The day wouldn’t be so bad if he would just go to sleep at night! How many times have you heard this plea from parents of your patients with ADHD? Sleep is important for everyone, but getting enough is both more important and more difficult for children with ADHD. About three-quarters of children with ADHD have significant problems with sleep, most even before any medication treatment. And inadequate sleep can exacerbate or even cause ADHD symptoms!

SeventyFour/iStock/Getty Images

Solving sleep problems for children with ADHD is not always simple. The kinds of sleep issues that are more common in children (and adults) with ADHD, compared with typical children, include behavioral bedtime resistance, circadian rhythm sleep disorder (CRSD), insomnia, morning sleepiness, night waking, periodic limb movement disorder (PLMD), restless leg syndrome (RLS), and sleep disordered breathing (SDB). Such a broad differential means a careful history and sometimes even lab studies may be needed.

Both initial and follow-up visits for ADHD should include a sleep history or, ideally, a tool such as BEARS sleep screening tool or Children’s Sleep Habits Questionnaire and a 2-week sleep diary (http://www.sleepfoundation.org/). These are good ways to collect signs of allergies or apnea (for SDB), limb movements or limb pain (for RLS or PLMD), mouth breathing, night waking, and snoring.

You also need to ask about alcohol, drugs, caffeine, and nicotine; asthma; comorbid conditions such as mental health disorders or their treatments; and enuresis (alone or part of nocturnal seizures).

Do I need to remind you to find out about electronics activating the child before bedtime – hidden under the covers, or signaling messages from friends in the middle of the night – and to encourage limits on these? Some sleep disorders warrant polysomnography in a sleep lab or from MyZeo.com (for PLMD and some SDB) or ferritin less than 50 mg/L (for RLS) for diagnosis and to guide treatment. Nasal steroids, antihistamines, or montelukast may help SDB when there are enlarged tonsils or adenoids, but adenotonsillectomy is usually curative.

The first line and most effective treatment for sleep problems in children with or without ADHD is improving sleep hygiene. Improved sleep “hygiene” sounds easy, but for children with ADHD and their parents, who often have ADHD too, changing behaviors can be tough! The key component is establishing habits for the entire sleep cycle: a steady pattern of reduced stimulation in the hour before bedtime (sans electronics); a friendly rather than irritated bedtime routine; and the same bedtime and wake up time, ideally 7 days per week. Bedtime stories read to the child can soothe at any age, not just toddlers! Of course, both children and families want fun and special occasions. For most, varying bedtime by up to 1 hour won’t mess up their biological clock, but for some even this should be avoided. Sleeping alone in a cool, dark, quiet room, nightly in the same bed (not used for other activities), is considered the ideal. Earplugs, white noise generators, and eye masks may be helpful. If sleeping with siblings is a necessity, bedtimes can be staggered to put the child to bed earlier or after others are asleep.

Struggles postponing bedtime may be part of a pattern of oppositionality common in ADHD, but the child may not be tired due to being off schedule (from CRSD), napping on the bus or after school, sleeping in mornings, or unrealistic parent expectations for sleep duration. Parents may want their hyperactive children to give them a break and go to bed at 8 p.m., but children aged 6-10 years need only 10-11 hours and those aged 10-17 years need 8.5-9.25 hours of sleep.

Not tired may instead be “wired” from lingering stimulant effects or even lack of such medication leaving the child overactive or rebounding from earlier medications. Lower afternoon doses or shorter-acting medication may solve lasting medication issues, but sometimes an additional low dose of stimulants actually will help a child with ADHD settle at bedtime. All stimulant medications can prolong sleep onset, often by 30 minutes, but this varies by individual and tends to resolve on its own a few weeks after a new or changed medicine. Switching medication category may allow a child to fall asleep faster. Atomoxetine and alpha agonists are less likely to delay sleep than methylphenidate (MPH).

What if sleep hygiene, behavioral methods, and adjusting ADHD medications is not enough? If sleep issues are causing significant problems, medication for sleep is worth a try. Controlled-release melatonin 1-2 hours before bedtime has data for effectiveness. There is no defined dose, so the lowest effective dose should be used, but 3-6 mg may be needed. Because many families with a child with ADHD are not organized enough to give medicine on this schedule, sublingual melatonin that acts in 15-20 minutes is a good alternative or even first choice. Clonidine 0.05-0.2 mg 1 hour before bedtime speeds sleep onset, lasts 3 hours, and does not carry over to sedation the next day. Stronger psychopharmaceuticals can assist sleep onset, including low dose mirtazapine or trazodone, but have the side effect of daytime sleepiness.

Management of waking in the middle of the night can be more difficult to treat as sleep drive has been dissipated. First, consider whether trips out of bed reflect a sleep association that has not been extinguished. Daytime atomoxetine or, better yet, MPH may improve night waking, and sometimes even a low-dose evening, long-acting medication, such as osmotic release oral system (OROS) extended release methylphenidate HCL (OROS MPH), helps. Short-acting clonidine or melatonin in the middle of the night or bedtime mirtazapine or trazodone also may be worth a try.

When dealing with sleep, keep in mind that 50% or more of children with ADHD have a coexisting mental health disorder. Anxiety, separation anxiety, depression, and dysthymia all often affect sleep onset, night waking, and sometimes early morning waking. The child or teen may need extra reassurance or company at bedtime (siblings or pets may suffice). Reading positive stories or playing soft music may be better at setting a positive mood and sense of safety for sleep, certainly more so than social media, which should be avoided.

Keep in mind that substance use is more common in ADHD as well as with those other mental health conditions and can interfere with restful sleep and make RLS worse. Bipolar disorder can be mistaken for ADHD as it often presents with hyperactivity but also can be comorbid. Sleep problems are increased sixfold when both are present. Prolonged periods awake at night and diminished need for sleep are signs that help differentiate bipolar from ADHD. Medication management for the bipolar disorder with atypicals can reduce sleep latency and reduce REM sleep, but also causes morning fatigue. Medications to treat other mental health problems can help sleep onset (for example, anticonvulsants, atypicals), or prolong it (SSRIs), change REM states (atypicals), and even exacerbate RLS (SSRIs). You can make changes or work with the child’s mental health specialist if medications are causing significant sleep problems.

When we help improve sleep for children with ADHD, it can lessen not only ADHD symptoms but also some symptoms of other mental health disorders, improve learning and behavior, and greatly improve family quality of life!
 

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at pdnews@mdedge.com.

The day wouldn’t be so bad if he would just go to sleep at night! How many times have you heard this plea from parents of your patients with ADHD? Sleep is important for everyone, but getting enough is both more important and more difficult for children with ADHD. About three-quarters of children with ADHD have significant problems with sleep, most even before any medication treatment. And inadequate sleep can exacerbate or even cause ADHD symptoms!

SeventyFour/iStock/Getty Images

Solving sleep problems for children with ADHD is not always simple. The kinds of sleep issues that are more common in children (and adults) with ADHD, compared with typical children, include behavioral bedtime resistance, circadian rhythm sleep disorder (CRSD), insomnia, morning sleepiness, night waking, periodic limb movement disorder (PLMD), restless leg syndrome (RLS), and sleep disordered breathing (SDB). Such a broad differential means a careful history and sometimes even lab studies may be needed.

Both initial and follow-up visits for ADHD should include a sleep history or, ideally, a tool such as BEARS sleep screening tool or Children’s Sleep Habits Questionnaire and a 2-week sleep diary (http://www.sleepfoundation.org/). These are good ways to collect signs of allergies or apnea (for SDB), limb movements or limb pain (for RLS or PLMD), mouth breathing, night waking, and snoring.

You also need to ask about alcohol, drugs, caffeine, and nicotine; asthma; comorbid conditions such as mental health disorders or their treatments; and enuresis (alone or part of nocturnal seizures).

Do I need to remind you to find out about electronics activating the child before bedtime – hidden under the covers, or signaling messages from friends in the middle of the night – and to encourage limits on these? Some sleep disorders warrant polysomnography in a sleep lab or from MyZeo.com (for PLMD and some SDB) or ferritin less than 50 mg/L (for RLS) for diagnosis and to guide treatment. Nasal steroids, antihistamines, or montelukast may help SDB when there are enlarged tonsils or adenoids, but adenotonsillectomy is usually curative.

The first line and most effective treatment for sleep problems in children with or without ADHD is improving sleep hygiene. Improved sleep “hygiene” sounds easy, but for children with ADHD and their parents, who often have ADHD too, changing behaviors can be tough! The key component is establishing habits for the entire sleep cycle: a steady pattern of reduced stimulation in the hour before bedtime (sans electronics); a friendly rather than irritated bedtime routine; and the same bedtime and wake up time, ideally 7 days per week. Bedtime stories read to the child can soothe at any age, not just toddlers! Of course, both children and families want fun and special occasions. For most, varying bedtime by up to 1 hour won’t mess up their biological clock, but for some even this should be avoided. Sleeping alone in a cool, dark, quiet room, nightly in the same bed (not used for other activities), is considered the ideal. Earplugs, white noise generators, and eye masks may be helpful. If sleeping with siblings is a necessity, bedtimes can be staggered to put the child to bed earlier or after others are asleep.

Struggles postponing bedtime may be part of a pattern of oppositionality common in ADHD, but the child may not be tired due to being off schedule (from CRSD), napping on the bus or after school, sleeping in mornings, or unrealistic parent expectations for sleep duration. Parents may want their hyperactive children to give them a break and go to bed at 8 p.m., but children aged 6-10 years need only 10-11 hours and those aged 10-17 years need 8.5-9.25 hours of sleep.

Not tired may instead be “wired” from lingering stimulant effects or even lack of such medication leaving the child overactive or rebounding from earlier medications. Lower afternoon doses or shorter-acting medication may solve lasting medication issues, but sometimes an additional low dose of stimulants actually will help a child with ADHD settle at bedtime. All stimulant medications can prolong sleep onset, often by 30 minutes, but this varies by individual and tends to resolve on its own a few weeks after a new or changed medicine. Switching medication category may allow a child to fall asleep faster. Atomoxetine and alpha agonists are less likely to delay sleep than methylphenidate (MPH).

What if sleep hygiene, behavioral methods, and adjusting ADHD medications is not enough? If sleep issues are causing significant problems, medication for sleep is worth a try. Controlled-release melatonin 1-2 hours before bedtime has data for effectiveness. There is no defined dose, so the lowest effective dose should be used, but 3-6 mg may be needed. Because many families with a child with ADHD are not organized enough to give medicine on this schedule, sublingual melatonin that acts in 15-20 minutes is a good alternative or even first choice. Clonidine 0.05-0.2 mg 1 hour before bedtime speeds sleep onset, lasts 3 hours, and does not carry over to sedation the next day. Stronger psychopharmaceuticals can assist sleep onset, including low dose mirtazapine or trazodone, but have the side effect of daytime sleepiness.

Management of waking in the middle of the night can be more difficult to treat as sleep drive has been dissipated. First, consider whether trips out of bed reflect a sleep association that has not been extinguished. Daytime atomoxetine or, better yet, MPH may improve night waking, and sometimes even a low-dose evening, long-acting medication, such as osmotic release oral system (OROS) extended release methylphenidate HCL (OROS MPH), helps. Short-acting clonidine or melatonin in the middle of the night or bedtime mirtazapine or trazodone also may be worth a try.

When dealing with sleep, keep in mind that 50% or more of children with ADHD have a coexisting mental health disorder. Anxiety, separation anxiety, depression, and dysthymia all often affect sleep onset, night waking, and sometimes early morning waking. The child or teen may need extra reassurance or company at bedtime (siblings or pets may suffice). Reading positive stories or playing soft music may be better at setting a positive mood and sense of safety for sleep, certainly more so than social media, which should be avoided.

Keep in mind that substance use is more common in ADHD as well as with those other mental health conditions and can interfere with restful sleep and make RLS worse. Bipolar disorder can be mistaken for ADHD as it often presents with hyperactivity but also can be comorbid. Sleep problems are increased sixfold when both are present. Prolonged periods awake at night and diminished need for sleep are signs that help differentiate bipolar from ADHD. Medication management for the bipolar disorder with atypicals can reduce sleep latency and reduce REM sleep, but also causes morning fatigue. Medications to treat other mental health problems can help sleep onset (for example, anticonvulsants, atypicals), or prolong it (SSRIs), change REM states (atypicals), and even exacerbate RLS (SSRIs). You can make changes or work with the child’s mental health specialist if medications are causing significant sleep problems.

When we help improve sleep for children with ADHD, it can lessen not only ADHD symptoms but also some symptoms of other mental health disorders, improve learning and behavior, and greatly improve family quality of life!
 

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at pdnews@mdedge.com.

The day wouldn’t be so bad if he would just go to sleep at night! How many times have you heard this plea from parents of your patients with ADHD? Sleep is important for everyone, but getting enough is both more important and more difficult for children with ADHD. About three-quarters of children with ADHD have significant problems with sleep, most even before any medication treatment. And inadequate sleep can exacerbate or even cause ADHD symptoms!

SeventyFour/iStock/Getty Images

Solving sleep problems for children with ADHD is not always simple. The kinds of sleep issues that are more common in children (and adults) with ADHD, compared with typical children, include behavioral bedtime resistance, circadian rhythm sleep disorder (CRSD), insomnia, morning sleepiness, night waking, periodic limb movement disorder (PLMD), restless leg syndrome (RLS), and sleep disordered breathing (SDB). Such a broad differential means a careful history and sometimes even lab studies may be needed.

Both initial and follow-up visits for ADHD should include a sleep history or, ideally, a tool such as BEARS sleep screening tool or Children’s Sleep Habits Questionnaire and a 2-week sleep diary (http://www.sleepfoundation.org/). These are good ways to collect signs of allergies or apnea (for SDB), limb movements or limb pain (for RLS or PLMD), mouth breathing, night waking, and snoring.

You also need to ask about alcohol, drugs, caffeine, and nicotine; asthma; comorbid conditions such as mental health disorders or their treatments; and enuresis (alone or part of nocturnal seizures).

Do I need to remind you to find out about electronics activating the child before bedtime – hidden under the covers, or signaling messages from friends in the middle of the night – and to encourage limits on these? Some sleep disorders warrant polysomnography in a sleep lab or from MyZeo.com (for PLMD and some SDB) or ferritin less than 50 mg/L (for RLS) for diagnosis and to guide treatment. Nasal steroids, antihistamines, or montelukast may help SDB when there are enlarged tonsils or adenoids, but adenotonsillectomy is usually curative.

The first line and most effective treatment for sleep problems in children with or without ADHD is improving sleep hygiene. Improved sleep “hygiene” sounds easy, but for children with ADHD and their parents, who often have ADHD too, changing behaviors can be tough! The key component is establishing habits for the entire sleep cycle: a steady pattern of reduced stimulation in the hour before bedtime (sans electronics); a friendly rather than irritated bedtime routine; and the same bedtime and wake up time, ideally 7 days per week. Bedtime stories read to the child can soothe at any age, not just toddlers! Of course, both children and families want fun and special occasions. For most, varying bedtime by up to 1 hour won’t mess up their biological clock, but for some even this should be avoided. Sleeping alone in a cool, dark, quiet room, nightly in the same bed (not used for other activities), is considered the ideal. Earplugs, white noise generators, and eye masks may be helpful. If sleeping with siblings is a necessity, bedtimes can be staggered to put the child to bed earlier or after others are asleep.

Struggles postponing bedtime may be part of a pattern of oppositionality common in ADHD, but the child may not be tired due to being off schedule (from CRSD), napping on the bus or after school, sleeping in mornings, or unrealistic parent expectations for sleep duration. Parents may want their hyperactive children to give them a break and go to bed at 8 p.m., but children aged 6-10 years need only 10-11 hours and those aged 10-17 years need 8.5-9.25 hours of sleep.

Not tired may instead be “wired” from lingering stimulant effects or even lack of such medication leaving the child overactive or rebounding from earlier medications. Lower afternoon doses or shorter-acting medication may solve lasting medication issues, but sometimes an additional low dose of stimulants actually will help a child with ADHD settle at bedtime. All stimulant medications can prolong sleep onset, often by 30 minutes, but this varies by individual and tends to resolve on its own a few weeks after a new or changed medicine. Switching medication category may allow a child to fall asleep faster. Atomoxetine and alpha agonists are less likely to delay sleep than methylphenidate (MPH).

