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Why ustekinumab dosing differs in Crohn’s disease
ORLANDO – Preclinical studies and years of clinical experience using the monoclonal antibody ustekinumab (Stelara, Janssen Biotech) in psoriasis and psoriatic arthritis offer important clues to any gastroenterologist perplexed by the official Food and Drug Administration indication, dosing frequency, and intensity for Crohn’s disease. Phase II and phase III findings also reveal where the monoclonal antibody may offer particular advantages, compared with other agents.
“Ustekinumab landed in your lap in September. You’re probably all trying to figure out how to get the ID formulation paid for with insurance,” William J. Sanborn, MD, professor and chief of the division of gastroenterology at the University of California, San Diego, said at the Advances in Inflammatory Bowel Diseases meeting. “But this is now the reality that you have this in your Crohn’s practice.”
The FDA approved ustekinumab to treat adults with moderately to severely active Crohn’s disease who 1) failed or were intolerant to immune modulators or corticosteroids but did not fail tumor necrosis factor (TNF) blockers or 2) failed or were intolerant to one or more TNF blockers. Dr. Sanborn and colleagues observed a significant induction of clinical response in a subgroup of patients who previously failed a TNF blocker in an early efficacy study (Gastroenterology. 2008;135:1130-41). “This is where the idea of initially focusing on TNF failures came from,” he added at the meeting sponsored by the Crohn’s & Colitis Foundation of America.
Induction dosing in Crohn’s disease is intravenous versus subcutaneous in psoriasis and psoriatic arthritis, in part because of the same study. “It looked like relatively better bioavailability and relatively better effect with intravenous dosing,” Dr. Sanborn said. “In Crohn’s disease, it’s a completely different animal.”
Official induction dosing is approximately 6 mg/kg in three fixed doses according to patient weight in Crohn’s disease. The 6-mg/kg dose yielded the most consistent response, compared with 1-mg/kg or 3-mg/kg doses in a subsequent phase IIb study (N Engl J Med. 2012;367:1519-28).
The most consistent induction results at weeks 6 and 8 were observed with 6 mg/kg ustekinumab versus 1 mg/kg or 3 mg/kg.
Dr. Sanborn and coinvestigators also saw “numeric differences in drug versus placebo for remission at 6 and 8 weeks “but it was not that clear from the phase II trial what the remission efficacy was, so that needed more exploration to really understand.”
Another distinction for ustekinumab in Crohn’s disease is the approved maintenance dosing of 90 mg subcutaneously every 8 weeks versus a 12-week interval recommended for psoriasis. “Why so much more in Crohn’s disease, and is that necessary?” Dr. Sanborn asked.
Based on changes in C-reactive protein levels and a “rapid drop” in Crohn’s Disease Activity Index scores by 4 weeks, “clearly efficacy was there for induction,” he said. Ustekinumab has a “quick onset – analogous to the TNF blockers.”
“These were quite encouraging data, and paved the way to move on to phase III [studies],” Dr. Sanborn said. The preclinical studies up to this point focused on patients with Crohn’s disease who previously failed TNF blockers. However, “in clinical practice, we would be interested to know if it would work in anti-TNF naive or nonfailures as well.”
So two subsequent studies assessed safety and efficacy in a TNF blocker–failure population (UNITI-1 trial. Inflamm. Bowel Dis. 2016 Mar;22 Suppl 1:S1) and a non-TNF failure population of patients who did fail previous conventional therapy such as steroids or immunomodulators (UNITI-2 trial).
Clinical response and remission steadily rose following induction up to a significant difference versus placebo at 8 weeks in the non–TNF failure population. “Remember, in the phase IIa study, the remission rates were not as clear-cut, so this really nails down this as a good drug in both patient populations,” Dr. Sanborn said.
To evaluate long-term maintenance, investigators rerandomized all participants in the UNITI-1 and UNITI-2 studies. They saw a 15% gain in clinical remission out to week 44, compared with placebo. Dr. Sanborn noted that ustekinumab has a relatively long half-life, so the difference in patients switched to placebo may not have been as striking. “In practice it’s important to know the on-time and off-time of this agent, and I think the clinical trials make that clear.”
The trials also show that 12-week dosing works, Dr. Sanborn said. “You see about 20% gain for every 8-week dosing. You get extra 5% or 10% extra on all outcome measures at 8 weeks, compared to 12 weeks dosing, with no difference in safety signals.” He added, “So more intensive dosing of 90 mg every 8 weeks is what ended up getting approved in the United States.”
Safety profile
So what does all the preclinical evidence suggest about safety of ustekinumab? The UNITI trials combined included more than 1,000 patients, and there were no deaths, Dr. Sanborn said. “Usually with TNF blockers in 1,000 patients you would see a few deaths.”
Patient withdrawals from the preclinical studies were also relatively low, Dr. Sanborn reported. “With ustekinumab monotherapy, drug withdrawal is only 3% or 4%, so it seems to be different from TNF blockers in that sense [too].”
In addition, the rates of adverse events were similar between placebo (83.5%) and ustekinumab’s combined every 8 week and every 12 week dosing groups through 44 weeks (81.0%), Dr. Sanborn said. The rates of serious adverse events were likewise similar, 15.0% and 11.0%, respectively. Reported malignancy included two cases of basal cell skin cancers, one in the placebo group and one in the every-8-week dosing group, he added.
“So all those black box warnings you’re used to worrying about with TNF blockers – serious infections, about opportunistic infections, malignancy – there is no black box warning with this agent around that.”
Dr. Sanborn noted that the FDA labeling reports infections. “We know Crohn’s disease patients are [also] getting azathioprine, steroids, methotrexate, so you will see some infections, but there wasn’t a consistent opportunistic infection signal.”
One case of reversible posterior leukoencephalopathy syndrome is included on the labeling. Dr. Sanborn also put this in perspective: “With all the experience in psoriasis and psoriatic arthritis, and the clinical trials [in IBD], there is just one case. So the relationship is not very clear.”
“The safety signals with ustekinumab are really very good. It seems to be an extremely safe agent – we really don’t see much in terms of infections,” Brian Feagan, MD, an internist and gastroenterologist at the University of Western Ontario in London, said in a separate presentation at the conference. “We don’t have a lot of long-term experience with ustekinumab in Crohn’s disease, but we have a lot of experience in psoriasis, and it’s a safe drug.”
“Ustekinumab may be our first really valid monotherapy, with less immunogenicity,” Dr. Feagan said.
AGA Resource
AGA offers an IBD Clinical Service Line that provides tools to help you become more efficient, understand quality standards, and improve the process of care for patients. Learn more at http://www.gastro.org/patient-care/conditions-diseases/ibd
ORLANDO – Preclinical studies and years of clinical experience using the monoclonal antibody ustekinumab (Stelara, Janssen Biotech) in psoriasis and psoriatic arthritis offer important clues to any gastroenterologist perplexed by the official Food and Drug Administration indication, dosing frequency, and intensity for Crohn’s disease. Phase II and phase III findings also reveal where the monoclonal antibody may offer particular advantages, compared with other agents.
“Ustekinumab landed in your lap in September. You’re probably all trying to figure out how to get the ID formulation paid for with insurance,” William J. Sanborn, MD, professor and chief of the division of gastroenterology at the University of California, San Diego, said at the Advances in Inflammatory Bowel Diseases meeting. “But this is now the reality that you have this in your Crohn’s practice.”
The FDA approved ustekinumab to treat adults with moderately to severely active Crohn’s disease who 1) failed or were intolerant to immune modulators or corticosteroids but did not fail tumor necrosis factor (TNF) blockers or 2) failed or were intolerant to one or more TNF blockers. Dr. Sanborn and colleagues observed a significant induction of clinical response in a subgroup of patients who previously failed a TNF blocker in an early efficacy study (Gastroenterology. 2008;135:1130-41). “This is where the idea of initially focusing on TNF failures came from,” he added at the meeting sponsored by the Crohn’s & Colitis Foundation of America.
Induction dosing in Crohn’s disease is intravenous versus subcutaneous in psoriasis and psoriatic arthritis, in part because of the same study. “It looked like relatively better bioavailability and relatively better effect with intravenous dosing,” Dr. Sanborn said. “In Crohn’s disease, it’s a completely different animal.”
Official induction dosing is approximately 6 mg/kg in three fixed doses according to patient weight in Crohn’s disease. The 6-mg/kg dose yielded the most consistent response, compared with 1-mg/kg or 3-mg/kg doses in a subsequent phase IIb study (N Engl J Med. 2012;367:1519-28).
The most consistent induction results at weeks 6 and 8 were observed with 6 mg/kg ustekinumab versus 1 mg/kg or 3 mg/kg.
Dr. Sanborn and coinvestigators also saw “numeric differences in drug versus placebo for remission at 6 and 8 weeks “but it was not that clear from the phase II trial what the remission efficacy was, so that needed more exploration to really understand.”
Another distinction for ustekinumab in Crohn’s disease is the approved maintenance dosing of 90 mg subcutaneously every 8 weeks versus a 12-week interval recommended for psoriasis. “Why so much more in Crohn’s disease, and is that necessary?” Dr. Sanborn asked.
Based on changes in C-reactive protein levels and a “rapid drop” in Crohn’s Disease Activity Index scores by 4 weeks, “clearly efficacy was there for induction,” he said. Ustekinumab has a “quick onset – analogous to the TNF blockers.”
“These were quite encouraging data, and paved the way to move on to phase III [studies],” Dr. Sanborn said. The preclinical studies up to this point focused on patients with Crohn’s disease who previously failed TNF blockers. However, “in clinical practice, we would be interested to know if it would work in anti-TNF naive or nonfailures as well.”
So two subsequent studies assessed safety and efficacy in a TNF blocker–failure population (UNITI-1 trial. Inflamm. Bowel Dis. 2016 Mar;22 Suppl 1:S1) and a non-TNF failure population of patients who did fail previous conventional therapy such as steroids or immunomodulators (UNITI-2 trial).
Clinical response and remission steadily rose following induction up to a significant difference versus placebo at 8 weeks in the non–TNF failure population. “Remember, in the phase IIa study, the remission rates were not as clear-cut, so this really nails down this as a good drug in both patient populations,” Dr. Sanborn said.
To evaluate long-term maintenance, investigators rerandomized all participants in the UNITI-1 and UNITI-2 studies. They saw a 15% gain in clinical remission out to week 44, compared with placebo. Dr. Sanborn noted that ustekinumab has a relatively long half-life, so the difference in patients switched to placebo may not have been as striking. “In practice it’s important to know the on-time and off-time of this agent, and I think the clinical trials make that clear.”
The trials also show that 12-week dosing works, Dr. Sanborn said. “You see about 20% gain for every 8-week dosing. You get extra 5% or 10% extra on all outcome measures at 8 weeks, compared to 12 weeks dosing, with no difference in safety signals.” He added, “So more intensive dosing of 90 mg every 8 weeks is what ended up getting approved in the United States.”
Safety profile
So what does all the preclinical evidence suggest about safety of ustekinumab? The UNITI trials combined included more than 1,000 patients, and there were no deaths, Dr. Sanborn said. “Usually with TNF blockers in 1,000 patients you would see a few deaths.”
