenawald’s team screened 31 children (aged 7-17 years) with CF and 34 children with asthma for anxiety, depression, and ADHD. The researchers also assessed the children’s sleep hygiene, sleep quality, and physical and emotional symptoms. Instruments included the validated Pediatric Daytime Sleepiness Scale (PDSS), Pediatric Quality of Life Inventory, and Patient-Reported Outcomes Measurement Information System Pediatric Anxiety Survey, plus an investigator-designed survey about sleep habits.

Just over half the children with CF (52%) and 14% of children with asthma had mental health diagnoses (P less than .01). The same proportion of patients with CF (52%) and nearly a third of patients with asthma (30%) reported they often or always felt they needed more sleep based on the PDSS. Further, 42% of children with CF and 55% of children with asthma said their symptoms kept them awake 1-2 nights a week. Only 6% of asthma patients and no CF patients said their symptoms keep them awake often, 3-4 nights a week. Just over a third of children with CF (36%) and 46% of those with asthma thought they would sleep better if they didn’t have a medical condition.

Yet, for the vast majority of children, the sleeping problems did not appear to result from worry about their illness: 85% of those with CF and nearly all of those with asthma (97%) did not have trouble sleeping as a result of anxiety about their medical condition.

The researchers identified nighttime use of technology that may affect the children’s sleep in ways similar to that of the general population. Many of the participants – 68% of those with CF and 47% of those with asthma – reported texting or using social media or other technology an hour before going to bed. In addition, 55% of those with CF and 25% of those with asthma said they use their phone after the lights are out at least 5 nights a week. One in five of those with CF (20%) said they go to bed later than they planned at least 5 days a week because of social media or texting, though only 6% of those with asthma said the same.

Despite the children’s reports of inadequate sleep, very few – 3.2% of children with CF and 5.9% of children with asthma – reported feeling low daytime energy.

The use of child self-reporting in the presence of family members is a study limitation, including potentially introducing social desirability bias.

The research was funded by the Nemours Summer Undergraduate Research Program. The authors reported no disclosures.

SOURCE: Greenawald L et al. ATS 2019, Abstract A2788.

DALLAS – Children with cystic fibrosis or asthma report sleep interruptions 1 or 2 nights a week caused by their symptoms, but nighttime use of technology may contribute more to sleep problems, according to a new study.

“Routinely addressing sleep concerns, sleep hygiene, and mental health is important in the care of pediatric patients with chronic illness,” concluded Lauren Greenawald, DO, and colleagues at the Alfred I. duPont Hospital for Children in Wilmington, Del. The researchers presented their findings on sleep quality and mental health of children with asthma or cystic fibrosis (CF) at the American Thoracic Society’s international conference.

Dr. Greenawald’s team screened 31 children (aged 7-17 years) with CF and 34 children with asthma for anxiety, depression, and ADHD. The researchers also assessed the children’s sleep hygiene, sleep quality, and physical and emotional symptoms. Instruments included the validated Pediatric Daytime Sleepiness Scale (PDSS), Pediatric Quality of Life Inventory, and Patient-Reported Outcomes Measurement Information System Pediatric Anxiety Survey, plus an investigator-designed survey about sleep habits.

Just over half the children with CF (52%) and 14% of children with asthma had mental health diagnoses (P less than .01). The same proportion of patients with CF (52%) and nearly a third of patients with asthma (30%) reported they often or always felt they needed more sleep based on the PDSS. Further, 42% of children with CF and 55% of children with asthma said their symptoms kept them awake 1-2 nights a week. Only 6% of asthma patients and no CF patients said their symptoms keep them awake often, 3-4 nights a week. Just over a third of children with CF (36%) and 46% of those with asthma thought they would sleep better if they didn’t have a medical condition.

Yet, for the vast majority of children, the sleeping problems did not appear to result from worry about their illness: 85% of those with CF and nearly all of those with asthma (97%) did not have trouble sleeping as a result of anxiety about their medical condition.

