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Researchers seek to characterize pediatric new daily persistent headache
CHARLOTTE, N.C. – according to research presented at the 48th national meeting of the Child Neurology Society. Most children with NDPH fulfill criteria for its migraine subtype, and one-third of pediatric patients with NDPH have comorbid medication overuse headache (MOH).
NDPH is defined as a daily, unremitting headache that lasts for at least 3 months. “Not many studies on NDPH focus on pediatrics,” said Emily Pierce, from Children’s National Medical Center in Washington. NDPH “is considered to be one of the most intractable headaches in children. Children are able to tell that they’ve had this different type of headache because there’s some kind of onset that is very memorable.”
Ms. Pierce and colleagues conducted an observational study to describe the characteristics of NDPH in pediatric patients who presented to a headache program at a tertiary referral center. The researchers included pediatric patients who visited the headache clinic at Children’s National Medical Center between 2016 and 2018 in their analysis. All patients were enrolled in patient registry that had been approved by an independent review board. Ms. Pierce and colleagues queried the registry for NDPH and reviewed these records to examine participants’ clinical presentations.
The investigators identified 3,260 patient encounters during the study period. Of these encounters, 454 patients (13.9%) were identified as having NDPH. Patients with NDPH were predominantly female (78%) and white (72%). The median age of the sample was 14.8 years.
The frontal head region was the most common location of headache pain, which often had a throbbing quality and was associated with photophobia, phonophobia, nausea, and decreased activity. The median pain intensity was 6 of 10. Approximately 72% of patients had tried abortive medication, and 56% of patients had failed at least one abortive medication. Excedrin, ibuprofen, and acetaminophen were among the common failed abortive medications.
Furthermore, 36% of patients were diagnosed with MOH. The most commonly overused medication was ibuprofen. MOH “is also considered to be intractable for patients with NDPH,” said Ms. Pierce. “Typically, if the patient stops overusing that medication, they’ll find relief from their headaches. However, with our NDPH patients, when they stop overusing that medication, they still are having headaches associated with NDPH.”
The data indicated “a strong difference between our male and female patients,” said Ms. Pierce. Female patients reported significantly more instances of photophobia, phonophobia, nausea, and dizziness than did male patients. Overall, 78% of participants had a diagnosis of an additional comorbidity, such as head trauma (18%), anxiety (14%), depression (8%), or other (37%).
Observational studies of pediatric NDPH offer “a better way for our providers to diagnose these patients, and also to better understand them and help them figure out a treatment that may work,” said Ms. Pierce. In future research, she and her colleagues intend to examine blood work and potential genetic associations in pediatric patients with NDPH.
The study was not supported by funding, and the investigators had no disclosures.
SOURCE: Pierce E et al. CNS 2019, Abstract 100.
CHARLOTTE, N.C. – according to research presented at the 48th national meeting of the Child Neurology Society. Most children with NDPH fulfill criteria for its migraine subtype, and one-third of pediatric patients with NDPH have comorbid medication overuse headache (MOH).
NDPH is defined as a daily, unremitting headache that lasts for at least 3 months. “Not many studies on NDPH focus on pediatrics,” said Emily Pierce, from Children’s National Medical Center in Washington. NDPH “is considered to be one of the most intractable headaches in children. Children are able to tell that they’ve had this different type of headache because there’s some kind of onset that is very memorable.”
Ms. Pierce and colleagues conducted an observational study to describe the characteristics of NDPH in pediatric patients who presented to a headache program at a tertiary referral center. The researchers included pediatric patients who visited the headache clinic at Children’s National Medical Center between 2016 and 2018 in their analysis. All patients were enrolled in patient registry that had been approved by an independent review board. Ms. Pierce and colleagues queried the registry for NDPH and reviewed these records to examine participants’ clinical presentations.
The investigators identified 3,260 patient encounters during the study period. Of these encounters, 454 patients (13.9%) were identified as having NDPH. Patients with NDPH were predominantly female (78%) and white (72%). The median age of the sample was 14.8 years.
The frontal head region was the most common location of headache pain, which often had a throbbing quality and was associated with photophobia, phonophobia, nausea, and decreased activity. The median pain intensity was 6 of 10. Approximately 72% of patients had tried abortive medication, and 56% of patients had failed at least one abortive medication. Excedrin, ibuprofen, and acetaminophen were among the common failed abortive medications.
Furthermore, 36% of patients were diagnosed with MOH. The most commonly overused medication was ibuprofen. MOH “is also considered to be intractable for patients with NDPH,” said Ms. Pierce. “Typically, if the patient stops overusing that medication, they’ll find relief from their headaches. However, with our NDPH patients, when they stop overusing that medication, they still are having headaches associated with NDPH.”
The data indicated “a strong difference between our male and female patients,” said Ms. Pierce. Female patients reported significantly more instances of photophobia, phonophobia, nausea, and dizziness than did male patients. Overall, 78% of participants had a diagnosis of an additional comorbidity, such as head trauma (18%), anxiety (14%), depression (8%), or other (37%).
Observational studies of pediatric NDPH offer “a better way for our providers to diagnose these patients, and also to better understand them and help them figure out a treatment that may work,” said Ms. Pierce. In future research, she and her colleagues intend to examine blood work and potential genetic associations in pediatric patients with NDPH.
The study was not supported by funding, and the investigators had no disclosures.
SOURCE: Pierce E et al. CNS 2019, Abstract 100.
CHARLOTTE, N.C. – according to research presented at the 48th national meeting of the Child Neurology Society. Most children with NDPH fulfill criteria for its migraine subtype, and one-third of pediatric patients with NDPH have comorbid medication overuse headache (MOH).
NDPH is defined as a daily, unremitting headache that lasts for at least 3 months. “Not many studies on NDPH focus on pediatrics,” said Emily Pierce, from Children’s National Medical Center in Washington. NDPH “is considered to be one of the most intractable headaches in children. Children are able to tell that they’ve had this different type of headache because there’s some kind of onset that is very memorable.”
Ms. Pierce and colleagues conducted an observational study to describe the characteristics of NDPH in pediatric patients who presented to a headache program at a tertiary referral center. The researchers included pediatric patients who visited the headache clinic at Children’s National Medical Center between 2016 and 2018 in their analysis. All patients were enrolled in patient registry that had been approved by an independent review board. Ms. Pierce and colleagues queried the registry for NDPH and reviewed these records to examine participants’ clinical presentations.
The investigators identified 3,260 patient encounters during the study period. Of these encounters, 454 patients (13.9%) were identified as having NDPH. Patients with NDPH were predominantly female (78%) and white (72%). The median age of the sample was 14.8 years.
The frontal head region was the most common location of headache pain, which often had a throbbing quality and was associated with photophobia, phonophobia, nausea, and decreased activity. The median pain intensity was 6 of 10. Approximately 72% of patients had tried abortive medication, and 56% of patients had failed at least one abortive medication. Excedrin, ibuprofen, and acetaminophen were among the common failed abortive medications.
Furthermore, 36% of patients were diagnosed with MOH. The most commonly overused medication was ibuprofen. MOH “is also considered to be intractable for patients with NDPH,” said Ms. Pierce. “Typically, if the patient stops overusing that medication, they’ll find relief from their headaches. However, with our NDPH patients, when they stop overusing that medication, they still are having headaches associated with NDPH.”
The data indicated “a strong difference between our male and female patients,” said Ms. Pierce. Female patients reported significantly more instances of photophobia, phonophobia, nausea, and dizziness than did male patients. Overall, 78% of participants had a diagnosis of an additional comorbidity, such as head trauma (18%), anxiety (14%), depression (8%), or other (37%).
Observational studies of pediatric NDPH offer “a better way for our providers to diagnose these patients, and also to better understand them and help them figure out a treatment that may work,” said Ms. Pierce. In future research, she and her colleagues intend to examine blood work and potential genetic associations in pediatric patients with NDPH.
The study was not supported by funding, and the investigators had no disclosures.
SOURCE: Pierce E et al. CNS 2019, Abstract 100.
REPORTING FROM CNS 2019
Many children who present to headache clinics have joint hypermobility
CHARLOTTE, N.C. – according to data presented at the 48th national meeting of the Child Neurology Society. Furthermore, patients with joint hypermobility have a high rate of headache disability, while patients without joint hypermobility have less headache disability, according to Dhwani Sahjwani, MD, a resident at Inova Fairfax Hospital in Falls Church, Va., and colleagues.
While conducting research in the headache clinic at Children’s National Hospital in Washington, D.C., Dr. Sahjwani saw several children with joint hypermobility and a diagnosis of a disorder such as Ehlers-Danlos syndrome. She and her colleagues began analyzing patients to evaluate the potential association between joint hypermobility and headache disability in children. The investigators included pediatric patients examined in the headache clinic at Children’s National Medical Center between October 2018 and January 2019 in their study. All headache clinic patients were enrolled in a patient registry that had been approved by an independent review board.
Dr. Sahjwani and colleagues measured patients’ headache disability with the Headache Impact Test–6 (HIT-6) questionnaire. Scores of 60 or greater on this questionnaire indicate severe headache disability. The researchers assessed joint hypermobility using the Beighton scoring system. In this system, scores greater than 4 indicate joint hypermobility.
Dr. Sahjwani’s group scored 76 patients using the Beighton system and HIT-6 questionnaire. Participants’ median age was 13.7 years. Approximately 26% of patients had Beighton scores that indicated joint hypermobility. About 65% of the patients with joint hypermobility had a diagnosis of migraine without aura. In addition, 80% of patients with joint hypermobility had severe headache disability, according to the HIT-6 disability criteria. The average pain intensity in patients with hypermobile joints was 6.1 out of 10. Among participants without significant joint hypermobility, 90% had mild headache disability.
Patients with joint hypermobility and increased tissue elasticity “tend to have a lower threshold for pain, in general, in all parts of their bodies,” said Dr. Sahjwani. Greater headache severity might be expected in this population, “because they have more pain if they have hypermobile joints or tissue.”
Headache treatments for this population are based solely on the type of headache that each patient has. Patients with joint hypermobility and migraine, for example, are candidates for rescue medication and long-term prophylactic medications. “I don’t think the joint hypermobility is going to change how you manage their headaches,” said Dr. Sahjwani.
The study results suggest that, when children present with severely debilitating headaches, a neurologist should consider examining them for joint hypermobility “to see if they have another diagnosis, such as Ehlers-Danlos syndrome ... that has to be managed in addition to their headaches,” Dr. Sahjwani concluded.
The study was not supported by funding. The authors did not report any disclosures.
SOURCE: Sahjwani D et al. CNS 2019, Abstract 101.
CHARLOTTE, N.C. – according to data presented at the 48th national meeting of the Child Neurology Society. Furthermore, patients with joint hypermobility have a high rate of headache disability, while patients without joint hypermobility have less headache disability, according to Dhwani Sahjwani, MD, a resident at Inova Fairfax Hospital in Falls Church, Va., and colleagues.
While conducting research in the headache clinic at Children’s National Hospital in Washington, D.C., Dr. Sahjwani saw several children with joint hypermobility and a diagnosis of a disorder such as Ehlers-Danlos syndrome. She and her colleagues began analyzing patients to evaluate the potential association between joint hypermobility and headache disability in children. The investigators included pediatric patients examined in the headache clinic at Children’s National Medical Center between October 2018 and January 2019 in their study. All headache clinic patients were enrolled in a patient registry that had been approved by an independent review board.
Dr. Sahjwani and colleagues measured patients’ headache disability with the Headache Impact Test–6 (HIT-6) questionnaire. Scores of 60 or greater on this questionnaire indicate severe headache disability. The researchers assessed joint hypermobility using the Beighton scoring system. In this system, scores greater than 4 indicate joint hypermobility.
Dr. Sahjwani’s group scored 76 patients using the Beighton system and HIT-6 questionnaire. Participants’ median age was 13.7 years. Approximately 26% of patients had Beighton scores that indicated joint hypermobility. About 65% of the patients with joint hypermobility had a diagnosis of migraine without aura. In addition, 80% of patients with joint hypermobility had severe headache disability, according to the HIT-6 disability criteria. The average pain intensity in patients with hypermobile joints was 6.1 out of 10. Among participants without significant joint hypermobility, 90% had mild headache disability.
Patients with joint hypermobility and increased tissue elasticity “tend to have a lower threshold for pain, in general, in all parts of their bodies,” said Dr. Sahjwani. Greater headache severity might be expected in this population, “because they have more pain if they have hypermobile joints or tissue.”
Headache treatments for this population are based solely on the type of headache that each patient has. Patients with joint hypermobility and migraine, for example, are candidates for rescue medication and long-term prophylactic medications. “I don’t think the joint hypermobility is going to change how you manage their headaches,” said Dr. Sahjwani.
The study results suggest that, when children present with severely debilitating headaches, a neurologist should consider examining them for joint hypermobility “to see if they have another diagnosis, such as Ehlers-Danlos syndrome ... that has to be managed in addition to their headaches,” Dr. Sahjwani concluded.
The study was not supported by funding. The authors did not report any disclosures.
SOURCE: Sahjwani D et al. CNS 2019, Abstract 101.
CHARLOTTE, N.C. – according to data presented at the 48th national meeting of the Child Neurology Society. Furthermore, patients with joint hypermobility have a high rate of headache disability, while patients without joint hypermobility have less headache disability, according to Dhwani Sahjwani, MD, a resident at Inova Fairfax Hospital in Falls Church, Va., and colleagues.
While conducting research in the headache clinic at Children’s National Hospital in Washington, D.C., Dr. Sahjwani saw several children with joint hypermobility and a diagnosis of a disorder such as Ehlers-Danlos syndrome. She and her colleagues began analyzing patients to evaluate the potential association between joint hypermobility and headache disability in children. The investigators included pediatric patients examined in the headache clinic at Children’s National Medical Center between October 2018 and January 2019 in their study. All headache clinic patients were enrolled in a patient registry that had been approved by an independent review board.
