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Newly described lung disorder strikes children with systemic juvenile idiopathic arthritis
An uncommon but potentially deadly inflammatory lung disease is emerging among children with systemic juvenile idiopathic arthritis, and its history appears to coincide with the rise of powerful biologics as first-line therapy for children with the disease.
Most confirmed cases of systemic juvenile idiopathic arthritis with lung disease (sJIA-LD) are in the United States. But it’s popping up in other places that have adopted early biologic treatment for sJIA – including Canada, South America, Europe, and the Middle East.
The respiratory symptoms are relatively subtle, so by the time of lung disease detection, the amount of affected lung can be extensive, said Elizabeth Mellins, MD, a Stanford (Calif.) University researcher who, along with first author Vivian Saper, MD, recently published the largest case series comprising reports from 37 institutions (Ann Rheum Dis. 2019 Sep 27. doi: 10.1136/annrheumdis-2019-216040). By the end of follow-up, 22 of the 61 children in her cohort had died, including all 12 patients who demonstrated excessively high neutrophil levels in bronchoalveolar lavage samples.
Another recent report, authored by Grant Schulert, MD, PhD, and colleagues of the Cincinnati Children’s Hospital Medical Center, described 18 patients, 9 of whom were also included in the Stanford cohort (Arthritis Rheumatol. 2019 Aug 5. doi: 10.1002/art.41073).
Both investigators have now identified new patients.
“We are aware of 60 additional cases beyond what were included in our series,” Dr. Mellins said in an interview, bringing her entire cohort to 121. Dr. Schulert also continues to expand his group, detailing nine new cases at a recent private meeting.
“We are up to 27 now,” he said. “The features of these new patients are all very similar: The children are very young, all have had macrophage activation syndrome in the past and very-difficult-to-control JIA. Reactions to tocilizumab [Actemra] were also not uncommon in this group.”
Dr. Mellins also saw this association with allergic-type tocilizumab reactions, severe delayed hypersensitivity reactions to anakinra (Kineret) or canakinumab (Ilaris). Although serious lung disease in sJIA patients is not unheard of, this phenotype was virtually unknown until about a decade ago. Both investigators said that it’s been rising steadily since 2010 – just about the time that powerful cytokine-inhibiting biologics were changing these patients’ world for the better. After decades of relying almost solely on steroids and methotrexate, with rather poor results and significant long-term side effects, children were not only improving, but thriving. Gone was the life-changing glucocorticoid-related growth inhibition. Biologics could halt fevers, rash, and joint destruction in their tracks.
“For the first time in history, these kids could look forward to a more or less normal life,” Dr. Schulert said.
But the emergence of this particular type of lung disease could throw a pall over that success story, he said. If sJIA-LD is temporally associated with increasing reliance on long-term interleukin-1/IL-6 inhibition in children with early-onset disease, could these drugs actually be the causative agent? The picture remains unclear.
Some of the 18 in his initial series have improved, while 36% of those in the Stanford series died. Most who do recover stay on their IL-1 or IL-6 blocking therapy with good disease control without further lung problems. Both investigators found compelling genetic hints, but nothing conclusive. Children with trisomy 21 appear especially vulnerable. Most patients are very young – around 2 years old – but others are school aged. Some had a history of macrophage activation syndrome. Some had hard-to-control disease and some were clinically well controlled when the lung disease presented.
There are simply no answers yet.
With so many potential links, all unproven, clinicians may question the wisdom of embarking on long-term biologic therapy for their children with sJIA. Peter Nigrovic, MD, of Boston Children’s Hospital, addressed this in an accompanying editorial (Arthritis Rheumatol. 2019 Aug 7. doi: 10.1002/art.41071).
“My take on this is that it’s a very worrisome trend,” he said in an interview. “We’ve been going full bore toward early biologic therapy in sJIA and at the same time we are seeing more of this lung disease. Is it guilt by association? Or is there something more? The challenge for us is not to jump too soon to that conclusion.”
Although the association is there, he said, association does not equal causation. And there’s no doubt that biologics have vastly improved the lives of sJIA patients. “The drugs might be causal, and I worry about that and think we need to study it. But we absolutely need stronger evidence before we change practice.”
“This is a new manifestation of the disease, and it’s coming at the same time we are changing the treatment paradigm,” Dr. Nigrovic continued. “It could be because of interleukin-1 or interleukin-6 blockade. There is biological plausibility for such a link. It could also be related to the fact that we are using less steroids and methotrexate, which might have been preventing this. The appearance of sJIA lung disease could also be that a distinct secular trend unrelated to treatment, just as we saw amyloid come and go in this population in Europe. These other therapies were actually preventing this. We just don’t know.”
Clinical characteristics
Children presented with similar symptoms. Respiratory symptoms are usually subtle and mild. These can include tachypnea, hypoxia (43% in the Stanford series), and pulmonary hypertension (30% in the Stanford series).
Digital clubbing, often with erythema, was a common finding. Some children showed pruritic, nonevanescent rashes. Eosinophilia occurred in 37% of the Stanford series and severe abdominal pain in 16%, although Dr. Mellins noted that belly pain may be underestimated, as it was only volunteered, not queried, information.
“There are some red flags that should raise suspicion even without obvious respiratory symptoms,” Dr. Mellins said. These include lymphopenia, unexplained abdominal pain, eosinophilia, an unusual rash, and finger clubbing with or without erythema.
Findings on imaging were consistent in both series. Several key clinic features emerged: pleural thickening, septal thickening, bronchial wall or peribronchovascular thickening, “tree-in-bud” opacities, “ground-glass” opacities, peripheral consolidation, and lymphadenopathy.
“The imaging findings correspond to two things,” Dr. Schulert said. “The first is inflammation in the interstitium, which is evidence of chronic and ongoing inflammation. The other thing is that the alveoli are filled with a lipoproteinaceous material which is actually surfactant that’s not being normally recycled by the lung macrophages. You can see these features in other conditions where there’s a problem with lung macrophages, like pulmonary alveolar proteinosis, genetic and autoimmune disorders, infections, or inhalants.”
Pathology showed alveolar filling – a location in the lung that hides usual symptoms until the lung disease is advanced. Prior drug reactions were common. Tocilizumab anaphylaxis occurred in close to 40% of the Stanford series – a surprising finding given the 0.6% reaction incidence in the drug’s sJIA trials. Dr. Schulert saw a similar story.
“In our cohort we also observed a striking number of adverse events to cytokine-targeted biologics exposure,” Dr. Schulert said. “Most of these reactions were to tocilizumab, and were described variously from pain and feeling unwell, to difficulty breathing, to anaphylaxis.”
In a risk analysis, Dr. Schulert determined that adverse events to cytokine-targeting biologics increased the likelihood of lung disease more than 13 times (odds ratio, 13.6).
“We also identified a statistically significant association with history of macrophage activation syndrome when compared to controls (OR, 14.5),” Dr. Schulert and associates wrote.
Genetics
Both the Cincinnati and Stanford teams conducted genetic analyses on some of their patients.
Among eight lung biopsy samples, Dr. Schulert found 37 differentially expressed genes: 36 with increased expression and 1 with decreased expression. Many of the up-regulated genes are involved in interferon-gamma response. Two (CXCL10 and CXCL9) are interferon-induced chemokines associated with macrophage activation syndrome. The down-regulated gene, PADI4, modulates immune response in lupus, and has been associated with the risk of interstitial lung disease in RA.
Dr. Mellins and her team analyzed whole-exome sequencing data from 20 patients and found some rare protein-altering gene variants in genes related to pulmonary alveolar proteinosis, all of which were heterozygous and shared with a healthy parent. But none of them could be directly tied to the disorder.
Another genetic puzzle demands attention, she said. About 10% of the children had trisomy 21 – a stark contrast to the typical 0.2% prevalence among a control group of sJIA patients without any known lung disease in the Childhood Arthritis and Rheumatology Research Alliance Registry cohort, similar to the background population rate. There were suggestions of more aggressive lung disease in all six of these children. Four presented with hypoxia, and two showed advanced interstitial fibrosis. Children with trisomy 21 also seemed more susceptible to infections; 83% had a viral or fungal lung infection at diagnosis, compared with 29% of those without trisomy 21.
Prior exposure to cytokine inhibitors
Parenchymal lung disease and pulmonary hypertension complicating sJIA was first highlighted in a series of 25 cases reported by Kimura et al. in 2013. These authors raised the question of the possible relationship of this and the increasing use of anti–IL-1 and anti–IL-6 biologics in sJIA treatment.
Following this lead, Dr. Mellins started looking into this new clinical entity in 2015. By then, she was identifying some past cases by autopsy records and current cases by clinical presentation. She saw a dramatic shift over time. From 2002 to 2011, she identified four cases, half of which had been exposed to IL-1/IL-6 inhibitors. From 2012 to 2014, eight new cases came to light, and seven had been exposed to those drugs. The crescendo continued from 2015 to 2017. During those years, Dr. Mellins and associates identified 10 new patients, 7 of whom had taken interleukin-inhibiting biologics. The mean time from initial drug exposure to diagnosis was a little more than 1 year.
An adjusted analysis comparing sJIA-LD patients and sJIA patients without lung disease didn’t find any significant difference in drug exposure. However, children with lung disease were more likely to have taken anakinra before the symptoms developed. Additionally, the symptoms of clubbing, abdominal pain, eosinophilia, hyperenhancing lymph nodes, and pulmonary alveolar proteinosis were much more common in children who’d taken the drugs.
The authors pointed out that this association does not prove causality and is confounded by the concomitant reduction in glucocorticoids with IL-1/IL-6 inhibitor use. And the vast majority of children with sJIA take cytokine inhibitors with no problems.
“Possibly, drug exposure may promote lung disease in a subset of children with sJIA, among the substantially larger group of patients who derive striking benefit from these drugs,” Dr. Mellins said, “Importantly, our results argue strongly for more investigation into a possible connection.”
Survival
After a mean follow-up of 1.7 years, the Stanford group saw high mortality. The 5-year survival rate translated to a mortality incidence of 159 deaths per 1,000 person-years, compared with 3.9 per 1,000 person-years in a historical cohort of sJIA patients who required biologic therapy.
Diffuse lung disease was the cause of 12 deaths; 5 of these patients also had macrophage activation syndrome at the time of death. Factors significantly associated with shortened survival included male sex, hypoxia at presentation, and neutrophilic bronchoalveolar lavage with more than 10 times the normal count. In an adjusted analysis, all of these variables fell out. However, none of the children with excessively high neutrophilic bronchoalveolar lavage survived.
Does it affect adults?
Could adults be experiencing the same disorder? There is some evidence to support it: The Food and Drug Administration adverse event website shows alveolar disease or pulmonary hypertension in 39 adults who have been exposed to IL-1 or IL-6 inhibition. Of these, 23 had RA, 11 adult-onset Still’s disease, and 5 unclassified rheumatic disorders.
The research groups were supported by grants from the sJIA Foundation, the Lucile Packard Foundation for Children’s Health, Stanford graduate fellowships, the Life Sciences Research Foundation, the Bill & Melinda Gates Foundation, Cincinnati Children’s Research Foundation, the Childhood Arthritis and Rheumatology Research Alliance, the Arthritis Foundation, and the National Institutes of Health. Many authors on both papers reported financial ties to Genentech, which markets tocilizumab, and other pharmaceutical companies*. Dr. Nigrovic reported receiving consulting fees and research support from Novartis and other companies.
SOURCES: Saper V et al. Ann Rheum Dis. 2019 Sep 27. doi: 10.1136/annrheumdis-2019-216040; Schulert GS et al. Arthritis Rheumatol. 2019 Aug 5. doi: 10.1002/art.41073; Nigrovic PA. Arthritis Rheumatol. 2019 Aug 7. doi: 10.1002/art.41071.
*Correction, 10/12/19: An earlier version of this article misstated the manufacturer of Actemra (tocilizumab).
This article was updated 10/14/19.
An uncommon but potentially deadly inflammatory lung disease is emerging among children with systemic juvenile idiopathic arthritis, and its history appears to coincide with the rise of powerful biologics as first-line therapy for children with the disease.
Most confirmed cases of systemic juvenile idiopathic arthritis with lung disease (sJIA-LD) are in the United States. But it’s popping up in other places that have adopted early biologic treatment for sJIA – including Canada, South America, Europe, and the Middle East.
The respiratory symptoms are relatively subtle, so by the time of lung disease detection, the amount of affected lung can be extensive, said Elizabeth Mellins, MD, a Stanford (Calif.) University researcher who, along with first author Vivian Saper, MD, recently published the largest case series comprising reports from 37 institutions (Ann Rheum Dis. 2019 Sep 27. doi: 10.1136/annrheumdis-2019-216040). By the end of follow-up, 22 of the 61 children in her cohort had died, including all 12 patients who demonstrated excessively high neutrophil levels in bronchoalveolar lavage samples.
Another recent report, authored by Grant Schulert, MD, PhD, and colleagues of the Cincinnati Children’s Hospital Medical Center, described 18 patients, 9 of whom were also included in the Stanford cohort (Arthritis Rheumatol. 2019 Aug 5. doi: 10.1002/art.41073).
Both investigators have now identified new patients.
“We are aware of 60 additional cases beyond what were included in our series,” Dr. Mellins said in an interview, bringing her entire cohort to 121. Dr. Schulert also continues to expand his group, detailing nine new cases at a recent private meeting.
“We are up to 27 now,” he said. “The features of these new patients are all very similar: The children are very young, all have had macrophage activation syndrome in the past and very-difficult-to-control JIA. Reactions to tocilizumab [Actemra] were also not uncommon in this group.”
Dr. Mellins also saw this association with allergic-type tocilizumab reactions, severe delayed hypersensitivity reactions to anakinra (Kineret) or canakinumab (Ilaris). Although serious lung disease in sJIA patients is not unheard of, this phenotype was virtually unknown until about a decade ago. Both investigators said that it’s been rising steadily since 2010 – just about the time that powerful cytokine-inhibiting biologics were changing these patients’ world for the better. After decades of relying almost solely on steroids and methotrexate, with rather poor results and significant long-term side effects, children were not only improving, but thriving. Gone was the life-changing glucocorticoid-related growth inhibition. Biologics could halt fevers, rash, and joint destruction in their tracks.
“For the first time in history, these kids could look forward to a more or less normal life,” Dr. Schulert said.
But the emergence of this particular type of lung disease could throw a pall over that success story, he said. If sJIA-LD is temporally associated with increasing reliance on long-term interleukin-1/IL-6 inhibition in children with early-onset disease, could these drugs actually be the causative agent? The picture remains unclear.
Some of the 18 in his initial series have improved, while 36% of those in the Stanford series died. Most who do recover stay on their IL-1 or IL-6 blocking therapy with good disease control without further lung problems. Both investigators found compelling genetic hints, but nothing conclusive. Children with trisomy 21 appear especially vulnerable. Most patients are very young – around 2 years old – but others are school aged. Some had a history of macrophage activation syndrome. Some had hard-to-control disease and some were clinically well controlled when the lung disease presented.
There are simply no answers yet.
With so many potential links, all unproven, clinicians may question the wisdom of embarking on long-term biologic therapy for their children with sJIA. Peter Nigrovic, MD, of Boston Children’s Hospital, addressed this in an accompanying editorial (Arthritis Rheumatol. 2019 Aug 7. doi: 10.1002/art.41071).
“My take on this is that it’s a very worrisome trend,” he said in an interview. “We’ve been going full bore toward early biologic therapy in sJIA and at the same time we are seeing more of this lung disease. Is it guilt by association? Or is there something more? The challenge for us is not to jump too soon to that conclusion.”
Although the association is there, he said, association does not equal causation. And there’s no doubt that biologics have vastly improved the lives of sJIA patients. “The drugs might be causal, and I worry about that and think we need to study it. But we absolutely need stronger evidence before we change practice.”
“This is a new manifestation of the disease, and it’s coming at the same time we are changing the treatment paradigm,” Dr. Nigrovic continued. “It could be because of interleukin-1 or interleukin-6 blockade. There is biological plausibility for such a link. It could also be related to the fact that we are using less steroids and methotrexate, which might have been preventing this. The appearance of sJIA lung disease could also be that a distinct secular trend unrelated to treatment, just as we saw amyloid come and go in this population in Europe. These other therapies were actually preventing this. We just don’t know.”
Clinical characteristics
Children presented with similar symptoms. Respiratory symptoms are usually subtle and mild. These can include tachypnea, hypoxia (43% in the Stanford series), and pulmonary hypertension (30% in the Stanford series).
Digital clubbing, often with erythema, was a common finding. Some children showed pruritic, nonevanescent rashes. Eosinophilia occurred in 37% of the Stanford series and severe abdominal pain in 16%, although Dr. Mellins noted that belly pain may be underestimated, as it was only volunteered, not queried, information.
“There are some red flags that should raise suspicion even without obvious respiratory symptoms,” Dr. Mellins said. These include lymphopenia, unexplained abdominal pain, eosinophilia, an unusual rash, and finger clubbing with or without erythema.
Findings on imaging were consistent in both series. Several key clinic features emerged: pleural thickening, septal thickening, bronchial wall or peribronchovascular thickening, “tree-in-bud” opacities, “ground-glass” opacities, peripheral consolidation, and lymphadenopathy.
“The imaging findings correspond to two things,” Dr. Schulert said. “The first is inflammation in the interstitium, which is evidence of chronic and ongoing inflammation. The other thing is that the alveoli are filled with a lipoproteinaceous material which is actually surfactant that’s not being normally recycled by the lung macrophages. You can see these features in other conditions where there’s a problem with lung macrophages, like pulmonary alveolar proteinosis, genetic and autoimmune disorders, infections, or inhalants.”
Pathology showed alveolar filling – a location in the lung that hides usual symptoms until the lung disease is advanced. Prior drug reactions were common. Tocilizumab anaphylaxis occurred in close to 40% of the Stanford series – a surprising finding given the 0.6% reaction incidence in the drug’s sJIA trials. Dr. Schulert saw a similar story.
“In our cohort we also observed a striking number of adverse events to cytokine-targeted biologics exposure,” Dr. Schulert said. “Most of these reactions were to tocilizumab, and were described variously from pain and feeling unwell, to difficulty breathing, to anaphylaxis.”
In a risk analysis, Dr. Schulert determined that adverse events to cytokine-targeting biologics increased the likelihood of lung disease more than 13 times (odds ratio, 13.6).