What if sleep hygiene, behavioral methods, and adjusting ADHD medications is not enough? If sleep issues are causing significant problems, medication for sleep is worth a try. Controlled-release melatonin 1-2 hours before bedtime has data for effectiveness. There is no defined dose, so the lowest effective dose should be used, but 3-6 mg may be needed. Because many families with a child with ADHD are not organized enough to give medicine on this schedule, sublingual melatonin that acts in 15-20 minutes is a good alternative or even first choice. Clonidine 0.05-0.2 mg 1 hour before bedtime speeds sleep onset, lasts 3 hours, and does not carry over to sedation the next day. Stronger psychopharmaceuticals can assist sleep onset, including low dose mirtazapine or trazodone, but have the side effect of daytime sleepiness.

Management of waking in the middle of the night can be more difficult to treat as sleep drive has been dissipated. First, consider whether trips out of bed reflect a sleep association that has not been extinguished. Daytime atomoxetine or, better yet, MPH may improve night waking, and sometimes even a low-dose evening, long-acting medication, such as osmotic release oral system (OROS) extended release methylphenidate HCL (OROS MPH), helps. Short-acting clonidine or melatonin in the middle of the night or bedtime mirtazapine or trazodone also may be worth a try.

When dealing with sleep, keep in mind that 50% or more of children with ADHD have a coexisting mental health disorder. Anxiety, separation anxiety, depression, and dysthymia all often affect sleep onset, night waking, and sometimes early morning waking. The child or teen may need extra reassurance or company at bedtime (siblings or pets may suffice). Reading positive stories or playing soft music may be better at setting a positive mood and sense of safety for sleep, certainly more so than social media, which should be avoided.

Keep in mind that substance use is more common in ADHD as well as with those other mental health conditions and can interfere with restful sleep and make RLS worse. Bipolar disorder can be mistaken for ADHD as it often presents with hyperactivity but also can be comorbid. Sleep problems are increased sixfold when both are present. Prolonged periods awake at night and diminished need for sleep are signs that help differentiate bipolar from ADHD. Medication management for the bipolar disorder with atypicals can reduce sleep latency and reduce REM sleep, but also causes morning fatigue. Medications to treat other mental health problems can help sleep onset (for example, anticonvulsants, atypicals), or prolong it (SSRIs), change REM states (atypicals), and even exacerbate RLS (SSRIs). You can make changes or work with the child’s mental health specialist if medications are causing significant sleep problems.

When we help improve sleep for children with ADHD, it can lessen not only ADHD symptoms but also some symptoms of other mental health disorders, improve learning and behavior, and greatly improve family quality of life!
 

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at pdnews@mdedge.com.

ORLANDO – An investigational selective inhibitor of the complement pathway, sutimlimab, induced rapid and sustained benefits in patients with cold agglutinin disease, a rare autoimmune hemolytic anemia with no currently approved effective therapies.

Neil Osterweil/MDedge News

Among 24 patients with cold agglutinin disease who received at least one dose of sutimlimab in a phase 3 trial, 20 had a mean increase in hemoglobin of at least 1 g/dL, and 17 remained transfusion free from weeks 5 to 26 following sutimlimab infusion.

“Sutimlimab has the potential to change treatment practices for patients with this disease,” said lead author Alexander Röth, MD, from the University of Duisburg-Essen (Germany), at a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Mean total bilirubin rapidly normalized within 1-3 weeks of infusion of sutimlimab, and patients had a mean improvement of 11 points on the Functional Assessment of Chronic Illness Therapy–Fatigue scale (FACIT-F), indicating a substantial improvement in their quality of life, Dr. Röth said.

Cold agglutinin disease is an acquired hemolytic anemia with an underlying lymphoproliferative disorder. The estimated prevalence of the disease is 16 per 1 million persons. The disease is characterized by hemolysis driven by activation of the complement pathway, leading to opsonization of erythrocytes (coating of erythrocytes with particles that facilitate phagocytosis and other immune reactions), extravascular hemolysis (primarily in the liver), intravascular hemolysis, and anemia.

Patients experience severe fatigue and poor quality of life, as well as increased risk for thrombosis and mortality, compared with matched cohorts.

Sutimlimab is a humanized monoclonal antibody that blocks the C1s component of the classical complement pathway, thereby stopping pathway activation while leaving alternative lectin pathways intact.

Dr. Röth presented results of the phase 3, open-label Cardinal study. Patients with cold agglutinin disease with baseline hemoglobin of 10 g/dL or less, active hemolysis signaled by total bilirubin levels above normal, and at least one blood transfusion within the past 6 months were eligible for the study. Patients with secondary cold agglutinin syndrome or rituximab therapy within the last 3 months or combination therapies within the last 6 months were excluded.

Sutimlimab was delivered intravenously at a dose of 6.5 g for patients under 75 kg in weight and 7.5 g for those 75 kg and over at day 0 and 7, then every 2 weeks thereafter.

A total of 24 patients with a mean age of 71 years were enrolled. Of the 24 patients, 15 (62.5%) were women.

The patients had received a mean of 3.2 transfusions (range 1-19) in the previous 6 months, and 15 had received one or more prior targeted therapies for the disease within the last 5 years. The mean baseline hemoglobin level was 8.6 (range 4.9-11.1) g/dL.

Hemoglobin levels increased rapidly after the first infusion, with a mean increase of 1.2 g/dL at the end of week 1, and 2.3 g/dL after week 3.

The estimated mean increase at treatment assessment (an average of weeks 23, 25, and 26) – the primary endpoint – was 2.6 g/dL, exceeding the prespecified increase of at least 2 g/dL. Normalization of hemoglobin to 12 g/dL or greater was an alternative primary endpoint. The trial met the primary endpoint, with 13 of 24 patients (54.2%) achieving either of the two prespecified events.

The mean overall hemoglobin level was maintained above 11 g/dL after week 3. Of the 24 patients, 20 had hemoglobin increases of 1 g/dL or greater.

Mean total bilirubin, a marker of hemolysis, dropped markedly within hours of infusion and was normalized by week 3.

As noted before, patient quality of life, as measured by the FACIT-F scale, improved by a mean of 11 points from a mean baseline of 32 out of 52 points.

All but two patients had one or more treatment-emergent adverse events, and seven of these patients had a serious treatment-related event, although none of the serious events were thought to be related to sutimlimab. One patient with liver cancer died from causes deemed unrelated to the drug. There were no meningococcal infections.

All 22 patients who completed the 26 weeks of therapy continued on an extended safety phase of the study.

The study results demonstrate that targeting the complement pathways is an novel and effective approach to managing cold agglutinin disease, Dr. Röth concluded.

Neil Osterweil/MDedge News

In a press briefing the day before the presentation, moderator Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School, Baltimore, who treats patients with cold agglutinin disease, said that the results “are very exciting.”

“These patients are very difficult to treat and there really is no approved drug,” he said. “Right now, we usually use [rituximab] first line, but only half of those patients respond, and usually it only lasts for 6 months or so, so this is a welcome addition.”

Sutimlimab was granted Breakthrough Therapy designation by the Food and Drug Administration, and Orphan Drug status by the FDA, European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency in Japan.

The study was supported by Sanofi. Dr. Röth reported financial relationships with Sanofi and other companies.

SOURCE: Röth A et al. ASH 2019, Abstract LBA-2.

ORLANDO – An investigational selective inhibitor of the complement pathway, sutimlimab, induced rapid and sustained benefits in patients with cold agglutinin disease, a rare autoimmune hemolytic anemia with no currently approved effective therapies.

Neil Osterweil/MDedge News

Among 24 patients with cold agglutinin disease who received at least one dose of sutimlimab in a phase 3 trial, 20 had a mean increase in hemoglobin of at least 1 g/dL, and 17 remained transfusion free from weeks 5 to 26 following sutimlimab infusion.

“Sutimlimab has the potential to change treatment practices for patients with this disease,” said lead author Alexander Röth, MD, from the University of Duisburg-Essen (Germany), at a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Mean total bilirubin rapidly normalized within 1-3 weeks of infusion of sutimlimab, and patients had a mean improvement of 11 points on the Functional Assessment of Chronic Illness Therapy–Fatigue scale (FACIT-F), indicating a substantial improvement in their quality of life, Dr. Röth said.

Cold agglutinin disease is an acquired hemolytic anemia with an underlying lymphoproliferative disorder. The estimated prevalence of the disease is 16 per 1 million persons. The disease is characterized by hemolysis driven by activation of the complement pathway, leading to opsonization of erythrocytes (coating of erythrocytes with particles that facilitate phagocytosis and other immune reactions), extravascular hemolysis (primarily in the liver), intravascular hemolysis, and anemia.

Patients experience severe fatigue and poor quality of life, as well as increased risk for thrombosis and mortality, compared with matched cohorts.

Sutimlimab is a humanized monoclonal antibody that blocks the C1s component of the classical complement pathway, thereby stopping pathway activation while leaving alternative lectin pathways intact.

Dr. Röth presented results of the phase 3, open-label Cardinal study. Patients with cold agglutinin disease with baseline hemoglobin of 10 g/dL or less, active hemolysis signaled by total bilirubin levels above normal, and at least one blood transfusion within the past 6 months were eligible for the study. Patients with secondary cold agglutinin syndrome or rituximab therapy within the last 3 months or combination therapies within the last 6 months were excluded.

Sutimlimab was delivered intravenously at a dose of 6.5 g for patients under 75 kg in weight and 7.5 g for those 75 kg and over at day 0 and 7, then every 2 weeks thereafter.

A total of 24 patients with a mean age of 71 years were enrolled. Of the 24 patients, 15 (62.5%) were women.

The patients had received a mean of 3.2 transfusions (range 1-19) in the previous 6 months, and 15 had received one or more prior targeted therapies for the disease within the last 5 years. The mean baseline hemoglobin level was 8.6 (range 4.9-11.1) g/dL.

Hemoglobin levels increased rapidly after the first infusion, with a mean increase of 1.2 g/dL at the end of week 1, and 2.3 g/dL after week 3.

The estimated mean increase at treatment assessment (an average of weeks 23, 25, and 26) – the primary endpoint – was 2.6 g/dL, exceeding the prespecified increase of at least 2 g/dL. Normalization of hemoglobin to 12 g/dL or greater was an alternative primary endpoint. The trial met the primary endpoint, with 13 of 24 patients (54.2%) achieving either of the two prespecified events.

The mean overall hemoglobin level was maintained above 11 g/dL after week 3. Of the 24 patients, 20 had hemoglobin increases of 1 g/dL or greater.

Mean total bilirubin, a marker of hemolysis, dropped markedly within hours of infusion and was normalized by week 3.

As noted before, patient quality of life, as measured by the FACIT-F scale, improved by a mean of 11 points from a mean baseline of 32 out of 52 points.

All but two patients had one or more treatment-emergent adverse events, and seven of these patients had a serious treatment-related event, although none of the serious events were thought to be related to sutimlimab. One patient with liver cancer died from causes deemed unrelated to the drug. There were no meningococcal infections.

All 22 patients who completed the 26 weeks of therapy continued on an extended safety phase of the study.

The study results demonstrate that targeting the complement pathways is an novel and effective approach to managing cold agglutinin disease, Dr. Röth concluded.

Neil Osterweil/MDedge News

In a press briefing the day before the presentation, moderator Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School, Baltimore, who treats patients with cold agglutinin disease, said that the results “are very exciting.”

“These patients are very difficult to treat and there really is no approved drug,” he said. “Right now, we usually use [rituximab] first line, but only half of those patients respond, and usually it only lasts for 6 months or so, so this is a welcome addition.”

Sutimlimab was granted Breakthrough Therapy designation by the Food and Drug Administration, and Orphan Drug status by the FDA, European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency in Japan.

The study was supported by Sanofi. Dr. Röth reported financial relationships with Sanofi and other companies.

SOURCE: Röth A et al. ASH 2019, Abstract LBA-2.

ORLANDO – An investigational selective inhibitor of the complement pathway, sutimlimab, induced rapid and sustained benefits in patients with cold agglutinin disease, a rare autoimmune hemolytic anemia with no currently approved effective therapies.

Neil Osterweil/MDedge News

Among 24 patients with cold agglutinin disease who received at least one dose of sutimlimab in a phase 3 trial, 20 had a mean increase in hemoglobin of at least 1 g/dL, and 17 remained transfusion free from weeks 5 to 26 following sutimlimab infusion.

“Sutimlimab has the potential to change treatment practices for patients with this disease,” said lead author Alexander Röth, MD, from the University of Duisburg-Essen (Germany), at a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Mean total bilirubin rapidly normalized within 1-3 weeks of infusion of sutimlimab, and patients had a mean improvement of 11 points on the Functional Assessment of Chronic Illness Therapy–Fatigue scale (FACIT-F), indicating a substantial improvement in their quality of life, Dr. Röth said.

Cold agglutinin disease is an acquired hemolytic anemia with an underlying lymphoproliferative disorder. The estimated prevalence of the disease is 16 per 1 million persons. The disease is characterized by hemolysis driven by activation of the complement pathway, leading to opsonization of erythrocytes (coating of erythrocytes with particles that facilitate phagocytosis and other immune reactions), extravascular hemolysis (primarily in the liver), intravascular hemolysis, and anemia.

Patients experience severe fatigue and poor quality of life, as well as increased risk for thrombosis and mortality, compared with matched cohorts.

Sutimlimab is a humanized monoclonal antibody that blocks the C1s component of the classical complement pathway, thereby stopping pathway activation while leaving alternative lectin pathways intact.

Dr. Röth presented results of the phase 3, open-label Cardinal study. Patients with cold agglutinin disease with baseline hemoglobin of 10 g/dL or less, active hemolysis signaled by total bilirubin levels above normal, and at least one blood transfusion within the past 6 months were eligible for the study. Patients with secondary cold agglutinin syndrome or rituximab therapy within the last 3 months or combination therapies within the last 6 months were excluded.

Sutimlimab was delivered intravenously at a dose of 6.5 g for patients under 75 kg in weight and 7.5 g for those 75 kg and over at day 0 and 7, then every 2 weeks thereafter.

A total of 24 patients with a mean age of 71 years were enrolled. Of the 24 patients, 15 (62.5%) were women.

The patients had received a mean of 3.2 transfusions (range 1-19) in the previous 6 months, and 15 had received one or more prior targeted therapies for the disease within the last 5 years. The mean baseline hemoglobin level was 8.6 (range 4.9-11.1) g/dL.

Hemoglobin levels increased rapidly after the first infusion, with a mean increase of 1.2 g/dL at the end of week 1, and 2.3 g/dL after week 3.

The estimated mean increase at treatment assessment (an average of weeks 23, 25, and 26) – the primary endpoint – was 2.6 g/dL, exceeding the prespecified increase of at least 2 g/dL. Normalization of hemoglobin to 12 g/dL or greater was an alternative primary endpoint. The trial met the primary endpoint, with 13 of 24 patients (54.2%) achieving either of the two prespecified events.

The mean overall hemoglobin level was maintained above 11 g/dL after week 3. Of the 24 patients, 20 had hemoglobin increases of 1 g/dL or greater.

Mean total bilirubin, a marker of hemolysis, dropped markedly within hours of infusion and was normalized by week 3.

As noted before, patient quality of life, as measured by the FACIT-F scale, improved by a mean of 11 points from a mean baseline of 32 out of 52 points.

All but two patients had one or more treatment-emergent adverse events, and seven of these patients had a serious treatment-related event, although none of the serious events were thought to be related to sutimlimab. One patient with liver cancer died from causes deemed unrelated to the drug. There were no meningococcal infections.

All 22 patients who completed the 26 weeks of therapy continued on an extended safety phase of the study.

The study results demonstrate that targeting the complement pathways is an novel and effective approach to managing cold agglutinin disease, Dr. Röth concluded.

Neil Osterweil/MDedge News

In a press briefing the day before the presentation, moderator Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School, Baltimore, who treats patients with cold agglutinin disease, said that the results “are very exciting.”

“These patients are very difficult to treat and there really is no approved drug,” he said. “Right now, we usually use [rituximab] first line, but only half of those patients respond, and usually it only lasts for 6 months or so, so this is a welcome addition.”

Sutimlimab was granted Breakthrough Therapy designation by the Food and Drug Administration, and Orphan Drug status by the FDA, European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency in Japan.

The study was supported by Sanofi. Dr. Röth reported financial relationships with Sanofi and other companies.

SOURCE: Röth A et al. ASH 2019, Abstract LBA-2.