Dr. Sahjwani and colleagues measured patients’ headache disability with the Headache Impact Test–6 (HIT-6) questionnaire. Scores of 60 or greater on this questionnaire indicate severe headache disability. The researchers assessed joint hypermobility using the Beighton scoring system. In this system, scores greater than 4 indicate joint hypermobility.
Dr. Sahjwani’s group scored 76 patients using the Beighton system and HIT-6 questionnaire. Participants’ median age was 13.7 years. Approximately 26% of patients had Beighton scores that indicated joint hypermobility. About 65% of the patients with joint hypermobility had a diagnosis of migraine without aura. In addition, 80% of patients with joint hypermobility had severe headache disability, according to the HIT-6 disability criteria. The average pain intensity in patients with hypermobile joints was 6.1 out of 10. Among participants without significant joint hypermobility, 90% had mild headache disability.
Patients with joint hypermobility and increased tissue elasticity “tend to have a lower threshold for pain, in general, in all parts of their bodies,” said Dr. Sahjwani. Greater headache severity might be expected in this population, “because they have more pain if they have hypermobile joints or tissue.”
Headache treatments for this population are based solely on the type of headache that each patient has. Patients with joint hypermobility and migraine, for example, are candidates for rescue medication and long-term prophylactic medications. “I don’t think the joint hypermobility is going to change how you manage their headaches,” said Dr. Sahjwani.
The study results suggest that, when children present with severely debilitating headaches, a neurologist should consider examining them for joint hypermobility “to see if they have another diagnosis, such as Ehlers-Danlos syndrome ... that has to be managed in addition to their headaches,” Dr. Sahjwani concluded.
The study was not supported by funding. The authors did not report any disclosures.
SOURCE: Sahjwani D et al. CNS 2019, Abstract 101.
REPORTING FROM CNS 2019
Fluoxetine tied to lower obsessive-compulsive scores among children with ASDs
Impact of the SSRI on those behaviors falls short in multiple secondary analyses
Fluoxetine appeared to lower scores for obsessive-compulsive behaviors among a group of children with autism spectrum disorders (ASDs), but the positive finding fell apart during multiple secondary analyses, Dinah S. Reddihough, MD, and colleagues have reported.
At 16 weeks, children and adolescents randomized to receive the SSRI had about a 2-point improvement on the Children’s Yale-Brown Obsessive Compulsive Scale, modified for pervasive developmental disorder (CYBOCS-PDD), compared with those taking placebo. But the finding lost significance in a multivariate analysis that accounted for a between-group difference in baseline scores – an uncontrollable variable that occurred during randomization, wrote Dr. Reddihough, of the Royal Children’s Hospital in Victoria, Australia, and coauthors.
“Moreover, repeating the analyses with multiple imputation to handle the missing data, arguably a preferable analysis, also failed to show evidence of benefit of fluoxetine compared with placebo irrespective of adjustment for the baseline imbalance,” the team noted. The study was published in JAMA.
Despite the null findings of the additional adjusted analyses, the authors held out hope for fluoxetine.
“Although cautious interpretation of the results from the primary analysis is warranted, all analyses of the primary outcome yielded 95% confidence intervals that extended well above the minimum clinically important difference of 2 points, indicating that fluoxetine may reduce the frequency and severity of obsessive-compulsive behaviors in children and adolescents with ASDs. Given the large amount of missing data, the study may have been underpowered to detect the minimum clinically important difference of 2 points.”
The study comprised 146 children (mean age, 11 years) recruited through three large practices in Australia. Children were randomized to fluoxetine or placebo for 16 weeks. Fluoxetine was weight-dosed and then titrated every week for the first month to a maximum of 20 mg/day.
The primary outcome was the difference between groups in the total score on the CYBOCS-PDD at 16 weeks. Secondary endpoints included changes on the Repetitive Behavior Scale–Revised, the Spence Children’s Anxiety Scale Aberrant Behavior Checklist–Community Version, the Clinical Global Impression Scale–Global Improvement and Efficacy Index, and a Disruptiveness Assessment.
Of the cohort, 85% were male, and 30% had an intellectual disability. The placebo group had higher scores on the Repetitive Behavior Scale–Revised and the Aberrant Behavior Checklist lethargy scale than did the fluoxetine groups.
There was a very high rate of nonadherence to study protocol, with 41% of those in the active group and 30% in the placebo group not completing the treatment regimen. The most often cited reasons for treatment discontinuation included parent decision to drop out (20 fluoxetine, 12 placebo), adverse events (5 fluoxetine, 4 placebo), and clinician decision (2 fluoxetine, 2 placebo).
The primary analysis found that scores on the CYBOCS-PDD were significantly lower in the fluoxetine group at 16 weeks; the fluoxetine group had decreased its score from 12.80 to 9.02, while the placebo group went from 13.13 to 10.89. This mean 2-point difference was statistically significant and, the authors wrote, met the minimum threshold for a clinically significant difference.
But the mean between-group difference decreased to a nonsignificant 1.17 points in the sensitivity analysis that controlled for sex, verbal ability, baseline CYBOCS-PDD, and imbalances found at baseline in some of the measures.
“Moreover, repeating the analyses with multiple imputation to handle the missing data, arguably a preferable analysis, also failed to show evidence of benefit of fluoxetine compared with placebo irrespective of adjustment for the baseline imbalance,” the team said.
There were no significant differences on any of the secondary measures.
Adverse events were similar in the active and placebo groups (45% and 42%, respectively). These included mood disturbances particularly irritability (9 fluoxetine, 12 placebo), gastrointestinal problems such as nausea and diarrhea (10 fluoxetine, 7 placebo), and sleep disorders (13 fluoxetine, 16 placebo). Two patients in the placebo group and none in the active group experienced suicidality.
Dr. Reddihough and coauthors cited the study’s high dropout rate as one of its limitations.
The study was supported by a federal grant from the Australian government. Dr. Reddihough had no financial disclosures.
SOURCE: Reddihough DS et al. JAMA. 2019;322(16):1561-9.
One could certainly take issue with the suggestion that this was presented as a positive trial on two levels: One, the prespecified primary outcome was not met, and two, the clinical significance (as distinct from statistical significance) of a 2-point change on that scale is problematic given the wide range of baseline scores allowed into the study.
The other thing that gets mixed up in this study is: Exactly what are obsessive-compulsive symptoms as distinct from repetitive behaviors? That question is a real challenge in this field when it comes to clinical trials for this target in autism, which tend to lump together heterogeneous repetitive behaviors.
The fact that there was absolutely no signal, or at least not a very strong one, is very challenging, considering how frequently this class of drugs is prescribed in autism.
This is not the first SSRI study for autism that’s come up empty. In this case, though, a negative study is still important because it confirms other negative studies. Another recently published study – the SOFIA fluoxetine study (J Autism Dev Disord. 2019 Jul 2. doi: 10:1007/s10803-019-04120-y) – also came up negative. SOFIA randomized 158 children to 14 weeks of fluoxetine or placebo. There were no significant differences on the primary endpoint, the Children’s Yale-Brown Obsessive-Compulsive Scale, and the placebo response rate was 41%.
However, it was clearly a heroic effort by Dr. Reddihough et al. to get this current study done: It took 7 years to get it over the finish line. This is probably because fluoxetine is so easily available. Why would a parent take a 50% chance of their child not getting a drug that might have some benefit – and that they could get without much trouble? And if it takes 7 years to complete a clinical trial, and we’re sitting around waiting for a definitive one, we are literally looking at potentially decades before we have some real answers that would inform your clinical practice in terms of this commonly prescribed drug.
As far as nailing the coffin shut on fluoxetine, I don’t think that will ever happen because some kids clearly improve. The placebo response in this population is very high. In our citalopram study (JAMA Pediatr. 2013 Nov;167[11]:1045-52), it was close to 33%. The improvement is dramatic and real, no less than any other response. If you see that response as a clinician and parent, it is very difficult to walk away from. Moreover, the population in clinical practice may be different from the population that shows up in a clinical trial specifically focused on restricted, repetitive behaviors.
One reason we may see a response in some is because SSRIs can help with anxiety, which is a common, arguably core symptom of autism. It appears to be part of the reason kids have catastrophic meltdowns when there are any changes in things they have come to expect, like a different route to school or a delay in their favorite TV show coming on. And if anxiety drives that, and an SSRI helps with anxiety, the child might be able to cope with something that would otherwise feel like the end of the world. Maybe that starts a positive feedback loop instead of a negative one, and maybe it propels more changes as the child and family experience success.
So, what are clinicians to do? The answer is still the same – they should use their best judgment about each child’s symptoms and about the risks and benefits that might occur with that individual. The fact that these trials are coming up negative for this indication in autism doesn’t mean that SSRIs might not be helpful for anxiety or depression, just as they are in the general population. I think we are back to basics. Clinicians need to use their best medical judgment according to each child’s unique needs.
These comments were adapted from an interview with Bryan H. King, MD, MBA. Dr. King is a professor of psychiatry at the University of California, San Francisco. He reported receiving personal fees from Genentech. Dr. King also commented on the study in an accompanying editorial (JAMA. 2019;322[16]:1557-8).
Impact of the SSRI on those behaviors falls short in multiple secondary analyses
Impact of the SSRI on those behaviors falls short in multiple secondary analyses
One could certainly take issue with the suggestion that this was presented as a positive trial on two levels: One, the prespecified primary outcome was not met, and two, the clinical significance (as distinct from statistical significance) of a 2-point change on that scale is problematic given the wide range of baseline scores allowed into the study.
The other thing that gets mixed up in this study is: Exactly what are obsessive-compulsive symptoms as distinct from repetitive behaviors? That question is a real challenge in this field when it comes to clinical trials for this target in autism, which tend to lump together heterogeneous repetitive behaviors.
The fact that there was absolutely no signal, or at least not a very strong one, is very challenging, considering how frequently this class of drugs is prescribed in autism.
This is not the first SSRI study for autism that’s come up empty. In this case, though, a negative study is still important because it confirms other negative studies. Another recently published study – the SOFIA fluoxetine study (J Autism Dev Disord. 2019 Jul 2. doi: 10:1007/s10803-019-04120-y) – also came up negative. SOFIA randomized 158 children to 14 weeks of fluoxetine or placebo. There were no significant differences on the primary endpoint, the Children’s Yale-Brown Obsessive-Compulsive Scale, and the placebo response rate was 41%.
However, it was clearly a heroic effort by Dr. Reddihough et al. to get this current study done: It took 7 years to get it over the finish line. This is probably because fluoxetine is so easily available. Why would a parent take a 50% chance of their child not getting a drug that might have some benefit – and that they could get without much trouble? And if it takes 7 years to complete a clinical trial, and we’re sitting around waiting for a definitive one, we are literally looking at potentially decades before we have some real answers that would inform your clinical practice in terms of this commonly prescribed drug.
As far as nailing the coffin shut on fluoxetine, I don’t think that will ever happen because some kids clearly improve. The placebo response in this population is very high. In our citalopram study (JAMA Pediatr. 2013 Nov;167[11]:1045-52), it was close to 33%. The improvement is dramatic and real, no less than any other response. If you see that response as a clinician and parent, it is very difficult to walk away from. Moreover, the population in clinical practice may be different from the population that shows up in a clinical trial specifically focused on restricted, repetitive behaviors.
One reason we may see a response in some is because SSRIs can help with anxiety, which is a common, arguably core symptom of autism. It appears to be part of the reason kids have catastrophic meltdowns when there are any changes in things they have come to expect, like a different route to school or a delay in their favorite TV show coming on. And if anxiety drives that, and an SSRI helps with anxiety, the child might be able to cope with something that would otherwise feel like the end of the world. Maybe that starts a positive feedback loop instead of a negative one, and maybe it propels more changes as the child and family experience success.
So, what are clinicians to do? The answer is still the same – they should use their best judgment about each child’s symptoms and about the risks and benefits that might occur with that individual. The fact that these trials are coming up negative for this indication in autism doesn’t mean that SSRIs might not be helpful for anxiety or depression, just as they are in the general population. I think we are back to basics. Clinicians need to use their best medical judgment according to each child’s unique needs.
These comments were adapted from an interview with Bryan H. King, MD, MBA. Dr. King is a professor of psychiatry at the University of California, San Francisco. He reported receiving personal fees from Genentech. Dr. King also commented on the study in an accompanying editorial (JAMA. 2019;322[16]:1557-8).
One could certainly take issue with the suggestion that this was presented as a positive trial on two levels: One, the prespecified primary outcome was not met, and two, the clinical significance (as distinct from statistical significance) of a 2-point change on that scale is problematic given the wide range of baseline scores allowed into the study.
The other thing that gets mixed up in this study is: Exactly what are obsessive-compulsive symptoms as distinct from repetitive behaviors? That question is a real challenge in this field when it comes to clinical trials for this target in autism, which tend to lump together heterogeneous repetitive behaviors.
The fact that there was absolutely no signal, or at least not a very strong one, is very challenging, considering how frequently this class of drugs is prescribed in autism.
This is not the first SSRI study for autism that’s come up empty. In this case, though, a negative study is still important because it confirms other negative studies. Another recently published study – the SOFIA fluoxetine study (J Autism Dev Disord. 2019 Jul 2. doi: 10:1007/s10803-019-04120-y) – also came up negative. SOFIA randomized 158 children to 14 weeks of fluoxetine or placebo. There were no significant differences on the primary endpoint, the Children’s Yale-Brown Obsessive-Compulsive Scale, and the placebo response rate was 41%.
However, it was clearly a heroic effort by Dr. Reddihough et al. to get this current study done: It took 7 years to get it over the finish line. This is probably because fluoxetine is so easily available. Why would a parent take a 50% chance of their child not getting a drug that might have some benefit – and that they could get without much trouble? And if it takes 7 years to complete a clinical trial, and we’re sitting around waiting for a definitive one, we are literally looking at potentially decades before we have some real answers that would inform your clinical practice in terms of this commonly prescribed drug.
As far as nailing the coffin shut on fluoxetine, I don’t think that will ever happen because some kids clearly improve. The placebo response in this population is very high. In our citalopram study (JAMA Pediatr. 2013 Nov;167[11]:1045-52), it was close to 33%. The improvement is dramatic and real, no less than any other response. If you see that response as a clinician and parent, it is very difficult to walk away from. Moreover, the population in clinical practice may be different from the population that shows up in a clinical trial specifically focused on restricted, repetitive behaviors.
One reason we may see a response in some is because SSRIs can help with anxiety, which is a common, arguably core symptom of autism. It appears to be part of the reason kids have catastrophic meltdowns when there are any changes in things they have come to expect, like a different route to school or a delay in their favorite TV show coming on. And if anxiety drives that, and an SSRI helps with anxiety, the child might be able to cope with something that would otherwise feel like the end of the world. Maybe that starts a positive feedback loop instead of a negative one, and maybe it propels more changes as the child and family experience success.
So, what are clinicians to do? The answer is still the same – they should use their best judgment about each child’s symptoms and about the risks and benefits that might occur with that individual. The fact that these trials are coming up negative for this indication in autism doesn’t mean that SSRIs might not be helpful for anxiety or depression, just as they are in the general population. I think we are back to basics. Clinicians need to use their best medical judgment according to each child’s unique needs.
These comments were adapted from an interview with Bryan H. King, MD, MBA. Dr. King is a professor of psychiatry at the University of California, San Francisco. He reported receiving personal fees from Genentech. Dr. King also commented on the study in an accompanying editorial (JAMA. 2019;322[16]:1557-8).
Fluoxetine appeared to lower scores for obsessive-compulsive behaviors among a group of children with autism spectrum disorders (ASDs), but the positive finding fell apart during multiple secondary analyses, Dinah S. Reddihough, MD, and colleagues have reported.
At 16 weeks, children and adolescents randomized to receive the SSRI had about a 2-point improvement on the Children’s Yale-Brown Obsessive Compulsive Scale, modified for pervasive developmental disorder (CYBOCS-PDD), compared with those taking placebo. But the finding lost significance in a multivariate analysis that accounted for a between-group difference in baseline scores – an uncontrollable variable that occurred during randomization, wrote Dr. Reddihough, of the Royal Children’s Hospital in Victoria, Australia, and coauthors.
“Moreover, repeating the analyses with multiple imputation to handle the missing data, arguably a preferable analysis, also failed to show evidence of benefit of fluoxetine compared with placebo irrespective of adjustment for the baseline imbalance,” the team noted. The study was published in JAMA.
Despite the null findings of the additional adjusted analyses, the authors held out hope for fluoxetine.
“Although cautious interpretation of the results from the primary analysis is warranted, all analyses of the primary outcome yielded 95% confidence intervals that extended well above the minimum clinically important difference of 2 points, indicating that fluoxetine may reduce the frequency and severity of obsessive-compulsive behaviors in children and adolescents with ASDs. Given the large amount of missing data, the study may have been underpowered to detect the minimum clinically important difference of 2 points.”
The study comprised 146 children (mean age, 11 years) recruited through three large practices in Australia. Children were randomized to fluoxetine or placebo for 16 weeks. Fluoxetine was weight-dosed and then titrated every week for the first month to a maximum of 20 mg/day.
The primary outcome was the difference between groups in the total score on the CYBOCS-PDD at 16 weeks. Secondary endpoints included changes on the Repetitive Behavior Scale–Revised, the Spence Children’s Anxiety Scale Aberrant Behavior Checklist–Community Version, the Clinical Global Impression Scale–Global Improvement and Efficacy Index, and a Disruptiveness Assessment.
Of the cohort, 85% were male, and 30% had an intellectual disability. The placebo group had higher scores on the Repetitive Behavior Scale–Revised and the Aberrant Behavior Checklist lethargy scale than did the fluoxetine groups.
There was a very high rate of nonadherence to study protocol, with 41% of those in the active group and 30% in the placebo group not completing the treatment regimen. The most often cited reasons for treatment discontinuation included parent decision to drop out (20 fluoxetine, 12 placebo), adverse events (5 fluoxetine, 4 placebo), and clinician decision (2 fluoxetine, 2 placebo).
The primary analysis found that scores on the CYBOCS-PDD were significantly lower in the fluoxetine group at 16 weeks; the fluoxetine group had decreased its score from 12.80 to 9.02, while the placebo group went from 13.13 to 10.89. This mean 2-point difference was statistically significant and, the authors wrote, met the minimum threshold for a clinically significant difference.
But the mean between-group difference decreased to a nonsignificant 1.17 points in the sensitivity analysis that controlled for sex, verbal ability, baseline CYBOCS-PDD, and imbalances found at baseline in some of the measures.
“Moreover, repeating the analyses with multiple imputation to handle the missing data, arguably a preferable analysis, also failed to show evidence of benefit of fluoxetine compared with placebo irrespective of adjustment for the baseline imbalance,” the team said.
There were no significant differences on any of the secondary measures.
Adverse events were similar in the active and placebo groups (45% and 42%, respectively). These included mood disturbances particularly irritability (9 fluoxetine, 12 placebo), gastrointestinal problems such as nausea and diarrhea (10 fluoxetine, 7 placebo), and sleep disorders (13 fluoxetine, 16 placebo). Two patients in the placebo group and none in the active group experienced suicidality.
Dr. Reddihough and coauthors cited the study’s high dropout rate as one of its limitations.
The study was supported by a federal grant from the Australian government. Dr. Reddihough had no financial disclosures.
SOURCE: Reddihough DS et al. JAMA. 2019;322(16):1561-9.
Fluoxetine appeared to lower scores for obsessive-compulsive behaviors among a group of children with autism spectrum disorders (ASDs), but the positive finding fell apart during multiple secondary analyses, Dinah S. Reddihough, MD, and colleagues have reported.
At 16 weeks, children and adolescents randomized to receive the SSRI had about a 2-point improvement on the Children’s Yale-Brown Obsessive Compulsive Scale, modified for pervasive developmental disorder (CYBOCS-PDD), compared with those taking placebo. But the finding lost significance in a multivariate analysis that accounted for a between-group difference in baseline scores – an uncontrollable variable that occurred during randomization, wrote Dr. Reddihough, of the Royal Children’s Hospital in Victoria, Australia, and coauthors.
“Moreover, repeating the analyses with multiple imputation to handle the missing data, arguably a preferable analysis, also failed to show evidence of benefit of fluoxetine compared with placebo irrespective of adjustment for the baseline imbalance,” the team noted. The study was published in JAMA.
Despite the null findings of the additional adjusted analyses, the authors held out hope for fluoxetine.
“Although cautious interpretation of the results from the primary analysis is warranted, all analyses of the primary outcome yielded 95% confidence intervals that extended well above the minimum clinically important difference of 2 points, indicating that fluoxetine may reduce the frequency and severity of obsessive-compulsive behaviors in children and adolescents with ASDs. Given the large amount of missing data, the study may have been underpowered to detect the minimum clinically important difference of 2 points.”
The study comprised 146 children (mean age, 11 years) recruited through three large practices in Australia. Children were randomized to fluoxetine or placebo for 16 weeks. Fluoxetine was weight-dosed and then titrated every week for the first month to a maximum of 20 mg/day.
The primary outcome was the difference between groups in the total score on the CYBOCS-PDD at 16 weeks. Secondary endpoints included changes on the Repetitive Behavior Scale–Revised, the Spence Children’s Anxiety Scale Aberrant Behavior Checklist–Community Version, the Clinical Global Impression Scale–Global Improvement and Efficacy Index, and a Disruptiveness Assessment.
Of the cohort, 85% were male, and 30% had an intellectual disability. The placebo group had higher scores on the Repetitive Behavior Scale–Revised and the Aberrant Behavior Checklist lethargy scale than did the fluoxetine groups.
There was a very high rate of nonadherence to study protocol, with 41% of those in the active group and 30% in the placebo group not completing the treatment regimen. The most often cited reasons for treatment discontinuation included parent decision to drop out (20 fluoxetine, 12 placebo), adverse events (5 fluoxetine, 4 placebo), and clinician decision (2 fluoxetine, 2 placebo).
The primary analysis found that scores on the CYBOCS-PDD were significantly lower in the fluoxetine group at 16 weeks; the fluoxetine group had decreased its score from 12.80 to 9.02, while the placebo group went from 13.13 to 10.89. This mean 2-point difference was statistically significant and, the authors wrote, met the minimum threshold for a clinically significant difference.
But the mean between-group difference decreased to a nonsignificant 1.17 points in the sensitivity analysis that controlled for sex, verbal ability, baseline CYBOCS-PDD, and imbalances found at baseline in some of the measures.
“Moreover, repeating the analyses with multiple imputation to handle the missing data, arguably a preferable analysis, also failed to show evidence of benefit of fluoxetine compared with placebo irrespective of adjustment for the baseline imbalance,” the team said.
There were no significant differences on any of the secondary measures.
Adverse events were similar in the active and placebo groups (45% and 42%, respectively). These included mood disturbances particularly irritability (9 fluoxetine, 12 placebo), gastrointestinal problems such as nausea and diarrhea (10 fluoxetine, 7 placebo), and sleep disorders (13 fluoxetine, 16 placebo). Two patients in the placebo group and none in the active group experienced suicidality.
Dr. Reddihough and coauthors cited the study’s high dropout rate as one of its limitations.
The study was supported by a federal grant from the Australian government. Dr. Reddihough had no financial disclosures.
SOURCE: Reddihough DS et al. JAMA. 2019;322(16):1561-9.
FROM JAMA
CMS has plan if ACA overturned in court; Verma silent on details
The Trump administration apparently plans to ensure Americans have access to health insurance in the event that the Affordable Care Act is struck down – but officials refuse to share that plan.
“The president has made clear that we will have a plan in action to make sure that Americans have access to affordable coverage” if or when courts negate the ACA, Seema Verma, administrator of the Centers for Medicare & Medicaid Services said Oct. 23 at a House Ways and Means Health Subcommittee hearing. “We do not have that today. There are many Americans today, they are not getting a subsidy. They can’t afford insurance today.”
When asked specifically about the provision to guarantee coverage for those with preexisting conditions, Ms. Verma replied that the president “has made clear that we will do everything we can to ensure that Americans with preexisting conditions maintain the protection that they have today.”
When pressed for details, Ms. Verma dodged the question, first by attempting to tell an anecdote about “a 55-year-old couple making $66,000 a year ...” before getting cut off. When the question was reiterated by Health Subcommittee Chair Diana DeGette (D-Colo.), Ms. Verma replied, “I am not going get into any specifics of a plan.”
Committee Chair Frank Pallone (D-N.J.) said it was “deceptive” that Ms. Verma would not provide any details and openly questioned whether a plan actually existed.
The hearing followed a partisan pattern.
Republican subcommittee members asked questions that allowed Ms Verma to highlight some of the actions taken by the CMS under her watch, such as lowering premiums for exchange plans, increasing the number of available plans and decreasing the number of states that had only one plan option available in the exchange, and other items that are focused on lowering the cost of health care.
“We’re trying to focus on actions that lower the cost of care for Americans,” she said. “If we do that, more people will be able to afford health care.”
Under questioning by panel Democrats, Ms. Verma took a more adversarial tone and tended to deflect rather than answer questions.
When pressed about Medicaid work requirement and the disruption in health care coverage they are causing, Ms. Verma had no answer, instead trying to talking about “community engagement requirements” before being cut off.
Ms. Verma also refused to address the coverage requirements, or lack thereof, of short-term, limited duration plans, which have been expanded under the Trump administration.
When asked whether plans could deny claims based on preexisting conditions, could implement coverage caps, charge more based on age or gender, or ignore other consumer protections in the ACA, she consistently defaulted to a comment that it “depends” on the plan and what they offer, without coming out and simply acknowledging that these plans have it within their power to ignore any and all consumer protections held within the Affordable Care Act.
“None of the actions that we have taken do anything to undermine the protections for people with preexisting conditions,” she said.
“Your testimony is not actually truthful to us today,” Rep. Ann Kuster (D-N.H.) replied.
The Trump administration apparently plans to ensure Americans have access to health insurance in the event that the Affordable Care Act is struck down – but officials refuse to share that plan.
“The president has made clear that we will have a plan in action to make sure that Americans have access to affordable coverage” if or when courts negate the ACA, Seema Verma, administrator of the Centers for Medicare & Medicaid Services said Oct. 23 at a House Ways and Means Health Subcommittee hearing. “We do not have that today. There are many Americans today, they are not getting a subsidy. They can’t afford insurance today.”
When asked specifically about the provision to guarantee coverage for those with preexisting conditions, Ms. Verma replied that the president “has made clear that we will do everything we can to ensure that Americans with preexisting conditions maintain the protection that they have today.”
When pressed for details, Ms. Verma dodged the question, first by attempting to tell an anecdote about “a 55-year-old couple making $66,000 a year ...” before getting cut off. When the question was reiterated by Health Subcommittee Chair Diana DeGette (D-Colo.), Ms. Verma replied, “I am not going get into any specifics of a plan.”
Committee Chair Frank Pallone (D-N.J.) said it was “deceptive” that Ms. Verma would not provide any details and openly questioned whether a plan actually existed.
The hearing followed a partisan pattern.
Republican subcommittee members asked questions that allowed Ms Verma to highlight some of the actions taken by the CMS under her watch, such as lowering premiums for exchange plans, increasing the number of available plans and decreasing the number of states that had only one plan option available in the exchange, and other items that are focused on lowering the cost of health care.
“We’re trying to focus on actions that lower the cost of care for Americans,” she said. “If we do that, more people will be able to afford health care.”
Under questioning by panel Democrats, Ms. Verma took a more adversarial tone and tended to deflect rather than answer questions.
When pressed about Medicaid work requirement and the disruption in health care coverage they are causing, Ms. Verma had no answer, instead trying to talking about “community engagement requirements” before being cut off.
Ms. Verma also refused to address the coverage requirements, or lack thereof, of short-term, limited duration plans, which have been expanded under the Trump administration.
When asked whether plans could deny claims based on preexisting conditions, could implement coverage caps, charge more based on age or gender, or ignore other consumer protections in the ACA, she consistently defaulted to a comment that it “depends” on the plan and what they offer, without coming out and simply acknowledging that these plans have it within their power to ignore any and all consumer protections held within the Affordable Care Act.
“None of the actions that we have taken do anything to undermine the protections for people with preexisting conditions,” she said.
“Your testimony is not actually truthful to us today,” Rep. Ann Kuster (D-N.H.) replied.
The Trump administration apparently plans to ensure Americans have access to health insurance in the event that the Affordable Care Act is struck down – but officials refuse to share that plan.
“The president has made clear that we will have a plan in action to make sure that Americans have access to affordable coverage” if or when courts negate the ACA, Seema Verma, administrator of the Centers for Medicare & Medicaid Services said Oct. 23 at a House Ways and Means Health Subcommittee hearing. “We do not have that today. There are many Americans today, they are not getting a subsidy. They can’t afford insurance today.”
When asked specifically about the provision to guarantee coverage for those with preexisting conditions, Ms. Verma replied that the president “has made clear that we will do everything we can to ensure that Americans with preexisting conditions maintain the protection that they have today.”
When pressed for details, Ms. Verma dodged the question, first by attempting to tell an anecdote about “a 55-year-old couple making $66,000 a year ...” before getting cut off. When the question was reiterated by Health Subcommittee Chair Diana DeGette (D-Colo.), Ms. Verma replied, “I am not going get into any specifics of a plan.”
Committee Chair Frank Pallone (D-N.J.) said it was “deceptive” that Ms. Verma would not provide any details and openly questioned whether a plan actually existed.
The hearing followed a partisan pattern.
Republican subcommittee members asked questions that allowed Ms Verma to highlight some of the actions taken by the CMS under her watch, such as lowering premiums for exchange plans, increasing the number of available plans and decreasing the number of states that had only one plan option available in the exchange, and other items that are focused on lowering the cost of health care.
“We’re trying to focus on actions that lower the cost of care for Americans,” she said. “If we do that, more people will be able to afford health care.”
Under questioning by panel Democrats, Ms. Verma took a more adversarial tone and tended to deflect rather than answer questions.
When pressed about Medicaid work requirement and the disruption in health care coverage they are causing, Ms. Verma had no answer, instead trying to talking about “community engagement requirements” before being cut off.
Ms. Verma also refused to address the coverage requirements, or lack thereof, of short-term, limited duration plans, which have been expanded under the Trump administration.
When asked whether plans could deny claims based on preexisting conditions, could implement coverage caps, charge more based on age or gender, or ignore other consumer protections in the ACA, she consistently defaulted to a comment that it “depends” on the plan and what they offer, without coming out and simply acknowledging that these plans have it within their power to ignore any and all consumer protections held within the Affordable Care Act.
“None of the actions that we have taken do anything to undermine the protections for people with preexisting conditions,” she said.
“Your testimony is not actually truthful to us today,” Rep. Ann Kuster (D-N.H.) replied.
REPORTING FROM a HOUSE ENERGY AND COMMERCE HEALTH SUBCOMMITTEE HEARING
Basal Cell Carcinoma Arising in Nevus Sebaceous During Pregnancy
To the Editor:
Nevus sebaceous of Jadassohn (or nevus sebaceous [NS]) is a congenital hamartomatous disorder initially described by Jadassohn1 in 1895. Nevus sebaceous occurs in 0.3% of newborns2 and is most commonly identified on the face and scalp.3,4 Mehregan and Pinkus5 characterized NS as an organoid tumor containing multiple skin components with 3 life stages. The first stage—occurring during infancy—consists of immature hair follicles and sebaceous glands. The second stage—beginning at puberty—shows development of sebaceous glands, epidermal hyperplasia, and maturation of apocrine glands. The final stage involves formation of secondary benign and malignant neoplasms.
Historically, basal cell carcinoma (BCC) was thought to be the most common neoplasm arising in NS.5-8 In 1993, Ackerman et al9 introduced a new definition of trichoblastoma (TB), expanding the definition to encompass previously excluded benign follicular neoplasms. Large studies conducted after this new definition was proposed suggested that syringocystadenoma papilliferum and TB develop more frequently than does BCC.3,4,10-15 Furthermore, Cribier et al4 and Merrot et al15 reviewed prior cases of NS using the new definition and asserted that the majority of previously diagnosed cases of BCC were considered to be TB under the new criteria. With the advent of modern diagnostic testing, the rate of secondary benign neoplasm growth is now thought to be between 7% and 19%, with syringocystadenoma papilliferum arising in 2% to 13% of cases and TB in 1.5% to 7%.3,4,10-14 Malignant neoplasms are observed much less frequently, with BCC arising in 0% to 1% of NS cases.
Nevus sebaceous lesions typically enlarge during puberty, while malignant neoplasms occur almost exclusively in adulthood,4,10-12 suggesting that hormones contribute to NS stage progression. We present the case of a woman who developed BCC in a previously asymptomatic NS during pregnancy.
A 32-year-old woman who was otherwise healthy presented to our dermatology clinic with a pink-yellow verrucous plaque on the right temporal hairline extending to the preauricular area of the face. The patient had no personal or family history of skin cancer and no history of tanning bed use. She reported that the lesion had been present since birth. A diagnosis of NS was made.
Two years later, she presented with a new bleeding growth atop the previously diagnosed NS that had been present for approximately 4 months (Figure). At this visit she was pregnant (30 weeks’ gestation). Physical examination revealed a 4-mm, brown, pearly papule at the inferior margin of the previously noted pink verrucous plaque on the right temporal hairline. A biopsy was performed and histopathology displayed aggregates of basaloid cells with a high nuclear to cytoplasmic ratio, peripheral palisading, and abundant melanin, consistent with pigmented BCC. The patient was referred for Mohs micrographic surgery; the lesion was removed with clear margins. The patient had no recurrence of BCC at 36-month follow-up.
Few studies have looked at the signal transduction pathways leading to malignant neoplasm formation in NS. Nevus sebaceous lesions are theorized to result from postzygotic genetic mutations in HRAS and KRAS oncogenes,16,17 which also are altered in squamous cell carcinoma and BCC.18 Similarly, Xin et al19 detected loss of heterozygosity of the human patched gene, PTCH, a tumor suppressor in the hedgehog pathway that has been implicated in sporadic BCC formation, suggesting that this loss of heterozygosity may predispose to secondary BCC formation.20,21 However, loss of PTCH heterozygosity could not be replicated by Takata et al22 and Levinsohn et al.16
Increased numbers of androgen receptors have been demonstrated in NS basal keratinocytes and sebaceous glands.23 Nevus sebaceous lesions enlarge during puberty,5 and malignant neoplasms arise almost exclusively in adulthood.3,4,10-13 The androgen surge during puberty and increased androgen levels in adulthood may promote sebaceous gland development and epidermal hyperplasia that result in progression of NS lesions from the first stage to the second stage. Basal cell carcinomas also express androgen receptors and have abnormal androgen hormone metabolism,24,25 though they do not display a notable number of estrogen or progesterone receptors.26 Therefore, increased androgen levels in adulthood also may contribute to progression to secondary neoplasm formation in the third stage.
Similarly, cases of rapid growth of NS lesions during pregnancy, a state of increased testosterone production,27 have
- Jadassohn J. Bemerkugen zur Histologie der systematisirten Naevi und uber “Talgdru˝sen-Naevi”. Arch Dermatol Syph. 1895;33:355-372.
- Alper J, Holmes LB, Mihm MC Jr. Birthmarks with serious medical significance: nevocullular nevi, sebaceous nevi, and multiple café au lait spots. J Pediatr. 1979;95:696-700.
- Muñoz-Pérez MA, García-Hernandez MJ, Ríos JJ, et al. Sebaceus naevi: a clinicopathologic study. J Eur Acad Dermatol Venereol. 2002;16:319-324.
- Cribier B, Scrivener Y, Grosshans E. Tumors arising in nevus sebaceus: a study of 596 cases. J Am Acad Dermatol. 2000;42:263-268.
- Mehregan AH, Pinkus H. Life history of organoid nevi. Special reference to nevus sebaceus of Jadassohn. Arch Dermatol. 1965;91:574-588.
- Jones EW, Heyl T. Naevus sebaceus. a report of 140 cases with special regard to the development of secondary malignant tumours. Br J Dermatol. 1970;82:99-117.
- Serpas de López RM, Hernández-Pérez E. Jadassohn’s sebaceous nevus. J Dermatol Surg Oncol. 1985;11:68-72.
- Smolin T, Hundeiker M. Squamous epithelial and basal cell carcinomas in naevus sebaceus (Jadassohn). Z Hautkr. 1986;61:267-282.
- Ackerman B, Reddy VB, Soyer HP. Neoplasms with Follicular Differentiation. New York, NY: Ardor Scribendi; 1993.
- Kaddu S, Schäppi H, Kerl H, et al. Trichoblastoma and sebaceoma in nevus sebaceus. Am J Dermatopathol. 1999;21:552-556.
- Idriss MH, Elston DM. Secondary neoplasms associated with nevus sebaceus of Jadassohn: a study of 707 cases. J Am Acad Dermatol. 2014;70:332-337.
- Hsu MC, Liau JY, Hong JL, et al. Secondary neoplasms arising from nevus sebaceus: a retrospective study of 450 cases in Taiwan. J Dermatol. 2016;43:175-180.
- Santibanez-Gallerani A, Marshall D, Duarte AM, et al. Should nevus sebaceus of Jadassohn in children be excised? a study of 757 cases, and literature review. J Craniofac Surg. 2003;14:658-660.
- Jaqueti G, Requena L, Sánchez Yus E. Trichoblastoma is the most common neoplasm developed in nevus sebaceus of Jadassohn: a clinicopathologic study of a series of 155 cases. Am J Dermatopathol. 2000;22:108-118.
- Merrot O, Cotten H, Patenotre P, et al. Sebaceous hamartoma of Jadassohn: trichoblastoma mimicking basal cell carcinoma? Ann Chir Plast Esthet. 2002;47:210-213.
- Levinsohn JL, Tian LC, Boyden LM, et al. Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceus. J Invest Dermatol. 2013;133:827-830.
- Groesser L, Herschberger E, Ruetten A, et al. Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nat Genet. 2012;44:783-787.
- Pierceall WE, Goldberg LH, Tainsky MA, et al. Ras gene mutation and amplification in human nonmelanoma skin cancers. Mol Carcinog. 1991;4:196-202.
- Xin H, Matt D, Qin JZ, et al. The sebaceous nevus: a nevus with deletions of the PTCH gene. Cancer Res. 1999;59:1834-1836.
- Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996;272:1668-1671.
- Gailani MR, Ståhle-Bäckdahl M, Leffell DJ, et al. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet. 1996;14:78-81.
- Takata M, Tojo M, Hatta N, et al. No evidence of deregulated patched-hedgehog signaling pathway in trichoblastomas and other tumors arising within nevus sebaceous. J Invest Dermatol. 2001;117:1666-1670.
- Hamilton KS, Johnson S, Smoller BR. The role of androgen receptors in the clinical course of nevus sebaceus of Jadassohn. Mod Pathol. 2001;14:539-542.
- Moretti G, Cardo P, Rampini E, et al. Testosterone metabolism in basal cell epitheliomas. J Invest Dermatol. 1978;71:361-362.
- Bayer-Garner IB, Givens V, Smoller B. Immunohistochemical staining for androgen receptors: a sensitive marker of sebaceous differentiation. Am J Dermatopathol. 1999;21:426-431.
- Rogers GS, Flowers JL, Pollack SV, et al. Determination of sex steroid receptor in human basal cell carcinoma. J Am Acad Dermatol. 1988;18:1039-1043.
- Bammann BL, Coulam CB, Jiang NS. Total and free testosterone during pregnancy. Am J Obstet Gynecol. 1980;137:293-298.
- Terenzi V, Indrizzi E, Buonaccorsi S, et al. Nevus sebaceus of Jadassohn. J Craniofac Surg. 2006;17:1234-1239.
- Moody MN, Landau JM, Goldberg LH. Nevus sebaceous revisited. Pediatr Dermatol. 2012;29:15-23.
- Lillis PJ, Ceilley RI. Multiple tumors arising in nevus sebaceus. Cutis. 1979;23:310-314.
- Chun K, Vázquez M, Sánchez JL. Nevus sebaceus: clinical outcomeand considerations for prophylactic excision. Int J Dermatol. 1995;34:538-541.
To the Editor:
Nevus sebaceous of Jadassohn (or nevus sebaceous [NS]) is a congenital hamartomatous disorder initially described by Jadassohn1 in 1895. Nevus sebaceous occurs in 0.3% of newborns2 and is most commonly identified on the face and scalp.3,4 Mehregan and Pinkus5 characterized NS as an organoid tumor containing multiple skin components with 3 life stages. The first stage—occurring during infancy—consists of immature hair follicles and sebaceous glands. The second stage—beginning at puberty—shows development of sebaceous glands, epidermal hyperplasia, and maturation of apocrine glands. The final stage involves formation of secondary benign and malignant neoplasms.
Historically, basal cell carcinoma (BCC) was thought to be the most common neoplasm arising in NS.5-8 In 1993, Ackerman et al9 introduced a new definition of trichoblastoma (TB), expanding the definition to encompass previously excluded benign follicular neoplasms. Large studies conducted after this new definition was proposed suggested that syringocystadenoma papilliferum and TB develop more frequently than does BCC.3,4,10-15 Furthermore, Cribier et al4 and Merrot et al15 reviewed prior cases of NS using the new definition and asserted that the majority of previously diagnosed cases of BCC were considered to be TB under the new criteria. With the advent of modern diagnostic testing, the rate of secondary benign neoplasm growth is now thought to be between 7% and 19%, with syringocystadenoma papilliferum arising in 2% to 13% of cases and TB in 1.5% to 7%.3,4,10-14 Malignant neoplasms are observed much less frequently, with BCC arising in 0% to 1% of NS cases.
Nevus sebaceous lesions typically enlarge during puberty, while malignant neoplasms occur almost exclusively in adulthood,4,10-12 suggesting that hormones contribute to NS stage progression. We present the case of a woman who developed BCC in a previously asymptomatic NS during pregnancy.
A 32-year-old woman who was otherwise healthy presented to our dermatology clinic with a pink-yellow verrucous plaque on the right temporal hairline extending to the preauricular area of the face. The patient had no personal or family history of skin cancer and no history of tanning bed use. She reported that the lesion had been present since birth. A diagnosis of NS was made.
Two years later, she presented with a new bleeding growth atop the previously diagnosed NS that had been present for approximately 4 months (Figure). At this visit she was pregnant (30 weeks’ gestation). Physical examination revealed a 4-mm, brown, pearly papule at the inferior margin of the previously noted pink verrucous plaque on the right temporal hairline. A biopsy was performed and histopathology displayed aggregates of basaloid cells with a high nuclear to cytoplasmic ratio, peripheral palisading, and abundant melanin, consistent with pigmented BCC. The patient was referred for Mohs micrographic surgery; the lesion was removed with clear margins. The patient had no recurrence of BCC at 36-month follow-up.
Few studies have looked at the signal transduction pathways leading to malignant neoplasm formation in NS. Nevus sebaceous lesions are theorized to result from postzygotic genetic mutations in HRAS and KRAS oncogenes,16,17 which also are altered in squamous cell carcinoma and BCC.18 Similarly, Xin et al19 detected loss of heterozygosity of the human patched gene, PTCH, a tumor suppressor in the hedgehog pathway that has been implicated in sporadic BCC formation, suggesting that this loss of heterozygosity may predispose to secondary BCC formation.20,21 However, loss of PTCH heterozygosity could not be replicated by Takata et al22 and Levinsohn et al.16
Increased numbers of androgen receptors have been demonstrated in NS basal keratinocytes and sebaceous glands.23 Nevus sebaceous lesions enlarge during puberty,5 and malignant neoplasms arise almost exclusively in adulthood.3,4,10-13 The androgen surge during puberty and increased androgen levels in adulthood may promote sebaceous gland development and epidermal hyperplasia that result in progression of NS lesions from the first stage to the second stage. Basal cell carcinomas also express androgen receptors and have abnormal androgen hormone metabolism,24,25 though they do not display a notable number of estrogen or progesterone receptors.26 Therefore, increased androgen levels in adulthood also may contribute to progression to secondary neoplasm formation in the third stage.
Similarly, cases of rapid growth of NS lesions during pregnancy, a state of increased testosterone production,27 have
To the Editor:
Nevus sebaceous of Jadassohn (or nevus sebaceous [NS]) is a congenital hamartomatous disorder initially described by Jadassohn1 in 1895. Nevus sebaceous occurs in 0.3% of newborns2 and is most commonly identified on the face and scalp.3,4 Mehregan and Pinkus5 characterized NS as an organoid tumor containing multiple skin components with 3 life stages. The first stage—occurring during infancy—consists of immature hair follicles and sebaceous glands. The second stage—beginning at puberty—shows development of sebaceous glands, epidermal hyperplasia, and maturation of apocrine glands. The final stage involves formation of secondary benign and malignant neoplasms.
Historically, basal cell carcinoma (BCC) was thought to be the most common neoplasm arising in NS.5-8 In 1993, Ackerman et al9 introduced a new definition of trichoblastoma (TB), expanding the definition to encompass previously excluded benign follicular neoplasms. Large studies conducted after this new definition was proposed suggested that syringocystadenoma papilliferum and TB develop more frequently than does BCC.3,4,10-15 Furthermore, Cribier et al4 and Merrot et al15 reviewed prior cases of NS using the new definition and asserted that the majority of previously diagnosed cases of BCC were considered to be TB under the new criteria. With the advent of modern diagnostic testing, the rate of secondary benign neoplasm growth is now thought to be between 7% and 19%, with syringocystadenoma papilliferum arising in 2% to 13% of cases and TB in 1.5% to 7%.3,4,10-14 Malignant neoplasms are observed much less frequently, with BCC arising in 0% to 1% of NS cases.
Nevus sebaceous lesions typically enlarge during puberty, while malignant neoplasms occur almost exclusively in adulthood,4,10-12 suggesting that hormones contribute to NS stage progression. We present the case of a woman who developed BCC in a previously asymptomatic NS during pregnancy.
A 32-year-old woman who was otherwise healthy presented to our dermatology clinic with a pink-yellow verrucous plaque on the right temporal hairline extending to the preauricular area of the face. The patient had no personal or family history of skin cancer and no history of tanning bed use. She reported that the lesion had been present since birth. A diagnosis of NS was made.
Two years later, she presented with a new bleeding growth atop the previously diagnosed NS that had been present for approximately 4 months (Figure). At this visit she was pregnant (30 weeks’ gestation). Physical examination revealed a 4-mm, brown, pearly papule at the inferior margin of the previously noted pink verrucous plaque on the right temporal hairline. A biopsy was performed and histopathology displayed aggregates of basaloid cells with a high nuclear to cytoplasmic ratio, peripheral palisading, and abundant melanin, consistent with pigmented BCC. The patient was referred for Mohs micrographic surgery; the lesion was removed with clear margins. The patient had no recurrence of BCC at 36-month follow-up.
Few studies have looked at the signal transduction pathways leading to malignant neoplasm formation in NS. Nevus sebaceous lesions are theorized to result from postzygotic genetic mutations in HRAS and KRAS oncogenes,16,17 which also are altered in squamous cell carcinoma and BCC.18 Similarly, Xin et al19 detected loss of heterozygosity of the human patched gene, PTCH, a tumor suppressor in the hedgehog pathway that has been implicated in sporadic BCC formation, suggesting that this loss of heterozygosity may predispose to secondary BCC formation.20,21 However, loss of PTCH heterozygosity could not be replicated by Takata et al22 and Levinsohn et al.16
Increased numbers of androgen receptors have been demonstrated in NS basal keratinocytes and sebaceous glands.23 Nevus sebaceous lesions enlarge during puberty,5 and malignant neoplasms arise almost exclusively in adulthood.3,4,10-13 The androgen surge during puberty and increased androgen levels in adulthood may promote sebaceous gland development and epidermal hyperplasia that result in progression of NS lesions from the first stage to the second stage. Basal cell carcinomas also express androgen receptors and have abnormal androgen hormone metabolism,24,25 though they do not display a notable number of estrogen or progesterone receptors.26 Therefore, increased androgen levels in adulthood also may contribute to progression to secondary neoplasm formation in the third stage.
Similarly, cases of rapid growth of NS lesions during pregnancy, a state of increased testosterone production,27 have
- Jadassohn J. Bemerkugen zur Histologie der systematisirten Naevi und uber “Talgdru˝sen-Naevi”. Arch Dermatol Syph. 1895;33:355-372.
- Alper J, Holmes LB, Mihm MC Jr. Birthmarks with serious medical significance: nevocullular nevi, sebaceous nevi, and multiple café au lait spots. J Pediatr. 1979;95:696-700.
- Muñoz-Pérez MA, García-Hernandez MJ, Ríos JJ, et al. Sebaceus naevi: a clinicopathologic study. J Eur Acad Dermatol Venereol. 2002;16:319-324.
- Cribier B, Scrivener Y, Grosshans E. Tumors arising in nevus sebaceus: a study of 596 cases. J Am Acad Dermatol. 2000;42:263-268.
- Mehregan AH, Pinkus H. Life history of organoid nevi. Special reference to nevus sebaceus of Jadassohn. Arch Dermatol. 1965;91:574-588.
- Jones EW, Heyl T. Naevus sebaceus. a report of 140 cases with special regard to the development of secondary malignant tumours. Br J Dermatol. 1970;82:99-117.
- Serpas de López RM, Hernández-Pérez E. Jadassohn’s sebaceous nevus. J Dermatol Surg Oncol. 1985;11:68-72.
- Smolin T, Hundeiker M. Squamous epithelial and basal cell carcinomas in naevus sebaceus (Jadassohn). Z Hautkr. 1986;61:267-282.
- Ackerman B, Reddy VB, Soyer HP. Neoplasms with Follicular Differentiation. New York, NY: Ardor Scribendi; 1993.
- Kaddu S, Schäppi H, Kerl H, et al. Trichoblastoma and sebaceoma in nevus sebaceus. Am J Dermatopathol. 1999;21:552-556.
- Idriss MH, Elston DM. Secondary neoplasms associated with nevus sebaceus of Jadassohn: a study of 707 cases. J Am Acad Dermatol. 2014;70:332-337.
- Hsu MC, Liau JY, Hong JL, et al. Secondary neoplasms arising from nevus sebaceus: a retrospective study of 450 cases in Taiwan. J Dermatol. 2016;43:175-180.
- Santibanez-Gallerani A, Marshall D, Duarte AM, et al. Should nevus sebaceus of Jadassohn in children be excised? a study of 757 cases, and literature review. J Craniofac Surg. 2003;14:658-660.
- Jaqueti G, Requena L, Sánchez Yus E. Trichoblastoma is the most common neoplasm developed in nevus sebaceus of Jadassohn: a clinicopathologic study of a series of 155 cases. Am J Dermatopathol. 2000;22:108-118.
- Merrot O, Cotten H, Patenotre P, et al. Sebaceous hamartoma of Jadassohn: trichoblastoma mimicking basal cell carcinoma? Ann Chir Plast Esthet. 2002;47:210-213.
- Levinsohn JL, Tian LC, Boyden LM, et al. Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceus. J Invest Dermatol. 2013;133:827-830.
- Groesser L, Herschberger E, Ruetten A, et al. Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nat Genet. 2012;44:783-787.
- Pierceall WE, Goldberg LH, Tainsky MA, et al. Ras gene mutation and amplification in human nonmelanoma skin cancers. Mol Carcinog. 1991;4:196-202.
- Xin H, Matt D, Qin JZ, et al. The sebaceous nevus: a nevus with deletions of the PTCH gene. Cancer Res. 1999;59:1834-1836.
- Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996;272:1668-1671.
- Gailani MR, Ståhle-Bäckdahl M, Leffell DJ, et al. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet. 1996;14:78-81.
- Takata M, Tojo M, Hatta N, et al. No evidence of deregulated patched-hedgehog signaling pathway in trichoblastomas and other tumors arising within nevus sebaceous. J Invest Dermatol. 2001;117:1666-1670.
- Hamilton KS, Johnson S, Smoller BR. The role of androgen receptors in the clinical course of nevus sebaceus of Jadassohn. Mod Pathol. 2001;14:539-542.
- Moretti G, Cardo P, Rampini E, et al. Testosterone metabolism in basal cell epitheliomas. J Invest Dermatol. 1978;71:361-362.
- Bayer-Garner IB, Givens V, Smoller B. Immunohistochemical staining for androgen receptors: a sensitive marker of sebaceous differentiation. Am J Dermatopathol. 1999;21:426-431.
- Rogers GS, Flowers JL, Pollack SV, et al. Determination of sex steroid receptor in human basal cell carcinoma. J Am Acad Dermatol. 1988;18:1039-1043.
- Bammann BL, Coulam CB, Jiang NS. Total and free testosterone during pregnancy. Am J Obstet Gynecol. 1980;137:293-298.
- Terenzi V, Indrizzi E, Buonaccorsi S, et al. Nevus sebaceus of Jadassohn. J Craniofac Surg. 2006;17:1234-1239.
- Moody MN, Landau JM, Goldberg LH. Nevus sebaceous revisited. Pediatr Dermatol. 2012;29:15-23.
- Lillis PJ, Ceilley RI. Multiple tumors arising in nevus sebaceus. Cutis. 1979;23:310-314.
- Chun K, Vázquez M, Sánchez JL. Nevus sebaceus: clinical outcomeand considerations for prophylactic excision. Int J Dermatol. 1995;34:538-541.
- Jadassohn J. Bemerkugen zur Histologie der systematisirten Naevi und uber “Talgdru˝sen-Naevi”. Arch Dermatol Syph. 1895;33:355-372.
- Alper J, Holmes LB, Mihm MC Jr. Birthmarks with serious medical significance: nevocullular nevi, sebaceous nevi, and multiple café au lait spots. J Pediatr. 1979;95:696-700.
- Muñoz-Pérez MA, García-Hernandez MJ, Ríos JJ, et al. Sebaceus naevi: a clinicopathologic study. J Eur Acad Dermatol Venereol. 2002;16:319-324.
- Cribier B, Scrivener Y, Grosshans E. Tumors arising in nevus sebaceus: a study of 596 cases. J Am Acad Dermatol. 2000;42:263-268.
- Mehregan AH, Pinkus H. Life history of organoid nevi. Special reference to nevus sebaceus of Jadassohn. Arch Dermatol. 1965;91:574-588.
- Jones EW, Heyl T. Naevus sebaceus. a report of 140 cases with special regard to the development of secondary malignant tumours. Br J Dermatol. 1970;82:99-117.
- Serpas de López RM, Hernández-Pérez E. Jadassohn’s sebaceous nevus. J Dermatol Surg Oncol. 1985;11:68-72.
- Smolin T, Hundeiker M. Squamous epithelial and basal cell carcinomas in naevus sebaceus (Jadassohn). Z Hautkr. 1986;61:267-282.
- Ackerman B, Reddy VB, Soyer HP. Neoplasms with Follicular Differentiation. New York, NY: Ardor Scribendi; 1993.
- Kaddu S, Schäppi H, Kerl H, et al. Trichoblastoma and sebaceoma in nevus sebaceus. Am J Dermatopathol. 1999;21:552-556.
- Idriss MH, Elston DM. Secondary neoplasms associated with nevus sebaceus of Jadassohn: a study of 707 cases. J Am Acad Dermatol. 2014;70:332-337.
- Hsu MC, Liau JY, Hong JL, et al. Secondary neoplasms arising from nevus sebaceus: a retrospective study of 450 cases in Taiwan. J Dermatol. 2016;43:175-180.
- Santibanez-Gallerani A, Marshall D, Duarte AM, et al. Should nevus sebaceus of Jadassohn in children be excised? a study of 757 cases, and literature review. J Craniofac Surg. 2003;14:658-660.
- Jaqueti G, Requena L, Sánchez Yus E. Trichoblastoma is the most common neoplasm developed in nevus sebaceus of Jadassohn: a clinicopathologic study of a series of 155 cases. Am J Dermatopathol. 2000;22:108-118.
- Merrot O, Cotten H, Patenotre P, et al. Sebaceous hamartoma of Jadassohn: trichoblastoma mimicking basal cell carcinoma? Ann Chir Plast Esthet. 2002;47:210-213.
- Levinsohn JL, Tian LC, Boyden LM, et al. Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceus. J Invest Dermatol. 2013;133:827-830.
- Groesser L, Herschberger E, Ruetten A, et al. Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nat Genet. 2012;44:783-787.
- Pierceall WE, Goldberg LH, Tainsky MA, et al. Ras gene mutation and amplification in human nonmelanoma skin cancers. Mol Carcinog. 1991;4:196-202.
- Xin H, Matt D, Qin JZ, et al. The sebaceous nevus: a nevus with deletions of the PTCH gene. Cancer Res. 1999;59:1834-1836.
- Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996;272:1668-1671.
- Gailani MR, Ståhle-Bäckdahl M, Leffell DJ, et al. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet. 1996;14:78-81.
- Takata M, Tojo M, Hatta N, et al. No evidence of deregulated patched-hedgehog signaling pathway in trichoblastomas and other tumors arising within nevus sebaceous. J Invest Dermatol. 2001;117:1666-1670.
- Hamilton KS, Johnson S, Smoller BR. The role of androgen receptors in the clinical course of nevus sebaceus of Jadassohn. Mod Pathol. 2001;14:539-542.
- Moretti G, Cardo P, Rampini E, et al. Testosterone metabolism in basal cell epitheliomas. J Invest Dermatol. 1978;71:361-362.
- Bayer-Garner IB, Givens V, Smoller B. Immunohistochemical staining for androgen receptors: a sensitive marker of sebaceous differentiation. Am J Dermatopathol. 1999;21:426-431.
- Rogers GS, Flowers JL, Pollack SV, et al. Determination of sex steroid receptor in human basal cell carcinoma. J Am Acad Dermatol. 1988;18:1039-1043.
- Bammann BL, Coulam CB, Jiang NS. Total and free testosterone during pregnancy. Am J Obstet Gynecol. 1980;137:293-298.
- Terenzi V, Indrizzi E, Buonaccorsi S, et al. Nevus sebaceus of Jadassohn. J Craniofac Surg. 2006;17:1234-1239.
- Moody MN, Landau JM, Goldberg LH. Nevus sebaceous revisited. Pediatr Dermatol. 2012;29:15-23.
- Lillis PJ, Ceilley RI. Multiple tumors arising in nevus sebaceus. Cutis. 1979;23:310-314.
- Chun K, Vázquez M, Sánchez JL. Nevus sebaceus: clinical outcomeand considerations for prophylactic excision. Int J Dermatol. 1995;34:538-541.
Practice Points
- Benign neoplasms arise more frequently in nevus sebaceous (NS) lesions than do malignant neoplasms.
- The hormonal changes that occur during pregnancy and puberty appear to play a role in the development of neoplasms in NS lesions.
- Monitoring NS lesions more closely during periods of hormonal change may help diagnose malignant transformations in these patients.
Pelosi drug pricing bill passes Ways and Means on party line vote
The House Ways and Means Committee is the latest to pass H.R. 3, a bill aimed at driving the price of prescription drugs down.
During an Oct. 22, 2019, markup of the bill, Republican members criticized committee leadership for abandoning bipartisan efforts to reign in drug prices in favor of a partisan bill that so far gained no support from the minority party. H.R. 3 was passed by the Ways and Means Committee on a 24-17 party line vote.
Both “Democrats and Republicans support lowering drug prices, cracking down on overpriced drugs, giving patients more power to choose affordable medicines, and removing the wrong incentives in federal health programs that reward bad actors for raising prices,” Committee Ranking Member Kevin Brady (R-Tex.) said in his opening statement. In fact, at the request of Committee Chairman Richard Neal (D-Mass.), “both parties in this committee were working together toward that important goal. At least until Speaker Nancy Pelosi (D-Calif.) trashed the bipartisan work and forced through a secretly written, deeply controversial, and highly partisan drug bill to cure political illnesses rather than real ones.”
H.R. 3, recently renamed the Elijah E. Cummings Lower Drug Costs Now Act of 2019, would give the secretary of the Department of Health & Human Services the ability to negotiate drug prices for Medicare Part D (something explicitly banned under current law), implement an excise tax on drugs that see price hikes above the rate of inflation, cap out-of-pocket expenditures annually for Medicare Part D beneficiaries at $2,000, and use an international pricing index to help bring prices for drugs sold in the United States more in line with the lower prices in foreign countries.
But panel Democrats praised the bill as a step forward in helping to lower the cost of prescription drugs.
“H.R. 3 levels the playing field for U.S. consumers who, on average, pay four times more than patients in other countries for the exact same drugs,” Chairman Neal said in a statement following the passage.
He highlighted specifically the provision that caps out-of-pocket expenses in Part D and the HHS’ negotiating power, noting that “more people will be able to afford the drugs they need that they may have previously forgone due to high costs. With more Americans taking the medicines they’re prescribed, families will be healthier, and premiums will go down.”
Republican committee members argued that these same provisions would stifle innovation and ultimately would reduce access to medicine. Most attempts at altering the provisions through amendments were met with strict party line rejection.
The House Ways and Means Committee is the latest to pass H.R. 3, a bill aimed at driving the price of prescription drugs down.
During an Oct. 22, 2019, markup of the bill, Republican members criticized committee leadership for abandoning bipartisan efforts to reign in drug prices in favor of a partisan bill that so far gained no support from the minority party. H.R. 3 was passed by the Ways and Means Committee on a 24-17 party line vote.
Both “Democrats and Republicans support lowering drug prices, cracking down on overpriced drugs, giving patients more power to choose affordable medicines, and removing the wrong incentives in federal health programs that reward bad actors for raising prices,” Committee Ranking Member Kevin Brady (R-Tex.) said in his opening statement. In fact, at the request of Committee Chairman Richard Neal (D-Mass.), “both parties in this committee were working together toward that important goal. At least until Speaker Nancy Pelosi (D-Calif.) trashed the bipartisan work and forced through a secretly written, deeply controversial, and highly partisan drug bill to cure political illnesses rather than real ones.”
H.R. 3, recently renamed the Elijah E. Cummings Lower Drug Costs Now Act of 2019, would give the secretary of the Department of Health & Human Services the ability to negotiate drug prices for Medicare Part D (something explicitly banned under current law), implement an excise tax on drugs that see price hikes above the rate of inflation, cap out-of-pocket expenditures annually for Medicare Part D beneficiaries at $2,000, and use an international pricing index to help bring prices for drugs sold in the United States more in line with the lower prices in foreign countries.
But panel Democrats praised the bill as a step forward in helping to lower the cost of prescription drugs.
“H.R. 3 levels the playing field for U.S. consumers who, on average, pay four times more than patients in other countries for the exact same drugs,” Chairman Neal said in a statement following the passage.
He highlighted specifically the provision that caps out-of-pocket expenses in Part D and the HHS’ negotiating power, noting that “more people will be able to afford the drugs they need that they may have previously forgone due to high costs. With more Americans taking the medicines they’re prescribed, families will be healthier, and premiums will go down.”
Republican committee members argued that these same provisions would stifle innovation and ultimately would reduce access to medicine. Most attempts at altering the provisions through amendments were met with strict party line rejection.
The House Ways and Means Committee is the latest to pass H.R. 3, a bill aimed at driving the price of prescription drugs down.
During an Oct. 22, 2019, markup of the bill, Republican members criticized committee leadership for abandoning bipartisan efforts to reign in drug prices in favor of a partisan bill that so far gained no support from the minority party. H.R. 3 was passed by the Ways and Means Committee on a 24-17 party line vote.
Both “Democrats and Republicans support lowering drug prices, cracking down on overpriced drugs, giving patients more power to choose affordable medicines, and removing the wrong incentives in federal health programs that reward bad actors for raising prices,” Committee Ranking Member Kevin Brady (R-Tex.) said in his opening statement. In fact, at the request of Committee Chairman Richard Neal (D-Mass.), “both parties in this committee were working together toward that important goal. At least until Speaker Nancy Pelosi (D-Calif.) trashed the bipartisan work and forced through a secretly written, deeply controversial, and highly partisan drug bill to cure political illnesses rather than real ones.”
H.R. 3, recently renamed the Elijah E. Cummings Lower Drug Costs Now Act of 2019, would give the secretary of the Department of Health & Human Services the ability to negotiate drug prices for Medicare Part D (something explicitly banned under current law), implement an excise tax on drugs that see price hikes above the rate of inflation, cap out-of-pocket expenditures annually for Medicare Part D beneficiaries at $2,000, and use an international pricing index to help bring prices for drugs sold in the United States more in line with the lower prices in foreign countries.
But panel Democrats praised the bill as a step forward in helping to lower the cost of prescription drugs.
“H.R. 3 levels the playing field for U.S. consumers who, on average, pay four times more than patients in other countries for the exact same drugs,” Chairman Neal said in a statement following the passage.
He highlighted specifically the provision that caps out-of-pocket expenses in Part D and the HHS’ negotiating power, noting that “more people will be able to afford the drugs they need that they may have previously forgone due to high costs. With more Americans taking the medicines they’re prescribed, families will be healthier, and premiums will go down.”
Republican committee members argued that these same provisions would stifle innovation and ultimately would reduce access to medicine. Most attempts at altering the provisions through amendments were met with strict party line rejection.
New drug improves sex drive, at least on paper
The novel drug bremelanotide shows promise in acquired female hypoactive sexual desire disorder, according to the results of two randomized, controlled trials and a 52-week open-label extension study published online in Obstetrics & Gynecology.
Bremelanotide, which received Food and Drug Administration approval for this indication in June 2019, is an analog of the endogenous neuropeptide alpha-melanocyte-stimulating hormone.
Two separate, identically designed phase 3 studies (RECONNECT) were performed by Sheryl Kingsburg, MD, of the Cleveland Medical Center, and associates. Combined, 1,267 premenopausal women in monogamous relationships with acquired hypoactive sexual desire disorder were randomized to bremelanotide or placebo. Women in the treatment arm had significant improvement in female sexual function index–desire domain (FSFI-D) scores from baseline to week 24 (integrated studies: 0.35; P less than .001; effect size, 0.39), compared with placebo. They also experienced significant improvement in the FSFI-desire/arousal/orgasm (FSFI-DAO) domain (integrated studies: –0.33; P less than .001; effect size, 0.27).
The most common adverse events were nausea (integrated: 40% versus 1% in placebo), flushing (20% versus 0.3%), and headache (11% versus 2%). Overall, 77% in the treatment group reported a treatment-emergent adverse event, compared with 58% in the placebo group.
The open-label follow-up study was led by James Simon, MD, of George Washington University and IntimMedicine Specialists, Washington. Of the 684 participants who opted to enter the extension study, 40% completed it. In those who received bremelanotide during the randomized trial, the change in FSFI-D scores from baseline to the end of the open-label study ranged from 1.25 to 1.30, while the change in FSFI-DAO ranged from –1.4 to –1.7. In patients originally on placebo, the changes were 0.70-0.77 and –0.9, respectively.
Both groups surpassed the minimally clinically important difference for the FSFI-D score, which is considered to be 0.6.
“Patients switching from placebo experienced a higher incidence of adverse events than those continuing on bremelanotide during the open-label extension (79% versus 63%, respectively),” Dr. Simon and associates said.
The treatment is subcutaneous and can be self-administered up to about 45 minutes before a sexual event, no more than once during a 24-hour period, and no more than 8 doses per month, according to an FDA press release. The drug is contraindicated for women with cardiovascular disease or uncontrolled hypertension due to observations of transiently, slightly increased blood pressure.
The trials were funded by Palatin Technologies and AMAG Pharmaceuticals. The authors and coauthors have extensive financial relationships with pharmaceutical companies. Dr. Carson reported no financial conflicts.
SOURCE: Obstet Gynecol. 2019 Oct 8. doi: 10.1097/AOG.0000000000003500; Obstet Gynecol. 2019 Oct 8. doi: 10.1097/AOG.0000000000003514.
The results indicate that sex is more satisfying in the treatment arm, but there is no evidence of an increase in the number of sexual events.
But the drug appears safe and offers a second option for women experiencing this concern.
Sandra Ann Carson, MD is in the departments of obstetrics, gynecology, and reproductive sciences, and reproductive endocrinology and infertility, at Yale University, New Haven, Conn. She made these comments in an editorial accompanying the articles by Kingsburg et al. and Simon et al. (Obstet Gynecol. 2019 Nov 134;[5]:897-8). Dr. Carson said she had no financial conflicts.
The results indicate that sex is more satisfying in the treatment arm, but there is no evidence of an increase in the number of sexual events.
But the drug appears safe and offers a second option for women experiencing this concern.
Sandra Ann Carson, MD is in the departments of obstetrics, gynecology, and reproductive sciences, and reproductive endocrinology and infertility, at Yale University, New Haven, Conn. She made these comments in an editorial accompanying the articles by Kingsburg et al. and Simon et al. (Obstet Gynecol. 2019 Nov 134;[5]:897-8). Dr. Carson said she had no financial conflicts.
The results indicate that sex is more satisfying in the treatment arm, but there is no evidence of an increase in the number of sexual events.
But the drug appears safe and offers a second option for women experiencing this concern.
Sandra Ann Carson, MD is in the departments of obstetrics, gynecology, and reproductive sciences, and reproductive endocrinology and infertility, at Yale University, New Haven, Conn. She made these comments in an editorial accompanying the articles by Kingsburg et al. and Simon et al. (Obstet Gynecol. 2019 Nov 134;[5]:897-8). Dr. Carson said she had no financial conflicts.
The novel drug bremelanotide shows promise in acquired female hypoactive sexual desire disorder, according to the results of two randomized, controlled trials and a 52-week open-label extension study published online in Obstetrics & Gynecology.
Bremelanotide, which received Food and Drug Administration approval for this indication in June 2019, is an analog of the endogenous neuropeptide alpha-melanocyte-stimulating hormone.
Two separate, identically designed phase 3 studies (RECONNECT) were performed by Sheryl Kingsburg, MD, of the Cleveland Medical Center, and associates. Combined, 1,267 premenopausal women in monogamous relationships with acquired hypoactive sexual desire disorder were randomized to bremelanotide or placebo. Women in the treatment arm had significant improvement in female sexual function index–desire domain (FSFI-D) scores from baseline to week 24 (integrated studies: 0.35; P less than .001; effect size, 0.39), compared with placebo. They also experienced significant improvement in the FSFI-desire/arousal/orgasm (FSFI-DAO) domain (integrated studies: –0.33; P less than .001; effect size, 0.27).
The most common adverse events were nausea (integrated: 40% versus 1% in placebo), flushing (20% versus 0.3%), and headache (11% versus 2%). Overall, 77% in the treatment group reported a treatment-emergent adverse event, compared with 58% in the placebo group.
The open-label follow-up study was led by James Simon, MD, of George Washington University and IntimMedicine Specialists, Washington. Of the 684 participants who opted to enter the extension study, 40% completed it. In those who received bremelanotide during the randomized trial, the change in FSFI-D scores from baseline to the end of the open-label study ranged from 1.25 to 1.30, while the change in FSFI-DAO ranged from –1.4 to –1.7. In patients originally on placebo, the changes were 0.70-0.77 and –0.9, respectively.
Both groups surpassed the minimally clinically important difference for the FSFI-D score, which is considered to be 0.6.
“Patients switching from placebo experienced a higher incidence of adverse events than those continuing on bremelanotide during the open-label extension (79% versus 63%, respectively),” Dr. Simon and associates said.
The treatment is subcutaneous and can be self-administered up to about 45 minutes before a sexual event, no more than once during a 24-hour period, and no more than 8 doses per month, according to an FDA press release. The drug is contraindicated for women with cardiovascular disease or uncontrolled hypertension due to observations of transiently, slightly increased blood pressure.
The trials were funded by Palatin Technologies and AMAG Pharmaceuticals. The authors and coauthors have extensive financial relationships with pharmaceutical companies. Dr. Carson reported no financial conflicts.
SOURCE: Obstet Gynecol. 2019 Oct 8. doi: 10.1097/AOG.0000000000003500; Obstet Gynecol. 2019 Oct 8. doi: 10.1097/AOG.0000000000003514.
The novel drug bremelanotide shows promise in acquired female hypoactive sexual desire disorder, according to the results of two randomized, controlled trials and a 52-week open-label extension study published online in Obstetrics & Gynecology.
Bremelanotide, which received Food and Drug Administration approval for this indication in June 2019, is an analog of the endogenous neuropeptide alpha-melanocyte-stimulating hormone.
Two separate, identically designed phase 3 studies (RECONNECT) were performed by Sheryl Kingsburg, MD, of the Cleveland Medical Center, and associates. Combined, 1,267 premenopausal women in monogamous relationships with acquired hypoactive sexual desire disorder were randomized to bremelanotide or placebo. Women in the treatment arm had significant improvement in female sexual function index–desire domain (FSFI-D) scores from baseline to week 24 (integrated studies: 0.35; P less than .001; effect size, 0.39), compared with placebo. They also experienced significant improvement in the FSFI-desire/arousal/orgasm (FSFI-DAO) domain (integrated studies: –0.33; P less than .001; effect size, 0.27).
The most common adverse events were nausea (integrated: 40% versus 1% in placebo), flushing (20% versus 0.3%), and headache (11% versus 2%). Overall, 77% in the treatment group reported a treatment-emergent adverse event, compared with 58% in the placebo group.
The open-label follow-up study was led by James Simon, MD, of George Washington University and IntimMedicine Specialists, Washington. Of the 684 participants who opted to enter the extension study, 40% completed it. In those who received bremelanotide during the randomized trial, the change in FSFI-D scores from baseline to the end of the open-label study ranged from 1.25 to 1.30, while the change in FSFI-DAO ranged from –1.4 to –1.7. In patients originally on placebo, the changes were 0.70-0.77 and –0.9, respectively.
Both groups surpassed the minimally clinically important difference for the FSFI-D score, which is considered to be 0.6.
“Patients switching from placebo experienced a higher incidence of adverse events than those continuing on bremelanotide during the open-label extension (79% versus 63%, respectively),” Dr. Simon and associates said.
The treatment is subcutaneous and can be self-administered up to about 45 minutes before a sexual event, no more than once during a 24-hour period, and no more than 8 doses per month, according to an FDA press release. The drug is contraindicated for women with cardiovascular disease or uncontrolled hypertension due to observations of transiently, slightly increased blood pressure.
The trials were funded by Palatin Technologies and AMAG Pharmaceuticals. The authors and coauthors have extensive financial relationships with pharmaceutical companies. Dr. Carson reported no financial conflicts.
SOURCE: Obstet Gynecol. 2019 Oct 8. doi: 10.1097/AOG.0000000000003500; Obstet Gynecol. 2019 Oct 8. doi: 10.1097/AOG.0000000000003514.
FROM OBSTETRICS & GYNECOLOGY
Suicide deaths rising in children aged 10-19 years
according to the National Center for Health Statistics.
Death rates from suicide for children aged 10-14 years jumped by 178% from 2007 to 2017, while teenagers aged 15-19 years experienced a 76% increase over that period, with both changes reaching significance, the NCHS said in a recent data brief based on data from the National Vital Statistics System.
The actual rate for teens was higher to begin with, however, so in absolute terms the increase is larger for the older group. In 2007, deaths from suicide occurred at a rate of 6.7 per 100,000 persons for persons aged 15-19 years, and by 2017 that rate was up significantly to 11.8 per 100,000. Among children aged 10-14 years, the suicide-related death rate climbed from 0.9 per 100,000 in 2007 to 2.5 in 2014, the NCHS investigators reported.
The news was somewhat better on the other side of the violent death coin. Homicides are down by a significant 18% since 2000 among children aged 10-14 years, as the rate dropped from 1.1 per 100,000 in 2000 to 0.9 in 2017. The homicide rate since 2000 is down slightly for teens aged 15-19 years, but it has risen 32% in recent years, going from 6.6 deaths per 100,000 in 2013 to 8.7 in 2017, they said.
Suicide was the second-leading cause of death in both age groups in 2017, and homicide was third for those aged 15-19 and fifth among 10- to 14-year-olds, the investigators noted.
according to the National Center for Health Statistics.
Death rates from suicide for children aged 10-14 years jumped by 178% from 2007 to 2017, while teenagers aged 15-19 years experienced a 76% increase over that period, with both changes reaching significance, the NCHS said in a recent data brief based on data from the National Vital Statistics System.
The actual rate for teens was higher to begin with, however, so in absolute terms the increase is larger for the older group. In 2007, deaths from suicide occurred at a rate of 6.7 per 100,000 persons for persons aged 15-19 years, and by 2017 that rate was up significantly to 11.8 per 100,000. Among children aged 10-14 years, the suicide-related death rate climbed from 0.9 per 100,000 in 2007 to 2.5 in 2014, the NCHS investigators reported.
The news was somewhat better on the other side of the violent death coin. Homicides are down by a significant 18% since 2000 among children aged 10-14 years, as the rate dropped from 1.1 per 100,000 in 2000 to 0.9 in 2017. The homicide rate since 2000 is down slightly for teens aged 15-19 years, but it has risen 32% in recent years, going from 6.6 deaths per 100,000 in 2013 to 8.7 in 2017, they said.
Suicide was the second-leading cause of death in both age groups in 2017, and homicide was third for those aged 15-19 and fifth among 10- to 14-year-olds, the investigators noted.
according to the National Center for Health Statistics.
Death rates from suicide for children aged 10-14 years jumped by 178% from 2007 to 2017, while teenagers aged 15-19 years experienced a 76% increase over that period, with both changes reaching significance, the NCHS said in a recent data brief based on data from the National Vital Statistics System.
The actual rate for teens was higher to begin with, however, so in absolute terms the increase is larger for the older group. In 2007, deaths from suicide occurred at a rate of 6.7 per 100,000 persons for persons aged 15-19 years, and by 2017 that rate was up significantly to 11.8 per 100,000. Among children aged 10-14 years, the suicide-related death rate climbed from 0.9 per 100,000 in 2007 to 2.5 in 2014, the NCHS investigators reported.
The news was somewhat better on the other side of the violent death coin. Homicides are down by a significant 18% since 2000 among children aged 10-14 years, as the rate dropped from 1.1 per 100,000 in 2000 to 0.9 in 2017. The homicide rate since 2000 is down slightly for teens aged 15-19 years, but it has risen 32% in recent years, going from 6.6 deaths per 100,000 in 2013 to 8.7 in 2017, they said.
Suicide was the second-leading cause of death in both age groups in 2017, and homicide was third for those aged 15-19 and fifth among 10- to 14-year-olds, the investigators noted.
Trials examine T2T strategy in axial spondyloarthritis
Three international clinical trials in Europe are examining the effectiveness of treat-to-target (T2T) therapeutic regimens in patients with axial spondyloarthritis (axSpA), including two that will be the first randomized trial evidence to support or refute the T2T strategy for patients ranging from those with nonradiographic disease to patients with ankylosing spondylitis.
T2T has proved before to work in patients with rheumatoid arthritis and psoriatic arthritis with evidence from the TICORA (Tight Control of Rheumatoid Arthritis) and TICOPA (Tight Control in Psoriatic Arthritis) trials.
Two T2T trials in axSpA are still in the recruiting phase, and one has completed enrollment, with no results available yet.
Tight control in spondyloarthritis (TICOSPA)
TICOSPA is a 1-year, ongoing, multinational, cluster-randomized, prospective cohort study that has enrolled 163 patients with a diagnosis of active axial spondyloarthritis to evaluate the potential benefit of a T2T strategy in which the rheumatologist will agree to monitor very closely – at least every 4 weeks – and treat patients in accordance with a predefined strategy. The T2T strategy is compared with usual care as given by the treating rheumatologist. Prior to the trial, patients were on nonoptimal NSAID treatment.
“Tight control” in this study refers to the time from treatment initiation to adequate assessment of efficacy and safety, which for efficacy should be at 2-4 weeks for NSAIDs and 12-16 weeks for tumor necrosis factor inhibitors but can be a very short time frame for evaluating safety, “based on the occurrence of adverse events,” according to the study description at clinicaltrials.gov.
The primary endpoint is change on the Assessment of SpondyloArthritis international Society (ASAS) Health Index-Numerical Rating Score over the 1 year of follow-up.
There are 11 secondary endpoints, including:
- Percentage reaching major improvement in the Ankylosing Spondylitis Disease Activity Scale score (ASDAS).
- Percentage reaching 50% improvement of the initial Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score at 1 year.
- Change in the ASAS-NSAID score over 1 year.
- Change in the Work Productivity and Activity Impairment questionnaire.
The study is being conducted at 18 centers in Belgium, France, and the Netherlands and is sponsored by the Association de Recherche Clinique en Rhumatologie.
AScalate: Treat-to-target in axial spondyloarthritis
The Novartis-sponsored AScalate study seeks to enroll 300 patients with active disease despite NSAID therapy. The 36-week, randomized, parallel-group, open-label, multicenter trial will be conducted at seven sites in Germany.
The study will randomize patients to either of two arms: An active group will receive T2T therapy with secukinumab as a first-line biologic in escalating doses of 150-300 mg, determined by patient response until the T2T goal had been reached. Patients who don’t respond to secukinumab will be switched to an adalimumab biosimilar. The comparator group will receive standard-of-care therapy up to the maximum recommended dose at the discretion of the investigator.
The primary endpoint is the percentage of patients in each group who meet ASAS 40 response criteria by 24 weeks.
There are 11 secondary endpoints, including:
- Percentage achieving an ASAS40 response at 12 weeks.
- Percentage achieving ASAS20 and ASAS partial response at 12 and 24 weeks.
- Proportion of patients meeting the ASDAS definition of inactive disease, ASDAS clinically important and major improvement, and ASDAS low disease activity.
- Proportion of patients achieving 50% improvement of the initial BASDAI score.
Treat-to-target with secukinumab in axial spondyloarthritis (TRACE)
TRACE is a Novartis-sponsored phase 4 study examining reductions of inflammation seen on MRI of sacroiliac joints and spine at 16-24 weeks in patients who achieve ASDAS remission (score of less than 1.3) on 150 mg secukinumab by 16 weeks. The comparator group will be patients who are not in remission by week 16 and need a dose increase to 300 mg. The Danish trial seeks 88 participants with high disease activity and MRI signs of inflammation in the sacroiliac joints and/ or the spine.
After an initial four weekly doses of secukinumab 150 mg, patients will receive monthly secukinumab 150-mg doses out to week 16. Nonresponders at week 16 will escalate to 300 mg. If by 24 weeks these patients do not respond, they will be switched to a TNF inhibitor.
The primary outcome is the proportion of patients with a positive change in MRI-inflammation as measured by the sum of the Spondyloarthritis Research Consortium of Canada (SPARCC) sacroiliac joint and spine inflammation indices.
Three international clinical trials in Europe are examining the effectiveness of treat-to-target (T2T) therapeutic regimens in patients with axial spondyloarthritis (axSpA), including two that will be the first randomized trial evidence to support or refute the T2T strategy for patients ranging from those with nonradiographic disease to patients with ankylosing spondylitis.
T2T has proved before to work in patients with rheumatoid arthritis and psoriatic arthritis with evidence from the TICORA (Tight Control of Rheumatoid Arthritis) and TICOPA (Tight Control in Psoriatic Arthritis) trials.
Two T2T trials in axSpA are still in the recruiting phase, and one has completed enrollment, with no results available yet.
Tight control in spondyloarthritis (TICOSPA)
TICOSPA is a 1-year, ongoing, multinational, cluster-randomized, prospective cohort study that has enrolled 163 patients with a diagnosis of active axial spondyloarthritis to evaluate the potential benefit of a T2T strategy in which the rheumatologist will agree to monitor very closely – at least every 4 weeks – and treat patients in accordance with a predefined strategy. The T2T strategy is compared with usual care as given by the treating rheumatologist. Prior to the trial, patients were on nonoptimal NSAID treatment.
“Tight control” in this study refers to the time from treatment initiation to adequate assessment of efficacy and safety, which for efficacy should be at 2-4 weeks for NSAIDs and 12-16 weeks for tumor necrosis factor inhibitors but can be a very short time frame for evaluating safety, “based on the occurrence of adverse events,” according to the study description at clinicaltrials.gov.
The primary endpoint is change on the Assessment of SpondyloArthritis international Society (ASAS) Health Index-Numerical Rating Score over the 1 year of follow-up.
There are 11 secondary endpoints, including:
- Percentage reaching major improvement in the Ankylosing Spondylitis Disease Activity Scale score (ASDAS).
- Percentage reaching 50% improvement of the initial Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score at 1 year.
- Change in the ASAS-NSAID score over 1 year.
- Change in the Work Productivity and Activity Impairment questionnaire.
The study is being conducted at 18 centers in Belgium, France, and the Netherlands and is sponsored by the Association de Recherche Clinique en Rhumatologie.
AScalate: Treat-to-target in axial spondyloarthritis
The Novartis-sponsored AScalate study seeks to enroll 300 patients with active disease despite NSAID therapy. The 36-week, randomized, parallel-group, open-label, multicenter trial will be conducted at seven sites in Germany.
The study will randomize patients to either of two arms: An active group will receive T2T therapy with secukinumab as a first-line biologic in escalating doses of 150-300 mg, determined by patient response until the T2T goal had been reached. Patients who don’t respond to secukinumab will be switched to an adalimumab biosimilar. The comparator group will receive standard-of-care therapy up to the maximum recommended dose at the discretion of the investigator.
The primary endpoint is the percentage of patients in each group who meet ASAS 40 response criteria by 24 weeks.
There are 11 secondary endpoints, including:
- Percentage achieving an ASAS40 response at 12 weeks.
- Percentage achieving ASAS20 and ASAS partial response at 12 and 24 weeks.
- Proportion of patients meeting the ASDAS definition of inactive disease, ASDAS clinically important and major improvement, and ASDAS low disease activity.
- Proportion of patients achieving 50% improvement of the initial BASDAI score.
Treat-to-target with secukinumab in axial spondyloarthritis (TRACE)
TRACE is a Novartis-sponsored phase 4 study examining reductions of inflammation seen on MRI of sacroiliac joints and spine at 16-24 weeks in patients who achieve ASDAS remission (score of less than 1.3) on 150 mg secukinumab by 16 weeks. The comparator group will be patients who are not in remission by week 16 and need a dose increase to 300 mg. The Danish trial seeks 88 participants with high disease activity and MRI signs of inflammation in the sacroiliac joints and/ or the spine.
After an initial four weekly doses of secukinumab 150 mg, patients will receive monthly secukinumab 150-mg doses out to week 16. Nonresponders at week 16 will escalate to 300 mg. If by 24 weeks these patients do not respond, they will be switched to a TNF inhibitor.
The primary outcome is the proportion of patients with a positive change in MRI-inflammation as measured by the sum of the Spondyloarthritis Research Consortium of Canada (SPARCC) sacroiliac joint and spine inflammation indices.
Three international clinical trials in Europe are examining the effectiveness of treat-to-target (T2T) therapeutic regimens in patients with axial spondyloarthritis (axSpA), including two that will be the first randomized trial evidence to support or refute the T2T strategy for patients ranging from those with nonradiographic disease to patients with ankylosing spondylitis.
T2T has proved before to work in patients with rheumatoid arthritis and psoriatic arthritis with evidence from the TICORA (Tight Control of Rheumatoid Arthritis) and TICOPA (Tight Control in Psoriatic Arthritis) trials.
Two T2T trials in axSpA are still in the recruiting phase, and one has completed enrollment, with no results available yet.
Tight control in spondyloarthritis (TICOSPA)
TICOSPA is a 1-year, ongoing, multinational, cluster-randomized, prospective cohort study that has enrolled 163 patients with a diagnosis of active axial spondyloarthritis to evaluate the potential benefit of a T2T strategy in which the rheumatologist will agree to monitor very closely – at least every 4 weeks – and treat patients in accordance with a predefined strategy. The T2T strategy is compared with usual care as given by the treating rheumatologist. Prior to the trial, patients were on nonoptimal NSAID treatment.
“Tight control” in this study refers to the time from treatment initiation to adequate assessment of efficacy and safety, which for efficacy should be at 2-4 weeks for NSAIDs and 12-16 weeks for tumor necrosis factor inhibitors but can be a very short time frame for evaluating safety, “based on the occurrence of adverse events,” according to the study description at clinicaltrials.gov.
The primary endpoint is change on the Assessment of SpondyloArthritis international Society (ASAS) Health Index-Numerical Rating Score over the 1 year of follow-up.
There are 11 secondary endpoints, including:
- Percentage reaching major improvement in the Ankylosing Spondylitis Disease Activity Scale score (ASDAS).
- Percentage reaching 50% improvement of the initial Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score at 1 year.
- Change in the ASAS-NSAID score over 1 year.
- Change in the Work Productivity and Activity Impairment questionnaire.
The study is being conducted at 18 centers in Belgium, France, and the Netherlands and is sponsored by the Association de Recherche Clinique en Rhumatologie.
AScalate: Treat-to-target in axial spondyloarthritis
The Novartis-sponsored AScalate study seeks to enroll 300 patients with active disease despite NSAID therapy. The 36-week, randomized, parallel-group, open-label, multicenter trial will be conducted at seven sites in Germany.
The study will randomize patients to either of two arms: An active group will receive T2T therapy with secukinumab as a first-line biologic in escalating doses of 150-300 mg, determined by patient response until the T2T goal had been reached. Patients who don’t respond to secukinumab will be switched to an adalimumab biosimilar. The comparator group will receive standard-of-care therapy up to the maximum recommended dose at the discretion of the investigator.
The primary endpoint is the percentage of patients in each group who meet ASAS 40 response criteria by 24 weeks.
There are 11 secondary endpoints, including:
- Percentage achieving an ASAS40 response at 12 weeks.
- Percentage achieving ASAS20 and ASAS partial response at 12 and 24 weeks.
- Proportion of patients meeting the ASDAS definition of inactive disease, ASDAS clinically important and major improvement, and ASDAS low disease activity.
- Proportion of patients achieving 50% improvement of the initial BASDAI score.
Treat-to-target with secukinumab in axial spondyloarthritis (TRACE)
TRACE is a Novartis-sponsored phase 4 study examining reductions of inflammation seen on MRI of sacroiliac joints and spine at 16-24 weeks in patients who achieve ASDAS remission (score of less than 1.3) on 150 mg secukinumab by 16 weeks. The comparator group will be patients who are not in remission by week 16 and need a dose increase to 300 mg. The Danish trial seeks 88 participants with high disease activity and MRI signs of inflammation in the sacroiliac joints and/ or the spine.
After an initial four weekly doses of secukinumab 150 mg, patients will receive monthly secukinumab 150-mg doses out to week 16. Nonresponders at week 16 will escalate to 300 mg. If by 24 weeks these patients do not respond, they will be switched to a TNF inhibitor.
The primary outcome is the proportion of patients with a positive change in MRI-inflammation as measured by the sum of the Spondyloarthritis Research Consortium of Canada (SPARCC) sacroiliac joint and spine inflammation indices.
When patient autonomy gets in the way
“Why didn’t you see that patient?”
The hospitalist on the phone was angry. He’d wanted the patient seen by neurology and cleared for discharge. Apparently, I hadn’t complied.
Actually, that isn’t true. I was on call, so I had dutifully dragged myself in (with the help of some coffee), reviewed the chart, and gone in to see the fellow.
The patient, however, had other ideas. He said he was sick of doctors, didn’t like them, didn’t want to see me, and asked me to leave. So I did.
This threw off the hospitalist’s well-choreographed day of admissions and discharges. Without me seeing the patient, he had to either discharge him on his own decision or find another neurologist who would do it.
Sorry, but I’m not going to force this issue. If a patient doesn’t want to see me, it’s not worth fighting over. Believe me, I get paid to see patients, so I don’t have much incentive to just walk away.
But at the same time I have to respect patients’ decisions. While a neurology consult is pretty noninvasive, it’s still a part of medicine. If a patient doesn’t want to see me, I’m not going to force them to.
Granted, there are exceptions. Obviously, if the patient is fairly demented or otherwise not mentally competent to make such a decision, I’ll see them. In those cases, their deteriorating mental status is likely the reason for the consult.
But the fellow that day seemed alert and reasonable, and there was nothing in the chart about confusion. So I’m going to assume he knew what he was doing when he told me to go away.
The hospitalist didn’t see this as an issue, but I did. I’m sorry if it messes up the discharge planning, but that’s not my fault. It’s the patient’s decision.
While I may disagree at times with patients’ decisions, their autonomy is still central to medicine. I respect and believe in that, even if it makes things more difficult for those around them.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
“Why didn’t you see that patient?”
The hospitalist on the phone was angry. He’d wanted the patient seen by neurology and cleared for discharge. Apparently, I hadn’t complied.
Actually, that isn’t true. I was on call, so I had dutifully dragged myself in (with the help of some coffee), reviewed the chart, and gone in to see the fellow.
The patient, however, had other ideas. He said he was sick of doctors, didn’t like them, didn’t want to see me, and asked me to leave. So I did.
This threw off the hospitalist’s well-choreographed day of admissions and discharges. Without me seeing the patient, he had to either discharge him on his own decision or find another neurologist who would do it.
Sorry, but I’m not going to force this issue. If a patient doesn’t want to see me, it’s not worth fighting over. Believe me, I get paid to see patients, so I don’t have much incentive to just walk away.
But at the same time I have to respect patients’ decisions. While a neurology consult is pretty noninvasive, it’s still a part of medicine. If a patient doesn’t want to see me, I’m not going to force them to.
Granted, there are exceptions. Obviously, if the patient is fairly demented or otherwise not mentally competent to make such a decision, I’ll see them. In those cases, their deteriorating mental status is likely the reason for the consult.
But the fellow that day seemed alert and reasonable, and there was nothing in the chart about confusion. So I’m going to assume he knew what he was doing when he told me to go away.
The hospitalist didn’t see this as an issue, but I did. I’m sorry if it messes up the discharge planning, but that’s not my fault. It’s the patient’s decision.
While I may disagree at times with patients’ decisions, their autonomy is still central to medicine. I respect and believe in that, even if it makes things more difficult for those around them.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
“Why didn’t you see that patient?”
The hospitalist on the phone was angry. He’d wanted the patient seen by neurology and cleared for discharge. Apparently, I hadn’t complied.
Actually, that isn’t true. I was on call, so I had dutifully dragged myself in (with the help of some coffee), reviewed the chart, and gone in to see the fellow.
The patient, however, had other ideas. He said he was sick of doctors, didn’t like them, didn’t want to see me, and asked me to leave. So I did.
This threw off the hospitalist’s well-choreographed day of admissions and discharges. Without me seeing the patient, he had to either discharge him on his own decision or find another neurologist who would do it.
Sorry, but I’m not going to force this issue. If a patient doesn’t want to see me, it’s not worth fighting over. Believe me, I get paid to see patients, so I don’t have much incentive to just walk away.
But at the same time I have to respect patients’ decisions. While a neurology consult is pretty noninvasive, it’s still a part of medicine. If a patient doesn’t want to see me, I’m not going to force them to.
Granted, there are exceptions. Obviously, if the patient is fairly demented or otherwise not mentally competent to make such a decision, I’ll see them. In those cases, their deteriorating mental status is likely the reason for the consult.
But the fellow that day seemed alert and reasonable, and there was nothing in the chart about confusion. So I’m going to assume he knew what he was doing when he told me to go away.
The hospitalist didn’t see this as an issue, but I did. I’m sorry if it messes up the discharge planning, but that’s not my fault. It’s the patient’s decision.
While I may disagree at times with patients’ decisions, their autonomy is still central to medicine. I respect and believe in that, even if it makes things more difficult for those around them.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.