The researchers identified nighttime use of technology that may affect the children’s sleep in ways similar to that of the general population. Many of the participants – 68% of those with CF and 47% of those with asthma – reported texting or using social media or other technology an hour before going to bed. In addition, 55% of those with CF and 25% of those with asthma said they use their phone after the lights are out at least 5 nights a week. One in five of those with CF (20%) said they go to bed later than they planned at least 5 days a week because of social media or texting, though only 6% of those with asthma said the same.

Despite the children’s reports of inadequate sleep, very few – 3.2% of children with CF and 5.9% of children with asthma – reported feeling low daytime energy.

The use of child self-reporting in the presence of family members is a study limitation, including potentially introducing social desirability bias.

The research was funded by the Nemours Summer Undergraduate Research Program. The authors reported no disclosures.

SOURCE: Greenawald L et al. ATS 2019, Abstract A2788.

DALLAS – Children with cystic fibrosis or asthma report sleep interruptions 1 or 2 nights a week caused by their symptoms, but nighttime use of technology may contribute more to sleep problems, according to a new study.

“Routinely addressing sleep concerns, sleep hygiene, and mental health is important in the care of pediatric patients with chronic illness,” concluded Lauren Greenawald, DO, and colleagues at the Alfred I. duPont Hospital for Children in Wilmington, Del. The researchers presented their findings on sleep quality and mental health of children with asthma or cystic fibrosis (CF) at the American Thoracic Society’s international conference.

Dr. Greenawald’s team screened 31 children (aged 7-17 years) with CF and 34 children with asthma for anxiety, depression, and ADHD. The researchers also assessed the children’s sleep hygiene, sleep quality, and physical and emotional symptoms. Instruments included the validated Pediatric Daytime Sleepiness Scale (PDSS), Pediatric Quality of Life Inventory, and Patient-Reported Outcomes Measurement Information System Pediatric Anxiety Survey, plus an investigator-designed survey about sleep habits.

Just over half the children with CF (52%) and 14% of children with asthma had mental health diagnoses (P less than .01). The same proportion of patients with CF (52%) and nearly a third of patients with asthma (30%) reported they often or always felt they needed more sleep based on the PDSS. Further, 42% of children with CF and 55% of children with asthma said their symptoms kept them awake 1-2 nights a week. Only 6% of asthma patients and no CF patients said their symptoms keep them awake often, 3-4 nights a week. Just over a third of children with CF (36%) and 46% of those with asthma thought they would sleep better if they didn’t have a medical condition.

Yet, for the vast majority of children, the sleeping problems did not appear to result from worry about their illness: 85% of those with CF and nearly all of those with asthma (97%) did not have trouble sleeping as a result of anxiety about their medical condition.

The researchers identified nighttime use of technology that may affect the children’s sleep in ways similar to that of the general population. Many of the participants – 68% of those with CF and 47% of those with asthma – reported texting or using social media or other technology an hour before going to bed. In addition, 55% of those with CF and 25% of those with asthma said they use their phone after the lights are out at least 5 nights a week. One in five of those with CF (20%) said they go to bed later than they planned at least 5 days a week because of social media or texting, though only 6% of those with asthma said the same.

Despite the children’s reports of inadequate sleep, very few – 3.2% of children with CF and 5.9% of children with asthma – reported feeling low daytime energy.

The use of child self-reporting in the presence of family members is a study limitation, including potentially introducing social desirability bias.

The research was funded by the Nemours Summer Undergraduate Research Program. The authors reported no disclosures.

SOURCE: Greenawald L et al. ATS 2019, Abstract A2788.

Key clinical point: Structural and functional network MRI measures predict long-term worsening in multiple sclerosis.

Major finding: The odds ratio of worsening for patients with abnormally high baseline resting state functional connectivity is 1.67.

Study details: A prospective imaging study of 233 patients with multiple sclerosis and 77 healthy controls.

Disclosures: Dr. Filippi has received research support from Biogen, Merck Serono, Novartis, Teva, and Roche.

Citation: Filippi M et al. AAN 2019, Abstract S49.004.