The Diagnosis: Dermatitis Herpetiformis 

Dermatitis herpetiformis (DH), also known as Duhring disease, is a rare autoimmune disease. It is the cutaneous manifestation of gluten sensitivity with antibodies targeting epidermal transglutaminase.¹ Symptoms of DH generally arise in the fourth decade of life, and children are less commonly affected,² though the diagnosis should be considered at any age, as our patient was aged 19 years at the time of presentation. Dermatitis herpetiformis predominantly affects white individuals of Northern European heritage, and males more often are affected than females.² There is a strong association with HLA-B8, HLA-DR3, and HLA-DQw2.³ It also is associated with other autoimmune disorders, including autoimmune thyroid disease, type 1 diabetes mellitus, and pernicious anemia.² 

Clinically, DH is characterized by groups of intensely pruritic papulovesicles that are symmetrically located on the extensor surfaces of the upper and lower extremities, scalp, nuchal area, back, and buttocks (quiz image). Less often, the groin also may be involved, as it was in our patient (Figure 1).⁴ Lesions can be papulovesicular or bullous, though they often are excoriated, and primary lesions may be difficult to identify.² The disease may have spontaneous remissions with frequent relapses. Most patients with DH have an asymptomatic gluten-sensitive enteropathy.³ 

A punch biopsy of a representative nonexcoriated lesion from our patient showed the characteristic collections of neutrophils and fibrin at the tips of dermal papillae on hematoxylin and eosin staining (Figure 2). These findings are suggestive of DH.¹ However, other bullous diseases, such as linear IgA dermatosis and epidermolysis bullosa acquisita, may have similar appearance on histology.¹ Direct immunofluorescence (DIF) of perilesional skin is the gold standard for diagnosing DH, with a sensitivity and specificity close to 100%.¹ Deposits of IgA generally are concentrated in previously involved skin or noninflamed perilesional skin; DIF of erythematous or lesional skin may be false negative.⁵ In our patient, DIF of perilesional uninvolved skin showed granular deposits of IgA at the dermoepidermal junction with accentuation in the dermal papillae (Figure 3), further suggestive of the diagnosis of DH.⁶ 

Patients with DH frequently will have specific IgA antibodies including anti-tissue transglutaminase (tTG), anti-epidermal transglutaminase, antiendomysial antibodies, and anti-synthetic deamidated gliadin peptides.¹ Only some of these tests are widely available, and the anti-tTG enzyme-linked immunosorbent assay is the least expensive and easiest to perform. A positive anti-tTG antibody test has a sensitivity ranging from 47% to 95% and a specificity greater than 90%.¹ Our patient tested positive for anti-tTG and anti-deamidated synthetic gliadin-derived peptides. A diagnostic algorithm based on current evidence suggests that in patients with clinical evidence of DH, typical DIF findings combined with positive anti-tTG antibodies confirms the diagnosis of DH, as was seen in our patient.^1,7 In situations where histopathology and/or antibody testing are inconclusive, additional testing to include HLA antigen typing, duodenal biopsy, and supplemental skin biopsies may be performed to help confirm or exclude a diagnosis of DH. It is unnecessary to perform a duodenal biopsy in patients with a confirmed diagnosis of DH, as DH is considered the specific cutaneous manifestation of celiac disease, and the diagnosis of DH is a diagnosis of celiac disease.¹  

Although pruritic papules may be found in several conditions, clinical, histopathologic, and DIF findings can help to confirm the diagnosis. Allergic contact dermatitis is a type IV hypersensitivity reaction causing eruptions of varying morphology, generally manifesting as pruritic scaly plaques that can occur anywhere on the body exposed to the offending allergen. Key histopathologic features of allergic contact dermatitis are eosinophilic spongiosis and exocytosis of eosinophils and lymphocytes.⁸ Papular urticaria is a hypersensitivity disorder to insect bites that consists of pruritic papules on exposed areas of skin, typically in children younger than 10 years. Genital and axillary areas usually are spared. The diagnosis is clinical.⁹ Recurrent herpes simplex virus infection is a short-lived outbreak that generally improves within 10 days. Herpes simplex virus infections usually are comprised of small vesicular or ulcerative lesions. Tzanck smear, skin biopsy, direct fluorescent antibody, viral culture, and polymerase chain reaction are diagnostic methods for herpes simplex virus.¹⁰ Scabies lesions typically are pruritic, erythematous, often excoriated papules and burrows located most commonly in the webs of fingers, wrists, axillae, areolae, waist, and genitalia. Diagnosis can be confirmed with scabies preparation (skin scraping showing mites, eggs, or feces), dermoscopy showing mites and burrows in vivo, or biopsy.¹¹  

First-line treatment in patients with DH and celiac disease is a strict gluten-free diet (GFD).¹ A GFD will resolve the cutaneous and gastrointestinal manifestations and is the only thing that will reduce the risk for lymphoma and other diseases associated with gluten-induced enteropathy.^1,2 A GFD alone will provide symptomatic relief over several months; dapsone and sulfapyridine can provide rapid relief of the pruritus and skin manifestations and usually can be weaned or discontinued after several months of following a strict GFD.¹² Patients on sulfone therapy require regular follow-up and monitoring due to the risk for hemolytic anemia and other adverse effects as well as to determine the appropriate time to discontinue the medication.¹² Although some patients are able to tolerate reintroduction of gluten into their diets after a period of remission, most will experience recurrent dermatologic manifestations if they continue to consume gluten.³ 

Because of our patient's impending move out of the area, no oral medications were started, and he was instructed to follow a GFD and seek medical care at his new location. The patient was contacted 6 months later and reported resolution of all skin lesions with just a GFD. The patient continued to follow-up with a dermatologist and gastroenterologist at his new location.

The Diagnosis: Dermatitis Herpetiformis 

Dermatitis herpetiformis (DH), also known as Duhring disease, is a rare autoimmune disease. It is the cutaneous manifestation of gluten sensitivity with antibodies targeting epidermal transglutaminase.¹ Symptoms of DH generally arise in the fourth decade of life, and children are less commonly affected,² though the diagnosis should be considered at any age, as our patient was aged 19 years at the time of presentation. Dermatitis herpetiformis predominantly affects white individuals of Northern European heritage, and males more often are affected than females.² There is a strong association with HLA-B8, HLA-DR3, and HLA-DQw2.³ It also is associated with other autoimmune disorders, including autoimmune thyroid disease, type 1 diabetes mellitus, and pernicious anemia.² 

Clinically, DH is characterized by groups of intensely pruritic papulovesicles that are symmetrically located on the extensor surfaces of the upper and lower extremities, scalp, nuchal area, back, and buttocks (quiz image). Less often, the groin also may be involved, as it was in our patient (Figure 1).⁴ Lesions can be papulovesicular or bullous, though they often are excoriated, and primary lesions may be difficult to identify.² The disease may have spontaneous remissions with frequent relapses. Most patients with DH have an asymptomatic gluten-sensitive enteropathy.³ 

A punch biopsy of a representative nonexcoriated lesion from our patient showed the characteristic collections of neutrophils and fibrin at the tips of dermal papillae on hematoxylin and eosin staining (Figure 2). These findings are suggestive of DH.¹ However, other bullous diseases, such as linear IgA dermatosis and epidermolysis bullosa acquisita, may have similar appearance on histology.¹ Direct immunofluorescence (DIF) of perilesional skin is the gold standard for diagnosing DH, with a sensitivity and specificity close to 100%.¹ Deposits of IgA generally are concentrated in previously involved skin or noninflamed perilesional skin; DIF of erythematous or lesional skin may be false negative.⁵ In our patient, DIF of perilesional uninvolved skin showed granular deposits of IgA at the dermoepidermal junction with accentuation in the dermal papillae (Figure 3), further suggestive of the diagnosis of DH.⁶ 

Patients with DH frequently will have specific IgA antibodies including anti-tissue transglutaminase (tTG), anti-epidermal transglutaminase, antiendomysial antibodies, and anti-synthetic deamidated gliadin peptides.¹ Only some of these tests are widely available, and the anti-tTG enzyme-linked immunosorbent assay is the least expensive and easiest to perform. A positive anti-tTG antibody test has a sensitivity ranging from 47% to 95% and a specificity greater than 90%.¹ Our patient tested positive for anti-tTG and anti-deamidated synthetic gliadin-derived peptides. A diagnostic algorithm based on current evidence suggests that in patients with clinical evidence of DH, typical DIF findings combined with positive anti-tTG antibodies confirms the diagnosis of DH, as was seen in our patient.^1,7 In situations where histopathology and/or antibody testing are inconclusive, additional testing to include HLA antigen typing, duodenal biopsy, and supplemental skin biopsies may be performed to help confirm or exclude a diagnosis of DH. It is unnecessary to perform a duodenal biopsy in patients with a confirmed diagnosis of DH, as DH is considered the specific cutaneous manifestation of celiac disease, and the diagnosis of DH is a diagnosis of celiac disease.¹  

Although pruritic papules may be found in several conditions, clinical, histopathologic, and DIF findings can help to confirm the diagnosis. Allergic contact dermatitis is a type IV hypersensitivity reaction causing eruptions of varying morphology, generally manifesting as pruritic scaly plaques that can occur anywhere on the body exposed to the offending allergen. Key histopathologic features of allergic contact dermatitis are eosinophilic spongiosis and exocytosis of eosinophils and lymphocytes.⁸ Papular urticaria is a hypersensitivity disorder to insect bites that consists of pruritic papules on exposed areas of skin, typically in children younger than 10 years. Genital and axillary areas usually are spared. The diagnosis is clinical.⁹ Recurrent herpes simplex virus infection is a short-lived outbreak that generally improves within 10 days. Herpes simplex virus infections usually are comprised of small vesicular or ulcerative lesions. Tzanck smear, skin biopsy, direct fluorescent antibody, viral culture, and polymerase chain reaction are diagnostic methods for herpes simplex virus.¹⁰ Scabies lesions typically are pruritic, erythematous, often excoriated papules and burrows located most commonly in the webs of fingers, wrists, axillae, areolae, waist, and genitalia. Diagnosis can be confirmed with scabies preparation (skin scraping showing mites, eggs, or feces), dermoscopy showing mites and burrows in vivo, or biopsy.¹¹  

First-line treatment in patients with DH and celiac disease is a strict gluten-free diet (GFD).¹ A GFD will resolve the cutaneous and gastrointestinal manifestations and is the only thing that will reduce the risk for lymphoma and other diseases associated with gluten-induced enteropathy.^1,2 A GFD alone will provide symptomatic relief over several months; dapsone and sulfapyridine can provide rapid relief of the pruritus and skin manifestations and usually can be weaned or discontinued after several months of following a strict GFD.¹² Patients on sulfone therapy require regular follow-up and monitoring due to the risk for hemolytic anemia and other adverse effects as well as to determine the appropriate time to discontinue the medication.¹² Although some patients are able to tolerate reintroduction of gluten into their diets after a period of remission, most will experience recurrent dermatologic manifestations if they continue to consume gluten.³ 

Because of our patient's impending move out of the area, no oral medications were started, and he was instructed to follow a GFD and seek medical care at his new location. The patient was contacted 6 months later and reported resolution of all skin lesions with just a GFD. The patient continued to follow-up with a dermatologist and gastroenterologist at his new location.

The Diagnosis: Dermatitis Herpetiformis 

Dermatitis herpetiformis (DH), also known as Duhring disease, is a rare autoimmune disease. It is the cutaneous manifestation of gluten sensitivity with antibodies targeting epidermal transglutaminase.¹ Symptoms of DH generally arise in the fourth decade of life, and children are less commonly affected,² though the diagnosis should be considered at any age, as our patient was aged 19 years at the time of presentation. Dermatitis herpetiformis predominantly affects white individuals of Northern European heritage, and males more often are affected than females.² There is a strong association with HLA-B8, HLA-DR3, and HLA-DQw2.³ It also is associated with other autoimmune disorders, including autoimmune thyroid disease, type 1 diabetes mellitus, and pernicious anemia.² 

Clinically, DH is characterized by groups of intensely pruritic papulovesicles that are symmetrically located on the extensor surfaces of the upper and lower extremities, scalp, nuchal area, back, and buttocks (quiz image). Less often, the groin also may be involved, as it was in our patient (Figure 1).⁴ Lesions can be papulovesicular or bullous, though they often are excoriated, and primary lesions may be difficult to identify.² The disease may have spontaneous remissions with frequent relapses. Most patients with DH have an asymptomatic gluten-sensitive enteropathy.³ 

A punch biopsy of a representative nonexcoriated lesion from our patient showed the characteristic collections of neutrophils and fibrin at the tips of dermal papillae on hematoxylin and eosin staining (Figure 2). These findings are suggestive of DH.¹ However, other bullous diseases, such as linear IgA dermatosis and epidermolysis bullosa acquisita, may have similar appearance on histology.¹ Direct immunofluorescence (DIF) of perilesional skin is the gold standard for diagnosing DH, with a sensitivity and specificity close to 100%.¹ Deposits of IgA generally are concentrated in previously involved skin or noninflamed perilesional skin; DIF of erythematous or lesional skin may be false negative.⁵ In our patient, DIF of perilesional uninvolved skin showed granular deposits of IgA at the dermoepidermal junction with accentuation in the dermal papillae (Figure 3), further suggestive of the diagnosis of DH.⁶ 

Patients with DH frequently will have specific IgA antibodies including anti-tissue transglutaminase (tTG), anti-epidermal transglutaminase, antiendomysial antibodies, and anti-synthetic deamidated gliadin peptides.¹ Only some of these tests are widely available, and the anti-tTG enzyme-linked immunosorbent assay is the least expensive and easiest to perform. A positive anti-tTG antibody test has a sensitivity ranging from 47% to 95% and a specificity greater than 90%.¹ Our patient tested positive for anti-tTG and anti-deamidated synthetic gliadin-derived peptides. A diagnostic algorithm based on current evidence suggests that in patients with clinical evidence of DH, typical DIF findings combined with positive anti-tTG antibodies confirms the diagnosis of DH, as was seen in our patient.^1,7 In situations where histopathology and/or antibody testing are inconclusive, additional testing to include HLA antigen typing, duodenal biopsy, and supplemental skin biopsies may be performed to help confirm or exclude a diagnosis of DH. It is unnecessary to perform a duodenal biopsy in patients with a confirmed diagnosis of DH, as DH is considered the specific cutaneous manifestation of celiac disease, and the diagnosis of DH is a diagnosis of celiac disease.¹  

Although pruritic papules may be found in several conditions, clinical, histopathologic, and DIF findings can help to confirm the diagnosis. Allergic contact dermatitis is a type IV hypersensitivity reaction causing eruptions of varying morphology, generally manifesting as pruritic scaly plaques that can occur anywhere on the body exposed to the offending allergen. Key histopathologic features of allergic contact dermatitis are eosinophilic spongiosis and exocytosis of eosinophils and lymphocytes.⁸ Papular urticaria is a hypersensitivity disorder to insect bites that consists of pruritic papules on exposed areas of skin, typically in children younger than 10 years. Genital and axillary areas usually are spared. The diagnosis is clinical.⁹ Recurrent herpes simplex virus infection is a short-lived outbreak that generally improves within 10 days. Herpes simplex virus infections usually are comprised of small vesicular or ulcerative lesions. Tzanck smear, skin biopsy, direct fluorescent antibody, viral culture, and polymerase chain reaction are diagnostic methods for herpes simplex virus.¹⁰ Scabies lesions typically are pruritic, erythematous, often excoriated papules and burrows located most commonly in the webs of fingers, wrists, axillae, areolae, waist, and genitalia. Diagnosis can be confirmed with scabies preparation (skin scraping showing mites, eggs, or feces), dermoscopy showing mites and burrows in vivo, or biopsy.¹¹  

First-line treatment in patients with DH and celiac disease is a strict gluten-free diet (GFD).¹ A GFD will resolve the cutaneous and gastrointestinal manifestations and is the only thing that will reduce the risk for lymphoma and other diseases associated with gluten-induced enteropathy.^1,2 A GFD alone will provide symptomatic relief over several months; dapsone and sulfapyridine can provide rapid relief of the pruritus and skin manifestations and usually can be weaned or discontinued after several months of following a strict GFD.¹² Patients on sulfone therapy require regular follow-up and monitoring due to the risk for hemolytic anemia and other adverse effects as well as to determine the appropriate time to discontinue the medication.¹² Although some patients are able to tolerate reintroduction of gluten into their diets after a period of remission, most will experience recurrent dermatologic manifestations if they continue to consume gluten.³ 

Because of our patient's impending move out of the area, no oral medications were started, and he was instructed to follow a GFD and seek medical care at his new location. The patient was contacted 6 months later and reported resolution of all skin lesions with just a GFD. The patient continued to follow-up with a dermatologist and gastroenterologist at his new location.

More work is needed to address how addiction is handled both within the military and for veterans after they serve. Removing the stigma around addiction treatment is key to addressing the issue, Anthony Dekker, DO, Northern Arizona VA Healthcare System, said at the AMSUS annual meeting on December 4, 2019.

