The grip that opioid addiction has on adolescents often resembles that on addicted adults. Both groups crave the next high at all costs.
“Basically, they’re living to find their next heroin or opioids because their ‘feeling good’ completely depends on it,” Steven C. Matson, MD, , chief of the division of adolescent medicine at Nationwide Children’s Hospital, Columbus, Ohio, said in an interview. “They’re up in the morning, out trying to hustle money constantly, and then using and rebounding, and doing it over and over again. It gets to be a pretty dismal way of life.”
courtesy Lindsey Pulfer, RN
Dr. Steven C. Matson
After losing several friends to opioid overdoses, a 17-year-old patient of Leslie Hulvershorn, MD, became so emotionally hardened that she thought little of her own young life. “She suffers from depression and PTSD and has talked from time to time about how she doesn’t really care if she lives or dies,” said Dr. Hulvershorn, a child and adolescent psychiatrist who runs an adolescent addiction treatment outpatient program at Riley Hospital for Children, Indianapolis.
Parents often have no clue that their child is addicted to opioids, whether prescription forms like oxycodone or synthetic forms like heroin. “It usually only becomes clear when it comes to the attention of a probation officer or a school that insists on treatment,” said Dr. Hulvershorn, who is also medical director for the State of Indiana’s Division of Mental Health and Addiction, which licenses and certifies all of the opioid treatment programs in the state. “It’s not uncommon to see adolescents who get out of the house at night and go out and use or sell or do something that’s really dangerous. The situations are usually very high risk, very concerning.”
Dr. Leslie Hulvershorn
The scope of the problem
The 2015 National Survey on Drug Use and Health (NSDUH) found that 6.5 million Americans over the age of 12 years used controlled prescription medicines nonmedically during the past month, second only to marijuana and more than past-month users of cocaine, heroin, and hallucinogens combined. According to the Centers for Disease Control and Prevention, 91 Americans die every day from an overdose of opioids. In fact, opioid overdoses in the United States increased four times since 1999 and were highest among persons 25-54 years of age. In 2015, the five states with the highest rates of death resulting from drug overdose were West Virginia (41.5 per 100,000), New Hampshire (34.3 per 100,000), Kentucky (29.9 per 100,000), Ohio (29.9 per 100,000), and Rhode Island (28.2 per 100,000).
The CDC also found that, between 2013 and 2014, the number of children aged 0-14 years who died from a drug overdose increased slightly from 105 to 109. The number of children aged 15-24 years who died from a drug overdose rose from 3,664 to 3,798, an increase of 3.6%. While the precise path to opioid addiction differs from patient to patient, experts interviewed for this story noted that adolescents who currently smoke marijuana or drink alcohol on a regular basis face an increased risk of progressing to opioid use, compared with peers who lack substance abuse problems. In such cases, “go ahead and refer for substance abuse treatment at that point, rather than waiting for them to get into something much more dangerous,” Dr. Hulvershorn advised. “Neither of those drugs is good for adolescents either, but you could easily be preventing a worse outcome later. Sometimes physicians will ask, ‘You really want me to refer kids who are smoking pot?’ The answer is, ‘Absolutely.’ That’s probably our best shot at providing them with skills early on, before they get into heavier stuff.”
Dr. Marc Potenza
In October 2016, as part of the Comprehensive Addiction and Recovery Act, the Drug Enforcement Agency announced plans to reduce the amount of almost every Schedule II opiate and opioid medication that may be manufactured in the United States in 2017 by 25% or more. That – coupled with increased media attention in recent years to the perils of opioid addiction in adults, mandatory prescriber education on the use of opioids pain management, and other national efforts to promote safe prescribing practices – has helped to stymie the supply of opioids for illicit use. However, addicts young and old are turning to dangerous alternatives, like heroin, which may be tainted with fentanyl.
“There are even stronger agents like carfentanil, or carfentanyl, a strong veterinary opioid, which is used to put elephants to sleep,” Dr. Matson said. “Suddenly, you read that 18 people die because they got a hold of that. It’s hard to understand. It doesn’t make a lot of sense why somebody trying to make money off of selling drugs would sell you something that would kill you, but most people develop tolerance after long enough use of heroin. People are always trying to reach that new level of high.”
The implication of developing an opioid addiction at such a young age rarely registers with users, yet it can interfere with development “in substantial ways,” said Marc N. Potenza, MD, PhD, professor of psychiatry in the Child Study Center at Yale School of Medicine, New Haven, Conn. “If one is addicted, a lot of time, effort, energy, and attention is focused on the addiction, rather than on things like school, family, and friends.”
How to spot a troubled teen
Pediatricians can do their part to detect addiction by regularly asking about drug use during office visits. One quick screen Dr. Matson recommends is the HEADSS (Home, Education/employment, peer group Activities, Drugs, Sexuality, and Suicide/depression).
But, simply being attuned to how patients are performing in general domains can help you spot a troubled teen. “If a kid is still playing football and getting straight A’s, there’s probably a pretty low chance he’s having a serious problem,” he said. “A big part of addiction is secret, so I think when parents start to see their kids be more secretive, hiding their phone,” that’s a red flag. Or maybe their child has a new set of friends that “don’t seem as ‘good’ as the previous set of friends.” Other signs might be “losing a job that they were doing well at before, grades starting to go down, [or] loss of interest in the things they normally like to do. In general, I think kids work their way up to opioid addiction. If parents know their kids smoke cigarettes and think they might be doing some weed, those are the kids that are at risk for moving on to a bigger high.”
Many kids start with pills that they find or take from someone. “They may not think of them as a drug, so you would need to specifically ask, ‘Have you ever used a pill like a pain medication that you may have found or gotten from a family member or a friend for recreational use or for something other than how it was prescribed?’ ” Dr. Hulvershorn said.
The amount of parental supervision also factors in. “There’s been a lot of research showing that, if parents don’t have any idea where their kids are after school or what they’re up do, those kids are much more likely to be using,” she said. “So, you want to ask parents, ‘Are there times when your adolescent is unsupervised?’ ”
If you suspect that one of your adolescent patients is using opioids, but he or she won’t open up about it, consider intermittent urine screening, Dr. Hulvershorn said. If a screen comes back positive, be familiar with patient privacy regulations in your state, because special federal protections apply to adolescents and adults with respect to substance abuse disorder assessment and treatment. For example, in Indiana there is no age limit. Anyone under the age of 18 has the same protection as an adult. “I cannot legally release that information to the parent without the adolescent’s consent, which is really unusual,” she said. “Each state determines the age where that might apply. The best approach is to try to get the adolescent on board, and say, ‘Here’s what we found. We really need to get this out in the open and get you some treatment. I’d really like to have a conversation with your parents.’ Sometimes you can get them to agree, and sometimes you can’t. Nonetheless, you would try to proceed with treatment. You don’t need parental consent for treatment.”
Once Dr. Matson establishes confidentiality with patients, he spends time helping them understand where they fall in the “continuum of use.” He asks for permission to share information with them about the negative aspects of drug use instead of force-feeding it.
“A lot of these kids are hanging around the same kinds of kids and somehow, in their minds, think that what they’re doing is normal,” he said. “To me, somebody smoking weed twice a day every day is a problem, and they probably are addicted. It’s hard to know whether you’d be ready to pull a parent [into the room] at that point or at least give the kid a chance to think if they ... could cut down. If they would, maybe see them back with a warning that, if it’s not going to get much better, you might have to inform parents.
“Weed is always a big issue, especially in kids with ADHD. Those kids are at high risk for substance abuse, especially if they aren’t maintained on their [ADHD] drugs later on,” Dr. Matson said.
Adolescents on opioids “usually are going to present in a more dramatic fashion because they’re starting to get into trouble. They might have gotten arrested or might have been driving under the influence with both alcohol and opioids. To support their habit, a lot of kids have to steal things, so a kid who gets caught shoplifting is someone to be concerned about,” he said.
Treatment options
In 2016, the American Academy of Pediatrics issued a new policy statement, “Medication-Assisted Treatment for Adolescents with Opioid Disorders,” which recommends that pediatricians consider offering medication-assisted treatments to their adolescent and young adult patients with opioid use disorders or refer them to other providers who can. Ideally, pediatricians should refer patients to clinicians who have expertise in treating substance abuse disorders in adolescents, typically psychiatrists.
Psychiatrists “tend to have quite a bit of experience with addiction, but they can be very hard to find,” Dr. Hulvershorn said. “Sometimes, it’s a mental health center provider who treats adults with addiction. Addiction is a different beast in kids, but that might be the next best thing.”
Three medicines indicated for treating severe opioid disorder include buprenorphine (the “gold standard,” Dr. Matson said), methadone, and naltrexone, which is Dr. Hulvershorn’s typical drug of choice, “because it’s not a drug of abuse. It’s an opioid antagonist, so it blocks the euphoria that you might get when you are using a drug of abuse such as an opioid.”
“It might mean that you partner with a substance use provider who can do more comprehensive services but not the prescribing,” Dr. Hulvershorn said. “You certainly don’t want to treat these kids in a vacuum by yourself, because it’s very complicated to treat them.”
Still, the office-based practice of prescribing opioid withdrawal medication “is a very successful approach and a reasonable alternative to other approaches that have been used historically, like methadone maintenance programs,” noted Dr. Potenza, emphasizing that physicians have to understand how to help patients with addiction.
Physicians interviewed for this story underscored the importance of a comprehensive approach that includes behavioral treatment, medication, and support from family and friends.
“A lot of kids who get into these problems come from families that don’t have many resources,” Dr. Matson said, noting that, often, it is a generational problem, in which grandparents and parents are drug users. “But, for kids who take a wrong path, encouraging words really can come true. It’s really a matter of how many people you have cheerleading for you and keeping an eye on you.”
When Dr. Matson’s clinic began treating patients with opioid use disorders 8 years ago, only about 25% of adolescents returned for a second visit, and the rate of abstinence at 1 year was only 9%. The clinic has undertake a large quality improvement project to improve that percentage. “We learned to not scare people right away with a bunch of assignments they have to get done but to just welcome them in, get them started on the medication, and give them positive messages. For short-term remission at 3 months, we’re at 50%-60%, which is pretty good. It’s probably as good as any adult program. I think we’re at 35%-40% remission at 1 year for people first time in recovery,” he said.
Where to go from here
Reflecting on what he’d like opioid use disorder treatment to look like 5 or 10 years down the road, Dr. Matson emphasized the prominent role that pediatricians can play.
“We’re really the ones that could make a difference if we can try to intervene,” he said. “I’m not sure I can prove it, but my pipe dream is, the earlier that we catch people and the less time they’ve been using drugs, it’s got to be easier to stop it then, than if they’ve been using for 5 or 10 years.”
That’s the kind of hope Dr. Hulvershorn holds for the17-year-old patient she’s treating who suffers from depression and PTSD.
“She has decided that it’s important for her to come clean,” said Dr. Hulvershorn, who added that the patient has received mental health and trauma counseling. “Part of our treatment program involves helping patients reorganize their life so that activities they’re involved with are not drug-related. That involves finding new friends and new activities, which can take some time. She is really committed to graduating from high school now that she’s clean. She’s really made a 180.”
Dr. Potenza disclosed having been a consultant to Jazz Pharmaceuticals and Opiant Pharmaceuticals. Dr. Matson and Dr. Hulvershorn reported having no relevant financial disclosures.
Role of a pediatrician’s support is vital
The way Deepa R. Camenga, MD, sees it, pediatricians play a vital role in not only counseling adolescents struggling with opioid use disorders but in helping to prevent it in the first place.
Prevention starts with advising parents or caregivers to manage any prescription medication that adolescents may receive for medical indications such as wisdom tooth extractions or sports injuries. “There is some risk for misuse or using it inappropriately or recreationally,” said Dr. Camenga, a pediatrician at Yale School of Medicine, New Haven, Conn., who is also board certified in addiction medicine. “The parents should be highly involved in the administration of these medications to teenagers.”
Dr. Deepa Camenga
Other risk factors for opioid use disorders include alcohol, marijuana, or other recreational drugs use or the presence of undiagnosed or undertreated mental health conditions such as ADHD, anxiety, and depression.
“In the primary care setting, I’ve seen a real increase in marijuana use over the last 10 years,” she said. “Some teens are moving on to opiates, but, luckily, it’s still a rarer thing than using marijuana or alcohol. Identifying these conditions is important because, in the act of screening and helping parents and kids link to treatment, pediatricians are preventing drug use.”
Other red flags include poor academic performance and a lack of connectedness in the community. “When we are doing the well-child exams, we often ask about the home and school environment,” Dr. Camenga said. “Looking for positive healthy activities and attachment is essential. If a kid doesn’t have these protective factors, it puts them at higher risk for drug initiation.”
Any time an adolescent’s drug use is escalating in frequency, leading to parental concern or a decrease in function or problems, consider referring the child to a higher level of treatment with a specialist. “Even among teens with low levels of drug use, there are teens who have many risk factors for escalating to a higher level of use,” said Dr. Camenga, who has treated approximately 50 adolescents with opioid use disorders over the past 2 years. “In this case, you may consider referring them earlier rather than later.”
Broaching the conversation about referral to a specialist in substance abuse treatment can be tricky. She recommends saying something like, “ ‘They [the substance use treatment providers] are not going to force you to do anything you don’t want to do,’ because that’s a concern for the teens. ‘They’re going to discuss different options to help you over time, because, physically, it’s very difficult to stop on your own.’ ”
One young patient with several chronic medical conditions was referred to Dr. Camenga after being hospitalized in a psychiatric facility because she was using heroin and stimulants, which triggered a seizure.
“She came into treatment, and it took about 6 months for stabilization, but now she’s doing well,” the pediatrician said. “She’s been in recovery for 2 years and is not using opioids. She’s working, and she’s trying to obtain a higher education certificate.”
Although the American Academy of Pediatrics published a policy statement recommending that pediatricians consider offering buprenorphine and other medication-assisted treatment options for adolescents coping with opioid use disorder (Pediatrics. 2016 Aug. doi: 10.1542/peds.2016-1893). Dr. Camenga said that some physicians are reluctant to do so “because there are concerns about exposing the developing brain to another opiate over time, and there are generally few studies that examine the efficacy of buprenorphine in adolescents specifically. However, the adolescents I’ve had on it do well. I’ve had several adolescents go through an entire treatment course and into recovery on buprenorphine.”
“At first it may seem overwhelming, but you can make a huge impact by treating two or three people,” she said. “When you do the training through Substance Abuse and Mental Health Services Administration–supported programs (including one at www.asam.org), they provide lots of resources for mentorship or support from providers across the nation who work with special populations, including adolescents. Reach out to them. When I was learning, I talked a lot with my colleagues in different states because there are very few people who treat adolescents and who have the comfort in treating children. We’re all very supportive of each other and reach out to discuss cases.”
Dr. Camenga emphasized that pediatricians play a role in supporting parents and families of adolescents impacted by addiction to opioids.
“It’s a rampant disease and we all know someone affected by it,” she said. “Even if we feel powerless, perhaps, with this epidemic, we have a unique skill in supporting families. More awareness and less stigmatization, and support of families who are going through this, is important.
“We as a society have stigmatized this disease. I think that inhibits some young people getting treatment earlier rather than later. We also need to focus on prevention,” Dr. Camenga emphasized.
She reported having no relevant financial disclosures.
The grip that opioid addiction has on adolescents often resembles that on addicted adults. Both groups crave the next high at all costs.
“Basically, they’re living to find their next heroin or opioids because their ‘feeling good’ completely depends on it,” Steven C. Matson, MD, , chief of the division of adolescent medicine at Nationwide Children’s Hospital, Columbus, Ohio, said in an interview. “They’re up in the morning, out trying to hustle money constantly, and then using and rebounding, and doing it over and over again. It gets to be a pretty dismal way of life.”
courtesy Lindsey Pulfer, RN
Dr. Steven C. Matson
After losing several friends to opioid overdoses, a 17-year-old patient of Leslie Hulvershorn, MD, became so emotionally hardened that she thought little of her own young life. “She suffers from depression and PTSD and has talked from time to time about how she doesn’t really care if she lives or dies,” said Dr. Hulvershorn, a child and adolescent psychiatrist who runs an adolescent addiction treatment outpatient program at Riley Hospital for Children, Indianapolis.
Parents often have no clue that their child is addicted to opioids, whether prescription forms like oxycodone or synthetic forms like heroin. “It usually only becomes clear when it comes to the attention of a probation officer or a school that insists on treatment,” said Dr. Hulvershorn, who is also medical director for the State of Indiana’s Division of Mental Health and Addiction, which licenses and certifies all of the opioid treatment programs in the state. “It’s not uncommon to see adolescents who get out of the house at night and go out and use or sell or do something that’s really dangerous. The situations are usually very high risk, very concerning.”