Key clinical point: Structural and functional network MRI measures predict long-term worsening in multiple sclerosis.

Major finding: The odds ratio of worsening for patients with abnormally high baseline resting state functional connectivity is 1.67.

Study details: A prospective imaging study of 233 patients with multiple sclerosis and 77 healthy controls.

Disclosures: Dr. Filippi has received research support from Biogen, Merck Serono, Novartis, Teva, and Roche.

Citation: Filippi M et al. AAN 2019, Abstract S49.004.

Key clinical point: Structural and functional network MRI measures predict long-term worsening in multiple sclerosis.

Major finding: The odds ratio of worsening for patients with abnormally high baseline resting state functional connectivity is 1.67.

Study details: A prospective imaging study of 233 patients with multiple sclerosis and 77 healthy controls.

Disclosures: Dr. Filippi has received research support from Biogen, Merck Serono, Novartis, Teva, and Roche.

Citation: Filippi M et al. AAN 2019, Abstract S49.004.

Key clinical point: Among patients with multiple sclerosis, consumption of sugar-sweetened beverages may be associated with more severe disability.

Major finding: Patients in the top quartile of sugar-sweetened beverage intake had an average EDSS of 4.1 and patients in the bottom quartile had an average EDSS of 3.4.

Study details: Cross-sectional study of 135 patients with MS.

Disclosures: Dr. Meier-Gerdingh had no disclosures. Coauthors reported research support and personal compensation from pharmaceutical companies.

Citation: Meier-Gerdingh E et al. AAN 2019, Abstract P4.2-063.

Key clinical point: Among patients with multiple sclerosis, consumption of sugar-sweetened beverages may be associated with more severe disability.

Major finding: Patients in the top quartile of sugar-sweetened beverage intake had an average EDSS of 4.1 and patients in the bottom quartile had an average EDSS of 3.4.

Study details: Cross-sectional study of 135 patients with MS.

Disclosures: Dr. Meier-Gerdingh had no disclosures. Coauthors reported research support and personal compensation from pharmaceutical companies.

Citation: Meier-Gerdingh E et al. AAN 2019, Abstract P4.2-063.

Key clinical point: Among patients with multiple sclerosis, consumption of sugar-sweetened beverages may be associated with more severe disability.

Major finding: Patients in the top quartile of sugar-sweetened beverage intake had an average EDSS of 4.1 and patients in the bottom quartile had an average EDSS of 3.4.

Study details: Cross-sectional study of 135 patients with MS.

Disclosures: Dr. Meier-Gerdingh had no disclosures. Coauthors reported research support and personal compensation from pharmaceutical companies.

Citation: Meier-Gerdingh E et al. AAN 2019, Abstract P4.2-063.

Key clinical point: The relationship between vitamin D status and MS outcome in children relates to skin pigmentation.

Major finding: About 46% of children with MS were HLA-DRB1*15 positive.

Study details: A multisite, prospective study of 259 children with MS.

Disclosures: Ms. Dunn had no disclosures, but various coauthors have received compensation from companies such as Novartis, Merck, Teva, Celgene, and Genentech.

Citation: Dunn C et al. AAN 2019, Abstract S19.007.

Key clinical point: The relationship between vitamin D status and MS outcome in children relates to skin pigmentation.

Major finding: About 46% of children with MS were HLA-DRB1*15 positive.

Study details: A multisite, prospective study of 259 children with MS.

Disclosures: Ms. Dunn had no disclosures, but various coauthors have received compensation from companies such as Novartis, Merck, Teva, Celgene, and Genentech.

Citation: Dunn C et al. AAN 2019, Abstract S19.007.

Key clinical point: The relationship between vitamin D status and MS outcome in children relates to skin pigmentation.

Major finding: About 46% of children with MS were HLA-DRB1*15 positive.

Study details: A multisite, prospective study of 259 children with MS.

Disclosures: Ms. Dunn had no disclosures, but various coauthors have received compensation from companies such as Novartis, Merck, Teva, Celgene, and Genentech.

Citation: Dunn C et al. AAN 2019, Abstract S19.007.

