Nine infants younger than 1 year of age were infected with the virus that causes COVID-19 and hospitalized in China between Dec. 8, 2019, and Feb. 6, 2020, based on data from the Chinese central government and local health departments.

Courtesy NIAID-RML

“As of February 6, 2020, China reported 31,211 confirmed cases of COVID-19 and 637 fatalities,” wrote Min Wei, MD, of Wuhan University, China, and colleagues. However, “few infections in children have been reported.”

In a research letter published in JAMA, the investigators reviewed data from nine infants aged 28 days to 1 year who were hospitalized with a diagnosis of COVID-19 between Dec. 8, 2019, and Feb. 6, 2020. The ages of the infants ranged from 1 month to 11 months, and seven were female. The patients included two children from Beijing, two from Hainan, and one each from the areas of Guangdong, Anhui, Shanghai, Zhejiang, and Guizhou.

All infected infants had at least one infected family member, and the infants’ infections occurred after the family members’ infections; seven infants lived in Wuhan or had family members who had visited Wuhan.

One of the infants had no symptoms but tested positive for the 2019 novel coronavirus, and two others had a diagnosis but missing information on any symptoms. Fever occurred in four patients, and mild upper respiratory tract symptoms occurred in two patients.

None of the infants died, and none reported severe complications or the need for intensive care or mechanical ventilation, the investigators said. The fact that most of the infants were female might suggest that they are more susceptible to the virus than males, although overall COVID-19 viral infections have been more common in adult men, especially those with chronic comorbidities, Dr. Wei and associates noted.

The study findings were limited by the small sample size and lack of symptom data for some patients, the researchers said. However, the results confirm that the COVID-19 virus is transmissible to infants younger than 1 year, and adult caregivers should exercise protective measures including wearing masks, washing hands before contact with infants, and routinely sterilizing toys and tableware, they emphasized.

The study was supported by the National Natural Science Foundation of China and the Fundamental Research Funds for the Central Universities. The researchers had no financial conflicts to disclose.

SOURCE: Wei M et al. JAMA. 2020 Feb 14. doi:10.1001/jama.2020.2131.

Nine infants younger than 1 year of age were infected with the virus that causes COVID-19 and hospitalized in China between Dec. 8, 2019, and Feb. 6, 2020, based on data from the Chinese central government and local health departments.

Courtesy NIAID-RML

“As of February 6, 2020, China reported 31,211 confirmed cases of COVID-19 and 637 fatalities,” wrote Min Wei, MD, of Wuhan University, China, and colleagues. However, “few infections in children have been reported.”

In a research letter published in JAMA, the investigators reviewed data from nine infants aged 28 days to 1 year who were hospitalized with a diagnosis of COVID-19 between Dec. 8, 2019, and Feb. 6, 2020. The ages of the infants ranged from 1 month to 11 months, and seven were female. The patients included two children from Beijing, two from Hainan, and one each from the areas of Guangdong, Anhui, Shanghai, Zhejiang, and Guizhou.

All infected infants had at least one infected family member, and the infants’ infections occurred after the family members’ infections; seven infants lived in Wuhan or had family members who had visited Wuhan.

One of the infants had no symptoms but tested positive for the 2019 novel coronavirus, and two others had a diagnosis but missing information on any symptoms. Fever occurred in four patients, and mild upper respiratory tract symptoms occurred in two patients.

None of the infants died, and none reported severe complications or the need for intensive care or mechanical ventilation, the investigators said. The fact that most of the infants were female might suggest that they are more susceptible to the virus than males, although overall COVID-19 viral infections have been more common in adult men, especially those with chronic comorbidities, Dr. Wei and associates noted.

The study findings were limited by the small sample size and lack of symptom data for some patients, the researchers said. However, the results confirm that the COVID-19 virus is transmissible to infants younger than 1 year, and adult caregivers should exercise protective measures including wearing masks, washing hands before contact with infants, and routinely sterilizing toys and tableware, they emphasized.

The study was supported by the National Natural Science Foundation of China and the Fundamental Research Funds for the Central Universities. The researchers had no financial conflicts to disclose.

SOURCE: Wei M et al. JAMA. 2020 Feb 14. doi:10.1001/jama.2020.2131.

Nine infants younger than 1 year of age were infected with the virus that causes COVID-19 and hospitalized in China between Dec. 8, 2019, and Feb. 6, 2020, based on data from the Chinese central government and local health departments.

Courtesy NIAID-RML

“As of February 6, 2020, China reported 31,211 confirmed cases of COVID-19 and 637 fatalities,” wrote Min Wei, MD, of Wuhan University, China, and colleagues. However, “few infections in children have been reported.”

In a research letter published in JAMA, the investigators reviewed data from nine infants aged 28 days to 1 year who were hospitalized with a diagnosis of COVID-19 between Dec. 8, 2019, and Feb. 6, 2020. The ages of the infants ranged from 1 month to 11 months, and seven were female. The patients included two children from Beijing, two from Hainan, and one each from the areas of Guangdong, Anhui, Shanghai, Zhejiang, and Guizhou.

All infected infants had at least one infected family member, and the infants’ infections occurred after the family members’ infections; seven infants lived in Wuhan or had family members who had visited Wuhan.

One of the infants had no symptoms but tested positive for the 2019 novel coronavirus, and two others had a diagnosis but missing information on any symptoms. Fever occurred in four patients, and mild upper respiratory tract symptoms occurred in two patients.

None of the infants died, and none reported severe complications or the need for intensive care or mechanical ventilation, the investigators said. The fact that most of the infants were female might suggest that they are more susceptible to the virus than males, although overall COVID-19 viral infections have been more common in adult men, especially those with chronic comorbidities, Dr. Wei and associates noted.

The study findings were limited by the small sample size and lack of symptom data for some patients, the researchers said. However, the results confirm that the COVID-19 virus is transmissible to infants younger than 1 year, and adult caregivers should exercise protective measures including wearing masks, washing hands before contact with infants, and routinely sterilizing toys and tableware, they emphasized.

The study was supported by the National Natural Science Foundation of China and the Fundamental Research Funds for the Central Universities. The researchers had no financial conflicts to disclose.

SOURCE: Wei M et al. JAMA. 2020 Feb 14. doi:10.1001/jama.2020.2131.

A 13-year-old boy with ADHD, combined type, presents to his family physician with his parents. His parents called for an appointment outside of his routine follow-up care to discuss what they should do to address their son’s new “aggressive behaviors.” He will throw objects when angry, yell, and slam doors at home when he is told to turn off video games. He used to play soccer but doesn’t anymore. He has maintained very good grades and friends. There is not a concern for substance abuse at this time.He speaks in curt sentences during the appointment, and he has his arms crossed or is looking out of the window the entire time.

His parents share in front on him that he has always been a “difficult child” (their words), but they now are struggling to adjust to his aggressive tendencies as he ages. He is growing bigger and angrier. He will not attend therapy and will not see a consultation psychiatrist in the office. A variety of stimulant trials including Ritalin and amphetamine preparations to manage impulsivity in ADHD were ineffective to curb his aggression, and he doesn’t want to take any medication.

They ask, what do we do? They are not worried for their safety but living like this is eroding their quality of life as a family, and the dynamic seems destined to get worse before it gets better.

They wonder, is there a next medication step to manage his aggression?

A family physician presented the above situation to me in my role as a child and adolescent psychiatrist in the medical home. It led us to a fruitful discussion of aggression and what can be done to help families who are all too often in situations like the above, then in your office looking for immediate solutions. The questions are, what can be done with an aggressive child, even and especially without the child’s buy-in to work on that as a problem?

Markus Wegmann/Thinkstock

Psychoeducation can go a long way in helping families rethink aggression as a symptom of something deeper, either in the environment or a diagnosis, although we all can empathize with the desire to reconcile the above behavior immediately.
 

Characterize the aggression

First, it can be helpful to identify a child’s aggression type. There are two types of aggression, reactive and proactive. We most often see reactive aggression in our clinics, which is aggression as a defensive and impulsive response to something in the environment (often limit-setting, as above). Proactive aggression is premeditated and may appear as aggression for aggression’s sake without the emotional drive behind it.

Secondly, it also can be helpful to know that externalizing and internalizing symptoms can represent different sides of the same coin, with the proverbial “coin” as “emotion” and the associated behaviors (throwing objects, in the above example) as the “signs” that there is a complex difficulty in managing painful emotions. Some children (and adults too!) tend to “externalize” strong emotions as aggression or irritability with others, while others “internalize” them by retreating with internal suffering such as “anxiety and depression.” These styles also can be similar among children and their parents.

With those two points in mind, it’s important to consider the diagnosis, which would guide treatment. It’s generally agreed upon that “reactive aggression” is more likely to be related to underlying untreated ADHD, or a depressive or anxiety disorder. This is much more amenable to treatment than aggression related to oppositional defiant disorder or conduct disorder, which are more defined by proactive forms of aggression.

You can pick up on family dynamics that may inadvertently reinforce the same behaviors they so wish to change. In the above example, the parents have clearly identified their son as “the problem.” You can imagine the difficulty of going to school and being a “problem,” and then coming home and feeling the same way. This negative perception can erode a child’s self-esteem over time, which may appear as disengagement or simply not caring in an appointment. It may become harder and harder to engage the child in psychotherapy or even in taking a medication as their only means of resistance to that painful notion about oneself as the “problem.”

It can be useful to begin appointments with “what is going well?” (in the example above, he “has friends and is maintaining grades”) and “what do you like most about your child?” As we all know, positive reinforcement is more powerful than its counterpart. Also problems in a family often are complex, and may involve many family members needing to change to meet their goals, not just the child.
 

 

Why you should try behavioral interventions first

Behavioral interventions are the first step always. Parents can do behavioral interventions and change their parenting and family environment through their own behavioral changes – commonly called parent management training. They can assess antecedents of aggression and their own responses, which may contribute or perpetuate a cycle of the aggression – such as giving attention or giving in to fewer limitations to avoid a fight. This small but important point can help protect against a feeling of helplessness that a child will not engage in therapy or skills-building.

In answering the clinician’s question about what to do next, I often feel like the question embedded in this is “what medication is next?” There is a felt pressure to do something “right now” conveyed to a clinician. This drives the impulse to prescribe something immediately – and likely more risky and with less of an evidence base – even before trying the known psychotherapy interventions that have the most evidence to change aggressive tendencies.

In looking deeper into this consultation case, I also found more “food for thought” for one’s thinking about aggression and psychopharmacology in cases like the above: Aggression isn’t an uncomplicated symptom that one can address immediately, and therefore we cannot rely on symptom-specific management to eradicate it. This is similar to prescribing Tylenol to manage a general ache or pain; if the pain persists, we want to know the “whys” of the pain persisting.

Thankfully, there are ways that a parent can better understand behaviors with this philosophy in mind. Applied Behavioral Analysis¹ offers some helpful ideas, not only for children with autism spectrum disorder, but that can be applied to one’s understanding of other’s behavior in general. ABA pays attention to antecedents, perpetuating factors, and consequences as well as their interplay in understanding behaviors. You can encourage a family – rather than wanting to “get rid of a problem behavior” – to try to understand it and come up, with help from a psychotherapist or other professional, with a deeper evaluation of the behavior and a specific, collaborative plan.

Most experts see that ADHD, anxiety disorders, depressive disorders, and unrecognized learning disabilities, in sum, are more common underpinnings than not with aggressive children. This also can be confounded by an environment with parents who have those diagnoses untreated as well. Aggression should raise a red flag in our clinics to consider the above even if a family or child simply says aggression is the one issue, and it’s only the child with the issue.

While there have been attempts to find a “spot treatment” for aggression in a medication, medications not only fail to address the underlying issues many times, but have little evidence that support them and may do more harm long term than good.²

Kids need outlets for “normal aggressive drives.” And puberty, as in the case above, is a time of intense emotions of all varieties. In the example above, you may notice that the child is no longer playing soccer, which was likely serving some protective function in many ways for him and as a positive outlet for aggression. In the same way, you may see that kids who are more sedentary or idle (playing unrestricted video games now instead of sports, ) would benefit from revisiting outlets or finding new ones as a family.
 

 

Consider medications if the underlying diagnosis merits it

We generally seek to find and treat the underlying diagnosis, if it exists, in the following ways.

If a child has ADHD, as in the case above, you can trial a stimulant or an alpha-adrenergic agent to target impulsivity if that is suspected as the driver of aggression. This may include guanfacine (long-acting Intuniv at night, but I would choose lower dosing such as 0.5 mg to 1 mg at bedtime) to manage ADHD. However, the evidence base that management of ADHD improves aggressive behaviors at all or on their own, is scant. In addition, these medications can represent more harm than good as well, although they are perceived as more innocuous than their antipsychotic counterparts. For example, some patients can begin to have bed-wetting accidents in the evening or become sleepy in classes, which can further erode their sense of self-confidence even if this is clearly attributable to a medication side effect and resolves once the agent is reduced or removed.

In the same way to reorient to diagnosis with children with aggression, you can consider an SSRI for an anxiety disorder or irritable depression. But know that it’s a rare thing for children to say specifically that they are struggling with their emotions, whether they are angry, sad, or nervous and that a deeper dive into this may be warranted. Data by Connor DF et al.³ may indicate anxiety disorders should be highest on one’s differential diagnosis in aggression, followed by consideration for ADHD, which may be a different assumption than one would expect.

Mood stabilizers –lamotrigine (Lamictal), divalproex sodium (Depakote), and lithium – and antipsychotics – aripiprazole (Abilify) and risperidone (Risperdal) – are risky medications and the use of them contradicts the first point, agreed upon by most experts, that diagnosis should drive treatment. One is hardly ever treating a young child for psychosis or bipolar disorder in these circumstances of episodic, reactive aggression. Antipsychotics also carry the notorious risks of metabolic syndrome, among other risks to overall health, which becomes an additive risk over time and potentially into adulthood. I once heard in my child adolescent psychiatry training the haunting phase, “yes, they can ‘work’ quickly but they can work ‘almost too well,’ ” meaning they can sedate or tranquilize an aggressive child when the real goal should be to understand, diagnose, and intervene in ways that see the “big picture” of aggression.

Benzodiazepines generally are avoided in children due to disinhibition and often not even considered, in these circumstances, as they are in adults to manage agitation or aggression, due to this fact.

In many instances in working with families, our role in primary care can be one of illuminating children’s behaviors not just as symptoms to treat, but to understand deeply. This is as true for aggression as it is for anxiety.

Finally, I am reminded of the common question I receive from adult patients in primary care who ask me if anyone has yet made a medication to lose weight that’s safe and effective. Then the counseling commences on our fantasies, from our patients and ourselves, about what medications can do for us and our risks therein.
 

Dr. Pawlowski is an adult, adolescent, and child psychiatrist at the University of Vermont Medical Center and assistant professor of psychiatry at the Larner College of Medicine at UVM in Burlington. Email her at pdnews@mdedge.com.
 

References

1. ABA in the Treatment of Aggressive Behavior Disorder and Lack of Impulse Control.

2. Managing Aggression in Children: A Practical Approach, The Carlat Child Psychiatry Report, May 2010, The Explosive Child.

3. Child Psychiatry Hum Dev. 2006 May;37[1]:1-14.

A 13-year-old boy with ADHD, combined type, presents to his family physician with his parents. His parents called for an appointment outside of his routine follow-up care to discuss what they should do to address their son’s new “aggressive behaviors.” He will throw objects when angry, yell, and slam doors at home when he is told to turn off video games. He used to play soccer but doesn’t anymore. He has maintained very good grades and friends. There is not a concern for substance abuse at this time.He speaks in curt sentences during the appointment, and he has his arms crossed or is looking out of the window the entire time.

