Bianca Nogrady

Surgery may be more effective than medical therapy, according to results from a randomized trial in 78 patients with reflux-related heartburn refractory to proton pump inhibitors (PPIs).

Stuart J. Spechler, MD, from Baylor University Medical Center, Dallas, and coauthors wrote in the New England Journal of Medicine that, for these patients, there were no medical treatment options that had been shown to have long-term benefit, so PPIs were often continued despite not offering adequate symptom relief. Other medical options such as baclofen and neuromodulators often have unacceptable side effects, and studies of their efficacy were few and of short duration.

In this study, patients were randomized either to laparoscopic Nissen fundoplication, treatment with omeprazole plus baclofen with desipramine depending on symptoms, or a control treatment of omeprazole plus placebo.

At 1 year, researchers saw a significantly higher rate of treatment success – defined as 50% or greater improvement in gastroesophageal reflux disease health-related quality of life score – in the surgery group (67%), compared with the medical-treatment group (28%) and control-medical group (12%).

This translated to an unadjusted 138% greater chance of treatment success with surgery, compared with active medical treatment, and a greater than 400% increase for surgery, compared with the control medical treatment.

Researchers also did a prespecified subgroup analysis among people with reflex hypersensitivity or abnormal acid reflux, and found the incidence of success with surgery was 71% and 62%, respectively.

They described this finding as “noteworthy,” given that reflux hypersensitivity was considered a functional disorder that would not be expected to improve with a procedure that didn’t alter abnormal esophageal pain perception.

However, they acknowledged that, as the study did not include a sham-surgery group, they couldn’t determine how much the placebo effect might have contributed to the treatment success of surgery.

They also stressed that the randomized group was a highly selected group of patients, and that the systematic work-up including esophageal multichannel intraluminal impedance pH monitoring could identify a subgroup that might have a better response to surgery than to medical treatment.

Four patients in the surgery group experienced a total of five serious adverse events, including one patients who had a herniated fundoplication treated with repeat surgery; four patients in the active-medical group experienced four serious adverse events; and three patients in the control-medical group experienced five serious adverse events.

The authors noted that 366 patients with PPI-refractory heartburn were originally enrolled in the study, then treated with 20 mg of omeprazole twice daily for 2 weeks with strict instructions to take 20 minutes before breakfast and dinner. Of these patients, 42 had their symptoms relieved by the omeprazole treatment and so were excluded from the randomization.

The “strict instructions” on how to take omeprazole were important, because PPIs only bind to gastric proton pumps that are actively secreting acid, the authors wrote. They also commented that the relative potencies of individual PPIs can vary, so patients not on omeprazole before the study may have responded better to this than other PPIs.

Before randomizations, patients also underwent endoscopy, esophageal biopsy, esophageal manometry, and multichannel intraluminal impedance pH monitoring. This excluded another 23 patients who were found to have non–gastroesophageal reflux disease, including eosinophilic esophagitis, other endoscopic or histologic abnormalities, and manometric abnormalities.

“This trial highlights the critical importance of systematic evaluation, similar to that recommended by Gyawali and Fass for managing the care of patients with PPI-refractory heartburn,” they wrote. “Many patients would not complete this rigorous evaluation, and among those who did, the cause of heartburn in most of them was not [gastroesophageal reflux disease].”

The study was funded by the Department of Veterans Affairs Cooperative Studies Program. Four authors declared consultancies with and/or grants from the pharmaceutical sector.

SOURCE: Spechler SJ et al. N Engl J Med. 2019 Oct 16. doi: 10.1056/NEJMoa1811424.

Surgery may be more effective than medical therapy, according to results from a randomized trial in 78 patients with reflux-related heartburn refractory to proton pump inhibitors (PPIs).

Stuart J. Spechler, MD, from Baylor University Medical Center, Dallas, and coauthors wrote in the New England Journal of Medicine that, for these patients, there were no medical treatment options that had been shown to have long-term benefit, so PPIs were often continued despite not offering adequate symptom relief. Other medical options such as baclofen and neuromodulators often have unacceptable side effects, and studies of their efficacy were few and of short duration.

In this study, patients were randomized either to laparoscopic Nissen fundoplication, treatment with omeprazole plus baclofen with desipramine depending on symptoms, or a control treatment of omeprazole plus placebo.

At 1 year, researchers saw a significantly higher rate of treatment success – defined as 50% or greater improvement in gastroesophageal reflux disease health-related quality of life score – in the surgery group (67%), compared with the medical-treatment group (28%) and control-medical group (12%).

This translated to an unadjusted 138% greater chance of treatment success with surgery, compared with active medical treatment, and a greater than 400% increase for surgery, compared with the control medical treatment.

Researchers also did a prespecified subgroup analysis among people with reflex hypersensitivity or abnormal acid reflux, and found the incidence of success with surgery was 71% and 62%, respectively.

They described this finding as “noteworthy,” given that reflux hypersensitivity was considered a functional disorder that would not be expected to improve with a procedure that didn’t alter abnormal esophageal pain perception.

However, they acknowledged that, as the study did not include a sham-surgery group, they couldn’t determine how much the placebo effect might have contributed to the treatment success of surgery.

They also stressed that the randomized group was a highly selected group of patients, and that the systematic work-up including esophageal multichannel intraluminal impedance pH monitoring could identify a subgroup that might have a better response to surgery than to medical treatment.

Four patients in the surgery group experienced a total of five serious adverse events, including one patients who had a herniated fundoplication treated with repeat surgery; four patients in the active-medical group experienced four serious adverse events; and three patients in the control-medical group experienced five serious adverse events.

The authors noted that 366 patients with PPI-refractory heartburn were originally enrolled in the study, then treated with 20 mg of omeprazole twice daily for 2 weeks with strict instructions to take 20 minutes before breakfast and dinner. Of these patients, 42 had their symptoms relieved by the omeprazole treatment and so were excluded from the randomization.

The “strict instructions” on how to take omeprazole were important, because PPIs only bind to gastric proton pumps that are actively secreting acid, the authors wrote. They also commented that the relative potencies of individual PPIs can vary, so patients not on omeprazole before the study may have responded better to this than other PPIs.

Before randomizations, patients also underwent endoscopy, esophageal biopsy, esophageal manometry, and multichannel intraluminal impedance pH monitoring. This excluded another 23 patients who were found to have non–gastroesophageal reflux disease, including eosinophilic esophagitis, other endoscopic or histologic abnormalities, and manometric abnormalities.

“This trial highlights the critical importance of systematic evaluation, similar to that recommended by Gyawali and Fass for managing the care of patients with PPI-refractory heartburn,” they wrote. “Many patients would not complete this rigorous evaluation, and among those who did, the cause of heartburn in most of them was not [gastroesophageal reflux disease].”

The study was funded by the Department of Veterans Affairs Cooperative Studies Program. Four authors declared consultancies with and/or grants from the pharmaceutical sector.

SOURCE: Spechler SJ et al. N Engl J Med. 2019 Oct 16. doi: 10.1056/NEJMoa1811424.

Surgery may be more effective than medical therapy, according to results from a randomized trial in 78 patients with reflux-related heartburn refractory to proton pump inhibitors (PPIs).

Stuart J. Spechler, MD, from Baylor University Medical Center, Dallas, and coauthors wrote in the New England Journal of Medicine that, for these patients, there were no medical treatment options that had been shown to have long-term benefit, so PPIs were often continued despite not offering adequate symptom relief. Other medical options such as baclofen and neuromodulators often have unacceptable side effects, and studies of their efficacy were few and of short duration.

In this study, patients were randomized either to laparoscopic Nissen fundoplication, treatment with omeprazole plus baclofen with desipramine depending on symptoms, or a control treatment of omeprazole plus placebo.

At 1 year, researchers saw a significantly higher rate of treatment success – defined as 50% or greater improvement in gastroesophageal reflux disease health-related quality of life score – in the surgery group (67%), compared with the medical-treatment group (28%) and control-medical group (12%).

This translated to an unadjusted 138% greater chance of treatment success with surgery, compared with active medical treatment, and a greater than 400% increase for surgery, compared with the control medical treatment.

Researchers also did a prespecified subgroup analysis among people with reflex hypersensitivity or abnormal acid reflux, and found the incidence of success with surgery was 71% and 62%, respectively.

They described this finding as “noteworthy,” given that reflux hypersensitivity was considered a functional disorder that would not be expected to improve with a procedure that didn’t alter abnormal esophageal pain perception.

However, they acknowledged that, as the study did not include a sham-surgery group, they couldn’t determine how much the placebo effect might have contributed to the treatment success of surgery.

They also stressed that the randomized group was a highly selected group of patients, and that the systematic work-up including esophageal multichannel intraluminal impedance pH monitoring could identify a subgroup that might have a better response to surgery than to medical treatment.

Four patients in the surgery group experienced a total of five serious adverse events, including one patients who had a herniated fundoplication treated with repeat surgery; four patients in the active-medical group experienced four serious adverse events; and three patients in the control-medical group experienced five serious adverse events.

The authors noted that 366 patients with PPI-refractory heartburn were originally enrolled in the study, then treated with 20 mg of omeprazole twice daily for 2 weeks with strict instructions to take 20 minutes before breakfast and dinner. Of these patients, 42 had their symptoms relieved by the omeprazole treatment and so were excluded from the randomization.

The “strict instructions” on how to take omeprazole were important, because PPIs only bind to gastric proton pumps that are actively secreting acid, the authors wrote. They also commented that the relative potencies of individual PPIs can vary, so patients not on omeprazole before the study may have responded better to this than other PPIs.

Before randomizations, patients also underwent endoscopy, esophageal biopsy, esophageal manometry, and multichannel intraluminal impedance pH monitoring. This excluded another 23 patients who were found to have non–gastroesophageal reflux disease, including eosinophilic esophagitis, other endoscopic or histologic abnormalities, and manometric abnormalities.

“This trial highlights the critical importance of systematic evaluation, similar to that recommended by Gyawali and Fass for managing the care of patients with PPI-refractory heartburn,” they wrote. “Many patients would not complete this rigorous evaluation, and among those who did, the cause of heartburn in most of them was not [gastroesophageal reflux disease].”

The study was funded by the Department of Veterans Affairs Cooperative Studies Program. Four authors declared consultancies with and/or grants from the pharmaceutical sector.

SOURCE: Spechler SJ et al. N Engl J Med. 2019 Oct 16. doi: 10.1056/NEJMoa1811424.

More conservative oxygen therapy during mechanical ventilation in intensive care does not appear to increase the number of ventilator-free days or reduce mortality, according to a study published online in the New England Journal of Medicine.

Diane Mackle of the Medical Research Institute of New Zealand and her co-authors wrote that hyperoxemia in adults undergoing mechanical ventilation has been associated with increased mortality, as well as fewer days free of ventilation, but there was a lack of data to guide oxygen administration.

In a parallel-group trial, 1,000 adults who were expected to require mechanical ventilation – with an intention-to-treat population of 965 – were randomized either to conservative oxygen therapy or usual therapy. For the conservative therapy, the upper limit of the pulse oximetry alarm would sound when levels reached 97% and the F10₂ was decreased to 0.21 if the pulse oximetry was above the acceptable lower limit, while usual therapy involved no specific limiting measures. In both groups, the default lower limit for oxygen saturation was 90%.

At day 28 after ventilation, there was no significant difference between the conservative and usual care groups in the number of ventilator-free days (21.3 days vs. 22.1 days). The patients in the conservative oxygen group spent a median of 29 hours receiving an F10₂ level of 0.21, compared with 1 hour in the usual care group.

The mortality rate at day 180 was 35.7% in the conservative oxygen group, and 34.5% in the usual-oxygen group (HR 1.05, 95% CI 0.85 – 1.30). Researchers also saw no differences between the two groups in paid employment and cognitive function.

In patients with suspected hypoxic-ischemic encephalopathy between-group differences were apparent; At day 28, those in the conservative-oxygen group had a median of 21.1 ventilator-free days, compared with none in the usual-oxygen group. The usual-oxygen group also had a higher 180-day mortality rate than those in the conservative-oxygen group (43% vs. 59%).

“Our data are suggestive of a possible benefit of conservative oxygen therapy in patients with suspected hypoxic-ischemic encephalopathy,” the authors wrote. “It is biologically plausible that conservative oxygen therapy reduces the incidence of secondary brain damage after resuscitation from cardiac arrest, and observational data suggest that exposure to hyperoxemia in such patients may be harmful.”

The authors noted that their trial did not rule out the possibility of benefit or harm had they used a more liberal oxygen regimen in their usual-care group, and that different conservative regimens might also have achieved different outcomes.