The Food and Drug Administration has granted a Priority Review to the supplemental new drug application for icosapent ethyl (Vascepa).

Wikimedia Commons/FitzColinGerald/Creative Commons License

If approved, Vascepa – which is produced by Amarin – would be the first drug indicated to reduce residual cardiovascular risk in patients with LDL cholesterol managed by statins who still have persistent elevated triglycerides. The drug is now approved for reducing triglyceride levels in patients with baseline values of 500 mg/dL or greater.

The Priority Review is based on results of REDUCE-IT, a landmark cardiovascular outcomes trial whose primary results were presented at the American Heart Association scientific sessions last November and published in the New England Journal of Medicine. Vascepa achieved the primary study endpoint, reducing the relative risk for the first occurrence of a major adverse cardiovascular event significantly, by 25%.

The drug also met the study’s key secondary endpoint, reducing the incidence of a composite of cardiovascular death, nonfatal heart attack, and nonfatal stroke by 26%. Significant adverse events associated with Vascepa in the trial were peripheral edema, constipation, and atrial fibrillation.

Vascepa is currently indicated as an adjunct to diet to reduce triglyceride in adults with severe hypertriglyceridemia, a significantly smaller population than that represented in REDUCE-IT.

“We expect earlier approval of an expanded indication for Vascepa to lead to faster improvements in care for millions of patients with residual cardiovascular risk after statin therapy,” John F. Thero, president and CEO of Amarin, said in the statement.

The FDA is expected to issue a complete response by the end of September. Find the full press release on the Amarin website.

lfranki@mdedge.com

The Food and Drug Administration has granted a Priority Review to the supplemental new drug application for icosapent ethyl (Vascepa).

Wikimedia Commons/FitzColinGerald/Creative Commons License

If approved, Vascepa – which is produced by Amarin – would be the first drug indicated to reduce residual cardiovascular risk in patients with LDL cholesterol managed by statins who still have persistent elevated triglycerides. The drug is now approved for reducing triglyceride levels in patients with baseline values of 500 mg/dL or greater.

The Priority Review is based on results of REDUCE-IT, a landmark cardiovascular outcomes trial whose primary results were presented at the American Heart Association scientific sessions last November and published in the New England Journal of Medicine. Vascepa achieved the primary study endpoint, reducing the relative risk for the first occurrence of a major adverse cardiovascular event significantly, by 25%.

The drug also met the study’s key secondary endpoint, reducing the incidence of a composite of cardiovascular death, nonfatal heart attack, and nonfatal stroke by 26%. Significant adverse events associated with Vascepa in the trial were peripheral edema, constipation, and atrial fibrillation.

Vascepa is currently indicated as an adjunct to diet to reduce triglyceride in adults with severe hypertriglyceridemia, a significantly smaller population than that represented in REDUCE-IT.

“We expect earlier approval of an expanded indication for Vascepa to lead to faster improvements in care for millions of patients with residual cardiovascular risk after statin therapy,” John F. Thero, president and CEO of Amarin, said in the statement.

The FDA is expected to issue a complete response by the end of September. Find the full press release on the Amarin website.

lfranki@mdedge.com

The Food and Drug Administration has granted a Priority Review to the supplemental new drug application for icosapent ethyl (Vascepa).

Wikimedia Commons/FitzColinGerald/Creative Commons License

If approved, Vascepa – which is produced by Amarin – would be the first drug indicated to reduce residual cardiovascular risk in patients with LDL cholesterol managed by statins who still have persistent elevated triglycerides. The drug is now approved for reducing triglyceride levels in patients with baseline values of 500 mg/dL or greater.

The Priority Review is based on results of REDUCE-IT, a landmark cardiovascular outcomes trial whose primary results were presented at the American Heart Association scientific sessions last November and published in the New England Journal of Medicine. Vascepa achieved the primary study endpoint, reducing the relative risk for the first occurrence of a major adverse cardiovascular event significantly, by 25%.

The drug also met the study’s key secondary endpoint, reducing the incidence of a composite of cardiovascular death, nonfatal heart attack, and nonfatal stroke by 26%. Significant adverse events associated with Vascepa in the trial were peripheral edema, constipation, and atrial fibrillation.

Vascepa is currently indicated as an adjunct to diet to reduce triglyceride in adults with severe hypertriglyceridemia, a significantly smaller population than that represented in REDUCE-IT.

“We expect earlier approval of an expanded indication for Vascepa to lead to faster improvements in care for millions of patients with residual cardiovascular risk after statin therapy,” John F. Thero, president and CEO of Amarin, said in the statement.

The FDA is expected to issue a complete response by the end of September. Find the full press release on the Amarin website.

lfranki@mdedge.com

The Food and Drug Administration has approved Jafaki (ruxolitinib) for treatment of steroid-refractory acute graft-versus-host disease (GVHD) in adult and pediatric patients 12 years and older.

Ruxolitinib will be made available to appropriate patients immediately, according to a statement from Incyte, which markets the drug. The company noted that ruxolitinib is the first FDA-approved treatment for this indication.

The approval is based on data from the open-label, single-arm, multicenter REACH1 trial, which studied ruxolitinib in combination with corticosteroids. The 71 patients in the trial had grade 2-4 acute GVHD after allogeneic hematopoietic stem cell transplant; of these patients, 49 were refractory to steroids alone, 12 had received at least two prior therapies for GVHD, and 10 did not otherwise meet the FDA definition of steroid refractory.

The trial’s primary endpoints were day-28 overall response rate and response duration. Among the 49 patients with steroid only–refractory GVHD, the overall response rate was 100% for grade 2 GVHD, 40.7% for grade 3, and 44.4% for grade 4. Median response duration was 16 days. For all 49 of these patients, the overall response rate was 57%, and the complete response rate was 31%.

Among all 71 participants, the most frequently reported adverse reactions were infections (55%) and edema (51%); anemia (71%), thrombocytopenia (75%), and neutropenia (58%) were the most common laboratory abnormalities.

cpalmer@mdedge.com

The Food and Drug Administration has approved Jafaki (ruxolitinib) for treatment of steroid-refractory acute graft-versus-host disease (GVHD) in adult and pediatric patients 12 years and older.

Ruxolitinib will be made available to appropriate patients immediately, according to a statement from Incyte, which markets the drug. The company noted that ruxolitinib is the first FDA-approved treatment for this indication.

The approval is based on data from the open-label, single-arm, multicenter REACH1 trial, which studied ruxolitinib in combination with corticosteroids. The 71 patients in the trial had grade 2-4 acute GVHD after allogeneic hematopoietic stem cell transplant; of these patients, 49 were refractory to steroids alone, 12 had received at least two prior therapies for GVHD, and 10 did not otherwise meet the FDA definition of steroid refractory.

The trial’s primary endpoints were day-28 overall response rate and response duration. Among the 49 patients with steroid only–refractory GVHD, the overall response rate was 100% for grade 2 GVHD, 40.7% for grade 3, and 44.4% for grade 4. Median response duration was 16 days. For all 49 of these patients, the overall response rate was 57%, and the complete response rate was 31%.

Among all 71 participants, the most frequently reported adverse reactions were infections (55%) and edema (51%); anemia (71%), thrombocytopenia (75%), and neutropenia (58%) were the most common laboratory abnormalities.

cpalmer@mdedge.com

The Food and Drug Administration has approved Jafaki (ruxolitinib) for treatment of steroid-refractory acute graft-versus-host disease (GVHD) in adult and pediatric patients 12 years and older.

Ruxolitinib will be made available to appropriate patients immediately, according to a statement from Incyte, which markets the drug. The company noted that ruxolitinib is the first FDA-approved treatment for this indication.

The approval is based on data from the open-label, single-arm, multicenter REACH1 trial, which studied ruxolitinib in combination with corticosteroids. The 71 patients in the trial had grade 2-4 acute GVHD after allogeneic hematopoietic stem cell transplant; of these patients, 49 were refractory to steroids alone, 12 had received at least two prior therapies for GVHD, and 10 did not otherwise meet the FDA definition of steroid refractory.

The trial’s primary endpoints were day-28 overall response rate and response duration. Among the 49 patients with steroid only–refractory GVHD, the overall response rate was 100% for grade 2 GVHD, 40.7% for grade 3, and 44.4% for grade 4. Median response duration was 16 days. For all 49 of these patients, the overall response rate was 57%, and the complete response rate was 31%.

Among all 71 participants, the most frequently reported adverse reactions were infections (55%) and edema (51%); anemia (71%), thrombocytopenia (75%), and neutropenia (58%) were the most common laboratory abnormalities.

cpalmer@mdedge.com

Variants in the apolipoprotein B gene (APOB), which creates the main protein in low-density and very low-density cholesterol, may be associated with early-onset Alzheimer’s disease, Thomas Wingo, MD, and his colleagues have determined.

Kheng guan Toh/Thinkstock

The finding may help fill out the genetic risk picture for early-onset Alzheimer’s disease (EOAD), said Dr. Wingo of the Atlanta Veterans Affairs Medical Center. The study found that the already-known genetic markers for EOAD – mutations of the presenilin (PSEN) 1 and 2 genes and amyloid precursor protein (APP) – account for just a small fraction of cases.

“To place the genetic association between APOB and EOAD in context, we note that only 3.4% of all EOAD cases in our combined data set showed a known pathogenic mutation, and we found a stronger association between EOAD and rare coding variants in APOB, compared with PSEN1 in our fully adjusted analysis,” the team wrote. However, “approximately 5.0% of patients with EOAD and 1.7% of controls were found to harbor a rare coding polymorphism in APOB that is likely to disrupt the structure, functions, or abundance of ApoB protein.”

The team conducted genetic analysis on plasma samples from 2,125 EOAD and control subjects included in several research cohorts. They first determined the association between cholesterol and EOAD, and then the frequency of variants in apolipoprotein E epsilon 4 (APOE e4), APP, PSEN1, PSEN2, and ApoB. Gene sequencing revealed that 3.4% of samples showed mutations in APP, PSEN1, or PSEN2.

“Given the strong associations between APOE e4 and EOAD and elevated circulating LDL cholesterol levels, we expected individuals with EOAD to have elevated LDL levels,” the team said. But an analysis of 267 of the samples for lipid levels found that, even after the researchers controlled for APOE e4, EOAD cases had higher total cholesterol, low-density cholesterol, and plasma ApoB, compared with controls. However, they found no association between EOAD and high-density lipoprotein or triglycerides.

“Because total cholesterol largely consists of LDL-C, and ApoB is the main lipoprotein of LDL-C, these findings are consistent with one another.

“From these data, we estimated that LDL-C explains 7.6% of the variance in liability to EOAD, independently of APOE e4 ... These results demonstrate that elevated levels of LDL-C [and ApoB] were significantly associated with increased EOAD risk, and this effect was only partially mediated by APOE e4 genotype.”

The results also raised a question: What was driving the association between LDL and EOAD? Because variants of the ApoB gene can either raise or lower LDL, the team examined variants associated with coding changes. These variants were significantly more common in EOAD cases than in controls (5.0% vs. 1.7%).

“Two affected individuals ... were compound heterozygotes, with the remainder being heterozygotes,” the researchers wrote. “Each compound heterozygote case was heterozygous for two different rare coding sites ... Of these four variants, only [one] has been previously described.”

“Our finding of a significant association between rare coding variants in APOB and EOAD independently of APOE is novel, important, and consistent with multiple genome-wide association studies that revealed strong associations between late-onset AD and common intron markers of genes involved in brain cholesterol metabolism [ABCA7, BIN1, CLU, and SORL1]. Furthermore, mice overexpressing ApoB show hyperlipidemia, neurodegeneration, increases in APP, accumulation of amyloid plaques, and cognitive impairment similar to mice overexpressing wild-type human APP. Collectively, these studies and our findings suggest an important role of cholesterol metabolism in AD pathogenesis.”

This research was supported by grants from the Veterans Health Administration, the National Institutes of Health, the To Remember Foundation, the Douglas French Alzheimer’s Foundation, and a contract with the State of California Department of Health Services. Several authors reported financial ties to pharmaceutical companies outside of this work.

msullivan@mdedge.com

SOURCE: Wingo TS et al. JAMA Neurol. 2019 May 28. doi: 10.1001/jamaneurol.2019.0648.

Variants in the apolipoprotein B gene (APOB), which creates the main protein in low-density and very low-density cholesterol, may be associated with early-onset Alzheimer’s disease, Thomas Wingo, MD, and his colleagues have determined.

Kheng guan Toh/Thinkstock

The finding may help fill out the genetic risk picture for early-onset Alzheimer’s disease (EOAD), said Dr. Wingo of the Atlanta Veterans Affairs Medical Center. The study found that the already-known genetic markers for EOAD – mutations of the presenilin (PSEN) 1 and 2 genes and amyloid precursor protein (APP) – account for just a small fraction of cases.

“To place the genetic association between APOB and EOAD in context, we note that only 3.4% of all EOAD cases in our combined data set showed a known pathogenic mutation, and we found a stronger association between EOAD and rare coding variants in APOB, compared with PSEN1 in our fully adjusted analysis,” the team wrote. However, “approximately 5.0% of patients with EOAD and 1.7% of controls were found to harbor a rare coding polymorphism in APOB that is likely to disrupt the structure, functions, or abundance of ApoB protein.”

The team conducted genetic analysis on plasma samples from 2,125 EOAD and control subjects included in several research cohorts. They first determined the association between cholesterol and EOAD, and then the frequency of variants in apolipoprotein E epsilon 4 (APOE e4), APP, PSEN1, PSEN2, and ApoB. Gene sequencing revealed that 3.4% of samples showed mutations in APP, PSEN1, or PSEN2.

“Given the strong associations between APOE e4 and EOAD and elevated circulating LDL cholesterol levels, we expected individuals with EOAD to have elevated LDL levels,” the team said. But an analysis of 267 of the samples for lipid levels found that, even after the researchers controlled for APOE e4, EOAD cases had higher total cholesterol, low-density cholesterol, and plasma ApoB, compared with controls. However, they found no association between EOAD and high-density lipoprotein or triglycerides.

“Because total cholesterol largely consists of LDL-C, and ApoB is the main lipoprotein of LDL-C, these findings are consistent with one another.

“From these data, we estimated that LDL-C explains 7.6% of the variance in liability to EOAD, independently of APOE e4 ... These results demonstrate that elevated levels of LDL-C [and ApoB] were significantly associated with increased EOAD risk, and this effect was only partially mediated by APOE e4 genotype.”

The results also raised a question: What was driving the association between LDL and EOAD? Because variants of the ApoB gene can either raise or lower LDL, the team examined variants associated with coding changes. These variants were significantly more common in EOAD cases than in controls (5.0% vs. 1.7%).

“Two affected individuals ... were compound heterozygotes, with the remainder being heterozygotes,” the researchers wrote. “Each compound heterozygote case was heterozygous for two different rare coding sites ... Of these four variants, only [one] has been previously described.”

“Our finding of a significant association between rare coding variants in APOB and EOAD independently of APOE is novel, important, and consistent with multiple genome-wide association studies that revealed strong associations between late-onset AD and common intron markers of genes involved in brain cholesterol metabolism [ABCA7, BIN1, CLU, and SORL1]. Furthermore, mice overexpressing ApoB show hyperlipidemia, neurodegeneration, increases in APP, accumulation of amyloid plaques, and cognitive impairment similar to mice overexpressing wild-type human APP. Collectively, these studies and our findings suggest an important role of cholesterol metabolism in AD pathogenesis.”

This research was supported by grants from the Veterans Health Administration, the National Institutes of Health, the To Remember Foundation, the Douglas French Alzheimer’s Foundation, and a contract with the State of California Department of Health Services. Several authors reported financial ties to pharmaceutical companies outside of this work.

msullivan@mdedge.com

SOURCE: Wingo TS et al. JAMA Neurol. 2019 May 28. doi: 10.1001/jamaneurol.2019.0648.

Variants in the apolipoprotein B gene (APOB), which creates the main protein in low-density and very low-density cholesterol, may be associated with early-onset Alzheimer’s disease, Thomas Wingo, MD, and his colleagues have determined.

Kheng guan Toh/Thinkstock

The finding may help fill out the genetic risk picture for early-onset Alzheimer’s disease (EOAD), said Dr. Wingo of the Atlanta Veterans Affairs Medical Center. The study found that the already-known genetic markers for EOAD – mutations of the presenilin (PSEN) 1 and 2 genes and amyloid precursor protein (APP) – account for just a small fraction of cases.

“To place the genetic association between APOB and EOAD in context, we note that only 3.4% of all EOAD cases in our combined data set showed a known pathogenic mutation, and we found a stronger association between EOAD and rare coding variants in APOB, compared with PSEN1 in our fully adjusted analysis,” the team wrote. However, “approximately 5.0% of patients with EOAD and 1.7% of controls were found to harbor a rare coding polymorphism in APOB that is likely to disrupt the structure, functions, or abundance of ApoB protein.”

The team conducted genetic analysis on plasma samples from 2,125 EOAD and control subjects included in several research cohorts. They first determined the association between cholesterol and EOAD, and then the frequency of variants in apolipoprotein E epsilon 4 (APOE e4), APP, PSEN1, PSEN2, and ApoB. Gene sequencing revealed that 3.4% of samples showed mutations in APP, PSEN1, or PSEN2.

“Given the strong associations between APOE e4 and EOAD and elevated circulating LDL cholesterol levels, we expected individuals with EOAD to have elevated LDL levels,” the team said. But an analysis of 267 of the samples for lipid levels found that, even after the researchers controlled for APOE e4, EOAD cases had higher total cholesterol, low-density cholesterol, and plasma ApoB, compared with controls. However, they found no association between EOAD and high-density lipoprotein or triglycerides.

“Because total cholesterol largely consists of LDL-C, and ApoB is the main lipoprotein of LDL-C, these findings are consistent with one another.

“From these data, we estimated that LDL-C explains 7.6% of the variance in liability to EOAD, independently of APOE e4 ... These results demonstrate that elevated levels of LDL-C [and ApoB] were significantly associated with increased EOAD risk, and this effect was only partially mediated by APOE e4 genotype.”

The results also raised a question: What was driving the association between LDL and EOAD? Because variants of the ApoB gene can either raise or lower LDL, the team examined variants associated with coding changes. These variants were significantly more common in EOAD cases than in controls (5.0% vs. 1.7%).

“Two affected individuals ... were compound heterozygotes, with the remainder being heterozygotes,” the researchers wrote. “Each compound heterozygote case was heterozygous for two different rare coding sites ... Of these four variants, only [one] has been previously described.”

“Our finding of a significant association between rare coding variants in APOB and EOAD independently of APOE is novel, important, and consistent with multiple genome-wide association studies that revealed strong associations between late-onset AD and common intron markers of genes involved in brain cholesterol metabolism [ABCA7, BIN1, CLU, and SORL1]. Furthermore, mice overexpressing ApoB show hyperlipidemia, neurodegeneration, increases in APP, accumulation of amyloid plaques, and cognitive impairment similar to mice overexpressing wild-type human APP. Collectively, these studies and our findings suggest an important role of cholesterol metabolism in AD pathogenesis.”

This research was supported by grants from the Veterans Health Administration, the National Institutes of Health, the To Remember Foundation, the Douglas French Alzheimer’s Foundation, and a contract with the State of California Department of Health Services. Several authors reported financial ties to pharmaceutical companies outside of this work.

msullivan@mdedge.com

SOURCE: Wingo TS et al. JAMA Neurol. 2019 May 28. doi: 10.1001/jamaneurol.2019.0648.