Dr. Leslie Hulvershorn
The scope of the problem
The 2015 National Survey on Drug Use and Health (NSDUH) found that 6.5 million Americans over the age of 12 years used controlled prescription medicines nonmedically during the past month, second only to marijuana and more than past-month users of cocaine, heroin, and hallucinogens combined. According to the Centers for Disease Control and Prevention, 91 Americans die every day from an overdose of opioids. In fact, opioid overdoses in the United States increased four times since 1999 and were highest among persons 25-54 years of age. In 2015, the five states with the highest rates of death resulting from drug overdose were West Virginia (41.5 per 100,000), New Hampshire (34.3 per 100,000), Kentucky (29.9 per 100,000), Ohio (29.9 per 100,000), and Rhode Island (28.2 per 100,000).
The CDC also found that, between 2013 and 2014, the number of children aged 0-14 years who died from a drug overdose increased slightly from 105 to 109. The number of children aged 15-24 years who died from a drug overdose rose from 3,664 to 3,798, an increase of 3.6%. While the precise path to opioid addiction differs from patient to patient, experts interviewed for this story noted that adolescents who currently smoke marijuana or drink alcohol on a regular basis face an increased risk of progressing to opioid use, compared with peers who lack substance abuse problems. In such cases, “go ahead and refer for substance abuse treatment at that point, rather than waiting for them to get into something much more dangerous,” Dr. Hulvershorn advised. “Neither of those drugs is good for adolescents either, but you could easily be preventing a worse outcome later. Sometimes physicians will ask, ‘You really want me to refer kids who are smoking pot?’ The answer is, ‘Absolutely.’ That’s probably our best shot at providing them with skills early on, before they get into heavier stuff.”
Dr. Marc Potenza
In October 2016, as part of the Comprehensive Addiction and Recovery Act, the Drug Enforcement Agency announced plans to reduce the amount of almost every Schedule II opiate and opioid medication that may be manufactured in the United States in 2017 by 25% or more. That – coupled with increased media attention in recent years to the perils of opioid addiction in adults, mandatory prescriber education on the use of opioids pain management, and other national efforts to promote safe prescribing practices – has helped to stymie the supply of opioids for illicit use. However, addicts young and old are turning to dangerous alternatives, like heroin, which may be tainted with fentanyl.
“There are even stronger agents like carfentanil, or carfentanyl, a strong veterinary opioid, which is used to put elephants to sleep,” Dr. Matson said. “Suddenly, you read that 18 people die because they got a hold of that. It’s hard to understand. It doesn’t make a lot of sense why somebody trying to make money off of selling drugs would sell you something that would kill you, but most people develop tolerance after long enough use of heroin. People are always trying to reach that new level of high.”
The implication of developing an opioid addiction at such a young age rarely registers with users, yet it can interfere with development “in substantial ways,” said Marc N. Potenza, MD, PhD, professor of psychiatry in the Child Study Center at Yale School of Medicine, New Haven, Conn. “If one is addicted, a lot of time, effort, energy, and attention is focused on the addiction, rather than on things like school, family, and friends.”
How to spot a troubled teen
Pediatricians can do their part to detect addiction by regularly asking about drug use during office visits. One quick screen Dr. Matson recommends is the HEADSS (Home, Education/employment, peer group Activities, Drugs, Sexuality, and Suicide/depression).
But, simply being attuned to how patients are performing in general domains can help you spot a troubled teen. “If a kid is still playing football and getting straight A’s, there’s probably a pretty low chance he’s having a serious problem,” he said. “A big part of addiction is secret, so I think when parents start to see their kids be more secretive, hiding their phone,” that’s a red flag. Or maybe their child has a new set of friends that “don’t seem as ‘good’ as the previous set of friends.” Other signs might be “losing a job that they were doing well at before, grades starting to go down, [or] loss of interest in the things they normally like to do. In general, I think kids work their way up to opioid addiction. If parents know their kids smoke cigarettes and think they might be doing some weed, those are the kids that are at risk for moving on to a bigger high.”
Many kids start with pills that they find or take from someone. “They may not think of them as a drug, so you would need to specifically ask, ‘Have you ever used a pill like a pain medication that you may have found or gotten from a family member or a friend for recreational use or for something other than how it was prescribed?’ ” Dr. Hulvershorn said.
The amount of parental supervision also factors in. “There’s been a lot of research showing that, if parents don’t have any idea where their kids are after school or what they’re up do, those kids are much more likely to be using,” she said. “So, you want to ask parents, ‘Are there times when your adolescent is unsupervised?’ ”
If you suspect that one of your adolescent patients is using opioids, but he or she won’t open up about it, consider intermittent urine screening, Dr. Hulvershorn said. If a screen comes back positive, be familiar with patient privacy regulations in your state, because special federal protections apply to adolescents and adults with respect to substance abuse disorder assessment and treatment. For example, in Indiana there is no age limit. Anyone under the age of 18 has the same protection as an adult. “I cannot legally release that information to the parent without the adolescent’s consent, which is really unusual,” she said. “Each state determines the age where that might apply. The best approach is to try to get the adolescent on board, and say, ‘Here’s what we found. We really need to get this out in the open and get you some treatment. I’d really like to have a conversation with your parents.’ Sometimes you can get them to agree, and sometimes you can’t. Nonetheless, you would try to proceed with treatment. You don’t need parental consent for treatment.”
Once Dr. Matson establishes confidentiality with patients, he spends time helping them understand where they fall in the “continuum of use.” He asks for permission to share information with them about the negative aspects of drug use instead of force-feeding it.
“A lot of these kids are hanging around the same kinds of kids and somehow, in their minds, think that what they’re doing is normal,” he said. “To me, somebody smoking weed twice a day every day is a problem, and they probably are addicted. It’s hard to know whether you’d be ready to pull a parent [into the room] at that point or at least give the kid a chance to think if they ... could cut down. If they would, maybe see them back with a warning that, if it’s not going to get much better, you might have to inform parents.
“Weed is always a big issue, especially in kids with ADHD. Those kids are at high risk for substance abuse, especially if they aren’t maintained on their [ADHD] drugs later on,” Dr. Matson said.
Adolescents on opioids “usually are going to present in a more dramatic fashion because they’re starting to get into trouble. They might have gotten arrested or might have been driving under the influence with both alcohol and opioids. To support their habit, a lot of kids have to steal things, so a kid who gets caught shoplifting is someone to be concerned about,” he said.
Treatment options
In 2016, the American Academy of Pediatrics issued a new policy statement, “Medication-Assisted Treatment for Adolescents with Opioid Disorders,” which recommends that pediatricians consider offering medication-assisted treatments to their adolescent and young adult patients with opioid use disorders or refer them to other providers who can. Ideally, pediatricians should refer patients to clinicians who have expertise in treating substance abuse disorders in adolescents, typically psychiatrists.
Psychiatrists “tend to have quite a bit of experience with addiction, but they can be very hard to find,” Dr. Hulvershorn said. “Sometimes, it’s a mental health center provider who treats adults with addiction. Addiction is a different beast in kids, but that might be the next best thing.”
Three medicines indicated for treating severe opioid disorder include buprenorphine (the “gold standard,” Dr. Matson said), methadone, and naltrexone, which is Dr. Hulvershorn’s typical drug of choice, “because it’s not a drug of abuse. It’s an opioid antagonist, so it blocks the euphoria that you might get when you are using a drug of abuse such as an opioid.”
“It might mean that you partner with a substance use provider who can do more comprehensive services but not the prescribing,” Dr. Hulvershorn said. “You certainly don’t want to treat these kids in a vacuum by yourself, because it’s very complicated to treat them.”
Still, the office-based practice of prescribing opioid withdrawal medication “is a very successful approach and a reasonable alternative to other approaches that have been used historically, like methadone maintenance programs,” noted Dr. Potenza, emphasizing that physicians have to understand how to help patients with addiction.
Physicians interviewed for this story underscored the importance of a comprehensive approach that includes behavioral treatment, medication, and support from family and friends.
“A lot of kids who get into these problems come from families that don’t have many resources,” Dr. Matson said, noting that, often, it is a generational problem, in which grandparents and parents are drug users. “But, for kids who take a wrong path, encouraging words really can come true. It’s really a matter of how many people you have cheerleading for you and keeping an eye on you.”
When Dr. Matson’s clinic began treating patients with opioid use disorders 8 years ago, only about 25% of adolescents returned for a second visit, and the rate of abstinence at 1 year was only 9%. The clinic has undertake a large quality improvement project to improve that percentage. “We learned to not scare people right away with a bunch of assignments they have to get done but to just welcome them in, get them started on the medication, and give them positive messages. For short-term remission at 3 months, we’re at 50%-60%, which is pretty good. It’s probably as good as any adult program. I think we’re at 35%-40% remission at 1 year for people first time in recovery,” he said.
Where to go from here
Reflecting on what he’d like opioid use disorder treatment to look like 5 or 10 years down the road, Dr. Matson emphasized the prominent role that pediatricians can play.
“We’re really the ones that could make a difference if we can try to intervene,” he said. “I’m not sure I can prove it, but my pipe dream is, the earlier that we catch people and the less time they’ve been using drugs, it’s got to be easier to stop it then, than if they’ve been using for 5 or 10 years.”
That’s the kind of hope Dr. Hulvershorn holds for the17-year-old patient she’s treating who suffers from depression and PTSD.
“She has decided that it’s important for her to come clean,” said Dr. Hulvershorn, who added that the patient has received mental health and trauma counseling. “Part of our treatment program involves helping patients reorganize their life so that activities they’re involved with are not drug-related. That involves finding new friends and new activities, which can take some time. She is really committed to graduating from high school now that she’s clean. She’s really made a 180.”
Dr. Potenza disclosed having been a consultant to Jazz Pharmaceuticals and Opiant Pharmaceuticals. Dr. Matson and Dr. Hulvershorn reported having no relevant financial disclosures.
Role of a pediatrician’s support is vital
The way Deepa R. Camenga, MD, sees it, pediatricians play a vital role in not only counseling adolescents struggling with opioid use disorders but in helping to prevent it in the first place.
Prevention starts with advising parents or caregivers to manage any prescription medication that adolescents may receive for medical indications such as wisdom tooth extractions or sports injuries. “There is some risk for misuse or using it inappropriately or recreationally,” said Dr. Camenga, a pediatrician at Yale School of Medicine, New Haven, Conn., who is also board certified in addiction medicine. “The parents should be highly involved in the administration of these medications to teenagers.”
Dr. Deepa Camenga
Other risk factors for opioid use disorders include alcohol, marijuana, or other recreational drugs use or the presence of undiagnosed or undertreated mental health conditions such as ADHD, anxiety, and depression.
“In the primary care setting, I’ve seen a real increase in marijuana use over the last 10 years,” she said. “Some teens are moving on to opiates, but, luckily, it’s still a rarer thing than using marijuana or alcohol. Identifying these conditions is important because, in the act of screening and helping parents and kids link to treatment, pediatricians are preventing drug use.”
Other red flags include poor academic performance and a lack of connectedness in the community. “When we are doing the well-child exams, we often ask about the home and school environment,” Dr. Camenga said. “Looking for positive healthy activities and attachment is essential. If a kid doesn’t have these protective factors, it puts them at higher risk for drug initiation.”
Any time an adolescent’s drug use is escalating in frequency, leading to parental concern or a decrease in function or problems, consider referring the child to a higher level of treatment with a specialist. “Even among teens with low levels of drug use, there are teens who have many risk factors for escalating to a higher level of use,” said Dr. Camenga, who has treated approximately 50 adolescents with opioid use disorders over the past 2 years. “In this case, you may consider referring them earlier rather than later.”
Broaching the conversation about referral to a specialist in substance abuse treatment can be tricky. She recommends saying something like, “ ‘They [the substance use treatment providers] are not going to force you to do anything you don’t want to do,’ because that’s a concern for the teens. ‘They’re going to discuss different options to help you over time, because, physically, it’s very difficult to stop on your own.’ ”
One young patient with several chronic medical conditions was referred to Dr. Camenga after being hospitalized in a psychiatric facility because she was using heroin and stimulants, which triggered a seizure.
“She came into treatment, and it took about 6 months for stabilization, but now she’s doing well,” the pediatrician said. “She’s been in recovery for 2 years and is not using opioids. She’s working, and she’s trying to obtain a higher education certificate.”
Although the American Academy of Pediatrics published a policy statement recommending that pediatricians consider offering buprenorphine and other medication-assisted treatment options for adolescents coping with opioid use disorder (Pediatrics. 2016 Aug. doi: 10.1542/peds.2016-1893). Dr. Camenga said that some physicians are reluctant to do so “because there are concerns about exposing the developing brain to another opiate over time, and there are generally few studies that examine the efficacy of buprenorphine in adolescents specifically. However, the adolescents I’ve had on it do well. I’ve had several adolescents go through an entire treatment course and into recovery on buprenorphine.”
“At first it may seem overwhelming, but you can make a huge impact by treating two or three people,” she said. “When you do the training through Substance Abuse and Mental Health Services Administration–supported programs (including one at www.asam.org), they provide lots of resources for mentorship or support from providers across the nation who work with special populations, including adolescents. Reach out to them. When I was learning, I talked a lot with my colleagues in different states because there are very few people who treat adolescents and who have the comfort in treating children. We’re all very supportive of each other and reach out to discuss cases.”
Dr. Camenga emphasized that pediatricians play a role in supporting parents and families of adolescents impacted by addiction to opioids.
“It’s a rampant disease and we all know someone affected by it,” she said. “Even if we feel powerless, perhaps, with this epidemic, we have a unique skill in supporting families. More awareness and less stigmatization, and support of families who are going through this, is important.
“We as a society have stigmatized this disease. I think that inhibits some young people getting treatment earlier rather than later. We also need to focus on prevention,” Dr. Camenga emphasized.
She reported having no relevant financial disclosures.
The grip that opioid addiction has on adolescents often resembles that on addicted adults. Both groups crave the next high at all costs.
“Basically, they’re living to find their next heroin or opioids because their ‘feeling good’ completely depends on it,” Steven C. Matson, MD, , chief of the division of adolescent medicine at Nationwide Children’s Hospital, Columbus, Ohio, said in an interview. “They’re up in the morning, out trying to hustle money constantly, and then using and rebounding, and doing it over and over again. It gets to be a pretty dismal way of life.”
courtesy Lindsey Pulfer, RN
Dr. Steven C. Matson
After losing several friends to opioid overdoses, a 17-year-old patient of Leslie Hulvershorn, MD, became so emotionally hardened that she thought little of her own young life. “She suffers from depression and PTSD and has talked from time to time about how she doesn’t really care if she lives or dies,” said Dr. Hulvershorn, a child and adolescent psychiatrist who runs an adolescent addiction treatment outpatient program at Riley Hospital for Children, Indianapolis.
Parents often have no clue that their child is addicted to opioids, whether prescription forms like oxycodone or synthetic forms like heroin. “It usually only becomes clear when it comes to the attention of a probation officer or a school that insists on treatment,” said Dr. Hulvershorn, who is also medical director for the State of Indiana’s Division of Mental Health and Addiction, which licenses and certifies all of the opioid treatment programs in the state. “It’s not uncommon to see adolescents who get out of the house at night and go out and use or sell or do something that’s really dangerous. The situations are usually very high risk, very concerning.”
Dr. Leslie Hulvershorn
The scope of the problem
The 2015 National Survey on Drug Use and Health (NSDUH) found that 6.5 million Americans over the age of 12 years used controlled prescription medicines nonmedically during the past month, second only to marijuana and more than past-month users of cocaine, heroin, and hallucinogens combined. According to the Centers for Disease Control and Prevention, 91 Americans die every day from an overdose of opioids. In fact, opioid overdoses in the United States increased four times since 1999 and were highest among persons 25-54 years of age. In 2015, the five states with the highest rates of death resulting from drug overdose were West Virginia (41.5 per 100,000), New Hampshire (34.3 per 100,000), Kentucky (29.9 per 100,000), Ohio (29.9 per 100,000), and Rhode Island (28.2 per 100,000).
The CDC also found that, between 2013 and 2014, the number of children aged 0-14 years who died from a drug overdose increased slightly from 105 to 109. The number of children aged 15-24 years who died from a drug overdose rose from 3,664 to 3,798, an increase of 3.6%. While the precise path to opioid addiction differs from patient to patient, experts interviewed for this story noted that adolescents who currently smoke marijuana or drink alcohol on a regular basis face an increased risk of progressing to opioid use, compared with peers who lack substance abuse problems. In such cases, “go ahead and refer for substance abuse treatment at that point, rather than waiting for them to get into something much more dangerous,” Dr. Hulvershorn advised. “Neither of those drugs is good for adolescents either, but you could easily be preventing a worse outcome later. Sometimes physicians will ask, ‘You really want me to refer kids who are smoking pot?’ The answer is, ‘Absolutely.’ That’s probably our best shot at providing them with skills early on, before they get into heavier stuff.”