The study was funded by the New Zealand Health Research Council. Six authors declared research support for the trial from the study funder, and two declared unrelated research grants from private industry. No other conflicts of interest were declared.

SOURCE: Mackle D et al. NJEM 2019, October 14. DOI:10.1056/NEJMoa1903297.

More conservative oxygen therapy during mechanical ventilation in intensive care does not appear to increase the number of ventilator-free days or reduce mortality, according to a study published online in the New England Journal of Medicine.

Diane Mackle of the Medical Research Institute of New Zealand and her co-authors wrote that hyperoxemia in adults undergoing mechanical ventilation has been associated with increased mortality, as well as fewer days free of ventilation, but there was a lack of data to guide oxygen administration.

In a parallel-group trial, 1,000 adults who were expected to require mechanical ventilation – with an intention-to-treat population of 965 – were randomized either to conservative oxygen therapy or usual therapy. For the conservative therapy, the upper limit of the pulse oximetry alarm would sound when levels reached 97% and the F10₂ was decreased to 0.21 if the pulse oximetry was above the acceptable lower limit, while usual therapy involved no specific limiting measures. In both groups, the default lower limit for oxygen saturation was 90%.

At day 28 after ventilation, there was no significant difference between the conservative and usual care groups in the number of ventilator-free days (21.3 days vs. 22.1 days). The patients in the conservative oxygen group spent a median of 29 hours receiving an F10₂ level of 0.21, compared with 1 hour in the usual care group.

The mortality rate at day 180 was 35.7% in the conservative oxygen group, and 34.5% in the usual-oxygen group (HR 1.05, 95% CI 0.85 – 1.30). Researchers also saw no differences between the two groups in paid employment and cognitive function.

In patients with suspected hypoxic-ischemic encephalopathy between-group differences were apparent; At day 28, those in the conservative-oxygen group had a median of 21.1 ventilator-free days, compared with none in the usual-oxygen group. The usual-oxygen group also had a higher 180-day mortality rate than those in the conservative-oxygen group (43% vs. 59%).

“Our data are suggestive of a possible benefit of conservative oxygen therapy in patients with suspected hypoxic-ischemic encephalopathy,” the authors wrote. “It is biologically plausible that conservative oxygen therapy reduces the incidence of secondary brain damage after resuscitation from cardiac arrest, and observational data suggest that exposure to hyperoxemia in such patients may be harmful.”

The authors noted that their trial did not rule out the possibility of benefit or harm had they used a more liberal oxygen regimen in their usual-care group, and that different conservative regimens might also have achieved different outcomes.

The study was funded by the New Zealand Health Research Council. Six authors declared research support for the trial from the study funder, and two declared unrelated research grants from private industry. No other conflicts of interest were declared.

SOURCE: Mackle D et al. NJEM 2019, October 14. DOI:10.1056/NEJMoa1903297.

More conservative oxygen therapy during mechanical ventilation in intensive care does not appear to increase the number of ventilator-free days or reduce mortality, according to a study published online in the New England Journal of Medicine.

Diane Mackle of the Medical Research Institute of New Zealand and her co-authors wrote that hyperoxemia in adults undergoing mechanical ventilation has been associated with increased mortality, as well as fewer days free of ventilation, but there was a lack of data to guide oxygen administration.

In a parallel-group trial, 1,000 adults who were expected to require mechanical ventilation – with an intention-to-treat population of 965 – were randomized either to conservative oxygen therapy or usual therapy. For the conservative therapy, the upper limit of the pulse oximetry alarm would sound when levels reached 97% and the F10₂ was decreased to 0.21 if the pulse oximetry was above the acceptable lower limit, while usual therapy involved no specific limiting measures. In both groups, the default lower limit for oxygen saturation was 90%.

At day 28 after ventilation, there was no significant difference between the conservative and usual care groups in the number of ventilator-free days (21.3 days vs. 22.1 days). The patients in the conservative oxygen group spent a median of 29 hours receiving an F10₂ level of 0.21, compared with 1 hour in the usual care group.

The mortality rate at day 180 was 35.7% in the conservative oxygen group, and 34.5% in the usual-oxygen group (HR 1.05, 95% CI 0.85 – 1.30). Researchers also saw no differences between the two groups in paid employment and cognitive function.

In patients with suspected hypoxic-ischemic encephalopathy between-group differences were apparent; At day 28, those in the conservative-oxygen group had a median of 21.1 ventilator-free days, compared with none in the usual-oxygen group. The usual-oxygen group also had a higher 180-day mortality rate than those in the conservative-oxygen group (43% vs. 59%).

“Our data are suggestive of a possible benefit of conservative oxygen therapy in patients with suspected hypoxic-ischemic encephalopathy,” the authors wrote. “It is biologically plausible that conservative oxygen therapy reduces the incidence of secondary brain damage after resuscitation from cardiac arrest, and observational data suggest that exposure to hyperoxemia in such patients may be harmful.”

The authors noted that their trial did not rule out the possibility of benefit or harm had they used a more liberal oxygen regimen in their usual-care group, and that different conservative regimens might also have achieved different outcomes.

The study was funded by the New Zealand Health Research Council. Six authors declared research support for the trial from the study funder, and two declared unrelated research grants from private industry. No other conflicts of interest were declared.

SOURCE: Mackle D et al. NJEM 2019, October 14. DOI:10.1056/NEJMoa1903297.

Patients with bipolar disorder may be at increased risk of Parkinson’s disease in later life, according to a systematic review and meta-analysis published in JAMA Neurology.

Patrícia R. Faustino, MD, from the faculty of medicine at the University of Lisboa (Portgual), and coauthors reviewed and analyzed seven articles – four cohort studies and three cross-sectional studies – that reported data on idiopathic Parkinson’s disease in patients with bipolar disorder, compared with those without. The meta-analysis found that individuals with a previous diagnosis of bipolar disorder had a 235% higher risk of being later diagnosed with Parkinson’s disease. Even after removing studies with a high risk of bias, the risk was still 3.21 times higher in those with bipolar disorder, compared with those without.

“The pathophysiological rationale between bipolar disorder and Parkinson’s disease might be explained by the dopamine dysregulation hypothesis, which states that the cyclical process of bipolar disorder in manic states leads to a down-regulation of dopamine receptor sensitivity (depression phase), which is later compensated by up-regulation (manic state),” the authors wrote. “Over time, this phenomenon may lead to an overall reduction of dopaminergic activity, the prototypical Parkinson’s disease state.”

Subgroup analysis revealed that subgroups with shorter follow-up periods – less than 9 years – had a greater increase in the risk of a later Parkinson’s disease diagnosis. The authors noted that this could represent misdiagnosis of parkinsonism – possibly drug induced – as Parkinson’s disease. The researchers also raised the possibility that the increased risk of Parkinson’s disease in patients with bipolar disorder could relate to long-term lithium use, rather than being a causal relationship. “However, treatment with lithium is foundational in bipolar disorder, and so to separate the causal effect from a potential confounder would be particularly difficult,” they wrote.

One of the studies included did explore the use of lithium, and found that lithium monotherapy was associated with a significant increase in the risk of being diagnosed with Parkinson’s disease or taking antiparkinsonism medication, compared with antidepressant therapy. However the authors commented that the diagnostic code may not differentiate Parkinson’s disease from other causes of parkinsonism.

Given their findings, the authors suggested that, if patients with bipolar disorder present with parkinsonism features, it may not necessarily be drug induced. In these patients, they recommended an investigation for Parkinson’s disease, perhaps using functional neuroimaging “as Parkinson’s disease classically presents with nigrostriatal degeneration while drug-induced parkinsonism does not.”

Two authors declared grants and personal fees from the pharmaceutical sector. No other conflicts of interest were reported.

SOURCE: Faustino PR et al. JAMA Neurol. 2019 Oct 14. doi: 10.1001/jamaneurol.2019.3446.

Patients with bipolar disorder may be at increased risk of Parkinson’s disease in later life, according to a systematic review and meta-analysis published in JAMA Neurology.

Patrícia R. Faustino, MD, from the faculty of medicine at the University of Lisboa (Portgual), and coauthors reviewed and analyzed seven articles – four cohort studies and three cross-sectional studies – that reported data on idiopathic Parkinson’s disease in patients with bipolar disorder, compared with those without. The meta-analysis found that individuals with a previous diagnosis of bipolar disorder had a 235% higher risk of being later diagnosed with Parkinson’s disease. Even after removing studies with a high risk of bias, the risk was still 3.21 times higher in those with bipolar disorder, compared with those without.

“The pathophysiological rationale between bipolar disorder and Parkinson’s disease might be explained by the dopamine dysregulation hypothesis, which states that the cyclical process of bipolar disorder in manic states leads to a down-regulation of dopamine receptor sensitivity (depression phase), which is later compensated by up-regulation (manic state),” the authors wrote. “Over time, this phenomenon may lead to an overall reduction of dopaminergic activity, the prototypical Parkinson’s disease state.”

Subgroup analysis revealed that subgroups with shorter follow-up periods – less than 9 years – had a greater increase in the risk of a later Parkinson’s disease diagnosis. The authors noted that this could represent misdiagnosis of parkinsonism – possibly drug induced – as Parkinson’s disease. The researchers also raised the possibility that the increased risk of Parkinson’s disease in patients with bipolar disorder could relate to long-term lithium use, rather than being a causal relationship. “However, treatment with lithium is foundational in bipolar disorder, and so to separate the causal effect from a potential confounder would be particularly difficult,” they wrote.

One of the studies included did explore the use of lithium, and found that lithium monotherapy was associated with a significant increase in the risk of being diagnosed with Parkinson’s disease or taking antiparkinsonism medication, compared with antidepressant therapy. However the authors commented that the diagnostic code may not differentiate Parkinson’s disease from other causes of parkinsonism.

Given their findings, the authors suggested that, if patients with bipolar disorder present with parkinsonism features, it may not necessarily be drug induced. In these patients, they recommended an investigation for Parkinson’s disease, perhaps using functional neuroimaging “as Parkinson’s disease classically presents with nigrostriatal degeneration while drug-induced parkinsonism does not.”

Two authors declared grants and personal fees from the pharmaceutical sector. No other conflicts of interest were reported.

SOURCE: Faustino PR et al. JAMA Neurol. 2019 Oct 14. doi: 10.1001/jamaneurol.2019.3446.

Patients with bipolar disorder may be at increased risk of Parkinson’s disease in later life, according to a systematic review and meta-analysis published in JAMA Neurology.

Patrícia R. Faustino, MD, from the faculty of medicine at the University of Lisboa (Portgual), and coauthors reviewed and analyzed seven articles – four cohort studies and three cross-sectional studies – that reported data on idiopathic Parkinson’s disease in patients with bipolar disorder, compared with those without. The meta-analysis found that individuals with a previous diagnosis of bipolar disorder had a 235% higher risk of being later diagnosed with Parkinson’s disease. Even after removing studies with a high risk of bias, the risk was still 3.21 times higher in those with bipolar disorder, compared with those without.

“The pathophysiological rationale between bipolar disorder and Parkinson’s disease might be explained by the dopamine dysregulation hypothesis, which states that the cyclical process of bipolar disorder in manic states leads to a down-regulation of dopamine receptor sensitivity (depression phase), which is later compensated by up-regulation (manic state),” the authors wrote. “Over time, this phenomenon may lead to an overall reduction of dopaminergic activity, the prototypical Parkinson’s disease state.”

Subgroup analysis revealed that subgroups with shorter follow-up periods – less than 9 years – had a greater increase in the risk of a later Parkinson’s disease diagnosis. The authors noted that this could represent misdiagnosis of parkinsonism – possibly drug induced – as Parkinson’s disease. The researchers also raised the possibility that the increased risk of Parkinson’s disease in patients with bipolar disorder could relate to long-term lithium use, rather than being a causal relationship. “However, treatment with lithium is foundational in bipolar disorder, and so to separate the causal effect from a potential confounder would be particularly difficult,” they wrote.

One of the studies included did explore the use of lithium, and found that lithium monotherapy was associated with a significant increase in the risk of being diagnosed with Parkinson’s disease or taking antiparkinsonism medication, compared with antidepressant therapy. However the authors commented that the diagnostic code may not differentiate Parkinson’s disease from other causes of parkinsonism.

Given their findings, the authors suggested that, if patients with bipolar disorder present with parkinsonism features, it may not necessarily be drug induced. In these patients, they recommended an investigation for Parkinson’s disease, perhaps using functional neuroimaging “as Parkinson’s disease classically presents with nigrostriatal degeneration while drug-induced parkinsonism does not.”

Two authors declared grants and personal fees from the pharmaceutical sector. No other conflicts of interest were reported.