“When we are talking about treating addiction in the military and the VA, those are 2 different issues,” Dr. Dekker said. “In the VA, it should be understood this is a service that needs to be provided. In the military, it is highly dependent on command. Some commands are in favor of treatment. Some commands are in favor of separation.”

But that separation comes with a cost. Dr. Dekker noted that the military spends about $200,000 to get a person from recruitment to an E-5 pay grade and about $400,000 to an O-5 pay grade. That can be a huge investment loss considering the cost of treatment for someone who is suffering from a use disorder.

“Treatment is going to cost about $44,000,” he said. “That will be treatment in a residential center. That was a person who is serious enough to come into a residential center, follow up with a partial hospital program and continue with ongoing [treatment] that would last a year.”

He touted some of the successes addiction treatment programs have had, recalling data from 2008-2009 from 110 military active-duty service members treated across 5 residential treatment centers in the Washington, DC, area. Within a year, 91% had separated from the military either because of a command decision before treatment or because of loss of recover.

“We know what works in addiction,” he said, noting that program changes that involved using a combination of medication-assisted treatments with regular substance use screenings and medical practitioner follow-up has helped to reduce the rate of lost recovery to 12%. He also noted that in 2013-2014, 41 active military members who received treatment in the same centers were able to be redeployed to Afghanistan and had no relapses during that deployment. 

“We try to take the stigma away,” Dr. Dekker said. “So if you have leadership who has a stigma against addiction treatment, you are going to have a steep incline to work against, whereas if you have leadership that were, I would say, endowed with a different sense of knowledge and experience,” there is a much greater chance for helping both military service members and veterans alike.

He called on the US Department of Veterans Affairs (VA) to look more closely at how it is prescribing opioids. While acknowledging the opioid addiction epidemic, he noted that simply cutting back on prescribing may not be the right solution because it is having a ripple effect and causing other problems, namely that although the VA has written 60% fewer opioid prescriptions from 2012 to 2019, overdose rates have doubled as military members and veterans are seeking opioids from other sources outside of a controlled, safer medical environment.

It can be especially problematic for those who have a legitimate medical need for opioids but have a disqualifying event that causes the pain medication to be cut off.

“We need to have a different answer to this because termination of opioids because a patient is positive for marijuana or even positive for cocaine doesn’t mean you take services away. You ramp services up,” Dr. Dekker said. “If I have a patient who has a chronic pain syndrome, the only thing that is going to push him out of my system is if they threaten my staff.…The loss from recovery is not a reason to lose treatment. That is another concept that needs to be addressed and we need to really look at that.”

He also called on VA leadership to be more encouraging in prescribing buprenorphine, noting that many doctors and nurses have waivers to prescribe it, but there is a lot of reluctance to do so, even though there is a lot of success with that treatment.

More work is needed to address how addiction is handled both within the military and for veterans after they serve. Removing the stigma around addiction treatment is key to addressing the issue, Anthony Dekker, DO, Northern Arizona VA Healthcare System, said at the AMSUS annual meeting on December 4, 2019.

“When we are talking about treating addiction in the military and the VA, those are 2 different issues,” Dr. Dekker said. “In the VA, it should be understood this is a service that needs to be provided. In the military, it is highly dependent on command. Some commands are in favor of treatment. Some commands are in favor of separation.”

But that separation comes with a cost. Dr. Dekker noted that the military spends about $200,000 to get a person from recruitment to an E-5 pay grade and about $400,000 to an O-5 pay grade. That can be a huge investment loss considering the cost of treatment for someone who is suffering from a use disorder.

“Treatment is going to cost about $44,000,” he said. “That will be treatment in a residential center. That was a person who is serious enough to come into a residential center, follow up with a partial hospital program and continue with ongoing [treatment] that would last a year.”

He touted some of the successes addiction treatment programs have had, recalling data from 2008-2009 from 110 military active-duty service members treated across 5 residential treatment centers in the Washington, DC, area. Within a year, 91% had separated from the military either because of a command decision before treatment or because of loss of recover.

“We know what works in addiction,” he said, noting that program changes that involved using a combination of medication-assisted treatments with regular substance use screenings and medical practitioner follow-up has helped to reduce the rate of lost recovery to 12%. He also noted that in 2013-2014, 41 active military members who received treatment in the same centers were able to be redeployed to Afghanistan and had no relapses during that deployment. 

“We try to take the stigma away,” Dr. Dekker said. “So if you have leadership who has a stigma against addiction treatment, you are going to have a steep incline to work against, whereas if you have leadership that were, I would say, endowed with a different sense of knowledge and experience,” there is a much greater chance for helping both military service members and veterans alike.

He called on the US Department of Veterans Affairs (VA) to look more closely at how it is prescribing opioids. While acknowledging the opioid addiction epidemic, he noted that simply cutting back on prescribing may not be the right solution because it is having a ripple effect and causing other problems, namely that although the VA has written 60% fewer opioid prescriptions from 2012 to 2019, overdose rates have doubled as military members and veterans are seeking opioids from other sources outside of a controlled, safer medical environment.

It can be especially problematic for those who have a legitimate medical need for opioids but have a disqualifying event that causes the pain medication to be cut off.

“We need to have a different answer to this because termination of opioids because a patient is positive for marijuana or even positive for cocaine doesn’t mean you take services away. You ramp services up,” Dr. Dekker said. “If I have a patient who has a chronic pain syndrome, the only thing that is going to push him out of my system is if they threaten my staff.…The loss from recovery is not a reason to lose treatment. That is another concept that needs to be addressed and we need to really look at that.”

He also called on VA leadership to be more encouraging in prescribing buprenorphine, noting that many doctors and nurses have waivers to prescribe it, but there is a lot of reluctance to do so, even though there is a lot of success with that treatment.

More work is needed to address how addiction is handled both within the military and for veterans after they serve. Removing the stigma around addiction treatment is key to addressing the issue, Anthony Dekker, DO, Northern Arizona VA Healthcare System, said at the AMSUS annual meeting on December 4, 2019.

“When we are talking about treating addiction in the military and the VA, those are 2 different issues,” Dr. Dekker said. “In the VA, it should be understood this is a service that needs to be provided. In the military, it is highly dependent on command. Some commands are in favor of treatment. Some commands are in favor of separation.”

But that separation comes with a cost. Dr. Dekker noted that the military spends about $200,000 to get a person from recruitment to an E-5 pay grade and about $400,000 to an O-5 pay grade. That can be a huge investment loss considering the cost of treatment for someone who is suffering from a use disorder.

“Treatment is going to cost about $44,000,” he said. “That will be treatment in a residential center. That was a person who is serious enough to come into a residential center, follow up with a partial hospital program and continue with ongoing [treatment] that would last a year.”

He touted some of the successes addiction treatment programs have had, recalling data from 2008-2009 from 110 military active-duty service members treated across 5 residential treatment centers in the Washington, DC, area. Within a year, 91% had separated from the military either because of a command decision before treatment or because of loss of recover.

“We know what works in addiction,” he said, noting that program changes that involved using a combination of medication-assisted treatments with regular substance use screenings and medical practitioner follow-up has helped to reduce the rate of lost recovery to 12%. He also noted that in 2013-2014, 41 active military members who received treatment in the same centers were able to be redeployed to Afghanistan and had no relapses during that deployment. 

“We try to take the stigma away,” Dr. Dekker said. “So if you have leadership who has a stigma against addiction treatment, you are going to have a steep incline to work against, whereas if you have leadership that were, I would say, endowed with a different sense of knowledge and experience,” there is a much greater chance for helping both military service members and veterans alike.

He called on the US Department of Veterans Affairs (VA) to look more closely at how it is prescribing opioids. While acknowledging the opioid addiction epidemic, he noted that simply cutting back on prescribing may not be the right solution because it is having a ripple effect and causing other problems, namely that although the VA has written 60% fewer opioid prescriptions from 2012 to 2019, overdose rates have doubled as military members and veterans are seeking opioids from other sources outside of a controlled, safer medical environment.

It can be especially problematic for those who have a legitimate medical need for opioids but have a disqualifying event that causes the pain medication to be cut off.

“We need to have a different answer to this because termination of opioids because a patient is positive for marijuana or even positive for cocaine doesn’t mean you take services away. You ramp services up,” Dr. Dekker said. “If I have a patient who has a chronic pain syndrome, the only thing that is going to push him out of my system is if they threaten my staff.…The loss from recovery is not a reason to lose treatment. That is another concept that needs to be addressed and we need to really look at that.”

He also called on VA leadership to be more encouraging in prescribing buprenorphine, noting that many doctors and nurses have waivers to prescribe it, but there is a lot of reluctance to do so, even though there is a lot of success with that treatment.

ATLANTA – Patients with Raynaud’s phenomenon and puffy fingers, disease-specific antibodies, and/or nailfold video capillaroscopy abnormalities were more likely to progress to systemic sclerosis within 5 years than were patients without those features, according to recent results from the Very Early Diagnosis Of Systemic Sclerosis (VEDOSS) study presented at the annual meeting of the American College of Rheumatology.

“Our data show that thanks [to a] combination of the signs that characterize the various phases of the disease, patients can be diagnosed [with systemic sclerosis] in the very early stages,” first author Silvia Bellando-Randone, MD, PhD, assistant professor in the division of rheumatology at the University of Florence (Italy), said in her presentation.

Dr. Bellando-Randone and colleagues performed a longitudinal, observational study of 742 patients (mean 45.7 years old) at 42 centers in a cohort of mostly women (90%), nearly all of whom had had Raynaud’s phenomenon for longer than 36 months (97.5%). Patients were excluded if they had systemic sclerosis based on ACR 1980 classification criteria and/or ACR–European League Against Rheumatism 2013 criteria, had systemic sclerosis together with other connective-tissue diseases, or were unlikely to be present for three consecutive annual exams. Data collection began in March 2012 with follow-up of 5 years.

The researchers determined the positive predictive values (PPV) and negative predictive values (NPV) of clinical features, systemic sclerosis–specific antibodies, and nailfold video capillaroscopy (NVC) abnormalities on progression from Raynaud’s phenomenon to systemic sclerosis. Laboratory data collected at baseline included presence of antinuclear antibodies (ANA), anticentromere antibodies (ACA), anti-DNA topoisomerase I antibodies (anti-Scl-70), anti-U1RNP antibodies, anti-RNA polymerase III antibodies (ARA), N-terminal pro b-type natriuretic peptides (NT-proBNP), and C-reactive protein/erythrocyte sedimentation rate. Dr. Bellando-Randone and colleagues also collected clinical, pulmonary function, lung high-resolution CT, echocardiographic, and ECG data at baseline.

Predictions were based on these factors alone and in combination. Overall, 65% of patients had positive ANA. Other baseline characteristics present in patients that predicted systemic sclerosis included positive ACA/anti-Scl-70/ARA (32%), NVC abnormalities such as giant capillaries (25%), and puffy fingers (17%).

Using Kaplan-Meier analysis, the researchers found 7.4% of 401 patients who were ANA positive progressed to meet ACR-EULAR 2013 criteria, and the percentage of these patients increased to 29.3% at 3 years and 44.1% at 5 years. When the researchers considered disease-specific antibodies alone, 10.6% of 90 patients progressed from Raynaud’s phenomenon to systemic sclerosis within 1 year, 39.6% within 3 years, and 50.3% within 5 years. When the researchers analyzed disease-specific antibodies and NVC abnormalities together, 16% of 72 patients progressed to systemic sclerosis within 1 year, 61.7% within 3 years, and 77.4% within 5 years.

Puffy fingers also were a predictor of progression, and 14.4% of 69 patients with puffy fingers alone progressed from Raynaud’s phenomenon to systemic sclerosis at 1 year, 47.7% at 3 years, and 67.9% at 5 years. Considering puffy fingers and disease-specific antibodies together, 20% of 27 patients progressed at 1 year, 56.3% at 3 years, and 91.3% at 5 years. No patients with puffy fingers together and NVC abnormalities progressed to systemic sclerosis at 1 year, but 60.4% of 22 patients progressed at 3 years before plateauing at 5 years. For patients with NVC abnormalities alone, 7.1% progressed to systemic sclerosis from Raynaud’s phenomenon at 1 year, 39.4% at 3 years, and 52.7% at 5 years.

“Regarding capillaroscopy, we have to say that not all centers that participated were equally screened in capillaroscopy, and so we cannot assume the accuracy of this data,” she said.

Dr. Bellando-Randone noted that, apart from puffy fingers, disease-specific antibodies, and NVC abnormalities, patients were more likely to have a history of esophageal symptoms if they progressed to systemic sclerosis (37.3%), compared with patients who did not progress (23.6%; P = .003).

Puffy fingers alone were an independent predictor of systemic sclerosis (PPV, 78.9%; NPV, 45.1%) as well as in combination with disease-specific antibodies (PPV, 94.1%; NPV, 43.9%). The combination of disease-specific antibodies plus NVC abnormalities also independently predicted progression to systemic sclerosis (PPV, 82.2%; NPV, 50.4%). In a Cox multivariate analysis, disease-specific antibodies (relative risk, 5.4; 95% confidence interval, 3.7-7.9) and puffy fingers (RR, 3.0; 95% CI, 2.0-4.4) together were strongly predictive of progression from Raynaud’s phenomenon to systemic sclerosis (RR, 4.3; 95% CI, 2.6-7.3).

“This is really important for the risk stratification of patients [in] the very early stages of the disease, even if these data should be corroborated by larger data in larger studies in the future,” said Dr. Bellando-Randone.

The investigators reported having no conflicts of interest.

SOURCE: Bellando-Randone S et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 2914.

ATLANTA – Patients with Raynaud’s phenomenon and puffy fingers, disease-specific antibodies, and/or nailfold video capillaroscopy abnormalities were more likely to progress to systemic sclerosis within 5 years than were patients without those features, according to recent results from the Very Early Diagnosis Of Systemic Sclerosis (VEDOSS) study presented at the annual meeting of the American College of Rheumatology.

“Our data show that thanks [to a] combination of the signs that characterize the various phases of the disease, patients can be diagnosed [with systemic sclerosis] in the very early stages,” first author Silvia Bellando-Randone, MD, PhD, assistant professor in the division of rheumatology at the University of Florence (Italy), said in her presentation.

Dr. Bellando-Randone and colleagues performed a longitudinal, observational study of 742 patients (mean 45.7 years old) at 42 centers in a cohort of mostly women (90%), nearly all of whom had had Raynaud’s phenomenon for longer than 36 months (97.5%). Patients were excluded if they had systemic sclerosis based on ACR 1980 classification criteria and/or ACR–European League Against Rheumatism 2013 criteria, had systemic sclerosis together with other connective-tissue diseases, or were unlikely to be present for three consecutive annual exams. Data collection began in March 2012 with follow-up of 5 years.

The researchers determined the positive predictive values (PPV) and negative predictive values (NPV) of clinical features, systemic sclerosis–specific antibodies, and nailfold video capillaroscopy (NVC) abnormalities on progression from Raynaud’s phenomenon to systemic sclerosis. Laboratory data collected at baseline included presence of antinuclear antibodies (ANA), anticentromere antibodies (ACA), anti-DNA topoisomerase I antibodies (anti-Scl-70), anti-U1RNP antibodies, anti-RNA polymerase III antibodies (ARA), N-terminal pro b-type natriuretic peptides (NT-proBNP), and C-reactive protein/erythrocyte sedimentation rate. Dr. Bellando-Randone and colleagues also collected clinical, pulmonary function, lung high-resolution CT, echocardiographic, and ECG data at baseline.

Predictions were based on these factors alone and in combination. Overall, 65% of patients had positive ANA. Other baseline characteristics present in patients that predicted systemic sclerosis included positive ACA/anti-Scl-70/ARA (32%), NVC abnormalities such as giant capillaries (25%), and puffy fingers (17%).

Using Kaplan-Meier analysis, the researchers found 7.4% of 401 patients who were ANA positive progressed to meet ACR-EULAR 2013 criteria, and the percentage of these patients increased to 29.3% at 3 years and 44.1% at 5 years. When the researchers considered disease-specific antibodies alone, 10.6% of 90 patients progressed from Raynaud’s phenomenon to systemic sclerosis within 1 year, 39.6% within 3 years, and 50.3% within 5 years. When the researchers analyzed disease-specific antibodies and NVC abnormalities together, 16% of 72 patients progressed to systemic sclerosis within 1 year, 61.7% within 3 years, and 77.4% within 5 years.