His parents share in front on him that he has always been a “difficult child” (their words), but they now are struggling to adjust to his aggressive tendencies as he ages. He is growing bigger and angrier. He will not attend therapy and will not see a consultation psychiatrist in the office. A variety of stimulant trials including Ritalin and amphetamine preparations to manage impulsivity in ADHD were ineffective to curb his aggression, and he doesn’t want to take any medication.

They ask, what do we do? They are not worried for their safety but living like this is eroding their quality of life as a family, and the dynamic seems destined to get worse before it gets better.

They wonder, is there a next medication step to manage his aggression?

A family physician presented the above situation to me in my role as a child and adolescent psychiatrist in the medical home. It led us to a fruitful discussion of aggression and what can be done to help families who are all too often in situations like the above, then in your office looking for immediate solutions. The questions are, what can be done with an aggressive child, even and especially without the child’s buy-in to work on that as a problem?

Markus Wegmann/Thinkstock

Psychoeducation can go a long way in helping families rethink aggression as a symptom of something deeper, either in the environment or a diagnosis, although we all can empathize with the desire to reconcile the above behavior immediately.
 

Characterize the aggression

First, it can be helpful to identify a child’s aggression type. There are two types of aggression, reactive and proactive. We most often see reactive aggression in our clinics, which is aggression as a defensive and impulsive response to something in the environment (often limit-setting, as above). Proactive aggression is premeditated and may appear as aggression for aggression’s sake without the emotional drive behind it.

Secondly, it also can be helpful to know that externalizing and internalizing symptoms can represent different sides of the same coin, with the proverbial “coin” as “emotion” and the associated behaviors (throwing objects, in the above example) as the “signs” that there is a complex difficulty in managing painful emotions. Some children (and adults too!) tend to “externalize” strong emotions as aggression or irritability with others, while others “internalize” them by retreating with internal suffering such as “anxiety and depression.” These styles also can be similar among children and their parents.

With those two points in mind, it’s important to consider the diagnosis, which would guide treatment. It’s generally agreed upon that “reactive aggression” is more likely to be related to underlying untreated ADHD, or a depressive or anxiety disorder. This is much more amenable to treatment than aggression related to oppositional defiant disorder or conduct disorder, which are more defined by proactive forms of aggression.

You can pick up on family dynamics that may inadvertently reinforce the same behaviors they so wish to change. In the above example, the parents have clearly identified their son as “the problem.” You can imagine the difficulty of going to school and being a “problem,” and then coming home and feeling the same way. This negative perception can erode a child’s self-esteem over time, which may appear as disengagement or simply not caring in an appointment. It may become harder and harder to engage the child in psychotherapy or even in taking a medication as their only means of resistance to that painful notion about oneself as the “problem.”

It can be useful to begin appointments with “what is going well?” (in the example above, he “has friends and is maintaining grades”) and “what do you like most about your child?” As we all know, positive reinforcement is more powerful than its counterpart. Also problems in a family often are complex, and may involve many family members needing to change to meet their goals, not just the child.
 

 

Why you should try behavioral interventions first

Behavioral interventions are the first step always. Parents can do behavioral interventions and change their parenting and family environment through their own behavioral changes – commonly called parent management training. They can assess antecedents of aggression and their own responses, which may contribute or perpetuate a cycle of the aggression – such as giving attention or giving in to fewer limitations to avoid a fight. This small but important point can help protect against a feeling of helplessness that a child will not engage in therapy or skills-building.

In answering the clinician’s question about what to do next, I often feel like the question embedded in this is “what medication is next?” There is a felt pressure to do something “right now” conveyed to a clinician. This drives the impulse to prescribe something immediately – and likely more risky and with less of an evidence base – even before trying the known psychotherapy interventions that have the most evidence to change aggressive tendencies.

In looking deeper into this consultation case, I also found more “food for thought” for one’s thinking about aggression and psychopharmacology in cases like the above: Aggression isn’t an uncomplicated symptom that one can address immediately, and therefore we cannot rely on symptom-specific management to eradicate it. This is similar to prescribing Tylenol to manage a general ache or pain; if the pain persists, we want to know the “whys” of the pain persisting.

Thankfully, there are ways that a parent can better understand behaviors with this philosophy in mind. Applied Behavioral Analysis¹ offers some helpful ideas, not only for children with autism spectrum disorder, but that can be applied to one’s understanding of other’s behavior in general. ABA pays attention to antecedents, perpetuating factors, and consequences as well as their interplay in understanding behaviors. You can encourage a family – rather than wanting to “get rid of a problem behavior” – to try to understand it and come up, with help from a psychotherapist or other professional, with a deeper evaluation of the behavior and a specific, collaborative plan.

Most experts see that ADHD, anxiety disorders, depressive disorders, and unrecognized learning disabilities, in sum, are more common underpinnings than not with aggressive children. This also can be confounded by an environment with parents who have those diagnoses untreated as well. Aggression should raise a red flag in our clinics to consider the above even if a family or child simply says aggression is the one issue, and it’s only the child with the issue.

While there have been attempts to find a “spot treatment” for aggression in a medication, medications not only fail to address the underlying issues many times, but have little evidence that support them and may do more harm long term than good.²

Kids need outlets for “normal aggressive drives.” And puberty, as in the case above, is a time of intense emotions of all varieties. In the example above, you may notice that the child is no longer playing soccer, which was likely serving some protective function in many ways for him and as a positive outlet for aggression. In the same way, you may see that kids who are more sedentary or idle (playing unrestricted video games now instead of sports, ) would benefit from revisiting outlets or finding new ones as a family.
 

 

Consider medications if the underlying diagnosis merits it

We generally seek to find and treat the underlying diagnosis, if it exists, in the following ways.

If a child has ADHD, as in the case above, you can trial a stimulant or an alpha-adrenergic agent to target impulsivity if that is suspected as the driver of aggression. This may include guanfacine (long-acting Intuniv at night, but I would choose lower dosing such as 0.5 mg to 1 mg at bedtime) to manage ADHD. However, the evidence base that management of ADHD improves aggressive behaviors at all or on their own, is scant. In addition, these medications can represent more harm than good as well, although they are perceived as more innocuous than their antipsychotic counterparts. For example, some patients can begin to have bed-wetting accidents in the evening or become sleepy in classes, which can further erode their sense of self-confidence even if this is clearly attributable to a medication side effect and resolves once the agent is reduced or removed.

In the same way to reorient to diagnosis with children with aggression, you can consider an SSRI for an anxiety disorder or irritable depression. But know that it’s a rare thing for children to say specifically that they are struggling with their emotions, whether they are angry, sad, or nervous and that a deeper dive into this may be warranted. Data by Connor DF et al.³ may indicate anxiety disorders should be highest on one’s differential diagnosis in aggression, followed by consideration for ADHD, which may be a different assumption than one would expect.

Mood stabilizers –lamotrigine (Lamictal), divalproex sodium (Depakote), and lithium – and antipsychotics – aripiprazole (Abilify) and risperidone (Risperdal) – are risky medications and the use of them contradicts the first point, agreed upon by most experts, that diagnosis should drive treatment. One is hardly ever treating a young child for psychosis or bipolar disorder in these circumstances of episodic, reactive aggression. Antipsychotics also carry the notorious risks of metabolic syndrome, among other risks to overall health, which becomes an additive risk over time and potentially into adulthood. I once heard in my child adolescent psychiatry training the haunting phase, “yes, they can ‘work’ quickly but they can work ‘almost too well,’ ” meaning they can sedate or tranquilize an aggressive child when the real goal should be to understand, diagnose, and intervene in ways that see the “big picture” of aggression.

Benzodiazepines generally are avoided in children due to disinhibition and often not even considered, in these circumstances, as they are in adults to manage agitation or aggression, due to this fact.

In many instances in working with families, our role in primary care can be one of illuminating children’s behaviors not just as symptoms to treat, but to understand deeply. This is as true for aggression as it is for anxiety.

Finally, I am reminded of the common question I receive from adult patients in primary care who ask me if anyone has yet made a medication to lose weight that’s safe and effective. Then the counseling commences on our fantasies, from our patients and ourselves, about what medications can do for us and our risks therein.
 

Dr. Pawlowski is an adult, adolescent, and child psychiatrist at the University of Vermont Medical Center and assistant professor of psychiatry at the Larner College of Medicine at UVM in Burlington. Email her at pdnews@mdedge.com.
 

References

1. ABA in the Treatment of Aggressive Behavior Disorder and Lack of Impulse Control.

2. Managing Aggression in Children: A Practical Approach, The Carlat Child Psychiatry Report, May 2010, The Explosive Child.

3. Child Psychiatry Hum Dev. 2006 May;37[1]:1-14.

A 13-year-old boy with ADHD, combined type, presents to his family physician with his parents. His parents called for an appointment outside of his routine follow-up care to discuss what they should do to address their son’s new “aggressive behaviors.” He will throw objects when angry, yell, and slam doors at home when he is told to turn off video games. He used to play soccer but doesn’t anymore. He has maintained very good grades and friends. There is not a concern for substance abuse at this time.He speaks in curt sentences during the appointment, and he has his arms crossed or is looking out of the window the entire time.

His parents share in front on him that he has always been a “difficult child” (their words), but they now are struggling to adjust to his aggressive tendencies as he ages. He is growing bigger and angrier. He will not attend therapy and will not see a consultation psychiatrist in the office. A variety of stimulant trials including Ritalin and amphetamine preparations to manage impulsivity in ADHD were ineffective to curb his aggression, and he doesn’t want to take any medication.

They ask, what do we do? They are not worried for their safety but living like this is eroding their quality of life as a family, and the dynamic seems destined to get worse before it gets better.

They wonder, is there a next medication step to manage his aggression?

A family physician presented the above situation to me in my role as a child and adolescent psychiatrist in the medical home. It led us to a fruitful discussion of aggression and what can be done to help families who are all too often in situations like the above, then in your office looking for immediate solutions. The questions are, what can be done with an aggressive child, even and especially without the child’s buy-in to work on that as a problem?

Markus Wegmann/Thinkstock

Psychoeducation can go a long way in helping families rethink aggression as a symptom of something deeper, either in the environment or a diagnosis, although we all can empathize with the desire to reconcile the above behavior immediately.
 

Characterize the aggression

First, it can be helpful to identify a child’s aggression type. There are two types of aggression, reactive and proactive. We most often see reactive aggression in our clinics, which is aggression as a defensive and impulsive response to something in the environment (often limit-setting, as above). Proactive aggression is premeditated and may appear as aggression for aggression’s sake without the emotional drive behind it.

Secondly, it also can be helpful to know that externalizing and internalizing symptoms can represent different sides of the same coin, with the proverbial “coin” as “emotion” and the associated behaviors (throwing objects, in the above example) as the “signs” that there is a complex difficulty in managing painful emotions. Some children (and adults too!) tend to “externalize” strong emotions as aggression or irritability with others, while others “internalize” them by retreating with internal suffering such as “anxiety and depression.” These styles also can be similar among children and their parents.

With those two points in mind, it’s important to consider the diagnosis, which would guide treatment. It’s generally agreed upon that “reactive aggression” is more likely to be related to underlying untreated ADHD, or a depressive or anxiety disorder. This is much more amenable to treatment than aggression related to oppositional defiant disorder or conduct disorder, which are more defined by proactive forms of aggression.

You can pick up on family dynamics that may inadvertently reinforce the same behaviors they so wish to change. In the above example, the parents have clearly identified their son as “the problem.” You can imagine the difficulty of going to school and being a “problem,” and then coming home and feeling the same way. This negative perception can erode a child’s self-esteem over time, which may appear as disengagement or simply not caring in an appointment. It may become harder and harder to engage the child in psychotherapy or even in taking a medication as their only means of resistance to that painful notion about oneself as the “problem.”

It can be useful to begin appointments with “what is going well?” (in the example above, he “has friends and is maintaining grades”) and “what do you like most about your child?” As we all know, positive reinforcement is more powerful than its counterpart. Also problems in a family often are complex, and may involve many family members needing to change to meet their goals, not just the child.
 

 

Why you should try behavioral interventions first

Behavioral interventions are the first step always. Parents can do behavioral interventions and change their parenting and family environment through their own behavioral changes – commonly called parent management training. They can assess antecedents of aggression and their own responses, which may contribute or perpetuate a cycle of the aggression – such as giving attention or giving in to fewer limitations to avoid a fight. This small but important point can help protect against a feeling of helplessness that a child will not engage in therapy or skills-building.

In answering the clinician’s question about what to do next, I often feel like the question embedded in this is “what medication is next?” There is a felt pressure to do something “right now” conveyed to a clinician. This drives the impulse to prescribe something immediately – and likely more risky and with less of an evidence base – even before trying the known psychotherapy interventions that have the most evidence to change aggressive tendencies.

In looking deeper into this consultation case, I also found more “food for thought” for one’s thinking about aggression and psychopharmacology in cases like the above: Aggression isn’t an uncomplicated symptom that one can address immediately, and therefore we cannot rely on symptom-specific management to eradicate it. This is similar to prescribing Tylenol to manage a general ache or pain; if the pain persists, we want to know the “whys” of the pain persisting.

Thankfully, there are ways that a parent can better understand behaviors with this philosophy in mind. Applied Behavioral Analysis¹ offers some helpful ideas, not only for children with autism spectrum disorder, but that can be applied to one’s understanding of other’s behavior in general. ABA pays attention to antecedents, perpetuating factors, and consequences as well as their interplay in understanding behaviors. You can encourage a family – rather than wanting to “get rid of a problem behavior” – to try to understand it and come up, with help from a psychotherapist or other professional, with a deeper evaluation of the behavior and a specific, collaborative plan.

Most experts see that ADHD, anxiety disorders, depressive disorders, and unrecognized learning disabilities, in sum, are more common underpinnings than not with aggressive children. This also can be confounded by an environment with parents who have those diagnoses untreated as well. Aggression should raise a red flag in our clinics to consider the above even if a family or child simply says aggression is the one issue, and it’s only the child with the issue.

While there have been attempts to find a “spot treatment” for aggression in a medication, medications not only fail to address the underlying issues many times, but have little evidence that support them and may do more harm long term than good.²

Kids need outlets for “normal aggressive drives.” And puberty, as in the case above, is a time of intense emotions of all varieties. In the example above, you may notice that the child is no longer playing soccer, which was likely serving some protective function in many ways for him and as a positive outlet for aggression. In the same way, you may see that kids who are more sedentary or idle (playing unrestricted video games now instead of sports, ) would benefit from revisiting outlets or finding new ones as a family.
 

 

Consider medications if the underlying diagnosis merits it

We generally seek to find and treat the underlying diagnosis, if it exists, in the following ways.

If a child has ADHD, as in the case above, you can trial a stimulant or an alpha-adrenergic agent to target impulsivity if that is suspected as the driver of aggression. This may include guanfacine (long-acting Intuniv at night, but I would choose lower dosing such as 0.5 mg to 1 mg at bedtime) to manage ADHD. However, the evidence base that management of ADHD improves aggressive behaviors at all or on their own, is scant. In addition, these medications can represent more harm than good as well, although they are perceived as more innocuous than their antipsychotic counterparts. For example, some patients can begin to have bed-wetting accidents in the evening or become sleepy in classes, which can further erode their sense of self-confidence even if this is clearly attributable to a medication side effect and resolves once the agent is reduced or removed.