SOURCE: Faustino PR et al. JAMA Neurol. 2019 Oct 14. doi: 10.1001/jamaneurol.2019.3446.

Adhesive tape strips can be used for skin sampling in children with atopic dermatitis (AD) to provide information on biomarkers associated with the disease instead of using tissue biopsies for this purpose, according to a study published online on October 9 in JAMA Dermatology.

“Minimally invasive approaches that accurately capture key immune and barrier biomarkers in the skin of patients with early-onset pediatric AD are needed,” wrote Emma Guttman-Yassky, MD, professor of dermatology at the Icahn School of Medicine at Mount Sinai, New York, and coauthors. “Because tissue biopsies are considered the criterion standard for evaluating dysregulation in AD lesional and nonlesional skin, it is crucial to understand whether tape-strip profiling can accurately yield key AD-related biomarkers.”

In their cross-sectional study, researchers used large D-Squame tape strips to collect skin samples from 51 children under the age of 5 years (mean, 1.7-1.8 years), including 21 with moderate to severe AD and 30 controls who did not have AD. Samples were collected from lesional skin inside the crook of the elbow and nonlesional skin, on the same arm, then subjected to gene- and protein-expression analysis to identify skin biomarkers of disease.

The participants tolerated the tape stripping well, and there were no clinical effects of the procedure. The authors were able to detect mRNA in 70 of 71 samples.

They then analyzed a panel of 15 cellular markers that assessed markers of monocytes and macrophages, T cells, activated T_H2 cells, dendritic cells and dendritic-cell subsets, and Langerhans cells. They found that most showed significant differences between lesional AD skin and normal skin.

They also found that levels of OX40 ligand receptor, a marker associated with atopic dendritic cells, the inducible T-cell costimulatory activation marker, CD209, CD123, and langerin protein, were also significantly higher in nonlesional AD skin.

When comparing lesional and nonlesional skin samples in the AD patients, the authors saw significant differences only in levels of colony-stimulating factor 1 and 2.

The authors noted that some of the mediators detected from the tape-strip samples had not been detected or evaluated in previous studies of the use of tape strips in AD. These included measures of cellular infiltrates, atopic dendritic cells, and key inflammatory markers.

“The novel epidermal cytokines IL [interleukin]–33 and IL-17C, which are currently targeted in clinical trials of patients with AD, were also highlighted as novel tape-strip biomarkers and demonstrated significant correlations with AD severity,” they wrote.

“Because tape stripping is painless, nonscarring, and allows repeated sampling, it may be associated with benefits for longitudinal pediatric studies and clinical trials, in which serial measures are needed to identify predictors of response, course, and comorbidities,” the authors concluded.

The study was supported by the Northwestern University Skin Disease Research Center and the Northwestern University Clinical and Translational Sciences Institute, and partly by a grant to two authors from Regeneron and Sanofi. Dr. Guttman-Yassky reported receiving grants from Regeneron during the study, and had other disclosures related to multiple pharmaceutical companies. Another author also received grants from Regeneron during the study, and another author had disclosures related to various manufacturers; no disclosures were reported for the remaining authors.

SOURCE: Guttman-Yassky E et al. JAMA Dermatol. 2019 Oct 9. doi: 10.1001/jamadermatol.2019.2983.

Adhesive tape strips can be used for skin sampling in children with atopic dermatitis (AD) to provide information on biomarkers associated with the disease instead of using tissue biopsies for this purpose, according to a study published online on October 9 in JAMA Dermatology.

“Minimally invasive approaches that accurately capture key immune and barrier biomarkers in the skin of patients with early-onset pediatric AD are needed,” wrote Emma Guttman-Yassky, MD, professor of dermatology at the Icahn School of Medicine at Mount Sinai, New York, and coauthors. “Because tissue biopsies are considered the criterion standard for evaluating dysregulation in AD lesional and nonlesional skin, it is crucial to understand whether tape-strip profiling can accurately yield key AD-related biomarkers.”

In their cross-sectional study, researchers used large D-Squame tape strips to collect skin samples from 51 children under the age of 5 years (mean, 1.7-1.8 years), including 21 with moderate to severe AD and 30 controls who did not have AD. Samples were collected from lesional skin inside the crook of the elbow and nonlesional skin, on the same arm, then subjected to gene- and protein-expression analysis to identify skin biomarkers of disease.

The participants tolerated the tape stripping well, and there were no clinical effects of the procedure. The authors were able to detect mRNA in 70 of 71 samples.

They then analyzed a panel of 15 cellular markers that assessed markers of monocytes and macrophages, T cells, activated T_H2 cells, dendritic cells and dendritic-cell subsets, and Langerhans cells. They found that most showed significant differences between lesional AD skin and normal skin.

They also found that levels of OX40 ligand receptor, a marker associated with atopic dendritic cells, the inducible T-cell costimulatory activation marker, CD209, CD123, and langerin protein, were also significantly higher in nonlesional AD skin.

When comparing lesional and nonlesional skin samples in the AD patients, the authors saw significant differences only in levels of colony-stimulating factor 1 and 2.

The authors noted that some of the mediators detected from the tape-strip samples had not been detected or evaluated in previous studies of the use of tape strips in AD. These included measures of cellular infiltrates, atopic dendritic cells, and key inflammatory markers.

“The novel epidermal cytokines IL [interleukin]–33 and IL-17C, which are currently targeted in clinical trials of patients with AD, were also highlighted as novel tape-strip biomarkers and demonstrated significant correlations with AD severity,” they wrote.

“Because tape stripping is painless, nonscarring, and allows repeated sampling, it may be associated with benefits for longitudinal pediatric studies and clinical trials, in which serial measures are needed to identify predictors of response, course, and comorbidities,” the authors concluded.

The study was supported by the Northwestern University Skin Disease Research Center and the Northwestern University Clinical and Translational Sciences Institute, and partly by a grant to two authors from Regeneron and Sanofi. Dr. Guttman-Yassky reported receiving grants from Regeneron during the study, and had other disclosures related to multiple pharmaceutical companies. Another author also received grants from Regeneron during the study, and another author had disclosures related to various manufacturers; no disclosures were reported for the remaining authors.

SOURCE: Guttman-Yassky E et al. JAMA Dermatol. 2019 Oct 9. doi: 10.1001/jamadermatol.2019.2983.

Adhesive tape strips can be used for skin sampling in children with atopic dermatitis (AD) to provide information on biomarkers associated with the disease instead of using tissue biopsies for this purpose, according to a study published online on October 9 in JAMA Dermatology.

“Minimally invasive approaches that accurately capture key immune and barrier biomarkers in the skin of patients with early-onset pediatric AD are needed,” wrote Emma Guttman-Yassky, MD, professor of dermatology at the Icahn School of Medicine at Mount Sinai, New York, and coauthors. “Because tissue biopsies are considered the criterion standard for evaluating dysregulation in AD lesional and nonlesional skin, it is crucial to understand whether tape-strip profiling can accurately yield key AD-related biomarkers.”

In their cross-sectional study, researchers used large D-Squame tape strips to collect skin samples from 51 children under the age of 5 years (mean, 1.7-1.8 years), including 21 with moderate to severe AD and 30 controls who did not have AD. Samples were collected from lesional skin inside the crook of the elbow and nonlesional skin, on the same arm, then subjected to gene- and protein-expression analysis to identify skin biomarkers of disease.

The participants tolerated the tape stripping well, and there were no clinical effects of the procedure. The authors were able to detect mRNA in 70 of 71 samples.

They then analyzed a panel of 15 cellular markers that assessed markers of monocytes and macrophages, T cells, activated T_H2 cells, dendritic cells and dendritic-cell subsets, and Langerhans cells. They found that most showed significant differences between lesional AD skin and normal skin.

They also found that levels of OX40 ligand receptor, a marker associated with atopic dendritic cells, the inducible T-cell costimulatory activation marker, CD209, CD123, and langerin protein, were also significantly higher in nonlesional AD skin.

When comparing lesional and nonlesional skin samples in the AD patients, the authors saw significant differences only in levels of colony-stimulating factor 1 and 2.

The authors noted that some of the mediators detected from the tape-strip samples had not been detected or evaluated in previous studies of the use of tape strips in AD. These included measures of cellular infiltrates, atopic dendritic cells, and key inflammatory markers.

“The novel epidermal cytokines IL [interleukin]–33 and IL-17C, which are currently targeted in clinical trials of patients with AD, were also highlighted as novel tape-strip biomarkers and demonstrated significant correlations with AD severity,” they wrote.

“Because tape stripping is painless, nonscarring, and allows repeated sampling, it may be associated with benefits for longitudinal pediatric studies and clinical trials, in which serial measures are needed to identify predictors of response, course, and comorbidities,” the authors concluded.

The study was supported by the Northwestern University Skin Disease Research Center and the Northwestern University Clinical and Translational Sciences Institute, and partly by a grant to two authors from Regeneron and Sanofi. Dr. Guttman-Yassky reported receiving grants from Regeneron during the study, and had other disclosures related to multiple pharmaceutical companies. Another author also received grants from Regeneron during the study, and another author had disclosures related to various manufacturers; no disclosures were reported for the remaining authors.

SOURCE: Guttman-Yassky E et al. JAMA Dermatol. 2019 Oct 9. doi: 10.1001/jamadermatol.2019.2983.

All adult patients with primary sclerosing cholangitis should be screened at least annually for cholangiocarcinoma and gallbladder cancer, particularly in the first year after their diagnosis, according to a clinical practice update published in Clinical Gastroenterology and Hepatology.

Individuals with primary sclerosing cholangitis have a 400-fold higher risk of cholangiocarcinoma, compared with the general population, and around one-third of cancers are detected within 1 year of the cholangitis diagnosis, Christopher L. Bowlus, MD, of the University of California, Davis, and coauthors wrote.

The clinical practice update from the American Gastroenterological Association was in response to the observation that, while there is significant evidence for an increasing incidence of cirrhosis, hepatic decompensation, hepatocellular carcinoma, and liver transplant listing among patients with primary sclerosing cholangitis, there is a lack of good evidence to guide cholangiocarcinoma surveillance in these patients.

“The low prevalence and long duration of PSC [primary sclerosing cholangitis] present substantial barriers to better understanding risk stratification, developing biomarkers, and measuring the impact surveillance has on clinical outcomes,” they wrote.

The first recommendation was that surveillance for cholangiocarcinoma and gallbladder cancer should be considered in all adult patients with primary sclerosing cholangitis, regardless of their disease stage. The authors especially emphasized the importance of surveillance in the first year after a diagnosis of primary sclerosing cholangitis, in patients who also have ulcerative colitis, and in those diagnosed at an older age.

They cited one study that found regular surveillance of patients with primary sclerosing cholangitis was associated with significantly higher 5-year survival rates, compared with those no regular screening (68% vs. 20%; P less than .0061).

In terms of surveillance modalities, the update suggested 6- to 12-monthly imaging of the biliary tree with ultrasound computed tomography, computed tomography, or magnetic resonance imaging – with or without serum carbohydrate antigen 19-9. However the authors wrote that MRI was often preferred to CT because of its superior sensitivity.

They advised against endoscopic retrograde cholangiopancreatography with brush cytology for routine surveillance because of procedural risks. On the other hand, they suggested this procedure, with or without fluorescence in situ hybridization analysis and/or cholangioscopy, could be used for investigation.

“In addition to ERCP [endoscopic retrograde cholangiopancreatography] with brushings, endoscopic ultrasound, intraductal ultrasonography, and cholangioscopy may be used to direct biopsy sampling,” they wrote. Symptoms such as increasing cholestatic biochemistry values, jaundice, fever, right upper quadrant pain, or pruritus should trigger evaluation for cholangiocarcinoma.

However the authors advised “great caution” with the use of fine-needle aspiration of perihilar biliary strictures in liver transplant candidates because of the risk of tumor seeding if the lesion turned out to be cholangiocarcinoma.

On the question of cholangiocarcinoma surveillance in pediatric patients and those with small-duct primary sclerosing cholangitis, the authors wrote that cholangiocarcinoma was so rare in these patients that routine cholangiocarcinoma surveillance was not required.

The clinical update also looked at the prevalence and risk factors for gallbladder cancer, which affects around 2% of individuals with primary sclerosing cholangitis. Two studies found gallbladder polyps in 10%-17% of patients, but the authors noted that “the optimal modality for diagnosis of gallbladder polyps in PSC remains unknown”.

“Because of the high risk of malignancy in gallbladder mass lesions and a 5-year survival rate of 5% to 10% for gallbladder cancer, patients should undergo annual US [ultrasound] screening,” they wrote.