Puffy fingers also were a predictor of progression, and 14.4% of 69 patients with puffy fingers alone progressed from Raynaud’s phenomenon to systemic sclerosis at 1 year, 47.7% at 3 years, and 67.9% at 5 years. Considering puffy fingers and disease-specific antibodies together, 20% of 27 patients progressed at 1 year, 56.3% at 3 years, and 91.3% at 5 years. No patients with puffy fingers together and NVC abnormalities progressed to systemic sclerosis at 1 year, but 60.4% of 22 patients progressed at 3 years before plateauing at 5 years. For patients with NVC abnormalities alone, 7.1% progressed to systemic sclerosis from Raynaud’s phenomenon at 1 year, 39.4% at 3 years, and 52.7% at 5 years.

“Regarding capillaroscopy, we have to say that not all centers that participated were equally screened in capillaroscopy, and so we cannot assume the accuracy of this data,” she said.

Dr. Bellando-Randone noted that, apart from puffy fingers, disease-specific antibodies, and NVC abnormalities, patients were more likely to have a history of esophageal symptoms if they progressed to systemic sclerosis (37.3%), compared with patients who did not progress (23.6%; P = .003).

Puffy fingers alone were an independent predictor of systemic sclerosis (PPV, 78.9%; NPV, 45.1%) as well as in combination with disease-specific antibodies (PPV, 94.1%; NPV, 43.9%). The combination of disease-specific antibodies plus NVC abnormalities also independently predicted progression to systemic sclerosis (PPV, 82.2%; NPV, 50.4%). In a Cox multivariate analysis, disease-specific antibodies (relative risk, 5.4; 95% confidence interval, 3.7-7.9) and puffy fingers (RR, 3.0; 95% CI, 2.0-4.4) together were strongly predictive of progression from Raynaud’s phenomenon to systemic sclerosis (RR, 4.3; 95% CI, 2.6-7.3).

“This is really important for the risk stratification of patients [in] the very early stages of the disease, even if these data should be corroborated by larger data in larger studies in the future,” said Dr. Bellando-Randone.

The investigators reported having no conflicts of interest.

SOURCE: Bellando-Randone S et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 2914.

ATLANTA – Patients with Raynaud’s phenomenon and puffy fingers, disease-specific antibodies, and/or nailfold video capillaroscopy abnormalities were more likely to progress to systemic sclerosis within 5 years than were patients without those features, according to recent results from the Very Early Diagnosis Of Systemic Sclerosis (VEDOSS) study presented at the annual meeting of the American College of Rheumatology.

“Our data show that thanks [to a] combination of the signs that characterize the various phases of the disease, patients can be diagnosed [with systemic sclerosis] in the very early stages,” first author Silvia Bellando-Randone, MD, PhD, assistant professor in the division of rheumatology at the University of Florence (Italy), said in her presentation.

Dr. Bellando-Randone and colleagues performed a longitudinal, observational study of 742 patients (mean 45.7 years old) at 42 centers in a cohort of mostly women (90%), nearly all of whom had had Raynaud’s phenomenon for longer than 36 months (97.5%). Patients were excluded if they had systemic sclerosis based on ACR 1980 classification criteria and/or ACR–European League Against Rheumatism 2013 criteria, had systemic sclerosis together with other connective-tissue diseases, or were unlikely to be present for three consecutive annual exams. Data collection began in March 2012 with follow-up of 5 years.

The researchers determined the positive predictive values (PPV) and negative predictive values (NPV) of clinical features, systemic sclerosis–specific antibodies, and nailfold video capillaroscopy (NVC) abnormalities on progression from Raynaud’s phenomenon to systemic sclerosis. Laboratory data collected at baseline included presence of antinuclear antibodies (ANA), anticentromere antibodies (ACA), anti-DNA topoisomerase I antibodies (anti-Scl-70), anti-U1RNP antibodies, anti-RNA polymerase III antibodies (ARA), N-terminal pro b-type natriuretic peptides (NT-proBNP), and C-reactive protein/erythrocyte sedimentation rate. Dr. Bellando-Randone and colleagues also collected clinical, pulmonary function, lung high-resolution CT, echocardiographic, and ECG data at baseline.

Predictions were based on these factors alone and in combination. Overall, 65% of patients had positive ANA. Other baseline characteristics present in patients that predicted systemic sclerosis included positive ACA/anti-Scl-70/ARA (32%), NVC abnormalities such as giant capillaries (25%), and puffy fingers (17%).

Using Kaplan-Meier analysis, the researchers found 7.4% of 401 patients who were ANA positive progressed to meet ACR-EULAR 2013 criteria, and the percentage of these patients increased to 29.3% at 3 years and 44.1% at 5 years. When the researchers considered disease-specific antibodies alone, 10.6% of 90 patients progressed from Raynaud’s phenomenon to systemic sclerosis within 1 year, 39.6% within 3 years, and 50.3% within 5 years. When the researchers analyzed disease-specific antibodies and NVC abnormalities together, 16% of 72 patients progressed to systemic sclerosis within 1 year, 61.7% within 3 years, and 77.4% within 5 years.

Puffy fingers also were a predictor of progression, and 14.4% of 69 patients with puffy fingers alone progressed from Raynaud’s phenomenon to systemic sclerosis at 1 year, 47.7% at 3 years, and 67.9% at 5 years. Considering puffy fingers and disease-specific antibodies together, 20% of 27 patients progressed at 1 year, 56.3% at 3 years, and 91.3% at 5 years. No patients with puffy fingers together and NVC abnormalities progressed to systemic sclerosis at 1 year, but 60.4% of 22 patients progressed at 3 years before plateauing at 5 years. For patients with NVC abnormalities alone, 7.1% progressed to systemic sclerosis from Raynaud’s phenomenon at 1 year, 39.4% at 3 years, and 52.7% at 5 years.

“Regarding capillaroscopy, we have to say that not all centers that participated were equally screened in capillaroscopy, and so we cannot assume the accuracy of this data,” she said.

Dr. Bellando-Randone noted that, apart from puffy fingers, disease-specific antibodies, and NVC abnormalities, patients were more likely to have a history of esophageal symptoms if they progressed to systemic sclerosis (37.3%), compared with patients who did not progress (23.6%; P = .003).

Puffy fingers alone were an independent predictor of systemic sclerosis (PPV, 78.9%; NPV, 45.1%) as well as in combination with disease-specific antibodies (PPV, 94.1%; NPV, 43.9%). The combination of disease-specific antibodies plus NVC abnormalities also independently predicted progression to systemic sclerosis (PPV, 82.2%; NPV, 50.4%). In a Cox multivariate analysis, disease-specific antibodies (relative risk, 5.4; 95% confidence interval, 3.7-7.9) and puffy fingers (RR, 3.0; 95% CI, 2.0-4.4) together were strongly predictive of progression from Raynaud’s phenomenon to systemic sclerosis (RR, 4.3; 95% CI, 2.6-7.3).

“This is really important for the risk stratification of patients [in] the very early stages of the disease, even if these data should be corroborated by larger data in larger studies in the future,” said Dr. Bellando-Randone.

The investigators reported having no conflicts of interest.

SOURCE: Bellando-Randone S et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 2914.

One theme emerged from multiple military healthy system (MHS) leaders at the recent AMSUS annual conference: Significant change is coming to the MHS, and military health care providers can either embrace and shape that change or somebody else will. “If we don’t shape our future, others will step in and do it for us,” Tom McCaffrey, Assistant Secretary of Defense for Health Affairs; Defense Health Agency (DHA), and the Uniformed Service University for the Health Sciences (USU) told the audience.

The “historic” changes are underway, as the DHA has already begun to take over control of many military treatment facilities (MTFs) that were formerly operated by the separate services. In the next step of the transition, nearly 250 individual MTFs will be combined—along with TRICARE providers—in 21 geographically based “markets” in order to streamline management and avoid redundancies.

The exact details of the changes in store have not been released. McCaffrey noted that US Department of Defense (DoD) leadership will submit the “framework” for their assessment of the MHS to Congress “very soon, and at that point we will begin the hard work of detailed implementation of the results of that assessment and recommendations from the department.” Changes are expected to continue through fiscal year 2021, and some sources have estimated that as many as 18,000 jobs could be eliminated in the process.

Although Congress drove these changes in the National Defense Authorization Act of 2017, MHS leaders insist they are determining how to make the transformation without hurting medical readiness. “We the senior leadership of the MHS must continue to work together to shape our system to meet the challenges of the new environment,” McCaffrey insisted.

It seems as though all elements of the MHS are on the table. One report has suggested that the USU budget could be cut by a third. “Given the USU’s track record of excellence, we were alarmed to learn that the department is considering cuts as high as 30% to the university’s budget for research, development, testing, and evaluation, and 34% to university operations and maintenance... includ[ing] the cancellation of a $445 million military construction project and closure of the USU medical school,” US senators Chris Van Hollen (D-MD), Ben Cardin (D-MD.), Jack Reed (D-RI), and Congressman Jamie Raskin (D-MD) wrote in a November 21, 2019, letter to US Department of Defense Secretary Mark Esper. “These cuts, even if only partially implemented or scaled back, will adversely impact the enterprise across recruitment, retention, access to research funding, and severely impact medical readiness at a time when demand is increasing.”

The medical readiness of military health care providers remains one of the thorniest challenges revolving around the DHA transition. “As an infantryman, from my perspective if you can't maintain effectiveness on the trauma side than it is not worth getting more efficient,” argued LTG (Ret) Jeffrey S. Buchannon, who formerly served as senior commander of Fort Sam Houston, which includes Brooke Army Medical Center, the military’s only level 1 trauma center and 1 of only 2 trauma centers in San Antonio. “We need the home game in order to prepare for the away game,”

In its review, DoD is looking at how the MTFs support inpatient and/or outpatient services to maintain medical force readiness. “We need to identify those areas where we can expand capacity at MTFs that offer potential for sustaining the skills and knowledge of our members,” said McCaffrey. “But we also must examine those areas where facilities do not offer now and likely will not be able to offer in the future a platform for maximizing capabilities to support medical readiness. In those situations, we must be open to right sizing MTF services and capabilities so as to ensure that we are using finite resources most efficiently while not compromising our ability to meet the mission.”

“Our military healthy system is the envy of the world. Any great power competitor would trade its health care and battlefield medicine capabilities for the system you have built,” McCaffrey said. “But just as America’s combat supremacy is not guaranteed nor is the supremacy of the MHS.” The US faces new global security challenges, McCaffrey argued, and “we must adapt and evolve if we are to successfully meet these challenges.”

One theme emerged from multiple military healthy system (MHS) leaders at the recent AMSUS annual conference: Significant change is coming to the MHS, and military health care providers can either embrace and shape that change or somebody else will. “If we don’t shape our future, others will step in and do it for us,” Tom McCaffrey, Assistant Secretary of Defense for Health Affairs; Defense Health Agency (DHA), and the Uniformed Service University for the Health Sciences (USU) told the audience.

The “historic” changes are underway, as the DHA has already begun to take over control of many military treatment facilities (MTFs) that were formerly operated by the separate services. In the next step of the transition, nearly 250 individual MTFs will be combined—along with TRICARE providers—in 21 geographically based “markets” in order to streamline management and avoid redundancies.

The exact details of the changes in store have not been released. McCaffrey noted that US Department of Defense (DoD) leadership will submit the “framework” for their assessment of the MHS to Congress “very soon, and at that point we will begin the hard work of detailed implementation of the results of that assessment and recommendations from the department.” Changes are expected to continue through fiscal year 2021, and some sources have estimated that as many as 18,000 jobs could be eliminated in the process.

Although Congress drove these changes in the National Defense Authorization Act of 2017, MHS leaders insist they are determining how to make the transformation without hurting medical readiness. “We the senior leadership of the MHS must continue to work together to shape our system to meet the challenges of the new environment,” McCaffrey insisted.

It seems as though all elements of the MHS are on the table. One report has suggested that the USU budget could be cut by a third. “Given the USU’s track record of excellence, we were alarmed to learn that the department is considering cuts as high as 30% to the university’s budget for research, development, testing, and evaluation, and 34% to university operations and maintenance... includ[ing] the cancellation of a $445 million military construction project and closure of the USU medical school,” US senators Chris Van Hollen (D-MD), Ben Cardin (D-MD.), Jack Reed (D-RI), and Congressman Jamie Raskin (D-MD) wrote in a November 21, 2019, letter to US Department of Defense Secretary Mark Esper. “These cuts, even if only partially implemented or scaled back, will adversely impact the enterprise across recruitment, retention, access to research funding, and severely impact medical readiness at a time when demand is increasing.”

The medical readiness of military health care providers remains one of the thorniest challenges revolving around the DHA transition. “As an infantryman, from my perspective if you can't maintain effectiveness on the trauma side than it is not worth getting more efficient,” argued LTG (Ret) Jeffrey S. Buchannon, who formerly served as senior commander of Fort Sam Houston, which includes Brooke Army Medical Center, the military’s only level 1 trauma center and 1 of only 2 trauma centers in San Antonio. “We need the home game in order to prepare for the away game,”

In its review, DoD is looking at how the MTFs support inpatient and/or outpatient services to maintain medical force readiness. “We need to identify those areas where we can expand capacity at MTFs that offer potential for sustaining the skills and knowledge of our members,” said McCaffrey. “But we also must examine those areas where facilities do not offer now and likely will not be able to offer in the future a platform for maximizing capabilities to support medical readiness. In those situations, we must be open to right sizing MTF services and capabilities so as to ensure that we are using finite resources most efficiently while not compromising our ability to meet the mission.”

“Our military healthy system is the envy of the world. Any great power competitor would trade its health care and battlefield medicine capabilities for the system you have built,” McCaffrey said. “But just as America’s combat supremacy is not guaranteed nor is the supremacy of the MHS.” The US faces new global security challenges, McCaffrey argued, and “we must adapt and evolve if we are to successfully meet these challenges.”

One theme emerged from multiple military healthy system (MHS) leaders at the recent AMSUS annual conference: Significant change is coming to the MHS, and military health care providers can either embrace and shape that change or somebody else will. “If we don’t shape our future, others will step in and do it for us,” Tom McCaffrey, Assistant Secretary of Defense for Health Affairs; Defense Health Agency (DHA), and the Uniformed Service University for the Health Sciences (USU) told the audience.

The “historic” changes are underway, as the DHA has already begun to take over control of many military treatment facilities (MTFs) that were formerly operated by the separate services. In the next step of the transition, nearly 250 individual MTFs will be combined—along with TRICARE providers—in 21 geographically based “markets” in order to streamline management and avoid redundancies.

The exact details of the changes in store have not been released. McCaffrey noted that US Department of Defense (DoD) leadership will submit the “framework” for their assessment of the MHS to Congress “very soon, and at that point we will begin the hard work of detailed implementation of the results of that assessment and recommendations from the department.” Changes are expected to continue through fiscal year 2021, and some sources have estimated that as many as 18,000 jobs could be eliminated in the process.

Although Congress drove these changes in the National Defense Authorization Act of 2017, MHS leaders insist they are determining how to make the transformation without hurting medical readiness. “We the senior leadership of the MHS must continue to work together to shape our system to meet the challenges of the new environment,” McCaffrey insisted.

It seems as though all elements of the MHS are on the table. One report has suggested that the USU budget could be cut by a third. “Given the USU’s track record of excellence, we were alarmed to learn that the department is considering cuts as high as 30% to the university’s budget for research, development, testing, and evaluation, and 34% to university operations and maintenance... includ[ing] the cancellation of a $445 million military construction project and closure of the USU medical school,” US senators Chris Van Hollen (D-MD), Ben Cardin (D-MD.), Jack Reed (D-RI), and Congressman Jamie Raskin (D-MD) wrote in a November 21, 2019, letter to US Department of Defense Secretary Mark Esper. “These cuts, even if only partially implemented or scaled back, will adversely impact the enterprise across recruitment, retention, access to research funding, and severely impact medical readiness at a time when demand is increasing.”

The medical readiness of military health care providers remains one of the thorniest challenges revolving around the DHA transition. “As an infantryman, from my perspective if you can't maintain effectiveness on the trauma side than it is not worth getting more efficient,” argued LTG (Ret) Jeffrey S. Buchannon, who formerly served as senior commander of Fort Sam Houston, which includes Brooke Army Medical Center, the military’s only level 1 trauma center and 1 of only 2 trauma centers in San Antonio. “We need the home game in order to prepare for the away game,”

In its review, DoD is looking at how the MTFs support inpatient and/or outpatient services to maintain medical force readiness. “We need to identify those areas where we can expand capacity at MTFs that offer potential for sustaining the skills and knowledge of our members,” said McCaffrey. “But we also must examine those areas where facilities do not offer now and likely will not be able to offer in the future a platform for maximizing capabilities to support medical readiness. In those situations, we must be open to right sizing MTF services and capabilities so as to ensure that we are using finite resources most efficiently while not compromising our ability to meet the mission.”