In the same way to reorient to diagnosis with children with aggression, you can consider an SSRI for an anxiety disorder or irritable depression. But know that it’s a rare thing for children to say specifically that they are struggling with their emotions, whether they are angry, sad, or nervous and that a deeper dive into this may be warranted. Data by Connor DF et al.³ may indicate anxiety disorders should be highest on one’s differential diagnosis in aggression, followed by consideration for ADHD, which may be a different assumption than one would expect.

Mood stabilizers –lamotrigine (Lamictal), divalproex sodium (Depakote), and lithium – and antipsychotics – aripiprazole (Abilify) and risperidone (Risperdal) – are risky medications and the use of them contradicts the first point, agreed upon by most experts, that diagnosis should drive treatment. One is hardly ever treating a young child for psychosis or bipolar disorder in these circumstances of episodic, reactive aggression. Antipsychotics also carry the notorious risks of metabolic syndrome, among other risks to overall health, which becomes an additive risk over time and potentially into adulthood. I once heard in my child adolescent psychiatry training the haunting phase, “yes, they can ‘work’ quickly but they can work ‘almost too well,’ ” meaning they can sedate or tranquilize an aggressive child when the real goal should be to understand, diagnose, and intervene in ways that see the “big picture” of aggression.

Benzodiazepines generally are avoided in children due to disinhibition and often not even considered, in these circumstances, as they are in adults to manage agitation or aggression, due to this fact.

In many instances in working with families, our role in primary care can be one of illuminating children’s behaviors not just as symptoms to treat, but to understand deeply. This is as true for aggression as it is for anxiety.

Finally, I am reminded of the common question I receive from adult patients in primary care who ask me if anyone has yet made a medication to lose weight that’s safe and effective. Then the counseling commences on our fantasies, from our patients and ourselves, about what medications can do for us and our risks therein.
 

Dr. Pawlowski is an adult, adolescent, and child psychiatrist at the University of Vermont Medical Center and assistant professor of psychiatry at the Larner College of Medicine at UVM in Burlington. Email her at pdnews@mdedge.com.
 

References

1. ABA in the Treatment of Aggressive Behavior Disorder and Lack of Impulse Control.

2. Managing Aggression in Children: A Practical Approach, The Carlat Child Psychiatry Report, May 2010, The Explosive Child.

3. Child Psychiatry Hum Dev. 2006 May;37[1]:1-14.

LAS VEGAS – The risk-benefit ratio of new and emerging drugs for depression is going to be under the spotlight more than ever before, according to an expert in mood disorders.

Doug Brunk/MDedge News

“We’ve seen a shift in the landscape,” Alan F. Schatzberg, MD, said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “We’ve gone from the development of ‘me too’ agents such as venlafaxine and fluoxetine to developing drugs that may have more dramatic effects, but they also may have more baggage in terms of risks. The risk-benefit ratio is going to become increasingly more of a focus in drug development, in terms of increasing risk.”

The development of the SSRIs, he continued, led to the introduction of agents that were generally effective and well tolerated.

“Particularly, they were well tolerated in terms of their wide safety margin,” said Dr. Schatzberg, who directs the Mood Disorders Center at Stanford (Calif.) University. “It’s difficult to [die by suicide] on an SSRI. Because of that, we had greater numbers of individuals treated than we did with the tricyclics.” The introduction of SSRIs led to “widening of the net in terms of the numbers of depressed patients,” he said. “Combine that with DSM-III, and DSM-IV having relatively easy criteria to obtain a diagnosis [of depression, and] you see a large group of subjects who are exposed to treatment. But a lot of those people may not respond to a particular agent. As new treatments are promulgated and tried, what you find is [that] a reasonable number of subjects are, in fact, truly resistant. That becomes a tough nut to crack for all of us who treat depression.”

Drugs for depression that clinicians commonly have in their armamentarium commonly revolve around monoaminergic function. New and emerging agents include hallucinatory serotonin 2a agonists, glutamatergic drugs such as ketamine, GABAergic neurosteroids, opioid modulators, and onabotulinumtoxinA.

In 2013, the Food and Drug Administration approved the multimodal agent vortioxetine for the treatment of major depressive disorder. The recommended dosing is 20 mg/day, and the drug appears to have a positive effect on cognition. A meta-analysis of vortioxetine, duloxetine, and placebo comparison trials evaluated the effect of each treatment on the Digit Symbol Substitution Test (Int J Neuropsychopharmacol. 2016 Jun 15;19[10]). Vortioxetine was superior to placebo in all three trials and was superior to duloxetine in two trials. Duloxetine was not superior to placebo in two trials.

In two double-blind studies, researchers evaluated the effects of psilocybin in cancer patients with comorbid depression and anxiety. Full doses of psilocybin were 0.3 mg/kg or 22-30 mg per 70 kg. Both studies demonstrated sustained responses at full doses (J Psychopharmacol. 2016 Nov 30;30[12]:1181-97 and J Psychopharmacol. 2016 Nov 30;30[12]:1165-80).

In an open label study of psilocybin in refractory major depression, 12 patients received 10 mg on day 1 and 25 mg on day 8. Eight of 12 patients responded at 1 week, and 7 of the 12 maintained response at 3 months (Lancet Psychiatry. 2016 Jul;3[7]:619-27). According to Dr. Schatzberg, this trial became the basis for a blinded study that Compass is conducting in the United States and in the United Kingdom in which refractory patients are going to be randomized to 1 mg, 10 mg, or 25 mg psilocybin using an independent rater. “These patients are accompanied during this experience by two therapists for up to 8 hours. It’s not quite a guided therapy; it’s kind of a safety net therapy if the patient needs [help]. We’ll see what happens.”

Another agent being studied is ketamine, which works on the glutamate system, an excitatory neurotransmitter. “Glutamate is the juice that keeps us going,” said Dr. Schatzberg, who is also the Kenneth T. Norris Jr. professor of psychiatry and behavioral sciences at the university. “We can’t live without glutamate.” An anesthetic agent that has been used for 50 years, ketamine is a N-methyl-d-aspartate antagonist that has mu opioid agonist effects and stimulant properties. “It causes a psychotomimetic dissociative kind of reaction,” he said. “The doses used in depression are subanesthetic. They may put the patient asleep, but they usually don’t. The problem with the antidepressant effect is that 70% of people who initially respond don’t continue to respond beyond 1 week.”

In a randomized, placebo-controlled, double-blind crossover study of patients with treatment-resistant depression, subjects who received ketamine showed significant improvement in depression, compared with subjects who received placebo within 110 minutes after injection, which remained significant throughout the following week (Arch Gen Psychiatry. 2006;63:856-64). Specifically, of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week.

In an effort to further evaluate the antidepressive effects of ketamine, researchers conducted a two-site, parallel-arm, randomized, controlled trial of a single infusion of ketamine, compared with an active placebo control condition, the anesthetic midazolam (Am J Psychiatry. 2013 Oct;170[10]:1134-42). After adjustment for baseline scores and site, the Montgomery-Åsberg Depression Rating Scale score was lower in the ketamine group than in the midazolam group by 7.95 points. The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18), with response rates of 64% and 28%, respectively.

In 2019, the FDA approved esketamine nasal spray, in conjunction with an oral antidepressant, for the treatment of depression in adults with treatment-resistant depression. In three phase 3 double-blind studies of esketamine in treatment-refractory depression, one was positive, two were nearly positive, and the effect sizes were mild. One maintenance discontinuation trial was positive. Based on this data, Dr. Schatzberg said, there “is not much evidence” that patients get further gain beyond an antidepressant alone in the first 24-48 hours following ketamine administration. “It makes me wonder: Should we be continuing to give this drug intranasally beyond 48 hours?” he asked. “The reason I have concern is that in certain cultures, ketamine is a highly abusable drug.”

He and Gerard Sanacora, PhD, MD, addressed the topic in a 2015 opinion piece entitled, “Ketamine: Promising path or false prophecy in the development of novel therapeutics for mood disorders?”

“If we step back for a moment and look at where we are – an intravenously administered agent that is a street drug of abuse, works rapidly, and whose enantiomers are being studied by industry for intranasal use – we should be anxious, “ they wrote (Neuropsychopharmacology. 2015 Jan;40[2]:259-67). “We need to be as careful and conservative as possible and understand how it is acting and rule out the possibility of whether it acts as an opioid.”

Dr. Schatzberg disclosed that he has served a consultant to Alkermes, Avanir, Bracket, Compass, Delpor, Epiodyne, Janssen, Jazz, Lundbeck, McKinsey, Merck, Myriad Genetics, Owl, Neuronetics, Pfizer, Sage, and Sunovion. He has received research funding from Janssen and also holds an ownership interest in Corcept, Dermira, Delpor, Epiodyne, Incyte Genetics, Madrigal, Maerck, Owl Analytics, Seattle Genetics, Titan, and Xhale.

dbrunk@mdedge.com

LAS VEGAS – The risk-benefit ratio of new and emerging drugs for depression is going to be under the spotlight more than ever before, according to an expert in mood disorders.

Doug Brunk/MDedge News

“We’ve seen a shift in the landscape,” Alan F. Schatzberg, MD, said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “We’ve gone from the development of ‘me too’ agents such as venlafaxine and fluoxetine to developing drugs that may have more dramatic effects, but they also may have more baggage in terms of risks. The risk-benefit ratio is going to become increasingly more of a focus in drug development, in terms of increasing risk.”

The development of the SSRIs, he continued, led to the introduction of agents that were generally effective and well tolerated.

“Particularly, they were well tolerated in terms of their wide safety margin,” said Dr. Schatzberg, who directs the Mood Disorders Center at Stanford (Calif.) University. “It’s difficult to [die by suicide] on an SSRI. Because of that, we had greater numbers of individuals treated than we did with the tricyclics.” The introduction of SSRIs led to “widening of the net in terms of the numbers of depressed patients,” he said. “Combine that with DSM-III, and DSM-IV having relatively easy criteria to obtain a diagnosis [of depression, and] you see a large group of subjects who are exposed to treatment. But a lot of those people may not respond to a particular agent. As new treatments are promulgated and tried, what you find is [that] a reasonable number of subjects are, in fact, truly resistant. That becomes a tough nut to crack for all of us who treat depression.”

Drugs for depression that clinicians commonly have in their armamentarium commonly revolve around monoaminergic function. New and emerging agents include hallucinatory serotonin 2a agonists, glutamatergic drugs such as ketamine, GABAergic neurosteroids, opioid modulators, and onabotulinumtoxinA.

In 2013, the Food and Drug Administration approved the multimodal agent vortioxetine for the treatment of major depressive disorder. The recommended dosing is 20 mg/day, and the drug appears to have a positive effect on cognition. A meta-analysis of vortioxetine, duloxetine, and placebo comparison trials evaluated the effect of each treatment on the Digit Symbol Substitution Test (Int J Neuropsychopharmacol. 2016 Jun 15;19[10]). Vortioxetine was superior to placebo in all three trials and was superior to duloxetine in two trials. Duloxetine was not superior to placebo in two trials.

In two double-blind studies, researchers evaluated the effects of psilocybin in cancer patients with comorbid depression and anxiety. Full doses of psilocybin were 0.3 mg/kg or 22-30 mg per 70 kg. Both studies demonstrated sustained responses at full doses (J Psychopharmacol. 2016 Nov 30;30[12]:1181-97 and J Psychopharmacol. 2016 Nov 30;30[12]:1165-80).

In an open label study of psilocybin in refractory major depression, 12 patients received 10 mg on day 1 and 25 mg on day 8. Eight of 12 patients responded at 1 week, and 7 of the 12 maintained response at 3 months (Lancet Psychiatry. 2016 Jul;3[7]:619-27). According to Dr. Schatzberg, this trial became the basis for a blinded study that Compass is conducting in the United States and in the United Kingdom in which refractory patients are going to be randomized to 1 mg, 10 mg, or 25 mg psilocybin using an independent rater. “These patients are accompanied during this experience by two therapists for up to 8 hours. It’s not quite a guided therapy; it’s kind of a safety net therapy if the patient needs [help]. We’ll see what happens.”

Another agent being studied is ketamine, which works on the glutamate system, an excitatory neurotransmitter. “Glutamate is the juice that keeps us going,” said Dr. Schatzberg, who is also the Kenneth T. Norris Jr. professor of psychiatry and behavioral sciences at the university. “We can’t live without glutamate.” An anesthetic agent that has been used for 50 years, ketamine is a N-methyl-d-aspartate antagonist that has mu opioid agonist effects and stimulant properties. “It causes a psychotomimetic dissociative kind of reaction,” he said. “The doses used in depression are subanesthetic. They may put the patient asleep, but they usually don’t. The problem with the antidepressant effect is that 70% of people who initially respond don’t continue to respond beyond 1 week.”

In a randomized, placebo-controlled, double-blind crossover study of patients with treatment-resistant depression, subjects who received ketamine showed significant improvement in depression, compared with subjects who received placebo within 110 minutes after injection, which remained significant throughout the following week (Arch Gen Psychiatry. 2006;63:856-64). Specifically, of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week.

In an effort to further evaluate the antidepressive effects of ketamine, researchers conducted a two-site, parallel-arm, randomized, controlled trial of a single infusion of ketamine, compared with an active placebo control condition, the anesthetic midazolam (Am J Psychiatry. 2013 Oct;170[10]:1134-42). After adjustment for baseline scores and site, the Montgomery-Åsberg Depression Rating Scale score was lower in the ketamine group than in the midazolam group by 7.95 points. The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18), with response rates of 64% and 28%, respectively.

In 2019, the FDA approved esketamine nasal spray, in conjunction with an oral antidepressant, for the treatment of depression in adults with treatment-resistant depression. In three phase 3 double-blind studies of esketamine in treatment-refractory depression, one was positive, two were nearly positive, and the effect sizes were mild. One maintenance discontinuation trial was positive. Based on this data, Dr. Schatzberg said, there “is not much evidence” that patients get further gain beyond an antidepressant alone in the first 24-48 hours following ketamine administration. “It makes me wonder: Should we be continuing to give this drug intranasally beyond 48 hours?” he asked. “The reason I have concern is that in certain cultures, ketamine is a highly abusable drug.”

He and Gerard Sanacora, PhD, MD, addressed the topic in a 2015 opinion piece entitled, “Ketamine: Promising path or false prophecy in the development of novel therapeutics for mood disorders?”

“If we step back for a moment and look at where we are – an intravenously administered agent that is a street drug of abuse, works rapidly, and whose enantiomers are being studied by industry for intranasal use – we should be anxious, “ they wrote (Neuropsychopharmacology. 2015 Jan;40[2]:259-67). “We need to be as careful and conservative as possible and understand how it is acting and rule out the possibility of whether it acts as an opioid.”

Dr. Schatzberg disclosed that he has served a consultant to Alkermes, Avanir, Bracket, Compass, Delpor, Epiodyne, Janssen, Jazz, Lundbeck, McKinsey, Merck, Myriad Genetics, Owl, Neuronetics, Pfizer, Sage, and Sunovion. He has received research funding from Janssen and also holds an ownership interest in Corcept, Dermira, Delpor, Epiodyne, Incyte Genetics, Madrigal, Maerck, Owl Analytics, Seattle Genetics, Titan, and Xhale.

dbrunk@mdedge.com

LAS VEGAS – The risk-benefit ratio of new and emerging drugs for depression is going to be under the spotlight more than ever before, according to an expert in mood disorders.

Doug Brunk/MDedge News

“We’ve seen a shift in the landscape,” Alan F. Schatzberg, MD, said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “We’ve gone from the development of ‘me too’ agents such as venlafaxine and fluoxetine to developing drugs that may have more dramatic effects, but they also may have more baggage in terms of risks. The risk-benefit ratio is going to become increasingly more of a focus in drug development, in terms of increasing risk.”

The development of the SSRIs, he continued, led to the introduction of agents that were generally effective and well tolerated.