They said the question of whether to perform a cholecystectomy in patients with gallbladder polyps should be guided by the size and growth of the polyps because there is an increased risk of gallbladder cancer in polyps larger than 8 mm and by the clinical status of the patient.

Finally, the update examined the issue of hepatocellular carcinoma in patients with primary sclerosing cholangitis, which – while rare – may increase with the presence of cirrhosis.

The authors advised that patients with primary sclerosing cholangitis and cirrhosis should undergo surveillance for hepatocellular carcinoma every 6 months with ultrasound, CT, or MRI.

“We anticipate that with the development of large patient cohorts, advances in uncovering genetic and other risk factors for cholangiocarcinoma, and development of effective treatments for PSC, further refinement of this practice update will be required.”

Two authors declared consultancies, grants and research contracts with the pharmaceutical sector. No other conflicts of interest were declared.

SOURCE: Bowlus C et al. Clin Gastroenterol Hepatol. 2019 Jul 12. doi 10.1016/j.cgh.2019.07.011.

All adult patients with primary sclerosing cholangitis should be screened at least annually for cholangiocarcinoma and gallbladder cancer, particularly in the first year after their diagnosis, according to a clinical practice update published in Clinical Gastroenterology and Hepatology.

Individuals with primary sclerosing cholangitis have a 400-fold higher risk of cholangiocarcinoma, compared with the general population, and around one-third of cancers are detected within 1 year of the cholangitis diagnosis, Christopher L. Bowlus, MD, of the University of California, Davis, and coauthors wrote.

The clinical practice update from the American Gastroenterological Association was in response to the observation that, while there is significant evidence for an increasing incidence of cirrhosis, hepatic decompensation, hepatocellular carcinoma, and liver transplant listing among patients with primary sclerosing cholangitis, there is a lack of good evidence to guide cholangiocarcinoma surveillance in these patients.

“The low prevalence and long duration of PSC [primary sclerosing cholangitis] present substantial barriers to better understanding risk stratification, developing biomarkers, and measuring the impact surveillance has on clinical outcomes,” they wrote.

The first recommendation was that surveillance for cholangiocarcinoma and gallbladder cancer should be considered in all adult patients with primary sclerosing cholangitis, regardless of their disease stage. The authors especially emphasized the importance of surveillance in the first year after a diagnosis of primary sclerosing cholangitis, in patients who also have ulcerative colitis, and in those diagnosed at an older age.

They cited one study that found regular surveillance of patients with primary sclerosing cholangitis was associated with significantly higher 5-year survival rates, compared with those no regular screening (68% vs. 20%; P less than .0061).

In terms of surveillance modalities, the update suggested 6- to 12-monthly imaging of the biliary tree with ultrasound computed tomography, computed tomography, or magnetic resonance imaging – with or without serum carbohydrate antigen 19-9. However the authors wrote that MRI was often preferred to CT because of its superior sensitivity.

They advised against endoscopic retrograde cholangiopancreatography with brush cytology for routine surveillance because of procedural risks. On the other hand, they suggested this procedure, with or without fluorescence in situ hybridization analysis and/or cholangioscopy, could be used for investigation.

“In addition to ERCP [endoscopic retrograde cholangiopancreatography] with brushings, endoscopic ultrasound, intraductal ultrasonography, and cholangioscopy may be used to direct biopsy sampling,” they wrote. Symptoms such as increasing cholestatic biochemistry values, jaundice, fever, right upper quadrant pain, or pruritus should trigger evaluation for cholangiocarcinoma.

However the authors advised “great caution” with the use of fine-needle aspiration of perihilar biliary strictures in liver transplant candidates because of the risk of tumor seeding if the lesion turned out to be cholangiocarcinoma.

On the question of cholangiocarcinoma surveillance in pediatric patients and those with small-duct primary sclerosing cholangitis, the authors wrote that cholangiocarcinoma was so rare in these patients that routine cholangiocarcinoma surveillance was not required.

The clinical update also looked at the prevalence and risk factors for gallbladder cancer, which affects around 2% of individuals with primary sclerosing cholangitis. Two studies found gallbladder polyps in 10%-17% of patients, but the authors noted that “the optimal modality for diagnosis of gallbladder polyps in PSC remains unknown”.

“Because of the high risk of malignancy in gallbladder mass lesions and a 5-year survival rate of 5% to 10% for gallbladder cancer, patients should undergo annual US [ultrasound] screening,” they wrote.

They said the question of whether to perform a cholecystectomy in patients with gallbladder polyps should be guided by the size and growth of the polyps because there is an increased risk of gallbladder cancer in polyps larger than 8 mm and by the clinical status of the patient.

Finally, the update examined the issue of hepatocellular carcinoma in patients with primary sclerosing cholangitis, which – while rare – may increase with the presence of cirrhosis.

The authors advised that patients with primary sclerosing cholangitis and cirrhosis should undergo surveillance for hepatocellular carcinoma every 6 months with ultrasound, CT, or MRI.

“We anticipate that with the development of large patient cohorts, advances in uncovering genetic and other risk factors for cholangiocarcinoma, and development of effective treatments for PSC, further refinement of this practice update will be required.”

Two authors declared consultancies, grants and research contracts with the pharmaceutical sector. No other conflicts of interest were declared.

SOURCE: Bowlus C et al. Clin Gastroenterol Hepatol. 2019 Jul 12. doi 10.1016/j.cgh.2019.07.011.

All adult patients with primary sclerosing cholangitis should be screened at least annually for cholangiocarcinoma and gallbladder cancer, particularly in the first year after their diagnosis, according to a clinical practice update published in Clinical Gastroenterology and Hepatology.

Individuals with primary sclerosing cholangitis have a 400-fold higher risk of cholangiocarcinoma, compared with the general population, and around one-third of cancers are detected within 1 year of the cholangitis diagnosis, Christopher L. Bowlus, MD, of the University of California, Davis, and coauthors wrote.

The clinical practice update from the American Gastroenterological Association was in response to the observation that, while there is significant evidence for an increasing incidence of cirrhosis, hepatic decompensation, hepatocellular carcinoma, and liver transplant listing among patients with primary sclerosing cholangitis, there is a lack of good evidence to guide cholangiocarcinoma surveillance in these patients.

“The low prevalence and long duration of PSC [primary sclerosing cholangitis] present substantial barriers to better understanding risk stratification, developing biomarkers, and measuring the impact surveillance has on clinical outcomes,” they wrote.

The first recommendation was that surveillance for cholangiocarcinoma and gallbladder cancer should be considered in all adult patients with primary sclerosing cholangitis, regardless of their disease stage. The authors especially emphasized the importance of surveillance in the first year after a diagnosis of primary sclerosing cholangitis, in patients who also have ulcerative colitis, and in those diagnosed at an older age.

They cited one study that found regular surveillance of patients with primary sclerosing cholangitis was associated with significantly higher 5-year survival rates, compared with those no regular screening (68% vs. 20%; P less than .0061).

In terms of surveillance modalities, the update suggested 6- to 12-monthly imaging of the biliary tree with ultrasound computed tomography, computed tomography, or magnetic resonance imaging – with or without serum carbohydrate antigen 19-9. However the authors wrote that MRI was often preferred to CT because of its superior sensitivity.

They advised against endoscopic retrograde cholangiopancreatography with brush cytology for routine surveillance because of procedural risks. On the other hand, they suggested this procedure, with or without fluorescence in situ hybridization analysis and/or cholangioscopy, could be used for investigation.

“In addition to ERCP [endoscopic retrograde cholangiopancreatography] with brushings, endoscopic ultrasound, intraductal ultrasonography, and cholangioscopy may be used to direct biopsy sampling,” they wrote. Symptoms such as increasing cholestatic biochemistry values, jaundice, fever, right upper quadrant pain, or pruritus should trigger evaluation for cholangiocarcinoma.

However the authors advised “great caution” with the use of fine-needle aspiration of perihilar biliary strictures in liver transplant candidates because of the risk of tumor seeding if the lesion turned out to be cholangiocarcinoma.

On the question of cholangiocarcinoma surveillance in pediatric patients and those with small-duct primary sclerosing cholangitis, the authors wrote that cholangiocarcinoma was so rare in these patients that routine cholangiocarcinoma surveillance was not required.

The clinical update also looked at the prevalence and risk factors for gallbladder cancer, which affects around 2% of individuals with primary sclerosing cholangitis. Two studies found gallbladder polyps in 10%-17% of patients, but the authors noted that “the optimal modality for diagnosis of gallbladder polyps in PSC remains unknown”.

“Because of the high risk of malignancy in gallbladder mass lesions and a 5-year survival rate of 5% to 10% for gallbladder cancer, patients should undergo annual US [ultrasound] screening,” they wrote.

They said the question of whether to perform a cholecystectomy in patients with gallbladder polyps should be guided by the size and growth of the polyps because there is an increased risk of gallbladder cancer in polyps larger than 8 mm and by the clinical status of the patient.

Finally, the update examined the issue of hepatocellular carcinoma in patients with primary sclerosing cholangitis, which – while rare – may increase with the presence of cirrhosis.

The authors advised that patients with primary sclerosing cholangitis and cirrhosis should undergo surveillance for hepatocellular carcinoma every 6 months with ultrasound, CT, or MRI.

“We anticipate that with the development of large patient cohorts, advances in uncovering genetic and other risk factors for cholangiocarcinoma, and development of effective treatments for PSC, further refinement of this practice update will be required.”

Two authors declared consultancies, grants and research contracts with the pharmaceutical sector. No other conflicts of interest were declared.

SOURCE: Bowlus C et al. Clin Gastroenterol Hepatol. 2019 Jul 12. doi 10.1016/j.cgh.2019.07.011.

A study of dupilumab in adolescents with atopic dermatitis (AD) has provided longer term efficacy and safety data, with no new safety signals and continued evidence of efficacy for up to 52 weeks, reported the authors of the study, published online Oct. 9 in the British Journal of Dermatology.

The phase 2a open-label, ascending-dose cohort study of dupilumab in 40 adolescents with moderate to severe AD was followed by a 48-week phase 3 open-label extension study in 36 of those participants. Dupilumab is a monoclonal antibody that inhibits signaling of interleukin (IL)-4 and IL-13.

In the phase 2a study, participants were treated with a single subcutaneous dose of dupilumab – either 2 mg/kg or 4 mg/kg – and had 8 weeks of pharmacokinetic sampling. They subsequently received that same dose weekly for 4 weeks, with an 8-week-long safety follow-up period. Those who participated in the open-label extension continued their weekly dose to a maximum of 300 mg. per kg

The most common treatment-emergent adverse events (a primary endpoint) seen in both the phase 2a and phase 3 studies were nasopharyngitis and exacerbation of AD – in the phase 2a study, exacerbations were seen in the period when patients weren’t taking the treatment. In the 2-mg and 4-mg groups, the incidence of skin infections was 29% and 42%, respectively, and the incidence of injection site reactions – which were mostly mild – were 18% and 11%, respectively. Researchers also noted conjunctivitis in 18% and 16% of the patients in the 2-mg and 4-mg groups, respectively, but none of the cases were considered serious and all resolved over the course of the study. In the phase 2a study, 50% of patients on the 2-mg/kg dose and 65% of those on the 4-mg/kg dose experienced an adverse event, while in the open-label extension all reported at least one adverse event.

There was one case of suicidal behavior and one case of systemic or severe hypersensitivity reported in the 2-mg/kg groups, both of which were considered adverse events of special interest. There were no deaths.

However none of the serious adverse events – which included infected AD, palpitations, patent ductus arteriosus, and food allergy – were linked to the study treatment, and no adverse events led to study discontinuation, the authors reported.

By week 12, 70% of participants in the 2-mg/kg group and 75% in the 4-mg/kg group had achieved a 50% or greater improvement in their Eczema Area and Severity Index (EASI) scores, which was a secondary outcome. By week 52, that had increased to 100% and 89% respectively.

More than half the patients (55%) in the 2-mg/kg group, and 40% of those in the 4-mg/kg group achieved a 75% or more improvement in their EASI scores by week 12, which increased to 88% and 78%, respectively, by week 52 in the open label phase.

“The results from these studies support use of dupilumab for the long-term management of moderate to severe AD in adolescents,” wrote Michael J. Cork, MD, professor of dermatology, University of Sheffield, England, and coauthors. No new safety signals were identified, “compared with the known safety profile of dupilumab in adults with moderate to severe AD,” and “the PK profile was characterized by nonlinear, target-mediated kinetics, consistent with the profile in adults with moderate to severe AD,” they added.