Patient withdrawals from the preclinical studies were also relatively low, Dr. Sanborn reported. “With ustekinumab monotherapy, drug withdrawal is only 3% or 4%, so it seems to be different from TNF blockers in that sense [too].”
In addition, the rates of adverse events were similar between placebo (83.5%) and ustekinumab’s combined every 8 week and every 12 week dosing groups through 44 weeks (81.0%), Dr. Sanborn said. The rates of serious adverse events were likewise similar, 15.0% and 11.0%, respectively. Reported malignancy included two cases of basal cell skin cancers, one in the placebo group and one in the every-8-week dosing group, he added.
“So all those black box warnings you’re used to worrying about with TNF blockers – serious infections, about opportunistic infections, malignancy – there is no black box warning with this agent around that.”
Dr. Sanborn noted that the FDA labeling reports infections. “We know Crohn’s disease patients are [also] getting azathioprine, steroids, methotrexate, so you will see some infections, but there wasn’t a consistent opportunistic infection signal.”
One case of reversible posterior leukoencephalopathy syndrome is included on the labeling. Dr. Sanborn also put this in perspective: “With all the experience in psoriasis and psoriatic arthritis, and the clinical trials [in IBD], there is just one case. So the relationship is not very clear.”
“The safety signals with ustekinumab are really very good. It seems to be an extremely safe agent – we really don’t see much in terms of infections,” Brian Feagan, MD, an internist and gastroenterologist at the University of Western Ontario in London, said in a separate presentation at the conference. “We don’t have a lot of long-term experience with ustekinumab in Crohn’s disease, but we have a lot of experience in psoriasis, and it’s a safe drug.”
“Ustekinumab may be our first really valid monotherapy, with less immunogenicity,” Dr. Feagan said.
AGA Resource
AGA offers an IBD Clinical Service Line that provides tools to help you become more efficient, understand quality standards, and improve the process of care for patients. Learn more at http://www.gastro.org/patient-care/conditions-diseases/ibd
ORLANDO – Preclinical studies and years of clinical experience using the monoclonal antibody ustekinumab (Stelara, Janssen Biotech) in psoriasis and psoriatic arthritis offer important clues to any gastroenterologist perplexed by the official Food and Drug Administration indication, dosing frequency, and intensity for Crohn’s disease. Phase II and phase III findings also reveal where the monoclonal antibody may offer particular advantages, compared with other agents.
“Ustekinumab landed in your lap in September. You’re probably all trying to figure out how to get the ID formulation paid for with insurance,” William J. Sanborn, MD, professor and chief of the division of gastroenterology at the University of California, San Diego, said at the Advances in Inflammatory Bowel Diseases meeting. “But this is now the reality that you have this in your Crohn’s practice.”
The FDA approved ustekinumab to treat adults with moderately to severely active Crohn’s disease who 1) failed or were intolerant to immune modulators or corticosteroids but did not fail tumor necrosis factor (TNF) blockers or 2) failed or were intolerant to one or more TNF blockers. Dr. Sanborn and colleagues observed a significant induction of clinical response in a subgroup of patients who previously failed a TNF blocker in an early efficacy study (Gastroenterology. 2008;135:1130-41). “This is where the idea of initially focusing on TNF failures came from,” he added at the meeting sponsored by the Crohn’s & Colitis Foundation of America.
Induction dosing in Crohn’s disease is intravenous versus subcutaneous in psoriasis and psoriatic arthritis, in part because of the same study. “It looked like relatively better bioavailability and relatively better effect with intravenous dosing,” Dr. Sanborn said. “In Crohn’s disease, it’s a completely different animal.”
Official induction dosing is approximately 6 mg/kg in three fixed doses according to patient weight in Crohn’s disease. The 6-mg/kg dose yielded the most consistent response, compared with 1-mg/kg or 3-mg/kg doses in a subsequent phase IIb study (N Engl J Med. 2012;367:1519-28).
The most consistent induction results at weeks 6 and 8 were observed with 6 mg/kg ustekinumab versus 1 mg/kg or 3 mg/kg.
Dr. Sanborn and coinvestigators also saw “numeric differences in drug versus placebo for remission at 6 and 8 weeks “but it was not that clear from the phase II trial what the remission efficacy was, so that needed more exploration to really understand.”
Another distinction for ustekinumab in Crohn’s disease is the approved maintenance dosing of 90 mg subcutaneously every 8 weeks versus a 12-week interval recommended for psoriasis. “Why so much more in Crohn’s disease, and is that necessary?” Dr. Sanborn asked.
Based on changes in C-reactive protein levels and a “rapid drop” in Crohn’s Disease Activity Index scores by 4 weeks, “clearly efficacy was there for induction,” he said. Ustekinumab has a “quick onset – analogous to the TNF blockers.”
“These were quite encouraging data, and paved the way to move on to phase III [studies],” Dr. Sanborn said. The preclinical studies up to this point focused on patients with Crohn’s disease who previously failed TNF blockers. However, “in clinical practice, we would be interested to know if it would work in anti-TNF naive or nonfailures as well.”
So two subsequent studies assessed safety and efficacy in a TNF blocker–failure population (UNITI-1 trial. Inflamm. Bowel Dis. 2016 Mar;22 Suppl 1:S1) and a non-TNF failure population of patients who did fail previous conventional therapy such as steroids or immunomodulators (UNITI-2 trial).
Clinical response and remission steadily rose following induction up to a significant difference versus placebo at 8 weeks in the non–TNF failure population. “Remember, in the phase IIa study, the remission rates were not as clear-cut, so this really nails down this as a good drug in both patient populations,” Dr. Sanborn said.
To evaluate long-term maintenance, investigators rerandomized all participants in the UNITI-1 and UNITI-2 studies. They saw a 15% gain in clinical remission out to week 44, compared with placebo. Dr. Sanborn noted that ustekinumab has a relatively long half-life, so the difference in patients switched to placebo may not have been as striking. “In practice it’s important to know the on-time and off-time of this agent, and I think the clinical trials make that clear.”
The trials also show that 12-week dosing works, Dr. Sanborn said. “You see about 20% gain for every 8-week dosing. You get extra 5% or 10% extra on all outcome measures at 8 weeks, compared to 12 weeks dosing, with no difference in safety signals.” He added, “So more intensive dosing of 90 mg every 8 weeks is what ended up getting approved in the United States.”
Safety profile
So what does all the preclinical evidence suggest about safety of ustekinumab? The UNITI trials combined included more than 1,000 patients, and there were no deaths, Dr. Sanborn said. “Usually with TNF blockers in 1,000 patients you would see a few deaths.”
Patient withdrawals from the preclinical studies were also relatively low, Dr. Sanborn reported. “With ustekinumab monotherapy, drug withdrawal is only 3% or 4%, so it seems to be different from TNF blockers in that sense [too].”
In addition, the rates of adverse events were similar between placebo (83.5%) and ustekinumab’s combined every 8 week and every 12 week dosing groups through 44 weeks (81.0%), Dr. Sanborn said. The rates of serious adverse events were likewise similar, 15.0% and 11.0%, respectively. Reported malignancy included two cases of basal cell skin cancers, one in the placebo group and one in the every-8-week dosing group, he added.
“So all those black box warnings you’re used to worrying about with TNF blockers – serious infections, about opportunistic infections, malignancy – there is no black box warning with this agent around that.”
Dr. Sanborn noted that the FDA labeling reports infections. “We know Crohn’s disease patients are [also] getting azathioprine, steroids, methotrexate, so you will see some infections, but there wasn’t a consistent opportunistic infection signal.”
One case of reversible posterior leukoencephalopathy syndrome is included on the labeling. Dr. Sanborn also put this in perspective: “With all the experience in psoriasis and psoriatic arthritis, and the clinical trials [in IBD], there is just one case. So the relationship is not very clear.”
“The safety signals with ustekinumab are really very good. It seems to be an extremely safe agent – we really don’t see much in terms of infections,” Brian Feagan, MD, an internist and gastroenterologist at the University of Western Ontario in London, said in a separate presentation at the conference. “We don’t have a lot of long-term experience with ustekinumab in Crohn’s disease, but we have a lot of experience in psoriasis, and it’s a safe drug.”
“Ustekinumab may be our first really valid monotherapy, with less immunogenicity,” Dr. Feagan said.
AGA Resource
AGA offers an IBD Clinical Service Line that provides tools to help you become more efficient, understand quality standards, and improve the process of care for patients. Learn more at http://www.gastro.org/patient-care/conditions-diseases/ibd
Guidelines for diagnosing TB in adults, children
A clinical practice guideline for diagnosing pulmonary, extrapulmonary, and latent tuberculosis in adults and children has been released jointly by the American Thoracic Society, the Centers for Disease Control and Prevention, and the Infectious Diseases Society of America.
The American Academy of Pediatrics also provided input to the guideline, which includes 23 evidence-based recommendations. The document is intended to assist clinicians in high-resource countries with a low incidence of TB disease and latent TB infection, such as the United States, said David M. Lewinsohn, MD, PhD, and his associates on the joint task force that wrote the guideline.
Even though the case rate is relatively low in the United States and has declined in recent years, “an estimated 11 million persons are infected with Mycobacterium tuberculosis. Thus … there remains a large reservoir of individuals who are infected. Without the application of improved diagnosis and effective treatment for latent [disease], new cases of TB will develop from within this group,” they noted (Clin Infect Dis. 2016 Dec 8;64[2]:e1-33. doi: 10.1093/cid/ciw694).
Among the guidelines’ strongest recommendations:
• Acid-fast bacilli smear microscopy should be performed in all patients suspected of having pulmonary TB, using at least three sputum samples. A sputum volume of at least 3 mL is needed, but 5-10 mL would be better.
• Both liquid and solid mycobacterial cultures should be performed on every specimen from patients suspected of having TB disease, rather than either type alone.
• A diagnostic nucleic acid amplification test should be performed on the initial specimen from patients suspected of having pulmonary TB.
• Rapid molecular drug susceptibility testing of respiratory specimens is advised for certain patients, with a focus on testing for rifampin susceptibility with or without isoniazid.
• Patients suspected of having extrapulmonary TB also should have mycobacterial cultures performed on all specimens.
• For all mycobacterial cultures that are positive for TB, a culture isolate should be submitted for genotyping to a regional genotyping laboratory.
• For patients aged 5 and older who are suspected of having latent TB infection, an interferon-gamma release assay (IGRA) is advised rather than a tuberculin skin test, especially if the patient is not likely to return to have the test result read. A tuberculin skin test is an acceptable alternative if IGRA is not available, is too expensive, or is too burdensome.
The guideline also addresses bronchoscopic sampling, cell counts and chemistries from fluid specimens collected from sites suspected of harboring extrapulmonary TB (such as pleural, cerebrospinal, ascetic, or joint fluids), and measurement of adenosine deaminase levels.
This work was supported by the American Thoracic Society, the Centers for Disease Control and Prevention, and the Infectious Diseases Society of America, with input from the American Academy of Pediatrics. Dr. Lewinsohn reported having no relevant financial disclosures; his associates reported ties to numerous industry sources.
A clinical practice guideline for diagnosing pulmonary, extrapulmonary, and latent tuberculosis in adults and children has been released jointly by the American Thoracic Society, the Centers for Disease Control and Prevention, and the Infectious Diseases Society of America.