“Particularly, they were well tolerated in terms of their wide safety margin,” said Dr. Schatzberg, who directs the Mood Disorders Center at Stanford (Calif.) University. “It’s difficult to [die by suicide] on an SSRI. Because of that, we had greater numbers of individuals treated than we did with the tricyclics.” The introduction of SSRIs led to “widening of the net in terms of the numbers of depressed patients,” he said. “Combine that with DSM-III, and DSM-IV having relatively easy criteria to obtain a diagnosis [of depression, and] you see a large group of subjects who are exposed to treatment. But a lot of those people may not respond to a particular agent. As new treatments are promulgated and tried, what you find is [that] a reasonable number of subjects are, in fact, truly resistant. That becomes a tough nut to crack for all of us who treat depression.”

Drugs for depression that clinicians commonly have in their armamentarium commonly revolve around monoaminergic function. New and emerging agents include hallucinatory serotonin 2a agonists, glutamatergic drugs such as ketamine, GABAergic neurosteroids, opioid modulators, and onabotulinumtoxinA.

In 2013, the Food and Drug Administration approved the multimodal agent vortioxetine for the treatment of major depressive disorder. The recommended dosing is 20 mg/day, and the drug appears to have a positive effect on cognition. A meta-analysis of vortioxetine, duloxetine, and placebo comparison trials evaluated the effect of each treatment on the Digit Symbol Substitution Test (Int J Neuropsychopharmacol. 2016 Jun 15;19[10]). Vortioxetine was superior to placebo in all three trials and was superior to duloxetine in two trials. Duloxetine was not superior to placebo in two trials.

In two double-blind studies, researchers evaluated the effects of psilocybin in cancer patients with comorbid depression and anxiety. Full doses of psilocybin were 0.3 mg/kg or 22-30 mg per 70 kg. Both studies demonstrated sustained responses at full doses (J Psychopharmacol. 2016 Nov 30;30[12]:1181-97 and J Psychopharmacol. 2016 Nov 30;30[12]:1165-80).

In an open label study of psilocybin in refractory major depression, 12 patients received 10 mg on day 1 and 25 mg on day 8. Eight of 12 patients responded at 1 week, and 7 of the 12 maintained response at 3 months (Lancet Psychiatry. 2016 Jul;3[7]:619-27). According to Dr. Schatzberg, this trial became the basis for a blinded study that Compass is conducting in the United States and in the United Kingdom in which refractory patients are going to be randomized to 1 mg, 10 mg, or 25 mg psilocybin using an independent rater. “These patients are accompanied during this experience by two therapists for up to 8 hours. It’s not quite a guided therapy; it’s kind of a safety net therapy if the patient needs [help]. We’ll see what happens.”

Another agent being studied is ketamine, which works on the glutamate system, an excitatory neurotransmitter. “Glutamate is the juice that keeps us going,” said Dr. Schatzberg, who is also the Kenneth T. Norris Jr. professor of psychiatry and behavioral sciences at the university. “We can’t live without glutamate.” An anesthetic agent that has been used for 50 years, ketamine is a N-methyl-d-aspartate antagonist that has mu opioid agonist effects and stimulant properties. “It causes a psychotomimetic dissociative kind of reaction,” he said. “The doses used in depression are subanesthetic. They may put the patient asleep, but they usually don’t. The problem with the antidepressant effect is that 70% of people who initially respond don’t continue to respond beyond 1 week.”

In a randomized, placebo-controlled, double-blind crossover study of patients with treatment-resistant depression, subjects who received ketamine showed significant improvement in depression, compared with subjects who received placebo within 110 minutes after injection, which remained significant throughout the following week (Arch Gen Psychiatry. 2006;63:856-64). Specifically, of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week.

In an effort to further evaluate the antidepressive effects of ketamine, researchers conducted a two-site, parallel-arm, randomized, controlled trial of a single infusion of ketamine, compared with an active placebo control condition, the anesthetic midazolam (Am J Psychiatry. 2013 Oct;170[10]:1134-42). After adjustment for baseline scores and site, the Montgomery-Åsberg Depression Rating Scale score was lower in the ketamine group than in the midazolam group by 7.95 points. The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18), with response rates of 64% and 28%, respectively.

In 2019, the FDA approved esketamine nasal spray, in conjunction with an oral antidepressant, for the treatment of depression in adults with treatment-resistant depression. In three phase 3 double-blind studies of esketamine in treatment-refractory depression, one was positive, two were nearly positive, and the effect sizes were mild. One maintenance discontinuation trial was positive. Based on this data, Dr. Schatzberg said, there “is not much evidence” that patients get further gain beyond an antidepressant alone in the first 24-48 hours following ketamine administration. “It makes me wonder: Should we be continuing to give this drug intranasally beyond 48 hours?” he asked. “The reason I have concern is that in certain cultures, ketamine is a highly abusable drug.”

He and Gerard Sanacora, PhD, MD, addressed the topic in a 2015 opinion piece entitled, “Ketamine: Promising path or false prophecy in the development of novel therapeutics for mood disorders?”

“If we step back for a moment and look at where we are – an intravenously administered agent that is a street drug of abuse, works rapidly, and whose enantiomers are being studied by industry for intranasal use – we should be anxious, “ they wrote (Neuropsychopharmacology. 2015 Jan;40[2]:259-67). “We need to be as careful and conservative as possible and understand how it is acting and rule out the possibility of whether it acts as an opioid.”

Dr. Schatzberg disclosed that he has served a consultant to Alkermes, Avanir, Bracket, Compass, Delpor, Epiodyne, Janssen, Jazz, Lundbeck, McKinsey, Merck, Myriad Genetics, Owl, Neuronetics, Pfizer, Sage, and Sunovion. He has received research funding from Janssen and also holds an ownership interest in Corcept, Dermira, Delpor, Epiodyne, Incyte Genetics, Madrigal, Maerck, Owl Analytics, Seattle Genetics, Titan, and Xhale.

dbrunk@mdedge.com

LAS VEGAS – No evidence-based medications are approved for the treatment of avoidant/restrictive food intake disorder, but olanzapine is a sensible option to consider, according to Timothy D. Brewerton, MD.

Doug Brunk/MDedge News

A newly classified disorder in the DSM-5, avoidant/restrictive food intake disorder (ARFID) is an eating/feeding disturbance manifested by the persistent failure to meet appropriate nutritional energy needs associated with one or more of the following factors: significant weight loss or failure to achieve expected growth, significant nutritional deficiency, dependence on enteral feeding or oral nutritional supplements to survive, and marked interference with psychosocial functioning. ARFID “is not better explained by lack of available food or by culturally sanctioned practices,” Dr. Brewerton, an affiliate professor of psychiatry and behavioral sciences at the Medical University of South Carolina, Charleston, said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “It does not occur during the course of anorexia nervosa or bulimia nervosa, and there is no evidence of a disturbance in the way in which one’s body weight or shape is experienced. That’s what distinguishes it from anorexia nervosa.”

He added that, although many cases of ARFID have autism spectrum disorder traits, ARFID “is not attributable to a concurrent medical condition or to mental disorder.” When it does occur, the severity of the feeding disorder far outweighs that of the medical condition.”

Several ARFID case reports have been published in the medical literature, yet no randomized controlled trials exist to date. “Treatment is multidisciplinary and involves cognitive-behavioral therapy, sometimes occupational therapy,” said Dr. Brewerton, who is a founding fellow and former board member of the Academy for Eating Disorders.

He and his colleagues published a report on nine ARFID cases treated in an eating disorders program (J Child Adolesc Psychopharmacol. 2017;27[10]:920-2). The patients were treated with adjunctive olanzapine at a starting dose of 0.9 mg/day and discharge dose 2.8 mg/day. For the starting dose, “you have to break the [olanzapine pills] in pieces,” he said. “You have to have a pill cutter. What you don’t want to do is overwhelm the patient or their family members with oversedation. Too often, people start them with 2.5 mg or 5 mg [of olanzapine] right off the bat.”

The researchers found a significant increase in weight gain pre- versus post-olanzapine treatment (a mean of 3.3 pounds vs. 13.1 pounds, respectively; P less than .04) and BMI-for-weight percentiles (P less than .009). “Patients also had improvements in their Clinical Global Impressions Scale scores and a reduction in their associated anxious, depressive, and cognitive symptoms,” Dr. Brewerton said.

Similar findings were observed in a subsequent Canadian study of six ARFID cases (J Eat Disord. 2018;6:20). Five females and one male were treated with a combination of medical monitoring, family therapy, medication (including olanzapine, fluoxetine and in two cases, cyproheptadine), and CBT. At treatment termination, all six patients had achieved their goal weight.

At the University of California, San Diego, researchers led by Emily Gray, MD, conducted a retrospective chart review of six females and eight males with ARFID who ranged in age from 7 to 23 years. All but one of the 14 patients had a co-occurring diagnosis, including general anxiety disorder, social anxiety, unspecified anxiety, ADHD, major depressive disorder, and autism spectrum disorder (J Am Acad Child Adoles Psychiatry. 2018;57[4]:288-9). They were treated with mirtazapine at a dosing range of 7.5-45 mg per day. The average change in BMI per week rose from 0.10 BMI points per week pretreatment to 0.23 BMI points per week post-treatment (P less than .05).

“These cases illustrate that the judicious use of low-dose olanzapine, when used as an adjunct to other treatment modalities, may facilitate eating, weight gain, and the reduction of anxious, depressive, and cognitive symptoms,” said Dr. Brewerton, who also has a private practice in Charleston.

Dr. Brewerton disclosed that he is a consultant to Monte Nido & Affiliates and Sunovion. He receives royalties from Taylor & Francis and Springer-Verlag, and holds ownership interest in Monte Nido & Affiliates.

dbrunk@mdedge.com

LAS VEGAS – No evidence-based medications are approved for the treatment of avoidant/restrictive food intake disorder, but olanzapine is a sensible option to consider, according to Timothy D. Brewerton, MD.

Doug Brunk/MDedge News

A newly classified disorder in the DSM-5, avoidant/restrictive food intake disorder (ARFID) is an eating/feeding disturbance manifested by the persistent failure to meet appropriate nutritional energy needs associated with one or more of the following factors: significant weight loss or failure to achieve expected growth, significant nutritional deficiency, dependence on enteral feeding or oral nutritional supplements to survive, and marked interference with psychosocial functioning. ARFID “is not better explained by lack of available food or by culturally sanctioned practices,” Dr. Brewerton, an affiliate professor of psychiatry and behavioral sciences at the Medical University of South Carolina, Charleston, said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “It does not occur during the course of anorexia nervosa or bulimia nervosa, and there is no evidence of a disturbance in the way in which one’s body weight or shape is experienced. That’s what distinguishes it from anorexia nervosa.”

He added that, although many cases of ARFID have autism spectrum disorder traits, ARFID “is not attributable to a concurrent medical condition or to mental disorder.” When it does occur, the severity of the feeding disorder far outweighs that of the medical condition.”

Several ARFID case reports have been published in the medical literature, yet no randomized controlled trials exist to date. “Treatment is multidisciplinary and involves cognitive-behavioral therapy, sometimes occupational therapy,” said Dr. Brewerton, who is a founding fellow and former board member of the Academy for Eating Disorders.

He and his colleagues published a report on nine ARFID cases treated in an eating disorders program (J Child Adolesc Psychopharmacol. 2017;27[10]:920-2). The patients were treated with adjunctive olanzapine at a starting dose of 0.9 mg/day and discharge dose 2.8 mg/day. For the starting dose, “you have to break the [olanzapine pills] in pieces,” he said. “You have to have a pill cutter. What you don’t want to do is overwhelm the patient or their family members with oversedation. Too often, people start them with 2.5 mg or 5 mg [of olanzapine] right off the bat.”

The researchers found a significant increase in weight gain pre- versus post-olanzapine treatment (a mean of 3.3 pounds vs. 13.1 pounds, respectively; P less than .04) and BMI-for-weight percentiles (P less than .009). “Patients also had improvements in their Clinical Global Impressions Scale scores and a reduction in their associated anxious, depressive, and cognitive symptoms,” Dr. Brewerton said.

Similar findings were observed in a subsequent Canadian study of six ARFID cases (J Eat Disord. 2018;6:20). Five females and one male were treated with a combination of medical monitoring, family therapy, medication (including olanzapine, fluoxetine and in two cases, cyproheptadine), and CBT. At treatment termination, all six patients had achieved their goal weight.

At the University of California, San Diego, researchers led by Emily Gray, MD, conducted a retrospective chart review of six females and eight males with ARFID who ranged in age from 7 to 23 years. All but one of the 14 patients had a co-occurring diagnosis, including general anxiety disorder, social anxiety, unspecified anxiety, ADHD, major depressive disorder, and autism spectrum disorder (J Am Acad Child Adoles Psychiatry. 2018;57[4]:288-9). They were treated with mirtazapine at a dosing range of 7.5-45 mg per day. The average change in BMI per week rose from 0.10 BMI points per week pretreatment to 0.23 BMI points per week post-treatment (P less than .05).

“These cases illustrate that the judicious use of low-dose olanzapine, when used as an adjunct to other treatment modalities, may facilitate eating, weight gain, and the reduction of anxious, depressive, and cognitive symptoms,” said Dr. Brewerton, who also has a private practice in Charleston.

Dr. Brewerton disclosed that he is a consultant to Monte Nido & Affiliates and Sunovion. He receives royalties from Taylor & Francis and Springer-Verlag, and holds ownership interest in Monte Nido & Affiliates.

dbrunk@mdedge.com

LAS VEGAS – No evidence-based medications are approved for the treatment of avoidant/restrictive food intake disorder, but olanzapine is a sensible option to consider, according to Timothy D. Brewerton, MD.

Doug Brunk/MDedge News

A newly classified disorder in the DSM-5, avoidant/restrictive food intake disorder (ARFID) is an eating/feeding disturbance manifested by the persistent failure to meet appropriate nutritional energy needs associated with one or more of the following factors: significant weight loss or failure to achieve expected growth, significant nutritional deficiency, dependence on enteral feeding or oral nutritional supplements to survive, and marked interference with psychosocial functioning. ARFID “is not better explained by lack of available food or by culturally sanctioned practices,” Dr. Brewerton, an affiliate professor of psychiatry and behavioral sciences at the Medical University of South Carolina, Charleston, said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “It does not occur during the course of anorexia nervosa or bulimia nervosa, and there is no evidence of a disturbance in the way in which one’s body weight or shape is experienced. That’s what distinguishes it from anorexia nervosa.”

He added that, although many cases of ARFID have autism spectrum disorder traits, ARFID “is not attributable to a concurrent medical condition or to mental disorder.” When it does occur, the severity of the feeding disorder far outweighs that of the medical condition.”

Several ARFID case reports have been published in the medical literature, yet no randomized controlled trials exist to date. “Treatment is multidisciplinary and involves cognitive-behavioral therapy, sometimes occupational therapy,” said Dr. Brewerton, who is a founding fellow and former board member of the Academy for Eating Disorders.

He and his colleagues published a report on nine ARFID cases treated in an eating disorders program (J Child Adolesc Psychopharmacol. 2017;27[10]:920-2). The patients were treated with adjunctive olanzapine at a starting dose of 0.9 mg/day and discharge dose 2.8 mg/day. For the starting dose, “you have to break the [olanzapine pills] in pieces,” he said. “You have to have a pill cutter. What you don’t want to do is overwhelm the patient or their family members with oversedation. Too often, people start them with 2.5 mg or 5 mg [of olanzapine] right off the bat.”