Dupilumab was approved in the United States in March 2019 for adolescents with moderate to severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

The study was sponsored by dupilumab manufacturers Sanofi and Regeneron Pharmaceuticals, which market dupilumab as Dupixent in the United States. Dr. Cork disclosures included those related to Sanofi Genzyme and Regeneron; other authors included employees of the companies.

SOURCE: Cork M et al. Br J Dermatol. 2019 Oct 9. doi: 10.1111/bjd.18476.

A study of dupilumab in adolescents with atopic dermatitis (AD) has provided longer term efficacy and safety data, with no new safety signals and continued evidence of efficacy for up to 52 weeks, reported the authors of the study, published online Oct. 9 in the British Journal of Dermatology.

The phase 2a open-label, ascending-dose cohort study of dupilumab in 40 adolescents with moderate to severe AD was followed by a 48-week phase 3 open-label extension study in 36 of those participants. Dupilumab is a monoclonal antibody that inhibits signaling of interleukin (IL)-4 and IL-13.

In the phase 2a study, participants were treated with a single subcutaneous dose of dupilumab – either 2 mg/kg or 4 mg/kg – and had 8 weeks of pharmacokinetic sampling. They subsequently received that same dose weekly for 4 weeks, with an 8-week-long safety follow-up period. Those who participated in the open-label extension continued their weekly dose to a maximum of 300 mg. per kg

The most common treatment-emergent adverse events (a primary endpoint) seen in both the phase 2a and phase 3 studies were nasopharyngitis and exacerbation of AD – in the phase 2a study, exacerbations were seen in the period when patients weren’t taking the treatment. In the 2-mg and 4-mg groups, the incidence of skin infections was 29% and 42%, respectively, and the incidence of injection site reactions – which were mostly mild – were 18% and 11%, respectively. Researchers also noted conjunctivitis in 18% and 16% of the patients in the 2-mg and 4-mg groups, respectively, but none of the cases were considered serious and all resolved over the course of the study. In the phase 2a study, 50% of patients on the 2-mg/kg dose and 65% of those on the 4-mg/kg dose experienced an adverse event, while in the open-label extension all reported at least one adverse event.

There was one case of suicidal behavior and one case of systemic or severe hypersensitivity reported in the 2-mg/kg groups, both of which were considered adverse events of special interest. There were no deaths.

However none of the serious adverse events – which included infected AD, palpitations, patent ductus arteriosus, and food allergy – were linked to the study treatment, and no adverse events led to study discontinuation, the authors reported.

By week 12, 70% of participants in the 2-mg/kg group and 75% in the 4-mg/kg group had achieved a 50% or greater improvement in their Eczema Area and Severity Index (EASI) scores, which was a secondary outcome. By week 52, that had increased to 100% and 89% respectively.

More than half the patients (55%) in the 2-mg/kg group, and 40% of those in the 4-mg/kg group achieved a 75% or more improvement in their EASI scores by week 12, which increased to 88% and 78%, respectively, by week 52 in the open label phase.

“The results from these studies support use of dupilumab for the long-term management of moderate to severe AD in adolescents,” wrote Michael J. Cork, MD, professor of dermatology, University of Sheffield, England, and coauthors. No new safety signals were identified, “compared with the known safety profile of dupilumab in adults with moderate to severe AD,” and “the PK profile was characterized by nonlinear, target-mediated kinetics, consistent with the profile in adults with moderate to severe AD,” they added.

Dupilumab was approved in the United States in March 2019 for adolescents with moderate to severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

The study was sponsored by dupilumab manufacturers Sanofi and Regeneron Pharmaceuticals, which market dupilumab as Dupixent in the United States. Dr. Cork disclosures included those related to Sanofi Genzyme and Regeneron; other authors included employees of the companies.

SOURCE: Cork M et al. Br J Dermatol. 2019 Oct 9. doi: 10.1111/bjd.18476.

A study of dupilumab in adolescents with atopic dermatitis (AD) has provided longer term efficacy and safety data, with no new safety signals and continued evidence of efficacy for up to 52 weeks, reported the authors of the study, published online Oct. 9 in the British Journal of Dermatology.

The phase 2a open-label, ascending-dose cohort study of dupilumab in 40 adolescents with moderate to severe AD was followed by a 48-week phase 3 open-label extension study in 36 of those participants. Dupilumab is a monoclonal antibody that inhibits signaling of interleukin (IL)-4 and IL-13.

In the phase 2a study, participants were treated with a single subcutaneous dose of dupilumab – either 2 mg/kg or 4 mg/kg – and had 8 weeks of pharmacokinetic sampling. They subsequently received that same dose weekly for 4 weeks, with an 8-week-long safety follow-up period. Those who participated in the open-label extension continued their weekly dose to a maximum of 300 mg. per kg

The most common treatment-emergent adverse events (a primary endpoint) seen in both the phase 2a and phase 3 studies were nasopharyngitis and exacerbation of AD – in the phase 2a study, exacerbations were seen in the period when patients weren’t taking the treatment. In the 2-mg and 4-mg groups, the incidence of skin infections was 29% and 42%, respectively, and the incidence of injection site reactions – which were mostly mild – were 18% and 11%, respectively. Researchers also noted conjunctivitis in 18% and 16% of the patients in the 2-mg and 4-mg groups, respectively, but none of the cases were considered serious and all resolved over the course of the study. In the phase 2a study, 50% of patients on the 2-mg/kg dose and 65% of those on the 4-mg/kg dose experienced an adverse event, while in the open-label extension all reported at least one adverse event.

There was one case of suicidal behavior and one case of systemic or severe hypersensitivity reported in the 2-mg/kg groups, both of which were considered adverse events of special interest. There were no deaths.

However none of the serious adverse events – which included infected AD, palpitations, patent ductus arteriosus, and food allergy – were linked to the study treatment, and no adverse events led to study discontinuation, the authors reported.

By week 12, 70% of participants in the 2-mg/kg group and 75% in the 4-mg/kg group had achieved a 50% or greater improvement in their Eczema Area and Severity Index (EASI) scores, which was a secondary outcome. By week 52, that had increased to 100% and 89% respectively.

More than half the patients (55%) in the 2-mg/kg group, and 40% of those in the 4-mg/kg group achieved a 75% or more improvement in their EASI scores by week 12, which increased to 88% and 78%, respectively, by week 52 in the open label phase.

“The results from these studies support use of dupilumab for the long-term management of moderate to severe AD in adolescents,” wrote Michael J. Cork, MD, professor of dermatology, University of Sheffield, England, and coauthors. No new safety signals were identified, “compared with the known safety profile of dupilumab in adults with moderate to severe AD,” and “the PK profile was characterized by nonlinear, target-mediated kinetics, consistent with the profile in adults with moderate to severe AD,” they added.

Dupilumab was approved in the United States in March 2019 for adolescents with moderate to severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

The study was sponsored by dupilumab manufacturers Sanofi and Regeneron Pharmaceuticals, which market dupilumab as Dupixent in the United States. Dr. Cork disclosures included those related to Sanofi Genzyme and Regeneron; other authors included employees of the companies.

SOURCE: Cork M et al. Br J Dermatol. 2019 Oct 9. doi: 10.1111/bjd.18476.

Pregnant women taking oral corticosteroids for rheumatoid arthritis may be at increased risk of preterm birth, according to research published online Sept. 30 in Rheumatology.

Antonio_Diaz/Thinkstock

A study of 528 pregnant women with rheumatoid arthritis enrolled in the MotherToBaby Pregnancy Studies found that those taking a daily dose of 10 mg or more of prednisone equivalent – representing a mean cumulative dose of 2,208.6 mg over the first 139 days of pregnancy – had 4.77-fold higher odds of preterm birth, compared with those not taking oral corticosteroids. Women on medium doses – with a mean cumulative dose of 883 mg – had 81% higher odds of preterm birth, while those on low cumulative doses of 264.9 mg showed a nonsignificant 38% increase in preterm birth risk.

Women who did not use oral corticosteroids before day 140 of pregnancy had a 2.2% risk of early preterm birth. Among women with low use of oral corticosteroids, the risk was 3.4%, among those with medium use the risk was 3.3%, but among those with high use the risk was 26.7%.

After day 140 of gestation, there was a nonsignificant 64% increase in the risk for preterm birth with any use of oral corticosteroids, compared with no use. But among women taking 10 mg or more of prednisone equivalent per day, the risk was 2.45-fold higher, whereas those taking under 10 mg showed no significant increase in risk.

“Systemic corticosteroid use has been associated with serious infection in pregnant women and serious and nonserious infection in individuals with autoimmune diseases, independent of other immunosuppressive medications, especially for doses of 10 mg of prednisone equivalent per day and greater,” wrote Kristin Palmsten, ScD, a research investigator with HealthPartners Institute in Minneapolis, Minn., and coauthors.

Given that intrauterine infection is believed to contribute to preterm birth, some have suggested that the immunosuppressive effects of oral corticosteroids could be associated with an increased risk of preterm birth because of subclinical intra-amniotic infection, they wrote.

However, they noted that there was a lack of information on the effect of dose and timing of oral corticosteroids during pregnancy on the risk of preterm birth.

The authors acknowledged that dosage of oral corticosteroids during pregnancy was linked to disease activity, which was itself associated with preterm birth risk. They adjusted for self-assessed rheumatoid arthritis severity at enrollment, which was generally during the first trimester, and found that this did attenuate the association with preterm birth.

“Ideally, we would have measures of disease severity at the time of every medication start, stop, or dose change to account for time-varying confounding later in pregnancy,” they wrote.

The study did not find any effect of biologic or nonbiologic disease-modifying antirheumatic drugs, either before or after the first 140 days of gestation.

The authors also looked at pregnancy outcomes among women with inflammatory bowel disease and asthma who were taking corticosteroids for those conditions.

While noting that these estimates were “imprecise,” they did see the suggestion of an increase in preterm birth among women taking oral corticosteroids for asthma, especially when used in the first half of pregnancy. There was also a suggestion of increased preterm birth risk associated with high oral corticosteroid use for inflammatory bowel disease, but these estimates were unadjusted, they noted.

“Overall, IBD and asthma exploratory analyses align with the direction of the associations in the RA analysis despite limitations of precision and inability to adjust for IBD severity,” they wrote.

The conclusions to be drawn from the study are limited by its small size, the investigators noted, as well as a lack of information on the type of rheumatoid arthritis and longitudinal disease severity. They added that while the hypothesized mechanism of action linking oral corticosteroid use to preterm birth was subclinical intrauterine infection, they did not have access to placental pathology to confirm this.

The study was supported by the National Institutes of Health, and the MotherToBaby Pregnancy Studies are supported by research grants from a number of pharmaceutical companies. No other conflicts of interest were declared.

SOURCE: Palmsten K et al. Rheumatology 2019 Sep 30. doi: 10.1093/rheumatology/kez405.

Pregnant women taking oral corticosteroids for rheumatoid arthritis may be at increased risk of preterm birth, according to research published online Sept. 30 in Rheumatology.

Antonio_Diaz/Thinkstock

A study of 528 pregnant women with rheumatoid arthritis enrolled in the MotherToBaby Pregnancy Studies found that those taking a daily dose of 10 mg or more of prednisone equivalent – representing a mean cumulative dose of 2,208.6 mg over the first 139 days of pregnancy – had 4.77-fold higher odds of preterm birth, compared with those not taking oral corticosteroids. Women on medium doses – with a mean cumulative dose of 883 mg – had 81% higher odds of preterm birth, while those on low cumulative doses of 264.9 mg showed a nonsignificant 38% increase in preterm birth risk.

Women who did not use oral corticosteroids before day 140 of pregnancy had a 2.2% risk of early preterm birth. Among women with low use of oral corticosteroids, the risk was 3.4%, among those with medium use the risk was 3.3%, but among those with high use the risk was 26.7%.

After day 140 of gestation, there was a nonsignificant 64% increase in the risk for preterm birth with any use of oral corticosteroids, compared with no use. But among women taking 10 mg or more of prednisone equivalent per day, the risk was 2.45-fold higher, whereas those taking under 10 mg showed no significant increase in risk.

“Systemic corticosteroid use has been associated with serious infection in pregnant women and serious and nonserious infection in individuals with autoimmune diseases, independent of other immunosuppressive medications, especially for doses of 10 mg of prednisone equivalent per day and greater,” wrote Kristin Palmsten, ScD, a research investigator with HealthPartners Institute in Minneapolis, Minn., and coauthors.

Given that intrauterine infection is believed to contribute to preterm birth, some have suggested that the immunosuppressive effects of oral corticosteroids could be associated with an increased risk of preterm birth because of subclinical intra-amniotic infection, they wrote.

However, they noted that there was a lack of information on the effect of dose and timing of oral corticosteroids during pregnancy on the risk of preterm birth.

The authors acknowledged that dosage of oral corticosteroids during pregnancy was linked to disease activity, which was itself associated with preterm birth risk. They adjusted for self-assessed rheumatoid arthritis severity at enrollment, which was generally during the first trimester, and found that this did attenuate the association with preterm birth.

“Ideally, we would have measures of disease severity at the time of every medication start, stop, or dose change to account for time-varying confounding later in pregnancy,” they wrote.

The study did not find any effect of biologic or nonbiologic disease-modifying antirheumatic drugs, either before or after the first 140 days of gestation.

The authors also looked at pregnancy outcomes among women with inflammatory bowel disease and asthma who were taking corticosteroids for those conditions.

While noting that these estimates were “imprecise,” they did see the suggestion of an increase in preterm birth among women taking oral corticosteroids for asthma, especially when used in the first half of pregnancy. There was also a suggestion of increased preterm birth risk associated with high oral corticosteroid use for inflammatory bowel disease, but these estimates were unadjusted, they noted.

“Overall, IBD and asthma exploratory analyses align with the direction of the associations in the RA analysis despite limitations of precision and inability to adjust for IBD severity,” they wrote.

The conclusions to be drawn from the study are limited by its small size, the investigators noted, as well as a lack of information on the type of rheumatoid arthritis and longitudinal disease severity. They added that while the hypothesized mechanism of action linking oral corticosteroid use to preterm birth was subclinical intrauterine infection, they did not have access to placental pathology to confirm this.

The study was supported by the National Institutes of Health, and the MotherToBaby Pregnancy Studies are supported by research grants from a number of pharmaceutical companies. No other conflicts of interest were declared.

SOURCE: Palmsten K et al. Rheumatology 2019 Sep 30. doi: 10.1093/rheumatology/kez405.

Pregnant women taking oral corticosteroids for rheumatoid arthritis may be at increased risk of preterm birth, according to research published online Sept. 30 in Rheumatology.

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A study of 528 pregnant women with rheumatoid arthritis enrolled in the MotherToBaby Pregnancy Studies found that those taking a daily dose of 10 mg or more of prednisone equivalent – representing a mean cumulative dose of 2,208.6 mg over the first 139 days of pregnancy – had 4.77-fold higher odds of preterm birth, compared with those not taking oral corticosteroids. Women on medium doses – with a mean cumulative dose of 883 mg – had 81% higher odds of preterm birth, while those on low cumulative doses of 264.9 mg showed a nonsignificant 38% increase in preterm birth risk.

Women who did not use oral corticosteroids before day 140 of pregnancy had a 2.2% risk of early preterm birth. Among women with low use of oral corticosteroids, the risk was 3.4%, among those with medium use the risk was 3.3%, but among those with high use the risk was 26.7%.

After day 140 of gestation, there was a nonsignificant 64% increase in the risk for preterm birth with any use of oral corticosteroids, compared with no use. But among women taking 10 mg or more of prednisone equivalent per day, the risk was 2.45-fold higher, whereas those taking under 10 mg showed no significant increase in risk.

“Systemic corticosteroid use has been associated with serious infection in pregnant women and serious and nonserious infection in individuals with autoimmune diseases, independent of other immunosuppressive medications, especially for doses of 10 mg of prednisone equivalent per day and greater,” wrote Kristin Palmsten, ScD, a research investigator with HealthPartners Institute in Minneapolis, Minn., and coauthors.

Given that intrauterine infection is believed to contribute to preterm birth, some have suggested that the immunosuppressive effects of oral corticosteroids could be associated with an increased risk of preterm birth because of subclinical intra-amniotic infection, they wrote.

However, they noted that there was a lack of information on the effect of dose and timing of oral corticosteroids during pregnancy on the risk of preterm birth.

The authors acknowledged that dosage of oral corticosteroids during pregnancy was linked to disease activity, which was itself associated with preterm birth risk. They adjusted for self-assessed rheumatoid arthritis severity at enrollment, which was generally during the first trimester, and found that this did attenuate the association with preterm birth.

“Ideally, we would have measures of disease severity at the time of every medication start, stop, or dose change to account for time-varying confounding later in pregnancy,” they wrote.

The study did not find any effect of biologic or nonbiologic disease-modifying antirheumatic drugs, either before or after the first 140 days of gestation.

The authors also looked at pregnancy outcomes among women with inflammatory bowel disease and asthma who were taking corticosteroids for those conditions.

While noting that these estimates were “imprecise,” they did see the suggestion of an increase in preterm birth among women taking oral corticosteroids for asthma, especially when used in the first half of pregnancy. There was also a suggestion of increased preterm birth risk associated with high oral corticosteroid use for inflammatory bowel disease, but these estimates were unadjusted, they noted.

“Overall, IBD and asthma exploratory analyses align with the direction of the associations in the RA analysis despite limitations of precision and inability to adjust for IBD severity,” they wrote.

The conclusions to be drawn from the study are limited by its small size, the investigators noted, as well as a lack of information on the type of rheumatoid arthritis and longitudinal disease severity. They added that while the hypothesized mechanism of action linking oral corticosteroid use to preterm birth was subclinical intrauterine infection, they did not have access to placental pathology to confirm this.

The study was supported by the National Institutes of Health, and the MotherToBaby Pregnancy Studies are supported by research grants from a number of pharmaceutical companies. No other conflicts of interest were declared.

SOURCE: Palmsten K et al. Rheumatology 2019 Sep 30. doi: 10.1093/rheumatology/kez405.

A study of 305 cases of acute flaccid myelitis has found further evidence of a viral etiology but is yet to identify a single pathogen as the primary cause.

Writing in Pediatrics, researchers published an analysis of patients presenting with acute flaccid limb weakness from January 2015 to December 2017 across 43 states.

A total of 25 cases were judged as probable for acute flaccid myelitis (AFM) because they met clinical criteria and had a white blood cell count above 5 cells per mm³ in cerebrospinal fluid, while 193 were judged as confirmed cases based on the additional presence of spinal cord gray matter lesions on MRI.

Overall, 83% of patients had experienced fever, cough, runny nose, vomiting, and/or diarrhea for a median of 5 days before limb weakness began. Two-thirds of patients had experienced a respiratory illness, 62% had experienced a fever, and 29% had experienced gastrointestinal illness.

Overall, 47% of the 193 patients who had specimens tested at a Centers for Disease Control and Prevention or non-CDC laboratory had a pathogen found at any site, 10% had a pathogen detected from a sterile site such as cerebrospinal fluid or sera, and 42% had a pathogen detected from a nonsterile site.

Among 72 patients who had serum specimens tested at the CDC, 2 were positive for enteroviruses. Among the 90 patients who had upper respiratory specimens tested, 36% were positive for either enteroviruses or rhinoviruses.

A number of stool specimens were also tested; 15% were positive for enteroviruses or rhinoviruses and one was positive for parechovirus.

Cerebrospinal fluid was tested in 170 patients, of which 4 were positive for enteroviruses. The testing also found adenovirus, Epstein-Barr virus, human herpesvirus 6, and mycoplasma in six patients. Sera testing of 123 patients found 9 were positive for enteroviruses, West Nile virus, mycoplasma, and coxsackievirus B.

“In our summary of national AFM surveillance from 2015 to 2017, we demonstrate that cases were widely distributed across the United States, the majority of cases occurred in late summer or fall, children were predominantly affected, there is a spectrum of clinical severity, and no single pathogen was identified as the primary cause of AFM,” wrote Tracy Ayers, PhD, from the National Center for Immunization and Respiratory Diseases, and coauthors. “We conclude that symptoms of a viral syndrome within the week before limb weakness, detection of viral pathogens from sterile and nonsterile sites from almost half of patients, and seasonality of AFM incidence, particularly during the 2016 peak year, strongly suggest a viral etiology, including [enteroviruses].”

The authors of an accompanying editorial noted that the clinical syndrome of acute flaccid paralysis caused by myelitis in the gray matter of the spinal cord has previously been associated with a range of viruses, including poliovirus, enteroviruses, and flaviviruses, so a single etiology to explain all cases would not be expected.

“The central question remains: What is driving seasonal biennial nationwide outbreaks of AFM since 2014?” wrote Kevin Messaca, MD, and colleagues from the University of Colorado at Denver, Aurora.

Two authors declared consultancies, grants, and research contracts with the pharmaceutical sector. No other conflicts of interest were declared. One editorial author declared funding from the National Institute of Allergy and Infectious Diseases.

SOURCE: Ayers T et al. Pediatrics. 2019 Oct 7. doi: 10.1542/peds.2019-1619.

*Updated 10/14/2019.

A study of 305 cases of acute flaccid myelitis has found further evidence of a viral etiology but is yet to identify a single pathogen as the primary cause.

Writing in Pediatrics, researchers published an analysis of patients presenting with acute flaccid limb weakness from January 2015 to December 2017 across 43 states.

A total of 25 cases were judged as probable for acute flaccid myelitis (AFM) because they met clinical criteria and had a white blood cell count above 5 cells per mm³ in cerebrospinal fluid, while 193 were judged as confirmed cases based on the additional presence of spinal cord gray matter lesions on MRI.

Overall, 83% of patients had experienced fever, cough, runny nose, vomiting, and/or diarrhea for a median of 5 days before limb weakness began. Two-thirds of patients had experienced a respiratory illness, 62% had experienced a fever, and 29% had experienced gastrointestinal illness.

Overall, 47% of the 193 patients who had specimens tested at a Centers for Disease Control and Prevention or non-CDC laboratory had a pathogen found at any site, 10% had a pathogen detected from a sterile site such as cerebrospinal fluid or sera, and 42% had a pathogen detected from a nonsterile site.

Among 72 patients who had serum specimens tested at the CDC, 2 were positive for enteroviruses. Among the 90 patients who had upper respiratory specimens tested, 36% were positive for either enteroviruses or rhinoviruses.

A number of stool specimens were also tested; 15% were positive for enteroviruses or rhinoviruses and one was positive for parechovirus.

Cerebrospinal fluid was tested in 170 patients, of which 4 were positive for enteroviruses. The testing also found adenovirus, Epstein-Barr virus, human herpesvirus 6, and mycoplasma in six patients. Sera testing of 123 patients found 9 were positive for enteroviruses, West Nile virus, mycoplasma, and coxsackievirus B.

“In our summary of national AFM surveillance from 2015 to 2017, we demonstrate that cases were widely distributed across the United States, the majority of cases occurred in late summer or fall, children were predominantly affected, there is a spectrum of clinical severity, and no single pathogen was identified as the primary cause of AFM,” wrote Tracy Ayers, PhD, from the National Center for Immunization and Respiratory Diseases, and coauthors. “We conclude that symptoms of a viral syndrome within the week before limb weakness, detection of viral pathogens from sterile and nonsterile sites from almost half of patients, and seasonality of AFM incidence, particularly during the 2016 peak year, strongly suggest a viral etiology, including [enteroviruses].”

The authors of an accompanying editorial noted that the clinical syndrome of acute flaccid paralysis caused by myelitis in the gray matter of the spinal cord has previously been associated with a range of viruses, including poliovirus, enteroviruses, and flaviviruses, so a single etiology to explain all cases would not be expected.

“The central question remains: What is driving seasonal biennial nationwide outbreaks of AFM since 2014?” wrote Kevin Messaca, MD, and colleagues from the University of Colorado at Denver, Aurora.

Two authors declared consultancies, grants, and research contracts with the pharmaceutical sector. No other conflicts of interest were declared. One editorial author declared funding from the National Institute of Allergy and Infectious Diseases.

SOURCE: Ayers T et al. Pediatrics. 2019 Oct 7. doi: 10.1542/peds.2019-1619.

*Updated 10/14/2019.

A study of 305 cases of acute flaccid myelitis has found further evidence of a viral etiology but is yet to identify a single pathogen as the primary cause.

Writing in Pediatrics, researchers published an analysis of patients presenting with acute flaccid limb weakness from January 2015 to December 2017 across 43 states.

A total of 25 cases were judged as probable for acute flaccid myelitis (AFM) because they met clinical criteria and had a white blood cell count above 5 cells per mm³ in cerebrospinal fluid, while 193 were judged as confirmed cases based on the additional presence of spinal cord gray matter lesions on MRI.

Overall, 83% of patients had experienced fever, cough, runny nose, vomiting, and/or diarrhea for a median of 5 days before limb weakness began. Two-thirds of patients had experienced a respiratory illness, 62% had experienced a fever, and 29% had experienced gastrointestinal illness.