The American Academy of Pediatrics also provided input to the guideline, which includes 23 evidence-based recommendations. The document is intended to assist clinicians in high-resource countries with a low incidence of TB disease and latent TB infection, such as the United States, said David M. Lewinsohn, MD, PhD, and his associates on the joint task force that wrote the guideline.
Even though the case rate is relatively low in the United States and has declined in recent years, “an estimated 11 million persons are infected with Mycobacterium tuberculosis. Thus … there remains a large reservoir of individuals who are infected. Without the application of improved diagnosis and effective treatment for latent [disease], new cases of TB will develop from within this group,” they noted (Clin Infect Dis. 2016 Dec 8;64[2]:e1-33. doi: 10.1093/cid/ciw694).
Among the guidelines’ strongest recommendations:
• Acid-fast bacilli smear microscopy should be performed in all patients suspected of having pulmonary TB, using at least three sputum samples. A sputum volume of at least 3 mL is needed, but 5-10 mL would be better.
• Both liquid and solid mycobacterial cultures should be performed on every specimen from patients suspected of having TB disease, rather than either type alone.
• A diagnostic nucleic acid amplification test should be performed on the initial specimen from patients suspected of having pulmonary TB.
• Rapid molecular drug susceptibility testing of respiratory specimens is advised for certain patients, with a focus on testing for rifampin susceptibility with or without isoniazid.
• Patients suspected of having extrapulmonary TB also should have mycobacterial cultures performed on all specimens.
• For all mycobacterial cultures that are positive for TB, a culture isolate should be submitted for genotyping to a regional genotyping laboratory.
• For patients aged 5 and older who are suspected of having latent TB infection, an interferon-gamma release assay (IGRA) is advised rather than a tuberculin skin test, especially if the patient is not likely to return to have the test result read. A tuberculin skin test is an acceptable alternative if IGRA is not available, is too expensive, or is too burdensome.
The guideline also addresses bronchoscopic sampling, cell counts and chemistries from fluid specimens collected from sites suspected of harboring extrapulmonary TB (such as pleural, cerebrospinal, ascetic, or joint fluids), and measurement of adenosine deaminase levels.
This work was supported by the American Thoracic Society, the Centers for Disease Control and Prevention, and the Infectious Diseases Society of America, with input from the American Academy of Pediatrics. Dr. Lewinsohn reported having no relevant financial disclosures; his associates reported ties to numerous industry sources.
A clinical practice guideline for diagnosing pulmonary, extrapulmonary, and latent tuberculosis in adults and children has been released jointly by the American Thoracic Society, the Centers for Disease Control and Prevention, and the Infectious Diseases Society of America.
The American Academy of Pediatrics also provided input to the guideline, which includes 23 evidence-based recommendations. The document is intended to assist clinicians in high-resource countries with a low incidence of TB disease and latent TB infection, such as the United States, said David M. Lewinsohn, MD, PhD, and his associates on the joint task force that wrote the guideline.
Even though the case rate is relatively low in the United States and has declined in recent years, “an estimated 11 million persons are infected with Mycobacterium tuberculosis. Thus … there remains a large reservoir of individuals who are infected. Without the application of improved diagnosis and effective treatment for latent [disease], new cases of TB will develop from within this group,” they noted (Clin Infect Dis. 2016 Dec 8;64[2]:e1-33. doi: 10.1093/cid/ciw694).
Among the guidelines’ strongest recommendations:
• Acid-fast bacilli smear microscopy should be performed in all patients suspected of having pulmonary TB, using at least three sputum samples. A sputum volume of at least 3 mL is needed, but 5-10 mL would be better.
• Both liquid and solid mycobacterial cultures should be performed on every specimen from patients suspected of having TB disease, rather than either type alone.
• A diagnostic nucleic acid amplification test should be performed on the initial specimen from patients suspected of having pulmonary TB.
• Rapid molecular drug susceptibility testing of respiratory specimens is advised for certain patients, with a focus on testing for rifampin susceptibility with or without isoniazid.
• Patients suspected of having extrapulmonary TB also should have mycobacterial cultures performed on all specimens.
• For all mycobacterial cultures that are positive for TB, a culture isolate should be submitted for genotyping to a regional genotyping laboratory.
• For patients aged 5 and older who are suspected of having latent TB infection, an interferon-gamma release assay (IGRA) is advised rather than a tuberculin skin test, especially if the patient is not likely to return to have the test result read. A tuberculin skin test is an acceptable alternative if IGRA is not available, is too expensive, or is too burdensome.
The guideline also addresses bronchoscopic sampling, cell counts and chemistries from fluid specimens collected from sites suspected of harboring extrapulmonary TB (such as pleural, cerebrospinal, ascetic, or joint fluids), and measurement of adenosine deaminase levels.
This work was supported by the American Thoracic Society, the Centers for Disease Control and Prevention, and the Infectious Diseases Society of America, with input from the American Academy of Pediatrics. Dr. Lewinsohn reported having no relevant financial disclosures; his associates reported ties to numerous industry sources.
FROM CLINICAL INFECTIOUS DISEASES
Key clinical point: jointly by the American Thoracic Society, the Centers for Disease Control and Prevention, and the Infectious Diseases Society of America.
Major finding: The clinical practice guideline includes 23 evidence-based recommendations concerning diagnostic testing for latent, pulmonary, or extrapulmonary tuberculosis in adults and children.
Data source: A compilation of 23 evidence-based recommendations about diagnostic testing for tuberculosis.
Disclosures: This work was supported by the American Thoracic Society, the Centers for Disease Control and Prevention, and the Infectious Diseases Society of America, with input from the American Academy of Pediatrics. Dr. Lewinsohn reported having no relevant financial disclosures; his associates reported ties to numerous industry sources.
Non-MD CT Surgical Team Scientific Poster Opportunity
Non-MD cardiothoracic team professionals can submit a scientific poster for the Perioperative/Team-Based Care Poster Competition. Winning posters will be displayed at the AATS Centennial, April 29 – May 3 in Boston, MA.
The competition winner will receive a $1,000 stipend to offset travel and accommodation costs.
Deadline: January 20, 2017
Share:
Non-MD cardiothoracic team professionals can submit a scientific poster for the Perioperative/Team-Based Care Poster Competition. Winning posters will be displayed at the AATS Centennial, April 29 – May 3 in Boston, MA.
The competition winner will receive a $1,000 stipend to offset travel and accommodation costs.
Deadline: January 20, 2017
Share:
Non-MD cardiothoracic team professionals can submit a scientific poster for the Perioperative/Team-Based Care Poster Competition. Winning posters will be displayed at the AATS Centennial, April 29 – May 3 in Boston, MA.
The competition winner will receive a $1,000 stipend to offset travel and accommodation costs.
Deadline: January 20, 2017
Share:
Non-MD CT Surgical Team Scientific Poster Opportunity
Non-MD cardiothoracic team professionals can submit a scientific poster for the Perioperative/Team-Based Care Poster Competition. Winning posters will be displayed at the AATS Centennial, April 29 – May 3 in Boston, MA.
The competition winner will receive a $1,000 stipend to offset travel and accommodation costs.
Deadline: January 20, 2017
Share:
Non-MD cardiothoracic team professionals can submit a scientific poster for the Perioperative/Team-Based Care Poster Competition. Winning posters will be displayed at the AATS Centennial, April 29 – May 3 in Boston, MA.
The competition winner will receive a $1,000 stipend to offset travel and accommodation costs.
Deadline: January 20, 2017
Share:
Non-MD cardiothoracic team professionals can submit a scientific poster for the Perioperative/Team-Based Care Poster Competition. Winning posters will be displayed at the AATS Centennial, April 29 – May 3 in Boston, MA.
The competition winner will receive a $1,000 stipend to offset travel and accommodation costs.
Deadline: January 20, 2017
Share:
First drug for spinal muscular atrophy approved
The antisense oligonucleotide drug nusinersen is the first therapy approved by the U.S. Food and Drug Administration to treat children and adults with spinal muscular atrophy.
The drug was developed by Ionis Pharmaceuticals and will be marketed by Biogen under the brand name Spinraza. The antisense oligonucleotide drug is administered via an intrathecal injection and promotes transcription of the full-length survival motor neuron (SMN) protein from the SMN2 gene.
The efficacy of nusinersen was tested during a randomized clinical trial in 121 patients with infantile-onset spinal muscular atrophy who were diagnosed before the age of 6 months or were younger than 7 months at the time of their first dose. Patients were randomized 2:1 to receive an injection of nusinersen into the fluid surrounding the spinal cord or undergo a mock procedure without drug injection (a skin prick).
A total of 82 of 121 patients who were randomized were eligible for an interim analysis of the results that was requested by the FDA. The results showed 40% of patients treated with nusinersen achieved improvement in motor milestones as defined in the study, whereas none of the control patients did. The side effects during the clinical trials among patients on nusinersen included upper respiratory infection, lower respiratory infection, and constipation. Warnings and precautions include low blood platelet count and renal toxicity. Neurotoxicity was observed in animal studies.
Read the full announcement from the agency here.
The antisense oligonucleotide drug nusinersen is the first therapy approved by the U.S. Food and Drug Administration to treat children and adults with spinal muscular atrophy.
The drug was developed by Ionis Pharmaceuticals and will be marketed by Biogen under the brand name Spinraza. The antisense oligonucleotide drug is administered via an intrathecal injection and promotes transcription of the full-length survival motor neuron (SMN) protein from the SMN2 gene.
The efficacy of nusinersen was tested during a randomized clinical trial in 121 patients with infantile-onset spinal muscular atrophy who were diagnosed before the age of 6 months or were younger than 7 months at the time of their first dose. Patients were randomized 2:1 to receive an injection of nusinersen into the fluid surrounding the spinal cord or undergo a mock procedure without drug injection (a skin prick).
A total of 82 of 121 patients who were randomized were eligible for an interim analysis of the results that was requested by the FDA. The results showed 40% of patients treated with nusinersen achieved improvement in motor milestones as defined in the study, whereas none of the control patients did. The side effects during the clinical trials among patients on nusinersen included upper respiratory infection, lower respiratory infection, and constipation. Warnings and precautions include low blood platelet count and renal toxicity. Neurotoxicity was observed in animal studies.
Read the full announcement from the agency here.
The antisense oligonucleotide drug nusinersen is the first therapy approved by the U.S. Food and Drug Administration to treat children and adults with spinal muscular atrophy.
The drug was developed by Ionis Pharmaceuticals and will be marketed by Biogen under the brand name Spinraza. The antisense oligonucleotide drug is administered via an intrathecal injection and promotes transcription of the full-length survival motor neuron (SMN) protein from the SMN2 gene.
The efficacy of nusinersen was tested during a randomized clinical trial in 121 patients with infantile-onset spinal muscular atrophy who were diagnosed before the age of 6 months or were younger than 7 months at the time of their first dose. Patients were randomized 2:1 to receive an injection of nusinersen into the fluid surrounding the spinal cord or undergo a mock procedure without drug injection (a skin prick).
A total of 82 of 121 patients who were randomized were eligible for an interim analysis of the results that was requested by the FDA. The results showed 40% of patients treated with nusinersen achieved improvement in motor milestones as defined in the study, whereas none of the control patients did. The side effects during the clinical trials among patients on nusinersen included upper respiratory infection, lower respiratory infection, and constipation. Warnings and precautions include low blood platelet count and renal toxicity. Neurotoxicity was observed in animal studies.