The researchers found a significant increase in weight gain pre- versus post-olanzapine treatment (a mean of 3.3 pounds vs. 13.1 pounds, respectively; P less than .04) and BMI-for-weight percentiles (P less than .009). “Patients also had improvements in their Clinical Global Impressions Scale scores and a reduction in their associated anxious, depressive, and cognitive symptoms,” Dr. Brewerton said.

Similar findings were observed in a subsequent Canadian study of six ARFID cases (J Eat Disord. 2018;6:20). Five females and one male were treated with a combination of medical monitoring, family therapy, medication (including olanzapine, fluoxetine and in two cases, cyproheptadine), and CBT. At treatment termination, all six patients had achieved their goal weight.

At the University of California, San Diego, researchers led by Emily Gray, MD, conducted a retrospective chart review of six females and eight males with ARFID who ranged in age from 7 to 23 years. All but one of the 14 patients had a co-occurring diagnosis, including general anxiety disorder, social anxiety, unspecified anxiety, ADHD, major depressive disorder, and autism spectrum disorder (J Am Acad Child Adoles Psychiatry. 2018;57[4]:288-9). They were treated with mirtazapine at a dosing range of 7.5-45 mg per day. The average change in BMI per week rose from 0.10 BMI points per week pretreatment to 0.23 BMI points per week post-treatment (P less than .05).

“These cases illustrate that the judicious use of low-dose olanzapine, when used as an adjunct to other treatment modalities, may facilitate eating, weight gain, and the reduction of anxious, depressive, and cognitive symptoms,” said Dr. Brewerton, who also has a private practice in Charleston.

Dr. Brewerton disclosed that he is a consultant to Monte Nido & Affiliates and Sunovion. He receives royalties from Taylor & Francis and Springer-Verlag, and holds ownership interest in Monte Nido & Affiliates.

dbrunk@mdedge.com

The first quarterly meeting of your CHEST Board of Regents for the 2019-2020 CHEST year occurred from January 30 to February 1. We were welcomed to Coronado, California, by CHEST's new President Stephanie M. Levine, MD, FCCP, who began by reviewing the success of the CHEST 2019 Annual Meeting. The meeting had both the highest attendance of medical professionals and the highest total attendance in CHEST history, as well as CHEST's largest Fellow-in-Training attendance. There was also a significant increase in the number of international colleagues who attended the meeting. Dr. Levine next reported on upcoming CHEST activities including six live-learning courses scheduled to occur before May, the CHEST Congress in collaboration with the Italian delegation in Bologna, Italy in June, ongoing planning for CHEST 2020, the next volume of SEEK Critical Care and two additional cough guidelines. 
 

Both the CHEST Boards and our members benefit from an incredibly talented staff. As for any team whose members bring a variety of talents and background experiences, aligning to propel the team mission forward requires excellent understanding on individual strengths and weaknesses and strong communication.  For several months, under the guidance of CHEST EVP/CEO Robert Musacchio, PhD, CHEST senior staff have participated in team-development activities. Our Presidents, along with Dr. Musacchio and the executive leadership team, wanted to further the process by including all members of the Board of Regents and the Board of Trustees in team- and Board-development activities at this meeting. Exercises focused on the recognition of organizational strengths and opportunities, as well as improving team communication. The insight gained through these activities will undoubtedly pay dividends longitudinally as we continue to move CHEST toward the goals needed to meet the needs of our membership. 
Other agenda items covered during the Winter Board meeting included:     
The Governance Committee discussed continued efforts for Board orientation and mentorship of new members. A strategy of self-assessment and feedback has been planned to allow individuals to develop the skills that they need to strengthen the Boards as a whole.  
The Guidelines Task Force presented recommendations about the scope and scale of the CHEST Guidelines program moving forward, including several options as to how CHEST could deploy available resources to meet member needs, which led to a robust discussion about quality of guidelines, quantity of guidelines, and how they could both be optimized.  
The NetWorks Task Force reported on their progress toward designing a system that better allows the leaders of our 22 NetWorks opportunities to curate and create sustainable resources for NetWork members, increase their digital presence, and engage more CHEST members by creating more leadership opportunities within the current NetWork structure.  
The next face-to-face meeting of the Board of Regents will occur in April at CHEST Headquarters in Glenview, Illinois; the Spring meeting is also an opportunity for our main committees (Training and Transitions, Guidelines Oversight, Membership, Council of NetWorks, among others) to meet face-to-face to develop plans for the coming year. If you want to get more involved in CHEST, please watch for the upcoming call for applications for leadership positions coming this spring. 

The first quarterly meeting of your CHEST Board of Regents for the 2019-2020 CHEST year occurred from January 30 to February 1. We were welcomed to Coronado, California, by CHEST's new President Stephanie M. Levine, MD, FCCP, who began by reviewing the success of the CHEST 2019 Annual Meeting. The meeting had both the highest attendance of medical professionals and the highest total attendance in CHEST history, as well as CHEST's largest Fellow-in-Training attendance. There was also a significant increase in the number of international colleagues who attended the meeting. Dr. Levine next reported on upcoming CHEST activities including six live-learning courses scheduled to occur before May, the CHEST Congress in collaboration with the Italian delegation in Bologna, Italy in June, ongoing planning for CHEST 2020, the next volume of SEEK Critical Care and two additional cough guidelines. 
 

Both the CHEST Boards and our members benefit from an incredibly talented staff. As for any team whose members bring a variety of talents and background experiences, aligning to propel the team mission forward requires excellent understanding on individual strengths and weaknesses and strong communication.  For several months, under the guidance of CHEST EVP/CEO Robert Musacchio, PhD, CHEST senior staff have participated in team-development activities. Our Presidents, along with Dr. Musacchio and the executive leadership team, wanted to further the process by including all members of the Board of Regents and the Board of Trustees in team- and Board-development activities at this meeting. Exercises focused on the recognition of organizational strengths and opportunities, as well as improving team communication. The insight gained through these activities will undoubtedly pay dividends longitudinally as we continue to move CHEST toward the goals needed to meet the needs of our membership. 
Other agenda items covered during the Winter Board meeting included:     
The Governance Committee discussed continued efforts for Board orientation and mentorship of new members. A strategy of self-assessment and feedback has been planned to allow individuals to develop the skills that they need to strengthen the Boards as a whole.  
The Guidelines Task Force presented recommendations about the scope and scale of the CHEST Guidelines program moving forward, including several options as to how CHEST could deploy available resources to meet member needs, which led to a robust discussion about quality of guidelines, quantity of guidelines, and how they could both be optimized.  
The NetWorks Task Force reported on their progress toward designing a system that better allows the leaders of our 22 NetWorks opportunities to curate and create sustainable resources for NetWork members, increase their digital presence, and engage more CHEST members by creating more leadership opportunities within the current NetWork structure.  
The next face-to-face meeting of the Board of Regents will occur in April at CHEST Headquarters in Glenview, Illinois; the Spring meeting is also an opportunity for our main committees (Training and Transitions, Guidelines Oversight, Membership, Council of NetWorks, among others) to meet face-to-face to develop plans for the coming year. If you want to get more involved in CHEST, please watch for the upcoming call for applications for leadership positions coming this spring. 

The first quarterly meeting of your CHEST Board of Regents for the 2019-2020 CHEST year occurred from January 30 to February 1. We were welcomed to Coronado, California, by CHEST's new President Stephanie M. Levine, MD, FCCP, who began by reviewing the success of the CHEST 2019 Annual Meeting. The meeting had both the highest attendance of medical professionals and the highest total attendance in CHEST history, as well as CHEST's largest Fellow-in-Training attendance. There was also a significant increase in the number of international colleagues who attended the meeting. Dr. Levine next reported on upcoming CHEST activities including six live-learning courses scheduled to occur before May, the CHEST Congress in collaboration with the Italian delegation in Bologna, Italy in June, ongoing planning for CHEST 2020, the next volume of SEEK Critical Care and two additional cough guidelines. 
 

Both the CHEST Boards and our members benefit from an incredibly talented staff. As for any team whose members bring a variety of talents and background experiences, aligning to propel the team mission forward requires excellent understanding on individual strengths and weaknesses and strong communication.  For several months, under the guidance of CHEST EVP/CEO Robert Musacchio, PhD, CHEST senior staff have participated in team-development activities. Our Presidents, along with Dr. Musacchio and the executive leadership team, wanted to further the process by including all members of the Board of Regents and the Board of Trustees in team- and Board-development activities at this meeting. Exercises focused on the recognition of organizational strengths and opportunities, as well as improving team communication. The insight gained through these activities will undoubtedly pay dividends longitudinally as we continue to move CHEST toward the goals needed to meet the needs of our membership. 
Other agenda items covered during the Winter Board meeting included:     
The Governance Committee discussed continued efforts for Board orientation and mentorship of new members. A strategy of self-assessment and feedback has been planned to allow individuals to develop the skills that they need to strengthen the Boards as a whole.  
The Guidelines Task Force presented recommendations about the scope and scale of the CHEST Guidelines program moving forward, including several options as to how CHEST could deploy available resources to meet member needs, which led to a robust discussion about quality of guidelines, quantity of guidelines, and how they could both be optimized.  
The NetWorks Task Force reported on their progress toward designing a system that better allows the leaders of our 22 NetWorks opportunities to curate and create sustainable resources for NetWork members, increase their digital presence, and engage more CHEST members by creating more leadership opportunities within the current NetWork structure.  
The next face-to-face meeting of the Board of Regents will occur in April at CHEST Headquarters in Glenview, Illinois; the Spring meeting is also an opportunity for our main committees (Training and Transitions, Guidelines Oversight, Membership, Council of NetWorks, among others) to meet face-to-face to develop plans for the coming year. If you want to get more involved in CHEST, please watch for the upcoming call for applications for leadership positions coming this spring. 

LAHAINA, HAWAII – The pathophysiology of rosacea is complicated, which is why “we try to target our treatments to various areas in this pathogenic pathway” to achieve optimal results, according to Linda Stein Gold, MD, director of dermatology research at the Henry Ford Health System in Detroit.

For example, in a patient with papules and pustules, a topical or oral anti-inflammatory agent is needed “to calm that down.” If background erythema is present, separate from papules and pustules, use a topical alpha-adrenergic agonist, she advised. For telangiectasias, consider a device-based treatment, and for a phyma, a surgical approach, she recommended at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

For the background erythema of rosacea, which she described as “that pink face that’s always there,” the two alpha-adrenergic receptor agonists available, brimonidine gel 0.33%, approved by the Food and Drug Administration in 2013, and oxymetazoline cream 1%, approved in 2017, both work on the neurovascular junction, but on different receptors.

Brimonidine “kicks in very, very rapidly,” with a significant decrease in background erythema evident within 30 minutes and improvements that last over a 12-hour day, she said. It is effective over a year, but in longterm and postmarketing studies, about 20% of patients experienced exacerbation of erythema, with two peaks of redness. “One occurs at 3-6 hours,” and the other peak occurs when the drug is wearing off later in the day, Dr. Stein Gold said.

A study that sought to identify factors that might make patients more prone to this adverse effect found that “less is better” regarding brimonidine application, with an optimal application of one to three pea-sized dollops on the face, not five as instructed in the package insert. In addition, patients with more than five flushing episodes a week, particularly women, “tend to have more labile disease and [are] more likely to get that rebound erythema,” the study found.

Oxymetazoline 1% in a cream formulation has a “slightly more gentle onset of action and a more gentle offset of action,” without exacerbation of erythema and has been shown to have sustained efficacy over 52 weeks. In a yearlong safety study, there were “no new red flags and we weren’t seeing that redness at hours 3 to 6, or even when you take the patient off the drug,” she noted.

Dr. Stein Gold reported that she has served as a consultant, investigator, or speaker for Galderma, Dermira, Foamix Pharmaceuticals, Valeant, Allergan, Actavis, and Roche.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

emechcatie@mdedge.com

LAHAINA, HAWAII – The pathophysiology of rosacea is complicated, which is why “we try to target our treatments to various areas in this pathogenic pathway” to achieve optimal results, according to Linda Stein Gold, MD, director of dermatology research at the Henry Ford Health System in Detroit.

For example, in a patient with papules and pustules, a topical or oral anti-inflammatory agent is needed “to calm that down.” If background erythema is present, separate from papules and pustules, use a topical alpha-adrenergic agonist, she advised. For telangiectasias, consider a device-based treatment, and for a phyma, a surgical approach, she recommended at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

For the background erythema of rosacea, which she described as “that pink face that’s always there,” the two alpha-adrenergic receptor agonists available, brimonidine gel 0.33%, approved by the Food and Drug Administration in 2013, and oxymetazoline cream 1%, approved in 2017, both work on the neurovascular junction, but on different receptors.

Brimonidine “kicks in very, very rapidly,” with a significant decrease in background erythema evident within 30 minutes and improvements that last over a 12-hour day, she said. It is effective over a year, but in longterm and postmarketing studies, about 20% of patients experienced exacerbation of erythema, with two peaks of redness. “One occurs at 3-6 hours,” and the other peak occurs when the drug is wearing off later in the day, Dr. Stein Gold said.

A study that sought to identify factors that might make patients more prone to this adverse effect found that “less is better” regarding brimonidine application, with an optimal application of one to three pea-sized dollops on the face, not five as instructed in the package insert. In addition, patients with more than five flushing episodes a week, particularly women, “tend to have more labile disease and [are] more likely to get that rebound erythema,” the study found.

Oxymetazoline 1% in a cream formulation has a “slightly more gentle onset of action and a more gentle offset of action,” without exacerbation of erythema and has been shown to have sustained efficacy over 52 weeks. In a yearlong safety study, there were “no new red flags and we weren’t seeing that redness at hours 3 to 6, or even when you take the patient off the drug,” she noted.

Dr. Stein Gold reported that she has served as a consultant, investigator, or speaker for Galderma, Dermira, Foamix Pharmaceuticals, Valeant, Allergan, Actavis, and Roche.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

emechcatie@mdedge.com

LAHAINA, HAWAII – The pathophysiology of rosacea is complicated, which is why “we try to target our treatments to various areas in this pathogenic pathway” to achieve optimal results, according to Linda Stein Gold, MD, director of dermatology research at the Henry Ford Health System in Detroit.

For example, in a patient with papules and pustules, a topical or oral anti-inflammatory agent is needed “to calm that down.” If background erythema is present, separate from papules and pustules, use a topical alpha-adrenergic agonist, she advised. For telangiectasias, consider a device-based treatment, and for a phyma, a surgical approach, she recommended at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

For the background erythema of rosacea, which she described as “that pink face that’s always there,” the two alpha-adrenergic receptor agonists available, brimonidine gel 0.33%, approved by the Food and Drug Administration in 2013, and oxymetazoline cream 1%, approved in 2017, both work on the neurovascular junction, but on different receptors.

Brimonidine “kicks in very, very rapidly,” with a significant decrease in background erythema evident within 30 minutes and improvements that last over a 12-hour day, she said. It is effective over a year, but in longterm and postmarketing studies, about 20% of patients experienced exacerbation of erythema, with two peaks of redness. “One occurs at 3-6 hours,” and the other peak occurs when the drug is wearing off later in the day, Dr. Stein Gold said.

A study that sought to identify factors that might make patients more prone to this adverse effect found that “less is better” regarding brimonidine application, with an optimal application of one to three pea-sized dollops on the face, not five as instructed in the package insert. In addition, patients with more than five flushing episodes a week, particularly women, “tend to have more labile disease and [are] more likely to get that rebound erythema,” the study found.

Oxymetazoline 1% in a cream formulation has a “slightly more gentle onset of action and a more gentle offset of action,” without exacerbation of erythema and has been shown to have sustained efficacy over 52 weeks. In a yearlong safety study, there were “no new red flags and we weren’t seeing that redness at hours 3 to 6, or even when you take the patient off the drug,” she noted.