“Our military healthy system is the envy of the world. Any great power competitor would trade its health care and battlefield medicine capabilities for the system you have built,” McCaffrey said. “But just as America’s combat supremacy is not guaranteed nor is the supremacy of the MHS.” The US faces new global security challenges, McCaffrey argued, and “we must adapt and evolve if we are to successfully meet these challenges.”

ORLANDO – A novel Bruton tyrosine kinase inhibitor has produced favorable results in patients with relapsed or refractory mantle cell lymphoma, according to findings presented at the annual meeting of the American Society of Hematology.

Jennifer Smith/MDedge

In a phase 2 trial, orelabrutinib produced an overall response rate of 86% and a 12-month progression-free survival rate of 64%. Safety results with orelabrutinib were superior to historical results with ibrutinib.

The efficacy and safety profile of orelabrutinib, as well as its “convenient” dosing, may make it the “preferred therapeutic choice for B-cell malignancy,” said Lijuan Deng, MD, PhD, of Peking University Cancer Hospital & Institute, Beijing, who presented the phase 2 trial of orelabrutinib at ASH 2019.

The trial enrolled 106 patients with relapsed/refractory mantle cell lymphoma who were treated at 22 centers in China. At baseline, the patients had a median age of 62 years (range, 37-73 years), and 79.2% were men. Most patients (94.4%) had stage III-IV disease.

Prior therapies included CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-based (69.8%), EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin)-based (22.6%), DHAP (dexamethasone, cytarabine, and cisplatin)-based (22.6%), CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone)-based (12.3%), and ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin)-based (4.7%) regimens, and 88.7% of patients had received prior anti-CD20 therapy.

Patients received orelabrutinib at 100 mg twice daily (n = 20) or 150 mg once a day (n = 86). All 106 patients were evaluable for safety, and 99 were evaluable for efficacy.

Efficacy

“Orelabrutinib achieved high response and durable remissions,” Dr. Deng said.

The overall response rate was 85.9% in the evaluable efficacy population and 83.5% in the 150-mg dosing arm. The complete response rates were 27.3% and 29.1%, respectively. The median time to response, overall, was 1.9 months.

The median duration of response and median progression-free survival were not reached at a median follow-up of 10.5 months. At 12 months, 74.3% of patients were still in response, and the progression-free survival rate was 64%.

Safety

Most adverse events were grade 1-2 in nature. The most common grade 3 or higher events were platelet count decrease (11.3%), neutrophil count decrease (8.5%), anemia (7.5%), hypertension (3.8%), pneumonia (2.8%), white blood count decrease (1.9%), and hypokalemia (1.9%).

Adverse events of interest included grade 3 or higher hypertension (3.8%), diarrhea (6.6%), and infection (10.4%), as well as secondary malignancy (0.9%, n = 1). There were no cases of grade 3 or higher hemorrhage, grade 3 or higher atrial fibrillation/flutter, or grade 5 treatment-related adverse events.

Dr. Deng noted that rates of grade 3 or higher hemorrhage, atrial fibrillation, diarrhea, and infection, as well as rates of secondary malignancies, have historically been higher with ibrutinib (Blood. 2015 Aug 6;126[6]:739-45; Lancet. 2016 Feb 20;387[10020]:770-8).

“Orelabrutinib has an improved safety profile in patients with relapsed or refractory mantle cell lymphoma,” Dr. Deng said. “The most common adverse events were cytopenia and infections, which are considered mechanism based.”

The study was sponsored by InnoCare Pharma. Dr. Deng reported having no conflicts of interest.

jensmith@mdedge.com

SOURCE: Deng L et al. ASH 2019, Abstract 755.

ORLANDO – A novel Bruton tyrosine kinase inhibitor has produced favorable results in patients with relapsed or refractory mantle cell lymphoma, according to findings presented at the annual meeting of the American Society of Hematology.

Jennifer Smith/MDedge

In a phase 2 trial, orelabrutinib produced an overall response rate of 86% and a 12-month progression-free survival rate of 64%. Safety results with orelabrutinib were superior to historical results with ibrutinib.

The efficacy and safety profile of orelabrutinib, as well as its “convenient” dosing, may make it the “preferred therapeutic choice for B-cell malignancy,” said Lijuan Deng, MD, PhD, of Peking University Cancer Hospital & Institute, Beijing, who presented the phase 2 trial of orelabrutinib at ASH 2019.

The trial enrolled 106 patients with relapsed/refractory mantle cell lymphoma who were treated at 22 centers in China. At baseline, the patients had a median age of 62 years (range, 37-73 years), and 79.2% were men. Most patients (94.4%) had stage III-IV disease.

Prior therapies included CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-based (69.8%), EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin)-based (22.6%), DHAP (dexamethasone, cytarabine, and cisplatin)-based (22.6%), CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone)-based (12.3%), and ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin)-based (4.7%) regimens, and 88.7% of patients had received prior anti-CD20 therapy.

Patients received orelabrutinib at 100 mg twice daily (n = 20) or 150 mg once a day (n = 86). All 106 patients were evaluable for safety, and 99 were evaluable for efficacy.

Efficacy

“Orelabrutinib achieved high response and durable remissions,” Dr. Deng said.

The overall response rate was 85.9% in the evaluable efficacy population and 83.5% in the 150-mg dosing arm. The complete response rates were 27.3% and 29.1%, respectively. The median time to response, overall, was 1.9 months.

The median duration of response and median progression-free survival were not reached at a median follow-up of 10.5 months. At 12 months, 74.3% of patients were still in response, and the progression-free survival rate was 64%.

Safety

Most adverse events were grade 1-2 in nature. The most common grade 3 or higher events were platelet count decrease (11.3%), neutrophil count decrease (8.5%), anemia (7.5%), hypertension (3.8%), pneumonia (2.8%), white blood count decrease (1.9%), and hypokalemia (1.9%).

Adverse events of interest included grade 3 or higher hypertension (3.8%), diarrhea (6.6%), and infection (10.4%), as well as secondary malignancy (0.9%, n = 1). There were no cases of grade 3 or higher hemorrhage, grade 3 or higher atrial fibrillation/flutter, or grade 5 treatment-related adverse events.

Dr. Deng noted that rates of grade 3 or higher hemorrhage, atrial fibrillation, diarrhea, and infection, as well as rates of secondary malignancies, have historically been higher with ibrutinib (Blood. 2015 Aug 6;126[6]:739-45; Lancet. 2016 Feb 20;387[10020]:770-8).

“Orelabrutinib has an improved safety profile in patients with relapsed or refractory mantle cell lymphoma,” Dr. Deng said. “The most common adverse events were cytopenia and infections, which are considered mechanism based.”

The study was sponsored by InnoCare Pharma. Dr. Deng reported having no conflicts of interest.

jensmith@mdedge.com

SOURCE: Deng L et al. ASH 2019, Abstract 755.

ORLANDO – A novel Bruton tyrosine kinase inhibitor has produced favorable results in patients with relapsed or refractory mantle cell lymphoma, according to findings presented at the annual meeting of the American Society of Hematology.

Jennifer Smith/MDedge

In a phase 2 trial, orelabrutinib produced an overall response rate of 86% and a 12-month progression-free survival rate of 64%. Safety results with orelabrutinib were superior to historical results with ibrutinib.

The efficacy and safety profile of orelabrutinib, as well as its “convenient” dosing, may make it the “preferred therapeutic choice for B-cell malignancy,” said Lijuan Deng, MD, PhD, of Peking University Cancer Hospital & Institute, Beijing, who presented the phase 2 trial of orelabrutinib at ASH 2019.

The trial enrolled 106 patients with relapsed/refractory mantle cell lymphoma who were treated at 22 centers in China. At baseline, the patients had a median age of 62 years (range, 37-73 years), and 79.2% were men. Most patients (94.4%) had stage III-IV disease.

Prior therapies included CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-based (69.8%), EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin)-based (22.6%), DHAP (dexamethasone, cytarabine, and cisplatin)-based (22.6%), CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone)-based (12.3%), and ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin)-based (4.7%) regimens, and 88.7% of patients had received prior anti-CD20 therapy.

Patients received orelabrutinib at 100 mg twice daily (n = 20) or 150 mg once a day (n = 86). All 106 patients were evaluable for safety, and 99 were evaluable for efficacy.

Efficacy

“Orelabrutinib achieved high response and durable remissions,” Dr. Deng said.

The overall response rate was 85.9% in the evaluable efficacy population and 83.5% in the 150-mg dosing arm. The complete response rates were 27.3% and 29.1%, respectively. The median time to response, overall, was 1.9 months.

The median duration of response and median progression-free survival were not reached at a median follow-up of 10.5 months. At 12 months, 74.3% of patients were still in response, and the progression-free survival rate was 64%.

Safety

Most adverse events were grade 1-2 in nature. The most common grade 3 or higher events were platelet count decrease (11.3%), neutrophil count decrease (8.5%), anemia (7.5%), hypertension (3.8%), pneumonia (2.8%), white blood count decrease (1.9%), and hypokalemia (1.9%).

Adverse events of interest included grade 3 or higher hypertension (3.8%), diarrhea (6.6%), and infection (10.4%), as well as secondary malignancy (0.9%, n = 1). There were no cases of grade 3 or higher hemorrhage, grade 3 or higher atrial fibrillation/flutter, or grade 5 treatment-related adverse events.

Dr. Deng noted that rates of grade 3 or higher hemorrhage, atrial fibrillation, diarrhea, and infection, as well as rates of secondary malignancies, have historically been higher with ibrutinib (Blood. 2015 Aug 6;126[6]:739-45; Lancet. 2016 Feb 20;387[10020]:770-8).

“Orelabrutinib has an improved safety profile in patients with relapsed or refractory mantle cell lymphoma,” Dr. Deng said. “The most common adverse events were cytopenia and infections, which are considered mechanism based.”

The study was sponsored by InnoCare Pharma. Dr. Deng reported having no conflicts of interest.

jensmith@mdedge.com

SOURCE: Deng L et al. ASH 2019, Abstract 755.

SAN ANTONIO – Tucatinib, an investigational oral inhibitor of human epidermal growth factor receptor 2 (HER2) tyrosine kinase, constitutes a major advance in the treatment of heavily pretreated HER2-positive metastatic breast cancer – including patients with brain metastases, Rashmi K. Murthy, MD, declared at the San Antonio Breast Cancer Symposium.

Bruce Jancin/MDedge News

She presented the results of the pivotal HER2CLIMB trial, in which 612 women with heavily pretreated HER2-positive metastatic breast cancer were randomized two-to-one to oral tucatinib at 300 mg twice daily or placebo in combination with standard guideline-recommended treatment with trastuzumab and capecitabine. This landmark double-blind study, conducted at 155 sites in 15 countries, was the first-ever randomized trial to include HER2-positive metastatic breast cancer patients with baseline untreated or previously treated but progressing brain metastases; indeed, nearly half of participants had baseline brain metastases, 40% of which were untreated or treated and progressing.

Not only did tucatinib on top of background trastuzumab and capecitabine reduce the risk of death by 34% compared with placebo, it also more than doubled progression-free survival. And most encouragingly, it did so in patients with or without baseline brain metastases.

“I would like to take a minute here to highlight that this overall survival benefit was seen in patients who had already received trastuzumab, pertuzumab, and T-DM1 [trastuzumab emtansine] and included patients who had brain metastases. Tucatinib in combination with trastuzumab and capecitabine has the potential to become a new standard of care in this population with and without brain metastases,” said Dr. Murthy, a medical oncologist at the University of Texas MD Anderson Cancer Center, Houston.

Tucatinib, which crosses the blood-brain barrier, is highly selective for the kinase domain of HER2, with only miniscule inhibition of epidermal growth factor receptor. Its high selectivity is reflected in a favorable tolerability profile: Only 6% of patients discontinued tucatinib because of adverse events. This low discontinuation rate permitted longer treatment, even in this heavily pretreated population.

The most common adverse events in the tucatinib study arm were diarrhea, hand-foot syndrome, nausea, fatigue, and vomiting, with most cases being low grade. Diarrhea, the most common adverse event, occurred in 81% of tucatinib-treated patients and 53% of controls. However, only 13% of the tucatinib group experienced grade 3 or worse diarrhea. Notably, antidiarrheal prophylaxis wasn’t mandated in HER2CLIMB. Antidiarrheal medications were utilized in less than half of the treatment cycles where diarrhea was reported, and even then, for a median of only 3 days per cycle.

Median study follow-up was 14 months. The primary study endpoint – 1-year progression-free survival assessed by blinded independent central review – was 33% in the tucatinib group and 12% in controls. Thus, the risk of disease progression or death was reduced by 46% in the tucatinib group. The median duration of progression-free survival was 7.8 months in tucatinib-treated patients, compared with 5.6 months in controls.

Two-year estimated overall survival was 45% with tucatinib and 27% with placebo. The tucatinib group’s 21.9-month median overall survival was 4.5 months greater than in controls.

One-year estimated progression-free survival in patients with baseline brain metastases was 25% in the tucatinib group and zero in controls.

The confirmed objective response rate was 41% in the tucatinib group, nearly double the 23% figure in controls.

The overall and progression-free survival results were consistent across all prespecified subgroups based upon age, race, hormone receptor status, geographic location, and other factors.

The study met with an extremely favorable reception peppered with comments such as “tremendous results.”

“I think that the HER2CLIMB study is practice-changing,” Hope S. Rugo, MD, said in an interview.

“The overall survival benefit in all patients and in those who have brain metastases is clinically relevant for our patients who have HER2-positive metastatic breast cancer treated with trastuzumab, pertuzumab, and T-DMI. In addition, the toxicity profile is superior to prior oral TKIs, which is a huge issue for our patients with metastatic disease,” observed Dr. Rugo, professor of medicine and director of breast oncology and clinical trials education at the University of California, San Francisco.

The HER2CLIMB results raise an important question for future research: Namely, could tucatinib have a role in preventing brain metastases by giving the drug earlier in the course of treatment of patients who are at high risk for developing brain metastases, she added.

Simultaneously with Dr. Murthy’s presentation in San Antonio, the HER2CLIMB results were published online in the New England Journal of Medicine.

Dr. Murthy reported receiving institutional research support from and serving as a consultant to Seattle Genetics, sponsor of the HER2CLIMB trial, as well as from several other pharmaceutical companies.

bjancin@mdedge.com

SOURCE: Murthy RK. SABCS 2019 Abstract GS1-01.

SAN ANTONIO – Tucatinib, an investigational oral inhibitor of human epidermal growth factor receptor 2 (HER2) tyrosine kinase, constitutes a major advance in the treatment of heavily pretreated HER2-positive metastatic breast cancer – including patients with brain metastases, Rashmi K. Murthy, MD, declared at the San Antonio Breast Cancer Symposium.

Bruce Jancin/MDedge News

She presented the results of the pivotal HER2CLIMB trial, in which 612 women with heavily pretreated HER2-positive metastatic breast cancer were randomized two-to-one to oral tucatinib at 300 mg twice daily or placebo in combination with standard guideline-recommended treatment with trastuzumab and capecitabine. This landmark double-blind study, conducted at 155 sites in 15 countries, was the first-ever randomized trial to include HER2-positive metastatic breast cancer patients with baseline untreated or previously treated but progressing brain metastases; indeed, nearly half of participants had baseline brain metastases, 40% of which were untreated or treated and progressing.

Not only did tucatinib on top of background trastuzumab and capecitabine reduce the risk of death by 34% compared with placebo, it also more than doubled progression-free survival. And most encouragingly, it did so in patients with or without baseline brain metastases.

“I would like to take a minute here to highlight that this overall survival benefit was seen in patients who had already received trastuzumab, pertuzumab, and T-DM1 [trastuzumab emtansine] and included patients who had brain metastases. Tucatinib in combination with trastuzumab and capecitabine has the potential to become a new standard of care in this population with and without brain metastases,” said Dr. Murthy, a medical oncologist at the University of Texas MD Anderson Cancer Center, Houston.

Tucatinib, which crosses the blood-brain barrier, is highly selective for the kinase domain of HER2, with only miniscule inhibition of epidermal growth factor receptor. Its high selectivity is reflected in a favorable tolerability profile: Only 6% of patients discontinued tucatinib because of adverse events. This low discontinuation rate permitted longer treatment, even in this heavily pretreated population.

The most common adverse events in the tucatinib study arm were diarrhea, hand-foot syndrome, nausea, fatigue, and vomiting, with most cases being low grade. Diarrhea, the most common adverse event, occurred in 81% of tucatinib-treated patients and 53% of controls. However, only 13% of the tucatinib group experienced grade 3 or worse diarrhea. Notably, antidiarrheal prophylaxis wasn’t mandated in HER2CLIMB. Antidiarrheal medications were utilized in less than half of the treatment cycles where diarrhea was reported, and even then, for a median of only 3 days per cycle.