Read the full announcement from the agency here.
Ischemia-repairing cells fall short for treating intermittent claudication
NEW ORLEANS – Therapy with cells known to repair ischemic damage does not improve intermittent claudication of the legs in unselected patients, according to data from the randomized, phase II PACE trial reported at the American Heart Association scientific sessions. But some patients had evidence of new vessel formation.
“Administration of ALDH [aldehyde dehydrogenase] bright cells was feasible and safe, [but] administration at this dose and in this PAD [peripheral artery disease] cohort did not change peak walking time or MRI-based anatomic and perfusion endpoints,” reported Emerson C. Perin, MD, director of Clinical Research for Cardiovascular Medicine and medical director of the Stem Cell Center, both at the Texas Heart Institute, Houston.
However, “the MRI techniques developed and applied for the first time in a multicenter PAD clinical trial are now available for application in future PAD clinical research to determine if a clinically relevant therapeutic benefit might be achieved from cells or any other promising intervention,” he noted.
“One of the things in peripheral vascular disease that’s always been true is that peak walking time is a good clinical endpoint,” said session panelist Doris A. Taylor, PhD, director of Regenerative Medicine Research at the Texas Heart Institute. “[You] proposed some MRI parameters, but those didn’t correlate with peak walking time. So is the takeaway from this trial these MRI parameters? And if they don’t necessarily correlate, why would you advocate for them?”
Dr. Perin replied: “PAD is kind of the stepchild of cardiovascular medicine, it’s very poorly understood. And I think with the PACE trial, we’ve actually taken a huge step in understanding how we can treat these patients and how to study these patients.”
“Even though intermittent claudication or PAD starts with the flow limitation, what you wind up getting later down the road is not something that just relates to flow,” he elaborated. “We were able to study flow completely in this study – we owned it. What we weren’t able to study, and at the time we couldn’t, but now we can, is the metabolic, endothelial, and mitochondrial function. That is, what’s happening at the level of the muscle that is the missing link, together with the flow, that will give us these answers. So I think PACE [Patients With Intermittent Claudication Injected With ALDH Bright Cells] was very important to give us a greater understanding of where we can go now in PAD research.”
Trial details
Between 1 and 3 million people in the United States live with claudication, Dr. Perin noted when introducing the study. “It’s a very significant problem and a problem for which we really don’t have good solutions. We have one medicine [cilostazol], revascularization surgery, and stents that have recurrence – things that are less than perfect. There are also exercise programs, which not everyone has access to.”
The ALDH bright cells tested in PACE are collected from a patient’s bone marrow and express high levels of that enzyme. They are enriched for hematopoietic, endothelial progenitor, and multipotent mesenchymal colony-forming cells, and have shown ischemic repair capacity in preclinical models, with an increase in capillary density.
The investigators enrolled 82 patients with atherosclerotic peripheral arterial disease and symptom-limiting intermittent claudication of the legs. All had a pre-exercise ankle-brachial index of less than 0.9 or a pre-exercise toe-brachial index of less than 0.7, as well as stenosis greater than 50% or occlusion of infra-inguinal arteries by advanced imaging.
The patients were treated with 10 1-mL injections of ALDH bright cells or placebo into muscles of the posterior lower thigh and calf.
Results showed that after 6 months, peak treadmill walking time had improved by 2.2 minutes in the cell therapy group and 1.2 minutes in the placebo group, but the difference was not significant, Dr. Perin reported. The groups also were statistically indistinguishable overall with respect to changes in ankle-brachial index, walking impairment, and symptoms, and in MRI-assessed collateral count, peak hyperemic flow in the popliteal artery, and capillary perfusion.
However, among the subgroup of patients having a pre-exercise ankle-brachial index of 0.6 or less at baseline, collateral count increased by 2.4 in the cell therapy group, compared with 0.5 in the placebo group (P = .021).
In addition, among patients who had occluded femoral arteries at baseline (having more collateral vessels than peers with patent femoral arteries), the number of collaterals increased by 1.5 in the cell therapy group, compared with 0.3 in the placebo group (P = .047).
“This suggests an arteriogenic effect of cell therapy in patients with an occluded femoral artery substrate,” said Dr. Perin, who disclosed that he received a research grant from the National Heart, Lung, and Blood Institute.
NEW ORLEANS – Therapy with cells known to repair ischemic damage does not improve intermittent claudication of the legs in unselected patients, according to data from the randomized, phase II PACE trial reported at the American Heart Association scientific sessions. But some patients had evidence of new vessel formation.
“Administration of ALDH [aldehyde dehydrogenase] bright cells was feasible and safe, [but] administration at this dose and in this PAD [peripheral artery disease] cohort did not change peak walking time or MRI-based anatomic and perfusion endpoints,” reported Emerson C. Perin, MD, director of Clinical Research for Cardiovascular Medicine and medical director of the Stem Cell Center, both at the Texas Heart Institute, Houston.
However, “the MRI techniques developed and applied for the first time in a multicenter PAD clinical trial are now available for application in future PAD clinical research to determine if a clinically relevant therapeutic benefit might be achieved from cells or any other promising intervention,” he noted.
“One of the things in peripheral vascular disease that’s always been true is that peak walking time is a good clinical endpoint,” said session panelist Doris A. Taylor, PhD, director of Regenerative Medicine Research at the Texas Heart Institute. “[You] proposed some MRI parameters, but those didn’t correlate with peak walking time. So is the takeaway from this trial these MRI parameters? And if they don’t necessarily correlate, why would you advocate for them?”
Dr. Perin replied: “PAD is kind of the stepchild of cardiovascular medicine, it’s very poorly understood. And I think with the PACE trial, we’ve actually taken a huge step in understanding how we can treat these patients and how to study these patients.”
“Even though intermittent claudication or PAD starts with the flow limitation, what you wind up getting later down the road is not something that just relates to flow,” he elaborated. “We were able to study flow completely in this study – we owned it. What we weren’t able to study, and at the time we couldn’t, but now we can, is the metabolic, endothelial, and mitochondrial function. That is, what’s happening at the level of the muscle that is the missing link, together with the flow, that will give us these answers. So I think PACE [Patients With Intermittent Claudication Injected With ALDH Bright Cells] was very important to give us a greater understanding of where we can go now in PAD research.”
Trial details
Between 1 and 3 million people in the United States live with claudication, Dr. Perin noted when introducing the study. “It’s a very significant problem and a problem for which we really don’t have good solutions. We have one medicine [cilostazol], revascularization surgery, and stents that have recurrence – things that are less than perfect. There are also exercise programs, which not everyone has access to.”
The ALDH bright cells tested in PACE are collected from a patient’s bone marrow and express high levels of that enzyme. They are enriched for hematopoietic, endothelial progenitor, and multipotent mesenchymal colony-forming cells, and have shown ischemic repair capacity in preclinical models, with an increase in capillary density.
The investigators enrolled 82 patients with atherosclerotic peripheral arterial disease and symptom-limiting intermittent claudication of the legs. All had a pre-exercise ankle-brachial index of less than 0.9 or a pre-exercise toe-brachial index of less than 0.7, as well as stenosis greater than 50% or occlusion of infra-inguinal arteries by advanced imaging.
The patients were treated with 10 1-mL injections of ALDH bright cells or placebo into muscles of the posterior lower thigh and calf.
Results showed that after 6 months, peak treadmill walking time had improved by 2.2 minutes in the cell therapy group and 1.2 minutes in the placebo group, but the difference was not significant, Dr. Perin reported. The groups also were statistically indistinguishable overall with respect to changes in ankle-brachial index, walking impairment, and symptoms, and in MRI-assessed collateral count, peak hyperemic flow in the popliteal artery, and capillary perfusion.
However, among the subgroup of patients having a pre-exercise ankle-brachial index of 0.6 or less at baseline, collateral count increased by 2.4 in the cell therapy group, compared with 0.5 in the placebo group (P = .021).
In addition, among patients who had occluded femoral arteries at baseline (having more collateral vessels than peers with patent femoral arteries), the number of collaterals increased by 1.5 in the cell therapy group, compared with 0.3 in the placebo group (P = .047).
“This suggests an arteriogenic effect of cell therapy in patients with an occluded femoral artery substrate,” said Dr. Perin, who disclosed that he received a research grant from the National Heart, Lung, and Blood Institute.
NEW ORLEANS – Therapy with cells known to repair ischemic damage does not improve intermittent claudication of the legs in unselected patients, according to data from the randomized, phase II PACE trial reported at the American Heart Association scientific sessions. But some patients had evidence of new vessel formation.
“Administration of ALDH [aldehyde dehydrogenase] bright cells was feasible and safe, [but] administration at this dose and in this PAD [peripheral artery disease] cohort did not change peak walking time or MRI-based anatomic and perfusion endpoints,” reported Emerson C. Perin, MD, director of Clinical Research for Cardiovascular Medicine and medical director of the Stem Cell Center, both at the Texas Heart Institute, Houston.
However, “the MRI techniques developed and applied for the first time in a multicenter PAD clinical trial are now available for application in future PAD clinical research to determine if a clinically relevant therapeutic benefit might be achieved from cells or any other promising intervention,” he noted.
“One of the things in peripheral vascular disease that’s always been true is that peak walking time is a good clinical endpoint,” said session panelist Doris A. Taylor, PhD, director of Regenerative Medicine Research at the Texas Heart Institute. “[You] proposed some MRI parameters, but those didn’t correlate with peak walking time. So is the takeaway from this trial these MRI parameters? And if they don’t necessarily correlate, why would you advocate for them?”
Dr. Perin replied: “PAD is kind of the stepchild of cardiovascular medicine, it’s very poorly understood. And I think with the PACE trial, we’ve actually taken a huge step in understanding how we can treat these patients and how to study these patients.”
“Even though intermittent claudication or PAD starts with the flow limitation, what you wind up getting later down the road is not something that just relates to flow,” he elaborated. “We were able to study flow completely in this study – we owned it. What we weren’t able to study, and at the time we couldn’t, but now we can, is the metabolic, endothelial, and mitochondrial function. That is, what’s happening at the level of the muscle that is the missing link, together with the flow, that will give us these answers. So I think PACE [Patients With Intermittent Claudication Injected With ALDH Bright Cells] was very important to give us a greater understanding of where we can go now in PAD research.”
Trial details
Between 1 and 3 million people in the United States live with claudication, Dr. Perin noted when introducing the study. “It’s a very significant problem and a problem for which we really don’t have good solutions. We have one medicine [cilostazol], revascularization surgery, and stents that have recurrence – things that are less than perfect. There are also exercise programs, which not everyone has access to.”
The ALDH bright cells tested in PACE are collected from a patient’s bone marrow and express high levels of that enzyme. They are enriched for hematopoietic, endothelial progenitor, and multipotent mesenchymal colony-forming cells, and have shown ischemic repair capacity in preclinical models, with an increase in capillary density.
The investigators enrolled 82 patients with atherosclerotic peripheral arterial disease and symptom-limiting intermittent claudication of the legs. All had a pre-exercise ankle-brachial index of less than 0.9 or a pre-exercise toe-brachial index of less than 0.7, as well as stenosis greater than 50% or occlusion of infra-inguinal arteries by advanced imaging.