Dr. Stein Gold reported that she has served as a consultant, investigator, or speaker for Galderma, Dermira, Foamix Pharmaceuticals, Valeant, Allergan, Actavis, and Roche.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

emechcatie@mdedge.com

Only 26% of pulmonologists report that they are happy at work, with about twice as many happy outside of work, according to Medscape’s Pulmonologist Lifestyle, Happiness & Burnout Report 2020. Dermatologists are the happiest at work, at 41%, and neurologists are the least happy, at 18%.

According to the report, which surveyed more than 15,000 physicians from various specialties, 29% of pulmonologists report feeling burned out, with 5% reporting feeling depressed and 12% both depressed and burned out. An overabundance of bureaucratic tasks is the lead contributor to burnout (52%), according to pulmonologists, followed by lack of respect from administrators, employers, colleagues, and staff (38%) and spending too many hours at work (35%).

Pulmonologists report that exercise is the biggest way they cope with burnout (47%), compared with neurologists, for example, who ranked it third at 40%. Other ways they deal with burnout include isolating themselves from others (43%) and playing or listening to music (38%).

Among depressed or burned-out pulmonologists, 70% reported not planning to seek professional help or seeking it in the past, while 12% reported currently seeking professional help. Furthermore, almost half of pulmonologists (48%) say they’re unlikely to participate in workplace programs.

When asked for reasons they wouldn’t seek professional help, 60% said they deal with it without professional help and 49% didn’t think their symptoms were severe enough, while 31% were simply too busy.

The slideshow of the full report is available on Medscape.com.

cpalmer@mdedge.com

Only 26% of pulmonologists report that they are happy at work, with about twice as many happy outside of work, according to Medscape’s Pulmonologist Lifestyle, Happiness & Burnout Report 2020. Dermatologists are the happiest at work, at 41%, and neurologists are the least happy, at 18%.

According to the report, which surveyed more than 15,000 physicians from various specialties, 29% of pulmonologists report feeling burned out, with 5% reporting feeling depressed and 12% both depressed and burned out. An overabundance of bureaucratic tasks is the lead contributor to burnout (52%), according to pulmonologists, followed by lack of respect from administrators, employers, colleagues, and staff (38%) and spending too many hours at work (35%).

Pulmonologists report that exercise is the biggest way they cope with burnout (47%), compared with neurologists, for example, who ranked it third at 40%. Other ways they deal with burnout include isolating themselves from others (43%) and playing or listening to music (38%).

Among depressed or burned-out pulmonologists, 70% reported not planning to seek professional help or seeking it in the past, while 12% reported currently seeking professional help. Furthermore, almost half of pulmonologists (48%) say they’re unlikely to participate in workplace programs.

When asked for reasons they wouldn’t seek professional help, 60% said they deal with it without professional help and 49% didn’t think their symptoms were severe enough, while 31% were simply too busy.

The slideshow of the full report is available on Medscape.com.

cpalmer@mdedge.com

Only 26% of pulmonologists report that they are happy at work, with about twice as many happy outside of work, according to Medscape’s Pulmonologist Lifestyle, Happiness & Burnout Report 2020. Dermatologists are the happiest at work, at 41%, and neurologists are the least happy, at 18%.

According to the report, which surveyed more than 15,000 physicians from various specialties, 29% of pulmonologists report feeling burned out, with 5% reporting feeling depressed and 12% both depressed and burned out. An overabundance of bureaucratic tasks is the lead contributor to burnout (52%), according to pulmonologists, followed by lack of respect from administrators, employers, colleagues, and staff (38%) and spending too many hours at work (35%).

Pulmonologists report that exercise is the biggest way they cope with burnout (47%), compared with neurologists, for example, who ranked it third at 40%. Other ways they deal with burnout include isolating themselves from others (43%) and playing or listening to music (38%).

Among depressed or burned-out pulmonologists, 70% reported not planning to seek professional help or seeking it in the past, while 12% reported currently seeking professional help. Furthermore, almost half of pulmonologists (48%) say they’re unlikely to participate in workplace programs.

When asked for reasons they wouldn’t seek professional help, 60% said they deal with it without professional help and 49% didn’t think their symptoms were severe enough, while 31% were simply too busy.

The slideshow of the full report is available on Medscape.com.

cpalmer@mdedge.com

ORLANDO – While the impact of the 2019 novel coronavirus outbreak on hospitals outside of China remains to be determined, there are several practical points critical care professionals need to know to be prepared in the face of this dynamic and rapidly evolving outbreak, speakers said at the Critical Care Congress sponsored by the Society of Critical Care Medicine.

Andrew Bowser/MDedge News

“Priorities for us in our hospitals are early detection, infection prevention, staff safety, and obviously, taking care of sick people,” said Ryan C. Maves, MD, of the Naval Medical Center San Diego in a special session on the 2019 Novel Coronavirus outbreak.*

Approximately 72,000 cases of coronavirus disease 2019 (COVID-19) had been reported as of Feb. 17, 2020, the day of Dr. Maves’ talk, according to statistics from Johns Hopkins Center for Science and Engineering in Baltimore. A total of 1,775 deaths had been recorded, nearly all of which were in Hubei Province, the central point of the outbreak. In the United States, the number of cases stood at 15, with no deaths reported.

While the dynamics of the 2019 novel coronavirus are still being learned, the estimated range of spread for droplet transmission is 2 meters, according to Dr. Maves. The duration of environmental persistence is not yet known, but he said that other coronaviruses persist in low-humidity conditions for up to 4 days.

The number of secondary cases that arise from a primary infection, or R0, is estimated to be between 1.5 and 3, though it can change as exposure evolves; by comparison, the R0 for H1N1 influenza has been reported as 1.5, while measles is 12-18, indicating that it is “very contagious,” said Dr. Maves. Severe acute respiratory syndrome had an initial R0 of about 3.5, which he said declined rapidly to 0.7 as environmental and policy controls were put into place.

Critical care professionals need to know how to identify patients at risk of having COVID-19 and determine whether they need further work-up, according to Dr. Maves, who highlighted recent criteria released by the Centers for Disease Control and Prevention.

The highest-risk category, he said, are individuals exposed to a laboratory-confirmed coronavirus case, which along with fever or signs and symptoms of a lower respiratory illness would be sufficient to classify them as a “person of interest” requiring further evaluation for disease. A history of travel from Hubei Province plus fever and signs/symptoms of lower respiratory illness would also meet criteria for evaluation, according to the CDC, while travel to mainland China would also meet the threshold, if those symptoms required hospitalization.

The CDC also published a step-wise flowchart to evaluate patients who may have been exposed to the 2019 novel coronavirus. According to that flowchart, if an individual has traveled to China or had close contact with someone infected with the 2019 Novel Coronavirus within 14 days of symptoms, and that individual has fever or symptoms of lower respiratory illness such as cough or shortness of breath, then providers should isolate that individual and assess clinical status, in addition to contacting the local health department.

Andrew Bowser/MDedge News

Laura E. Evans, MD, MS, FCCM, of New York University, said she might recommend providers “flip the script” on that CDC algorithm when it comes to identifying patients who may have been exposed.

“I think perhaps what we should be doing at sites of entry is not talking about travel as the first question, but rather fever or symptoms of lower respiratory illnesses as the first question, and use that as the opportunity to implement risk mitigation at that stage,” Dr. Evans said in a presentation on preparing for COVID-19.

Even with “substantial uncertainty” about the potential impact of the 2019 Novel Coronavirus, a significant influx of seriously ill patients would put strain the U.S. health care delivery system, she added.

“None of us have tons of extra capacity in our emergency departments, inpatient units, or ICUs, and I think we need to be prepared for that,” she added. “We need to know what our process is for ‘identify, isolate, and inform,’ and we need to be testing that now.”

Dr. Maves and Dr. Evans both reported that they had no financial conflicts of interest to report. Dr. Maves indicated that the views expressed in his presentation did not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States government.

*Correction, 2/19/20: An earlier version of this article misstated the location of the naval center.

ORLANDO – While the impact of the 2019 novel coronavirus outbreak on hospitals outside of China remains to be determined, there are several practical points critical care professionals need to know to be prepared in the face of this dynamic and rapidly evolving outbreak, speakers said at the Critical Care Congress sponsored by the Society of Critical Care Medicine.

Andrew Bowser/MDedge News

“Priorities for us in our hospitals are early detection, infection prevention, staff safety, and obviously, taking care of sick people,” said Ryan C. Maves, MD, of the Naval Medical Center San Diego in a special session on the 2019 Novel Coronavirus outbreak.*

Approximately 72,000 cases of coronavirus disease 2019 (COVID-19) had been reported as of Feb. 17, 2020, the day of Dr. Maves’ talk, according to statistics from Johns Hopkins Center for Science and Engineering in Baltimore. A total of 1,775 deaths had been recorded, nearly all of which were in Hubei Province, the central point of the outbreak. In the United States, the number of cases stood at 15, with no deaths reported.

While the dynamics of the 2019 novel coronavirus are still being learned, the estimated range of spread for droplet transmission is 2 meters, according to Dr. Maves. The duration of environmental persistence is not yet known, but he said that other coronaviruses persist in low-humidity conditions for up to 4 days.

The number of secondary cases that arise from a primary infection, or R0, is estimated to be between 1.5 and 3, though it can change as exposure evolves; by comparison, the R0 for H1N1 influenza has been reported as 1.5, while measles is 12-18, indicating that it is “very contagious,” said Dr. Maves. Severe acute respiratory syndrome had an initial R0 of about 3.5, which he said declined rapidly to 0.7 as environmental and policy controls were put into place.

Critical care professionals need to know how to identify patients at risk of having COVID-19 and determine whether they need further work-up, according to Dr. Maves, who highlighted recent criteria released by the Centers for Disease Control and Prevention.

The highest-risk category, he said, are individuals exposed to a laboratory-confirmed coronavirus case, which along with fever or signs and symptoms of a lower respiratory illness would be sufficient to classify them as a “person of interest” requiring further evaluation for disease. A history of travel from Hubei Province plus fever and signs/symptoms of lower respiratory illness would also meet criteria for evaluation, according to the CDC, while travel to mainland China would also meet the threshold, if those symptoms required hospitalization.

The CDC also published a step-wise flowchart to evaluate patients who may have been exposed to the 2019 novel coronavirus. According to that flowchart, if an individual has traveled to China or had close contact with someone infected with the 2019 Novel Coronavirus within 14 days of symptoms, and that individual has fever or symptoms of lower respiratory illness such as cough or shortness of breath, then providers should isolate that individual and assess clinical status, in addition to contacting the local health department.

Andrew Bowser/MDedge News

Laura E. Evans, MD, MS, FCCM, of New York University, said she might recommend providers “flip the script” on that CDC algorithm when it comes to identifying patients who may have been exposed.

“I think perhaps what we should be doing at sites of entry is not talking about travel as the first question, but rather fever or symptoms of lower respiratory illnesses as the first question, and use that as the opportunity to implement risk mitigation at that stage,” Dr. Evans said in a presentation on preparing for COVID-19.

Even with “substantial uncertainty” about the potential impact of the 2019 Novel Coronavirus, a significant influx of seriously ill patients would put strain the U.S. health care delivery system, she added.

“None of us have tons of extra capacity in our emergency departments, inpatient units, or ICUs, and I think we need to be prepared for that,” she added. “We need to know what our process is for ‘identify, isolate, and inform,’ and we need to be testing that now.”

Dr. Maves and Dr. Evans both reported that they had no financial conflicts of interest to report. Dr. Maves indicated that the views expressed in his presentation did not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States government.

*Correction, 2/19/20: An earlier version of this article misstated the location of the naval center.

ORLANDO – While the impact of the 2019 novel coronavirus outbreak on hospitals outside of China remains to be determined, there are several practical points critical care professionals need to know to be prepared in the face of this dynamic and rapidly evolving outbreak, speakers said at the Critical Care Congress sponsored by the Society of Critical Care Medicine.

Andrew Bowser/MDedge News

“Priorities for us in our hospitals are early detection, infection prevention, staff safety, and obviously, taking care of sick people,” said Ryan C. Maves, MD, of the Naval Medical Center San Diego in a special session on the 2019 Novel Coronavirus outbreak.*

Approximately 72,000 cases of coronavirus disease 2019 (COVID-19) had been reported as of Feb. 17, 2020, the day of Dr. Maves’ talk, according to statistics from Johns Hopkins Center for Science and Engineering in Baltimore. A total of 1,775 deaths had been recorded, nearly all of which were in Hubei Province, the central point of the outbreak. In the United States, the number of cases stood at 15, with no deaths reported.

While the dynamics of the 2019 novel coronavirus are still being learned, the estimated range of spread for droplet transmission is 2 meters, according to Dr. Maves. The duration of environmental persistence is not yet known, but he said that other coronaviruses persist in low-humidity conditions for up to 4 days.

The number of secondary cases that arise from a primary infection, or R0, is estimated to be between 1.5 and 3, though it can change as exposure evolves; by comparison, the R0 for H1N1 influenza has been reported as 1.5, while measles is 12-18, indicating that it is “very contagious,” said Dr. Maves. Severe acute respiratory syndrome had an initial R0 of about 3.5, which he said declined rapidly to 0.7 as environmental and policy controls were put into place.

Critical care professionals need to know how to identify patients at risk of having COVID-19 and determine whether they need further work-up, according to Dr. Maves, who highlighted recent criteria released by the Centers for Disease Control and Prevention.

The highest-risk category, he said, are individuals exposed to a laboratory-confirmed coronavirus case, which along with fever or signs and symptoms of a lower respiratory illness would be sufficient to classify them as a “person of interest” requiring further evaluation for disease. A history of travel from Hubei Province plus fever and signs/symptoms of lower respiratory illness would also meet criteria for evaluation, according to the CDC, while travel to mainland China would also meet the threshold, if those symptoms required hospitalization.

The CDC also published a step-wise flowchart to evaluate patients who may have been exposed to the 2019 novel coronavirus. According to that flowchart, if an individual has traveled to China or had close contact with someone infected with the 2019 Novel Coronavirus within 14 days of symptoms, and that individual has fever or symptoms of lower respiratory illness such as cough or shortness of breath, then providers should isolate that individual and assess clinical status, in addition to contacting the local health department.

Andrew Bowser/MDedge News

Laura E. Evans, MD, MS, FCCM, of New York University, said she might recommend providers “flip the script” on that CDC algorithm when it comes to identifying patients who may have been exposed.

“I think perhaps what we should be doing at sites of entry is not talking about travel as the first question, but rather fever or symptoms of lower respiratory illnesses as the first question, and use that as the opportunity to implement risk mitigation at that stage,” Dr. Evans said in a presentation on preparing for COVID-19.

Even with “substantial uncertainty” about the potential impact of the 2019 Novel Coronavirus, a significant influx of seriously ill patients would put strain the U.S. health care delivery system, she added.

“None of us have tons of extra capacity in our emergency departments, inpatient units, or ICUs, and I think we need to be prepared for that,” she added. “We need to know what our process is for ‘identify, isolate, and inform,’ and we need to be testing that now.”

Dr. Maves and Dr. Evans both reported that they had no financial conflicts of interest to report. Dr. Maves indicated that the views expressed in his presentation did not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States government.

*Correction, 2/19/20: An earlier version of this article misstated the location of the naval center.

A new study has found an elevated risk of some adverse events in patients treated with low-dose methotrexate, compared with patients treated with placebo.

“The data presented here provide an important source of new evidence to improve the monitoring guidelines and safe prescribing of LD-MTX [low-dose methotrexate],” wrote Daniel H. Solomon, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, and coauthors. The study was published in Annals of Internal Medicine.

To determine the rates of adverse events (AEs) among LD-MTX users, along with assessing the risks of certain predefined AEs, the researchers enrolled 6,158 patients in the Cardiovascular Inflammation Reduction Trial (CIRT) and randomized 4,786 of those patients to two groups: those receiving LD-MTX (n = 2,391) and those receiving placebo (n = 2,395). The median dose was 15 mg per week, and median follow-up was 23 months. All participants in CIRT had a history of cardiovascular disease, along with diabetes or metabolic syndrome. Just over 81% of the participants were male, and nearly 85% were white. Their median age was nearly 66 years.

Of the participants in the LD-MTX group, 2,156 (90.2%) had an AE and 2,080 (87.0%) had an AE of interest, which included infectious, hematologic, pulmonary, hepatic, cancerous, and gastrointestinal AEs. Of the participants in the placebo group, 2,076 (86.7%) had an AE and 1,951 (81.5%) had an AE of interest. As such, the relative rate of an AE of interest was 17% higher in the LD-MTX group (hazard ratio, 1.17; 95% confidence interval, 1.10-1.25).

In regard to specific types of AEs, the rates of gastrointestinal (HR, 1.23; 95% CI, 1.03-1.47), pulmonary (HR, 1.42; 95% CI, 1.14-1.77), infectious (HR, 1.15; 95% CI, 1.01-1.30) and hematologic (HR, 1.22; 95% CI, 1.11-1.34) were higher for participants in the LD-MTX group. Five cases of cirrhosis were found in the LD-MTX group, compared with none in the placebo group; none of the patients with cirrhosis had severe liver test abnormalities before their diagnosis. While the risk of cancer overall was not elevated in the LD-MTX group, 53 participants in that group developed skin cancer, compared with 26 in the placebo group (HR, 2.04; 95% CI, 1.28-3.26). Renal AEs were among the few that decreased in LD-MTX users (HR, 0.85; 95% CI, 0.78-0.93).

“Methotrexate has become the standard of care for RA patients,” Dr. Solomon said in an interview, “and because it worked so well, we accepted it without large placebo-controlled trials and without a precise understanding of the risk factors for AEs. Until this study, our evidence basis for the side-effect profile was relatively weak.

“We had a limited data set but decades of experience,” he added. “Now we have better evidence, for example, that methotrexate is associated with elevations in liver function tests. We even found five cases of cirrhosis. And the people who developed cirrhosis didn’t have severe test abnormalities; just minor ones over many months. So now we have a better understanding of the potential impact of minor, yet chronic abnormalities.”

Dr. Solomon and coauthors acknowledged their study’s limitations, including CIRT not including patients with systemic rheumatic disease and the possibility that participants did not report AEs that occurred in between routine study visits. In addition, although the median follow-up of nearly 2 years was longer than in other LD-MTX trials, they noted that “it may still be too short to observe some AEs that require long-term exposure.”

Dr. Solomon and colleagues should be commended for undertaking a long-awaited randomized, placebo-controlled trial that adds much-needed insight into how and when to monitor patients being treated with MTX, Vivian P. Bykerk, MD, of the Hospital for Special Surgery and Weill Cornell Medical College in New York, wrote in an editorial (Ann Intern Med. 2020 Feb 17. doi: 10.7326/M20-0435).

Dr. Bykerk noted that although the results may not be applicable to patients with RA and other inflammatory arthritides who are treated with MTX – RA patients in particular are younger, more often female, have lower rates of diabetes, and usually receive higher doses than those used in CIRT — the risk estimates from the CIRT study are “largely congruent with those expected in MTX-treated patients with rheumatic diseases.”

Regardless, she emphasized that this is a step in a much-needed direction, reminding physicians that “MTX use has inherent risks” and that its AEs, although infrequent, are clinically serious.

The National Institutes of Health funded the study. Various authors reported receiving grants from the National Heart, Lung, and Blood Institute, along with grants, research support, and personal fees from numerous pharmaceutical companies before and during the study. Dr. Bykerk reported receiving personal fees, grants, and nonfinancial support from pharmaceutical companies, foundations, and the NIH.

SOURCE: Solomon DH et al. Ann Intern Med. 2020 Feb 17. doi: 10.7326/M19-3369.

A new study has found an elevated risk of some adverse events in patients treated with low-dose methotrexate, compared with patients treated with placebo.

“The data presented here provide an important source of new evidence to improve the monitoring guidelines and safe prescribing of LD-MTX [low-dose methotrexate],” wrote Daniel H. Solomon, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, and coauthors. The study was published in Annals of Internal Medicine.

To determine the rates of adverse events (AEs) among LD-MTX users, along with assessing the risks of certain predefined AEs, the researchers enrolled 6,158 patients in the Cardiovascular Inflammation Reduction Trial (CIRT) and randomized 4,786 of those patients to two groups: those receiving LD-MTX (n = 2,391) and those receiving placebo (n = 2,395). The median dose was 15 mg per week, and median follow-up was 23 months. All participants in CIRT had a history of cardiovascular disease, along with diabetes or metabolic syndrome. Just over 81% of the participants were male, and nearly 85% were white. Their median age was nearly 66 years.

Of the participants in the LD-MTX group, 2,156 (90.2%) had an AE and 2,080 (87.0%) had an AE of interest, which included infectious, hematologic, pulmonary, hepatic, cancerous, and gastrointestinal AEs. Of the participants in the placebo group, 2,076 (86.7%) had an AE and 1,951 (81.5%) had an AE of interest. As such, the relative rate of an AE of interest was 17% higher in the LD-MTX group (hazard ratio, 1.17; 95% confidence interval, 1.10-1.25).

In regard to specific types of AEs, the rates of gastrointestinal (HR, 1.23; 95% CI, 1.03-1.47), pulmonary (HR, 1.42; 95% CI, 1.14-1.77), infectious (HR, 1.15; 95% CI, 1.01-1.30) and hematologic (HR, 1.22; 95% CI, 1.11-1.34) were higher for participants in the LD-MTX group. Five cases of cirrhosis were found in the LD-MTX group, compared with none in the placebo group; none of the patients with cirrhosis had severe liver test abnormalities before their diagnosis. While the risk of cancer overall was not elevated in the LD-MTX group, 53 participants in that group developed skin cancer, compared with 26 in the placebo group (HR, 2.04; 95% CI, 1.28-3.26). Renal AEs were among the few that decreased in LD-MTX users (HR, 0.85; 95% CI, 0.78-0.93).

“Methotrexate has become the standard of care for RA patients,” Dr. Solomon said in an interview, “and because it worked so well, we accepted it without large placebo-controlled trials and without a precise understanding of the risk factors for AEs. Until this study, our evidence basis for the side-effect profile was relatively weak.

“We had a limited data set but decades of experience,” he added. “Now we have better evidence, for example, that methotrexate is associated with elevations in liver function tests. We even found five cases of cirrhosis. And the people who developed cirrhosis didn’t have severe test abnormalities; just minor ones over many months. So now we have a better understanding of the potential impact of minor, yet chronic abnormalities.”

Dr. Solomon and coauthors acknowledged their study’s limitations, including CIRT not including patients with systemic rheumatic disease and the possibility that participants did not report AEs that occurred in between routine study visits. In addition, although the median follow-up of nearly 2 years was longer than in other LD-MTX trials, they noted that “it may still be too short to observe some AEs that require long-term exposure.”

Dr. Solomon and colleagues should be commended for undertaking a long-awaited randomized, placebo-controlled trial that adds much-needed insight into how and when to monitor patients being treated with MTX, Vivian P. Bykerk, MD, of the Hospital for Special Surgery and Weill Cornell Medical College in New York, wrote in an editorial (Ann Intern Med. 2020 Feb 17. doi: 10.7326/M20-0435).

Dr. Bykerk noted that although the results may not be applicable to patients with RA and other inflammatory arthritides who are treated with MTX – RA patients in particular are younger, more often female, have lower rates of diabetes, and usually receive higher doses than those used in CIRT — the risk estimates from the CIRT study are “largely congruent with those expected in MTX-treated patients with rheumatic diseases.”

Regardless, she emphasized that this is a step in a much-needed direction, reminding physicians that “MTX use has inherent risks” and that its AEs, although infrequent, are clinically serious.

The National Institutes of Health funded the study. Various authors reported receiving grants from the National Heart, Lung, and Blood Institute, along with grants, research support, and personal fees from numerous pharmaceutical companies before and during the study. Dr. Bykerk reported receiving personal fees, grants, and nonfinancial support from pharmaceutical companies, foundations, and the NIH.

SOURCE: Solomon DH et al. Ann Intern Med. 2020 Feb 17. doi: 10.7326/M19-3369.

A new study has found an elevated risk of some adverse events in patients treated with low-dose methotrexate, compared with patients treated with placebo.

“The data presented here provide an important source of new evidence to improve the monitoring guidelines and safe prescribing of LD-MTX [low-dose methotrexate],” wrote Daniel H. Solomon, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, and coauthors. The study was published in Annals of Internal Medicine.

To determine the rates of adverse events (AEs) among LD-MTX users, along with assessing the risks of certain predefined AEs, the researchers enrolled 6,158 patients in the Cardiovascular Inflammation Reduction Trial (CIRT) and randomized 4,786 of those patients to two groups: those receiving LD-MTX (n = 2,391) and those receiving placebo (n = 2,395). The median dose was 15 mg per week, and median follow-up was 23 months. All participants in CIRT had a history of cardiovascular disease, along with diabetes or metabolic syndrome. Just over 81% of the participants were male, and nearly 85% were white. Their median age was nearly 66 years.

Of the participants in the LD-MTX group, 2,156 (90.2%) had an AE and 2,080 (87.0%) had an AE of interest, which included infectious, hematologic, pulmonary, hepatic, cancerous, and gastrointestinal AEs. Of the participants in the placebo group, 2,076 (86.7%) had an AE and 1,951 (81.5%) had an AE of interest. As such, the relative rate of an AE of interest was 17% higher in the LD-MTX group (hazard ratio, 1.17; 95% confidence interval, 1.10-1.25).

In regard to specific types of AEs, the rates of gastrointestinal (HR, 1.23; 95% CI, 1.03-1.47), pulmonary (HR, 1.42; 95% CI, 1.14-1.77), infectious (HR, 1.15; 95% CI, 1.01-1.30) and hematologic (HR, 1.22; 95% CI, 1.11-1.34) were higher for participants in the LD-MTX group. Five cases of cirrhosis were found in the LD-MTX group, compared with none in the placebo group; none of the patients with cirrhosis had severe liver test abnormalities before their diagnosis. While the risk of cancer overall was not elevated in the LD-MTX group, 53 participants in that group developed skin cancer, compared with 26 in the placebo group (HR, 2.04; 95% CI, 1.28-3.26). Renal AEs were among the few that decreased in LD-MTX users (HR, 0.85; 95% CI, 0.78-0.93).

“Methotrexate has become the standard of care for RA patients,” Dr. Solomon said in an interview, “and because it worked so well, we accepted it without large placebo-controlled trials and without a precise understanding of the risk factors for AEs. Until this study, our evidence basis for the side-effect profile was relatively weak.

“We had a limited data set but decades of experience,” he added. “Now we have better evidence, for example, that methotrexate is associated with elevations in liver function tests. We even found five cases of cirrhosis. And the people who developed cirrhosis didn’t have severe test abnormalities; just minor ones over many months. So now we have a better understanding of the potential impact of minor, yet chronic abnormalities.”

Dr. Solomon and coauthors acknowledged their study’s limitations, including CIRT not including patients with systemic rheumatic disease and the possibility that participants did not report AEs that occurred in between routine study visits. In addition, although the median follow-up of nearly 2 years was longer than in other LD-MTX trials, they noted that “it may still be too short to observe some AEs that require long-term exposure.”

Dr. Solomon and colleagues should be commended for undertaking a long-awaited randomized, placebo-controlled trial that adds much-needed insight into how and when to monitor patients being treated with MTX, Vivian P. Bykerk, MD, of the Hospital for Special Surgery and Weill Cornell Medical College in New York, wrote in an editorial (Ann Intern Med. 2020 Feb 17. doi: 10.7326/M20-0435).

Dr. Bykerk noted that although the results may not be applicable to patients with RA and other inflammatory arthritides who are treated with MTX – RA patients in particular are younger, more often female, have lower rates of diabetes, and usually receive higher doses than those used in CIRT — the risk estimates from the CIRT study are “largely congruent with those expected in MTX-treated patients with rheumatic diseases.”

Regardless, she emphasized that this is a step in a much-needed direction, reminding physicians that “MTX use has inherent risks” and that its AEs, although infrequent, are clinically serious.

The National Institutes of Health funded the study. Various authors reported receiving grants from the National Heart, Lung, and Blood Institute, along with grants, research support, and personal fees from numerous pharmaceutical companies before and during the study. Dr. Bykerk reported receiving personal fees, grants, and nonfinancial support from pharmaceutical companies, foundations, and the NIH.

SOURCE: Solomon DH et al. Ann Intern Med. 2020 Feb 17. doi: 10.7326/M19-3369.

LAHAINA, HAWAII – Most patients on dupilumab for the treatment of severe atopic dermatitis respond best on continuous long-term dosing of the selective Th2 cytokine inhibitor rather than treatment on an as-needed basis, Andrew Blauvelt, MD, advised at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Bruce Jancin/MDedge News

“I view atopic dermatitis as a chronic disease requiring chronic treatment. So be very careful about stopping. We know that if you start and stop biologics you’re going to be far more prone to develop antidrug antibodies resulting in drug resistance than with continual dosing,” said Dr. Blauvelt, a dermatologist and clinical trialist who is president of the Oregon Medical Research Center, Portland.

He said dupilumab (Dupixent) seldom induces disease remission as defined by clear skin while off all drugs for at least 1 year, although he has a few patients who seem to be exceptions. Yet clearly dupilumab doesn’t change an individual’s predisposing genetics or environmental allergen exposure pattern, so it’s best to think of it as a treatment for the long haul.

Dr. Blauvelt considers dupilumab far and away the best medication for treatment of adults and teenagers whose atopic dermatitis (AD) is uncontrolled with topical therapy. Payers often balk at authorizing dupilumab unless a patient has first undergone an unsuccessful trial of cyclosporine or methotrexate, which are far less expensive. But that’s not what the expert consensus guidelines recommend (Ann Allergy Asthma Immunol. 2018 Jan;120[1]:10-22.e2).

“The guidelines don’t suggest that failure on methotrexate or cyclosporine should be a prerequisite for dupilumab. So if you’re having problems with an insurance company and you really want to use dupilumab, you can point to this paper and say, ‘Look, the experts do not recommend step therapy, we can go directly to dupilumab.’ And the dupilumab label says simply that failure of topical therapy is required before being allowed to use dupilumab. So both the label and the experts say you don’t have to go through a bunch of steps in order to get to what I consider the very best drug for our patients,” he explained.

Both cyclosporine and methotrexate are far more broadly immunosuppressive and hence less safe than dupilumab. Both require laboratory monitoring. In contrast, blood work isn’t required in patients on dupilumab; in fact, Dr. Blauvelt considers it an unwise use of resources. Nor is tuberculosis testing advised prior to starting dupilumab.

When he can’t get authorization for dupilumab, Dr. Blauvelt’s go-to drug is methotrexate at 15-25 mg/week. It’s not as effective as cyclosporine for rapid clearing, but it’s safer for long-term use.

“Methotrexate is the devil we know – we know how to use it, and we know how to monitor for it,” he commented, adding that he reserves cyclosporine for a maximum of a month or 2 of acute crisis management, or as a bridge in getting patients off of systemic corticosteroids.
 

 

Set realistic efficacy expectations

Dermatologists who prescribe the newest biologics for psoriasis are accustomed to routinely seeing PASI 90 responses and even complete disease clearing. However, AD is a more challenging disease. In the landmark dupilumab phase 3 randomized trials, roughly two-thirds of patients achieved an Eczema Area and Severity Index (EASI) 75 response, with a mean 80% improvement in EASI symptom scores over baseline. Roughly 20% of dupilumab-treated adults with AD achieve disease clearance, and a similar percentage become almost clear. The improvements are durable in long-term follow-up studies.

“Dupilumab doesn’t get a lot of people to zero. They’re not going to be completely clearing their eczema. So they shouldn’t be freaking out if they still have eczema. What they can expect is diminution of the disease to much lower levels,” Dr. Blauvelt said.

The marked improvement in quality of life that occurs with dupilumab therapy isn’t adequately captured by EASI scores. “In my experience, more than 80%-90% of patients are happy on this drug,” Dr. Blauvelt said.

Conference codirector Linda Stein Gold, MD, agreed, commenting that she has found dupilumab to be “absolutely life altering” for her patients with severe AD.

“They know they still have AD, but now they can go whole days without thinking about it,” said Dr. Stein Gold, director of dermatology research and head of the division of dermatology at the Henry Ford Health System in Detroit.

Dr. Blauvelt noted that most of his patients on dupilumab remain on topical therapy, typically with triamcinolone on the body and hydrocortisone on the face. What he terms “miniflares” in patients on dupilumab are not at all unusual, but they’re readily manageable.

“Flares that used to last for weeks now last for a day or 2, maybe 3, and then it’s back to normal in patients on dupilumab,” Dr. Blauvelt said.
 

Safety

Dupilumab is a targeted inhibitor of interleukins-4 and -13, cytokines involved in allergy-mediated inflammation and the control of parasitic infections, but which have no bearing on control of bacterial or viral infections or malignancies. Indeed, the randomized trials have demonstrated that the incidence of skin infections is actually lower with dupilumab than with placebo.

“You’re improving the skin barrier so much that they’re not going to be getting staph or herpes simplex,” he explained.

The main side effect consists of dupilumab-associated eye issues. These occur in up to 20% of treated patients and encompass a spectrum ranging from dry eye to nonallergic conjunctivitis, inflammation of the eyelid, and keratitis. The mechanism is unknown. The condition is not infectious and doesn’t affect vision. Intriguingly, it doesn’t occur in patients with asthma, a disease for which dupilumab is also approved.

“Ask about eye issues at every office visit,” the dermatologist urged.

He sends all of his AD patients with dupilumab-associated eye issues to a single trusted local ophthalmologist and lets him manage the condition, which is generally mild to moderate. Eye issues have resulted in discontinuation of dupilumab in only 2 of the roughly 150 AD patients Dr. Blauvelt has placed on the biologic. The ophthalmologist generally relies upon lubricating eye drops and a couple of weeks of steroid eye drops or, in some cases, topical cyclosporine 0.05% ophthalmic emulsion, followed by episodic use of the steroid eye drops on an as-needed basis.

Residual facial disease in AD patients on dupilumab can be caused by a variety of causes, including breakthrough AD, rosacea, allergic contact dermatitis, steroid withdrawal, or photosensitivity, with Demodex thought to play a role in some cases.

Dr. Blauvelt reported serving as a scientific adviser to and paid clinical trial investigator for several dozen pharmaceutical companies. SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

bjancin@mdedge.com

LAHAINA, HAWAII – Most patients on dupilumab for the treatment of severe atopic dermatitis respond best on continuous long-term dosing of the selective Th2 cytokine inhibitor rather than treatment on an as-needed basis, Andrew Blauvelt, MD, advised at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Bruce Jancin/MDedge News

“I view atopic dermatitis as a chronic disease requiring chronic treatment. So be very careful about stopping. We know that if you start and stop biologics you’re going to be far more prone to develop antidrug antibodies resulting in drug resistance than with continual dosing,” said Dr. Blauvelt, a dermatologist and clinical trialist who is president of the Oregon Medical Research Center, Portland.

He said dupilumab (Dupixent) seldom induces disease remission as defined by clear skin while off all drugs for at least 1 year, although he has a few patients who seem to be exceptions. Yet clearly dupilumab doesn’t change an individual’s predisposing genetics or environmental allergen exposure pattern, so it’s best to think of it as a treatment for the long haul.

Dr. Blauvelt considers dupilumab far and away the best medication for treatment of adults and teenagers whose atopic dermatitis (AD) is uncontrolled with topical therapy. Payers often balk at authorizing dupilumab unless a patient has first undergone an unsuccessful trial of cyclosporine or methotrexate, which are far less expensive. But that’s not what the expert consensus guidelines recommend (Ann Allergy Asthma Immunol. 2018 Jan;120[1]:10-22.e2).

“The guidelines don’t suggest that failure on methotrexate or cyclosporine should be a prerequisite for dupilumab. So if you’re having problems with an insurance company and you really want to use dupilumab, you can point to this paper and say, ‘Look, the experts do not recommend step therapy, we can go directly to dupilumab.’ And the dupilumab label says simply that failure of topical therapy is required before being allowed to use dupilumab. So both the label and the experts say you don’t have to go through a bunch of steps in order to get to what I consider the very best drug for our patients,” he explained.

Both cyclosporine and methotrexate are far more broadly immunosuppressive and hence less safe than dupilumab. Both require laboratory monitoring. In contrast, blood work isn’t required in patients on dupilumab; in fact, Dr. Blauvelt considers it an unwise use of resources. Nor is tuberculosis testing advised prior to starting dupilumab.

When he can’t get authorization for dupilumab, Dr. Blauvelt’s go-to drug is methotrexate at 15-25 mg/week. It’s not as effective as cyclosporine for rapid clearing, but it’s safer for long-term use.

“Methotrexate is the devil we know – we know how to use it, and we know how to monitor for it,” he commented, adding that he reserves cyclosporine for a maximum of a month or 2 of acute crisis management, or as a bridge in getting patients off of systemic corticosteroids.
 

 

Set realistic efficacy expectations

Dermatologists who prescribe the newest biologics for psoriasis are accustomed to routinely seeing PASI 90 responses and even complete disease clearing. However, AD is a more challenging disease. In the landmark dupilumab phase 3 randomized trials, roughly two-thirds of patients achieved an Eczema Area and Severity Index (EASI) 75 response, with a mean 80% improvement in EASI symptom scores over baseline. Roughly 20% of dupilumab-treated adults with AD achieve disease clearance, and a similar percentage become almost clear. The improvements are durable in long-term follow-up studies.

“Dupilumab doesn’t get a lot of people to zero. They’re not going to be completely clearing their eczema. So they shouldn’t be freaking out if they still have eczema. What they can expect is diminution of the disease to much lower levels,” Dr. Blauvelt said.

The marked improvement in quality of life that occurs with dupilumab therapy isn’t adequately captured by EASI scores. “In my experience, more than 80%-90% of patients are happy on this drug,” Dr. Blauvelt said.

Conference codirector Linda Stein Gold, MD, agreed, commenting that she has found dupilumab to be “absolutely life altering” for her patients with severe AD.

“They know they still have AD, but now they can go whole days without thinking about it,” said Dr. Stein Gold, director of dermatology research and head of the division of dermatology at the Henry Ford Health System in Detroit.

Dr. Blauvelt noted that most of his patients on dupilumab remain on topical therapy, typically with triamcinolone on the body and hydrocortisone on the face. What he terms “miniflares” in patients on dupilumab are not at all unusual, but they’re readily manageable.

“Flares that used to last for weeks now last for a day or 2, maybe 3, and then it’s back to normal in patients on dupilumab,” Dr. Blauvelt said.
 

Safety

Dupilumab is a targeted inhibitor of interleukins-4 and -13, cytokines involved in allergy-mediated inflammation and the control of parasitic infections, but which have no bearing on control of bacterial or viral infections or malignancies. Indeed, the randomized trials have demonstrated that the incidence of skin infections is actually lower with dupilumab than with placebo.

“You’re improving the skin barrier so much that they’re not going to be getting staph or herpes simplex,” he explained.

The main side effect consists of dupilumab-associated eye issues. These occur in up to 20% of treated patients and encompass a spectrum ranging from dry eye to nonallergic conjunctivitis, inflammation of the eyelid, and keratitis. The mechanism is unknown. The condition is not infectious and doesn’t affect vision. Intriguingly, it doesn’t occur in patients with asthma, a disease for which dupilumab is also approved.

“Ask about eye issues at every office visit,” the dermatologist urged.

He sends all of his AD patients with dupilumab-associated eye issues to a single trusted local ophthalmologist and lets him manage the condition, which is generally mild to moderate. Eye issues have resulted in discontinuation of dupilumab in only 2 of the roughly 150 AD patients Dr. Blauvelt has placed on the biologic. The ophthalmologist generally relies upon lubricating eye drops and a couple of weeks of steroid eye drops or, in some cases, topical cyclosporine 0.05% ophthalmic emulsion, followed by episodic use of the steroid eye drops on an as-needed basis.

Residual facial disease in AD patients on dupilumab can be caused by a variety of causes, including breakthrough AD, rosacea, allergic contact dermatitis, steroid withdrawal, or photosensitivity, with Demodex thought to play a role in some cases.

Dr. Blauvelt reported serving as a scientific adviser to and paid clinical trial investigator for several dozen pharmaceutical companies. SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

bjancin@mdedge.com

LAHAINA, HAWAII – Most patients on dupilumab for the treatment of severe atopic dermatitis respond best on continuous long-term dosing of the selective Th2 cytokine inhibitor rather than treatment on an as-needed basis, Andrew Blauvelt, MD, advised at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Bruce Jancin/MDedge News

“I view atopic dermatitis as a chronic disease requiring chronic treatment. So be very careful about stopping. We know that if you start and stop biologics you’re going to be far more prone to develop antidrug antibodies resulting in drug resistance than with continual dosing,” said Dr. Blauvelt, a dermatologist and clinical trialist who is president of the Oregon Medical Research Center, Portland.

He said dupilumab (Dupixent) seldom induces disease remission as defined by clear skin while off all drugs for at least 1 year, although he has a few patients who seem to be exceptions. Yet clearly dupilumab doesn’t change an individual’s predisposing genetics or environmental allergen exposure pattern, so it’s best to think of it as a treatment for the long haul.

Dr. Blauvelt considers dupilumab far and away the best medication for treatment of adults and teenagers whose atopic dermatitis (AD) is uncontrolled with topical therapy. Payers often balk at authorizing dupilumab unless a patient has first undergone an unsuccessful trial of cyclosporine or methotrexate, which are far less expensive. But that’s not what the expert consensus guidelines recommend (Ann Allergy Asthma Immunol. 2018 Jan;120[1]:10-22.e2).

“The guidelines don’t suggest that failure on methotrexate or cyclosporine should be a prerequisite for dupilumab. So if you’re having problems with an insurance company and you really want to use dupilumab, you can point to this paper and say, ‘Look, the experts do not recommend step therapy, we can go directly to dupilumab.’ And the dupilumab label says simply that failure of topical therapy is required before being allowed to use dupilumab. So both the label and the experts say you don’t have to go through a bunch of steps in order to get to what I consider the very best drug for our patients,” he explained.

Both cyclosporine and methotrexate are far more broadly immunosuppressive and hence less safe than dupilumab. Both require laboratory monitoring. In contrast, blood work isn’t required in patients on dupilumab; in fact, Dr. Blauvelt considers it an unwise use of resources. Nor is tuberculosis testing advised prior to starting dupilumab.

When he can’t get authorization for dupilumab, Dr. Blauvelt’s go-to drug is methotrexate at 15-25 mg/week. It’s not as effective as cyclosporine for rapid clearing, but it’s safer for long-term use.

“Methotrexate is the devil we know – we know how to use it, and we know how to monitor for it,” he commented, adding that he reserves cyclosporine for a maximum of a month or 2 of acute crisis management, or as a bridge in getting patients off of systemic corticosteroids.
 

 

Set realistic efficacy expectations

Dermatologists who prescribe the newest biologics for psoriasis are accustomed to routinely seeing PASI 90 responses and even complete disease clearing. However, AD is a more challenging disease. In the landmark dupilumab phase 3 randomized trials, roughly two-thirds of patients achieved an Eczema Area and Severity Index (EASI) 75 response, with a mean 80% improvement in EASI symptom scores over baseline. Roughly 20% of dupilumab-treated adults with AD achieve disease clearance, and a similar percentage become almost clear. The improvements are durable in long-term follow-up studies.

“Dupilumab doesn’t get a lot of people to zero. They’re not going to be completely clearing their eczema. So they shouldn’t be freaking out if they still have eczema. What they can expect is diminution of the disease to much lower levels,” Dr. Blauvelt said.

The marked improvement in quality of life that occurs with dupilumab therapy isn’t adequately captured by EASI scores. “In my experience, more than 80%-90% of patients are happy on this drug,” Dr. Blauvelt said.

Conference codirector Linda Stein Gold, MD, agreed, commenting that she has found dupilumab to be “absolutely life altering” for her patients with severe AD.

“They know they still have AD, but now they can go whole days without thinking about it,” said Dr. Stein Gold, director of dermatology research and head of the division of dermatology at the Henry Ford Health System in Detroit.

Dr. Blauvelt noted that most of his patients on dupilumab remain on topical therapy, typically with triamcinolone on the body and hydrocortisone on the face. What he terms “miniflares” in patients on dupilumab are not at all unusual, but they’re readily manageable.

“Flares that used to last for weeks now last for a day or 2, maybe 3, and then it’s back to normal in patients on dupilumab,” Dr. Blauvelt said.
 

Safety

Dupilumab is a targeted inhibitor of interleukins-4 and -13, cytokines involved in allergy-mediated inflammation and the control of parasitic infections, but which have no bearing on control of bacterial or viral infections or malignancies. Indeed, the randomized trials have demonstrated that the incidence of skin infections is actually lower with dupilumab than with placebo.

“You’re improving the skin barrier so much that they’re not going to be getting staph or herpes simplex,” he explained.

The main side effect consists of dupilumab-associated eye issues. These occur in up to 20% of treated patients and encompass a spectrum ranging from dry eye to nonallergic conjunctivitis, inflammation of the eyelid, and keratitis. The mechanism is unknown. The condition is not infectious and doesn’t affect vision. Intriguingly, it doesn’t occur in patients with asthma, a disease for which dupilumab is also approved.

“Ask about eye issues at every office visit,” the dermatologist urged.

He sends all of his AD patients with dupilumab-associated eye issues to a single trusted local ophthalmologist and lets him manage the condition, which is generally mild to moderate. Eye issues have resulted in discontinuation of dupilumab in only 2 of the roughly 150 AD patients Dr. Blauvelt has placed on the biologic. The ophthalmologist generally relies upon lubricating eye drops and a couple of weeks of steroid eye drops or, in some cases, topical cyclosporine 0.05% ophthalmic emulsion, followed by episodic use of the steroid eye drops on an as-needed basis.

Residual facial disease in AD patients on dupilumab can be caused by a variety of causes, including breakthrough AD, rosacea, allergic contact dermatitis, steroid withdrawal, or photosensitivity, with Demodex thought to play a role in some cases.

Dr. Blauvelt reported serving as a scientific adviser to and paid clinical trial investigator for several dozen pharmaceutical companies. SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

bjancin@mdedge.com