Dr. Marc Potenza
In October 2016, as part of the Comprehensive Addiction and Recovery Act, the Drug Enforcement Agency announced plans to reduce the amount of almost every Schedule II opiate and opioid medication that may be manufactured in the United States in 2017 by 25% or more. That – coupled with increased media attention in recent years to the perils of opioid addiction in adults, mandatory prescriber education on the use of opioids pain management, and other national efforts to promote safe prescribing practices – has helped to stymie the supply of opioids for illicit use. However, addicts young and old are turning to dangerous alternatives, like heroin, which may be tainted with fentanyl.
“There are even stronger agents like carfentanil, or carfentanyl, a strong veterinary opioid, which is used to put elephants to sleep,” Dr. Matson said. “Suddenly, you read that 18 people die because they got a hold of that. It’s hard to understand. It doesn’t make a lot of sense why somebody trying to make money off of selling drugs would sell you something that would kill you, but most people develop tolerance after long enough use of heroin. People are always trying to reach that new level of high.”
The implication of developing an opioid addiction at such a young age rarely registers with users, yet it can interfere with development “in substantial ways,” said Marc N. Potenza, MD, PhD, professor of psychiatry in the Child Study Center at Yale School of Medicine, New Haven, Conn. “If one is addicted, a lot of time, effort, energy, and attention is focused on the addiction, rather than on things like school, family, and friends.”
How to spot a troubled teen
Pediatricians can do their part to detect addiction by regularly asking about drug use during office visits. One quick screen Dr. Matson recommends is the HEADSS (Home, Education/employment, peer group Activities, Drugs, Sexuality, and Suicide/depression).
But, simply being attuned to how patients are performing in general domains can help you spot a troubled teen. “If a kid is still playing football and getting straight A’s, there’s probably a pretty low chance he’s having a serious problem,” he said. “A big part of addiction is secret, so I think when parents start to see their kids be more secretive, hiding their phone,” that’s a red flag. Or maybe their child has a new set of friends that “don’t seem as ‘good’ as the previous set of friends.” Other signs might be “losing a job that they were doing well at before, grades starting to go down, [or] loss of interest in the things they normally like to do. In general, I think kids work their way up to opioid addiction. If parents know their kids smoke cigarettes and think they might be doing some weed, those are the kids that are at risk for moving on to a bigger high.”
Many kids start with pills that they find or take from someone. “They may not think of them as a drug, so you would need to specifically ask, ‘Have you ever used a pill like a pain medication that you may have found or gotten from a family member or a friend for recreational use or for something other than how it was prescribed?’ ” Dr. Hulvershorn said.
The amount of parental supervision also factors in. “There’s been a lot of research showing that, if parents don’t have any idea where their kids are after school or what they’re up do, those kids are much more likely to be using,” she said. “So, you want to ask parents, ‘Are there times when your adolescent is unsupervised?’ ”
If you suspect that one of your adolescent patients is using opioids, but he or she won’t open up about it, consider intermittent urine screening, Dr. Hulvershorn said. If a screen comes back positive, be familiar with patient privacy regulations in your state, because special federal protections apply to adolescents and adults with respect to substance abuse disorder assessment and treatment. For example, in Indiana there is no age limit. Anyone under the age of 18 has the same protection as an adult. “I cannot legally release that information to the parent without the adolescent’s consent, which is really unusual,” she said. “Each state determines the age where that might apply. The best approach is to try to get the adolescent on board, and say, ‘Here’s what we found. We really need to get this out in the open and get you some treatment. I’d really like to have a conversation with your parents.’ Sometimes you can get them to agree, and sometimes you can’t. Nonetheless, you would try to proceed with treatment. You don’t need parental consent for treatment.”
Once Dr. Matson establishes confidentiality with patients, he spends time helping them understand where they fall in the “continuum of use.” He asks for permission to share information with them about the negative aspects of drug use instead of force-feeding it.
“A lot of these kids are hanging around the same kinds of kids and somehow, in their minds, think that what they’re doing is normal,” he said. “To me, somebody smoking weed twice a day every day is a problem, and they probably are addicted. It’s hard to know whether you’d be ready to pull a parent [into the room] at that point or at least give the kid a chance to think if they ... could cut down. If they would, maybe see them back with a warning that, if it’s not going to get much better, you might have to inform parents.
“Weed is always a big issue, especially in kids with ADHD. Those kids are at high risk for substance abuse, especially if they aren’t maintained on their [ADHD] drugs later on,” Dr. Matson said.
Adolescents on opioids “usually are going to present in a more dramatic fashion because they’re starting to get into trouble. They might have gotten arrested or might have been driving under the influence with both alcohol and opioids. To support their habit, a lot of kids have to steal things, so a kid who gets caught shoplifting is someone to be concerned about,” he said.
Treatment options
In 2016, the American Academy of Pediatrics issued a new policy statement, “Medication-Assisted Treatment for Adolescents with Opioid Disorders,” which recommends that pediatricians consider offering medication-assisted treatments to their adolescent and young adult patients with opioid use disorders or refer them to other providers who can. Ideally, pediatricians should refer patients to clinicians who have expertise in treating substance abuse disorders in adolescents, typically psychiatrists.
Psychiatrists “tend to have quite a bit of experience with addiction, but they can be very hard to find,” Dr. Hulvershorn said. “Sometimes, it’s a mental health center provider who treats adults with addiction. Addiction is a different beast in kids, but that might be the next best thing.”
Three medicines indicated for treating severe opioid disorder include buprenorphine (the “gold standard,” Dr. Matson said), methadone, and naltrexone, which is Dr. Hulvershorn’s typical drug of choice, “because it’s not a drug of abuse. It’s an opioid antagonist, so it blocks the euphoria that you might get when you are using a drug of abuse such as an opioid.”
“It might mean that you partner with a substance use provider who can do more comprehensive services but not the prescribing,” Dr. Hulvershorn said. “You certainly don’t want to treat these kids in a vacuum by yourself, because it’s very complicated to treat them.”
Still, the office-based practice of prescribing opioid withdrawal medication “is a very successful approach and a reasonable alternative to other approaches that have been used historically, like methadone maintenance programs,” noted Dr. Potenza, emphasizing that physicians have to understand how to help patients with addiction.
Physicians interviewed for this story underscored the importance of a comprehensive approach that includes behavioral treatment, medication, and support from family and friends.
“A lot of kids who get into these problems come from families that don’t have many resources,” Dr. Matson said, noting that, often, it is a generational problem, in which grandparents and parents are drug users. “But, for kids who take a wrong path, encouraging words really can come true. It’s really a matter of how many people you have cheerleading for you and keeping an eye on you.”
When Dr. Matson’s clinic began treating patients with opioid use disorders 8 years ago, only about 25% of adolescents returned for a second visit, and the rate of abstinence at 1 year was only 9%. The clinic has undertake a large quality improvement project to improve that percentage. “We learned to not scare people right away with a bunch of assignments they have to get done but to just welcome them in, get them started on the medication, and give them positive messages. For short-term remission at 3 months, we’re at 50%-60%, which is pretty good. It’s probably as good as any adult program. I think we’re at 35%-40% remission at 1 year for people first time in recovery,” he said.
Where to go from here
Reflecting on what he’d like opioid use disorder treatment to look like 5 or 10 years down the road, Dr. Matson emphasized the prominent role that pediatricians can play.
“We’re really the ones that could make a difference if we can try to intervene,” he said. “I’m not sure I can prove it, but my pipe dream is, the earlier that we catch people and the less time they’ve been using drugs, it’s got to be easier to stop it then, than if they’ve been using for 5 or 10 years.”
That’s the kind of hope Dr. Hulvershorn holds for the17-year-old patient she’s treating who suffers from depression and PTSD.
“She has decided that it’s important for her to come clean,” said Dr. Hulvershorn, who added that the patient has received mental health and trauma counseling. “Part of our treatment program involves helping patients reorganize their life so that activities they’re involved with are not drug-related. That involves finding new friends and new activities, which can take some time. She is really committed to graduating from high school now that she’s clean. She’s really made a 180.”
Dr. Potenza disclosed having been a consultant to Jazz Pharmaceuticals and Opiant Pharmaceuticals. Dr. Matson and Dr. Hulvershorn reported having no relevant financial disclosures.
Role of a pediatrician’s support is vital
The way Deepa R. Camenga, MD, sees it, pediatricians play a vital role in not only counseling adolescents struggling with opioid use disorders but in helping to prevent it in the first place.
Prevention starts with advising parents or caregivers to manage any prescription medication that adolescents may receive for medical indications such as wisdom tooth extractions or sports injuries. “There is some risk for misuse or using it inappropriately or recreationally,” said Dr. Camenga, a pediatrician at Yale School of Medicine, New Haven, Conn., who is also board certified in addiction medicine. “The parents should be highly involved in the administration of these medications to teenagers.”
Dr. Deepa Camenga
Other risk factors for opioid use disorders include alcohol, marijuana, or other recreational drugs use or the presence of undiagnosed or undertreated mental health conditions such as ADHD, anxiety, and depression.
“In the primary care setting, I’ve seen a real increase in marijuana use over the last 10 years,” she said. “Some teens are moving on to opiates, but, luckily, it’s still a rarer thing than using marijuana or alcohol. Identifying these conditions is important because, in the act of screening and helping parents and kids link to treatment, pediatricians are preventing drug use.”
Other red flags include poor academic performance and a lack of connectedness in the community. “When we are doing the well-child exams, we often ask about the home and school environment,” Dr. Camenga said. “Looking for positive healthy activities and attachment is essential. If a kid doesn’t have these protective factors, it puts them at higher risk for drug initiation.”
Any time an adolescent’s drug use is escalating in frequency, leading to parental concern or a decrease in function or problems, consider referring the child to a higher level of treatment with a specialist. “Even among teens with low levels of drug use, there are teens who have many risk factors for escalating to a higher level of use,” said Dr. Camenga, who has treated approximately 50 adolescents with opioid use disorders over the past 2 years. “In this case, you may consider referring them earlier rather than later.”
Broaching the conversation about referral to a specialist in substance abuse treatment can be tricky. She recommends saying something like, “ ‘They [the substance use treatment providers] are not going to force you to do anything you don’t want to do,’ because that’s a concern for the teens. ‘They’re going to discuss different options to help you over time, because, physically, it’s very difficult to stop on your own.’ ”
One young patient with several chronic medical conditions was referred to Dr. Camenga after being hospitalized in a psychiatric facility because she was using heroin and stimulants, which triggered a seizure.
“She came into treatment, and it took about 6 months for stabilization, but now she’s doing well,” the pediatrician said. “She’s been in recovery for 2 years and is not using opioids. She’s working, and she’s trying to obtain a higher education certificate.”
Although the American Academy of Pediatrics published a policy statement recommending that pediatricians consider offering buprenorphine and other medication-assisted treatment options for adolescents coping with opioid use disorder (Pediatrics. 2016 Aug. doi: 10.1542/peds.2016-1893). Dr. Camenga said that some physicians are reluctant to do so “because there are concerns about exposing the developing brain to another opiate over time, and there are generally few studies that examine the efficacy of buprenorphine in adolescents specifically. However, the adolescents I’ve had on it do well. I’ve had several adolescents go through an entire treatment course and into recovery on buprenorphine.”
“At first it may seem overwhelming, but you can make a huge impact by treating two or three people,” she said. “When you do the training through Substance Abuse and Mental Health Services Administration–supported programs (including one at www.asam.org), they provide lots of resources for mentorship or support from providers across the nation who work with special populations, including adolescents. Reach out to them. When I was learning, I talked a lot with my colleagues in different states because there are very few people who treat adolescents and who have the comfort in treating children. We’re all very supportive of each other and reach out to discuss cases.”
Dr. Camenga emphasized that pediatricians play a role in supporting parents and families of adolescents impacted by addiction to opioids.
“It’s a rampant disease and we all know someone affected by it,” she said. “Even if we feel powerless, perhaps, with this epidemic, we have a unique skill in supporting families. More awareness and less stigmatization, and support of families who are going through this, is important.
“We as a society have stigmatized this disease. I think that inhibits some young people getting treatment earlier rather than later. We also need to focus on prevention,” Dr. Camenga emphasized.
She reported having no relevant financial disclosures.
GENEVA – Among older adults with stage III non–small cell lung cancer (NSCLC), the sequencing of chemotherapy and radiation has a significant effect on overall survival, a team of investigators from Hong Kong and the United States reported.
Among 2,033 adults who were 65 years or older with locally advanced NSCLC and treated with one of four combined-modality therapy (CMT) schedules, both chemotherapy induction followed by concurrent therapy (CMT-IND) and concurrent therapy followed by consolidation chemoradiation (CMT-CON) were associated with an approximately 30% improvement in survival, compared with either sequential chemotherapy followed by radiation (CMT-SEQ) or concurrent therapy only (CMT-ONLY), reported Hei Man Herbert Pang, MD, of the University of Hong Kong and his colleagues.
Neil Osterweil/Frontline Medical News
Dr. Hei Man Herbert Pang
“We used propensity score matching to try to account for potential confounders and found that, after controlling for variables, CMT-CON and CMT-IND had survival benefits over CMT-ONLY or CMT-Sequential,” he said in an interview at the European Lung Cancer Conference.
The investigators used retrospective data from U.S. and Chinese sources to compare the relative survival benefits with various combined modality therapies. These included a Surveillance, Epidemiology, and End Results–Medicare cohort of patients 65 years and older with stage IIIA or IIIB NSCLC treated with CMT from 2006 through 2010 and a cohort of patients with the same age and NSCLC treated at Queen Mary Hospital in Hong Kong from 2007 through 2016.
They assessed neutropenia using inpatient claims data for episodes occurring within 130 days of the first chemotherapy cycle.
In an unadjusted analysis, they found that median overall survival, in descending order, was 16.1 months for CMT-SEQ,15.0 months for CMT-ONLY, 12.0 months for CMT-IND, and 11.0 months for CMT-CON.
When they controlled for variables, however, a different picture began to emerge.
For example, patients who were treated with CMT-SEQ had lower Charlson Comorbidity Index scores and, thus, were comparatively healthier than patients treated with other combined modalities.
Hospitalizations for neutropenia were most common with CMT-CON, occurring in 13.3% of patients, compared with 9.8% of patients treated with CMT-ONLY, 9.2% with CMT-IND, and 2.3% with CMT-SEQ.
In multivariable models controlling for sex, race, ethnicity, histology, and Charlson score, CMT-CON and CMT-IND were associated with significantly better overall, compared with CMT-SEQ, with respective hazard ratios for death of 0.68 (P less than .001) and 0.67 (P = .001). In this model, CMT-ONLY was not associated with significantly better survival.
In a propensity score model adjusted for the same factors, the respective HRs for CMT-CON, CMT-IND, and CMT-ONLY vs. CMT-SEQ were 0.69, 0.70, and 0.86 (P less than .001 for all three comparisons).
“The findings on efficacy and toxicity are quite consistent with previously reported studies based on clinical trials or observational databases,” the investigators said.
The study was supported by grants from the U.S. National Institutes of Health and the Hong Kong Health and Medical Research Fund. All authors have declared no conflicts of interest.
GENEVA – Among older adults with stage III non–small cell lung cancer (NSCLC), the sequencing of chemotherapy and radiation has a significant effect on overall survival, a team of investigators from Hong Kong and the United States reported.
Among 2,033 adults who were 65 years or older with locally advanced NSCLC and treated with one of four combined-modality therapy (CMT) schedules, both chemotherapy induction followed by concurrent therapy (CMT-IND) and concurrent therapy followed by consolidation chemoradiation (CMT-CON) were associated with an approximately 30% improvement in survival, compared with either sequential chemotherapy followed by radiation (CMT-SEQ) or concurrent therapy only (CMT-ONLY), reported Hei Man Herbert Pang, MD, of the University of Hong Kong and his colleagues.
Neil Osterweil/Frontline Medical News
Dr. Hei Man Herbert Pang
“We used propensity score matching to try to account for potential confounders and found that, after controlling for variables, CMT-CON and CMT-IND had survival benefits over CMT-ONLY or CMT-Sequential,” he said in an interview at the European Lung Cancer Conference.