The patients were treated with 10 1-mL injections of ALDH bright cells or placebo into muscles of the posterior lower thigh and calf.
Results showed that after 6 months, peak treadmill walking time had improved by 2.2 minutes in the cell therapy group and 1.2 minutes in the placebo group, but the difference was not significant, Dr. Perin reported. The groups also were statistically indistinguishable overall with respect to changes in ankle-brachial index, walking impairment, and symptoms, and in MRI-assessed collateral count, peak hyperemic flow in the popliteal artery, and capillary perfusion.
However, among the subgroup of patients having a pre-exercise ankle-brachial index of 0.6 or less at baseline, collateral count increased by 2.4 in the cell therapy group, compared with 0.5 in the placebo group (P = .021).
In addition, among patients who had occluded femoral arteries at baseline (having more collateral vessels than peers with patent femoral arteries), the number of collaterals increased by 1.5 in the cell therapy group, compared with 0.3 in the placebo group (P = .047).
“This suggests an arteriogenic effect of cell therapy in patients with an occluded femoral artery substrate,” said Dr. Perin, who disclosed that he received a research grant from the National Heart, Lung, and Blood Institute.
Key clinical point:
Major finding: At 6 months, peak walking time had increased by 2.2 minutes in the cell therapy group and 1.2 minutes in the placebo group, a nonsignificant difference (P = .238).
Data source: PACE, a randomized phase II trial of 82 patients with PAD and symptom-limiting intermittent claudication of the legs.
Disclosures: Dr. Perin received a research grant from the National Heart, Lung, and Blood Institute.
A Rare Association in Down Syndrome: Milialike Idiopathic Calcinosis Cutis and Palpebral Syringoma
To the Editor:
Down syndrome (DS) is associated with rare dermatological disorders, and the prevalence of some common dermatoses is greater in patients with DS. We report a case of milialike idiopathic calcinosis cutis (MICC) associated with syringomas in a patient with DS. We emphasize that MICC is one of the rare dermatoses associated with DS.
A 4-year-old girl with DS presented with a 4-mm, flesh-colored, regular-bordered, exophytic papular lesion on the left upper eyelid of 8 months' duration (Figure 1). It was clinically recognized as syringoma. On dermatologic examination of the patient, there also were 1- to 3-mm, round, whitish, painless, milialike papules on the dorsal surface of the hands and wrists (Figure 2). Some of these papules were surrounded by erythema. There was no sign of perforation. Her personal and family history were unremarkable.
Histopathologic examination of a biopsy from a milialike lesion on the hand showed a hyperkeratotic epidermis. In the dermis there was a roundish calcific nodule surrounded by a fibrovascular rim. The patient's guardians refused a biopsy from the lesion on the eyelid.
Laboratory tests including serum vitamin D, thyroid and parathyroid hormone, calcium, phosphorus, and urinary calcium levels, as well as renal function tests, were within reference range. On the basis of these clinical and histopathological findings, the patient was diagnosed with MICC and palpebral syringoma.
Many dermatoses associated with DS have been reported including elastosis perforans serpiginosa, alopecia areata, and syringomas.1-3 Sano et al4 first described MICC and syringomas in a patient with DS in 1978. Milialike idiopathic calcinosis cutis is characterized by asymptomatic, millimetric, firm, round, whitish papules that are sometimes surrounded by erythema. These papules may show perforation leading to transepidermal elimination of calcium, similar to the transdermal elimination of elastic fibrils in elastosis perforans serpiginosa. Although MICC usually is described in acral sites of children with DS, it also is reported in adults without DS and on other parts of the body.5-7
The cause of MICC is unknown. One hypothesis of the development of MICC is an increase of the calcium content in the sweat leading to calcification of the acrosyringium.8 Milia are small keratin cysts that usually develop by occlusion of the hair follicle, sweat duct, or sebaceous duct. However, milia also can occur from occlusion of the eccrine ducts where syringomas originate.9 Therefore, syringomas can be seen in association with milia and calcium deposits.5,9-11
We believe that MICC in DS may be more common than usually recognized, as the lesions often are asymptomatic. It is important to differentiate MICC from other dermatological diseases such as molluscum contagiosum, verruca plana, milia, and inclusion cysts. Histopathology and dermoscopy could aid in the accurate diagnosis of MICC.
- Dourmishev A, Miteva L, Mitev V, et al. Cutaneous aspects of Down syndrome. Cutis. 2000;66:420-424.
- Madan V, Williams J, Lear JT. Dermatological manifestations of Down's syndrome. Clin Exp Dermatol. 2006;31:623-629.
- Schepis C, Barone C, Siragusa M, et al. An updated survey on skin conditions in Down syndrome. Dermatology. 2002;205:234-238.
- Sano T, Tate S, Ishikawa C. A case of Down's syndrome associated with syringoma, milia, and subepidermal calcified nodule. Jpn J Dermatol. 1978;88:740.
- Schepis C, Siragusa M, Palazzo R, et al. Perforating milia-like idiopathic calcinosis cutis and periorbital syringomas in a girl with Down syndrome. Pediatr Dermatol. 1994;11:258-260.
- Schepis C, Siragusa M, Palazzo R, et al. Milia like idiopathic calcinosis cutis: an unusual dermatosis associated with Down syndrome. Br J Dermatol. 1996;134:143-146.
- Houtappel M, Leguit R, Sigurdsson V. Milia-like idiopathic calcinosis cutis in an adult without Down's syndrome. J Dermatol Case Rep. 2007;1:16-19.
- Eng AM, Mandrea E. Perforating calcinosis cutis presenting as milia. J Cutan Pathol. 1981;8:247-250.
- Wang KH, Chu JS, Lin YH, et al. Milium-like syringoma: a case study on histogenesis. J Cutan Pathol. 2004;31:336-340.
- Weiss E, Paez E, Greenberg AS, et al. Eruptive syringomas associated with milia. Int J Dermatol. 1995;34:193-195.
- Kim SJ, Won YH, Chun IK. Subepidermal calcified nodules and syringoma. J Eur Acad Dermatol Venereol. 1997;8:51-52.
To the Editor:
Down syndrome (DS) is associated with rare dermatological disorders, and the prevalence of some common dermatoses is greater in patients with DS. We report a case of milialike idiopathic calcinosis cutis (MICC) associated with syringomas in a patient with DS. We emphasize that MICC is one of the rare dermatoses associated with DS.
A 4-year-old girl with DS presented with a 4-mm, flesh-colored, regular-bordered, exophytic papular lesion on the left upper eyelid of 8 months' duration (Figure 1). It was clinically recognized as syringoma. On dermatologic examination of the patient, there also were 1- to 3-mm, round, whitish, painless, milialike papules on the dorsal surface of the hands and wrists (Figure 2). Some of these papules were surrounded by erythema. There was no sign of perforation. Her personal and family history were unremarkable.
Histopathologic examination of a biopsy from a milialike lesion on the hand showed a hyperkeratotic epidermis. In the dermis there was a roundish calcific nodule surrounded by a fibrovascular rim. The patient's guardians refused a biopsy from the lesion on the eyelid.
Laboratory tests including serum vitamin D, thyroid and parathyroid hormone, calcium, phosphorus, and urinary calcium levels, as well as renal function tests, were within reference range. On the basis of these clinical and histopathological findings, the patient was diagnosed with MICC and palpebral syringoma.
Many dermatoses associated with DS have been reported including elastosis perforans serpiginosa, alopecia areata, and syringomas.1-3 Sano et al4 first described MICC and syringomas in a patient with DS in 1978. Milialike idiopathic calcinosis cutis is characterized by asymptomatic, millimetric, firm, round, whitish papules that are sometimes surrounded by erythema. These papules may show perforation leading to transepidermal elimination of calcium, similar to the transdermal elimination of elastic fibrils in elastosis perforans serpiginosa. Although MICC usually is described in acral sites of children with DS, it also is reported in adults without DS and on other parts of the body.5-7
The cause of MICC is unknown. One hypothesis of the development of MICC is an increase of the calcium content in the sweat leading to calcification of the acrosyringium.8 Milia are small keratin cysts that usually develop by occlusion of the hair follicle, sweat duct, or sebaceous duct. However, milia also can occur from occlusion of the eccrine ducts where syringomas originate.9 Therefore, syringomas can be seen in association with milia and calcium deposits.5,9-11
We believe that MICC in DS may be more common than usually recognized, as the lesions often are asymptomatic. It is important to differentiate MICC from other dermatological diseases such as molluscum contagiosum, verruca plana, milia, and inclusion cysts. Histopathology and dermoscopy could aid in the accurate diagnosis of MICC.
To the Editor:
Down syndrome (DS) is associated with rare dermatological disorders, and the prevalence of some common dermatoses is greater in patients with DS. We report a case of milialike idiopathic calcinosis cutis (MICC) associated with syringomas in a patient with DS. We emphasize that MICC is one of the rare dermatoses associated with DS.
A 4-year-old girl with DS presented with a 4-mm, flesh-colored, regular-bordered, exophytic papular lesion on the left upper eyelid of 8 months' duration (Figure 1). It was clinically recognized as syringoma. On dermatologic examination of the patient, there also were 1- to 3-mm, round, whitish, painless, milialike papules on the dorsal surface of the hands and wrists (Figure 2). Some of these papules were surrounded by erythema. There was no sign of perforation. Her personal and family history were unremarkable.
Histopathologic examination of a biopsy from a milialike lesion on the hand showed a hyperkeratotic epidermis. In the dermis there was a roundish calcific nodule surrounded by a fibrovascular rim. The patient's guardians refused a biopsy from the lesion on the eyelid.
Laboratory tests including serum vitamin D, thyroid and parathyroid hormone, calcium, phosphorus, and urinary calcium levels, as well as renal function tests, were within reference range. On the basis of these clinical and histopathological findings, the patient was diagnosed with MICC and palpebral syringoma.
Many dermatoses associated with DS have been reported including elastosis perforans serpiginosa, alopecia areata, and syringomas.1-3 Sano et al4 first described MICC and syringomas in a patient with DS in 1978. Milialike idiopathic calcinosis cutis is characterized by asymptomatic, millimetric, firm, round, whitish papules that are sometimes surrounded by erythema. These papules may show perforation leading to transepidermal elimination of calcium, similar to the transdermal elimination of elastic fibrils in elastosis perforans serpiginosa. Although MICC usually is described in acral sites of children with DS, it also is reported in adults without DS and on other parts of the body.5-7
The cause of MICC is unknown. One hypothesis of the development of MICC is an increase of the calcium content in the sweat leading to calcification of the acrosyringium.8 Milia are small keratin cysts that usually develop by occlusion of the hair follicle, sweat duct, or sebaceous duct. However, milia also can occur from occlusion of the eccrine ducts where syringomas originate.9 Therefore, syringomas can be seen in association with milia and calcium deposits.5,9-11
We believe that MICC in DS may be more common than usually recognized, as the lesions often are asymptomatic. It is important to differentiate MICC from other dermatological diseases such as molluscum contagiosum, verruca plana, milia, and inclusion cysts. Histopathology and dermoscopy could aid in the accurate diagnosis of MICC.
- Dourmishev A, Miteva L, Mitev V, et al. Cutaneous aspects of Down syndrome. Cutis. 2000;66:420-424.