Overall, 47% of the 193 patients who had specimens tested at a Centers for Disease Control and Prevention or non-CDC laboratory had a pathogen found at any site, 10% had a pathogen detected from a sterile site such as cerebrospinal fluid or sera, and 42% had a pathogen detected from a nonsterile site.

Among 72 patients who had serum specimens tested at the CDC, 2 were positive for enteroviruses. Among the 90 patients who had upper respiratory specimens tested, 36% were positive for either enteroviruses or rhinoviruses.

A number of stool specimens were also tested; 15% were positive for enteroviruses or rhinoviruses and one was positive for parechovirus.

Cerebrospinal fluid was tested in 170 patients, of which 4 were positive for enteroviruses. The testing also found adenovirus, Epstein-Barr virus, human herpesvirus 6, and mycoplasma in six patients. Sera testing of 123 patients found 9 were positive for enteroviruses, West Nile virus, mycoplasma, and coxsackievirus B.

“In our summary of national AFM surveillance from 2015 to 2017, we demonstrate that cases were widely distributed across the United States, the majority of cases occurred in late summer or fall, children were predominantly affected, there is a spectrum of clinical severity, and no single pathogen was identified as the primary cause of AFM,” wrote Tracy Ayers, PhD, from the National Center for Immunization and Respiratory Diseases, and coauthors. “We conclude that symptoms of a viral syndrome within the week before limb weakness, detection of viral pathogens from sterile and nonsterile sites from almost half of patients, and seasonality of AFM incidence, particularly during the 2016 peak year, strongly suggest a viral etiology, including [enteroviruses].”

The authors of an accompanying editorial noted that the clinical syndrome of acute flaccid paralysis caused by myelitis in the gray matter of the spinal cord has previously been associated with a range of viruses, including poliovirus, enteroviruses, and flaviviruses, so a single etiology to explain all cases would not be expected.

“The central question remains: What is driving seasonal biennial nationwide outbreaks of AFM since 2014?” wrote Kevin Messaca, MD, and colleagues from the University of Colorado at Denver, Aurora.

Two authors declared consultancies, grants, and research contracts with the pharmaceutical sector. No other conflicts of interest were declared. One editorial author declared funding from the National Institute of Allergy and Infectious Diseases.

SOURCE: Ayers T et al. Pediatrics. 2019 Oct 7. doi: 10.1542/peds.2019-1619.

*Updated 10/14/2019.

Recurrent invasive pneumococcal disease in children could be a signal of underlying primary immunodeficiency, according to a systematic review published in JAMA Pediatrics.

Coen Butters, BMed, DCH, of the Royal Children’s Hospital in Melbourne, and coauthors wrote that, even with optimal vaccine coverage, there is still a group of children with increased susceptibility to invasive pneumococcal disease (IPD), and this could be a potential marker of primary immunodeficiency.

They conducted a systematic review of 17 studies of 6,002 children to examine the evidence on the incidence of primary immunodeficiency in children who presented with IPD but without any other risk factors or predisposing conditions.

Overall, the frequency of primary immunodeficiency in children presenting with IPD who did not have any other predisposing condition ranged from 1% to 26%.

One study of 162 children with IPD, which had an overall frequency of primary immunodeficiency of 10%, found that children older than 2 years were significantly more likely to have primary immunodeficiency than those aged under 2 years (26% vs. 3%; P less than .001).

Primary antibody deficiency was the most commonly diagnosed immunodeficiency in these children with IPD, accounting for 71% of cases. These deficiencies presented as hypogammaglobulinemia, specific pneumococcal antibody deficiency, X-linked agammaglobulinemia, and IgG2 deficiency.

The review also included four studies that looked at the frequency of mannose-binding lectin deficiency in 1,493 children with primary IPD. Two of these studies reported a prevalence of mannose-binding lectin deficiency ranging from 31% in children aged younger than 2 years to 41% in children younger than 1 year.

Five studies looked at the rate of primary immunodeficiency in children presenting with recurrent IPD. In addition to other predisposing conditions such as sickle cell disease, cancer, and anatomical breach in the blood-brain barrier, the three studies that screened for primary immunodeficiency found rates ranging from 10% to 67%. The most common conditions were complement deficiency, pneumococcal antibody deficiency, and a single case of TLR-signaling defect.

In a study of 162 children with primary IPD, screening for asplenia identified a single case of congenital asplenia. In another study of 2,498 cases of IPD, 22 patients had asplenia at presentation, half of whom died at presentation.

Dr. Butters and associates concluded that “this review’s findings suggests that existing data support the immune evaluation of children older than 2 years without a known predisposing condition who present with their first episode of Streptococcus pneumoniae meningitis, pneumonia, or recurrent IPD. Immune evaluation should include assessment for immunoglobulin deficiency, pneumococcal antibody deficiency, complement disorders, and asplenia.”

In an accompanying editorial, Stephen I. Pelton, MD, of the Maxwell Finland Laboratory for Infectious Diseases at Boston Medical Center, and coauthors wrote that in children with recurrent episodes of IPD caused by nonvaccine serotypes – particularly those aged over 5 years – evaluation for primary immunodeficiencies could uncover immune defects.

“Once identified, direct and indirect protection, penicillin prophylaxis, or a combination of these offers great potential for disease prevention and reduction of mortality and morbidity in children with [primary immunodeficiency],” they wrote.

No funding or conflicts of interest were declared for the study. Two of the editorialists declared research funding or honoraria from the pharmaceutical sector.

SOURCES: Butters C et al. JAMA Pediatr. 2019 Sep 30. doi: 10.1001/jamapediatrics.2019.3203; Pelton SI et al. JAMA Pediatr. 2019 Sep 30. doi: 10.1001/jamapediatrics.2019.3185.

Recurrent invasive pneumococcal disease in children could be a signal of underlying primary immunodeficiency, according to a systematic review published in JAMA Pediatrics.

Coen Butters, BMed, DCH, of the Royal Children’s Hospital in Melbourne, and coauthors wrote that, even with optimal vaccine coverage, there is still a group of children with increased susceptibility to invasive pneumococcal disease (IPD), and this could be a potential marker of primary immunodeficiency.

They conducted a systematic review of 17 studies of 6,002 children to examine the evidence on the incidence of primary immunodeficiency in children who presented with IPD but without any other risk factors or predisposing conditions.

Overall, the frequency of primary immunodeficiency in children presenting with IPD who did not have any other predisposing condition ranged from 1% to 26%.

One study of 162 children with IPD, which had an overall frequency of primary immunodeficiency of 10%, found that children older than 2 years were significantly more likely to have primary immunodeficiency than those aged under 2 years (26% vs. 3%; P less than .001).

Primary antibody deficiency was the most commonly diagnosed immunodeficiency in these children with IPD, accounting for 71% of cases. These deficiencies presented as hypogammaglobulinemia, specific pneumococcal antibody deficiency, X-linked agammaglobulinemia, and IgG2 deficiency.

The review also included four studies that looked at the frequency of mannose-binding lectin deficiency in 1,493 children with primary IPD. Two of these studies reported a prevalence of mannose-binding lectin deficiency ranging from 31% in children aged younger than 2 years to 41% in children younger than 1 year.

Five studies looked at the rate of primary immunodeficiency in children presenting with recurrent IPD. In addition to other predisposing conditions such as sickle cell disease, cancer, and anatomical breach in the blood-brain barrier, the three studies that screened for primary immunodeficiency found rates ranging from 10% to 67%. The most common conditions were complement deficiency, pneumococcal antibody deficiency, and a single case of TLR-signaling defect.

In a study of 162 children with primary IPD, screening for asplenia identified a single case of congenital asplenia. In another study of 2,498 cases of IPD, 22 patients had asplenia at presentation, half of whom died at presentation.

Dr. Butters and associates concluded that “this review’s findings suggests that existing data support the immune evaluation of children older than 2 years without a known predisposing condition who present with their first episode of Streptococcus pneumoniae meningitis, pneumonia, or recurrent IPD. Immune evaluation should include assessment for immunoglobulin deficiency, pneumococcal antibody deficiency, complement disorders, and asplenia.”

In an accompanying editorial, Stephen I. Pelton, MD, of the Maxwell Finland Laboratory for Infectious Diseases at Boston Medical Center, and coauthors wrote that in children with recurrent episodes of IPD caused by nonvaccine serotypes – particularly those aged over 5 years – evaluation for primary immunodeficiencies could uncover immune defects.

“Once identified, direct and indirect protection, penicillin prophylaxis, or a combination of these offers great potential for disease prevention and reduction of mortality and morbidity in children with [primary immunodeficiency],” they wrote.

No funding or conflicts of interest were declared for the study. Two of the editorialists declared research funding or honoraria from the pharmaceutical sector.

SOURCES: Butters C et al. JAMA Pediatr. 2019 Sep 30. doi: 10.1001/jamapediatrics.2019.3203; Pelton SI et al. JAMA Pediatr. 2019 Sep 30. doi: 10.1001/jamapediatrics.2019.3185.

Recurrent invasive pneumococcal disease in children could be a signal of underlying primary immunodeficiency, according to a systematic review published in JAMA Pediatrics.

Coen Butters, BMed, DCH, of the Royal Children’s Hospital in Melbourne, and coauthors wrote that, even with optimal vaccine coverage, there is still a group of children with increased susceptibility to invasive pneumococcal disease (IPD), and this could be a potential marker of primary immunodeficiency.

They conducted a systematic review of 17 studies of 6,002 children to examine the evidence on the incidence of primary immunodeficiency in children who presented with IPD but without any other risk factors or predisposing conditions.

Overall, the frequency of primary immunodeficiency in children presenting with IPD who did not have any other predisposing condition ranged from 1% to 26%.

One study of 162 children with IPD, which had an overall frequency of primary immunodeficiency of 10%, found that children older than 2 years were significantly more likely to have primary immunodeficiency than those aged under 2 years (26% vs. 3%; P less than .001).

Primary antibody deficiency was the most commonly diagnosed immunodeficiency in these children with IPD, accounting for 71% of cases. These deficiencies presented as hypogammaglobulinemia, specific pneumococcal antibody deficiency, X-linked agammaglobulinemia, and IgG2 deficiency.

The review also included four studies that looked at the frequency of mannose-binding lectin deficiency in 1,493 children with primary IPD. Two of these studies reported a prevalence of mannose-binding lectin deficiency ranging from 31% in children aged younger than 2 years to 41% in children younger than 1 year.

Five studies looked at the rate of primary immunodeficiency in children presenting with recurrent IPD. In addition to other predisposing conditions such as sickle cell disease, cancer, and anatomical breach in the blood-brain barrier, the three studies that screened for primary immunodeficiency found rates ranging from 10% to 67%. The most common conditions were complement deficiency, pneumococcal antibody deficiency, and a single case of TLR-signaling defect.

In a study of 162 children with primary IPD, screening for asplenia identified a single case of congenital asplenia. In another study of 2,498 cases of IPD, 22 patients had asplenia at presentation, half of whom died at presentation.

Dr. Butters and associates concluded that “this review’s findings suggests that existing data support the immune evaluation of children older than 2 years without a known predisposing condition who present with their first episode of Streptococcus pneumoniae meningitis, pneumonia, or recurrent IPD. Immune evaluation should include assessment for immunoglobulin deficiency, pneumococcal antibody deficiency, complement disorders, and asplenia.”

In an accompanying editorial, Stephen I. Pelton, MD, of the Maxwell Finland Laboratory for Infectious Diseases at Boston Medical Center, and coauthors wrote that in children with recurrent episodes of IPD caused by nonvaccine serotypes – particularly those aged over 5 years – evaluation for primary immunodeficiencies could uncover immune defects.

“Once identified, direct and indirect protection, penicillin prophylaxis, or a combination of these offers great potential for disease prevention and reduction of mortality and morbidity in children with [primary immunodeficiency],” they wrote.

No funding or conflicts of interest were declared for the study. Two of the editorialists declared research funding or honoraria from the pharmaceutical sector.

SOURCES: Butters C et al. JAMA Pediatr. 2019 Sep 30. doi: 10.1001/jamapediatrics.2019.3203; Pelton SI et al. JAMA Pediatr. 2019 Sep 30. doi: 10.1001/jamapediatrics.2019.3185.

Relatively few of the adverse health outcomes attributed to antidepressants are supported by convincing evidence, reported the authors of a systematic review of 45 meta-analyses.

The authors did find convincing evidence linking the use of antidepressants and suicide attempt or completion among people under age 19 years and use of the medication and autism risk among offspring. “However, the few [studies] with convincing evidence associations did not reflect causality, and none of them remained at the convincing evidence level after accounting for confounding by indication,” wrote Elena Dragioti, PhD, of the Pain and Rehabilitation Centre at Linköping (Sweden) University and coauthors. The study was published in JAMA Psychiatry.

Dr. Dragioti and coauthors undertook a systematic “umbrella review” grading the evidence from the 45 meta-analyses of 695 observational studies into the association between antidepressant use and the risk of adverse health outcomes. All the meta-analyses included a control group not exposed to antidepressants, with the exception of one that compared the risk of gastrointestinal bleeding between two classes of antidepressants.

They found 120 possible adverse health associations described in the meta-analyses, 61.7% of which related to maternal and pregnancy-related adverse health outcomes. Two-thirds of the adverse health outcome associations involved selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

However, among the 120 adverse health associations, only three (2.5%) were supported by “convincing” evidence. One was the association between SSRIs and increased risk of suicide attempts and completion in children and adolescents. Convincing evidence also was found between any antidepressant use before pregnancy and autism spectrum disorder and between SSRI use during pregnancy and autism spectrum disorder. The evidence for the association with suicide risk was deemed high quality, but the two associations with autism spectrum disorder were only of moderate quality.

The authors commented that these findings needed to be considered when prescribing antidepressants in adolescents and children, particularly as another networked meta-analysis had found fluoxetine was the only antidepressant that worked better than placebo in children and adolescents. “In addition, the increased suicidality in children and adolescents who use antidepressants may be associated with the unsuccessful reduction of depressive symptoms in suicidal individuals rather than a direct result of antidepressant use,” they wrote.

The review found that 11 adverse health outcomes (9.2%) had “highly suggestive” evidence linking them to antidepressant use. These were ADHD in children, cataract development, severe bleeding at any site, upper gastrointestinal tract bleeding, postpartum hemorrhage, preterm birth, lower Apgar score at 5 minutes, osteoporotic fracture, and hip fracture.

Seven of those – ADHD in children, lower Apgar score, severe bleeding at any site, cataract development, osteoporotic features, preterm birth, and upper GI bleeding – had moderate-quality evidence. However, the authors noted that the effect sizes were small and had low prevalence.

The study also found highly suggestive evidence linking antidepressant use to a decreased risk of suicide attempts or completion in adults.

The authors said several of those adverse events in adults, such as GI bleeding and osteoporotic fractures, could be prevented with medication, so the advantages of antidepressant use in adults could outweigh the disadvantage of those preventable safety issues.

Twenty-one adverse health outcomes showed either suggestive, weak, or no evidence for their association with antidepressant use.

They also conducted a sensitivity analysis that limited the analysis to cohort studies, prospective cohort studies, studies that controlled for confounding by the treatment indication, and studies from North America. This showed that none of the associations for which there was originally deemed to be convincing evidence retained that same rank.

“Overall, the results showed that the association between antidepressant use and adverse health outcomes was not supported by robust evidence and that the underlying disease likely inflated the findings in a relevant way,” the authors wrote.

However, when they looked solely at prospective cohort studies, the association between preterm birth and use of any antidepressant was upgraded to having convincing evidence.

When the analysis focused on SSRIs only, the association with lower Apgar scores at 5 minutes also was upgraded to having convincing evidence. Similarly, the evidence for an association with preterm birth also was found to be convincing when the analysis was limited to other or mixed antidepressants.

Dr. Dragioti and coauthors cited several limitations, including the inability of some randomized, controlled trials to address adverse outcomes.

“Antidepressant use appears to be safe for the treatment of psychiatric disorders, but more studies matching for underlying disease are needed to clarify the degree of confounding by indication and other biases,” the authors wrote.

The study was funded by several entities, including the National Institute for Health Research’s Biomedical Research Centre at South London and Maudsley NHS Foundation Trust. Dr. Dragioti reported no disclosures. Four authors declared funding, consultancies, personal fees, royalties, or shares in the pharmaceutical sector. No other conflicts of interest were declared.

SOURCE: Dragioti E et al. JAMA Psychiatry. 2019 Oct 2. doi: 10.1001/jamapsychiatry.2019.2859.

Relatively few of the adverse health outcomes attributed to antidepressants are supported by convincing evidence, reported the authors of a systematic review of 45 meta-analyses.

The authors did find convincing evidence linking the use of antidepressants and suicide attempt or completion among people under age 19 years and use of the medication and autism risk among offspring. “However, the few [studies] with convincing evidence associations did not reflect causality, and none of them remained at the convincing evidence level after accounting for confounding by indication,” wrote Elena Dragioti, PhD, of the Pain and Rehabilitation Centre at Linköping (Sweden) University and coauthors. The study was published in JAMA Psychiatry.

Dr. Dragioti and coauthors undertook a systematic “umbrella review” grading the evidence from the 45 meta-analyses of 695 observational studies into the association between antidepressant use and the risk of adverse health outcomes. All the meta-analyses included a control group not exposed to antidepressants, with the exception of one that compared the risk of gastrointestinal bleeding between two classes of antidepressants.

They found 120 possible adverse health associations described in the meta-analyses, 61.7% of which related to maternal and pregnancy-related adverse health outcomes. Two-thirds of the adverse health outcome associations involved selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

However, among the 120 adverse health associations, only three (2.5%) were supported by “convincing” evidence. One was the association between SSRIs and increased risk of suicide attempts and completion in children and adolescents. Convincing evidence also was found between any antidepressant use before pregnancy and autism spectrum disorder and between SSRI use during pregnancy and autism spectrum disorder. The evidence for the association with suicide risk was deemed high quality, but the two associations with autism spectrum disorder were only of moderate quality.

The authors commented that these findings needed to be considered when prescribing antidepressants in adolescents and children, particularly as another networked meta-analysis had found fluoxetine was the only antidepressant that worked better than placebo in children and adolescents. “In addition, the increased suicidality in children and adolescents who use antidepressants may be associated with the unsuccessful reduction of depressive symptoms in suicidal individuals rather than a direct result of antidepressant use,” they wrote.

The review found that 11 adverse health outcomes (9.2%) had “highly suggestive” evidence linking them to antidepressant use. These were ADHD in children, cataract development, severe bleeding at any site, upper gastrointestinal tract bleeding, postpartum hemorrhage, preterm birth, lower Apgar score at 5 minutes, osteoporotic fracture, and hip fracture.

Seven of those – ADHD in children, lower Apgar score, severe bleeding at any site, cataract development, osteoporotic features, preterm birth, and upper GI bleeding – had moderate-quality evidence. However, the authors noted that the effect sizes were small and had low prevalence.

The study also found highly suggestive evidence linking antidepressant use to a decreased risk of suicide attempts or completion in adults.

The authors said several of those adverse events in adults, such as GI bleeding and osteoporotic fractures, could be prevented with medication, so the advantages of antidepressant use in adults could outweigh the disadvantage of those preventable safety issues.

Twenty-one adverse health outcomes showed either suggestive, weak, or no evidence for their association with antidepressant use.

They also conducted a sensitivity analysis that limited the analysis to cohort studies, prospective cohort studies, studies that controlled for confounding by the treatment indication, and studies from North America. This showed that none of the associations for which there was originally deemed to be convincing evidence retained that same rank.

“Overall, the results showed that the association between antidepressant use and adverse health outcomes was not supported by robust evidence and that the underlying disease likely inflated the findings in a relevant way,” the authors wrote.

However, when they looked solely at prospective cohort studies, the association between preterm birth and use of any antidepressant was upgraded to having convincing evidence.

When the analysis focused on SSRIs only, the association with lower Apgar scores at 5 minutes also was upgraded to having convincing evidence. Similarly, the evidence for an association with preterm birth also was found to be convincing when the analysis was limited to other or mixed antidepressants.

Dr. Dragioti and coauthors cited several limitations, including the inability of some randomized, controlled trials to address adverse outcomes.

“Antidepressant use appears to be safe for the treatment of psychiatric disorders, but more studies matching for underlying disease are needed to clarify the degree of confounding by indication and other biases,” the authors wrote.

The study was funded by several entities, including the National Institute for Health Research’s Biomedical Research Centre at South London and Maudsley NHS Foundation Trust. Dr. Dragioti reported no disclosures. Four authors declared funding, consultancies, personal fees, royalties, or shares in the pharmaceutical sector. No other conflicts of interest were declared.

SOURCE: Dragioti E et al. JAMA Psychiatry. 2019 Oct 2. doi: 10.1001/jamapsychiatry.2019.2859.

Relatively few of the adverse health outcomes attributed to antidepressants are supported by convincing evidence, reported the authors of a systematic review of 45 meta-analyses.

The authors did find convincing evidence linking the use of antidepressants and suicide attempt or completion among people under age 19 years and use of the medication and autism risk among offspring. “However, the few [studies] with convincing evidence associations did not reflect causality, and none of them remained at the convincing evidence level after accounting for confounding by indication,” wrote Elena Dragioti, PhD, of the Pain and Rehabilitation Centre at Linköping (Sweden) University and coauthors. The study was published in JAMA Psychiatry.

Dr. Dragioti and coauthors undertook a systematic “umbrella review” grading the evidence from the 45 meta-analyses of 695 observational studies into the association between antidepressant use and the risk of adverse health outcomes. All the meta-analyses included a control group not exposed to antidepressants, with the exception of one that compared the risk of gastrointestinal bleeding between two classes of antidepressants.

They found 120 possible adverse health associations described in the meta-analyses, 61.7% of which related to maternal and pregnancy-related adverse health outcomes. Two-thirds of the adverse health outcome associations involved selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

However, among the 120 adverse health associations, only three (2.5%) were supported by “convincing” evidence. One was the association between SSRIs and increased risk of suicide attempts and completion in children and adolescents. Convincing evidence also was found between any antidepressant use before pregnancy and autism spectrum disorder and between SSRI use during pregnancy and autism spectrum disorder. The evidence for the association with suicide risk was deemed high quality, but the two associations with autism spectrum disorder were only of moderate quality.

The authors commented that these findings needed to be considered when prescribing antidepressants in adolescents and children, particularly as another networked meta-analysis had found fluoxetine was the only antidepressant that worked better than placebo in children and adolescents. “In addition, the increased suicidality in children and adolescents who use antidepressants may be associated with the unsuccessful reduction of depressive symptoms in suicidal individuals rather than a direct result of antidepressant use,” they wrote.

The review found that 11 adverse health outcomes (9.2%) had “highly suggestive” evidence linking them to antidepressant use. These were ADHD in children, cataract development, severe bleeding at any site, upper gastrointestinal tract bleeding, postpartum hemorrhage, preterm birth, lower Apgar score at 5 minutes, osteoporotic fracture, and hip fracture.

Seven of those – ADHD in children, lower Apgar score, severe bleeding at any site, cataract development, osteoporotic features, preterm birth, and upper GI bleeding – had moderate-quality evidence. However, the authors noted that the effect sizes were small and had low prevalence.

The study also found highly suggestive evidence linking antidepressant use to a decreased risk of suicide attempts or completion in adults.

The authors said several of those adverse events in adults, such as GI bleeding and osteoporotic fractures, could be prevented with medication, so the advantages of antidepressant use in adults could outweigh the disadvantage of those preventable safety issues.

Twenty-one adverse health outcomes showed either suggestive, weak, or no evidence for their association with antidepressant use.

They also conducted a sensitivity analysis that limited the analysis to cohort studies, prospective cohort studies, studies that controlled for confounding by the treatment indication, and studies from North America. This showed that none of the associations for which there was originally deemed to be convincing evidence retained that same rank.

“Overall, the results showed that the association between antidepressant use and adverse health outcomes was not supported by robust evidence and that the underlying disease likely inflated the findings in a relevant way,” the authors wrote.

However, when they looked solely at prospective cohort studies, the association between preterm birth and use of any antidepressant was upgraded to having convincing evidence.

When the analysis focused on SSRIs only, the association with lower Apgar scores at 5 minutes also was upgraded to having convincing evidence. Similarly, the evidence for an association with preterm birth also was found to be convincing when the analysis was limited to other or mixed antidepressants.

Dr. Dragioti and coauthors cited several limitations, including the inability of some randomized, controlled trials to address adverse outcomes.

“Antidepressant use appears to be safe for the treatment of psychiatric disorders, but more studies matching for underlying disease are needed to clarify the degree of confounding by indication and other biases,” the authors wrote.

The study was funded by several entities, including the National Institute for Health Research’s Biomedical Research Centre at South London and Maudsley NHS Foundation Trust. Dr. Dragioti reported no disclosures. Four authors declared funding, consultancies, personal fees, royalties, or shares in the pharmaceutical sector. No other conflicts of interest were declared.

SOURCE: Dragioti E et al. JAMA Psychiatry. 2019 Oct 2. doi: 10.1001/jamapsychiatry.2019.2859.