The investigators used retrospective data from U.S. and Chinese sources to compare the relative survival benefits with various combined modality therapies. These included a Surveillance, Epidemiology, and End Results–Medicare cohort of patients 65 years and older with stage IIIA or IIIB NSCLC treated with CMT from 2006 through 2010 and a cohort of patients with the same age and NSCLC treated at Queen Mary Hospital in Hong Kong from 2007 through 2016.
They assessed neutropenia using inpatient claims data for episodes occurring within 130 days of the first chemotherapy cycle.
In an unadjusted analysis, they found that median overall survival, in descending order, was 16.1 months for CMT-SEQ,15.0 months for CMT-ONLY, 12.0 months for CMT-IND, and 11.0 months for CMT-CON.
When they controlled for variables, however, a different picture began to emerge.
For example, patients who were treated with CMT-SEQ had lower Charlson Comorbidity Index scores and, thus, were comparatively healthier than patients treated with other combined modalities.
Hospitalizations for neutropenia were most common with CMT-CON, occurring in 13.3% of patients, compared with 9.8% of patients treated with CMT-ONLY, 9.2% with CMT-IND, and 2.3% with CMT-SEQ.
In multivariable models controlling for sex, race, ethnicity, histology, and Charlson score, CMT-CON and CMT-IND were associated with significantly better overall, compared with CMT-SEQ, with respective hazard ratios for death of 0.68 (P less than .001) and 0.67 (P = .001). In this model, CMT-ONLY was not associated with significantly better survival.
In a propensity score model adjusted for the same factors, the respective HRs for CMT-CON, CMT-IND, and CMT-ONLY vs. CMT-SEQ were 0.69, 0.70, and 0.86 (P less than .001 for all three comparisons).
“The findings on efficacy and toxicity are quite consistent with previously reported studies based on clinical trials or observational databases,” the investigators said.
The study was supported by grants from the U.S. National Institutes of Health and the Hong Kong Health and Medical Research Fund. All authors have declared no conflicts of interest.
GENEVA – Among older adults with stage III non–small cell lung cancer (NSCLC), the sequencing of chemotherapy and radiation has a significant effect on overall survival, a team of investigators from Hong Kong and the United States reported.
Among 2,033 adults who were 65 years or older with locally advanced NSCLC and treated with one of four combined-modality therapy (CMT) schedules, both chemotherapy induction followed by concurrent therapy (CMT-IND) and concurrent therapy followed by consolidation chemoradiation (CMT-CON) were associated with an approximately 30% improvement in survival, compared with either sequential chemotherapy followed by radiation (CMT-SEQ) or concurrent therapy only (CMT-ONLY), reported Hei Man Herbert Pang, MD, of the University of Hong Kong and his colleagues.
Neil Osterweil/Frontline Medical News
Dr. Hei Man Herbert Pang
“We used propensity score matching to try to account for potential confounders and found that, after controlling for variables, CMT-CON and CMT-IND had survival benefits over CMT-ONLY or CMT-Sequential,” he said in an interview at the European Lung Cancer Conference.
The investigators used retrospective data from U.S. and Chinese sources to compare the relative survival benefits with various combined modality therapies. These included a Surveillance, Epidemiology, and End Results–Medicare cohort of patients 65 years and older with stage IIIA or IIIB NSCLC treated with CMT from 2006 through 2010 and a cohort of patients with the same age and NSCLC treated at Queen Mary Hospital in Hong Kong from 2007 through 2016.
They assessed neutropenia using inpatient claims data for episodes occurring within 130 days of the first chemotherapy cycle.
In an unadjusted analysis, they found that median overall survival, in descending order, was 16.1 months for CMT-SEQ,15.0 months for CMT-ONLY, 12.0 months for CMT-IND, and 11.0 months for CMT-CON.
When they controlled for variables, however, a different picture began to emerge.
For example, patients who were treated with CMT-SEQ had lower Charlson Comorbidity Index scores and, thus, were comparatively healthier than patients treated with other combined modalities.
Hospitalizations for neutropenia were most common with CMT-CON, occurring in 13.3% of patients, compared with 9.8% of patients treated with CMT-ONLY, 9.2% with CMT-IND, and 2.3% with CMT-SEQ.
In multivariable models controlling for sex, race, ethnicity, histology, and Charlson score, CMT-CON and CMT-IND were associated with significantly better overall, compared with CMT-SEQ, with respective hazard ratios for death of 0.68 (P less than .001) and 0.67 (P = .001). In this model, CMT-ONLY was not associated with significantly better survival.
In a propensity score model adjusted for the same factors, the respective HRs for CMT-CON, CMT-IND, and CMT-ONLY vs. CMT-SEQ were 0.69, 0.70, and 0.86 (P less than .001 for all three comparisons).
“The findings on efficacy and toxicity are quite consistent with previously reported studies based on clinical trials or observational databases,” the investigators said.
The study was supported by grants from the U.S. National Institutes of Health and the Hong Kong Health and Medical Research Fund. All authors have declared no conflicts of interest.
Key clinical point: Some combined modality therapy options for older adults with NSCLC are associated with better overall survival.
Major finding: CMT-IND and CMT-CON were associated with a 30% improvement in overall survival, compared with CMT-SEQ.
Data source: Retrospective review of data on 2,033 adults 65 years and older with NSCLC in the United States and Hong Kong.
Disclosures: The study was supported by grants from the U.S. National Institutes of Health and the Hong Kong Health and Medical Research Fund. All authors have declared no conflicts of interest.
SAN DIEGO – Obese women with a body mass index of 40 or greater are more likely to experience expulsion of levonorgestrel IUDs than women with lower BMI, according to findings from a retrospective cohort study.
Women with class III obesity (a BMI of 40 or greater) had a 3.06-times higher odds of expulsion (95% confidence interval, 1.69-5.57) with a levonorgestrel IUD, compared with a control group of women with a BMI of less than 35, Lynne Saito-Tom, MD, of the University of Hawaii at Manoa, Honolulu, reported at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.
Dr. Lynne Saito-Tom
The study included 1,071 women who had a levonorgestrel IUD inserted at Kaiser Permanente-Hawaii between January 2009 and December 2010. More than one-third of the women were obese, including 10% who were classified as class III.
Dr. Saito-Tom and her colleagues looked at other potential IUD complications, including infection, perforation, and pregnancy. Women with class III obesity also had a higher rate of all complications combined at 24%, compared with 10% among women with class I obesity.
Although complications were higher for more severely obese women, there were no differences between BMI groups in difficulty with insertion (P = .59) or 12-month continuation (P = .69).
The study was unique because it included a diverse ethnic population, with 36% Native Hawaiian/Pacific Islander women and 31% Asian women.
The study wasn’t powered to identify the reasons for greater expulsion in obese women, but some theories include that the IUD could be more difficult to place in larger women without adequate instrumentation or exam tables. Women with class III obesity also tend to have higher rates of heavy menstrual bleeding, which could be driving expulsion, Dr. Saito-Tom said.
However, the results should not deter physicians from placing hormonal IUD in these women, she said. While the expulsion rate was higher than seen generally, it is still an effective method for most obese women. “That’s much more beneficial than discouraging patients,” Dr. Saito-Tom said.
Physicians should continue to educate patients about the benefits of long-acting reversible contraceptives and encourage all patients to utilize them, regardless of their weight, she said.
Dr. Saito-Tom reported having no relevant financial disclosures. One of her colleagues reported grant support from Merck and being a consultant for UpToDate.
SAN DIEGO – Obese women with a body mass index of 40 or greater are more likely to experience expulsion of levonorgestrel IUDs than women with lower BMI, according to findings from a retrospective cohort study.
Women with class III obesity (a BMI of 40 or greater) had a 3.06-times higher odds of expulsion (95% confidence interval, 1.69-5.57) with a levonorgestrel IUD, compared with a control group of women with a BMI of less than 35, Lynne Saito-Tom, MD, of the University of Hawaii at Manoa, Honolulu, reported at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.
Dr. Lynne Saito-Tom
The study included 1,071 women who had a levonorgestrel IUD inserted at Kaiser Permanente-Hawaii between January 2009 and December 2010. More than one-third of the women were obese, including 10% who were classified as class III.
Dr. Saito-Tom and her colleagues looked at other potential IUD complications, including infection, perforation, and pregnancy. Women with class III obesity also had a higher rate of all complications combined at 24%, compared with 10% among women with class I obesity.
Although complications were higher for more severely obese women, there were no differences between BMI groups in difficulty with insertion (P = .59) or 12-month continuation (P = .69).
The study was unique because it included a diverse ethnic population, with 36% Native Hawaiian/Pacific Islander women and 31% Asian women.
The study wasn’t powered to identify the reasons for greater expulsion in obese women, but some theories include that the IUD could be more difficult to place in larger women without adequate instrumentation or exam tables. Women with class III obesity also tend to have higher rates of heavy menstrual bleeding, which could be driving expulsion, Dr. Saito-Tom said.
However, the results should not deter physicians from placing hormonal IUD in these women, she said. While the expulsion rate was higher than seen generally, it is still an effective method for most obese women. “That’s much more beneficial than discouraging patients,” Dr. Saito-Tom said.
Physicians should continue to educate patients about the benefits of long-acting reversible contraceptives and encourage all patients to utilize them, regardless of their weight, she said.
Dr. Saito-Tom reported having no relevant financial disclosures. One of her colleagues reported grant support from Merck and being a consultant for UpToDate.
SAN DIEGO – Obese women with a body mass index of 40 or greater are more likely to experience expulsion of levonorgestrel IUDs than women with lower BMI, according to findings from a retrospective cohort study.
Women with class III obesity (a BMI of 40 or greater) had a 3.06-times higher odds of expulsion (95% confidence interval, 1.69-5.57) with a levonorgestrel IUD, compared with a control group of women with a BMI of less than 35, Lynne Saito-Tom, MD, of the University of Hawaii at Manoa, Honolulu, reported at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.
Dr. Lynne Saito-Tom
The study included 1,071 women who had a levonorgestrel IUD inserted at Kaiser Permanente-Hawaii between January 2009 and December 2010. More than one-third of the women were obese, including 10% who were classified as class III.
Dr. Saito-Tom and her colleagues looked at other potential IUD complications, including infection, perforation, and pregnancy. Women with class III obesity also had a higher rate of all complications combined at 24%, compared with 10% among women with class I obesity.
Although complications were higher for more severely obese women, there were no differences between BMI groups in difficulty with insertion (P = .59) or 12-month continuation (P = .69).
The study was unique because it included a diverse ethnic population, with 36% Native Hawaiian/Pacific Islander women and 31% Asian women.
The study wasn’t powered to identify the reasons for greater expulsion in obese women, but some theories include that the IUD could be more difficult to place in larger women without adequate instrumentation or exam tables. Women with class III obesity also tend to have higher rates of heavy menstrual bleeding, which could be driving expulsion, Dr. Saito-Tom said.
However, the results should not deter physicians from placing hormonal IUD in these women, she said. While the expulsion rate was higher than seen generally, it is still an effective method for most obese women. “That’s much more beneficial than discouraging patients,” Dr. Saito-Tom said.
Physicians should continue to educate patients about the benefits of long-acting reversible contraceptives and encourage all patients to utilize them, regardless of their weight, she said.
Dr. Saito-Tom reported having no relevant financial disclosures. One of her colleagues reported grant support from Merck and being a consultant for UpToDate.
Key clinical point: Hormonal IUD expulsion was more likely in women with a BMI of 40 or greater.
Major finding: Women with class III obesity had 3.06 higher odds of levonorgestrel IUD expulsion, compared with a control group of women with a BMI of less than 35.
Data source: A retrospective cohort study of 1,071 women who had a levonorgestrel IUD inserted between January 2009 and December 2010.
Disclosures: Dr. Saito-Tom reported having no relevant financial disclosures. One of her colleagues reported grant support from Merck and being a consultant for UpToDate.
High mobility group box 1 (HMGB1) may be a new biomarker of celiac disease in children, said Sara Manti, MD, of the unit of pediatric genetics and immunology at the University of Messina, Italy, and her associates.
Serum HMGB1 levels were significantly higher in 49 children with celiac disease, compared with 44 healthy children in the control group (16.4 ng/mL vs. 6.23 ng/mL; P less than .001). Children with typical form celiac disease had significantly higher serum HMGB1 levels (22.03 ng/mL) than both children with atypical form (14.83 ng/mL) and silent form celiac disease (12.3 ng/mL). There was no statistically significant difference in serum HMGB1 levels between children with atypical form and silent form celiac disease.
Higher serum HMGB1 levels were correlated with severity of Marsh-Oberhüber classification.
These data, which need to be confirmed in further studies, suggest that HMGB1 is upregulated and linked to the severity of histologic damage in celiac disease. If other studies confirm these findings, it could be hypothesized that “asymptomatic children only with positive familial history and abnormal serum anti–tTG-IgA levels as well as normal serum HMGB1 levels need not be subjected to endoscopy to rule out the CD diagnosis,” the investigators said.
Perhaps, “neutralizing HMGB1 activity might be identified as a potential therapeutic target,” Dr. Manti and her associates noted.
High mobility group box 1 (HMGB1) may be a new biomarker of celiac disease in children, said Sara Manti, MD, of the unit of pediatric genetics and immunology at the University of Messina, Italy, and her associates.
Serum HMGB1 levels were significantly higher in 49 children with celiac disease, compared with 44 healthy children in the control group (16.4 ng/mL vs. 6.23 ng/mL; P less than .001). Children with typical form celiac disease had significantly higher serum HMGB1 levels (22.03 ng/mL) than both children with atypical form (14.83 ng/mL) and silent form celiac disease (12.3 ng/mL). There was no statistically significant difference in serum HMGB1 levels between children with atypical form and silent form celiac disease.
Higher serum HMGB1 levels were correlated with severity of Marsh-Oberhüber classification.
These data, which need to be confirmed in further studies, suggest that HMGB1 is upregulated and linked to the severity of histologic damage in celiac disease. If other studies confirm these findings, it could be hypothesized that “asymptomatic children only with positive familial history and abnormal serum anti–tTG-IgA levels as well as normal serum HMGB1 levels need not be subjected to endoscopy to rule out the CD diagnosis,” the investigators said.
Perhaps, “neutralizing HMGB1 activity might be identified as a potential therapeutic target,” Dr. Manti and her associates noted.
High mobility group box 1 (HMGB1) may be a new biomarker of celiac disease in children, said Sara Manti, MD, of the unit of pediatric genetics and immunology at the University of Messina, Italy, and her associates.
Serum HMGB1 levels were significantly higher in 49 children with celiac disease, compared with 44 healthy children in the control group (16.4 ng/mL vs. 6.23 ng/mL; P less than .001). Children with typical form celiac disease had significantly higher serum HMGB1 levels (22.03 ng/mL) than both children with atypical form (14.83 ng/mL) and silent form celiac disease (12.3 ng/mL). There was no statistically significant difference in serum HMGB1 levels between children with atypical form and silent form celiac disease.
Higher serum HMGB1 levels were correlated with severity of Marsh-Oberhüber classification.
These data, which need to be confirmed in further studies, suggest that HMGB1 is upregulated and linked to the severity of histologic damage in celiac disease. If other studies confirm these findings, it could be hypothesized that “asymptomatic children only with positive familial history and abnormal serum anti–tTG-IgA levels as well as normal serum HMGB1 levels need not be subjected to endoscopy to rule out the CD diagnosis,” the investigators said.
Perhaps, “neutralizing HMGB1 activity might be identified as a potential therapeutic target,” Dr. Manti and her associates noted.
LAS VEGAS – Bisphosphonates may slow the onset and progression of osteoarthritis (OA), according to data from the National Institutes of Health–sponsored Osteoarthritis Initiative. “Bisphosphonates warrant further study as potential disease-modifying agents in osteoarthritis,” Tuhina Neogi, MD, declared in presenting the study findings at the World Congress on Osteoarthritis.
In addition to the promising signal of a preventive effect for bisphosphonates, her analysis of Osteoarthritis Initiative data yielded two other major findings: Changes over time in the MRI-based three-dimensional bone shape of the knee constitute a novel structural imaging biomarker that appears to be of value in monitoring patients with OA or at high risk for the joint disease, and bisphosphonate-induced suppression of bone turnover had no adverse long-term impact on osteoarthritis risk.
“While bisphosphonates may have beneficial articular cartilage effects, there are potential theoretical concerns regarding long-term effects of bone turnover. This issue hasn’t previously been addressed. Bone turnover suppression may lead to more bone deposition and bone stiffness, with adverse biomechanical consequences. But it did not appear, in this sample at least, that suppression of bone turnover had a negative impact over the long term,” said Dr. Neogi, professor of medicine at Boston University.
The Osteoarthritis Initiative is a multicenter, longitudinal, prospective, observational study of knee osteoarthritis launched by the NIH in 2002. Dr. Neogi’s analysis was limited to the 1,071 female participants free of radiographic knee OA at baseline and who had 3-Tesla MRIs of the right knee at baseline and annually thereafter for 4 years. They were at increased risk for OA on the basis of their age – a mean of 62 years – along with their mean body mass index of 28.3 kg/m2. Just under one-quarter of the women were on bisphosphonate therapy.
Prior studies of the effects of bisphosphonates in patients with knee OA have yielded conflicting results, in part because radiographic findings are a relatively crude indicator of bone and joint changes. 3D bone shape of the knee has been shown to change much more quickly than traditional radiographic measures. These changes predict the incidence of knee OA even years later, the rheumatologist explained at the congress sponsored by the Osteoarthritis Research Society International.
Using bone shape analytic software developed by England-based Imorphics, she and her coinvestigators categorized the women into three distinct groups on the basis of the trajectory of MRI changes toward a more osteoarthritic bone shape over time. Of them, 23% fell into the fast-change group, 49% were in the intermediate group, and 28% were in the slowest-changing group. The rate of MRI bone shape progression toward knee OA was 2.7-times higher in the fastest, compared with the slowest, group.
The incidence of radiographic OA during 4 years of prospective follow-up was 14% in the fastest bone shape-changing group, 8% in the intermediate-speed group, and 4% in the slowest-changing group.
In a multivariate analysis adjusted for age, BMI, education, race, quadriceps strength, and history of knee injury, bisphosphonate users were 41% less likely to be in the fastest bone shape–changing group and 32% less likely to be in the intermediate group, compared with the slowest-changing group.
As a rheumatologist with a PhD in epidemiology, Dr. Neogi was readily prepared to critique her own study. The major limitation in her view was the potential for residual confounding, which is inherent in observational studies. In this instance, the possibility of confounding by indication cannot be excluded. Also, bone mineral density data wasn’t collected in the Osteoarthritis Initiative. Future studies should evaluate the impact over time of new-onset bisphosphonate therapy as a means of altering the slope of the trajectory of MRI-based 3D bone shape of the knee, Dr. Neogi said.
She reported having no financial conflicts regarding the NIH-sponsored study.
LAS VEGAS – Bisphosphonates may slow the onset and progression of osteoarthritis (OA), according to data from the National Institutes of Health–sponsored Osteoarthritis Initiative. “Bisphosphonates warrant further study as potential disease-modifying agents in osteoarthritis,” Tuhina Neogi, MD, declared in presenting the study findings at the World Congress on Osteoarthritis.
In addition to the promising signal of a preventive effect for bisphosphonates, her analysis of Osteoarthritis Initiative data yielded two other major findings: Changes over time in the MRI-based three-dimensional bone shape of the knee constitute a novel structural imaging biomarker that appears to be of value in monitoring patients with OA or at high risk for the joint disease, and bisphosphonate-induced suppression of bone turnover had no adverse long-term impact on osteoarthritis risk.
“While bisphosphonates may have beneficial articular cartilage effects, there are potential theoretical concerns regarding long-term effects of bone turnover. This issue hasn’t previously been addressed. Bone turnover suppression may lead to more bone deposition and bone stiffness, with adverse biomechanical consequences. But it did not appear, in this sample at least, that suppression of bone turnover had a negative impact over the long term,” said Dr. Neogi, professor of medicine at Boston University.
The Osteoarthritis Initiative is a multicenter, longitudinal, prospective, observational study of knee osteoarthritis launched by the NIH in 2002. Dr. Neogi’s analysis was limited to the 1,071 female participants free of radiographic knee OA at baseline and who had 3-Tesla MRIs of the right knee at baseline and annually thereafter for 4 years. They were at increased risk for OA on the basis of their age – a mean of 62 years – along with their mean body mass index of 28.3 kg/m2. Just under one-quarter of the women were on bisphosphonate therapy.
Prior studies of the effects of bisphosphonates in patients with knee OA have yielded conflicting results, in part because radiographic findings are a relatively crude indicator of bone and joint changes. 3D bone shape of the knee has been shown to change much more quickly than traditional radiographic measures. These changes predict the incidence of knee OA even years later, the rheumatologist explained at the congress sponsored by the Osteoarthritis Research Society International.
Using bone shape analytic software developed by England-based Imorphics, she and her coinvestigators categorized the women into three distinct groups on the basis of the trajectory of MRI changes toward a more osteoarthritic bone shape over time. Of them, 23% fell into the fast-change group, 49% were in the intermediate group, and 28% were in the slowest-changing group. The rate of MRI bone shape progression toward knee OA was 2.7-times higher in the fastest, compared with the slowest, group.
The incidence of radiographic OA during 4 years of prospective follow-up was 14% in the fastest bone shape-changing group, 8% in the intermediate-speed group, and 4% in the slowest-changing group.
In a multivariate analysis adjusted for age, BMI, education, race, quadriceps strength, and history of knee injury, bisphosphonate users were 41% less likely to be in the fastest bone shape–changing group and 32% less likely to be in the intermediate group, compared with the slowest-changing group.
As a rheumatologist with a PhD in epidemiology, Dr. Neogi was readily prepared to critique her own study. The major limitation in her view was the potential for residual confounding, which is inherent in observational studies. In this instance, the possibility of confounding by indication cannot be excluded. Also, bone mineral density data wasn’t collected in the Osteoarthritis Initiative. Future studies should evaluate the impact over time of new-onset bisphosphonate therapy as a means of altering the slope of the trajectory of MRI-based 3D bone shape of the knee, Dr. Neogi said.
She reported having no financial conflicts regarding the NIH-sponsored study.
LAS VEGAS – Bisphosphonates may slow the onset and progression of osteoarthritis (OA), according to data from the National Institutes of Health–sponsored Osteoarthritis Initiative. “Bisphosphonates warrant further study as potential disease-modifying agents in osteoarthritis,” Tuhina Neogi, MD, declared in presenting the study findings at the World Congress on Osteoarthritis.
In addition to the promising signal of a preventive effect for bisphosphonates, her analysis of Osteoarthritis Initiative data yielded two other major findings: Changes over time in the MRI-based three-dimensional bone shape of the knee constitute a novel structural imaging biomarker that appears to be of value in monitoring patients with OA or at high risk for the joint disease, and bisphosphonate-induced suppression of bone turnover had no adverse long-term impact on osteoarthritis risk.
“While bisphosphonates may have beneficial articular cartilage effects, there are potential theoretical concerns regarding long-term effects of bone turnover. This issue hasn’t previously been addressed. Bone turnover suppression may lead to more bone deposition and bone stiffness, with adverse biomechanical consequences. But it did not appear, in this sample at least, that suppression of bone turnover had a negative impact over the long term,” said Dr. Neogi, professor of medicine at Boston University.
The Osteoarthritis Initiative is a multicenter, longitudinal, prospective, observational study of knee osteoarthritis launched by the NIH in 2002. Dr. Neogi’s analysis was limited to the 1,071 female participants free of radiographic knee OA at baseline and who had 3-Tesla MRIs of the right knee at baseline and annually thereafter for 4 years. They were at increased risk for OA on the basis of their age – a mean of 62 years – along with their mean body mass index of 28.3 kg/m2. Just under one-quarter of the women were on bisphosphonate therapy.
Prior studies of the effects of bisphosphonates in patients with knee OA have yielded conflicting results, in part because radiographic findings are a relatively crude indicator of bone and joint changes. 3D bone shape of the knee has been shown to change much more quickly than traditional radiographic measures. These changes predict the incidence of knee OA even years later, the rheumatologist explained at the congress sponsored by the Osteoarthritis Research Society International.
Using bone shape analytic software developed by England-based Imorphics, she and her coinvestigators categorized the women into three distinct groups on the basis of the trajectory of MRI changes toward a more osteoarthritic bone shape over time. Of them, 23% fell into the fast-change group, 49% were in the intermediate group, and 28% were in the slowest-changing group. The rate of MRI bone shape progression toward knee OA was 2.7-times higher in the fastest, compared with the slowest, group.
The incidence of radiographic OA during 4 years of prospective follow-up was 14% in the fastest bone shape-changing group, 8% in the intermediate-speed group, and 4% in the slowest-changing group.
In a multivariate analysis adjusted for age, BMI, education, race, quadriceps strength, and history of knee injury, bisphosphonate users were 41% less likely to be in the fastest bone shape–changing group and 32% less likely to be in the intermediate group, compared with the slowest-changing group.
As a rheumatologist with a PhD in epidemiology, Dr. Neogi was readily prepared to critique her own study. The major limitation in her view was the potential for residual confounding, which is inherent in observational studies. In this instance, the possibility of confounding by indication cannot be excluded. Also, bone mineral density data wasn’t collected in the Osteoarthritis Initiative. Future studies should evaluate the impact over time of new-onset bisphosphonate therapy as a means of altering the slope of the trajectory of MRI-based 3D bone shape of the knee, Dr. Neogi said.
She reported having no financial conflicts regarding the NIH-sponsored study.
Key clinical point: Bisphosphonates may protect against knee osteoarthritis in high-risk women.
Major finding: Bisphosphonate users were 41% less likely to be in the group with the fastest trajectory of changes in bone shape known to be highly predictive of knee osteoarthritis.
Data source: This analysis of MRI-based changes in 3D bone shape of the knee over 4 years of follow-up included 1,071 female participants in the multicenter, prospective, observational Osteoarthritis Initiative.
Disclosures: The presenter reported having no financial conflicts regarding the NIH-sponsored study.
SAN DIEGO – Just over half of women who requested immediate postpartum sterilization received it in a prospective study of 334 women, with Medicaid paperwork serving as a barrier for many of the unfulfilled requests.
All of the women in the study delivered a baby and had requested immediate postpartum sterilization at some point before delivery, but just 173 women (52%) received the procedure, Taylor Hahn, MD, reported at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. A total of 161 women (48%) did not receive the procedure.
Dr. Taylor Hahn
The biggest barrier was completion of the Medicaid Consent to Sterilization form, which must be completed 30 days before the procedure is performed in a term pregnancy. Among women with unfulfilled requests for sterilization, an issue with the Medicaid consent form was the primary reason in 38% of cases.
Dr. Hahn, a fourth-year resident at Indiana University, Indianapolis, and her colleagues followed these women for up to 3 months post partum and found that, within the group that didn’t receive immediate postpartum sterilization, just six women – less than 10% – had received sterilization by the end of the follow-up period. The remaining women had chosen an alternative contraceptive method, were still awaiting interval sterilization, or did not receive postpartum care.
This is concerning, Dr. Hahn said, because Medicaid coverage for sterilization typically expires after 60 days post partum.
The consent form was developed in the 1970s to protect women in vulnerable populations from being coerced into sterilization, but Dr. Hahn said that, today, “it really has created such a barrier to these women getting the care that they want and desire.” She contrasted the Medicaid procedure with what is typical in private insurance, which generally covers immediate postpartum sterilization, and the decision can be made the same day.
The researchers reported having no relevant financial disclosures.
SAN DIEGO – Just over half of women who requested immediate postpartum sterilization received it in a prospective study of 334 women, with Medicaid paperwork serving as a barrier for many of the unfulfilled requests.
All of the women in the study delivered a baby and had requested immediate postpartum sterilization at some point before delivery, but just 173 women (52%) received the procedure, Taylor Hahn, MD, reported at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. A total of 161 women (48%) did not receive the procedure.
Dr. Taylor Hahn
The biggest barrier was completion of the Medicaid Consent to Sterilization form, which must be completed 30 days before the procedure is performed in a term pregnancy. Among women with unfulfilled requests for sterilization, an issue with the Medicaid consent form was the primary reason in 38% of cases.
Dr. Hahn, a fourth-year resident at Indiana University, Indianapolis, and her colleagues followed these women for up to 3 months post partum and found that, within the group that didn’t receive immediate postpartum sterilization, just six women – less than 10% – had received sterilization by the end of the follow-up period. The remaining women had chosen an alternative contraceptive method, were still awaiting interval sterilization, or did not receive postpartum care.
This is concerning, Dr. Hahn said, because Medicaid coverage for sterilization typically expires after 60 days post partum.
The consent form was developed in the 1970s to protect women in vulnerable populations from being coerced into sterilization, but Dr. Hahn said that, today, “it really has created such a barrier to these women getting the care that they want and desire.” She contrasted the Medicaid procedure with what is typical in private insurance, which generally covers immediate postpartum sterilization, and the decision can be made the same day.
The researchers reported having no relevant financial disclosures.
SAN DIEGO – Just over half of women who requested immediate postpartum sterilization received it in a prospective study of 334 women, with Medicaid paperwork serving as a barrier for many of the unfulfilled requests.
All of the women in the study delivered a baby and had requested immediate postpartum sterilization at some point before delivery, but just 173 women (52%) received the procedure, Taylor Hahn, MD, reported at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. A total of 161 women (48%) did not receive the procedure.
Dr. Taylor Hahn
The biggest barrier was completion of the Medicaid Consent to Sterilization form, which must be completed 30 days before the procedure is performed in a term pregnancy. Among women with unfulfilled requests for sterilization, an issue with the Medicaid consent form was the primary reason in 38% of cases.
Dr. Hahn, a fourth-year resident at Indiana University, Indianapolis, and her colleagues followed these women for up to 3 months post partum and found that, within the group that didn’t receive immediate postpartum sterilization, just six women – less than 10% – had received sterilization by the end of the follow-up period. The remaining women had chosen an alternative contraceptive method, were still awaiting interval sterilization, or did not receive postpartum care.
This is concerning, Dr. Hahn said, because Medicaid coverage for sterilization typically expires after 60 days post partum.
The consent form was developed in the 1970s to protect women in vulnerable populations from being coerced into sterilization, but Dr. Hahn said that, today, “it really has created such a barrier to these women getting the care that they want and desire.” She contrasted the Medicaid procedure with what is typical in private insurance, which generally covers immediate postpartum sterilization, and the decision can be made the same day.
The researchers reported having no relevant financial disclosures.
LAS VEGAS – Most of the improvement in knee pain that occurs following bariatric surgery in obese patients with knee osteoarthritis happens in the first month after surgery, well before the bulk of the weight loss takes place, Jonathan Samuels, MD, reported at the World Congress on Osteoarthritis.
This observation suggests that bariatric surgery’s mechanism of benefit in patients with knee osteoarthritis (OA) isn’t simply a matter of reduced mechanical load on the joints caused by a lessened weight burden, Dr. Samuels observed at the World Congress on Osteoarthritis, sponsored by the Osteoarthritis Research Society International.
Indeed, his prospective study of 150 obese patients with comorbid knee OA points to metabolic factors as likely playing a key role.
Bruce Jancin/Frontline Medical News
Dr. Jonathan Samuels
“Post–bariatric surgery changes in inflammatory biomarkers, especially leptin, may help to explain the symptomatic relief of knee pain – and potential joint preservation,” said Dr. Samuels, a rheumatologist at New York University.
His study, featuring 2 years of follow-up to date, showed that bariatric surgery improved knee OA proportionate to the percentage of excess weight loss achieved. The greatest reduction in knee pain as well as the most profound weight loss occurred in the 35 patients who underwent gastric bypass and the 97 who opted for sleeve gastrectomy; patients who underwent laparoscopic adjustable gastric banding had more modest outcomes on both scores.
The disparate timing of the reductions in excess weight and knee pain was particularly eye catching. With all three forms of bariatric surgery, weight loss continued steadily for roughly the first 12 months. It then plateaued and was generally maintained at the new body mass index for the second 12 months.
In contrast, improvement in knee pain according to the validated Knee Injury and Osteoarthritis Outcome Score (KOOS) leveled out after just 1 month post surgery and was then sustained through 23 months. Levels of the inflammatory cytokines and adipokines interleukin-6, interleukin-1 receptor antagonist, and lipopolysaccharides were elevated at baseline but dropped steadily in concert with the reduction in excess body weight during the first 12 months after surgery. In contrast, levels of the anti-inflammatory cytokine sRAGE (soluble receptor for advanced glycation end products) were abnormally low prior to surgery but increased sharply for the first 3 months afterward before leveling off. And levels of serum leptin, which were roughly sevenfold greater than in normal controls at baseline, fell precipitously during the first month after bariatric surgery before plateauing, following the same pattern as the improvement in knee pain.
“This suggests that perhaps leptin is the key mediator in this OA population,” said Dr. Samuels.
Obese patients with knee OA are in a catch-22 situation. Obese individuals are at greatly increased lifetime risk of developing knee OA, and patients with chronic knee pain have a tough time losing weight.
“The treatments that might work with either obesity or knee pain alone often fail when both of these are present,” he observed.
That’s why bariatric surgery is becoming an increasingly popular treatment strategy in these patients. Sleeve gastrectomy, gastric bypass, and laparoscopic adjustable gastric banding are all Food and Drug Administration approved treatments for obesity in the presence of at least one qualifying comorbid condition, and knee OA qualifies.
Dr. Samuels reported having no financial conflicts regarding his study.
LAS VEGAS – Most of the improvement in knee pain that occurs following bariatric surgery in obese patients with knee osteoarthritis happens in the first month after surgery, well before the bulk of the weight loss takes place, Jonathan Samuels, MD, reported at the World Congress on Osteoarthritis.
This observation suggests that bariatric surgery’s mechanism of benefit in patients with knee osteoarthritis (OA) isn’t simply a matter of reduced mechanical load on the joints caused by a lessened weight burden, Dr. Samuels observed at the World Congress on Osteoarthritis, sponsored by the Osteoarthritis Research Society International.
Indeed, his prospective study of 150 obese patients with comorbid knee OA points to metabolic factors as likely playing a key role.
Bruce Jancin/Frontline Medical News
Dr. Jonathan Samuels
“Post–bariatric surgery changes in inflammatory biomarkers, especially leptin, may help to explain the symptomatic relief of knee pain – and potential joint preservation,” said Dr. Samuels, a rheumatologist at New York University.
His study, featuring 2 years of follow-up to date, showed that bariatric surgery improved knee OA proportionate to the percentage of excess weight loss achieved. The greatest reduction in knee pain as well as the most profound weight loss occurred in the 35 patients who underwent gastric bypass and the 97 who opted for sleeve gastrectomy; patients who underwent laparoscopic adjustable gastric banding had more modest outcomes on both scores.
The disparate timing of the reductions in excess weight and knee pain was particularly eye catching. With all three forms of bariatric surgery, weight loss continued steadily for roughly the first 12 months. It then plateaued and was generally maintained at the new body mass index for the second 12 months.
In contrast, improvement in knee pain according to the validated Knee Injury and Osteoarthritis Outcome Score (KOOS) leveled out after just 1 month post surgery and was then sustained through 23 months. Levels of the inflammatory cytokines and adipokines interleukin-6, interleukin-1 receptor antagonist, and lipopolysaccharides were elevated at baseline but dropped steadily in concert with the reduction in excess body weight during the first 12 months after surgery. In contrast, levels of the anti-inflammatory cytokine sRAGE (soluble receptor for advanced glycation end products) were abnormally low prior to surgery but increased sharply for the first 3 months afterward before leveling off. And levels of serum leptin, which were roughly sevenfold greater than in normal controls at baseline, fell precipitously during the first month after bariatric surgery before plateauing, following the same pattern as the improvement in knee pain.
“This suggests that perhaps leptin is the key mediator in this OA population,” said Dr. Samuels.
Obese patients with knee OA are in a catch-22 situation. Obese individuals are at greatly increased lifetime risk of developing knee OA, and patients with chronic knee pain have a tough time losing weight.
“The treatments that might work with either obesity or knee pain alone often fail when both of these are present,” he observed.
That’s why bariatric surgery is becoming an increasingly popular treatment strategy in these patients. Sleeve gastrectomy, gastric bypass, and laparoscopic adjustable gastric banding are all Food and Drug Administration approved treatments for obesity in the presence of at least one qualifying comorbid condition, and knee OA qualifies.
Dr. Samuels reported having no financial conflicts regarding his study.
LAS VEGAS – Most of the improvement in knee pain that occurs following bariatric surgery in obese patients with knee osteoarthritis happens in the first month after surgery, well before the bulk of the weight loss takes place, Jonathan Samuels, MD, reported at the World Congress on Osteoarthritis.
This observation suggests that bariatric surgery’s mechanism of benefit in patients with knee osteoarthritis (OA) isn’t simply a matter of reduced mechanical load on the joints caused by a lessened weight burden, Dr. Samuels observed at the World Congress on Osteoarthritis, sponsored by the Osteoarthritis Research Society International.
Indeed, his prospective study of 150 obese patients with comorbid knee OA points to metabolic factors as likely playing a key role.
Bruce Jancin/Frontline Medical News
Dr. Jonathan Samuels
“Post–bariatric surgery changes in inflammatory biomarkers, especially leptin, may help to explain the symptomatic relief of knee pain – and potential joint preservation,” said Dr. Samuels, a rheumatologist at New York University.
His study, featuring 2 years of follow-up to date, showed that bariatric surgery improved knee OA proportionate to the percentage of excess weight loss achieved. The greatest reduction in knee pain as well as the most profound weight loss occurred in the 35 patients who underwent gastric bypass and the 97 who opted for sleeve gastrectomy; patients who underwent laparoscopic adjustable gastric banding had more modest outcomes on both scores.
The disparate timing of the reductions in excess weight and knee pain was particularly eye catching. With all three forms of bariatric surgery, weight loss continued steadily for roughly the first 12 months. It then plateaued and was generally maintained at the new body mass index for the second 12 months.
In contrast, improvement in knee pain according to the validated Knee Injury and Osteoarthritis Outcome Score (KOOS) leveled out after just 1 month post surgery and was then sustained through 23 months. Levels of the inflammatory cytokines and adipokines interleukin-6, interleukin-1 receptor antagonist, and lipopolysaccharides were elevated at baseline but dropped steadily in concert with the reduction in excess body weight during the first 12 months after surgery. In contrast, levels of the anti-inflammatory cytokine sRAGE (soluble receptor for advanced glycation end products) were abnormally low prior to surgery but increased sharply for the first 3 months afterward before leveling off. And levels of serum leptin, which were roughly sevenfold greater than in normal controls at baseline, fell precipitously during the first month after bariatric surgery before plateauing, following the same pattern as the improvement in knee pain.
“This suggests that perhaps leptin is the key mediator in this OA population,” said Dr. Samuels.
Obese patients with knee OA are in a catch-22 situation. Obese individuals are at greatly increased lifetime risk of developing knee OA, and patients with chronic knee pain have a tough time losing weight.
“The treatments that might work with either obesity or knee pain alone often fail when both of these are present,” he observed.
That’s why bariatric surgery is becoming an increasingly popular treatment strategy in these patients. Sleeve gastrectomy, gastric bypass, and laparoscopic adjustable gastric banding are all Food and Drug Administration approved treatments for obesity in the presence of at least one qualifying comorbid condition, and knee OA qualifies.
Dr. Samuels reported having no financial conflicts regarding his study.
Key clinical point: Rapid reduction of the proinflammatory cytokine leptin after bariatric surgery may play a major role in postsurgical improvement in knee osteoarthritis.
Major finding: Most of the improvement in knee pain – and most of the accompanying drop in serum leptin – happens in the first month following bariatric surgery, well before most weight loss has occurred.
Data source: A prospective observational study of 150 obese patients with knee osteoarthritis who underwent bariatric surgery.
Disclosures: The study presenter reported having no financial conflicts.
Sanofi and Regeneron Pharmaceuticals, Inc, announce US Food and Drug Administration approval of Dupixent (dupilumab) injection, a biologic for the treatment of adults with moderate to severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Dupixent is a human monoclonal antibody that inhibits overactive signaling of IL-4 and IL-3. It comes in a prefilled syringe and can be self-administered as a subcutaneous injection every other week after an initial loading dose. Dupixent MyWay will help eligible patients who are uninsured, lack coverage, or need assistance with out-of-pocket costs. For more information, visit www.dupixentHCP.com.
Renflexis
Samsung Bioepis Co, Ltd, announces US Food and Drug Administration approval of Renflexis (infliximab-abda) injection 100 mg, a biosimilar referencing infliximab. It is indicated in the United States for reducing signs and symptoms in patients with adult and pediatric Crohn disease, adult ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and adult plaque psoriasis. Renflexis will be marketed and distributed in the United States by Merck. For more information, visit www.samsungbioepis.com.
Replenix RetinolForte Treatment Serum
Topix Pharmaceuticals, Inc, introduces Replenix RetinolForte Treatment Serum containing all-trans-retinol, which helps increase cell turnover to reduce the appearance of fine lines and wrinkles, im- prove skin texture and tone, and promote a collagen-rich appearance. The micropolymer delivery system stabilizes the retinol to protect and shield it from oxidation while on the skin. Its time-released delivery system creates a reservoir that continuously bathes the skin and minimizes irritation. It also contains green tea polyphenols to soothe and calm the skin, caffeine to diminish the appearance of redness, and hyaluronic acid to help skin retain moisture to replenish and repair skin barrier function. For more information, visit www.topixpharm.com.
If you would like your product included in Product News, please email a press release to the Editorial Office atcutis@frontlinemedcom.com.
Sanofi and Regeneron Pharmaceuticals, Inc, announce US Food and Drug Administration approval of Dupixent (dupilumab) injection, a biologic for the treatment of adults with moderate to severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Dupixent is a human monoclonal antibody that inhibits overactive signaling of IL-4 and IL-3. It comes in a prefilled syringe and can be self-administered as a subcutaneous injection every other week after an initial loading dose. Dupixent MyWay will help eligible patients who are uninsured, lack coverage, or need assistance with out-of-pocket costs. For more information, visit www.dupixentHCP.com.
Renflexis
Samsung Bioepis Co, Ltd, announces US Food and Drug Administration approval of Renflexis (infliximab-abda) injection 100 mg, a biosimilar referencing infliximab. It is indicated in the United States for reducing signs and symptoms in patients with adult and pediatric Crohn disease, adult ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and adult plaque psoriasis. Renflexis will be marketed and distributed in the United States by Merck. For more information, visit www.samsungbioepis.com.
Replenix RetinolForte Treatment Serum
Topix Pharmaceuticals, Inc, introduces Replenix RetinolForte Treatment Serum containing all-trans-retinol, which helps increase cell turnover to reduce the appearance of fine lines and wrinkles, im- prove skin texture and tone, and promote a collagen-rich appearance. The micropolymer delivery system stabilizes the retinol to protect and shield it from oxidation while on the skin. Its time-released delivery system creates a reservoir that continuously bathes the skin and minimizes irritation. It also contains green tea polyphenols to soothe and calm the skin, caffeine to diminish the appearance of redness, and hyaluronic acid to help skin retain moisture to replenish and repair skin barrier function. For more information, visit www.topixpharm.com.
If you would like your product included in Product News, please email a press release to the Editorial Office atcutis@frontlinemedcom.com.
Dupixent
Sanofi and Regeneron Pharmaceuticals, Inc, announce US Food and Drug Administration approval of Dupixent (dupilumab) injection, a biologic for the treatment of adults with moderate to severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Dupixent is a human monoclonal antibody that inhibits overactive signaling of IL-4 and IL-3. It comes in a prefilled syringe and can be self-administered as a subcutaneous injection every other week after an initial loading dose. Dupixent MyWay will help eligible patients who are uninsured, lack coverage, or need assistance with out-of-pocket costs. For more information, visit www.dupixentHCP.com.
Renflexis
Samsung Bioepis Co, Ltd, announces US Food and Drug Administration approval of Renflexis (infliximab-abda) injection 100 mg, a biosimilar referencing infliximab. It is indicated in the United States for reducing signs and symptoms in patients with adult and pediatric Crohn disease, adult ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and adult plaque psoriasis. Renflexis will be marketed and distributed in the United States by Merck. For more information, visit www.samsungbioepis.com.
Replenix RetinolForte Treatment Serum
Topix Pharmaceuticals, Inc, introduces Replenix RetinolForte Treatment Serum containing all-trans-retinol, which helps increase cell turnover to reduce the appearance of fine lines and wrinkles, im- prove skin texture and tone, and promote a collagen-rich appearance. The micropolymer delivery system stabilizes the retinol to protect and shield it from oxidation while on the skin. Its time-released delivery system creates a reservoir that continuously bathes the skin and minimizes irritation. It also contains green tea polyphenols to soothe and calm the skin, caffeine to diminish the appearance of redness, and hyaluronic acid to help skin retain moisture to replenish and repair skin barrier function. For more information, visit www.topixpharm.com.
If you would like your product included in Product News, please email a press release to the Editorial Office atcutis@frontlinemedcom.com.
PORTLAND, ORE. – Janus kinase inhibitors are relatively safe and can produce a full head of hair in patients with moderate to severe alopecia areata (AA), although patients tend to shed hair after stopping treatment, Julian Mackay-Wiggan, MD, said at the annual meeting of the Society for Investigative Dermatology.
“At this point, there are 17 publications in the literature, from clinical trials to case reports, looking at JAK [Janus kinase] inhibitors in patients with alopecia areata,” said Dr. Mackay-Wiggan of the department of dermatology, Columbia University, New York, where she specializes in hair disorders. “Pretty much all report very positive findings. It definitely appears that Janus kinase inhibitors can play a very significant role in treatment.”
Amy Karon/Frontline Medical News
Dr. Julian Mackay-Wiggan
Despite a global lifetime incidence estimated at about 2%, alopecia has lacked effective treatment options (Clin Cosmet Investig Dermatol. 2015;8:397-403). However, ruxolitinib (Jakafi), which is approved by the Food and Drug Administration for treating polycythemia vera and myelofibrosis, has posted positive early results in AA.
In an open label, uncontrolled pilot study at Columbia, 9 of 12 (75%) patients with moderate to severe AA improved by at least 50% on the Severity of Alopecia Tool (SALT) after receiving 20 mg ruxolitinib twice daily for 3 to 6 months (JCI Insight. 2016 Sep 22;1[15]:e89790). Responses started with the first month, and all but one responder achieved at least 50% hair regrowth by week 12, said Dr. Mackay-Wiggan, who is also the director of the Dermatology Clinical Research Unit at Columbia.
By the end of treatment, seven of nine responders achieved more than 95% regrowth, one achieved 85% regrowth, and one achieved 55% regrowth. Importantly, none of these relatively healthy patients experienced serious adverse events on ruxolitinib, and none needed to stop treatment, although one patient experienced declining hemoglobin levels that resolved after dose modification.
Lab of Dr. Angela Christiano/Columbia University Medical Center
These photos show hair regrowth after treatment (at baseline, 3, and 4 months after treatment) with ruxolitinib in a patient with alopecia areata who was in the original pilot study at Columbia.
However, these notable responses were not necessarily durable. A third of responders began shedding hair 3 weeks after stopping ruxolitinib, with substantial hair loss after 12 weeks off the drug. The other six responders also reported increased shedding without major hair loss. The Columbia team also performed gene expression profiling that showed that nonresponders had relatively low baseline expression of genes encoding interferon-gamma and cytotoxic T lymphocytes, which mediate type I cellular immunity and thereby help drive the pathogenesis of AA. Compared with nonresponders, responders had significantly higher baseline expression of interferon gamma and cytotoxic T lymphocytes (P = .036), which markedly dropped as early as the second week of treatment.
Columbia researchers are also conducting an uncontrolled, open label pilot trial of the JAK inhibitor tofacitinib (Xeljanz) in 12 patients, of whom seven have moderate to severe patchy AA and five have alopecia totalis or universalis. Tofacitinib is approved for treating rheumatoid arthritis at a dose of 5 mg twice daily, but patients have needed up to 10 mg twice daily to achieve hair regrowth, Dr. Mackay-Wiggan said. To date, 11 (92%) have achieved at least some hair regrowth, and 8 (67%) have achieved at least 50% regrowth. So far, there have been no serious adverse events over 6 to 16 months of treatment, although one patient stopped treatment after developing hypertension, a known adverse effect of tofacitinib.
In this study, heatmaps of RNA sequencing of CD8+ T cell populations clearly showed pathogenic signatures for AA and a “robust molecular response to treatment,” Dr. Mackay-Wiggan said. “These two signatures also overlapped statistically, producing 114 genes that may be targetable mediators of disease.” But as with ruxolitinib, regrowth started to decline as patients were taken off treatment.
Research indicates that inhibiting the JAK-STAT signaling pathway induces anagen and subsequent hair growth, but activating STAT 5 in the dermal papilla is also important to induce the growth phase of the hair follicle, according to Dr. Mackay-Wiggan. “Bottom line, it’s complicated,” she added. “The mode of delivery – topical versus systemic – may be important, and the timing of delivery may be crucial.”
Other studies point to a role for JAK inhibition in treating AA. In an uncontrolled, retrospective study of 90 adults with alopecia totalis, alopecia universalis, or moderate to severe AA, 58% had SALT scores of 50% or better after receiving 5 mg tofacitinib twice daily for 4 to 18 months. Patients with AA improved more than those with alopecia totalis or universalis. There were no severe adverse effects, although nearly a third of patients developed upper respiratory tract infections. In another uncontrolled study of 13 patients with AA, totalis, or universalis, 9 (70%) patients achieved full regrowth and there were no serious adverse effects, although patients experienced headaches, upper respiratory infections, and mild increases in liver transaminase levels.
JAK inhibition also has a potential role for treating some scarring alopecias, including lichen planopilaris and frontal fibrosing alopecia. These diseases are histologically “identical” and both exhibit perifollicular erythema, papules, and scale, all of which suggest active inflammation, Dr. Mackay-Wiggan said. Hair follicles from affected patients show immune markers such as interferon-inducible chemokines, cytotoxic T cell responses, and expression of major histocompatibility complexes I and II. “The important message here is that JAK/STAT signaling may play a significant role in other types of hair loss other than alopecia areata,” Dr. Mackay-Wiggan said. “These diseases may also be autoimmune diseases, and may also be treatable with JAK inhibitors.”
Studies continue to evaluate JAK inhibitors for treating alopecia and its variants. Investigators at Yale and Stanford are conducting three uncontrolled trials of oral or topical tofacitinib, while Incyte, the manufacturer of ruxolitinib, is sponsoring a multicenter, randomized, placebo-controlled trial of ruxolitinib phosphate cream for adults with AA, with topline results expected in May 2018. Concert Pharmaceuticals also is recruiting for a trial of a modified, investigational form of ruxolitinib called CTP-543 for treating moderate to severe AA. “Many more trials are in development,” Dr. Mackay-Wiggan noted.
The ruxolitinib pilot study was funded by the Locks of Love Foundation, the Alopecia Areata Initiative, NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases, and by an Irving Institute for Clinical and Translational Research/Columbia University Medical Center Clinical and Translational Science Award. The ongoing tofacitinib pilot study is sponsored by Dr. Mackay-Wiggan, Locks of Love, and Columbia University.
Dr. Mackay-Wiggan also acknowledged support from the Alopecia Areata Initiative – the Gates Foundation, the National Alopecia Areata Registry, and the National Alopecia Areata Foundation. She had no other relevant financial disclosures.
PORTLAND, ORE. – Janus kinase inhibitors are relatively safe and can produce a full head of hair in patients with moderate to severe alopecia areata (AA), although patients tend to shed hair after stopping treatment, Julian Mackay-Wiggan, MD, said at the annual meeting of the Society for Investigative Dermatology.
“At this point, there are 17 publications in the literature, from clinical trials to case reports, looking at JAK [Janus kinase] inhibitors in patients with alopecia areata,” said Dr. Mackay-Wiggan of the department of dermatology, Columbia University, New York, where she specializes in hair disorders. “Pretty much all report very positive findings. It definitely appears that Janus kinase inhibitors can play a very significant role in treatment.”
Amy Karon/Frontline Medical News
Dr. Julian Mackay-Wiggan
Despite a global lifetime incidence estimated at about 2%, alopecia has lacked effective treatment options (Clin Cosmet Investig Dermatol. 2015;8:397-403). However, ruxolitinib (Jakafi), which is approved by the Food and Drug Administration for treating polycythemia vera and myelofibrosis, has posted positive early results in AA.
In an open label, uncontrolled pilot study at Columbia, 9 of 12 (75%) patients with moderate to severe AA improved by at least 50% on the Severity of Alopecia Tool (SALT) after receiving 20 mg ruxolitinib twice daily for 3 to 6 months (JCI Insight. 2016 Sep 22;1[15]:e89790). Responses started with the first month, and all but one responder achieved at least 50% hair regrowth by week 12, said Dr. Mackay-Wiggan, who is also the director of the Dermatology Clinical Research Unit at Columbia.
By the end of treatment, seven of nine responders achieved more than 95% regrowth, one achieved 85% regrowth, and one achieved 55% regrowth. Importantly, none of these relatively healthy patients experienced serious adverse events on ruxolitinib, and none needed to stop treatment, although one patient experienced declining hemoglobin levels that resolved after dose modification.
Lab of Dr. Angela Christiano/Columbia University Medical Center
These photos show hair regrowth after treatment (at baseline, 3, and 4 months after treatment) with ruxolitinib in a patient with alopecia areata who was in the original pilot study at Columbia.
However, these notable responses were not necessarily durable. A third of responders began shedding hair 3 weeks after stopping ruxolitinib, with substantial hair loss after 12 weeks off the drug. The other six responders also reported increased shedding without major hair loss. The Columbia team also performed gene expression profiling that showed that nonresponders had relatively low baseline expression of genes encoding interferon-gamma and cytotoxic T lymphocytes, which mediate type I cellular immunity and thereby help drive the pathogenesis of AA. Compared with nonresponders, responders had significantly higher baseline expression of interferon gamma and cytotoxic T lymphocytes (P = .036), which markedly dropped as early as the second week of treatment.
Columbia researchers are also conducting an uncontrolled, open label pilot trial of the JAK inhibitor tofacitinib (Xeljanz) in 12 patients, of whom seven have moderate to severe patchy AA and five have alopecia totalis or universalis. Tofacitinib is approved for treating rheumatoid arthritis at a dose of 5 mg twice daily, but patients have needed up to 10 mg twice daily to achieve hair regrowth, Dr. Mackay-Wiggan said. To date, 11 (92%) have achieved at least some hair regrowth, and 8 (67%) have achieved at least 50% regrowth. So far, there have been no serious adverse events over 6 to 16 months of treatment, although one patient stopped treatment after developing hypertension, a known adverse effect of tofacitinib.
In this study, heatmaps of RNA sequencing of CD8+ T cell populations clearly showed pathogenic signatures for AA and a “robust molecular response to treatment,” Dr. Mackay-Wiggan said. “These two signatures also overlapped statistically, producing 114 genes that may be targetable mediators of disease.” But as with ruxolitinib, regrowth started to decline as patients were taken off treatment.
Research indicates that inhibiting the JAK-STAT signaling pathway induces anagen and subsequent hair growth, but activating STAT 5 in the dermal papilla is also important to induce the growth phase of the hair follicle, according to Dr. Mackay-Wiggan. “Bottom line, it’s complicated,” she added. “The mode of delivery – topical versus systemic – may be important, and the timing of delivery may be crucial.”
Other studies point to a role for JAK inhibition in treating AA. In an uncontrolled, retrospective study of 90 adults with alopecia totalis, alopecia universalis, or moderate to severe AA, 58% had SALT scores of 50% or better after receiving 5 mg tofacitinib twice daily for 4 to 18 months. Patients with AA improved more than those with alopecia totalis or universalis. There were no severe adverse effects, although nearly a third of patients developed upper respiratory tract infections. In another uncontrolled study of 13 patients with AA, totalis, or universalis, 9 (70%) patients achieved full regrowth and there were no serious adverse effects, although patients experienced headaches, upper respiratory infections, and mild increases in liver transaminase levels.
JAK inhibition also has a potential role for treating some scarring alopecias, including lichen planopilaris and frontal fibrosing alopecia. These diseases are histologically “identical” and both exhibit perifollicular erythema, papules, and scale, all of which suggest active inflammation, Dr. Mackay-Wiggan said. Hair follicles from affected patients show immune markers such as interferon-inducible chemokines, cytotoxic T cell responses, and expression of major histocompatibility complexes I and II. “The important message here is that JAK/STAT signaling may play a significant role in other types of hair loss other than alopecia areata,” Dr. Mackay-Wiggan said. “These diseases may also be autoimmune diseases, and may also be treatable with JAK inhibitors.”
Studies continue to evaluate JAK inhibitors for treating alopecia and its variants. Investigators at Yale and Stanford are conducting three uncontrolled trials of oral or topical tofacitinib, while Incyte, the manufacturer of ruxolitinib, is sponsoring a multicenter, randomized, placebo-controlled trial of ruxolitinib phosphate cream for adults with AA, with topline results expected in May 2018. Concert Pharmaceuticals also is recruiting for a trial of a modified, investigational form of ruxolitinib called CTP-543 for treating moderate to severe AA. “Many more trials are in development,” Dr. Mackay-Wiggan noted.
The ruxolitinib pilot study was funded by the Locks of Love Foundation, the Alopecia Areata Initiative, NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases, and by an Irving Institute for Clinical and Translational Research/Columbia University Medical Center Clinical and Translational Science Award. The ongoing tofacitinib pilot study is sponsored by Dr. Mackay-Wiggan, Locks of Love, and Columbia University.
Dr. Mackay-Wiggan also acknowledged support from the Alopecia Areata Initiative – the Gates Foundation, the National Alopecia Areata Registry, and the National Alopecia Areata Foundation. She had no other relevant financial disclosures.
PORTLAND, ORE. – Janus kinase inhibitors are relatively safe and can produce a full head of hair in patients with moderate to severe alopecia areata (AA), although patients tend to shed hair after stopping treatment, Julian Mackay-Wiggan, MD, said at the annual meeting of the Society for Investigative Dermatology.
“At this point, there are 17 publications in the literature, from clinical trials to case reports, looking at JAK [Janus kinase] inhibitors in patients with alopecia areata,” said Dr. Mackay-Wiggan of the department of dermatology, Columbia University, New York, where she specializes in hair disorders. “Pretty much all report very positive findings. It definitely appears that Janus kinase inhibitors can play a very significant role in treatment.”
Amy Karon/Frontline Medical News
Dr. Julian Mackay-Wiggan
Despite a global lifetime incidence estimated at about 2%, alopecia has lacked effective treatment options (Clin Cosmet Investig Dermatol. 2015;8:397-403). However, ruxolitinib (Jakafi), which is approved by the Food and Drug Administration for treating polycythemia vera and myelofibrosis, has posted positive early results in AA.
In an open label, uncontrolled pilot study at Columbia, 9 of 12 (75%) patients with moderate to severe AA improved by at least 50% on the Severity of Alopecia Tool (SALT) after receiving 20 mg ruxolitinib twice daily for 3 to 6 months (JCI Insight. 2016 Sep 22;1[15]:e89790). Responses started with the first month, and all but one responder achieved at least 50% hair regrowth by week 12, said Dr. Mackay-Wiggan, who is also the director of the Dermatology Clinical Research Unit at Columbia.
By the end of treatment, seven of nine responders achieved more than 95% regrowth, one achieved 85% regrowth, and one achieved 55% regrowth. Importantly, none of these relatively healthy patients experienced serious adverse events on ruxolitinib, and none needed to stop treatment, although one patient experienced declining hemoglobin levels that resolved after dose modification.
Lab of Dr. Angela Christiano/Columbia University Medical Center
These photos show hair regrowth after treatment (at baseline, 3, and 4 months after treatment) with ruxolitinib in a patient with alopecia areata who was in the original pilot study at Columbia.
However, these notable responses were not necessarily durable. A third of responders began shedding hair 3 weeks after stopping ruxolitinib, with substantial hair loss after 12 weeks off the drug. The other six responders also reported increased shedding without major hair loss. The Columbia team also performed gene expression profiling that showed that nonresponders had relatively low baseline expression of genes encoding interferon-gamma and cytotoxic T lymphocytes, which mediate type I cellular immunity and thereby help drive the pathogenesis of AA. Compared with nonresponders, responders had significantly higher baseline expression of interferon gamma and cytotoxic T lymphocytes (P = .036), which markedly dropped as early as the second week of treatment.
Columbia researchers are also conducting an uncontrolled, open label pilot trial of the JAK inhibitor tofacitinib (Xeljanz) in 12 patients, of whom seven have moderate to severe patchy AA and five have alopecia totalis or universalis. Tofacitinib is approved for treating rheumatoid arthritis at a dose of 5 mg twice daily, but patients have needed up to 10 mg twice daily to achieve hair regrowth, Dr. Mackay-Wiggan said. To date, 11 (92%) have achieved at least some hair regrowth, and 8 (67%) have achieved at least 50% regrowth. So far, there have been no serious adverse events over 6 to 16 months of treatment, although one patient stopped treatment after developing hypertension, a known adverse effect of tofacitinib.
In this study, heatmaps of RNA sequencing of CD8+ T cell populations clearly showed pathogenic signatures for AA and a “robust molecular response to treatment,” Dr. Mackay-Wiggan said. “These two signatures also overlapped statistically, producing 114 genes that may be targetable mediators of disease.” But as with ruxolitinib, regrowth started to decline as patients were taken off treatment.
Research indicates that inhibiting the JAK-STAT signaling pathway induces anagen and subsequent hair growth, but activating STAT 5 in the dermal papilla is also important to induce the growth phase of the hair follicle, according to Dr. Mackay-Wiggan. “Bottom line, it’s complicated,” she added. “The mode of delivery – topical versus systemic – may be important, and the timing of delivery may be crucial.”
Other studies point to a role for JAK inhibition in treating AA. In an uncontrolled, retrospective study of 90 adults with alopecia totalis, alopecia universalis, or moderate to severe AA, 58% had SALT scores of 50% or better after receiving 5 mg tofacitinib twice daily for 4 to 18 months. Patients with AA improved more than those with alopecia totalis or universalis. There were no severe adverse effects, although nearly a third of patients developed upper respiratory tract infections. In another uncontrolled study of 13 patients with AA, totalis, or universalis, 9 (70%) patients achieved full regrowth and there were no serious adverse effects, although patients experienced headaches, upper respiratory infections, and mild increases in liver transaminase levels.
JAK inhibition also has a potential role for treating some scarring alopecias, including lichen planopilaris and frontal fibrosing alopecia. These diseases are histologically “identical” and both exhibit perifollicular erythema, papules, and scale, all of which suggest active inflammation, Dr. Mackay-Wiggan said. Hair follicles from affected patients show immune markers such as interferon-inducible chemokines, cytotoxic T cell responses, and expression of major histocompatibility complexes I and II. “The important message here is that JAK/STAT signaling may play a significant role in other types of hair loss other than alopecia areata,” Dr. Mackay-Wiggan said. “These diseases may also be autoimmune diseases, and may also be treatable with JAK inhibitors.”
Studies continue to evaluate JAK inhibitors for treating alopecia and its variants. Investigators at Yale and Stanford are conducting three uncontrolled trials of oral or topical tofacitinib, while Incyte, the manufacturer of ruxolitinib, is sponsoring a multicenter, randomized, placebo-controlled trial of ruxolitinib phosphate cream for adults with AA, with topline results expected in May 2018. Concert Pharmaceuticals also is recruiting for a trial of a modified, investigational form of ruxolitinib called CTP-543 for treating moderate to severe AA. “Many more trials are in development,” Dr. Mackay-Wiggan noted.
The ruxolitinib pilot study was funded by the Locks of Love Foundation, the Alopecia Areata Initiative, NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases, and by an Irving Institute for Clinical and Translational Research/Columbia University Medical Center Clinical and Translational Science Award. The ongoing tofacitinib pilot study is sponsored by Dr. Mackay-Wiggan, Locks of Love, and Columbia University.
Dr. Mackay-Wiggan also acknowledged support from the Alopecia Areata Initiative – the Gates Foundation, the National Alopecia Areata Registry, and the National Alopecia Areata Foundation. She had no other relevant financial disclosures.
An 85-year-old woman with a history of hypertension, hyperlipidemia, stroke, hypothyroidism, chronic obstructive pulmonary disease, and chronic myeloproliferative disorder presented to our clinic for evaluation of brown lesions on the hands and discoloration of the fingernails and toenails of 4 months’ duration. Six months prior to visiting our clinic she was admitted to the hospital for a pulmonary embolism. On admission she was noted to have a platelet count of more than 2 million/μL (reference range, 150,000–350,000/μL). She received urgent plasmapheresis and started hydroxyurea 500 mg twice daily, which she continued as an outpatient.
On physical examination at our clinic she had diffusely scattered red and brown macules on the bilateral palms and transverse hyperpigmented bands of various intensities on all fingernails and toenails (Figure). Her platelet count was 372,000/μL, white blood cell count was 5200/μL (reference range, 4500–11,000/μL), hemoglobin was 12.6 g/dL (reference range, 14.0–17.5 g/dL), hematocrit was 39.0% (reference range, 41%–50%), and mean corpuscular volume was 87.5 fL per red cell (reference range, 80–96 fL per red cell).
Melanonychia with transverse hyperpigmented bands of various intensities on the fingernails (A) and toenails (B).
The patient was diagnosed with hydroxyurea-induced nail hyperpigmentation and was counseled on the benign nature of the condition. Three months later her platelet count decreased to below 100,000/μL, and hydroxyurea was discontinued. She noticed considerable improvement in the lesions on the hands and nails with the cessation of hydroxyurea.
Hydroxyurea is a cytostatic agent that has been used for more than 40 years in the treatment of myeloproliferative disorders including chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, and sickle cell anemia.1 It inhibits ribonucleoside diphosphate reductase and promotes cell death in the S phase of the cell cycle.1-3
Several adverse cutaneous reactions have been associated with hydroxyurea including increased pigmentation, hyperkeratosis, skin atrophy, xerosis, lichenoid eruptions, palmoplantar keratoderma, cutaneous vasculitis, alopecia, chronic leg ulcers, cutaneous carcinomas, and melanonychia.3,4
Hydroxyurea-induced melanonychia most often occurs after several months of therapy but has been reported to occur as early as 4 months and as late as 5 years after initiating the drug.1,4-6 The prevalence of melanonychia in the general population has been estimated at 1% and is thought to increase to approximately 4% in patients treated with hydroxyurea.1,2,6,7 The prevalence of affected individuals increases with age; it is more common in females as well as black and Hispanic patients.2
Multiple patterns of hydroxyurea-induced melanonychia have been described, including longitudinal bands, transverse bands, and diffuse hyperpigmentation.1-3,6 By far the most common pattern described in the literature is longitudinal banding1-3,8; transverse bands are more rare. Although there are sporadic case reports linking the transverse bands with hydroxyurea, these bands occur more frequently with systemic chemotherapy such as doxorubicin and cyclosphosphamide.1,6
The exact pathogenesis of hydroxyurea-induced melanonychia remains unclear, though it is thought to result from focal melanogenesis in the nail bed or matrix followed by deposition of melanin granules on the nail plate.5,8 When these melanocytes are activated, melanosomes filled with melanin are transferred to differentiating matrix cells, which migrate distally as they become nail plate oncocytes, resulting in a visible band of pigmentation in the nail plate.2 There also may be a genetic and photosensitivity component.1,2
Prior case series have described spontaneous remission of nail hyperpigmentation following discontinuation of hydroxyurea therapy.1 In many patients, however, the chronic nature of the myeloproliferative disorder and lack of alternative treatments make a therapeutic change difficult. Although the melanonychia itself is benign, it may precede the appearance of more serious mucocutaneous side effects, such as skin ulceration or development of cutaneous carcinomas, so careful monitoring should be performed.2
Our patient presented with melanonychia that was transverse, polydactylic, monochromic, stable in size and shape, and associated with palmar hyperpigmentation. Of note, the pigmentation remitted over time along with discontinuation of the drug. Although this presentation did not warrant a nail matrix biopsy, it should be noted that patients with single nail melanonychia suspicious for melanoma should have a biopsy, even with concomitant use of hydroxyurea.2 Although transverse melanonychia most commonly is associated with other systemic chemotherapeutics, in the absence of such medications hydroxyurea was the likely culprit in our patient. The palmar hyperpigmentation, which has previously been reported with hydroxyurea use, further solidifies the diagnosis.
References
Aste N, Futmo G, Contu F, et al. Nail pigmentation caused by hydroxyurea: report of 9 cases. J Am Acad Dermatol. 2002;47:146-147.
Murray N, Tapia P, Porcell J, et al. Acquired melanonychia in Chilean patients with essential thrombocythemia treated with hydroxyurea: a report of 7 clinical cases and review of the literature [published online February 7, 2013]. ISRN Dermatol. 2013;2013:325246.
Utas S. A case of hydroxyurea-induced longitudinal melanonychia. Int J Dermatol. 2010;49:469-470.
Saraceno R, Teoli M, Chimenti S. Hydroxyurea associated with concomitant occurrence of diffuse longitudinal melanonychia and multiple squamous cell carcinomas in an elderly subject. Clin Ther. 2008;30:1324-1329.
Cohen AD, Hallel-Halevy D, Hatskelzon L, et al. Longitudinal melanonychia associated with hydroxyurea therapy in a patient with essential thrombocytosis. J Eur Acad Dermatol. 1999;13:137-139.
Hernández-Martín A, Ros-Forteza S, de Unamuno P. Longitudinal, transverse, and diffuse nail hyperpigmentation induced by hydroxyurea. J Am Acad Dermatol. 1999;41(2, pt 2):333-334.
Kwong Y. Hydroxyurea-induced nail pigmentation. J Am Acad Dermatol. 1996;35:275-276.
O’Branski E, Ware R, Prose N, et al. Skin and nail changes in children with sickle cell anemia receiving hydroxyurea therapy. J Am Acad Dermatol. 2001;44:859-861.
All from Drexel University College of Medicine, Philadelphia, Pennsylvania. Drs. Schoenfeld and Tulbert also are from Hahnemann University Hospital, Philadelphia.
All from Drexel University College of Medicine, Philadelphia, Pennsylvania. Drs. Schoenfeld and Tulbert also are from Hahnemann University Hospital, Philadelphia.
All from Drexel University College of Medicine, Philadelphia, Pennsylvania. Drs. Schoenfeld and Tulbert also are from Hahnemann University Hospital, Philadelphia.
An 85-year-old woman with a history of hypertension, hyperlipidemia, stroke, hypothyroidism, chronic obstructive pulmonary disease, and chronic myeloproliferative disorder presented to our clinic for evaluation of brown lesions on the hands and discoloration of the fingernails and toenails of 4 months’ duration. Six months prior to visiting our clinic she was admitted to the hospital for a pulmonary embolism. On admission she was noted to have a platelet count of more than 2 million/μL (reference range, 150,000–350,000/μL). She received urgent plasmapheresis and started hydroxyurea 500 mg twice daily, which she continued as an outpatient.
On physical examination at our clinic she had diffusely scattered red and brown macules on the bilateral palms and transverse hyperpigmented bands of various intensities on all fingernails and toenails (Figure). Her platelet count was 372,000/μL, white blood cell count was 5200/μL (reference range, 4500–11,000/μL), hemoglobin was 12.6 g/dL (reference range, 14.0–17.5 g/dL), hematocrit was 39.0% (reference range, 41%–50%), and mean corpuscular volume was 87.5 fL per red cell (reference range, 80–96 fL per red cell).
Melanonychia with transverse hyperpigmented bands of various intensities on the fingernails (A) and toenails (B).
The patient was diagnosed with hydroxyurea-induced nail hyperpigmentation and was counseled on the benign nature of the condition. Three months later her platelet count decreased to below 100,000/μL, and hydroxyurea was discontinued. She noticed considerable improvement in the lesions on the hands and nails with the cessation of hydroxyurea.
Hydroxyurea is a cytostatic agent that has been used for more than 40 years in the treatment of myeloproliferative disorders including chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, and sickle cell anemia.1 It inhibits ribonucleoside diphosphate reductase and promotes cell death in the S phase of the cell cycle.1-3
Several adverse cutaneous reactions have been associated with hydroxyurea including increased pigmentation, hyperkeratosis, skin atrophy, xerosis, lichenoid eruptions, palmoplantar keratoderma, cutaneous vasculitis, alopecia, chronic leg ulcers, cutaneous carcinomas, and melanonychia.3,4
Hydroxyurea-induced melanonychia most often occurs after several months of therapy but has been reported to occur as early as 4 months and as late as 5 years after initiating the drug.1,4-6 The prevalence of melanonychia in the general population has been estimated at 1% and is thought to increase to approximately 4% in patients treated with hydroxyurea.1,2,6,7 The prevalence of affected individuals increases with age; it is more common in females as well as black and Hispanic patients.2
Multiple patterns of hydroxyurea-induced melanonychia have been described, including longitudinal bands, transverse bands, and diffuse hyperpigmentation.1-3,6 By far the most common pattern described in the literature is longitudinal banding1-3,8; transverse bands are more rare. Although there are sporadic case reports linking the transverse bands with hydroxyurea, these bands occur more frequently with systemic chemotherapy such as doxorubicin and cyclosphosphamide.1,6
The exact pathogenesis of hydroxyurea-induced melanonychia remains unclear, though it is thought to result from focal melanogenesis in the nail bed or matrix followed by deposition of melanin granules on the nail plate.5,8 When these melanocytes are activated, melanosomes filled with melanin are transferred to differentiating matrix cells, which migrate distally as they become nail plate oncocytes, resulting in a visible band of pigmentation in the nail plate.2 There also may be a genetic and photosensitivity component.1,2
Prior case series have described spontaneous remission of nail hyperpigmentation following discontinuation of hydroxyurea therapy.1 In many patients, however, the chronic nature of the myeloproliferative disorder and lack of alternative treatments make a therapeutic change difficult. Although the melanonychia itself is benign, it may precede the appearance of more serious mucocutaneous side effects, such as skin ulceration or development of cutaneous carcinomas, so careful monitoring should be performed.2
Our patient presented with melanonychia that was transverse, polydactylic, monochromic, stable in size and shape, and associated with palmar hyperpigmentation. Of note, the pigmentation remitted over time along with discontinuation of the drug. Although this presentation did not warrant a nail matrix biopsy, it should be noted that patients with single nail melanonychia suspicious for melanoma should have a biopsy, even with concomitant use of hydroxyurea.2 Although transverse melanonychia most commonly is associated with other systemic chemotherapeutics, in the absence of such medications hydroxyurea was the likely culprit in our patient. The palmar hyperpigmentation, which has previously been reported with hydroxyurea use, further solidifies the diagnosis.
To the Editor:
An 85-year-old woman with a history of hypertension, hyperlipidemia, stroke, hypothyroidism, chronic obstructive pulmonary disease, and chronic myeloproliferative disorder presented to our clinic for evaluation of brown lesions on the hands and discoloration of the fingernails and toenails of 4 months’ duration. Six months prior to visiting our clinic she was admitted to the hospital for a pulmonary embolism. On admission she was noted to have a platelet count of more than 2 million/μL (reference range, 150,000–350,000/μL). She received urgent plasmapheresis and started hydroxyurea 500 mg twice daily, which she continued as an outpatient.
On physical examination at our clinic she had diffusely scattered red and brown macules on the bilateral palms and transverse hyperpigmented bands of various intensities on all fingernails and toenails (Figure). Her platelet count was 372,000/μL, white blood cell count was 5200/μL (reference range, 4500–11,000/μL), hemoglobin was 12.6 g/dL (reference range, 14.0–17.5 g/dL), hematocrit was 39.0% (reference range, 41%–50%), and mean corpuscular volume was 87.5 fL per red cell (reference range, 80–96 fL per red cell).
Melanonychia with transverse hyperpigmented bands of various intensities on the fingernails (A) and toenails (B).
The patient was diagnosed with hydroxyurea-induced nail hyperpigmentation and was counseled on the benign nature of the condition. Three months later her platelet count decreased to below 100,000/μL, and hydroxyurea was discontinued. She noticed considerable improvement in the lesions on the hands and nails with the cessation of hydroxyurea.
Hydroxyurea is a cytostatic agent that has been used for more than 40 years in the treatment of myeloproliferative disorders including chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, and sickle cell anemia.1 It inhibits ribonucleoside diphosphate reductase and promotes cell death in the S phase of the cell cycle.1-3
Several adverse cutaneous reactions have been associated with hydroxyurea including increased pigmentation, hyperkeratosis, skin atrophy, xerosis, lichenoid eruptions, palmoplantar keratoderma, cutaneous vasculitis, alopecia, chronic leg ulcers, cutaneous carcinomas, and melanonychia.3,4
Hydroxyurea-induced melanonychia most often occurs after several months of therapy but has been reported to occur as early as 4 months and as late as 5 years after initiating the drug.1,4-6 The prevalence of melanonychia in the general population has been estimated at 1% and is thought to increase to approximately 4% in patients treated with hydroxyurea.1,2,6,7 The prevalence of affected individuals increases with age; it is more common in females as well as black and Hispanic patients.2
Multiple patterns of hydroxyurea-induced melanonychia have been described, including longitudinal bands, transverse bands, and diffuse hyperpigmentation.1-3,6 By far the most common pattern described in the literature is longitudinal banding1-3,8; transverse bands are more rare. Although there are sporadic case reports linking the transverse bands with hydroxyurea, these bands occur more frequently with systemic chemotherapy such as doxorubicin and cyclosphosphamide.1,6
The exact pathogenesis of hydroxyurea-induced melanonychia remains unclear, though it is thought to result from focal melanogenesis in the nail bed or matrix followed by deposition of melanin granules on the nail plate.5,8 When these melanocytes are activated, melanosomes filled with melanin are transferred to differentiating matrix cells, which migrate distally as they become nail plate oncocytes, resulting in a visible band of pigmentation in the nail plate.2 There also may be a genetic and photosensitivity component.1,2
Prior case series have described spontaneous remission of nail hyperpigmentation following discontinuation of hydroxyurea therapy.1 In many patients, however, the chronic nature of the myeloproliferative disorder and lack of alternative treatments make a therapeutic change difficult. Although the melanonychia itself is benign, it may precede the appearance of more serious mucocutaneous side effects, such as skin ulceration or development of cutaneous carcinomas, so careful monitoring should be performed.2
Our patient presented with melanonychia that was transverse, polydactylic, monochromic, stable in size and shape, and associated with palmar hyperpigmentation. Of note, the pigmentation remitted over time along with discontinuation of the drug. Although this presentation did not warrant a nail matrix biopsy, it should be noted that patients with single nail melanonychia suspicious for melanoma should have a biopsy, even with concomitant use of hydroxyurea.2 Although transverse melanonychia most commonly is associated with other systemic chemotherapeutics, in the absence of such medications hydroxyurea was the likely culprit in our patient. The palmar hyperpigmentation, which has previously been reported with hydroxyurea use, further solidifies the diagnosis.
References
Aste N, Futmo G, Contu F, et al. Nail pigmentation caused by hydroxyurea: report of 9 cases. J Am Acad Dermatol. 2002;47:146-147.
Murray N, Tapia P, Porcell J, et al. Acquired melanonychia in Chilean patients with essential thrombocythemia treated with hydroxyurea: a report of 7 clinical cases and review of the literature [published online February 7, 2013]. ISRN Dermatol. 2013;2013:325246.
Utas S. A case of hydroxyurea-induced longitudinal melanonychia. Int J Dermatol. 2010;49:469-470.
Saraceno R, Teoli M, Chimenti S. Hydroxyurea associated with concomitant occurrence of diffuse longitudinal melanonychia and multiple squamous cell carcinomas in an elderly subject. Clin Ther. 2008;30:1324-1329.
Cohen AD, Hallel-Halevy D, Hatskelzon L, et al. Longitudinal melanonychia associated with hydroxyurea therapy in a patient with essential thrombocytosis. J Eur Acad Dermatol. 1999;13:137-139.
Hernández-Martín A, Ros-Forteza S, de Unamuno P. Longitudinal, transverse, and diffuse nail hyperpigmentation induced by hydroxyurea. J Am Acad Dermatol. 1999;41(2, pt 2):333-334.
Kwong Y. Hydroxyurea-induced nail pigmentation. J Am Acad Dermatol. 1996;35:275-276.
O’Branski E, Ware R, Prose N, et al. Skin and nail changes in children with sickle cell anemia receiving hydroxyurea therapy. J Am Acad Dermatol. 2001;44:859-861.
References
Aste N, Futmo G, Contu F, et al. Nail pigmentation caused by hydroxyurea: report of 9 cases. J Am Acad Dermatol. 2002;47:146-147.
Murray N, Tapia P, Porcell J, et al. Acquired melanonychia in Chilean patients with essential thrombocythemia treated with hydroxyurea: a report of 7 clinical cases and review of the literature [published online February 7, 2013]. ISRN Dermatol. 2013;2013:325246.
Utas S. A case of hydroxyurea-induced longitudinal melanonychia. Int J Dermatol. 2010;49:469-470.
Saraceno R, Teoli M, Chimenti S. Hydroxyurea associated with concomitant occurrence of diffuse longitudinal melanonychia and multiple squamous cell carcinomas in an elderly subject. Clin Ther. 2008;30:1324-1329.
Cohen AD, Hallel-Halevy D, Hatskelzon L, et al. Longitudinal melanonychia associated with hydroxyurea therapy in a patient with essential thrombocytosis. J Eur Acad Dermatol. 1999;13:137-139.
Hernández-Martín A, Ros-Forteza S, de Unamuno P. Longitudinal, transverse, and diffuse nail hyperpigmentation induced by hydroxyurea. J Am Acad Dermatol. 1999;41(2, pt 2):333-334.
Kwong Y. Hydroxyurea-induced nail pigmentation. J Am Acad Dermatol. 1996;35:275-276.
O’Branski E, Ware R, Prose N, et al. Skin and nail changes in children with sickle cell anemia receiving hydroxyurea therapy. J Am Acad Dermatol. 2001;44:859-861.
Transverse melanonychia may result as a side effect of hydroxyurea.
Discontinuation of hydroxyurea typically results in a resolution of symptoms. If the medication cannot be stopped, however, pigmentary changes may precede the development of severe mucocutaneous side effects and close monitoring is warranted.
Patients with single nail melanonychia suspicious for melanoma should have a biopsy, even with concomitant use of hydroxyurea.