- Madan V, Williams J, Lear JT. Dermatological manifestations of Down's syndrome. Clin Exp Dermatol. 2006;31:623-629.
- Schepis C, Barone C, Siragusa M, et al. An updated survey on skin conditions in Down syndrome. Dermatology. 2002;205:234-238.
- Sano T, Tate S, Ishikawa C. A case of Down's syndrome associated with syringoma, milia, and subepidermal calcified nodule. Jpn J Dermatol. 1978;88:740.
- Schepis C, Siragusa M, Palazzo R, et al. Perforating milia-like idiopathic calcinosis cutis and periorbital syringomas in a girl with Down syndrome. Pediatr Dermatol. 1994;11:258-260.
- Schepis C, Siragusa M, Palazzo R, et al. Milia like idiopathic calcinosis cutis: an unusual dermatosis associated with Down syndrome. Br J Dermatol. 1996;134:143-146.
- Houtappel M, Leguit R, Sigurdsson V. Milia-like idiopathic calcinosis cutis in an adult without Down's syndrome. J Dermatol Case Rep. 2007;1:16-19.
- Eng AM, Mandrea E. Perforating calcinosis cutis presenting as milia. J Cutan Pathol. 1981;8:247-250.
- Wang KH, Chu JS, Lin YH, et al. Milium-like syringoma: a case study on histogenesis. J Cutan Pathol. 2004;31:336-340.
- Weiss E, Paez E, Greenberg AS, et al. Eruptive syringomas associated with milia. Int J Dermatol. 1995;34:193-195.
- Kim SJ, Won YH, Chun IK. Subepidermal calcified nodules and syringoma. J Eur Acad Dermatol Venereol. 1997;8:51-52.
- Dourmishev A, Miteva L, Mitev V, et al. Cutaneous aspects of Down syndrome. Cutis. 2000;66:420-424.
- Madan V, Williams J, Lear JT. Dermatological manifestations of Down's syndrome. Clin Exp Dermatol. 2006;31:623-629.
- Schepis C, Barone C, Siragusa M, et al. An updated survey on skin conditions in Down syndrome. Dermatology. 2002;205:234-238.
- Sano T, Tate S, Ishikawa C. A case of Down's syndrome associated with syringoma, milia, and subepidermal calcified nodule. Jpn J Dermatol. 1978;88:740.
- Schepis C, Siragusa M, Palazzo R, et al. Perforating milia-like idiopathic calcinosis cutis and periorbital syringomas in a girl with Down syndrome. Pediatr Dermatol. 1994;11:258-260.
- Schepis C, Siragusa M, Palazzo R, et al. Milia like idiopathic calcinosis cutis: an unusual dermatosis associated with Down syndrome. Br J Dermatol. 1996;134:143-146.
- Houtappel M, Leguit R, Sigurdsson V. Milia-like idiopathic calcinosis cutis in an adult without Down's syndrome. J Dermatol Case Rep. 2007;1:16-19.
- Eng AM, Mandrea E. Perforating calcinosis cutis presenting as milia. J Cutan Pathol. 1981;8:247-250.
- Wang KH, Chu JS, Lin YH, et al. Milium-like syringoma: a case study on histogenesis. J Cutan Pathol. 2004;31:336-340.
- Weiss E, Paez E, Greenberg AS, et al. Eruptive syringomas associated with milia. Int J Dermatol. 1995;34:193-195.
- Kim SJ, Won YH, Chun IK. Subepidermal calcified nodules and syringoma. J Eur Acad Dermatol Venereol. 1997;8:51-52.
Practice Points
- Down syndrome is associated with rare dermatological disorders and an increased prevalence of common dermatoses.
- It is important to differentiate milialike idiopathic calcinosis cutis from other dermatological diseases using histopathology and dermoscopy.
Mesh fixation method had no impact on chronic postop pain in TAPP
WASHINGTON – Mesh fixation technique is not a factor in persistent pain after transabdominal preperitoneal (TAPP) groin hernia surgery, a study showed.
“Persistent pain is a well-known phenomenon after groin hernia surgery,” said Jakob Burcharth, MD, of University Hospital of Sjaelland Koge (Denmark). “The way that we fixate the mesh in laparoscopic surgery has been hypothesized to have an [impact] on the risk of persistent pain.”
In a study presented by Dr. Burcharth and his associates at the American College of Surgeons Clinical Congress, a total of 1,421 patients were examined. Each patient completed a validated pain questionnaire through the Danish Hernia Database from 2009 to 2012. The patients were divided into two groups: Group 1 had spray fibrin sealant (34%) for mesh fixation, and group 2 had tacks (66%). The results showed no difference between the groups in terms of pain in getting up from a chair, sitting or standing for more than 30 minutes, walking stairs, driving a car, or exercising, or in the need for postoperative analgesics or postoperative sick leave (all P greater than .20).
Dr. Burcharth concluded that a high number of patients reported persistent pain regardless of mesh fixation technique, which emphasizes the need for preoperative information.
Dr. Burcharth reported having no relevant financial disclosures.
WASHINGTON – Mesh fixation technique is not a factor in persistent pain after transabdominal preperitoneal (TAPP) groin hernia surgery, a study showed.
“Persistent pain is a well-known phenomenon after groin hernia surgery,” said Jakob Burcharth, MD, of University Hospital of Sjaelland Koge (Denmark). “The way that we fixate the mesh in laparoscopic surgery has been hypothesized to have an [impact] on the risk of persistent pain.”
In a study presented by Dr. Burcharth and his associates at the American College of Surgeons Clinical Congress, a total of 1,421 patients were examined. Each patient completed a validated pain questionnaire through the Danish Hernia Database from 2009 to 2012. The patients were divided into two groups: Group 1 had spray fibrin sealant (34%) for mesh fixation, and group 2 had tacks (66%). The results showed no difference between the groups in terms of pain in getting up from a chair, sitting or standing for more than 30 minutes, walking stairs, driving a car, or exercising, or in the need for postoperative analgesics or postoperative sick leave (all P greater than .20).
Dr. Burcharth concluded that a high number of patients reported persistent pain regardless of mesh fixation technique, which emphasizes the need for preoperative information.
Dr. Burcharth reported having no relevant financial disclosures.
WASHINGTON – Mesh fixation technique is not a factor in persistent pain after transabdominal preperitoneal (TAPP) groin hernia surgery, a study showed.
“Persistent pain is a well-known phenomenon after groin hernia surgery,” said Jakob Burcharth, MD, of University Hospital of Sjaelland Koge (Denmark). “The way that we fixate the mesh in laparoscopic surgery has been hypothesized to have an [impact] on the risk of persistent pain.”
In a study presented by Dr. Burcharth and his associates at the American College of Surgeons Clinical Congress, a total of 1,421 patients were examined. Each patient completed a validated pain questionnaire through the Danish Hernia Database from 2009 to 2012. The patients were divided into two groups: Group 1 had spray fibrin sealant (34%) for mesh fixation, and group 2 had tacks (66%). The results showed no difference between the groups in terms of pain in getting up from a chair, sitting or standing for more than 30 minutes, walking stairs, driving a car, or exercising, or in the need for postoperative analgesics or postoperative sick leave (all P greater than .20).
Dr. Burcharth concluded that a high number of patients reported persistent pain regardless of mesh fixation technique, which emphasizes the need for preoperative information.
Dr. Burcharth reported having no relevant financial disclosures.
Key clinical point:
Major finding: There was no difference between the groups in terms of pain in getting up from a chair, sitting or standing for more than 30 minutes, walking stairs, driving a car, or doing exercise, or in the need for postoperative analgesics or postoperative sick leave (all P greater than .20).
Data source: 1,421 patients who were examined and completed a validated pain questionnaire.
Disclosures: Dr. Burcharth reported having no relevant financial disclosures.
BRAIN Initiative could help end mental illness stigma
BETHESDA, MD – Top researchers are optimistic that billions in funding for basic neuroscience research made possible by the 21st Century Cures Act will lead to breakthroughs in the understanding of brain function and dysfunction that could help end the stigma of mental illness.
Under the new law, $6.3 billion are slated for health initiatives over the next decade. The Cancer Moonshot will receive $1.8 billion, precision medicine will receive just under $1.5 billion, and the BRAIN Initiative (Brain Research Through Advancing Innovative Neurotechnologies) will receive just over that amount.
“I know there have been some anxieties about the program’s fragilities given the change in administration,” Dr. Collins told an audience at a meeting of the NIH Brain Institute investigators. “But [passage of the 21st Century Cures Act] should be a source of great reassurance.”
The actual cost of the BRAIN Initiative is expected to top $4.5 billion by the year 2025, funded by a mix of federal and private monies. The National Institute of Mental Health’s typical annual budget is just under $1.5 billion – essentially the same as the amount provided for in the new law. The funds will benefit neuroscience generally, and if successful, understanding of the brain specifically.
The BRAIN Initiative funding is not for clinical studies, however. Instead, it will be spread across what Dr. Collins dubbed, “Team Science,” a multidisciplinary band of investigators, all of whom are expected to help not only identify the brain’s biologic processes but also create the tools needed to reengineer the brain’s circuitry when it malfunctions. Some current BRAIN projects Dr. Collins singled out as worth watching were the use of ultrasound neuromodulation in nonhuman primates, the analysis of individual methylone in cell nuclei, and the development of ultrahigh-resolution 3D brain imaging technology.
“We are moving toward a full bore effort toward technologies that allow us to see what is happening in real time in circuits in the brain,” Dr. Collins said. “Maybe there are certain fundamental operating principles that may have eluded us in the past but which may start to appear.”
In 2016, there were as many neuroscientists as there were engineers of all types – 141 each – named as the principal investigators of projects funded by the initiative, according to NIMH Director Joshua A. Gordon, MD, PhD, who also spoke at the meeting. Among the other disciplines Dr. Gordon said were represented in the 2016 roster of investigators were 61 radiologists, 33 biostatisticians, 47 neurosurgeons, and 69 psychiatrists and psychologists.
The enormous focus on bench science – about 85% of all NIMH funding is for nonclinical research – is not without its critics. In a recent editorial, several prominent academic clinicians urged the NIMH to spend less on futuristic neuroscience and more on the application of therapies for those with mental illness, and on their psychosocial needs (Br J Psychiatry. 2016;208[6]507-9). The last-minute inclusion in the 21st Century Cures Act of several provisions that will have a direct impact in the near future on the plight of those with severe mental illness has the potential to allay some concerns, however.
“My hope is that the [law] will be interpreted from the perspective of making effective treatments available for ... those who are already ill,” Susan M. Essock, PhD, the Edna L. Edison Professor of Medical Psychology (in Psychiatry) at Columbia University, New York, and a cosigner of the editorial, said in an interview.
The law aims to drive evidence-based grant making for programs such as the Recovery After an Initial Schizophrenia Episode (RAISE) integrated care model and expands assisted outpatient treatment for children with serious emotional disturbance, or adults with serious mental illness, among several other provisions.
For some, the initiative’s cross-specialty structure and hefty price tag are worthwhile if it means filling the void of basic science necessary to explain the mechanics of mental illness, a void often filled with attitudes leading to the stigmatization of people who are ill.