“We also identified a statistically significant association with history of macrophage activation syndrome when compared to controls (OR, 14.5),” Dr. Schulert and associates wrote.
Genetics
Both the Cincinnati and Stanford teams conducted genetic analyses on some of their patients.
Among eight lung biopsy samples, Dr. Schulert found 37 differentially expressed genes: 36 with increased expression and 1 with decreased expression. Many of the up-regulated genes are involved in interferon-gamma response. Two (CXCL10 and CXCL9) are interferon-induced chemokines associated with macrophage activation syndrome. The down-regulated gene, PADI4, modulates immune response in lupus, and has been associated with the risk of interstitial lung disease in RA.
Dr. Mellins and her team analyzed whole-exome sequencing data from 20 patients and found some rare protein-altering gene variants in genes related to pulmonary alveolar proteinosis, all of which were heterozygous and shared with a healthy parent. But none of them could be directly tied to the disorder.
Another genetic puzzle demands attention, she said. About 10% of the children had trisomy 21 – a stark contrast to the typical 0.2% prevalence among a control group of sJIA patients without any known lung disease in the Childhood Arthritis and Rheumatology Research Alliance Registry cohort, similar to the background population rate. There were suggestions of more aggressive lung disease in all six of these children. Four presented with hypoxia, and two showed advanced interstitial fibrosis. Children with trisomy 21 also seemed more susceptible to infections; 83% had a viral or fungal lung infection at diagnosis, compared with 29% of those without trisomy 21.
Prior exposure to cytokine inhibitors
Parenchymal lung disease and pulmonary hypertension complicating sJIA was first highlighted in a series of 25 cases reported by Kimura et al. in 2013. These authors raised the question of the possible relationship of this and the increasing use of anti–IL-1 and anti–IL-6 biologics in sJIA treatment.
Following this lead, Dr. Mellins started looking into this new clinical entity in 2015. By then, she was identifying some past cases by autopsy records and current cases by clinical presentation. She saw a dramatic shift over time. From 2002 to 2011, she identified four cases, half of which had been exposed to IL-1/IL-6 inhibitors. From 2012 to 2014, eight new cases came to light, and seven had been exposed to those drugs. The crescendo continued from 2015 to 2017. During those years, Dr. Mellins and associates identified 10 new patients, 7 of whom had taken interleukin-inhibiting biologics. The mean time from initial drug exposure to diagnosis was a little more than 1 year.
An adjusted analysis comparing sJIA-LD patients and sJIA patients without lung disease didn’t find any significant difference in drug exposure. However, children with lung disease were more likely to have taken anakinra before the symptoms developed. Additionally, the symptoms of clubbing, abdominal pain, eosinophilia, hyperenhancing lymph nodes, and pulmonary alveolar proteinosis were much more common in children who’d taken the drugs.
The authors pointed out that this association does not prove causality and is confounded by the concomitant reduction in glucocorticoids with IL-1/IL-6 inhibitor use. And the vast majority of children with sJIA take cytokine inhibitors with no problems.
“Possibly, drug exposure may promote lung disease in a subset of children with sJIA, among the substantially larger group of patients who derive striking benefit from these drugs,” Dr. Mellins said, “Importantly, our results argue strongly for more investigation into a possible connection.”
Survival
After a mean follow-up of 1.7 years, the Stanford group saw high mortality. The 5-year survival rate translated to a mortality incidence of 159 deaths per 1,000 person-years, compared with 3.9 per 1,000 person-years in a historical cohort of sJIA patients who required biologic therapy.
Diffuse lung disease was the cause of 12 deaths; 5 of these patients also had macrophage activation syndrome at the time of death. Factors significantly associated with shortened survival included male sex, hypoxia at presentation, and neutrophilic bronchoalveolar lavage with more than 10 times the normal count. In an adjusted analysis, all of these variables fell out. However, none of the children with excessively high neutrophilic bronchoalveolar lavage survived.
Does it affect adults?
Could adults be experiencing the same disorder? There is some evidence to support it: The Food and Drug Administration adverse event website shows alveolar disease or pulmonary hypertension in 39 adults who have been exposed to IL-1 or IL-6 inhibition. Of these, 23 had RA, 11 adult-onset Still’s disease, and 5 unclassified rheumatic disorders.
The research groups were supported by grants from the sJIA Foundation, the Lucile Packard Foundation for Children’s Health, Stanford graduate fellowships, the Life Sciences Research Foundation, the Bill & Melinda Gates Foundation, Cincinnati Children’s Research Foundation, the Childhood Arthritis and Rheumatology Research Alliance, the Arthritis Foundation, and the National Institutes of Health. Many authors on both papers reported financial ties to Genentech, which markets tocilizumab, and other pharmaceutical companies*. Dr. Nigrovic reported receiving consulting fees and research support from Novartis and other companies.
SOURCES: Saper V et al. Ann Rheum Dis. 2019 Sep 27. doi: 10.1136/annrheumdis-2019-216040; Schulert GS et al. Arthritis Rheumatol. 2019 Aug 5. doi: 10.1002/art.41073; Nigrovic PA. Arthritis Rheumatol. 2019 Aug 7. doi: 10.1002/art.41071.
*Correction, 10/12/19: An earlier version of this article misstated the manufacturer of Actemra (tocilizumab).
This article was updated 10/14/19.
An uncommon but potentially deadly inflammatory lung disease is emerging among children with systemic juvenile idiopathic arthritis, and its history appears to coincide with the rise of powerful biologics as first-line therapy for children with the disease.
Most confirmed cases of systemic juvenile idiopathic arthritis with lung disease (sJIA-LD) are in the United States. But it’s popping up in other places that have adopted early biologic treatment for sJIA – including Canada, South America, Europe, and the Middle East.
The respiratory symptoms are relatively subtle, so by the time of lung disease detection, the amount of affected lung can be extensive, said Elizabeth Mellins, MD, a Stanford (Calif.) University researcher who, along with first author Vivian Saper, MD, recently published the largest case series comprising reports from 37 institutions (Ann Rheum Dis. 2019 Sep 27. doi: 10.1136/annrheumdis-2019-216040). By the end of follow-up, 22 of the 61 children in her cohort had died, including all 12 patients who demonstrated excessively high neutrophil levels in bronchoalveolar lavage samples.
Another recent report, authored by Grant Schulert, MD, PhD, and colleagues of the Cincinnati Children’s Hospital Medical Center, described 18 patients, 9 of whom were also included in the Stanford cohort (Arthritis Rheumatol. 2019 Aug 5. doi: 10.1002/art.41073).
Both investigators have now identified new patients.
“We are aware of 60 additional cases beyond what were included in our series,” Dr. Mellins said in an interview, bringing her entire cohort to 121. Dr. Schulert also continues to expand his group, detailing nine new cases at a recent private meeting.
“We are up to 27 now,” he said. “The features of these new patients are all very similar: The children are very young, all have had macrophage activation syndrome in the past and very-difficult-to-control JIA. Reactions to tocilizumab [Actemra] were also not uncommon in this group.”
Dr. Mellins also saw this association with allergic-type tocilizumab reactions, severe delayed hypersensitivity reactions to anakinra (Kineret) or canakinumab (Ilaris). Although serious lung disease in sJIA patients is not unheard of, this phenotype was virtually unknown until about a decade ago. Both investigators said that it’s been rising steadily since 2010 – just about the time that powerful cytokine-inhibiting biologics were changing these patients’ world for the better. After decades of relying almost solely on steroids and methotrexate, with rather poor results and significant long-term side effects, children were not only improving, but thriving. Gone was the life-changing glucocorticoid-related growth inhibition. Biologics could halt fevers, rash, and joint destruction in their tracks.
“For the first time in history, these kids could look forward to a more or less normal life,” Dr. Schulert said.
But the emergence of this particular type of lung disease could throw a pall over that success story, he said. If sJIA-LD is temporally associated with increasing reliance on long-term interleukin-1/IL-6 inhibition in children with early-onset disease, could these drugs actually be the causative agent? The picture remains unclear.
Some of the 18 in his initial series have improved, while 36% of those in the Stanford series died. Most who do recover stay on their IL-1 or IL-6 blocking therapy with good disease control without further lung problems. Both investigators found compelling genetic hints, but nothing conclusive. Children with trisomy 21 appear especially vulnerable. Most patients are very young – around 2 years old – but others are school aged. Some had a history of macrophage activation syndrome. Some had hard-to-control disease and some were clinically well controlled when the lung disease presented.
There are simply no answers yet.
With so many potential links, all unproven, clinicians may question the wisdom of embarking on long-term biologic therapy for their children with sJIA. Peter Nigrovic, MD, of Boston Children’s Hospital, addressed this in an accompanying editorial (Arthritis Rheumatol. 2019 Aug 7. doi: 10.1002/art.41071).
“My take on this is that it’s a very worrisome trend,” he said in an interview. “We’ve been going full bore toward early biologic therapy in sJIA and at the same time we are seeing more of this lung disease. Is it guilt by association? Or is there something more? The challenge for us is not to jump too soon to that conclusion.”
Although the association is there, he said, association does not equal causation. And there’s no doubt that biologics have vastly improved the lives of sJIA patients. “The drugs might be causal, and I worry about that and think we need to study it. But we absolutely need stronger evidence before we change practice.”
“This is a new manifestation of the disease, and it’s coming at the same time we are changing the treatment paradigm,” Dr. Nigrovic continued. “It could be because of interleukin-1 or interleukin-6 blockade. There is biological plausibility for such a link. It could also be related to the fact that we are using less steroids and methotrexate, which might have been preventing this. The appearance of sJIA lung disease could also be that a distinct secular trend unrelated to treatment, just as we saw amyloid come and go in this population in Europe. These other therapies were actually preventing this. We just don’t know.”
Clinical characteristics
Children presented with similar symptoms. Respiratory symptoms are usually subtle and mild. These can include tachypnea, hypoxia (43% in the Stanford series), and pulmonary hypertension (30% in the Stanford series).
Digital clubbing, often with erythema, was a common finding. Some children showed pruritic, nonevanescent rashes. Eosinophilia occurred in 37% of the Stanford series and severe abdominal pain in 16%, although Dr. Mellins noted that belly pain may be underestimated, as it was only volunteered, not queried, information.
“There are some red flags that should raise suspicion even without obvious respiratory symptoms,” Dr. Mellins said. These include lymphopenia, unexplained abdominal pain, eosinophilia, an unusual rash, and finger clubbing with or without erythema.
Findings on imaging were consistent in both series. Several key clinic features emerged: pleural thickening, septal thickening, bronchial wall or peribronchovascular thickening, “tree-in-bud” opacities, “ground-glass” opacities, peripheral consolidation, and lymphadenopathy.
“The imaging findings correspond to two things,” Dr. Schulert said. “The first is inflammation in the interstitium, which is evidence of chronic and ongoing inflammation. The other thing is that the alveoli are filled with a lipoproteinaceous material which is actually surfactant that’s not being normally recycled by the lung macrophages. You can see these features in other conditions where there’s a problem with lung macrophages, like pulmonary alveolar proteinosis, genetic and autoimmune disorders, infections, or inhalants.”
Pathology showed alveolar filling – a location in the lung that hides usual symptoms until the lung disease is advanced. Prior drug reactions were common. Tocilizumab anaphylaxis occurred in close to 40% of the Stanford series – a surprising finding given the 0.6% reaction incidence in the drug’s sJIA trials. Dr. Schulert saw a similar story.
“In our cohort we also observed a striking number of adverse events to cytokine-targeted biologics exposure,” Dr. Schulert said. “Most of these reactions were to tocilizumab, and were described variously from pain and feeling unwell, to difficulty breathing, to anaphylaxis.”
In a risk analysis, Dr. Schulert determined that adverse events to cytokine-targeting biologics increased the likelihood of lung disease more than 13 times (odds ratio, 13.6).
“We also identified a statistically significant association with history of macrophage activation syndrome when compared to controls (OR, 14.5),” Dr. Schulert and associates wrote.
Genetics
Both the Cincinnati and Stanford teams conducted genetic analyses on some of their patients.
Among eight lung biopsy samples, Dr. Schulert found 37 differentially expressed genes: 36 with increased expression and 1 with decreased expression. Many of the up-regulated genes are involved in interferon-gamma response. Two (CXCL10 and CXCL9) are interferon-induced chemokines associated with macrophage activation syndrome. The down-regulated gene, PADI4, modulates immune response in lupus, and has been associated with the risk of interstitial lung disease in RA.
Dr. Mellins and her team analyzed whole-exome sequencing data from 20 patients and found some rare protein-altering gene variants in genes related to pulmonary alveolar proteinosis, all of which were heterozygous and shared with a healthy parent. But none of them could be directly tied to the disorder.
Another genetic puzzle demands attention, she said. About 10% of the children had trisomy 21 – a stark contrast to the typical 0.2% prevalence among a control group of sJIA patients without any known lung disease in the Childhood Arthritis and Rheumatology Research Alliance Registry cohort, similar to the background population rate. There were suggestions of more aggressive lung disease in all six of these children. Four presented with hypoxia, and two showed advanced interstitial fibrosis. Children with trisomy 21 also seemed more susceptible to infections; 83% had a viral or fungal lung infection at diagnosis, compared with 29% of those without trisomy 21.
Prior exposure to cytokine inhibitors
Parenchymal lung disease and pulmonary hypertension complicating sJIA was first highlighted in a series of 25 cases reported by Kimura et al. in 2013. These authors raised the question of the possible relationship of this and the increasing use of anti–IL-1 and anti–IL-6 biologics in sJIA treatment.
Following this lead, Dr. Mellins started looking into this new clinical entity in 2015. By then, she was identifying some past cases by autopsy records and current cases by clinical presentation. She saw a dramatic shift over time. From 2002 to 2011, she identified four cases, half of which had been exposed to IL-1/IL-6 inhibitors. From 2012 to 2014, eight new cases came to light, and seven had been exposed to those drugs. The crescendo continued from 2015 to 2017. During those years, Dr. Mellins and associates identified 10 new patients, 7 of whom had taken interleukin-inhibiting biologics. The mean time from initial drug exposure to diagnosis was a little more than 1 year.
An adjusted analysis comparing sJIA-LD patients and sJIA patients without lung disease didn’t find any significant difference in drug exposure. However, children with lung disease were more likely to have taken anakinra before the symptoms developed. Additionally, the symptoms of clubbing, abdominal pain, eosinophilia, hyperenhancing lymph nodes, and pulmonary alveolar proteinosis were much more common in children who’d taken the drugs.
The authors pointed out that this association does not prove causality and is confounded by the concomitant reduction in glucocorticoids with IL-1/IL-6 inhibitor use. And the vast majority of children with sJIA take cytokine inhibitors with no problems.
“Possibly, drug exposure may promote lung disease in a subset of children with sJIA, among the substantially larger group of patients who derive striking benefit from these drugs,” Dr. Mellins said, “Importantly, our results argue strongly for more investigation into a possible connection.”
Survival
After a mean follow-up of 1.7 years, the Stanford group saw high mortality. The 5-year survival rate translated to a mortality incidence of 159 deaths per 1,000 person-years, compared with 3.9 per 1,000 person-years in a historical cohort of sJIA patients who required biologic therapy.
Diffuse lung disease was the cause of 12 deaths; 5 of these patients also had macrophage activation syndrome at the time of death. Factors significantly associated with shortened survival included male sex, hypoxia at presentation, and neutrophilic bronchoalveolar lavage with more than 10 times the normal count. In an adjusted analysis, all of these variables fell out. However, none of the children with excessively high neutrophilic bronchoalveolar lavage survived.
Does it affect adults?
Could adults be experiencing the same disorder? There is some evidence to support it: The Food and Drug Administration adverse event website shows alveolar disease or pulmonary hypertension in 39 adults who have been exposed to IL-1 or IL-6 inhibition. Of these, 23 had RA, 11 adult-onset Still’s disease, and 5 unclassified rheumatic disorders.
The research groups were supported by grants from the sJIA Foundation, the Lucile Packard Foundation for Children’s Health, Stanford graduate fellowships, the Life Sciences Research Foundation, the Bill & Melinda Gates Foundation, Cincinnati Children’s Research Foundation, the Childhood Arthritis and Rheumatology Research Alliance, the Arthritis Foundation, and the National Institutes of Health. Many authors on both papers reported financial ties to Genentech, which markets tocilizumab, and other pharmaceutical companies*. Dr. Nigrovic reported receiving consulting fees and research support from Novartis and other companies.
SOURCES: Saper V et al. Ann Rheum Dis. 2019 Sep 27. doi: 10.1136/annrheumdis-2019-216040; Schulert GS et al. Arthritis Rheumatol. 2019 Aug 5. doi: 10.1002/art.41073; Nigrovic PA. Arthritis Rheumatol. 2019 Aug 7. doi: 10.1002/art.41071.
*Correction, 10/12/19: An earlier version of this article misstated the manufacturer of Actemra (tocilizumab).
This article was updated 10/14/19.
New practice guideline: CRC screening isn’t necessary for low-risk patients aged 50-75 years
Patients 50-79 years old with a demonstrably low risk of developing the disease within 15 years probably don’t need to be screened for colorectal cancer. But if their risk of disease is at least 3% over 15 years, patients should be screened, Lise M. Helsingen, MD, and colleagues wrote in BMJ (2019;367:l5515 doi: 10.1136/bmj.l5515).
For these patients, “We suggest screening with one of the four screening options: fecal immunochemical test (FIT) every year, FIT every 2 years, a single sigmoidoscopy, or a single colonoscopy,” wrote Dr. Helsingen of the University of Oslo, and her team.
She chaired a 22-member international panel that developed a collaborative effort from the MAGIC research and innovation program as a part of the BMJ Rapid Recommendations project. The team reviewed 12 research papers comprising almost 1.4 million patients from Denmark, Italy, the Netherlands, Norway, Poland, Spain, Sweden, the United Kingdom, and the United States. Follow-up ranged from 0 to 19.5 years for colorectal cancer incidence and up to 30 years for mortality.
Because of the dearth of relevant data in some studies, however, the projected outcomes had to be simulated, with benefits and harms calculations based on 100% screening adherence. However, the team noted, it’s impossible to achieve complete adherence. Most studies of colorectal screening don’t exceed a 50% adherence level.
“All the modeling data are of low certainty. It is a useful indication, but there is a high chance that new evidence will show a smaller or larger benefit, which in turn may alter these recommendations.”
Compared with no screening, all four screening models reduced the risk of colorectal cancer mortality to a similar level.
- FIT every year, 59%.
- FIT every 2 years, 50%.
- Single sigmoidoscopy, 52%.
- Single colonoscopy, 67%.
Screening had less of an impact on reducing the incidence of colorectal cancer:
- FIT every 2 years, 0.05%.
- FIT every year, 0.15%.
- Single sigmoidoscopy, 27%.
- Single colonoscopy, 34%.
The panel also assessed potential harms. Among almost 1 million patients, the colonoscopy-related mortality rate was 0.03 per 1,000 procedures. The perforation rate was 0.8 per 1,000 colonoscopies after a positive fecal test, and 1.4 per 1,000 screened with sigmoidoscopy. The bleeding rate was 1.9 per 1,000 colonoscopies performed after a positive fecal test, and 3-4 per 1,000 screened with sigmoidoscopy.
Successful implementation of these recommendations hinges on accurate risk assessment, however. The team recommended the QCancer platform as “one of the best performing models for both men and women.”
The calculator includes age, sex, ethnicity, smoking status, alcohol use, family history of gastrointestinal cancer, personal history of other cancers, diabetes, ulcerative colitis, colonic polyps, and body mass index.
“We suggest this model because it is available as an online calculator; includes only risk factors available in routine health care; has been validated in a population separate from the derivation population; has reasonable discriminatory ability; and has a good fit between predicted and observed outcomes. In addition, it is the only online risk calculator we know of that predicts risk over a 15-year time horizon.”
The team stressed that their recommendations can’t be applied to all patients. Because evidence for both screening recommendations was weak – largely because of the dearth of supporting data – patients and physicians should cocreate a personalized screening plan.
“Several factors influence individuals’ decisions whether to be screened, even when they are presented with the same information,” the authors said. These include variation in an individual’s values and preferences, a close balance of benefits versus harms and burdens, and personal preference.
“Some individuals may value a minimally invasive test such as FIT, and the possibility of invasive screening with colonoscopy might put them off screening altogether. Those who most value preventing colorectal cancer or avoiding repeated testing are likely to choose sigmoidoscopy or colonoscopy.”
The authors had no financial conflicts of interest.
SOURCE: BMJ 2019;367:l5515. doi: 10.1136/bmj.l5515.
There is compelling evidence that CRC screening of average-risk individuals is effective – screening with one of several modalities can reduce CRC incidence and mortality in average-risk individuals. Various guidelines throughout the world have recommended screening, usually beginning at age 50 years, in a one-size-fits-all manner. Despite our knowledge that different people have a different lifetime risk of CRC, no prior guidelines have suggested that risk stratification be built into the decision making.
All of the recommendations in this practice guideline are weak because they are derived from models that lack adequate precision. Nevertheless, the authors have proposed a new approach to CRC screening, similar to management plans for patients with cardiovascular disease. Before adopting such an approach, we need to be more comfortable with the precision of the risk estimates. These estimates, derived entirely from demographic and clinical information, may be enhanced by genomic data to achieve more precision. Further data on the willingness of the public to accept no screening if their risk is below a certain threshold needs to be evaluated. Despite these issues, the guideline presents a provocative approach which demands our attention.
David Lieberman, MD, AGAF, is professor of medicine and chief of the division of gastroenterology and hepatology, Oregon Health & Science University, Portland. He is Past President of the AGA Institute. He has no conflicts of interest.
There is compelling evidence that CRC screening of average-risk individuals is effective – screening with one of several modalities can reduce CRC incidence and mortality in average-risk individuals. Various guidelines throughout the world have recommended screening, usually beginning at age 50 years, in a one-size-fits-all manner. Despite our knowledge that different people have a different lifetime risk of CRC, no prior guidelines have suggested that risk stratification be built into the decision making.
All of the recommendations in this practice guideline are weak because they are derived from models that lack adequate precision. Nevertheless, the authors have proposed a new approach to CRC screening, similar to management plans for patients with cardiovascular disease. Before adopting such an approach, we need to be more comfortable with the precision of the risk estimates. These estimates, derived entirely from demographic and clinical information, may be enhanced by genomic data to achieve more precision. Further data on the willingness of the public to accept no screening if their risk is below a certain threshold needs to be evaluated. Despite these issues, the guideline presents a provocative approach which demands our attention.
David Lieberman, MD, AGAF, is professor of medicine and chief of the division of gastroenterology and hepatology, Oregon Health & Science University, Portland. He is Past President of the AGA Institute. He has no conflicts of interest.
There is compelling evidence that CRC screening of average-risk individuals is effective – screening with one of several modalities can reduce CRC incidence and mortality in average-risk individuals. Various guidelines throughout the world have recommended screening, usually beginning at age 50 years, in a one-size-fits-all manner. Despite our knowledge that different people have a different lifetime risk of CRC, no prior guidelines have suggested that risk stratification be built into the decision making.
All of the recommendations in this practice guideline are weak because they are derived from models that lack adequate precision. Nevertheless, the authors have proposed a new approach to CRC screening, similar to management plans for patients with cardiovascular disease. Before adopting such an approach, we need to be more comfortable with the precision of the risk estimates. These estimates, derived entirely from demographic and clinical information, may be enhanced by genomic data to achieve more precision. Further data on the willingness of the public to accept no screening if their risk is below a certain threshold needs to be evaluated. Despite these issues, the guideline presents a provocative approach which demands our attention.
David Lieberman, MD, AGAF, is professor of medicine and chief of the division of gastroenterology and hepatology, Oregon Health & Science University, Portland. He is Past President of the AGA Institute. He has no conflicts of interest.
Patients 50-79 years old with a demonstrably low risk of developing the disease within 15 years probably don’t need to be screened for colorectal cancer. But if their risk of disease is at least 3% over 15 years, patients should be screened, Lise M. Helsingen, MD, and colleagues wrote in BMJ (2019;367:l5515 doi: 10.1136/bmj.l5515).
For these patients, “We suggest screening with one of the four screening options: fecal immunochemical test (FIT) every year, FIT every 2 years, a single sigmoidoscopy, or a single colonoscopy,” wrote Dr. Helsingen of the University of Oslo, and her team.
She chaired a 22-member international panel that developed a collaborative effort from the MAGIC research and innovation program as a part of the BMJ Rapid Recommendations project. The team reviewed 12 research papers comprising almost 1.4 million patients from Denmark, Italy, the Netherlands, Norway, Poland, Spain, Sweden, the United Kingdom, and the United States. Follow-up ranged from 0 to 19.5 years for colorectal cancer incidence and up to 30 years for mortality.
Because of the dearth of relevant data in some studies, however, the projected outcomes had to be simulated, with benefits and harms calculations based on 100% screening adherence. However, the team noted, it’s impossible to achieve complete adherence. Most studies of colorectal screening don’t exceed a 50% adherence level.
“All the modeling data are of low certainty. It is a useful indication, but there is a high chance that new evidence will show a smaller or larger benefit, which in turn may alter these recommendations.”
Compared with no screening, all four screening models reduced the risk of colorectal cancer mortality to a similar level.
- FIT every year, 59%.
- FIT every 2 years, 50%.
- Single sigmoidoscopy, 52%.
- Single colonoscopy, 67%.
Screening had less of an impact on reducing the incidence of colorectal cancer:
- FIT every 2 years, 0.05%.
- FIT every year, 0.15%.
- Single sigmoidoscopy, 27%.
- Single colonoscopy, 34%.
The panel also assessed potential harms. Among almost 1 million patients, the colonoscopy-related mortality rate was 0.03 per 1,000 procedures. The perforation rate was 0.8 per 1,000 colonoscopies after a positive fecal test, and 1.4 per 1,000 screened with sigmoidoscopy. The bleeding rate was 1.9 per 1,000 colonoscopies performed after a positive fecal test, and 3-4 per 1,000 screened with sigmoidoscopy.
Successful implementation of these recommendations hinges on accurate risk assessment, however. The team recommended the QCancer platform as “one of the best performing models for both men and women.”
The calculator includes age, sex, ethnicity, smoking status, alcohol use, family history of gastrointestinal cancer, personal history of other cancers, diabetes, ulcerative colitis, colonic polyps, and body mass index.
“We suggest this model because it is available as an online calculator; includes only risk factors available in routine health care; has been validated in a population separate from the derivation population; has reasonable discriminatory ability; and has a good fit between predicted and observed outcomes. In addition, it is the only online risk calculator we know of that predicts risk over a 15-year time horizon.”
The team stressed that their recommendations can’t be applied to all patients. Because evidence for both screening recommendations was weak – largely because of the dearth of supporting data – patients and physicians should cocreate a personalized screening plan.
“Several factors influence individuals’ decisions whether to be screened, even when they are presented with the same information,” the authors said. These include variation in an individual’s values and preferences, a close balance of benefits versus harms and burdens, and personal preference.
“Some individuals may value a minimally invasive test such as FIT, and the possibility of invasive screening with colonoscopy might put them off screening altogether. Those who most value preventing colorectal cancer or avoiding repeated testing are likely to choose sigmoidoscopy or colonoscopy.”
The authors had no financial conflicts of interest.
SOURCE: BMJ 2019;367:l5515. doi: 10.1136/bmj.l5515.
Patients 50-79 years old with a demonstrably low risk of developing the disease within 15 years probably don’t need to be screened for colorectal cancer. But if their risk of disease is at least 3% over 15 years, patients should be screened, Lise M. Helsingen, MD, and colleagues wrote in BMJ (2019;367:l5515 doi: 10.1136/bmj.l5515).
For these patients, “We suggest screening with one of the four screening options: fecal immunochemical test (FIT) every year, FIT every 2 years, a single sigmoidoscopy, or a single colonoscopy,” wrote Dr. Helsingen of the University of Oslo, and her team.
She chaired a 22-member international panel that developed a collaborative effort from the MAGIC research and innovation program as a part of the BMJ Rapid Recommendations project. The team reviewed 12 research papers comprising almost 1.4 million patients from Denmark, Italy, the Netherlands, Norway, Poland, Spain, Sweden, the United Kingdom, and the United States. Follow-up ranged from 0 to 19.5 years for colorectal cancer incidence and up to 30 years for mortality.
Because of the dearth of relevant data in some studies, however, the projected outcomes had to be simulated, with benefits and harms calculations based on 100% screening adherence. However, the team noted, it’s impossible to achieve complete adherence. Most studies of colorectal screening don’t exceed a 50% adherence level.
“All the modeling data are of low certainty. It is a useful indication, but there is a high chance that new evidence will show a smaller or larger benefit, which in turn may alter these recommendations.”
Compared with no screening, all four screening models reduced the risk of colorectal cancer mortality to a similar level.
- FIT every year, 59%.
- FIT every 2 years, 50%.
- Single sigmoidoscopy, 52%.
- Single colonoscopy, 67%.
Screening had less of an impact on reducing the incidence of colorectal cancer:
- FIT every 2 years, 0.05%.
- FIT every year, 0.15%.
- Single sigmoidoscopy, 27%.
- Single colonoscopy, 34%.
The panel also assessed potential harms. Among almost 1 million patients, the colonoscopy-related mortality rate was 0.03 per 1,000 procedures. The perforation rate was 0.8 per 1,000 colonoscopies after a positive fecal test, and 1.4 per 1,000 screened with sigmoidoscopy. The bleeding rate was 1.9 per 1,000 colonoscopies performed after a positive fecal test, and 3-4 per 1,000 screened with sigmoidoscopy.
Successful implementation of these recommendations hinges on accurate risk assessment, however. The team recommended the QCancer platform as “one of the best performing models for both men and women.”
The calculator includes age, sex, ethnicity, smoking status, alcohol use, family history of gastrointestinal cancer, personal history of other cancers, diabetes, ulcerative colitis, colonic polyps, and body mass index.
“We suggest this model because it is available as an online calculator; includes only risk factors available in routine health care; has been validated in a population separate from the derivation population; has reasonable discriminatory ability; and has a good fit between predicted and observed outcomes. In addition, it is the only online risk calculator we know of that predicts risk over a 15-year time horizon.”
The team stressed that their recommendations can’t be applied to all patients. Because evidence for both screening recommendations was weak – largely because of the dearth of supporting data – patients and physicians should cocreate a personalized screening plan.
“Several factors influence individuals’ decisions whether to be screened, even when they are presented with the same information,” the authors said. These include variation in an individual’s values and preferences, a close balance of benefits versus harms and burdens, and personal preference.
“Some individuals may value a minimally invasive test such as FIT, and the possibility of invasive screening with colonoscopy might put them off screening altogether. Those who most value preventing colorectal cancer or avoiding repeated testing are likely to choose sigmoidoscopy or colonoscopy.”
The authors had no financial conflicts of interest.
SOURCE: BMJ 2019;367:l5515. doi: 10.1136/bmj.l5515.
FROM BMJ
Dysregulated sleep is common in children with eosinophilic esophagitis
, Rasintra Siriwat, MD, and colleagues have ascertained.
Children with eosinophilic esophagitis (EoE) also were found to have a high prevalence of atopic diseases, including allergic rhinitis and eczema – findings that could be driving the breathing problems, said Dr. Siriwat, a neurology fellow at the Cleveland Clinic, and coauthors.
The retrospective study comprised 81 children with a diagnosis of EoE who were referred to sleep clinics. In this group, 46 of the children had active EoE (having gastrointestinal symptoms, including feeding difficulties, dysphagia, reflux, nausea/vomiting, or epigastric pain at presentation). The other 35 had an EoE diagnosis but no symptoms on presentation and were categorized as having inactive EoE. Most were male (71.6%) and white (92.5%). The mean age in the cohort was 10 years and the mean body mass index for all subjects was 22 kg/m2. A control group of 192 children without an EoE diagnosis who had overnight polysomnography were included in the analysis.
Allergic-type comorbidities were common among those with active EoE, including allergic rhinitis (55.5%), food allergy (39.5%), and eczema (26%). In addition, a quarter had attention-deficit/hyperactivity disorder, 22% an autism spectrum disorder, 21% a neurological disease, and 29% a psychiatric disorder.
Several sleep complaints were common in the entire EoE cohort, including snoring (76.5 %), restless sleep (66.6%), legs jerking or leg discomfort (43.2%), and daytime sleepiness (58%).
All children underwent an overnight polysomnography. Compared with controls, the children with EoE had significantly higher non-REM2 sleep, significantly lower non-REM3 sleep, lower REM, increased periodic leg movement disorder, and increased arousal index.
“Of note, we found a much higher percentage of [periodic leg movement disorder] in active EoE compared to inactive EoE,” the authors said.
The most common sleep diagnosis for the children with EoE was sleep-disordered breathing. Of 62 children with EoE and sleep disordered breathing, 37% had obstructive sleep apnea (OSA). Two patients had central sleep apnea and five had nocturnal hypoventilation. Children with EoE also reported parasomnia symptoms such as sleep talking (35.8%), sleepwalking (16%), bruxism (23.4%), night terrors (28.4%), and nocturnal enuresis (21.2%).
Of the 59 children with leg movement, 20 had periodic limb movement disorder and 5 were diagnosed with restless leg syndrome. Two were diagnosed with narcolepsy and three with hypersomnia. Four children had a circadian rhythm disorder.
“Notably, the majority of children with EoE had symptoms of sleep-disordered breathing, and more than one-third of total subjects were diagnosed with OSA,” the authors noted. “However, most of them were mild-moderate OSA. It should be noted that the prevalence of OSA in the pediatric population is 1%-5% mostly between the ages of 2-8 years, while the mean age of our subjects was 10 years old. The high prevalence of mild-moderate OSA in the EoE population might be explained by the relationship between EoE and atopic disease.”
Dr. Siriwat had no financial disclosures. The study was supported by Cincinnati Children’s Hospital Research Fund.
SOURCE: Siriwat R et al. Sleep Med. 2019 Sep 11. doi: 10.1016/j.sleep.2019.08.018.
, Rasintra Siriwat, MD, and colleagues have ascertained.
Children with eosinophilic esophagitis (EoE) also were found to have a high prevalence of atopic diseases, including allergic rhinitis and eczema – findings that could be driving the breathing problems, said Dr. Siriwat, a neurology fellow at the Cleveland Clinic, and coauthors.
The retrospective study comprised 81 children with a diagnosis of EoE who were referred to sleep clinics. In this group, 46 of the children had active EoE (having gastrointestinal symptoms, including feeding difficulties, dysphagia, reflux, nausea/vomiting, or epigastric pain at presentation). The other 35 had an EoE diagnosis but no symptoms on presentation and were categorized as having inactive EoE. Most were male (71.6%) and white (92.5%). The mean age in the cohort was 10 years and the mean body mass index for all subjects was 22 kg/m2. A control group of 192 children without an EoE diagnosis who had overnight polysomnography were included in the analysis.
Allergic-type comorbidities were common among those with active EoE, including allergic rhinitis (55.5%), food allergy (39.5%), and eczema (26%). In addition, a quarter had attention-deficit/hyperactivity disorder, 22% an autism spectrum disorder, 21% a neurological disease, and 29% a psychiatric disorder.
Several sleep complaints were common in the entire EoE cohort, including snoring (76.5 %), restless sleep (66.6%), legs jerking or leg discomfort (43.2%), and daytime sleepiness (58%).
All children underwent an overnight polysomnography. Compared with controls, the children with EoE had significantly higher non-REM2 sleep, significantly lower non-REM3 sleep, lower REM, increased periodic leg movement disorder, and increased arousal index.
“Of note, we found a much higher percentage of [periodic leg movement disorder] in active EoE compared to inactive EoE,” the authors said.
The most common sleep diagnosis for the children with EoE was sleep-disordered breathing. Of 62 children with EoE and sleep disordered breathing, 37% had obstructive sleep apnea (OSA). Two patients had central sleep apnea and five had nocturnal hypoventilation. Children with EoE also reported parasomnia symptoms such as sleep talking (35.8%), sleepwalking (16%), bruxism (23.4%), night terrors (28.4%), and nocturnal enuresis (21.2%).
Of the 59 children with leg movement, 20 had periodic limb movement disorder and 5 were diagnosed with restless leg syndrome. Two were diagnosed with narcolepsy and three with hypersomnia. Four children had a circadian rhythm disorder.
“Notably, the majority of children with EoE had symptoms of sleep-disordered breathing, and more than one-third of total subjects were diagnosed with OSA,” the authors noted. “However, most of them were mild-moderate OSA. It should be noted that the prevalence of OSA in the pediatric population is 1%-5% mostly between the ages of 2-8 years, while the mean age of our subjects was 10 years old. The high prevalence of mild-moderate OSA in the EoE population might be explained by the relationship between EoE and atopic disease.”
Dr. Siriwat had no financial disclosures. The study was supported by Cincinnati Children’s Hospital Research Fund.
SOURCE: Siriwat R et al. Sleep Med. 2019 Sep 11. doi: 10.1016/j.sleep.2019.08.018.
, Rasintra Siriwat, MD, and colleagues have ascertained.
Children with eosinophilic esophagitis (EoE) also were found to have a high prevalence of atopic diseases, including allergic rhinitis and eczema – findings that could be driving the breathing problems, said Dr. Siriwat, a neurology fellow at the Cleveland Clinic, and coauthors.
The retrospective study comprised 81 children with a diagnosis of EoE who were referred to sleep clinics. In this group, 46 of the children had active EoE (having gastrointestinal symptoms, including feeding difficulties, dysphagia, reflux, nausea/vomiting, or epigastric pain at presentation). The other 35 had an EoE diagnosis but no symptoms on presentation and were categorized as having inactive EoE. Most were male (71.6%) and white (92.5%). The mean age in the cohort was 10 years and the mean body mass index for all subjects was 22 kg/m2. A control group of 192 children without an EoE diagnosis who had overnight polysomnography were included in the analysis.
Allergic-type comorbidities were common among those with active EoE, including allergic rhinitis (55.5%), food allergy (39.5%), and eczema (26%). In addition, a quarter had attention-deficit/hyperactivity disorder, 22% an autism spectrum disorder, 21% a neurological disease, and 29% a psychiatric disorder.
Several sleep complaints were common in the entire EoE cohort, including snoring (76.5 %), restless sleep (66.6%), legs jerking or leg discomfort (43.2%), and daytime sleepiness (58%).
All children underwent an overnight polysomnography. Compared with controls, the children with EoE had significantly higher non-REM2 sleep, significantly lower non-REM3 sleep, lower REM, increased periodic leg movement disorder, and increased arousal index.
“Of note, we found a much higher percentage of [periodic leg movement disorder] in active EoE compared to inactive EoE,” the authors said.
The most common sleep diagnosis for the children with EoE was sleep-disordered breathing. Of 62 children with EoE and sleep disordered breathing, 37% had obstructive sleep apnea (OSA). Two patients had central sleep apnea and five had nocturnal hypoventilation. Children with EoE also reported parasomnia symptoms such as sleep talking (35.8%), sleepwalking (16%), bruxism (23.4%), night terrors (28.4%), and nocturnal enuresis (21.2%).
Of the 59 children with leg movement, 20 had periodic limb movement disorder and 5 were diagnosed with restless leg syndrome. Two were diagnosed with narcolepsy and three with hypersomnia. Four children had a circadian rhythm disorder.
“Notably, the majority of children with EoE had symptoms of sleep-disordered breathing, and more than one-third of total subjects were diagnosed with OSA,” the authors noted. “However, most of them were mild-moderate OSA. It should be noted that the prevalence of OSA in the pediatric population is 1%-5% mostly between the ages of 2-8 years, while the mean age of our subjects was 10 years old. The high prevalence of mild-moderate OSA in the EoE population might be explained by the relationship between EoE and atopic disease.”
Dr. Siriwat had no financial disclosures. The study was supported by Cincinnati Children’s Hospital Research Fund.
SOURCE: Siriwat R et al. Sleep Med. 2019 Sep 11. doi: 10.1016/j.sleep.2019.08.018.
FROM SLEEP MEDICINE
Laparoscopic surgery has short-term advantages for elderly patients with colorectal cancer
Sicheng Zhou, and colleagues wrote in BMC Surgery.
“Laparoscopic surgery showed better results than the open surgery in short-term outcomes,” said Dr. Zhou of the Chinese Academy of Medical Sciences, and coauthors. “[Carcinoembryonic antigen] level, III/IV stage, and perineural invasion were all reliable predictors of overall survival and disease-free survival for the treatment of laparoscopic surgery and open surgery for elderly Chinese patients over 80 years old with colorectal cancer.”
The study comprised 313 patients aged 80 years or older who underwent surgery for colorectal cancer. The group was equally divided between those who had laparoscopic and open surgery. They were matched 1:1, for a total of 93 pairs included. The patients’ mean age was 82 years. Medical comorbidities were present in about 63%. The tumor was more likely to present in the in the rectum and right colon (about 34% each). The next most common disease site was the sigmoid colon (22%).
Most tumors were stage III (58%), and II (about 30%). About 70% were moderately differentiated and 20% poorly differentiated. Carcinoembryonic antigen was greater than 5 ng/mL in about three-fourths of the group, and higher in the reminder.
Surgery duration was somewhat shorter in the open group but not significantly so. However, intraoperative complications were higher in the open group, including transfusion (22.6% vs. 16% and blood loss 50.9 vs. 108 mL). There was a lower occurrence of postoperative complications (10.8% vs. 26.9%) in the laparoscopic group.
Intraoperative complications occurred in only one patient, who was in the laparoscopic group, but perioperative complications were significantly more common in the open group (17.2% vs. 6.5%). In the open group these included wound infection (9.7%), followed by ileus (5.4%), anastomosis leakage (4.3%), and delayed gastric emptying (4.3%). In the laparoscopic group, the most common morbidities were anastomosis leakage (2.2%), ileus (2.2%) and pneumonia (2.2%).
The number of retrieved lymph nodes was also significantly higher in the laparoscopic group (20 vs. 17).
Yet, despite the short-term perioperative advantages of the laparoscopic approach in elderly patients, the 3- and 5-year overall and disease-free survival rates were not significantly different in these groups. The investigators concluded “it is noteworthy that the 3-year and 5-year [overall survival] rates, and 3- year and 5-year [disease-free survival] rates of patients in the laparoscopic group were generally higher than the open group. The 5-year [disease-free survival] rate in the laparoscopic group was even higher than that in the open group by more than 10%. This difference might be due to the difference in the number of dissected lymph nodes between the open group and the laparoscopic group. Hence, although there was no significant difference in survival outcomes between the two surgical methods, the laparoscopic surgery in elderly patients with colorectal cancer might achieve better survival outcomes than the open surgery.”
The authors declared that they had no competing interests. This work was supported by the Beijing Hope Run Special Fund of Cancer Foundation of China and Capital Health Research and Development.
SOURCE: Zhou S et al. BMC Surg. 2019;19:137. doi: 10.1186/s12893-019-0596-3.
Sicheng Zhou, and colleagues wrote in BMC Surgery.
“Laparoscopic surgery showed better results than the open surgery in short-term outcomes,” said Dr. Zhou of the Chinese Academy of Medical Sciences, and coauthors. “[Carcinoembryonic antigen] level, III/IV stage, and perineural invasion were all reliable predictors of overall survival and disease-free survival for the treatment of laparoscopic surgery and open surgery for elderly Chinese patients over 80 years old with colorectal cancer.”
The study comprised 313 patients aged 80 years or older who underwent surgery for colorectal cancer. The group was equally divided between those who had laparoscopic and open surgery. They were matched 1:1, for a total of 93 pairs included. The patients’ mean age was 82 years. Medical comorbidities were present in about 63%. The tumor was more likely to present in the in the rectum and right colon (about 34% each). The next most common disease site was the sigmoid colon (22%).
Most tumors were stage III (58%), and II (about 30%). About 70% were moderately differentiated and 20% poorly differentiated. Carcinoembryonic antigen was greater than 5 ng/mL in about three-fourths of the group, and higher in the reminder.
Surgery duration was somewhat shorter in the open group but not significantly so. However, intraoperative complications were higher in the open group, including transfusion (22.6% vs. 16% and blood loss 50.9 vs. 108 mL). There was a lower occurrence of postoperative complications (10.8% vs. 26.9%) in the laparoscopic group.
Intraoperative complications occurred in only one patient, who was in the laparoscopic group, but perioperative complications were significantly more common in the open group (17.2% vs. 6.5%). In the open group these included wound infection (9.7%), followed by ileus (5.4%), anastomosis leakage (4.3%), and delayed gastric emptying (4.3%). In the laparoscopic group, the most common morbidities were anastomosis leakage (2.2%), ileus (2.2%) and pneumonia (2.2%).
The number of retrieved lymph nodes was also significantly higher in the laparoscopic group (20 vs. 17).
Yet, despite the short-term perioperative advantages of the laparoscopic approach in elderly patients, the 3- and 5-year overall and disease-free survival rates were not significantly different in these groups. The investigators concluded “it is noteworthy that the 3-year and 5-year [overall survival] rates, and 3- year and 5-year [disease-free survival] rates of patients in the laparoscopic group were generally higher than the open group. The 5-year [disease-free survival] rate in the laparoscopic group was even higher than that in the open group by more than 10%. This difference might be due to the difference in the number of dissected lymph nodes between the open group and the laparoscopic group. Hence, although there was no significant difference in survival outcomes between the two surgical methods, the laparoscopic surgery in elderly patients with colorectal cancer might achieve better survival outcomes than the open surgery.”
The authors declared that they had no competing interests. This work was supported by the Beijing Hope Run Special Fund of Cancer Foundation of China and Capital Health Research and Development.
SOURCE: Zhou S et al. BMC Surg. 2019;19:137. doi: 10.1186/s12893-019-0596-3.
Sicheng Zhou, and colleagues wrote in BMC Surgery.
“Laparoscopic surgery showed better results than the open surgery in short-term outcomes,” said Dr. Zhou of the Chinese Academy of Medical Sciences, and coauthors. “[Carcinoembryonic antigen] level, III/IV stage, and perineural invasion were all reliable predictors of overall survival and disease-free survival for the treatment of laparoscopic surgery and open surgery for elderly Chinese patients over 80 years old with colorectal cancer.”
The study comprised 313 patients aged 80 years or older who underwent surgery for colorectal cancer. The group was equally divided between those who had laparoscopic and open surgery. They were matched 1:1, for a total of 93 pairs included. The patients’ mean age was 82 years. Medical comorbidities were present in about 63%. The tumor was more likely to present in the in the rectum and right colon (about 34% each). The next most common disease site was the sigmoid colon (22%).
Most tumors were stage III (58%), and II (about 30%). About 70% were moderately differentiated and 20% poorly differentiated. Carcinoembryonic antigen was greater than 5 ng/mL in about three-fourths of the group, and higher in the reminder.
Surgery duration was somewhat shorter in the open group but not significantly so. However, intraoperative complications were higher in the open group, including transfusion (22.6% vs. 16% and blood loss 50.9 vs. 108 mL). There was a lower occurrence of postoperative complications (10.8% vs. 26.9%) in the laparoscopic group.
Intraoperative complications occurred in only one patient, who was in the laparoscopic group, but perioperative complications were significantly more common in the open group (17.2% vs. 6.5%). In the open group these included wound infection (9.7%), followed by ileus (5.4%), anastomosis leakage (4.3%), and delayed gastric emptying (4.3%). In the laparoscopic group, the most common morbidities were anastomosis leakage (2.2%), ileus (2.2%) and pneumonia (2.2%).
The number of retrieved lymph nodes was also significantly higher in the laparoscopic group (20 vs. 17).
Yet, despite the short-term perioperative advantages of the laparoscopic approach in elderly patients, the 3- and 5-year overall and disease-free survival rates were not significantly different in these groups. The investigators concluded “it is noteworthy that the 3-year and 5-year [overall survival] rates, and 3- year and 5-year [disease-free survival] rates of patients in the laparoscopic group were generally higher than the open group. The 5-year [disease-free survival] rate in the laparoscopic group was even higher than that in the open group by more than 10%. This difference might be due to the difference in the number of dissected lymph nodes between the open group and the laparoscopic group. Hence, although there was no significant difference in survival outcomes between the two surgical methods, the laparoscopic surgery in elderly patients with colorectal cancer might achieve better survival outcomes than the open surgery.”
The authors declared that they had no competing interests. This work was supported by the Beijing Hope Run Special Fund of Cancer Foundation of China and Capital Health Research and Development.
SOURCE: Zhou S et al. BMC Surg. 2019;19:137. doi: 10.1186/s12893-019-0596-3.
FROM BMC SURGERY
Risk of contralateral breast cancer highest for women under 40
Stray radiation exposure could be responsible for up to 28% of the contralateral breast cancer that occurs years after radiotherapy of the primary tumor.
The risk is highest among women initially treated when younger than 40 years, who had at lest 5 years’ lapse between the first and second occurrences, and had a higher genetic risk score, Gordon P. Watt, PhD, and colleagues reported in JAMA Network Open.
“These findings may support clinical decision making related to radiation treatment, particularly among women for whom other modalities may be considered,” wrote Dr. Watt of Memorial Sloan Kettering Cancer Center, New York, and coauthors. “For example, young women with a high [genetic risk] may consider partial-breast radiation therapy, rather than whole-breast radiation therapy when appropriate, opt for radiation therapy techniques that reduce integral dose (e.g., proton beam), or decide for non–radiation therapy–based locoregional management (e.g., mastectomy). These findings may be especially important in younger women with medially located breast cancers, where the scatter dose to the contralateral breast is likely to be higher.”
The investigators enrolled women who received a diagnosis for a first invasive local or regional breast cancer when they were younger than 55 years in a case-control study to investigate whether the NHEJ genetic risk score (GRS) could predict a woman’s risk of developing contralateral breast cancer after irradiation of a primary breast cancer. The risk score comprises 93 single nucleotide polymorphisms (SNPs) located in or near the seven genes in the NHEJ pathway, including DCLRE1C, LIG4, NHEJ1, PRKDC, XRCC4, XRCC5, and XRCC6. Dr. Watts’ team investigated risks associated with 69 of the SNPs.
The study comprised 3,732 women who were recruited from 2000 to 2012, with primary diagnosis occurring from 1985 to 2008. Of these, 1,521 had contralateral breast cancer; the remainder had unilateral disease and were used as controls.
At first diagnosis, they were aged a median of 46 years, although age ranged from 23 to 54 years. Most of the primary tumors (84%) were ductal. Among the recurrences, 9% were in situ, 63% local, 23% regional, and 2% distant. Stage was unknown on the remainder. Among these recurrent tumors, 54% were estrogen receptor positive and 24% were progesterone receptor positive, with unknown status on the remainder.
For women aged younger than 40 years at the time of the primary tumor, and at least 5 years out from treatment, radiation increased the risk of contralateral disease by 70%. But there was no significant risk to younger women with less than 5 years’ latency, or to women diagnosed at 40 years or older regardless of the time since treatment.
Age played a similar role when considering location-specific stray radiation dose. The risk was doubled in younger women who were exposed to at least 1 Gy and at least 5 years out from treatment, but there was no significantly increased risk to women older at first diagnosis.
Nor were the individual SNPs associated with increased risk. “The NHEJ GRS was approximately normally distributed and was dichotomized at the overall median for analysis; the median (range) GRS in the case group was 75 alleles and the median GRS in the control group was 74 alleles,” the investigators wrote.
But when examined by total GRS score, differences emerged.
“In the high NHEJ GRS group, among women who received the first diagnosis when they were younger than 40 years with a latency of 5 years or more, a stray radiation dose of 1.0 Gy or more was associated with threefold greater contralateral breast cancer risk, compared with no radiation exposure. In contrast, for women with an NHEJ GRS of 74 alleles or fewer in the same age and latency group, there was no association between radiation dose and contralateral breast cancer,” they wrote.
Again, there was no increased risk for women aged older than 40 years at first diagnosis.
“Based on these results, after a latency of 5 years or longer among women who received their first breast cancer diagnosis when they were younger than 40 years with a high NHEJ GRS, the population-attributable risk fraction of contralateral breast cancer attributable to stray radiation exposure to the contralateral breast was 28%. The corresponding population attributable risk fraction among women who received their first diagnosis when they were younger than 40 years after a latency of 5 years or more with a low NHEJ GRS was 18%,” the investigators wrote.
Five of the seven NHEJ pathway genes appeared to be driving these increased risks: LIG4, NHEJ1, XRCC4, XRCC5, and XRCC6. The expression quantitative trait loci (eQTLs) in each gene were always associated with a single direction of association; all risk alleles in XRCC4 were associated with decreased expression and all risk alleles in LIG4 were associated with increased expression.
“The consistent association of multiple NHEJ GRS risk alleles with eQTLs in a single direction suggests that the NHEJ GRS may be capturing the effect of SNP alleles on the transcription of one or more genes in the NHEJ pathway. This supports the hypothesis that the variation in this pathway may alter double-stranded DNA damage response, thereby increasing the risk of tumor development. However, the results from [the Genotype-Tissue Expression database] are drawn from multiple tissues that may not be appropriate proxies for breast tissue and the impact of genetic variation in the overall NHEJ pathway is likely to be complex,” the investigators wrote.
Dr. Watt had no financial disclosures. The research was funded by the National Cancer Institute.
SOURCE: Watt GP et al. JAMA Netw Open. 2019 Sep 27. doi: 10.1001/jamanetworkopen.2019.12259.
Stray radiation exposure could be responsible for up to 28% of the contralateral breast cancer that occurs years after radiotherapy of the primary tumor.
The risk is highest among women initially treated when younger than 40 years, who had at lest 5 years’ lapse between the first and second occurrences, and had a higher genetic risk score, Gordon P. Watt, PhD, and colleagues reported in JAMA Network Open.
“These findings may support clinical decision making related to radiation treatment, particularly among women for whom other modalities may be considered,” wrote Dr. Watt of Memorial Sloan Kettering Cancer Center, New York, and coauthors. “For example, young women with a high [genetic risk] may consider partial-breast radiation therapy, rather than whole-breast radiation therapy when appropriate, opt for radiation therapy techniques that reduce integral dose (e.g., proton beam), or decide for non–radiation therapy–based locoregional management (e.g., mastectomy). These findings may be especially important in younger women with medially located breast cancers, where the scatter dose to the contralateral breast is likely to be higher.”
The investigators enrolled women who received a diagnosis for a first invasive local or regional breast cancer when they were younger than 55 years in a case-control study to investigate whether the NHEJ genetic risk score (GRS) could predict a woman’s risk of developing contralateral breast cancer after irradiation of a primary breast cancer. The risk score comprises 93 single nucleotide polymorphisms (SNPs) located in or near the seven genes in the NHEJ pathway, including DCLRE1C, LIG4, NHEJ1, PRKDC, XRCC4, XRCC5, and XRCC6. Dr. Watts’ team investigated risks associated with 69 of the SNPs.
The study comprised 3,732 women who were recruited from 2000 to 2012, with primary diagnosis occurring from 1985 to 2008. Of these, 1,521 had contralateral breast cancer; the remainder had unilateral disease and were used as controls.
At first diagnosis, they were aged a median of 46 years, although age ranged from 23 to 54 years. Most of the primary tumors (84%) were ductal. Among the recurrences, 9% were in situ, 63% local, 23% regional, and 2% distant. Stage was unknown on the remainder. Among these recurrent tumors, 54% were estrogen receptor positive and 24% were progesterone receptor positive, with unknown status on the remainder.
For women aged younger than 40 years at the time of the primary tumor, and at least 5 years out from treatment, radiation increased the risk of contralateral disease by 70%. But there was no significant risk to younger women with less than 5 years’ latency, or to women diagnosed at 40 years or older regardless of the time since treatment.
Age played a similar role when considering location-specific stray radiation dose. The risk was doubled in younger women who were exposed to at least 1 Gy and at least 5 years out from treatment, but there was no significantly increased risk to women older at first diagnosis.
Nor were the individual SNPs associated with increased risk. “The NHEJ GRS was approximately normally distributed and was dichotomized at the overall median for analysis; the median (range) GRS in the case group was 75 alleles and the median GRS in the control group was 74 alleles,” the investigators wrote.
But when examined by total GRS score, differences emerged.
“In the high NHEJ GRS group, among women who received the first diagnosis when they were younger than 40 years with a latency of 5 years or more, a stray radiation dose of 1.0 Gy or more was associated with threefold greater contralateral breast cancer risk, compared with no radiation exposure. In contrast, for women with an NHEJ GRS of 74 alleles or fewer in the same age and latency group, there was no association between radiation dose and contralateral breast cancer,” they wrote.
Again, there was no increased risk for women aged older than 40 years at first diagnosis.
“Based on these results, after a latency of 5 years or longer among women who received their first breast cancer diagnosis when they were younger than 40 years with a high NHEJ GRS, the population-attributable risk fraction of contralateral breast cancer attributable to stray radiation exposure to the contralateral breast was 28%. The corresponding population attributable risk fraction among women who received their first diagnosis when they were younger than 40 years after a latency of 5 years or more with a low NHEJ GRS was 18%,” the investigators wrote.
Five of the seven NHEJ pathway genes appeared to be driving these increased risks: LIG4, NHEJ1, XRCC4, XRCC5, and XRCC6. The expression quantitative trait loci (eQTLs) in each gene were always associated with a single direction of association; all risk alleles in XRCC4 were associated with decreased expression and all risk alleles in LIG4 were associated with increased expression.
“The consistent association of multiple NHEJ GRS risk alleles with eQTLs in a single direction suggests that the NHEJ GRS may be capturing the effect of SNP alleles on the transcription of one or more genes in the NHEJ pathway. This supports the hypothesis that the variation in this pathway may alter double-stranded DNA damage response, thereby increasing the risk of tumor development. However, the results from [the Genotype-Tissue Expression database] are drawn from multiple tissues that may not be appropriate proxies for breast tissue and the impact of genetic variation in the overall NHEJ pathway is likely to be complex,” the investigators wrote.
Dr. Watt had no financial disclosures. The research was funded by the National Cancer Institute.
SOURCE: Watt GP et al. JAMA Netw Open. 2019 Sep 27. doi: 10.1001/jamanetworkopen.2019.12259.
Stray radiation exposure could be responsible for up to 28% of the contralateral breast cancer that occurs years after radiotherapy of the primary tumor.
The risk is highest among women initially treated when younger than 40 years, who had at lest 5 years’ lapse between the first and second occurrences, and had a higher genetic risk score, Gordon P. Watt, PhD, and colleagues reported in JAMA Network Open.
“These findings may support clinical decision making related to radiation treatment, particularly among women for whom other modalities may be considered,” wrote Dr. Watt of Memorial Sloan Kettering Cancer Center, New York, and coauthors. “For example, young women with a high [genetic risk] may consider partial-breast radiation therapy, rather than whole-breast radiation therapy when appropriate, opt for radiation therapy techniques that reduce integral dose (e.g., proton beam), or decide for non–radiation therapy–based locoregional management (e.g., mastectomy). These findings may be especially important in younger women with medially located breast cancers, where the scatter dose to the contralateral breast is likely to be higher.”
The investigators enrolled women who received a diagnosis for a first invasive local or regional breast cancer when they were younger than 55 years in a case-control study to investigate whether the NHEJ genetic risk score (GRS) could predict a woman’s risk of developing contralateral breast cancer after irradiation of a primary breast cancer. The risk score comprises 93 single nucleotide polymorphisms (SNPs) located in or near the seven genes in the NHEJ pathway, including DCLRE1C, LIG4, NHEJ1, PRKDC, XRCC4, XRCC5, and XRCC6. Dr. Watts’ team investigated risks associated with 69 of the SNPs.
The study comprised 3,732 women who were recruited from 2000 to 2012, with primary diagnosis occurring from 1985 to 2008. Of these, 1,521 had contralateral breast cancer; the remainder had unilateral disease and were used as controls.
At first diagnosis, they were aged a median of 46 years, although age ranged from 23 to 54 years. Most of the primary tumors (84%) were ductal. Among the recurrences, 9% were in situ, 63% local, 23% regional, and 2% distant. Stage was unknown on the remainder. Among these recurrent tumors, 54% were estrogen receptor positive and 24% were progesterone receptor positive, with unknown status on the remainder.
For women aged younger than 40 years at the time of the primary tumor, and at least 5 years out from treatment, radiation increased the risk of contralateral disease by 70%. But there was no significant risk to younger women with less than 5 years’ latency, or to women diagnosed at 40 years or older regardless of the time since treatment.
Age played a similar role when considering location-specific stray radiation dose. The risk was doubled in younger women who were exposed to at least 1 Gy and at least 5 years out from treatment, but there was no significantly increased risk to women older at first diagnosis.
Nor were the individual SNPs associated with increased risk. “The NHEJ GRS was approximately normally distributed and was dichotomized at the overall median for analysis; the median (range) GRS in the case group was 75 alleles and the median GRS in the control group was 74 alleles,” the investigators wrote.
But when examined by total GRS score, differences emerged.
“In the high NHEJ GRS group, among women who received the first diagnosis when they were younger than 40 years with a latency of 5 years or more, a stray radiation dose of 1.0 Gy or more was associated with threefold greater contralateral breast cancer risk, compared with no radiation exposure. In contrast, for women with an NHEJ GRS of 74 alleles or fewer in the same age and latency group, there was no association between radiation dose and contralateral breast cancer,” they wrote.
Again, there was no increased risk for women aged older than 40 years at first diagnosis.
“Based on these results, after a latency of 5 years or longer among women who received their first breast cancer diagnosis when they were younger than 40 years with a high NHEJ GRS, the population-attributable risk fraction of contralateral breast cancer attributable to stray radiation exposure to the contralateral breast was 28%. The corresponding population attributable risk fraction among women who received their first diagnosis when they were younger than 40 years after a latency of 5 years or more with a low NHEJ GRS was 18%,” the investigators wrote.
Five of the seven NHEJ pathway genes appeared to be driving these increased risks: LIG4, NHEJ1, XRCC4, XRCC5, and XRCC6. The expression quantitative trait loci (eQTLs) in each gene were always associated with a single direction of association; all risk alleles in XRCC4 were associated with decreased expression and all risk alleles in LIG4 were associated with increased expression.
“The consistent association of multiple NHEJ GRS risk alleles with eQTLs in a single direction suggests that the NHEJ GRS may be capturing the effect of SNP alleles on the transcription of one or more genes in the NHEJ pathway. This supports the hypothesis that the variation in this pathway may alter double-stranded DNA damage response, thereby increasing the risk of tumor development. However, the results from [the Genotype-Tissue Expression database] are drawn from multiple tissues that may not be appropriate proxies for breast tissue and the impact of genetic variation in the overall NHEJ pathway is likely to be complex,” the investigators wrote.
Dr. Watt had no financial disclosures. The research was funded by the National Cancer Institute.
SOURCE: Watt GP et al. JAMA Netw Open. 2019 Sep 27. doi: 10.1001/jamanetworkopen.2019.12259.
FROM JAMA NETWORK OPEN
No difference between ipilimumab/nivolumab combo and immunotherapy plus VEGF for metastatic RCC
There is no significant difference in response or survival rates between the combination of ipilimumab/nivolumab (ipi-nivo) and immuno-oncology plus vascular endothelial growth factor inhibition (IOVE) for patients with metastatic renal cell carcinoma.
Therefore, the treatment should probably be directed by patient preferences, among other things, Shaan Dudani, MD, and colleagues wrote in European Oncology.
“Given the current lack of evidence to suggest a difference in efficacy between treatment strategies, patients, clinicians and policy makers are likely to take into account other considerations, such as toxicity, cost, logistics, prognostic categories, and patient preferences in deciding between the various front-line [immuno-oncology] combination regimens,” wrote Dr. Dudani, of the University of Calgary, and coauthors.
The team examined response rates among 263 patients with metastatic renal cell carcinoma from the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) dataset. Patients treated with any first-line IOVE combination (n = 113) were compared with those treated with ipi-nivo (n = 75). Patients were about 62 years old. The most common sites of metastasis were liver (about 20%) and bone (about 33%), and about 20% had sarcomatoid features (about 20%). Most (about 75%) had multiple metastatic sites.
Thirty percent of those in the IOVE group and 40% in the ipi-nivo group had received second-line treatments. These included axitinib, levantinib plus severolimus, nivolumab alone, pazopanib, and sunitinib, as well as other treatments.
At a mean follow-up of 11.7 months, the response rates were 33% for IOVE and 40% for ipi-nivo. This difference was not statistically significant (between group difference, 7%; 95% confidence interval, –8% to 22%; P = .4). Complete response occurred in 2% in IOVE and 5% of the ipi-nivo group.
The time to treatment failure was 14.3 months for IOVE and 10.2 months for ipi-nivo – again not a significant difference (P = .2). Time to next treatment also was not significantly different (19.7 vs. 17.9 months; P = .4). Neither group met the study’s overall survival goal.
After adjustment for IMDC risk score, hazard ratios for death were 0.71 for IOVE and 1.74 for ipi-nivo. There were no significant between-group differences when comparing intermediate- and poor-risk patients or when the analysis was restricted only to favorable-risk patients. Among 55 who received second-line therapy, there was also no significant difference in time to treatment failure.
“It was interesting, though not surprising, to observe that the majority [88%] of second-line therapies in this cohort were VEGF-based following ipi-nivo vs. IOVE combinations,” the authors noted. “The higher response rates observed in patients receiving second-line VEGF combinations is noteworthy and thought provoking. Biologically, it is plausible that VEGF-based second-line therapy would be more likely to be effective in the VEGF-naive ipi-nivo cohort. It remains to be seen whether the numerical difference in time to treatment failure becomes significant with increased sample size and further follow-up, and whether this contributes to differences in overall survival, which ultimately impacts treatment selections in the first-line setting.”
Dr. Dudani had no financial disclosures.
SOURCE: Dudani S et al. Euro Onc. 2019 Aug 22. doi: 10.1016/j.eururo.2019.07.048.
There is no significant difference in response or survival rates between the combination of ipilimumab/nivolumab (ipi-nivo) and immuno-oncology plus vascular endothelial growth factor inhibition (IOVE) for patients with metastatic renal cell carcinoma.
Therefore, the treatment should probably be directed by patient preferences, among other things, Shaan Dudani, MD, and colleagues wrote in European Oncology.
“Given the current lack of evidence to suggest a difference in efficacy between treatment strategies, patients, clinicians and policy makers are likely to take into account other considerations, such as toxicity, cost, logistics, prognostic categories, and patient preferences in deciding between the various front-line [immuno-oncology] combination regimens,” wrote Dr. Dudani, of the University of Calgary, and coauthors.
The team examined response rates among 263 patients with metastatic renal cell carcinoma from the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) dataset. Patients treated with any first-line IOVE combination (n = 113) were compared with those treated with ipi-nivo (n = 75). Patients were about 62 years old. The most common sites of metastasis were liver (about 20%) and bone (about 33%), and about 20% had sarcomatoid features (about 20%). Most (about 75%) had multiple metastatic sites.
Thirty percent of those in the IOVE group and 40% in the ipi-nivo group had received second-line treatments. These included axitinib, levantinib plus severolimus, nivolumab alone, pazopanib, and sunitinib, as well as other treatments.
At a mean follow-up of 11.7 months, the response rates were 33% for IOVE and 40% for ipi-nivo. This difference was not statistically significant (between group difference, 7%; 95% confidence interval, –8% to 22%; P = .4). Complete response occurred in 2% in IOVE and 5% of the ipi-nivo group.
The time to treatment failure was 14.3 months for IOVE and 10.2 months for ipi-nivo – again not a significant difference (P = .2). Time to next treatment also was not significantly different (19.7 vs. 17.9 months; P = .4). Neither group met the study’s overall survival goal.
After adjustment for IMDC risk score, hazard ratios for death were 0.71 for IOVE and 1.74 for ipi-nivo. There were no significant between-group differences when comparing intermediate- and poor-risk patients or when the analysis was restricted only to favorable-risk patients. Among 55 who received second-line therapy, there was also no significant difference in time to treatment failure.
“It was interesting, though not surprising, to observe that the majority [88%] of second-line therapies in this cohort were VEGF-based following ipi-nivo vs. IOVE combinations,” the authors noted. “The higher response rates observed in patients receiving second-line VEGF combinations is noteworthy and thought provoking. Biologically, it is plausible that VEGF-based second-line therapy would be more likely to be effective in the VEGF-naive ipi-nivo cohort. It remains to be seen whether the numerical difference in time to treatment failure becomes significant with increased sample size and further follow-up, and whether this contributes to differences in overall survival, which ultimately impacts treatment selections in the first-line setting.”
Dr. Dudani had no financial disclosures.
SOURCE: Dudani S et al. Euro Onc. 2019 Aug 22. doi: 10.1016/j.eururo.2019.07.048.
There is no significant difference in response or survival rates between the combination of ipilimumab/nivolumab (ipi-nivo) and immuno-oncology plus vascular endothelial growth factor inhibition (IOVE) for patients with metastatic renal cell carcinoma.
Therefore, the treatment should probably be directed by patient preferences, among other things, Shaan Dudani, MD, and colleagues wrote in European Oncology.
“Given the current lack of evidence to suggest a difference in efficacy between treatment strategies, patients, clinicians and policy makers are likely to take into account other considerations, such as toxicity, cost, logistics, prognostic categories, and patient preferences in deciding between the various front-line [immuno-oncology] combination regimens,” wrote Dr. Dudani, of the University of Calgary, and coauthors.
The team examined response rates among 263 patients with metastatic renal cell carcinoma from the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) dataset. Patients treated with any first-line IOVE combination (n = 113) were compared with those treated with ipi-nivo (n = 75). Patients were about 62 years old. The most common sites of metastasis were liver (about 20%) and bone (about 33%), and about 20% had sarcomatoid features (about 20%). Most (about 75%) had multiple metastatic sites.
Thirty percent of those in the IOVE group and 40% in the ipi-nivo group had received second-line treatments. These included axitinib, levantinib plus severolimus, nivolumab alone, pazopanib, and sunitinib, as well as other treatments.
At a mean follow-up of 11.7 months, the response rates were 33% for IOVE and 40% for ipi-nivo. This difference was not statistically significant (between group difference, 7%; 95% confidence interval, –8% to 22%; P = .4). Complete response occurred in 2% in IOVE and 5% of the ipi-nivo group.
The time to treatment failure was 14.3 months for IOVE and 10.2 months for ipi-nivo – again not a significant difference (P = .2). Time to next treatment also was not significantly different (19.7 vs. 17.9 months; P = .4). Neither group met the study’s overall survival goal.
After adjustment for IMDC risk score, hazard ratios for death were 0.71 for IOVE and 1.74 for ipi-nivo. There were no significant between-group differences when comparing intermediate- and poor-risk patients or when the analysis was restricted only to favorable-risk patients. Among 55 who received second-line therapy, there was also no significant difference in time to treatment failure.
“It was interesting, though not surprising, to observe that the majority [88%] of second-line therapies in this cohort were VEGF-based following ipi-nivo vs. IOVE combinations,” the authors noted. “The higher response rates observed in patients receiving second-line VEGF combinations is noteworthy and thought provoking. Biologically, it is plausible that VEGF-based second-line therapy would be more likely to be effective in the VEGF-naive ipi-nivo cohort. It remains to be seen whether the numerical difference in time to treatment failure becomes significant with increased sample size and further follow-up, and whether this contributes to differences in overall survival, which ultimately impacts treatment selections in the first-line setting.”
Dr. Dudani had no financial disclosures.
SOURCE: Dudani S et al. Euro Onc. 2019 Aug 22. doi: 10.1016/j.eururo.2019.07.048.
FROM EUROPEAN ONCOLOGY
Four genetic variants link psychotic experiences to multiple mental disorders
Four genetic variations appear to link psychotic experiences with other psychiatric disorders, including schizophrenia, major depressive disorder, bipolar disorder, and neurodevelopmental disorders, a large genetic study has concluded.
, reported Sophie E. Legge, PhD, and colleagues. Their study was published in JAMA Psychiatry.
Although it is informative, the study is unlikely to expand the knowledge of schizophrenia-specific genetics.
“Consistent with other studies, the heritability estimate (1.71%) was low, and given that the variance explained in our polygenic risk analysis was also low, the finding suggests that understanding the genetics of psychotic experiences is unlikely to have an important effect on understanding the genetics of schizophrenia specifically,” wrote Dr. Legge, of the MRC Center for Neuropsychiatric Genetics and Genomics in the division of psychological medicine and clinical neurosciences at Cardiff (Wales) University, and colleagues.
The team conducted a genomewide association study (GWAS) using data from 127,966 individuals in the U.K. Biobank. Of these, 6,123 reported any psychotic experience, 2,143 reported distressing psychotic experiences, and 3,337 reported multiple experiences. The remainder served as controls. At the time of the biobank data collection, the subjects were a mean of 64 years of age; 56% were women.
First psychotic experience occurred at a mean of almost 32 years of age, but about a third reported that the first episode occurred before age 20, or that psychotic experiences had been happening ever since they could remember. Another third reported their first experience between ages 40 and 76 years.
The investigators conducted three GWAS studies: one for any psychotic experience, one for distressing experiences, and one for multiple experiences.
No significant genetic associations were found among those with multiple psychotic experiences, the authors said.
But they did find four variants significantly associated with the other experience categories.
Two variants were associated with any psychotic experience. Those with rs10994278, an intronic variant within Ankyrin-3 (ANK3), were 16% more likely to have a psychotic experience (odds ratio, 1.16). Those with intergenic variant rs549656827 were 39% less likely (OR, 0.61). “The ANK3 gene encodes ankyrin-G, a protein that has been shown to regulate the assembly of voltage-gated sodium channels and is essential for normal synaptic function,” the authors said. “ANK3 is one of strongest and most replicated genes for bipolar disorder, and variants within ANK3 have also been associated in the Psychiatric Genomics Consortium cross-disorder GWAS, and in a rare variant analysis of autism spectrum disorder.”
Two variants were linked to distressing psychotic experiences: rs75459873, intronic to cannabinoid receptor 2 (CNR2), decreased the risk by 34% (OR, 0.66). Intergenic variant rs3849810 increased the risk by 12% (OR, 1.12).
“CNR2 encodes for CB2, one of two well-characterized cannabinoid receptors. Several lines of evidence have implicated the endocannabinoid system in psychiatric disorders, including schizophrenia and depression. The main psychoactive agent of cannabis, tetrahydrocannabinol, can cause acute psychotic symptoms and cognitive impairment. Given that cannabis use is strongly associated with psychotic experiences, we tested, but found no evidence for, a mediating or moderating effect of cannabis use on the association of rs75459873 and distressing psychotic experiences. However, while no evidence was found in this study, a mediating effect of cannabis use cannot be ruled out given the relatively low power of such analyses and the potential measurement error.”
Also, significant genetic correlations were found between any psychotic experiences and major depressive disorder, autism spectrum disorder, ADHD, and schizophrenia. However, the polygenic risk scores for schizophrenia, major depressive disorder, bipolar disorder, ADHD, and autism spectrum disorder, were low.
“We also considered individual psychotic symptoms and found that polygenic risk scores for schizophrenia, bipolar disorder, depression, and ADHD were more strongly associated with delusions of persecution than with the other psychotic symptoms.”
Those with distressing psychotic experiences tended to have more copy number variations (CNVs) associated with schizophrenia (OR, 2.04) and neurodevelopmental disorders (OR, 1.75). The team also found significant associations between distressing experiences and major depressive disorder, ADHD, autism spectrum disorder, and schizophrenia.
“We found particular enrichment of these [polygenic risk scores] in distressing psychotic experiences and for delusions of persecution,” they noted. “ ... All schizophrenia-associated [copy number variations] are also associated with neurodevelopmental disorders such as intellectual disability and autism.”
The study’s strengths include its large sample size. Among its limitations, the researchers said, are the study’s retrospective measurement of psychotic experiences based on self-report from a questionnaire that was online. Gathering the data in that way raised the likelihood of possible error, they said.
Dr. Legge reported having no disclosures.
SOURCE: Legge SE et al. JAMA Psychiatry. 2019 Sep 25. doi: 10.1001/jamapsychiatry.2019.2508.
The genetic links uncovered in this study offer an intriguing, but incomplete look at the risks of psychotic experiences and their complicated intertwinings with other mental disorders, wrote Albert R. Powers III, MD, PhD.
“Penetrance of the genes in question likely depends at least in part on environmental influences, some of which have been studied extensively,” he wrote. “Recently, some have proposed risk stratification by exposome – a composite score of relevant exposures that may increase risk for psychosis and is analogous to the polygenic risk score used [here].
“The combination of environmental and genetic composite scores may lead to improved insight into individualized pathways toward psychotic experiences, highlighting genetic vulnerabilities to specific stressors likely to lead to phenotypic expression. Ultimately, this will require a more sophisticated mapping between phenomenology and biology than currently exists.”
One approach would be to combine deep phenotyping and behavioral analyses in a framework that could link all relevant levels from symptoms to neurophysiology.
“One such framework is predictive processing theory, which is linked closely with the free energy principle and the Bayesian brain hypothesis and attempts to explain perceptual and cognitive phenomena as manifestations of a drive to maintain as accurate an internal model of one’s surroundings as possible by minimizing prediction errors. This relatively simple scheme makes specific – and, importantly, falsifiable – assessments of the mathematical signatures of neurotypical processes and the ways they might break down to produce specific psychiatric symptoms.”
Dr. Powers is an assistant professor at the department of psychiatry at Yale University, New Haven, Conn., and serves as medical director of the PRIME Psychosis Research Clinic at Yale. His comments came in an accompanying editorial (JAMA Psychiatry. 2019 Sep 25. doi: 10.1001/jamapsychiatry.2019.2391 ).
The genetic links uncovered in this study offer an intriguing, but incomplete look at the risks of psychotic experiences and their complicated intertwinings with other mental disorders, wrote Albert R. Powers III, MD, PhD.
“Penetrance of the genes in question likely depends at least in part on environmental influences, some of which have been studied extensively,” he wrote. “Recently, some have proposed risk stratification by exposome – a composite score of relevant exposures that may increase risk for psychosis and is analogous to the polygenic risk score used [here].
“The combination of environmental and genetic composite scores may lead to improved insight into individualized pathways toward psychotic experiences, highlighting genetic vulnerabilities to specific stressors likely to lead to phenotypic expression. Ultimately, this will require a more sophisticated mapping between phenomenology and biology than currently exists.”
One approach would be to combine deep phenotyping and behavioral analyses in a framework that could link all relevant levels from symptoms to neurophysiology.
“One such framework is predictive processing theory, which is linked closely with the free energy principle and the Bayesian brain hypothesis and attempts to explain perceptual and cognitive phenomena as manifestations of a drive to maintain as accurate an internal model of one’s surroundings as possible by minimizing prediction errors. This relatively simple scheme makes specific – and, importantly, falsifiable – assessments of the mathematical signatures of neurotypical processes and the ways they might break down to produce specific psychiatric symptoms.”
Dr. Powers is an assistant professor at the department of psychiatry at Yale University, New Haven, Conn., and serves as medical director of the PRIME Psychosis Research Clinic at Yale. His comments came in an accompanying editorial (JAMA Psychiatry. 2019 Sep 25. doi: 10.1001/jamapsychiatry.2019.2391 ).
The genetic links uncovered in this study offer an intriguing, but incomplete look at the risks of psychotic experiences and their complicated intertwinings with other mental disorders, wrote Albert R. Powers III, MD, PhD.
“Penetrance of the genes in question likely depends at least in part on environmental influences, some of which have been studied extensively,” he wrote. “Recently, some have proposed risk stratification by exposome – a composite score of relevant exposures that may increase risk for psychosis and is analogous to the polygenic risk score used [here].
“The combination of environmental and genetic composite scores may lead to improved insight into individualized pathways toward psychotic experiences, highlighting genetic vulnerabilities to specific stressors likely to lead to phenotypic expression. Ultimately, this will require a more sophisticated mapping between phenomenology and biology than currently exists.”
One approach would be to combine deep phenotyping and behavioral analyses in a framework that could link all relevant levels from symptoms to neurophysiology.
“One such framework is predictive processing theory, which is linked closely with the free energy principle and the Bayesian brain hypothesis and attempts to explain perceptual and cognitive phenomena as manifestations of a drive to maintain as accurate an internal model of one’s surroundings as possible by minimizing prediction errors. This relatively simple scheme makes specific – and, importantly, falsifiable – assessments of the mathematical signatures of neurotypical processes and the ways they might break down to produce specific psychiatric symptoms.”
Dr. Powers is an assistant professor at the department of psychiatry at Yale University, New Haven, Conn., and serves as medical director of the PRIME Psychosis Research Clinic at Yale. His comments came in an accompanying editorial (JAMA Psychiatry. 2019 Sep 25. doi: 10.1001/jamapsychiatry.2019.2391 ).
Four genetic variations appear to link psychotic experiences with other psychiatric disorders, including schizophrenia, major depressive disorder, bipolar disorder, and neurodevelopmental disorders, a large genetic study has concluded.
, reported Sophie E. Legge, PhD, and colleagues. Their study was published in JAMA Psychiatry.
Although it is informative, the study is unlikely to expand the knowledge of schizophrenia-specific genetics.
“Consistent with other studies, the heritability estimate (1.71%) was low, and given that the variance explained in our polygenic risk analysis was also low, the finding suggests that understanding the genetics of psychotic experiences is unlikely to have an important effect on understanding the genetics of schizophrenia specifically,” wrote Dr. Legge, of the MRC Center for Neuropsychiatric Genetics and Genomics in the division of psychological medicine and clinical neurosciences at Cardiff (Wales) University, and colleagues.
The team conducted a genomewide association study (GWAS) using data from 127,966 individuals in the U.K. Biobank. Of these, 6,123 reported any psychotic experience, 2,143 reported distressing psychotic experiences, and 3,337 reported multiple experiences. The remainder served as controls. At the time of the biobank data collection, the subjects were a mean of 64 years of age; 56% were women.
First psychotic experience occurred at a mean of almost 32 years of age, but about a third reported that the first episode occurred before age 20, or that psychotic experiences had been happening ever since they could remember. Another third reported their first experience between ages 40 and 76 years.
The investigators conducted three GWAS studies: one for any psychotic experience, one for distressing experiences, and one for multiple experiences.
No significant genetic associations were found among those with multiple psychotic experiences, the authors said.
But they did find four variants significantly associated with the other experience categories.
Two variants were associated with any psychotic experience. Those with rs10994278, an intronic variant within Ankyrin-3 (ANK3), were 16% more likely to have a psychotic experience (odds ratio, 1.16). Those with intergenic variant rs549656827 were 39% less likely (OR, 0.61). “The ANK3 gene encodes ankyrin-G, a protein that has been shown to regulate the assembly of voltage-gated sodium channels and is essential for normal synaptic function,” the authors said. “ANK3 is one of strongest and most replicated genes for bipolar disorder, and variants within ANK3 have also been associated in the Psychiatric Genomics Consortium cross-disorder GWAS, and in a rare variant analysis of autism spectrum disorder.”
Two variants were linked to distressing psychotic experiences: rs75459873, intronic to cannabinoid receptor 2 (CNR2), decreased the risk by 34% (OR, 0.66). Intergenic variant rs3849810 increased the risk by 12% (OR, 1.12).
“CNR2 encodes for CB2, one of two well-characterized cannabinoid receptors. Several lines of evidence have implicated the endocannabinoid system in psychiatric disorders, including schizophrenia and depression. The main psychoactive agent of cannabis, tetrahydrocannabinol, can cause acute psychotic symptoms and cognitive impairment. Given that cannabis use is strongly associated with psychotic experiences, we tested, but found no evidence for, a mediating or moderating effect of cannabis use on the association of rs75459873 and distressing psychotic experiences. However, while no evidence was found in this study, a mediating effect of cannabis use cannot be ruled out given the relatively low power of such analyses and the potential measurement error.”
Also, significant genetic correlations were found between any psychotic experiences and major depressive disorder, autism spectrum disorder, ADHD, and schizophrenia. However, the polygenic risk scores for schizophrenia, major depressive disorder, bipolar disorder, ADHD, and autism spectrum disorder, were low.
“We also considered individual psychotic symptoms and found that polygenic risk scores for schizophrenia, bipolar disorder, depression, and ADHD were more strongly associated with delusions of persecution than with the other psychotic symptoms.”
Those with distressing psychotic experiences tended to have more copy number variations (CNVs) associated with schizophrenia (OR, 2.04) and neurodevelopmental disorders (OR, 1.75). The team also found significant associations between distressing experiences and major depressive disorder, ADHD, autism spectrum disorder, and schizophrenia.
“We found particular enrichment of these [polygenic risk scores] in distressing psychotic experiences and for delusions of persecution,” they noted. “ ... All schizophrenia-associated [copy number variations] are also associated with neurodevelopmental disorders such as intellectual disability and autism.”
The study’s strengths include its large sample size. Among its limitations, the researchers said, are the study’s retrospective measurement of psychotic experiences based on self-report from a questionnaire that was online. Gathering the data in that way raised the likelihood of possible error, they said.
Dr. Legge reported having no disclosures.
SOURCE: Legge SE et al. JAMA Psychiatry. 2019 Sep 25. doi: 10.1001/jamapsychiatry.2019.2508.
Four genetic variations appear to link psychotic experiences with other psychiatric disorders, including schizophrenia, major depressive disorder, bipolar disorder, and neurodevelopmental disorders, a large genetic study has concluded.
, reported Sophie E. Legge, PhD, and colleagues. Their study was published in JAMA Psychiatry.
Although it is informative, the study is unlikely to expand the knowledge of schizophrenia-specific genetics.
“Consistent with other studies, the heritability estimate (1.71%) was low, and given that the variance explained in our polygenic risk analysis was also low, the finding suggests that understanding the genetics of psychotic experiences is unlikely to have an important effect on understanding the genetics of schizophrenia specifically,” wrote Dr. Legge, of the MRC Center for Neuropsychiatric Genetics and Genomics in the division of psychological medicine and clinical neurosciences at Cardiff (Wales) University, and colleagues.
The team conducted a genomewide association study (GWAS) using data from 127,966 individuals in the U.K. Biobank. Of these, 6,123 reported any psychotic experience, 2,143 reported distressing psychotic experiences, and 3,337 reported multiple experiences. The remainder served as controls. At the time of the biobank data collection, the subjects were a mean of 64 years of age; 56% were women.
First psychotic experience occurred at a mean of almost 32 years of age, but about a third reported that the first episode occurred before age 20, or that psychotic experiences had been happening ever since they could remember. Another third reported their first experience between ages 40 and 76 years.
The investigators conducted three GWAS studies: one for any psychotic experience, one for distressing experiences, and one for multiple experiences.
No significant genetic associations were found among those with multiple psychotic experiences, the authors said.
But they did find four variants significantly associated with the other experience categories.
Two variants were associated with any psychotic experience. Those with rs10994278, an intronic variant within Ankyrin-3 (ANK3), were 16% more likely to have a psychotic experience (odds ratio, 1.16). Those with intergenic variant rs549656827 were 39% less likely (OR, 0.61). “The ANK3 gene encodes ankyrin-G, a protein that has been shown to regulate the assembly of voltage-gated sodium channels and is essential for normal synaptic function,” the authors said. “ANK3 is one of strongest and most replicated genes for bipolar disorder, and variants within ANK3 have also been associated in the Psychiatric Genomics Consortium cross-disorder GWAS, and in a rare variant analysis of autism spectrum disorder.”
Two variants were linked to distressing psychotic experiences: rs75459873, intronic to cannabinoid receptor 2 (CNR2), decreased the risk by 34% (OR, 0.66). Intergenic variant rs3849810 increased the risk by 12% (OR, 1.12).
“CNR2 encodes for CB2, one of two well-characterized cannabinoid receptors. Several lines of evidence have implicated the endocannabinoid system in psychiatric disorders, including schizophrenia and depression. The main psychoactive agent of cannabis, tetrahydrocannabinol, can cause acute psychotic symptoms and cognitive impairment. Given that cannabis use is strongly associated with psychotic experiences, we tested, but found no evidence for, a mediating or moderating effect of cannabis use on the association of rs75459873 and distressing psychotic experiences. However, while no evidence was found in this study, a mediating effect of cannabis use cannot be ruled out given the relatively low power of such analyses and the potential measurement error.”
Also, significant genetic correlations were found between any psychotic experiences and major depressive disorder, autism spectrum disorder, ADHD, and schizophrenia. However, the polygenic risk scores for schizophrenia, major depressive disorder, bipolar disorder, ADHD, and autism spectrum disorder, were low.
“We also considered individual psychotic symptoms and found that polygenic risk scores for schizophrenia, bipolar disorder, depression, and ADHD were more strongly associated with delusions of persecution than with the other psychotic symptoms.”
Those with distressing psychotic experiences tended to have more copy number variations (CNVs) associated with schizophrenia (OR, 2.04) and neurodevelopmental disorders (OR, 1.75). The team also found significant associations between distressing experiences and major depressive disorder, ADHD, autism spectrum disorder, and schizophrenia.
“We found particular enrichment of these [polygenic risk scores] in distressing psychotic experiences and for delusions of persecution,” they noted. “ ... All schizophrenia-associated [copy number variations] are also associated with neurodevelopmental disorders such as intellectual disability and autism.”
The study’s strengths include its large sample size. Among its limitations, the researchers said, are the study’s retrospective measurement of psychotic experiences based on self-report from a questionnaire that was online. Gathering the data in that way raised the likelihood of possible error, they said.
Dr. Legge reported having no disclosures.
SOURCE: Legge SE et al. JAMA Psychiatry. 2019 Sep 25. doi: 10.1001/jamapsychiatry.2019.2508.
FROM JAMA PSYCHIATRY
CDC reports most vaping lung disease linked to THC-containing cartridges
and most products used were prepackaged, prefilled cartridges, according to new data released by the Centers for Disease Control and Prevention.
The majority of these products (66%) were THC-containing cartridges marketed under the brand name Dank. Dank cartridges are available at legal dispensaries and online in areas where they are legal. The Dank company posted a statement on its website warning buyers about fake cartridges and showing images of genuine cartridges. However, 89% of the cartridges were obtained on the street, from dealers, online, or from friends or social contacts, Jennifer Layden, MD, of the Illinois Department of Public Health said during a CDC telebriefing.
The illness was first recognized in Wisconsin and Illinois. Marijuana is illegal in Wisconsin; Illinois licensed recreational marijuana in 2009.
Other commonalties among cases have also emerged, Anne Schuchat, MD, deputy director of CDC, said during the call. More than two-thirds of the 805 confirmed or probable cases were male, and the median age was 23 years. The illness crosses age barriers, she said. About 62% were 18-24 years of age, and 54% under age 25. However, among the 12 deaths so far reported, the median age was 50 years. The age range was wide, from 27 to 71 years. Dr. Schuchat said data about medical comorbidities potentially linking the deaths is not yet available, although it is part of the ongoing investigation.
Other clinical commonalities included intensive use of THC-containing products and, in a small number of cases, concomitant use of benzodiazepenes, opioids, and narcotics.
Cases have now emerged in 46 states and in the U.S. Virgin Islands, although the number reported each week is dropping. However, this decrease may not represent a drop in newly occurring cases, but instead reflect delays in clinical recognition or reporting to local health departments, Dr. Schuchat said.
Regardless of the recent decline in reported cases, she said, the epidemic is serious, far reaching, and ongoing.
“I want to stress that this is a serious, life-threatening disease occurring mostly in otherwise healthy young people. These illnesses and deaths are occurring in the context of a dynamic marketplace with mix of products with mixes of ingredients, including potentially illicit substances. Users don’t know what’s in them and cannot tell from the ingredients listed on the packaging.”
Dr. Schuchat drew her data from two reports issued in the Morbidity and Mortality Weekly Report: a national case update by Peter A. Briss, MD, chair of CDC’s Lung Injury Response Epidemiology/Surveillance Group, and colleagues, and a regional report coauthored by Dr. Layden of cases in Illinois and Wisconsin.
In the national report, 514 patients self-reported their history of e-cigarette and vaping use. Among those, 395 (76.9%) reported using THC-containing products, and 292 (56.8%) reported using nicotine-containing products in the 30 days preceding symptom onset. Almost half (210; 40.9%) reported using both THC- and nicotine-containing products.
But there appeared to be no clear pattern of use, said Dr. Briss, who also participated in the briefing. More than a third (185; 36.0%) reported exclusive use of THC-containing products, and 82 (16.0%) reported exclusive use of nicotine-containing products.
The regional report added additional details.
Among the 86 patients who self-reported details, there were 234 unique cases of e-cigarette or THC vaping in 87 brands.
“Patients reported using numerous products and brands,” Dr. Layden noted. “Those who reported using THC products used an average of 2.1 different products and those who reported using nicotine products used about 1.3 different ones. Some patients reported using up to seven different brands, and these were used at least daily and sometimes numerous times in the day.”
According to the MMWR regional report, among the urinary THC screens obtained for 32 patients, “29 (91%) were positive for THC. One of these patients reported smoking combustible marijuana. Urinary THC levels for four patients who reported using THC-containing products exceeded 400 ng/ml, indicating intensive use of THC or THC-containing products.”
About 40% of THC users and 65% of nicotine-product users reported using the product at least five times a day; 52% said they used combustible marijuana in addition to the vapes, and 24% reported also smoking combustible tobacco.
There was a very low level of concomitant drug use. Two patients reported using LSD; one reported misusing dextroamphetamine-amphetamine (Adderall), and one reported misusing oxycodone. Two tested positive for benzodiazepines and opioids, and one each for only benzodiazepines, only opioids, only amphetamines. One patient screened positive for unidentified narcotics.
and most products used were prepackaged, prefilled cartridges, according to new data released by the Centers for Disease Control and Prevention.
The majority of these products (66%) were THC-containing cartridges marketed under the brand name Dank. Dank cartridges are available at legal dispensaries and online in areas where they are legal. The Dank company posted a statement on its website warning buyers about fake cartridges and showing images of genuine cartridges. However, 89% of the cartridges were obtained on the street, from dealers, online, or from friends or social contacts, Jennifer Layden, MD, of the Illinois Department of Public Health said during a CDC telebriefing.
The illness was first recognized in Wisconsin and Illinois. Marijuana is illegal in Wisconsin; Illinois licensed recreational marijuana in 2009.
Other commonalties among cases have also emerged, Anne Schuchat, MD, deputy director of CDC, said during the call. More than two-thirds of the 805 confirmed or probable cases were male, and the median age was 23 years. The illness crosses age barriers, she said. About 62% were 18-24 years of age, and 54% under age 25. However, among the 12 deaths so far reported, the median age was 50 years. The age range was wide, from 27 to 71 years. Dr. Schuchat said data about medical comorbidities potentially linking the deaths is not yet available, although it is part of the ongoing investigation.
Other clinical commonalities included intensive use of THC-containing products and, in a small number of cases, concomitant use of benzodiazepenes, opioids, and narcotics.
Cases have now emerged in 46 states and in the U.S. Virgin Islands, although the number reported each week is dropping. However, this decrease may not represent a drop in newly occurring cases, but instead reflect delays in clinical recognition or reporting to local health departments, Dr. Schuchat said.
Regardless of the recent decline in reported cases, she said, the epidemic is serious, far reaching, and ongoing.
“I want to stress that this is a serious, life-threatening disease occurring mostly in otherwise healthy young people. These illnesses and deaths are occurring in the context of a dynamic marketplace with mix of products with mixes of ingredients, including potentially illicit substances. Users don’t know what’s in them and cannot tell from the ingredients listed on the packaging.”
Dr. Schuchat drew her data from two reports issued in the Morbidity and Mortality Weekly Report: a national case update by Peter A. Briss, MD, chair of CDC’s Lung Injury Response Epidemiology/Surveillance Group, and colleagues, and a regional report coauthored by Dr. Layden of cases in Illinois and Wisconsin.
In the national report, 514 patients self-reported their history of e-cigarette and vaping use. Among those, 395 (76.9%) reported using THC-containing products, and 292 (56.8%) reported using nicotine-containing products in the 30 days preceding symptom onset. Almost half (210; 40.9%) reported using both THC- and nicotine-containing products.
But there appeared to be no clear pattern of use, said Dr. Briss, who also participated in the briefing. More than a third (185; 36.0%) reported exclusive use of THC-containing products, and 82 (16.0%) reported exclusive use of nicotine-containing products.
The regional report added additional details.
Among the 86 patients who self-reported details, there were 234 unique cases of e-cigarette or THC vaping in 87 brands.
“Patients reported using numerous products and brands,” Dr. Layden noted. “Those who reported using THC products used an average of 2.1 different products and those who reported using nicotine products used about 1.3 different ones. Some patients reported using up to seven different brands, and these were used at least daily and sometimes numerous times in the day.”
According to the MMWR regional report, among the urinary THC screens obtained for 32 patients, “29 (91%) were positive for THC. One of these patients reported smoking combustible marijuana. Urinary THC levels for four patients who reported using THC-containing products exceeded 400 ng/ml, indicating intensive use of THC or THC-containing products.”
About 40% of THC users and 65% of nicotine-product users reported using the product at least five times a day; 52% said they used combustible marijuana in addition to the vapes, and 24% reported also smoking combustible tobacco.
There was a very low level of concomitant drug use. Two patients reported using LSD; one reported misusing dextroamphetamine-amphetamine (Adderall), and one reported misusing oxycodone. Two tested positive for benzodiazepines and opioids, and one each for only benzodiazepines, only opioids, only amphetamines. One patient screened positive for unidentified narcotics.
and most products used were prepackaged, prefilled cartridges, according to new data released by the Centers for Disease Control and Prevention.
The majority of these products (66%) were THC-containing cartridges marketed under the brand name Dank. Dank cartridges are available at legal dispensaries and online in areas where they are legal. The Dank company posted a statement on its website warning buyers about fake cartridges and showing images of genuine cartridges. However, 89% of the cartridges were obtained on the street, from dealers, online, or from friends or social contacts, Jennifer Layden, MD, of the Illinois Department of Public Health said during a CDC telebriefing.
The illness was first recognized in Wisconsin and Illinois. Marijuana is illegal in Wisconsin; Illinois licensed recreational marijuana in 2009.
Other commonalties among cases have also emerged, Anne Schuchat, MD, deputy director of CDC, said during the call. More than two-thirds of the 805 confirmed or probable cases were male, and the median age was 23 years. The illness crosses age barriers, she said. About 62% were 18-24 years of age, and 54% under age 25. However, among the 12 deaths so far reported, the median age was 50 years. The age range was wide, from 27 to 71 years. Dr. Schuchat said data about medical comorbidities potentially linking the deaths is not yet available, although it is part of the ongoing investigation.
Other clinical commonalities included intensive use of THC-containing products and, in a small number of cases, concomitant use of benzodiazepenes, opioids, and narcotics.
Cases have now emerged in 46 states and in the U.S. Virgin Islands, although the number reported each week is dropping. However, this decrease may not represent a drop in newly occurring cases, but instead reflect delays in clinical recognition or reporting to local health departments, Dr. Schuchat said.
Regardless of the recent decline in reported cases, she said, the epidemic is serious, far reaching, and ongoing.
“I want to stress that this is a serious, life-threatening disease occurring mostly in otherwise healthy young people. These illnesses and deaths are occurring in the context of a dynamic marketplace with mix of products with mixes of ingredients, including potentially illicit substances. Users don’t know what’s in them and cannot tell from the ingredients listed on the packaging.”
Dr. Schuchat drew her data from two reports issued in the Morbidity and Mortality Weekly Report: a national case update by Peter A. Briss, MD, chair of CDC’s Lung Injury Response Epidemiology/Surveillance Group, and colleagues, and a regional report coauthored by Dr. Layden of cases in Illinois and Wisconsin.
In the national report, 514 patients self-reported their history of e-cigarette and vaping use. Among those, 395 (76.9%) reported using THC-containing products, and 292 (56.8%) reported using nicotine-containing products in the 30 days preceding symptom onset. Almost half (210; 40.9%) reported using both THC- and nicotine-containing products.
But there appeared to be no clear pattern of use, said Dr. Briss, who also participated in the briefing. More than a third (185; 36.0%) reported exclusive use of THC-containing products, and 82 (16.0%) reported exclusive use of nicotine-containing products.
The regional report added additional details.
Among the 86 patients who self-reported details, there were 234 unique cases of e-cigarette or THC vaping in 87 brands.
“Patients reported using numerous products and brands,” Dr. Layden noted. “Those who reported using THC products used an average of 2.1 different products and those who reported using nicotine products used about 1.3 different ones. Some patients reported using up to seven different brands, and these were used at least daily and sometimes numerous times in the day.”
According to the MMWR regional report, among the urinary THC screens obtained for 32 patients, “29 (91%) were positive for THC. One of these patients reported smoking combustible marijuana. Urinary THC levels for four patients who reported using THC-containing products exceeded 400 ng/ml, indicating intensive use of THC or THC-containing products.”
About 40% of THC users and 65% of nicotine-product users reported using the product at least five times a day; 52% said they used combustible marijuana in addition to the vapes, and 24% reported also smoking combustible tobacco.
There was a very low level of concomitant drug use. Two patients reported using LSD; one reported misusing dextroamphetamine-amphetamine (Adderall), and one reported misusing oxycodone. Two tested positive for benzodiazepines and opioids, and one each for only benzodiazepines, only opioids, only amphetamines. One patient screened positive for unidentified narcotics.
Parent survey sheds light on suboptimal compliance with eczema medications
of children with AD.
Perceived effectiveness was the main driver of this variation, Alan Schwartz PhD, and Korey Capozza, MPH, wrote in the study, published in Pediatric Dermatology.
“Responses suggest parents may be willing to use therapies with concerning side effects if they can see a clear benefit for their child’s eczema, but when anticipated improvements fail to materialize, they may change their usage, usually in the direction of using less medication or stopping,” observed Dr. Schwartz, of the University of Illinois, Chicago, and Ms. Capozza, of Global Parents for Eczema Research.
“Addressing expectations related to effectiveness, rather than concerns about medication use, may thus be more likely to lead to taking medication as directed.”
The researchers posted a 15-question survey on the Facebook page of Global Parents for Eczema Research, an international coalition of parents of children with AD. During the month that the survey was posted, 86 parents completed it; questions pertained to adherence to medications and reasons for changing treatments. The mean age of their children was 6 years, most (about 83%) had moderate or severe eczema, and about half lived in the United States.
More than half (55%) reported using the AD medications as directed. But 30% said they took or applied less than prescribed, 13% had stopped the prescribed medication altogether, and 2% took or applied more (or more often) than prescribed.
There were several reasons stated for this variance. Concern over side effects was the most common (46%) reason for not using medications as directed. The next most common reasons were that the child’s symptoms went away (28%); or the “medication was not helping or was not helping as much,” in 23%.
A lack of physician trust or not agreeing with the physician’s recommendations accounted for 18% of the concerns. The remainder thought it wasn’t important to take the medication as prescribed, it was inconvenient or too time consuming, that they forgot, it was too expensive, or they were confused about the directions.
To the question asking “What would have made you more likely to use the medication as prescribed?” the most common answer was a clearer indication of effectiveness (56%). The next most common was “access to research or evidence about benefit and side effect profile” (14%).
A good relationship between the physician and patient was associated with taking medication as directed
“Improvement in adherence to topical treatments among children with AD could yield large gains in quality-of-life improvements and reduce exposure to costlier and potentially more toxic systemic agents,” the authors noted. “Given the large, documented gains in disease improvement, and even remission, achieved with interventions that address adherence among patients with other chronic diseases, strategies that address the underlying causes for poor adherence among parents of children with atopic dermatitis stand to provide a significant, untapped benefit.”
No financial disclosures were noted.
SOURCE: Pediatr Dermatol. 2019 Aug 28. doi: 10.1111/pde.13991.
of children with AD.
Perceived effectiveness was the main driver of this variation, Alan Schwartz PhD, and Korey Capozza, MPH, wrote in the study, published in Pediatric Dermatology.
“Responses suggest parents may be willing to use therapies with concerning side effects if they can see a clear benefit for their child’s eczema, but when anticipated improvements fail to materialize, they may change their usage, usually in the direction of using less medication or stopping,” observed Dr. Schwartz, of the University of Illinois, Chicago, and Ms. Capozza, of Global Parents for Eczema Research.
“Addressing expectations related to effectiveness, rather than concerns about medication use, may thus be more likely to lead to taking medication as directed.”
The researchers posted a 15-question survey on the Facebook page of Global Parents for Eczema Research, an international coalition of parents of children with AD. During the month that the survey was posted, 86 parents completed it; questions pertained to adherence to medications and reasons for changing treatments. The mean age of their children was 6 years, most (about 83%) had moderate or severe eczema, and about half lived in the United States.
More than half (55%) reported using the AD medications as directed. But 30% said they took or applied less than prescribed, 13% had stopped the prescribed medication altogether, and 2% took or applied more (or more often) than prescribed.
There were several reasons stated for this variance. Concern over side effects was the most common (46%) reason for not using medications as directed. The next most common reasons were that the child’s symptoms went away (28%); or the “medication was not helping or was not helping as much,” in 23%.
A lack of physician trust or not agreeing with the physician’s recommendations accounted for 18% of the concerns. The remainder thought it wasn’t important to take the medication as prescribed, it was inconvenient or too time consuming, that they forgot, it was too expensive, or they were confused about the directions.
To the question asking “What would have made you more likely to use the medication as prescribed?” the most common answer was a clearer indication of effectiveness (56%). The next most common was “access to research or evidence about benefit and side effect profile” (14%).
A good relationship between the physician and patient was associated with taking medication as directed
“Improvement in adherence to topical treatments among children with AD could yield large gains in quality-of-life improvements and reduce exposure to costlier and potentially more toxic systemic agents,” the authors noted. “Given the large, documented gains in disease improvement, and even remission, achieved with interventions that address adherence among patients with other chronic diseases, strategies that address the underlying causes for poor adherence among parents of children with atopic dermatitis stand to provide a significant, untapped benefit.”
No financial disclosures were noted.
SOURCE: Pediatr Dermatol. 2019 Aug 28. doi: 10.1111/pde.13991.
of children with AD.
Perceived effectiveness was the main driver of this variation, Alan Schwartz PhD, and Korey Capozza, MPH, wrote in the study, published in Pediatric Dermatology.
“Responses suggest parents may be willing to use therapies with concerning side effects if they can see a clear benefit for their child’s eczema, but when anticipated improvements fail to materialize, they may change their usage, usually in the direction of using less medication or stopping,” observed Dr. Schwartz, of the University of Illinois, Chicago, and Ms. Capozza, of Global Parents for Eczema Research.
“Addressing expectations related to effectiveness, rather than concerns about medication use, may thus be more likely to lead to taking medication as directed.”
The researchers posted a 15-question survey on the Facebook page of Global Parents for Eczema Research, an international coalition of parents of children with AD. During the month that the survey was posted, 86 parents completed it; questions pertained to adherence to medications and reasons for changing treatments. The mean age of their children was 6 years, most (about 83%) had moderate or severe eczema, and about half lived in the United States.
More than half (55%) reported using the AD medications as directed. But 30% said they took or applied less than prescribed, 13% had stopped the prescribed medication altogether, and 2% took or applied more (or more often) than prescribed.
There were several reasons stated for this variance. Concern over side effects was the most common (46%) reason for not using medications as directed. The next most common reasons were that the child’s symptoms went away (28%); or the “medication was not helping or was not helping as much,” in 23%.
A lack of physician trust or not agreeing with the physician’s recommendations accounted for 18% of the concerns. The remainder thought it wasn’t important to take the medication as prescribed, it was inconvenient or too time consuming, that they forgot, it was too expensive, or they were confused about the directions.
To the question asking “What would have made you more likely to use the medication as prescribed?” the most common answer was a clearer indication of effectiveness (56%). The next most common was “access to research or evidence about benefit and side effect profile” (14%).
A good relationship between the physician and patient was associated with taking medication as directed
“Improvement in adherence to topical treatments among children with AD could yield large gains in quality-of-life improvements and reduce exposure to costlier and potentially more toxic systemic agents,” the authors noted. “Given the large, documented gains in disease improvement, and even remission, achieved with interventions that address adherence among patients with other chronic diseases, strategies that address the underlying causes for poor adherence among parents of children with atopic dermatitis stand to provide a significant, untapped benefit.”
No financial disclosures were noted.
SOURCE: Pediatr Dermatol. 2019 Aug 28. doi: 10.1111/pde.13991.
FROM PEDIATRIC DERMATOLOGY
USPSTF: Screening pregnant women for asymptomatic bacteriuria cuts pyelonephritis risk
according to new recommendations set forth by the United States Preventive Services Task Force (USPSTF).
However, the investigating committee reported, there is evidence against screening nonpregnant women and adult men. In fact, the committee found “adequate” evidence of potential harm associated with treating asymptomatic bacteriuria in adults of both sexes, including adverse effects of antibiotics and on the microbiome.
The new document downgrades from A to B the group’s prior recommendation that urine culture screening for asymptomatic bacteriuria should be performed among pregnant women at 12-16 weeks’ gestation or at their first prenatal visit. The USPSTF recommendation to not screen nonpregnant adults retained its D rating, Jerome A. Leis, MD and Christine Soong, MD said in an accompanying editorial.
“Not screening or treating asymptomatic bacteriuria in this population has long been an ironclad recommendation endorsed by the Infectious Diseases Society of America, as well as numerous professional societies as part of the Choosing Wisely campaign,” wrote Dr. Leis of Sunnybrook Health Sciences Centre, Toronto, and Dr. Soong of the University of Toronto. “Restating this steadfast and pervasive recommendation may seem unremarkable and almost pedantic, yet it remains stubbornly disregarded by clinicians across multiple settings.”
The new recommendations were based on a review of 19 studies involving almost 8,500 pregnant and nonpregnant women, as well as a small number of adult men. Most were carried out in the 1960s or 1970s. The most recent ones were published in 2002 and 2015. The dearth of more recent data may have limited some conclusions and certainly highlighted the need for more research, said Jillian T. Henderson, PhD, chair of the committee assigned to investigate the evidence.
“Few studies of asymptomatic bacteriuria screening or treatment in pregnant populations have been conducted in the past 40 years,” wrote Dr. Henderson of Kaiser Permanente Northwest, Portland, and associates. “Historical evidence established asymptomatic bacteriuria screening and treatment as standard obstetric practice in the United States.” But these trials typically were less rigorous than modern studies, and the results are out of touch with modern clinical settings and treatment protocols, the team noted.
Additionally, Dr. Henderson and coauthors said, rates of pyelonephritis were about 10 times higher then than they are now. In the more recent studies, pyelonephritis rates in control groups were 2.2% and 2.5%; in most of the older studies, control group rates ranged from 33% to 36%.
In commissioning the investigation, the task force looked at the following four questions:
Does screening improve health outcomes?
Neither of two studies involving 5,289 women, one from Spain and one from Turkey, addressed this question in nonpregnant women; however, studies that looked at pregnant women generally found that screening did reduce the risk of pyelonephritis by about 70%. The investigators cautioned that these studies were out of date and perhaps methodologically flawed.
The only study that looked at newborn outcomes found no difference in birth weights or premature births between the screened and unscreened cohorts.
No study examined this question in nonpregnant women or men.
What are the harms of such screening?
A single study of 372 pregnant women described potential prenatal and perinatal harms associated with screening and treatment. It found a slight increase in congenital abnormalities in the screened cohort (1.6%), compared with those who were not screened (1.1%). However, those who were not screened were presumably not prescribed antibiotics.
Does treatment of screening-detected asymptomatic bacteriuria improve health outcomes?
Twelve trials of pregnant women (2,377) addressed this issue. All but two were conducted in the 1960s and 1970s. Treatment varied widely; sulfonamides were the most common, including the now discarded sulfamethazine and sulfadimethoxine. Dosages and duration of treatment also were considerably higher and longer than current practice.
In all but one study, there were higher rates of pyelonephritis in the control group. A pooled risk analysis indicated that treatment reduced the risk of pyelonephritis by nearly 80% (relative risk, 0.24).
Seven studies found higher rates of low birth weight in infants born to mothers who were treated, but two studies reported a significant reduction in the risk of low birth weight.
Among the six trials that examined perinatal mortality, none found significant associations with treatment.
Five studies examined treatment in nonpregnant women with screening-detected asymptomatic bacteriuria, and one included men as well. Of the four that reported the rate of symptomatic infection or pyelonephritis, none found a significant difference between treatment and control groups. The single study that included men also found no significant difference between treatment and control groups.
Among the three studies that focused on older adults, there also were no significant between-group differences in outcomes.
What harms are associated with treatment of screening-detected asymptomatic bacteriuria?
Seven studies comprised pregnant women. Five reported congenital malformations in the intervention and control groups. Overall, there were very few cases of malformations, with more – although not significantly more – in the control groups.
Evidence related to other infant and maternal harms was “sparsely and inconsistently reported,” Dr. Henderson and coauthors noted, “and there was a lack of evidence on long-term neonatal outcomes after antibiotic treatment of asymptomatic bacteriuria in pregnancy.”
Two studies listed maternal adverse events associated with different treatments including vaginitis and diarrhea with ampicillin and rashes and nausea with nalidixic acid.
In terms of nonpregnant women and men, four studies reported adverse events. None occurred with nitrofurantoin or trimethoprim treatment; however, one study that included daily treatment with ofloxacin noted that 6% withdrew because of adverse events – vertigo and gastrointestinal symptoms.
Treatments didn’t affect hematocrit, bilirubin, serum urea, or nitrogen, although some studies found a slight reduction in serum creatinine.
Although there’s a need for additional research into this question, the new recommendations provide a good reason to further reduce unnecessary antibiotic exposure, Lindsey E. Nicolle, MD, wrote in a second commentary.
These updated recommendations “contribute to the evolution of management of asymptomatic bacteriuria in healthy women,” wrote Dr. Nicolle of the University of Manitoba, Winnipeg. “However, questions remain about the risks and benefits of universal screening for and treatment of asymptomatic bacteriuria in pregnant women in the context of current clinical practice. The effects of changes in fetal-maternal care, of low- compared with high-risk pregnancies, and of health care access need to be understood. In the short term, application of current diagnostic recommendations for identification of persistent symptomatic bacteriuria with a second urine culture may provide an immediate opportunity to limit unnecessary antimicrobial use for some pregnant women.”
No conflicts of interest were reported by the USPSTF authors, nor by Dr. Leis, Dr. Soong, or Dr. Nicolle. The USPSTF report was funded by the Agency for Healthcare Research and Quality.
SOURCES: U.S. Preventive Services Task Force. JAMA. 2019;322(12):1188-94; Henderson JT et al. JAMA. 2019;322(12):1195-205; Leis JA and Soong C. JAMA. 2019. doi: 10.1001/jamainternmed.2019.4515; Nicolle LE. JAMA. 2019;322(12):1152-4.
according to new recommendations set forth by the United States Preventive Services Task Force (USPSTF).
However, the investigating committee reported, there is evidence against screening nonpregnant women and adult men. In fact, the committee found “adequate” evidence of potential harm associated with treating asymptomatic bacteriuria in adults of both sexes, including adverse effects of antibiotics and on the microbiome.
The new document downgrades from A to B the group’s prior recommendation that urine culture screening for asymptomatic bacteriuria should be performed among pregnant women at 12-16 weeks’ gestation or at their first prenatal visit. The USPSTF recommendation to not screen nonpregnant adults retained its D rating, Jerome A. Leis, MD and Christine Soong, MD said in an accompanying editorial.
“Not screening or treating asymptomatic bacteriuria in this population has long been an ironclad recommendation endorsed by the Infectious Diseases Society of America, as well as numerous professional societies as part of the Choosing Wisely campaign,” wrote Dr. Leis of Sunnybrook Health Sciences Centre, Toronto, and Dr. Soong of the University of Toronto. “Restating this steadfast and pervasive recommendation may seem unremarkable and almost pedantic, yet it remains stubbornly disregarded by clinicians across multiple settings.”
The new recommendations were based on a review of 19 studies involving almost 8,500 pregnant and nonpregnant women, as well as a small number of adult men. Most were carried out in the 1960s or 1970s. The most recent ones were published in 2002 and 2015. The dearth of more recent data may have limited some conclusions and certainly highlighted the need for more research, said Jillian T. Henderson, PhD, chair of the committee assigned to investigate the evidence.
“Few studies of asymptomatic bacteriuria screening or treatment in pregnant populations have been conducted in the past 40 years,” wrote Dr. Henderson of Kaiser Permanente Northwest, Portland, and associates. “Historical evidence established asymptomatic bacteriuria screening and treatment as standard obstetric practice in the United States.” But these trials typically were less rigorous than modern studies, and the results are out of touch with modern clinical settings and treatment protocols, the team noted.
Additionally, Dr. Henderson and coauthors said, rates of pyelonephritis were about 10 times higher then than they are now. In the more recent studies, pyelonephritis rates in control groups were 2.2% and 2.5%; in most of the older studies, control group rates ranged from 33% to 36%.
In commissioning the investigation, the task force looked at the following four questions:
Does screening improve health outcomes?
Neither of two studies involving 5,289 women, one from Spain and one from Turkey, addressed this question in nonpregnant women; however, studies that looked at pregnant women generally found that screening did reduce the risk of pyelonephritis by about 70%. The investigators cautioned that these studies were out of date and perhaps methodologically flawed.
The only study that looked at newborn outcomes found no difference in birth weights or premature births between the screened and unscreened cohorts.
No study examined this question in nonpregnant women or men.
What are the harms of such screening?
A single study of 372 pregnant women described potential prenatal and perinatal harms associated with screening and treatment. It found a slight increase in congenital abnormalities in the screened cohort (1.6%), compared with those who were not screened (1.1%). However, those who were not screened were presumably not prescribed antibiotics.
Does treatment of screening-detected asymptomatic bacteriuria improve health outcomes?
Twelve trials of pregnant women (2,377) addressed this issue. All but two were conducted in the 1960s and 1970s. Treatment varied widely; sulfonamides were the most common, including the now discarded sulfamethazine and sulfadimethoxine. Dosages and duration of treatment also were considerably higher and longer than current practice.
In all but one study, there were higher rates of pyelonephritis in the control group. A pooled risk analysis indicated that treatment reduced the risk of pyelonephritis by nearly 80% (relative risk, 0.24).
Seven studies found higher rates of low birth weight in infants born to mothers who were treated, but two studies reported a significant reduction in the risk of low birth weight.
Among the six trials that examined perinatal mortality, none found significant associations with treatment.
Five studies examined treatment in nonpregnant women with screening-detected asymptomatic bacteriuria, and one included men as well. Of the four that reported the rate of symptomatic infection or pyelonephritis, none found a significant difference between treatment and control groups. The single study that included men also found no significant difference between treatment and control groups.
Among the three studies that focused on older adults, there also were no significant between-group differences in outcomes.
What harms are associated with treatment of screening-detected asymptomatic bacteriuria?
Seven studies comprised pregnant women. Five reported congenital malformations in the intervention and control groups. Overall, there were very few cases of malformations, with more – although not significantly more – in the control groups.
Evidence related to other infant and maternal harms was “sparsely and inconsistently reported,” Dr. Henderson and coauthors noted, “and there was a lack of evidence on long-term neonatal outcomes after antibiotic treatment of asymptomatic bacteriuria in pregnancy.”
Two studies listed maternal adverse events associated with different treatments including vaginitis and diarrhea with ampicillin and rashes and nausea with nalidixic acid.
In terms of nonpregnant women and men, four studies reported adverse events. None occurred with nitrofurantoin or trimethoprim treatment; however, one study that included daily treatment with ofloxacin noted that 6% withdrew because of adverse events – vertigo and gastrointestinal symptoms.
Treatments didn’t affect hematocrit, bilirubin, serum urea, or nitrogen, although some studies found a slight reduction in serum creatinine.
Although there’s a need for additional research into this question, the new recommendations provide a good reason to further reduce unnecessary antibiotic exposure, Lindsey E. Nicolle, MD, wrote in a second commentary.
These updated recommendations “contribute to the evolution of management of asymptomatic bacteriuria in healthy women,” wrote Dr. Nicolle of the University of Manitoba, Winnipeg. “However, questions remain about the risks and benefits of universal screening for and treatment of asymptomatic bacteriuria in pregnant women in the context of current clinical practice. The effects of changes in fetal-maternal care, of low- compared with high-risk pregnancies, and of health care access need to be understood. In the short term, application of current diagnostic recommendations for identification of persistent symptomatic bacteriuria with a second urine culture may provide an immediate opportunity to limit unnecessary antimicrobial use for some pregnant women.”
No conflicts of interest were reported by the USPSTF authors, nor by Dr. Leis, Dr. Soong, or Dr. Nicolle. The USPSTF report was funded by the Agency for Healthcare Research and Quality.
SOURCES: U.S. Preventive Services Task Force. JAMA. 2019;322(12):1188-94; Henderson JT et al. JAMA. 2019;322(12):1195-205; Leis JA and Soong C. JAMA. 2019. doi: 10.1001/jamainternmed.2019.4515; Nicolle LE. JAMA. 2019;322(12):1152-4.
according to new recommendations set forth by the United States Preventive Services Task Force (USPSTF).
However, the investigating committee reported, there is evidence against screening nonpregnant women and adult men. In fact, the committee found “adequate” evidence of potential harm associated with treating asymptomatic bacteriuria in adults of both sexes, including adverse effects of antibiotics and on the microbiome.
The new document downgrades from A to B the group’s prior recommendation that urine culture screening for asymptomatic bacteriuria should be performed among pregnant women at 12-16 weeks’ gestation or at their first prenatal visit. The USPSTF recommendation to not screen nonpregnant adults retained its D rating, Jerome A. Leis, MD and Christine Soong, MD said in an accompanying editorial.
“Not screening or treating asymptomatic bacteriuria in this population has long been an ironclad recommendation endorsed by the Infectious Diseases Society of America, as well as numerous professional societies as part of the Choosing Wisely campaign,” wrote Dr. Leis of Sunnybrook Health Sciences Centre, Toronto, and Dr. Soong of the University of Toronto. “Restating this steadfast and pervasive recommendation may seem unremarkable and almost pedantic, yet it remains stubbornly disregarded by clinicians across multiple settings.”
The new recommendations were based on a review of 19 studies involving almost 8,500 pregnant and nonpregnant women, as well as a small number of adult men. Most were carried out in the 1960s or 1970s. The most recent ones were published in 2002 and 2015. The dearth of more recent data may have limited some conclusions and certainly highlighted the need for more research, said Jillian T. Henderson, PhD, chair of the committee assigned to investigate the evidence.
“Few studies of asymptomatic bacteriuria screening or treatment in pregnant populations have been conducted in the past 40 years,” wrote Dr. Henderson of Kaiser Permanente Northwest, Portland, and associates. “Historical evidence established asymptomatic bacteriuria screening and treatment as standard obstetric practice in the United States.” But these trials typically were less rigorous than modern studies, and the results are out of touch with modern clinical settings and treatment protocols, the team noted.
Additionally, Dr. Henderson and coauthors said, rates of pyelonephritis were about 10 times higher then than they are now. In the more recent studies, pyelonephritis rates in control groups were 2.2% and 2.5%; in most of the older studies, control group rates ranged from 33% to 36%.
In commissioning the investigation, the task force looked at the following four questions:
Does screening improve health outcomes?
Neither of two studies involving 5,289 women, one from Spain and one from Turkey, addressed this question in nonpregnant women; however, studies that looked at pregnant women generally found that screening did reduce the risk of pyelonephritis by about 70%. The investigators cautioned that these studies were out of date and perhaps methodologically flawed.
The only study that looked at newborn outcomes found no difference in birth weights or premature births between the screened and unscreened cohorts.
No study examined this question in nonpregnant women or men.
What are the harms of such screening?
A single study of 372 pregnant women described potential prenatal and perinatal harms associated with screening and treatment. It found a slight increase in congenital abnormalities in the screened cohort (1.6%), compared with those who were not screened (1.1%). However, those who were not screened were presumably not prescribed antibiotics.
Does treatment of screening-detected asymptomatic bacteriuria improve health outcomes?
Twelve trials of pregnant women (2,377) addressed this issue. All but two were conducted in the 1960s and 1970s. Treatment varied widely; sulfonamides were the most common, including the now discarded sulfamethazine and sulfadimethoxine. Dosages and duration of treatment also were considerably higher and longer than current practice.
In all but one study, there were higher rates of pyelonephritis in the control group. A pooled risk analysis indicated that treatment reduced the risk of pyelonephritis by nearly 80% (relative risk, 0.24).
Seven studies found higher rates of low birth weight in infants born to mothers who were treated, but two studies reported a significant reduction in the risk of low birth weight.
Among the six trials that examined perinatal mortality, none found significant associations with treatment.
Five studies examined treatment in nonpregnant women with screening-detected asymptomatic bacteriuria, and one included men as well. Of the four that reported the rate of symptomatic infection or pyelonephritis, none found a significant difference between treatment and control groups. The single study that included men also found no significant difference between treatment and control groups.
Among the three studies that focused on older adults, there also were no significant between-group differences in outcomes.
What harms are associated with treatment of screening-detected asymptomatic bacteriuria?
Seven studies comprised pregnant women. Five reported congenital malformations in the intervention and control groups. Overall, there were very few cases of malformations, with more – although not significantly more – in the control groups.
Evidence related to other infant and maternal harms was “sparsely and inconsistently reported,” Dr. Henderson and coauthors noted, “and there was a lack of evidence on long-term neonatal outcomes after antibiotic treatment of asymptomatic bacteriuria in pregnancy.”
Two studies listed maternal adverse events associated with different treatments including vaginitis and diarrhea with ampicillin and rashes and nausea with nalidixic acid.
In terms of nonpregnant women and men, four studies reported adverse events. None occurred with nitrofurantoin or trimethoprim treatment; however, one study that included daily treatment with ofloxacin noted that 6% withdrew because of adverse events – vertigo and gastrointestinal symptoms.
Treatments didn’t affect hematocrit, bilirubin, serum urea, or nitrogen, although some studies found a slight reduction in serum creatinine.
Although there’s a need for additional research into this question, the new recommendations provide a good reason to further reduce unnecessary antibiotic exposure, Lindsey E. Nicolle, MD, wrote in a second commentary.
These updated recommendations “contribute to the evolution of management of asymptomatic bacteriuria in healthy women,” wrote Dr. Nicolle of the University of Manitoba, Winnipeg. “However, questions remain about the risks and benefits of universal screening for and treatment of asymptomatic bacteriuria in pregnant women in the context of current clinical practice. The effects of changes in fetal-maternal care, of low- compared with high-risk pregnancies, and of health care access need to be understood. In the short term, application of current diagnostic recommendations for identification of persistent symptomatic bacteriuria with a second urine culture may provide an immediate opportunity to limit unnecessary antimicrobial use for some pregnant women.”
No conflicts of interest were reported by the USPSTF authors, nor by Dr. Leis, Dr. Soong, or Dr. Nicolle. The USPSTF report was funded by the Agency for Healthcare Research and Quality.
SOURCES: U.S. Preventive Services Task Force. JAMA. 2019;322(12):1188-94; Henderson JT et al. JAMA. 2019;322(12):1195-205; Leis JA and Soong C. JAMA. 2019. doi: 10.1001/jamainternmed.2019.4515; Nicolle LE. JAMA. 2019;322(12):1152-4.
FROM JAMA