Median study follow-up was 14 months. The primary study endpoint – 1-year progression-free survival assessed by blinded independent central review – was 33% in the tucatinib group and 12% in controls. Thus, the risk of disease progression or death was reduced by 46% in the tucatinib group. The median duration of progression-free survival was 7.8 months in tucatinib-treated patients, compared with 5.6 months in controls.

Two-year estimated overall survival was 45% with tucatinib and 27% with placebo. The tucatinib group’s 21.9-month median overall survival was 4.5 months greater than in controls.

One-year estimated progression-free survival in patients with baseline brain metastases was 25% in the tucatinib group and zero in controls.

The confirmed objective response rate was 41% in the tucatinib group, nearly double the 23% figure in controls.

The overall and progression-free survival results were consistent across all prespecified subgroups based upon age, race, hormone receptor status, geographic location, and other factors.

The study met with an extremely favorable reception peppered with comments such as “tremendous results.”

“I think that the HER2CLIMB study is practice-changing,” Hope S. Rugo, MD, said in an interview.

“The overall survival benefit in all patients and in those who have brain metastases is clinically relevant for our patients who have HER2-positive metastatic breast cancer treated with trastuzumab, pertuzumab, and T-DMI. In addition, the toxicity profile is superior to prior oral TKIs, which is a huge issue for our patients with metastatic disease,” observed Dr. Rugo, professor of medicine and director of breast oncology and clinical trials education at the University of California, San Francisco.

The HER2CLIMB results raise an important question for future research: Namely, could tucatinib have a role in preventing brain metastases by giving the drug earlier in the course of treatment of patients who are at high risk for developing brain metastases, she added.

Simultaneously with Dr. Murthy’s presentation in San Antonio, the HER2CLIMB results were published online in the New England Journal of Medicine.

Dr. Murthy reported receiving institutional research support from and serving as a consultant to Seattle Genetics, sponsor of the HER2CLIMB trial, as well as from several other pharmaceutical companies.

bjancin@mdedge.com

SOURCE: Murthy RK. SABCS 2019 Abstract GS1-01.

SAN ANTONIO – Tucatinib, an investigational oral inhibitor of human epidermal growth factor receptor 2 (HER2) tyrosine kinase, constitutes a major advance in the treatment of heavily pretreated HER2-positive metastatic breast cancer – including patients with brain metastases, Rashmi K. Murthy, MD, declared at the San Antonio Breast Cancer Symposium.

Bruce Jancin/MDedge News

She presented the results of the pivotal HER2CLIMB trial, in which 612 women with heavily pretreated HER2-positive metastatic breast cancer were randomized two-to-one to oral tucatinib at 300 mg twice daily or placebo in combination with standard guideline-recommended treatment with trastuzumab and capecitabine. This landmark double-blind study, conducted at 155 sites in 15 countries, was the first-ever randomized trial to include HER2-positive metastatic breast cancer patients with baseline untreated or previously treated but progressing brain metastases; indeed, nearly half of participants had baseline brain metastases, 40% of which were untreated or treated and progressing.

Not only did tucatinib on top of background trastuzumab and capecitabine reduce the risk of death by 34% compared with placebo, it also more than doubled progression-free survival. And most encouragingly, it did so in patients with or without baseline brain metastases.

“I would like to take a minute here to highlight that this overall survival benefit was seen in patients who had already received trastuzumab, pertuzumab, and T-DM1 [trastuzumab emtansine] and included patients who had brain metastases. Tucatinib in combination with trastuzumab and capecitabine has the potential to become a new standard of care in this population with and without brain metastases,” said Dr. Murthy, a medical oncologist at the University of Texas MD Anderson Cancer Center, Houston.

Tucatinib, which crosses the blood-brain barrier, is highly selective for the kinase domain of HER2, with only miniscule inhibition of epidermal growth factor receptor. Its high selectivity is reflected in a favorable tolerability profile: Only 6% of patients discontinued tucatinib because of adverse events. This low discontinuation rate permitted longer treatment, even in this heavily pretreated population.

The most common adverse events in the tucatinib study arm were diarrhea, hand-foot syndrome, nausea, fatigue, and vomiting, with most cases being low grade. Diarrhea, the most common adverse event, occurred in 81% of tucatinib-treated patients and 53% of controls. However, only 13% of the tucatinib group experienced grade 3 or worse diarrhea. Notably, antidiarrheal prophylaxis wasn’t mandated in HER2CLIMB. Antidiarrheal medications were utilized in less than half of the treatment cycles where diarrhea was reported, and even then, for a median of only 3 days per cycle.

Median study follow-up was 14 months. The primary study endpoint – 1-year progression-free survival assessed by blinded independent central review – was 33% in the tucatinib group and 12% in controls. Thus, the risk of disease progression or death was reduced by 46% in the tucatinib group. The median duration of progression-free survival was 7.8 months in tucatinib-treated patients, compared with 5.6 months in controls.

Two-year estimated overall survival was 45% with tucatinib and 27% with placebo. The tucatinib group’s 21.9-month median overall survival was 4.5 months greater than in controls.

One-year estimated progression-free survival in patients with baseline brain metastases was 25% in the tucatinib group and zero in controls.

The confirmed objective response rate was 41% in the tucatinib group, nearly double the 23% figure in controls.

The overall and progression-free survival results were consistent across all prespecified subgroups based upon age, race, hormone receptor status, geographic location, and other factors.

The study met with an extremely favorable reception peppered with comments such as “tremendous results.”

“I think that the HER2CLIMB study is practice-changing,” Hope S. Rugo, MD, said in an interview.

“The overall survival benefit in all patients and in those who have brain metastases is clinically relevant for our patients who have HER2-positive metastatic breast cancer treated with trastuzumab, pertuzumab, and T-DMI. In addition, the toxicity profile is superior to prior oral TKIs, which is a huge issue for our patients with metastatic disease,” observed Dr. Rugo, professor of medicine and director of breast oncology and clinical trials education at the University of California, San Francisco.

The HER2CLIMB results raise an important question for future research: Namely, could tucatinib have a role in preventing brain metastases by giving the drug earlier in the course of treatment of patients who are at high risk for developing brain metastases, she added.

Simultaneously with Dr. Murthy’s presentation in San Antonio, the HER2CLIMB results were published online in the New England Journal of Medicine.

Dr. Murthy reported receiving institutional research support from and serving as a consultant to Seattle Genetics, sponsor of the HER2CLIMB trial, as well as from several other pharmaceutical companies.

bjancin@mdedge.com

SOURCE: Murthy RK. SABCS 2019 Abstract GS1-01.

SAN ANTONIO –A novel antibody-drug conjugate pairing trastuzumab (Herceptin) with a topoisomerase I inhibitor as the toxic payload was associated with a good overall response rate in patients with heavily pretreated HER2-positive metastatic breast cancer.

The confirmed overall response rate among 184 patients treated with trastuzumab deruxtecan and followed for a median of 11.1 months was 60.9%, consisting of 6% complete responses and 54.9% partial responses, reported Ian Krop, MD, PhD, from the Dana-Farber Cancer Institute in Boston.

“These data demonstrate the potential of trastuzumab deruxtecan to establish a new standard of care for patients with advanced HER2-positive breast cancer,” he said at a briefing prior to presentation of the data at the San Antonio Breast Cancer Symposium.

Results of the open-label phase 2 DESTINY-BREAST01 study were also published online in the New England Journal of Medicine.

Although the antibody-drug conjugate was associated with a good response rate among heavily pretreated patients (median of six prior lines of therapy), it was also associated with interstitial lung disease (ILD), including 4 fatalities among 184 patients who received the drug at the recommended study dose of 5.4 mg/kg.

“ILD is confirmed as an important risk of trastuzumab deruxtecan, it can be severe, and requires careful monitoring and prompt intervention,” Dr. Krop said.

Trastuzumab deruxtecan is composed of a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab, and exatecan derivative as the topoisomerase I inhibitor payload conjugated by a tetrapeptide-based cleavable linker.

Although topoisomerase I inhibitors are not commonly used in breast cancer because of limited activity in clinical trials and toxicities when used systemically, the rationale for using a topoisomerase I inhibitor in this setting is that the toxic effects can be largely confined to the local tumor environment.

In addition, “this is an agent that the cancers generally haven’t been exposed to, so there is the hope this will be non–cross-resistant,” Dr. Krop said at the briefing.

The product has a high drug molecule-to-antibody ratio or approximately 8:1, which is higher than that seen with other antibody-drug conjugates, and the topoisomerase inhibitor payload is membrane permeable, giving it extra potency.
 

Study details

DESTINY-BREAST01 is an open-label, multicenter, phase 2 study consisting of a dose-finding phase and a continuous phase. Dr. Krop reported on all 184 patients who have been treated at the recommend 5.4-mg/kg dose.

As noted, the patients had received a median of 6 prior lines of therapy, with at least one patient receiving a staggering 27 prior lines. All had previously received trastuzumab and a different antibody-drug conjugate, ado-trastuzumab emtansine (T-DMI; Kadcyla). Two-thirds of patients (65.8%) had received pertuzumab (Perjeta), 54.3% received other anti-HER2 therapies. 48.9% had received hormone therapy, and 99.5% had received other systemic therapies.

ORR by independent review, the primary endpoint, was as noted before. In addition to the 60.9% ORR, 36.4% of patients had stable disease, for a disease control rate of 97.3%.

The median time to response was 1.6 month, and the median duration of response was 14.8 months.

The median progression-free survival at follow-up was 16.4 months. The median overall survival had not been reached at the time of data cutoff in August 2019.

Interstitial lung disease

After a median treatment duration of 10 months, all but one patient had at least one drug-related adverse event. Grade 3 or greater drug-related adverse events occurred in 48.4% of patients, and serious drug-related events occurred in 12.5%.

A total of 25 patients had ILD of any grade, including 5 with grade 1, 15 with grade 2, 1 with grade 4, and the aforementioned 4 patients who died from the disease.

In the four patients with fatal ILD, onset ranged from 63-146, with the deaths occurring 9-60 days after ILD diagnosis. Three of the patients had received steroids as part of their ILD treatment.

The investigators recommend close monitoring of patients for signs and symptoms of lung disease, including fever, cough, or dyspnea. They also recommend that patients with suspected ILD be evaluated with high-resolution CT and testing for pulmonary function and oxygen saturation, ideally under consultation with a pulmonologist.

However, despite the known cardiotoxic effects of trastuzumab, there were no reported cases of heart failure with decline in left ventricular ejection fraction, and only three patients had a decrease in left ventricular ejection fraction, none of which grade 4.

“The response rate and overall efficacy observed with trastuzumab deruxtecan in this study appear to substantially exceed those of currently available HER2-directed regimens and new agents in development, although cross-trial comparisons must be interpreted with caution,” the investigators wrote in the New England Journal of Medicine.

The study was funded by Daiichi Sankyo and AstraZeneca. Dr. Krop disclosed consulting fees, honoraria from each company, and research support from Genentech/Roche and Pfizer.

SOURCE: Krop I et al. SABCS 2019, Abstract GS1-03.

SAN ANTONIO –A novel antibody-drug conjugate pairing trastuzumab (Herceptin) with a topoisomerase I inhibitor as the toxic payload was associated with a good overall response rate in patients with heavily pretreated HER2-positive metastatic breast cancer.

The confirmed overall response rate among 184 patients treated with trastuzumab deruxtecan and followed for a median of 11.1 months was 60.9%, consisting of 6% complete responses and 54.9% partial responses, reported Ian Krop, MD, PhD, from the Dana-Farber Cancer Institute in Boston.

“These data demonstrate the potential of trastuzumab deruxtecan to establish a new standard of care for patients with advanced HER2-positive breast cancer,” he said at a briefing prior to presentation of the data at the San Antonio Breast Cancer Symposium.

Results of the open-label phase 2 DESTINY-BREAST01 study were also published online in the New England Journal of Medicine.

Although the antibody-drug conjugate was associated with a good response rate among heavily pretreated patients (median of six prior lines of therapy), it was also associated with interstitial lung disease (ILD), including 4 fatalities among 184 patients who received the drug at the recommended study dose of 5.4 mg/kg.

“ILD is confirmed as an important risk of trastuzumab deruxtecan, it can be severe, and requires careful monitoring and prompt intervention,” Dr. Krop said.

Trastuzumab deruxtecan is composed of a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab, and exatecan derivative as the topoisomerase I inhibitor payload conjugated by a tetrapeptide-based cleavable linker.

Although topoisomerase I inhibitors are not commonly used in breast cancer because of limited activity in clinical trials and toxicities when used systemically, the rationale for using a topoisomerase I inhibitor in this setting is that the toxic effects can be largely confined to the local tumor environment.

In addition, “this is an agent that the cancers generally haven’t been exposed to, so there is the hope this will be non–cross-resistant,” Dr. Krop said at the briefing.

The product has a high drug molecule-to-antibody ratio or approximately 8:1, which is higher than that seen with other antibody-drug conjugates, and the topoisomerase inhibitor payload is membrane permeable, giving it extra potency.
 

Study details

DESTINY-BREAST01 is an open-label, multicenter, phase 2 study consisting of a dose-finding phase and a continuous phase. Dr. Krop reported on all 184 patients who have been treated at the recommend 5.4-mg/kg dose.

As noted, the patients had received a median of 6 prior lines of therapy, with at least one patient receiving a staggering 27 prior lines. All had previously received trastuzumab and a different antibody-drug conjugate, ado-trastuzumab emtansine (T-DMI; Kadcyla). Two-thirds of patients (65.8%) had received pertuzumab (Perjeta), 54.3% received other anti-HER2 therapies. 48.9% had received hormone therapy, and 99.5% had received other systemic therapies.

ORR by independent review, the primary endpoint, was as noted before. In addition to the 60.9% ORR, 36.4% of patients had stable disease, for a disease control rate of 97.3%.

The median time to response was 1.6 month, and the median duration of response was 14.8 months.

The median progression-free survival at follow-up was 16.4 months. The median overall survival had not been reached at the time of data cutoff in August 2019.

Interstitial lung disease

After a median treatment duration of 10 months, all but one patient had at least one drug-related adverse event. Grade 3 or greater drug-related adverse events occurred in 48.4% of patients, and serious drug-related events occurred in 12.5%.

A total of 25 patients had ILD of any grade, including 5 with grade 1, 15 with grade 2, 1 with grade 4, and the aforementioned 4 patients who died from the disease.

In the four patients with fatal ILD, onset ranged from 63-146, with the deaths occurring 9-60 days after ILD diagnosis. Three of the patients had received steroids as part of their ILD treatment.

The investigators recommend close monitoring of patients for signs and symptoms of lung disease, including fever, cough, or dyspnea. They also recommend that patients with suspected ILD be evaluated with high-resolution CT and testing for pulmonary function and oxygen saturation, ideally under consultation with a pulmonologist.

However, despite the known cardiotoxic effects of trastuzumab, there were no reported cases of heart failure with decline in left ventricular ejection fraction, and only three patients had a decrease in left ventricular ejection fraction, none of which grade 4.

“The response rate and overall efficacy observed with trastuzumab deruxtecan in this study appear to substantially exceed those of currently available HER2-directed regimens and new agents in development, although cross-trial comparisons must be interpreted with caution,” the investigators wrote in the New England Journal of Medicine.

The study was funded by Daiichi Sankyo and AstraZeneca. Dr. Krop disclosed consulting fees, honoraria from each company, and research support from Genentech/Roche and Pfizer.

SOURCE: Krop I et al. SABCS 2019, Abstract GS1-03.

SAN ANTONIO –A novel antibody-drug conjugate pairing trastuzumab (Herceptin) with a topoisomerase I inhibitor as the toxic payload was associated with a good overall response rate in patients with heavily pretreated HER2-positive metastatic breast cancer.

The confirmed overall response rate among 184 patients treated with trastuzumab deruxtecan and followed for a median of 11.1 months was 60.9%, consisting of 6% complete responses and 54.9% partial responses, reported Ian Krop, MD, PhD, from the Dana-Farber Cancer Institute in Boston.

“These data demonstrate the potential of trastuzumab deruxtecan to establish a new standard of care for patients with advanced HER2-positive breast cancer,” he said at a briefing prior to presentation of the data at the San Antonio Breast Cancer Symposium.

Results of the open-label phase 2 DESTINY-BREAST01 study were also published online in the New England Journal of Medicine.

Although the antibody-drug conjugate was associated with a good response rate among heavily pretreated patients (median of six prior lines of therapy), it was also associated with interstitial lung disease (ILD), including 4 fatalities among 184 patients who received the drug at the recommended study dose of 5.4 mg/kg.

“ILD is confirmed as an important risk of trastuzumab deruxtecan, it can be severe, and requires careful monitoring and prompt intervention,” Dr. Krop said.

Trastuzumab deruxtecan is composed of a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab, and exatecan derivative as the topoisomerase I inhibitor payload conjugated by a tetrapeptide-based cleavable linker.

Although topoisomerase I inhibitors are not commonly used in breast cancer because of limited activity in clinical trials and toxicities when used systemically, the rationale for using a topoisomerase I inhibitor in this setting is that the toxic effects can be largely confined to the local tumor environment.

In addition, “this is an agent that the cancers generally haven’t been exposed to, so there is the hope this will be non–cross-resistant,” Dr. Krop said at the briefing.

The product has a high drug molecule-to-antibody ratio or approximately 8:1, which is higher than that seen with other antibody-drug conjugates, and the topoisomerase inhibitor payload is membrane permeable, giving it extra potency.
 

Study details

DESTINY-BREAST01 is an open-label, multicenter, phase 2 study consisting of a dose-finding phase and a continuous phase. Dr. Krop reported on all 184 patients who have been treated at the recommend 5.4-mg/kg dose.

As noted, the patients had received a median of 6 prior lines of therapy, with at least one patient receiving a staggering 27 prior lines. All had previously received trastuzumab and a different antibody-drug conjugate, ado-trastuzumab emtansine (T-DMI; Kadcyla). Two-thirds of patients (65.8%) had received pertuzumab (Perjeta), 54.3% received other anti-HER2 therapies. 48.9% had received hormone therapy, and 99.5% had received other systemic therapies.

ORR by independent review, the primary endpoint, was as noted before. In addition to the 60.9% ORR, 36.4% of patients had stable disease, for a disease control rate of 97.3%.

The median time to response was 1.6 month, and the median duration of response was 14.8 months.

The median progression-free survival at follow-up was 16.4 months. The median overall survival had not been reached at the time of data cutoff in August 2019.

Interstitial lung disease

After a median treatment duration of 10 months, all but one patient had at least one drug-related adverse event. Grade 3 or greater drug-related adverse events occurred in 48.4% of patients, and serious drug-related events occurred in 12.5%.

A total of 25 patients had ILD of any grade, including 5 with grade 1, 15 with grade 2, 1 with grade 4, and the aforementioned 4 patients who died from the disease.

In the four patients with fatal ILD, onset ranged from 63-146, with the deaths occurring 9-60 days after ILD diagnosis. Three of the patients had received steroids as part of their ILD treatment.

The investigators recommend close monitoring of patients for signs and symptoms of lung disease, including fever, cough, or dyspnea. They also recommend that patients with suspected ILD be evaluated with high-resolution CT and testing for pulmonary function and oxygen saturation, ideally under consultation with a pulmonologist.

However, despite the known cardiotoxic effects of trastuzumab, there were no reported cases of heart failure with decline in left ventricular ejection fraction, and only three patients had a decrease in left ventricular ejection fraction, none of which grade 4.

“The response rate and overall efficacy observed with trastuzumab deruxtecan in this study appear to substantially exceed those of currently available HER2-directed regimens and new agents in development, although cross-trial comparisons must be interpreted with caution,” the investigators wrote in the New England Journal of Medicine.

The study was funded by Daiichi Sankyo and AstraZeneca. Dr. Krop disclosed consulting fees, honoraria from each company, and research support from Genentech/Roche and Pfizer.

SOURCE: Krop I et al. SABCS 2019, Abstract GS1-03.

A cure for nosiness

Christmas may be just around the corner, but is there ever really a wrong time to huddle around a campfire and swap scary stories? So bundle up, get the fire going, and prepare yourselves for a pair of nasal-based horror stories that will frighten your Jingle Bells off!

RusN/iStock/Getty Images Plus

Our first tale of nostril terror comes all the way from southern India, where a 13-year-old boy jumped into a water well to cool off. Hey, southern India gets hot, even in November. But like something out of a bad sci-fi movie, his peaceful swim was interrupted when something swam up his nose, causing him extreme pain. After a 30-minute procedure, the doctor pulled out the culprit: A horrific alien parasite! Okay, we’re lying; it was a fish. But we had you going, didn’t we?

Well, maybe that didn’t get you frightened. But we have more rhinal dread to share! A young girl in Las Vegas stuck a pair of plastic doll shoes up her nose, one in each nostril. Her mother removed one shoe, but neither she nor urgent care could reach the second. A trip to the hospital was in order, and once there, the doctors were able to remove the foreign object in seconds.

But as with all things in U.S. medicine, a reckoning would soon come. You feel it now, the dread in this woman’s heart when the hospital bill came.

She takes the envelope, and opens it slowly.

The paper unfolds, rough and heavy in her hands.

Her eyes scan the page, looking for the number, where is it, where is it? It must be here, it must be ...

$3,000.

That’s right, for this simple procedure, performed with a pair of fancy tweezers, the hospital saw fit to charge the hapless mother $3,000! AHHHHHHHHHHHH!

Some say that the mother’s high-deductible insurance policy reduced the cost to $1,700. But we ask you, does that make the story any less spooky? We think not.
 

Hoverboarding down the root canal

Time spent in the dentist’s chair is among the most anxiety-inducing in anyone’s life. The needles. The grinding. The drilling. The rinsing. The spitting. The throbbing copays.

RobertoDavid/iStock/Getty Images Plus

But you know what might inject a few cc’s of fun into your oral hygiene visits?

Did you guess ... a hoverboard?

If you did, well, you’re probably dentist Steve Martin in “Little Shop of Horrors.” Or perhaps Alaska dentist Seth Lookhart, who authorities say performed a tooth extraction on a sedated patient while Dr. Lookhart also rode a hoverboard. There are also charges of felony Medicaid fraud and reckless endangerment. And allegations of hefty theft from his practice partners. Oh, and a state board apparently suspended Dr. Lookhart’s dental license in 2017.

But hey, pulling teeth while taming a hoverboard? Photos or it didn’t happen, right?

Unfortunately for the well-balanced dentist, there are photos. Actually, there’s an entire video. And when prosecutors showed it to Dr. Lookhart’s unwitting and horrified costar, she was about as happy as the impacted wisdom teeth your teen kid’s still toting around.

Dr. Lookhart denied the felony fraud charges. But he did cop to the hoverboard. Which puts him one up on his cinematic “Wild and Crazy Guy” doppelganger. Even as a neurosurgeon in “The Man With Two Brains,” Mr. Martin never attempted to hoverboard while performing double “cranial screw-top” brain surgeries.
 

CSI: Quebec

They may live in that eternally polite land on the other side of our northern border, but they know where the bodies are buried. Lots of bodies. Some of them in shallow graves. Some of them in vehicles.

MicroStockHub/iStock/Getty Images Plus

No, we are not talking about Gil Grissom and the gang at CSI. We’re talking about the Secure Site for Research in Thanatology, also known as the “body farm,” which is scheduled to open this spring in Becancour, Quebec.

It’s the first such outdoor forensic facility in Canada and the first in the world – there are also body farms in the United States, Australia, and the Netherlands – to be located in a northern climate.

“We’re particularly interested in understanding what happens when a body is in subzero temperatures, when there’s a lot of snow on the ground, and how that freeze and then the thaw process might actually change the rate of decomposition,” Shari Forbes, the farm’s director, told CTV News recently.

The science team will be out on the farm every day, meticulously checking each body – talk about making a list and checking it twice – for all the important CSI stuff: how long fingerprints and DNA evidence last, the effects of insect feeding and egg-laying, and the ability of dogs to detect scents.

The decomposition process in a cold climate will be a strange and wondrous journey, and the body farm’s work can, perhaps, best be summed up by none other than Mr. Grissom, who once said that getting to the evidence means having to destroy the evidence.

Then again, he also said that “dead men don’t ride roller coasters,” so the analogy only goes so far.

A cure for nosiness

Christmas may be just around the corner, but is there ever really a wrong time to huddle around a campfire and swap scary stories? So bundle up, get the fire going, and prepare yourselves for a pair of nasal-based horror stories that will frighten your Jingle Bells off!

RusN/iStock/Getty Images Plus

Our first tale of nostril terror comes all the way from southern India, where a 13-year-old boy jumped into a water well to cool off. Hey, southern India gets hot, even in November. But like something out of a bad sci-fi movie, his peaceful swim was interrupted when something swam up his nose, causing him extreme pain. After a 30-minute procedure, the doctor pulled out the culprit: A horrific alien parasite! Okay, we’re lying; it was a fish. But we had you going, didn’t we?

Well, maybe that didn’t get you frightened. But we have more rhinal dread to share! A young girl in Las Vegas stuck a pair of plastic doll shoes up her nose, one in each nostril. Her mother removed one shoe, but neither she nor urgent care could reach the second. A trip to the hospital was in order, and once there, the doctors were able to remove the foreign object in seconds.

But as with all things in U.S. medicine, a reckoning would soon come. You feel it now, the dread in this woman’s heart when the hospital bill came.

She takes the envelope, and opens it slowly.

The paper unfolds, rough and heavy in her hands.

Her eyes scan the page, looking for the number, where is it, where is it? It must be here, it must be ...

$3,000.

That’s right, for this simple procedure, performed with a pair of fancy tweezers, the hospital saw fit to charge the hapless mother $3,000! AHHHHHHHHHHHH!

Some say that the mother’s high-deductible insurance policy reduced the cost to $1,700. But we ask you, does that make the story any less spooky? We think not.
 

Hoverboarding down the root canal

Time spent in the dentist’s chair is among the most anxiety-inducing in anyone’s life. The needles. The grinding. The drilling. The rinsing. The spitting. The throbbing copays.

RobertoDavid/iStock/Getty Images Plus

But you know what might inject a few cc’s of fun into your oral hygiene visits?

Did you guess ... a hoverboard?

If you did, well, you’re probably dentist Steve Martin in “Little Shop of Horrors.” Or perhaps Alaska dentist Seth Lookhart, who authorities say performed a tooth extraction on a sedated patient while Dr. Lookhart also rode a hoverboard. There are also charges of felony Medicaid fraud and reckless endangerment. And allegations of hefty theft from his practice partners. Oh, and a state board apparently suspended Dr. Lookhart’s dental license in 2017.

But hey, pulling teeth while taming a hoverboard? Photos or it didn’t happen, right?

Unfortunately for the well-balanced dentist, there are photos. Actually, there’s an entire video. And when prosecutors showed it to Dr. Lookhart’s unwitting and horrified costar, she was about as happy as the impacted wisdom teeth your teen kid’s still toting around.

Dr. Lookhart denied the felony fraud charges. But he did cop to the hoverboard. Which puts him one up on his cinematic “Wild and Crazy Guy” doppelganger. Even as a neurosurgeon in “The Man With Two Brains,” Mr. Martin never attempted to hoverboard while performing double “cranial screw-top” brain surgeries.
 

CSI: Quebec

They may live in that eternally polite land on the other side of our northern border, but they know where the bodies are buried. Lots of bodies. Some of them in shallow graves. Some of them in vehicles.

MicroStockHub/iStock/Getty Images Plus

No, we are not talking about Gil Grissom and the gang at CSI. We’re talking about the Secure Site for Research in Thanatology, also known as the “body farm,” which is scheduled to open this spring in Becancour, Quebec.

It’s the first such outdoor forensic facility in Canada and the first in the world – there are also body farms in the United States, Australia, and the Netherlands – to be located in a northern climate.

“We’re particularly interested in understanding what happens when a body is in subzero temperatures, when there’s a lot of snow on the ground, and how that freeze and then the thaw process might actually change the rate of decomposition,” Shari Forbes, the farm’s director, told CTV News recently.

The science team will be out on the farm every day, meticulously checking each body – talk about making a list and checking it twice – for all the important CSI stuff: how long fingerprints and DNA evidence last, the effects of insect feeding and egg-laying, and the ability of dogs to detect scents.

The decomposition process in a cold climate will be a strange and wondrous journey, and the body farm’s work can, perhaps, best be summed up by none other than Mr. Grissom, who once said that getting to the evidence means having to destroy the evidence.

Then again, he also said that “dead men don’t ride roller coasters,” so the analogy only goes so far.

A cure for nosiness

Christmas may be just around the corner, but is there ever really a wrong time to huddle around a campfire and swap scary stories? So bundle up, get the fire going, and prepare yourselves for a pair of nasal-based horror stories that will frighten your Jingle Bells off!

RusN/iStock/Getty Images Plus

Our first tale of nostril terror comes all the way from southern India, where a 13-year-old boy jumped into a water well to cool off. Hey, southern India gets hot, even in November. But like something out of a bad sci-fi movie, his peaceful swim was interrupted when something swam up his nose, causing him extreme pain. After a 30-minute procedure, the doctor pulled out the culprit: A horrific alien parasite! Okay, we’re lying; it was a fish. But we had you going, didn’t we?

Well, maybe that didn’t get you frightened. But we have more rhinal dread to share! A young girl in Las Vegas stuck a pair of plastic doll shoes up her nose, one in each nostril. Her mother removed one shoe, but neither she nor urgent care could reach the second. A trip to the hospital was in order, and once there, the doctors were able to remove the foreign object in seconds.

But as with all things in U.S. medicine, a reckoning would soon come. You feel it now, the dread in this woman’s heart when the hospital bill came.

She takes the envelope, and opens it slowly.

The paper unfolds, rough and heavy in her hands.

Her eyes scan the page, looking for the number, where is it, where is it? It must be here, it must be ...

$3,000.

That’s right, for this simple procedure, performed with a pair of fancy tweezers, the hospital saw fit to charge the hapless mother $3,000! AHHHHHHHHHHHH!

Some say that the mother’s high-deductible insurance policy reduced the cost to $1,700. But we ask you, does that make the story any less spooky? We think not.
 

Hoverboarding down the root canal

Time spent in the dentist’s chair is among the most anxiety-inducing in anyone’s life. The needles. The grinding. The drilling. The rinsing. The spitting. The throbbing copays.

RobertoDavid/iStock/Getty Images Plus

But you know what might inject a few cc’s of fun into your oral hygiene visits?

Did you guess ... a hoverboard?

If you did, well, you’re probably dentist Steve Martin in “Little Shop of Horrors.” Or perhaps Alaska dentist Seth Lookhart, who authorities say performed a tooth extraction on a sedated patient while Dr. Lookhart also rode a hoverboard. There are also charges of felony Medicaid fraud and reckless endangerment. And allegations of hefty theft from his practice partners. Oh, and a state board apparently suspended Dr. Lookhart’s dental license in 2017.

But hey, pulling teeth while taming a hoverboard? Photos or it didn’t happen, right?

Unfortunately for the well-balanced dentist, there are photos. Actually, there’s an entire video. And when prosecutors showed it to Dr. Lookhart’s unwitting and horrified costar, she was about as happy as the impacted wisdom teeth your teen kid’s still toting around.

Dr. Lookhart denied the felony fraud charges. But he did cop to the hoverboard. Which puts him one up on his cinematic “Wild and Crazy Guy” doppelganger. Even as a neurosurgeon in “The Man With Two Brains,” Mr. Martin never attempted to hoverboard while performing double “cranial screw-top” brain surgeries.
 

CSI: Quebec

They may live in that eternally polite land on the other side of our northern border, but they know where the bodies are buried. Lots of bodies. Some of them in shallow graves. Some of them in vehicles.

MicroStockHub/iStock/Getty Images Plus

No, we are not talking about Gil Grissom and the gang at CSI. We’re talking about the Secure Site for Research in Thanatology, also known as the “body farm,” which is scheduled to open this spring in Becancour, Quebec.

It’s the first such outdoor forensic facility in Canada and the first in the world – there are also body farms in the United States, Australia, and the Netherlands – to be located in a northern climate.

“We’re particularly interested in understanding what happens when a body is in subzero temperatures, when there’s a lot of snow on the ground, and how that freeze and then the thaw process might actually change the rate of decomposition,” Shari Forbes, the farm’s director, told CTV News recently.

The science team will be out on the farm every day, meticulously checking each body – talk about making a list and checking it twice – for all the important CSI stuff: how long fingerprints and DNA evidence last, the effects of insect feeding and egg-laying, and the ability of dogs to detect scents.

The decomposition process in a cold climate will be a strange and wondrous journey, and the body farm’s work can, perhaps, best be summed up by none other than Mr. Grissom, who once said that getting to the evidence means having to destroy the evidence.

Then again, he also said that “dead men don’t ride roller coasters,” so the analogy only goes so far.