Dr. Mayberg said she believes that a “systems approach” to behavior will emerge over time as interdisciplinary BRAIN Initiative researchers are given the freedom to make necessary discoveries, often when least expected, and are urged to share what they find. “Real fundamental changes happen by accident, in my experience. They are rarely planned. It happens when there are a lot of clues. A diversified portfolio has to be the answer, because nobody is smart enough to do it all [alone]. The goal is diversified, evidence-based approaches. ... Science has to make fundamental progress on how the brain works, because we’re obviously missing something clinically,” she said.
The ultimate goals of the initiative are to understand human beings and to improve the human condition by alleviating suffering, according to Brian Litt, MD, professor of neurology and bioengineering at the University of Pennsylvania, Philadelphia, and a moderator of a panel focused on the clinical implications of BRAIN research.
“If you think about the fundamental problems that affect our society and many around the world, they’re not just diseases like Parkinson’s or epilepsy, they are the disorders of mood, addiction, violence, anger, and a number of other conditions that affect behavior that are part of the neurological spectrum that affects the way our society functions,” Dr. Litt, a clinician specializing in treating people with epilepsy, told the audience.
Rather than create a neuroengineered super race, he said, fundamental neuroscience is about helping humans reach their fullest potential. For his support of this, Dr. Litt said he makes “no apologies. As a clinician, I am not sorry to be involved in fundamental neuroscience where ... incremental discoveries can create cures.”
As science favors cures, policy inevitably will evolve, perhaps even making current interventions relics of ignorance. “Psychosocial intervention is what you do when you have an absence of knowing how to cure,” said Dr. Mayberg. “It might be that [currently] what we treat is maladaptation to the primary problem.”
The key for clinicians, she said, will be to keep up with the latest literature. “Clinicians have to be aware of what’s exciting, of what should be in their armamentarium.”
Dr. Collins, Dr. Gordon, Dr. Essock, and Dr. Mayberg had no disclosures. Dr. Litt has cofounded several companies, including Blackfynn and Neuropace, and has served as a consultant and licensed technology to several companies.
[email protected]
On Twitter @whitneymcknight
BETHESDA, MD – Top researchers are optimistic that billions in funding for basic neuroscience research made possible by the 21st Century Cures Act will lead to breakthroughs in the understanding of brain function and dysfunction that could help end the stigma of mental illness.
Under the new law, $6.3 billion are slated for health initiatives over the next decade. The Cancer Moonshot will receive $1.8 billion, precision medicine will receive just under $1.5 billion, and the BRAIN Initiative (Brain Research Through Advancing Innovative Neurotechnologies) will receive just over that amount.
“I know there have been some anxieties about the program’s fragilities given the change in administration,” Dr. Collins told an audience at a meeting of the NIH Brain Institute investigators. “But [passage of the 21st Century Cures Act] should be a source of great reassurance.”
The actual cost of the BRAIN Initiative is expected to top $4.5 billion by the year 2025, funded by a mix of federal and private monies. The National Institute of Mental Health’s typical annual budget is just under $1.5 billion – essentially the same as the amount provided for in the new law. The funds will benefit neuroscience generally, and if successful, understanding of the brain specifically.
The BRAIN Initiative funding is not for clinical studies, however. Instead, it will be spread across what Dr. Collins dubbed, “Team Science,” a multidisciplinary band of investigators, all of whom are expected to help not only identify the brain’s biologic processes but also create the tools needed to reengineer the brain’s circuitry when it malfunctions. Some current BRAIN projects Dr. Collins singled out as worth watching were the use of ultrasound neuromodulation in nonhuman primates, the analysis of individual methylone in cell nuclei, and the development of ultrahigh-resolution 3D brain imaging technology.
“We are moving toward a full bore effort toward technologies that allow us to see what is happening in real time in circuits in the brain,” Dr. Collins said. “Maybe there are certain fundamental operating principles that may have eluded us in the past but which may start to appear.”
In 2016, there were as many neuroscientists as there were engineers of all types – 141 each – named as the principal investigators of projects funded by the initiative, according to NIMH Director Joshua A. Gordon, MD, PhD, who also spoke at the meeting. Among the other disciplines Dr. Gordon said were represented in the 2016 roster of investigators were 61 radiologists, 33 biostatisticians, 47 neurosurgeons, and 69 psychiatrists and psychologists.
The enormous focus on bench science – about 85% of all NIMH funding is for nonclinical research – is not without its critics. In a recent editorial, several prominent academic clinicians urged the NIMH to spend less on futuristic neuroscience and more on the application of therapies for those with mental illness, and on their psychosocial needs (Br J Psychiatry. 2016;208[6]507-9). The last-minute inclusion in the 21st Century Cures Act of several provisions that will have a direct impact in the near future on the plight of those with severe mental illness has the potential to allay some concerns, however.
“My hope is that the [law] will be interpreted from the perspective of making effective treatments available for ... those who are already ill,” Susan M. Essock, PhD, the Edna L. Edison Professor of Medical Psychology (in Psychiatry) at Columbia University, New York, and a cosigner of the editorial, said in an interview.
The law aims to drive evidence-based grant making for programs such as the Recovery After an Initial Schizophrenia Episode (RAISE) integrated care model and expands assisted outpatient treatment for children with serious emotional disturbance, or adults with serious mental illness, among several other provisions.
For some, the initiative’s cross-specialty structure and hefty price tag are worthwhile if it means filling the void of basic science necessary to explain the mechanics of mental illness, a void often filled with attitudes leading to the stigmatization of people who are ill.
Dr. Mayberg said she believes that a “systems approach” to behavior will emerge over time as interdisciplinary BRAIN Initiative researchers are given the freedom to make necessary discoveries, often when least expected, and are urged to share what they find. “Real fundamental changes happen by accident, in my experience. They are rarely planned. It happens when there are a lot of clues. A diversified portfolio has to be the answer, because nobody is smart enough to do it all [alone]. The goal is diversified, evidence-based approaches. ... Science has to make fundamental progress on how the brain works, because we’re obviously missing something clinically,” she said.
The ultimate goals of the initiative are to understand human beings and to improve the human condition by alleviating suffering, according to Brian Litt, MD, professor of neurology and bioengineering at the University of Pennsylvania, Philadelphia, and a moderator of a panel focused on the clinical implications of BRAIN research.
“If you think about the fundamental problems that affect our society and many around the world, they’re not just diseases like Parkinson’s or epilepsy, they are the disorders of mood, addiction, violence, anger, and a number of other conditions that affect behavior that are part of the neurological spectrum that affects the way our society functions,” Dr. Litt, a clinician specializing in treating people with epilepsy, told the audience.
Rather than create a neuroengineered super race, he said, fundamental neuroscience is about helping humans reach their fullest potential. For his support of this, Dr. Litt said he makes “no apologies. As a clinician, I am not sorry to be involved in fundamental neuroscience where ... incremental discoveries can create cures.”
As science favors cures, policy inevitably will evolve, perhaps even making current interventions relics of ignorance. “Psychosocial intervention is what you do when you have an absence of knowing how to cure,” said Dr. Mayberg. “It might be that [currently] what we treat is maladaptation to the primary problem.”
The key for clinicians, she said, will be to keep up with the latest literature. “Clinicians have to be aware of what’s exciting, of what should be in their armamentarium.”
Dr. Collins, Dr. Gordon, Dr. Essock, and Dr. Mayberg had no disclosures. Dr. Litt has cofounded several companies, including Blackfynn and Neuropace, and has served as a consultant and licensed technology to several companies.
[email protected]
On Twitter @whitneymcknight
BETHESDA, MD – Top researchers are optimistic that billions in funding for basic neuroscience research made possible by the 21st Century Cures Act will lead to breakthroughs in the understanding of brain function and dysfunction that could help end the stigma of mental illness.
Under the new law, $6.3 billion are slated for health initiatives over the next decade. The Cancer Moonshot will receive $1.8 billion, precision medicine will receive just under $1.5 billion, and the BRAIN Initiative (Brain Research Through Advancing Innovative Neurotechnologies) will receive just over that amount.
“I know there have been some anxieties about the program’s fragilities given the change in administration,” Dr. Collins told an audience at a meeting of the NIH Brain Institute investigators. “But [passage of the 21st Century Cures Act] should be a source of great reassurance.”
The actual cost of the BRAIN Initiative is expected to top $4.5 billion by the year 2025, funded by a mix of federal and private monies. The National Institute of Mental Health’s typical annual budget is just under $1.5 billion – essentially the same as the amount provided for in the new law. The funds will benefit neuroscience generally, and if successful, understanding of the brain specifically.
The BRAIN Initiative funding is not for clinical studies, however. Instead, it will be spread across what Dr. Collins dubbed, “Team Science,” a multidisciplinary band of investigators, all of whom are expected to help not only identify the brain’s biologic processes but also create the tools needed to reengineer the brain’s circuitry when it malfunctions. Some current BRAIN projects Dr. Collins singled out as worth watching were the use of ultrasound neuromodulation in nonhuman primates, the analysis of individual methylone in cell nuclei, and the development of ultrahigh-resolution 3D brain imaging technology.
“We are moving toward a full bore effort toward technologies that allow us to see what is happening in real time in circuits in the brain,” Dr. Collins said. “Maybe there are certain fundamental operating principles that may have eluded us in the past but which may start to appear.”
In 2016, there were as many neuroscientists as there were engineers of all types – 141 each – named as the principal investigators of projects funded by the initiative, according to NIMH Director Joshua A. Gordon, MD, PhD, who also spoke at the meeting. Among the other disciplines Dr. Gordon said were represented in the 2016 roster of investigators were 61 radiologists, 33 biostatisticians, 47 neurosurgeons, and 69 psychiatrists and psychologists.
The enormous focus on bench science – about 85% of all NIMH funding is for nonclinical research – is not without its critics. In a recent editorial, several prominent academic clinicians urged the NIMH to spend less on futuristic neuroscience and more on the application of therapies for those with mental illness, and on their psychosocial needs (Br J Psychiatry. 2016;208[6]507-9). The last-minute inclusion in the 21st Century Cures Act of several provisions that will have a direct impact in the near future on the plight of those with severe mental illness has the potential to allay some concerns, however.
“My hope is that the [law] will be interpreted from the perspective of making effective treatments available for ... those who are already ill,” Susan M. Essock, PhD, the Edna L. Edison Professor of Medical Psychology (in Psychiatry) at Columbia University, New York, and a cosigner of the editorial, said in an interview.
The law aims to drive evidence-based grant making for programs such as the Recovery After an Initial Schizophrenia Episode (RAISE) integrated care model and expands assisted outpatient treatment for children with serious emotional disturbance, or adults with serious mental illness, among several other provisions.
For some, the initiative’s cross-specialty structure and hefty price tag are worthwhile if it means filling the void of basic science necessary to explain the mechanics of mental illness, a void often filled with attitudes leading to the stigmatization of people who are ill.
Dr. Mayberg said she believes that a “systems approach” to behavior will emerge over time as interdisciplinary BRAIN Initiative researchers are given the freedom to make necessary discoveries, often when least expected, and are urged to share what they find. “Real fundamental changes happen by accident, in my experience. They are rarely planned. It happens when there are a lot of clues. A diversified portfolio has to be the answer, because nobody is smart enough to do it all [alone]. The goal is diversified, evidence-based approaches. ... Science has to make fundamental progress on how the brain works, because we’re obviously missing something clinically,” she said.
The ultimate goals of the initiative are to understand human beings and to improve the human condition by alleviating suffering, according to Brian Litt, MD, professor of neurology and bioengineering at the University of Pennsylvania, Philadelphia, and a moderator of a panel focused on the clinical implications of BRAIN research.
“If you think about the fundamental problems that affect our society and many around the world, they’re not just diseases like Parkinson’s or epilepsy, they are the disorders of mood, addiction, violence, anger, and a number of other conditions that affect behavior that are part of the neurological spectrum that affects the way our society functions,” Dr. Litt, a clinician specializing in treating people with epilepsy, told the audience.
Rather than create a neuroengineered super race, he said, fundamental neuroscience is about helping humans reach their fullest potential. For his support of this, Dr. Litt said he makes “no apologies. As a clinician, I am not sorry to be involved in fundamental neuroscience where ... incremental discoveries can create cures.”
As science favors cures, policy inevitably will evolve, perhaps even making current interventions relics of ignorance. “Psychosocial intervention is what you do when you have an absence of knowing how to cure,” said Dr. Mayberg. “It might be that [currently] what we treat is maladaptation to the primary problem.”
The key for clinicians, she said, will be to keep up with the latest literature. “Clinicians have to be aware of what’s exciting, of what should be in their armamentarium.”
Dr. Collins, Dr. Gordon, Dr. Essock, and Dr. Mayberg had no disclosures. Dr. Litt has cofounded several companies, including Blackfynn and Neuropace, and has served as a consultant and licensed technology to several companies.
[email protected]
On Twitter @whitneymcknight
EXPERT ANALYSIS AT AN NIH ADVISORY COUNCIL MEETING
Pig-in-a-poke health insurance, dermatologists never say never!
One of the most acute issues facing dermatologists is the implementation of narrow networks by health insurers. Inaccurate physician rosters have long been a problem that insurers have been indifferent to, but this was not an acute problem since almost all providers were included in the networks.
However, the recent “ramp up” because of increased costs and cuts associated with the Affordable Care Act (ACA) has resulted in the delisting of many thousands of physicians (including hundreds of dermatologists) from insurance plans and refusal to allow them to enroll in new plans. All in a time of physician shortages and an acute shortage of dermatologists.
When I was president of the American Academy of Dermatology, I made it a priority that patients and the government, who pay or subsidize insurance companies for this hollow insurance, understand how they were being cheated on their health care dollars – or, as we say in Kentucky, being sold a “pig in a poke.” A pig in a poke is a pig (or another small farm animal) carried to market in a bag with only the head sticking out, disguising the skinny product within.
The AAD staff and I went to the White House, Congress, the Centers for Medicare and Medicaid Services (CMS), AHIP (America’s Health Insurance Plans trade association), PhRMA (Pharmaceutical Research and Manufacturers of America), and the Medicare Payment Advisory Commission (MedPac); and spoke to the Office of Inspector General (OIG), which agreed to investigate. We and the dermatology patient advocacy groups organized a letter writing campaign and solicited letters and complaints from members. We contacted the state health insurance commissioners and testified at their hearings. Our fellow dermatologist and AMA board of trustee member Jack Resneck, MD, researched and wrote an article in JAMA Dermatology, demonstrating how pathetically inaccurate the insurance company physician networks are (2014;150[12]:1290-7). We beat the drum loud and long, and it worked!
The OIG issued a scathing report about the lack of follow through by CMS on billions of health care dollars being paid by the federal government to Medicare Advantage plans. CMS agreed with their report, and agreed to investigate. A CMS survey reported in October 2016 that almost half of the doctor listings in their Medicare Advantage (Humana, Aetna, United, and Anthem senior plans) directories contained incorrect information, including inaccurate names and addresses; multiple, duplicate listings; and doctors who have died. CMS concluded that they expect this performance to improve over the next three study periods – or they will start to assess $25,000 a day in penalties.
Also published last year, a “secret shopper” survey of primary care providers in five insurance marketplace pricing regions found that fewer than 30% of consumers were able to schedule an appointment with the physician they had first selected (Health Aff [Millwood]. 2016 Jul 1;35[7]:1160-6).
Folks, the only way to improve the accuracy is to delete duplicated listings, delete physicians no longer seeing new patients, delete physicians incorrectly listed, and delete those who have died or moved on. We have to continue this effort on a state by state level, or insurers will quickly backslide, because if there are no doctors to see, there are no bills for them to pay.
Accurate rosters will reveal huge gaps in their directories, and insurers will be forced to recontract with delisted physicians. Physicians should watch for and anticipate this, and should not sign up at a disadvantage. Patients must continue to pressure their health insurers both personally and through their human resources departments at work. No one should have to buy “a pig in a poke.” This is huge national victory, for patients and physicians. Dermatologists, you should be proud of your AAD leading the charge, and following through on getting this issue addressed and fixed.
Dr. Coldiron is a past president of the American Academy of Dermatology. He is currently in private practice, but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics.
One of the most acute issues facing dermatologists is the implementation of narrow networks by health insurers. Inaccurate physician rosters have long been a problem that insurers have been indifferent to, but this was not an acute problem since almost all providers were included in the networks.
However, the recent “ramp up” because of increased costs and cuts associated with the Affordable Care Act (ACA) has resulted in the delisting of many thousands of physicians (including hundreds of dermatologists) from insurance plans and refusal to allow them to enroll in new plans. All in a time of physician shortages and an acute shortage of dermatologists.
When I was president of the American Academy of Dermatology, I made it a priority that patients and the government, who pay or subsidize insurance companies for this hollow insurance, understand how they were being cheated on their health care dollars – or, as we say in Kentucky, being sold a “pig in a poke.” A pig in a poke is a pig (or another small farm animal) carried to market in a bag with only the head sticking out, disguising the skinny product within.
The AAD staff and I went to the White House, Congress, the Centers for Medicare and Medicaid Services (CMS), AHIP (America’s Health Insurance Plans trade association), PhRMA (Pharmaceutical Research and Manufacturers of America), and the Medicare Payment Advisory Commission (MedPac); and spoke to the Office of Inspector General (OIG), which agreed to investigate. We and the dermatology patient advocacy groups organized a letter writing campaign and solicited letters and complaints from members. We contacted the state health insurance commissioners and testified at their hearings. Our fellow dermatologist and AMA board of trustee member Jack Resneck, MD, researched and wrote an article in JAMA Dermatology, demonstrating how pathetically inaccurate the insurance company physician networks are (2014;150[12]:1290-7). We beat the drum loud and long, and it worked!
The OIG issued a scathing report about the lack of follow through by CMS on billions of health care dollars being paid by the federal government to Medicare Advantage plans. CMS agreed with their report, and agreed to investigate. A CMS survey reported in October 2016 that almost half of the doctor listings in their Medicare Advantage (Humana, Aetna, United, and Anthem senior plans) directories contained incorrect information, including inaccurate names and addresses; multiple, duplicate listings; and doctors who have died. CMS concluded that they expect this performance to improve over the next three study periods – or they will start to assess $25,000 a day in penalties.
Also published last year, a “secret shopper” survey of primary care providers in five insurance marketplace pricing regions found that fewer than 30% of consumers were able to schedule an appointment with the physician they had first selected (Health Aff [Millwood]. 2016 Jul 1;35[7]:1160-6).
Folks, the only way to improve the accuracy is to delete duplicated listings, delete physicians no longer seeing new patients, delete physicians incorrectly listed, and delete those who have died or moved on. We have to continue this effort on a state by state level, or insurers will quickly backslide, because if there are no doctors to see, there are no bills for them to pay.
Accurate rosters will reveal huge gaps in their directories, and insurers will be forced to recontract with delisted physicians. Physicians should watch for and anticipate this, and should not sign up at a disadvantage. Patients must continue to pressure their health insurers both personally and through their human resources departments at work. No one should have to buy “a pig in a poke.” This is huge national victory, for patients and physicians. Dermatologists, you should be proud of your AAD leading the charge, and following through on getting this issue addressed and fixed.
Dr. Coldiron is a past president of the American Academy of Dermatology. He is currently in private practice, but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics.
One of the most acute issues facing dermatologists is the implementation of narrow networks by health insurers. Inaccurate physician rosters have long been a problem that insurers have been indifferent to, but this was not an acute problem since almost all providers were included in the networks.
However, the recent “ramp up” because of increased costs and cuts associated with the Affordable Care Act (ACA) has resulted in the delisting of many thousands of physicians (including hundreds of dermatologists) from insurance plans and refusal to allow them to enroll in new plans. All in a time of physician shortages and an acute shortage of dermatologists.
When I was president of the American Academy of Dermatology, I made it a priority that patients and the government, who pay or subsidize insurance companies for this hollow insurance, understand how they were being cheated on their health care dollars – or, as we say in Kentucky, being sold a “pig in a poke.” A pig in a poke is a pig (or another small farm animal) carried to market in a bag with only the head sticking out, disguising the skinny product within.
The AAD staff and I went to the White House, Congress, the Centers for Medicare and Medicaid Services (CMS), AHIP (America’s Health Insurance Plans trade association), PhRMA (Pharmaceutical Research and Manufacturers of America), and the Medicare Payment Advisory Commission (MedPac); and spoke to the Office of Inspector General (OIG), which agreed to investigate. We and the dermatology patient advocacy groups organized a letter writing campaign and solicited letters and complaints from members. We contacted the state health insurance commissioners and testified at their hearings. Our fellow dermatologist and AMA board of trustee member Jack Resneck, MD, researched and wrote an article in JAMA Dermatology, demonstrating how pathetically inaccurate the insurance company physician networks are (2014;150[12]:1290-7). We beat the drum loud and long, and it worked!
The OIG issued a scathing report about the lack of follow through by CMS on billions of health care dollars being paid by the federal government to Medicare Advantage plans. CMS agreed with their report, and agreed to investigate. A CMS survey reported in October 2016 that almost half of the doctor listings in their Medicare Advantage (Humana, Aetna, United, and Anthem senior plans) directories contained incorrect information, including inaccurate names and addresses; multiple, duplicate listings; and doctors who have died. CMS concluded that they expect this performance to improve over the next three study periods – or they will start to assess $25,000 a day in penalties.
Also published last year, a “secret shopper” survey of primary care providers in five insurance marketplace pricing regions found that fewer than 30% of consumers were able to schedule an appointment with the physician they had first selected (Health Aff [Millwood]. 2016 Jul 1;35[7]:1160-6).
Folks, the only way to improve the accuracy is to delete duplicated listings, delete physicians no longer seeing new patients, delete physicians incorrectly listed, and delete those who have died or moved on. We have to continue this effort on a state by state level, or insurers will quickly backslide, because if there are no doctors to see, there are no bills for them to pay.
Accurate rosters will reveal huge gaps in their directories, and insurers will be forced to recontract with delisted physicians. Physicians should watch for and anticipate this, and should not sign up at a disadvantage. Patients must continue to pressure their health insurers both personally and through their human resources departments at work. No one should have to buy “a pig in a poke.” This is huge national victory, for patients and physicians. Dermatologists, you should be proud of your AAD leading the charge, and following through on getting this issue addressed and fixed.
Dr. Coldiron is a past president of the American Academy of Dermatology. He is currently in private practice, but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics.