People who mostly ate foods with a low glycemic index had a lower likelihood of premature death and major cardiovascular disease (CVD) events, compared with those whose diet included more “poor-quality” food with a high glycemic index.

The results from the global PURE study of nearly 120,000 people provide evidence that helps cement glycemic index as a key measure of dietary health.

This new analysis from PURE (Prospective Urban and Rural Epidemiological Study) – a massive prospective epidemiologic study – shows people with a diet in the highest quintile of glycemic index had a significant 25% higher rate of combined total deaths and major CVD events during a median follow-up of nearly 10 years, compared with those with a diet in the lowest glycemic index quintile, in the report published online on Feb. 24, 2021, in the New England Journal of Medicine.

David J.A. Jenkins, MD, PhD, DSc, lead author, said people do not necessarily need to closely track the glycemic index of what they eat to follow the guidance that lower is better.

The link between lower glycemic load and fewer CVD events was even stronger among people with an established history of CVD at study entry. In this subset, which included 9% of the total cohort, people in the highest quintile for glycemic index consumption had a 51% higher rate of the composite primary endpoint, compared with those in the lowest quintile, in an analysis that adjusted for several potential confounders.

A simple but accurate and effective public health message is to follow existing dietary recommendations to eat better-quality food – more unprocessed fruits, vegetables, legumes, and whole grains – Dr. Jenkins advised. Those who prefer a more detailed approach could use the comprehensive glycemic index tables compiled by researchers at the University of Sydney.
 

‘All carbohydrates are not the same’

“What we’re saying is that all carbohydrates are not the same. Some seem to increase the risk for CVD, and others seem protective. This is not new, but worth restating in an era of low-carb and no-carb diets,” said Dr. Jenkins.

Low-glycemic-index foods are generally unprocessed foods in their native state, including fruits, vegetables, legumes, and unrefined whole grains. High-glycemic-index foods contain processed and refined carbohydrates that deliver jolts of glucose soon after eating, as the sugar in these carbohydrates quickly moves from the gut to the bloodstream.

An association between a diet with a lower glycemic index and better outcomes had appeared in prior reports from other studies, but not as unambiguously as in the new data from PURE, likely because of fewer study participants in previous studies.

Another feature of PURE that adds to the generalizability of the findings is the diversity of adults included in the study, from 20 countries on five continents.

“This clinches it,” Dr. Jenkins declared in an interview.
 

New PURE data tip the evidence balance

The NEJM article includes a new meta-analysis that adds the PURE findings to data from two large prior reports that were each less conclusive. The new calculation with the PURE numbers helps establish a clearer association between a diet with a higher glycemic index and the endpoint of CVD death, showing an overall 26% increase in the outcome.

The PURE data are especially informative because the investigators collected additional information on a range of potential confounders they incorporated into their analyses.

“We were able to include a lot of documentation on many potential confounders. That’s a strength of our data,” noted Dr. Jenkins, a professor of nutritional science and medicine at the University of Toronto.

Higher BMI associated with greater glycemic index effect

Another important analysis in the new report calculated the impact of a higher glycemic index diet among people with a body mass index (BMI) of less than 25 kg/m2 as well as higher BMIs.

Among people in the lower BMI subgroup, greater intake of high-glycemic-index foods showed slightly more incident primary outcome events. In contrast, people with a BMI of 25 or greater showed a steady increment in primary outcome events as the glycemic index of their diet increased.

People with higher BMIs in the quartile that ate the greatest amount of high-glycemic =-index foods had a significant 38% higher rate of primary outcome events, compared with people with similar BMIs in the lowest quartile for high-glycemic-index intake.

However, the study showed no impact on the primary association of high glycemic index and increased adverse outcomes by exercise habits, smoking, use of blood pressure medications, or use of statins. 

The new report complements a separate analysis from PURE published just a few weeks earlier in the BMJ that established a significant association between increased consumption of whole grains and fewer CVD events, compared with people who had more refined grains in their diet, as reported by this news organization.

This prior report on whole versus refined grains, which Dr. Jenkins coauthored, looked at carbohydrate quality using a two-pronged approach, while glycemic index is a continuous variable that provides more nuance and takes into account carbohydrates from sources other than grains, Dr. Jenkins said.

PURE enrolled roughly 225,000 people aged 35-70 years at entry. The glycemic index analysis focused on 119,575 people who had data available for the primary outcome. During a median follow-up of 9.5 years, these people had 14,075 primary outcome events, including 8,780 deaths.

Analyses that looked at the individual outcomes that comprised the composite endpoint showed significant associations between a high-glycemic-index diet and total mortality, CVD death, non-CVD death, and stroke, but showed no significant link with myocardial infarction or heart failure. These findings are consistent with prior results of other studies that showed a stronger link between stroke and a high glycemic index diet, compared with other nonfatal CVD events.

Dr. Jenkins suggested that the significant excess of non-CVD deaths linked with a high-glycemic-index diet may stem from the impact of this type of diet on cancer-associated mortality.

PURE received partial funding through unrestricted grants from several drug companies. Dr. Jenkins has reported receiving gifts from several food-related trade associations and food companies, as well as research grants from two legume-oriented trade associations.

A version of this article first appeared on Medscape.com.

People who mostly ate foods with a low glycemic index had a lower likelihood of premature death and major cardiovascular disease (CVD) events, compared with those whose diet included more “poor-quality” food with a high glycemic index.

The results from the global PURE study of nearly 120,000 people provide evidence that helps cement glycemic index as a key measure of dietary health.

This new analysis from PURE (Prospective Urban and Rural Epidemiological Study) – a massive prospective epidemiologic study – shows people with a diet in the highest quintile of glycemic index had a significant 25% higher rate of combined total deaths and major CVD events during a median follow-up of nearly 10 years, compared with those with a diet in the lowest glycemic index quintile, in the report published online on Feb. 24, 2021, in the New England Journal of Medicine.

David J.A. Jenkins, MD, PhD, DSc, lead author, said people do not necessarily need to closely track the glycemic index of what they eat to follow the guidance that lower is better.

The link between lower glycemic load and fewer CVD events was even stronger among people with an established history of CVD at study entry. In this subset, which included 9% of the total cohort, people in the highest quintile for glycemic index consumption had a 51% higher rate of the composite primary endpoint, compared with those in the lowest quintile, in an analysis that adjusted for several potential confounders.

A simple but accurate and effective public health message is to follow existing dietary recommendations to eat better-quality food – more unprocessed fruits, vegetables, legumes, and whole grains – Dr. Jenkins advised. Those who prefer a more detailed approach could use the comprehensive glycemic index tables compiled by researchers at the University of Sydney.
 

‘All carbohydrates are not the same’

“What we’re saying is that all carbohydrates are not the same. Some seem to increase the risk for CVD, and others seem protective. This is not new, but worth restating in an era of low-carb and no-carb diets,” said Dr. Jenkins.

Low-glycemic-index foods are generally unprocessed foods in their native state, including fruits, vegetables, legumes, and unrefined whole grains. High-glycemic-index foods contain processed and refined carbohydrates that deliver jolts of glucose soon after eating, as the sugar in these carbohydrates quickly moves from the gut to the bloodstream.

An association between a diet with a lower glycemic index and better outcomes had appeared in prior reports from other studies, but not as unambiguously as in the new data from PURE, likely because of fewer study participants in previous studies.

Another feature of PURE that adds to the generalizability of the findings is the diversity of adults included in the study, from 20 countries on five continents.

“This clinches it,” Dr. Jenkins declared in an interview.
 

New PURE data tip the evidence balance

The NEJM article includes a new meta-analysis that adds the PURE findings to data from two large prior reports that were each less conclusive. The new calculation with the PURE numbers helps establish a clearer association between a diet with a higher glycemic index and the endpoint of CVD death, showing an overall 26% increase in the outcome.

The PURE data are especially informative because the investigators collected additional information on a range of potential confounders they incorporated into their analyses.

“We were able to include a lot of documentation on many potential confounders. That’s a strength of our data,” noted Dr. Jenkins, a professor of nutritional science and medicine at the University of Toronto.

Higher BMI associated with greater glycemic index effect

Another important analysis in the new report calculated the impact of a higher glycemic index diet among people with a body mass index (BMI) of less than 25 kg/m2 as well as higher BMIs.

Among people in the lower BMI subgroup, greater intake of high-glycemic-index foods showed slightly more incident primary outcome events. In contrast, people with a BMI of 25 or greater showed a steady increment in primary outcome events as the glycemic index of their diet increased.

People with higher BMIs in the quartile that ate the greatest amount of high-glycemic =-index foods had a significant 38% higher rate of primary outcome events, compared with people with similar BMIs in the lowest quartile for high-glycemic-index intake.

However, the study showed no impact on the primary association of high glycemic index and increased adverse outcomes by exercise habits, smoking, use of blood pressure medications, or use of statins. 

The new report complements a separate analysis from PURE published just a few weeks earlier in the BMJ that established a significant association between increased consumption of whole grains and fewer CVD events, compared with people who had more refined grains in their diet, as reported by this news organization.

This prior report on whole versus refined grains, which Dr. Jenkins coauthored, looked at carbohydrate quality using a two-pronged approach, while glycemic index is a continuous variable that provides more nuance and takes into account carbohydrates from sources other than grains, Dr. Jenkins said.

PURE enrolled roughly 225,000 people aged 35-70 years at entry. The glycemic index analysis focused on 119,575 people who had data available for the primary outcome. During a median follow-up of 9.5 years, these people had 14,075 primary outcome events, including 8,780 deaths.

Analyses that looked at the individual outcomes that comprised the composite endpoint showed significant associations between a high-glycemic-index diet and total mortality, CVD death, non-CVD death, and stroke, but showed no significant link with myocardial infarction or heart failure. These findings are consistent with prior results of other studies that showed a stronger link between stroke and a high glycemic index diet, compared with other nonfatal CVD events.

Dr. Jenkins suggested that the significant excess of non-CVD deaths linked with a high-glycemic-index diet may stem from the impact of this type of diet on cancer-associated mortality.

PURE received partial funding through unrestricted grants from several drug companies. Dr. Jenkins has reported receiving gifts from several food-related trade associations and food companies, as well as research grants from two legume-oriented trade associations.

A version of this article first appeared on Medscape.com.

People who mostly ate foods with a low glycemic index had a lower likelihood of premature death and major cardiovascular disease (CVD) events, compared with those whose diet included more “poor-quality” food with a high glycemic index.

The results from the global PURE study of nearly 120,000 people provide evidence that helps cement glycemic index as a key measure of dietary health.

This new analysis from PURE (Prospective Urban and Rural Epidemiological Study) – a massive prospective epidemiologic study – shows people with a diet in the highest quintile of glycemic index had a significant 25% higher rate of combined total deaths and major CVD events during a median follow-up of nearly 10 years, compared with those with a diet in the lowest glycemic index quintile, in the report published online on Feb. 24, 2021, in the New England Journal of Medicine.

David J.A. Jenkins, MD, PhD, DSc, lead author, said people do not necessarily need to closely track the glycemic index of what they eat to follow the guidance that lower is better.

The link between lower glycemic load and fewer CVD events was even stronger among people with an established history of CVD at study entry. In this subset, which included 9% of the total cohort, people in the highest quintile for glycemic index consumption had a 51% higher rate of the composite primary endpoint, compared with those in the lowest quintile, in an analysis that adjusted for several potential confounders.

A simple but accurate and effective public health message is to follow existing dietary recommendations to eat better-quality food – more unprocessed fruits, vegetables, legumes, and whole grains – Dr. Jenkins advised. Those who prefer a more detailed approach could use the comprehensive glycemic index tables compiled by researchers at the University of Sydney.
 

‘All carbohydrates are not the same’

“What we’re saying is that all carbohydrates are not the same. Some seem to increase the risk for CVD, and others seem protective. This is not new, but worth restating in an era of low-carb and no-carb diets,” said Dr. Jenkins.

Low-glycemic-index foods are generally unprocessed foods in their native state, including fruits, vegetables, legumes, and unrefined whole grains. High-glycemic-index foods contain processed and refined carbohydrates that deliver jolts of glucose soon after eating, as the sugar in these carbohydrates quickly moves from the gut to the bloodstream.

An association between a diet with a lower glycemic index and better outcomes had appeared in prior reports from other studies, but not as unambiguously as in the new data from PURE, likely because of fewer study participants in previous studies.

Another feature of PURE that adds to the generalizability of the findings is the diversity of adults included in the study, from 20 countries on five continents.

“This clinches it,” Dr. Jenkins declared in an interview.
 

New PURE data tip the evidence balance

The NEJM article includes a new meta-analysis that adds the PURE findings to data from two large prior reports that were each less conclusive. The new calculation with the PURE numbers helps establish a clearer association between a diet with a higher glycemic index and the endpoint of CVD death, showing an overall 26% increase in the outcome.

The PURE data are especially informative because the investigators collected additional information on a range of potential confounders they incorporated into their analyses.

“We were able to include a lot of documentation on many potential confounders. That’s a strength of our data,” noted Dr. Jenkins, a professor of nutritional science and medicine at the University of Toronto.

Higher BMI associated with greater glycemic index effect

Another important analysis in the new report calculated the impact of a higher glycemic index diet among people with a body mass index (BMI) of less than 25 kg/m2 as well as higher BMIs.

Among people in the lower BMI subgroup, greater intake of high-glycemic-index foods showed slightly more incident primary outcome events. In contrast, people with a BMI of 25 or greater showed a steady increment in primary outcome events as the glycemic index of their diet increased.

People with higher BMIs in the quartile that ate the greatest amount of high-glycemic =-index foods had a significant 38% higher rate of primary outcome events, compared with people with similar BMIs in the lowest quartile for high-glycemic-index intake.

However, the study showed no impact on the primary association of high glycemic index and increased adverse outcomes by exercise habits, smoking, use of blood pressure medications, or use of statins. 

The new report complements a separate analysis from PURE published just a few weeks earlier in the BMJ that established a significant association between increased consumption of whole grains and fewer CVD events, compared with people who had more refined grains in their diet, as reported by this news organization.

This prior report on whole versus refined grains, which Dr. Jenkins coauthored, looked at carbohydrate quality using a two-pronged approach, while glycemic index is a continuous variable that provides more nuance and takes into account carbohydrates from sources other than grains, Dr. Jenkins said.

PURE enrolled roughly 225,000 people aged 35-70 years at entry. The glycemic index analysis focused on 119,575 people who had data available for the primary outcome. During a median follow-up of 9.5 years, these people had 14,075 primary outcome events, including 8,780 deaths.

Analyses that looked at the individual outcomes that comprised the composite endpoint showed significant associations between a high-glycemic-index diet and total mortality, CVD death, non-CVD death, and stroke, but showed no significant link with myocardial infarction or heart failure. These findings are consistent with prior results of other studies that showed a stronger link between stroke and a high glycemic index diet, compared with other nonfatal CVD events.

Dr. Jenkins suggested that the significant excess of non-CVD deaths linked with a high-glycemic-index diet may stem from the impact of this type of diet on cancer-associated mortality.

PURE received partial funding through unrestricted grants from several drug companies. Dr. Jenkins has reported receiving gifts from several food-related trade associations and food companies, as well as research grants from two legume-oriented trade associations.

A version of this article first appeared on Medscape.com.

Adding everolimus to adjuvant hormone therapy for early ER+, HER2- breast cancer does not offer any benefit over hormone therapy alone, according to results of the phase 3 UNIRAD study.

At a median follow-up of almost 3 years, rates of disease-free survival, distant metastasis-free survival, and overall survival were similar in the everolimus and hormone therapy-alone arms.

These findings were presented at the inaugural ESMO Virtual Plenary and published in Annals of Oncology.

The UNIRAD results contrast results from prior studies of everolimus in the advanced breast cancer setting. In the BOLERO-2 and BOLERO-4 studies, the mTOR inhibitor provided a progression-free survival benefit when added to hormone therapy.

“There clearly is rationale for targeted therapy in early ER+, HER2- breast cancer,” said Rebecca Dent, MD, of the National Cancer Center in Singapore, who chaired the ESMO Virtual Plenary in which the UNIRAD findings were presented.

“Patients with high-risk luminal breast cancer clearly have an unmet need. We probably still underestimate the risk of early and late recurrences, and chemotherapy is not necessarily the answer,” Dr. Dent said.

She observed that a lot has been learned about the mTOR pathway, including how complicated it is and its role in endocrine resistance. Since mTOR inhibition was standard care in the metastatic setting, “it really is appropriate now to test in early breast cancer,” she added.

Study details

The aim of the UNIRAD study was to compare the efficacy and safety of everolimus plus standard adjuvant hormone therapy to hormone therapy alone in women with ER+, HER2- early breast cancer who had a high risk of recurrence. High risk was defined as having more than four positive nodes, having one or more positive nodes after neoadjuvant chemotherapy or hormone therapy, or having one or more positive nodes and an EPclin score of 3.3 or higher.

The trial enrolled 1,278 patients. At baseline, their median age was 54 years (range, 48-63), 65.8% were postmenopausal, and 52.7% had four or more positive nodes.

The patients were randomized 1:1 to receive 2 years of everolimus plus hormone therapy or placebo plus hormone therapy. The type of hormone therapy was investigor’s choice.

Investigator Thomas Bachelot, MD, PhD, of Centre Leon Berard in Lyon, France, noted that the study started in 2013 and underwent several protocol amendments, first for accrual problems and then because of toxicity. This led to dropping the starting dose of everolimus from 10 mg to 5 mg.

“Acceptability was a concern; 50% of our patients stopped everolimus before study completion for toxicity or personal decision,” Dr. Bachelot acknowledged.

Grade 3 or higher adverse events were more frequent in patients taking everolimus (29.9%) than placebo (15.9%) in combination with hormone therapy. The rates of serious adverse events were a respective 11.8% and 9.3%.

Mucositis was one of the main adverse events, occurring in more than half of all patients treated with everolimus (33.8% grade 1, 25.4% grade 2, and 7.4% grade 3/4). The success of managing this side effect with a dexamethasone mouthwash was not known at the time of the UNIRAD trial design.

The study also showed no benefit of everolimus over placebo for the following efficacy outcomes:

• Disease-free survival – 88% and 89%, respectively (hazard ratio, 0.95; 95% confidence interval, 0.69-1.32; P = .78)
• Distant metastasis-free survival – 91% and 90%, respectively (HR, 0.88; 95% CI, 0.62-1.25)
• Overall survival – both 96% (HR, 1.09; 95% CI, 0.62-1.92).

With the exception of patients who had received tamoxifen rather than an aromatase inhibitor, a preplanned subgroup analysis suggested there was no population of patients who benefited from the addition of everolimus.
 

Problems interpreting data

There are several problems in interpreting the UNIRAD data, observed study discussant Peter Schmid, MD, PhD, of St. Bartholomew’s Hospital & Barts Cancer Institute in London.

For one, “whether we like it or not,” the trial was underpowered, he said. This was because the trial had been halted early for futility at the first interim analysis when about two-thirds of the intended study cohort had been accrued.

In addition, Dr. Schmid said, this is clearly not a trial that included patients with primary endocrine resistance. In all, 43% of patients had received less than 1 year of endocrine treatment, 42% had received 2-3 years, and 15% had received more than 3 years of endocrine treatment.

Dr. Schmid said that the starting dose of everolimus had to be lowered because of toxicity or poor acceptance. “As a result, two-thirds of patients received a 5-mg dose, and we don’t know whether that had an impact on efficacy,” he said.

Furthermore, the median time on treatment was less than half of what was initially planned, and 53% of patients had to stop everolimus before the end of the study.

Dr. Schmid noted that this discontinuation rate is higher than that seen in trials of CDK4/6 inhibitors added to endocrine treatment. Dropout rates were 19% in the negative Penelope-B trial with palbociclib, 42% in the negative PALLAS trial with palbociclib, and 27% in the positive monarchE trial with abemaciclib.

With such a high discontinuation rate in the UNIRAD trial, “we’re not sure whether we can ultimately evaluate really whether this trial did work,” Dr. Schmid said.

“Could the results change over time?” he asked. “I personally think it is unlikely, as the trial clearly has already an adequate follow-up for what it was supposed to show.”

Looking at whether the trial’s hypothesis is still valid, he added: “I think that is unclear to all of us, and we need to work out whether these compounds are cytostatic in nature, or cytotoxic. And that is something we need to learn over time.”

Commending the study overall, Dr. Schmid observed: “I think it was an excellent trial design based on what we knew at that time,” and the design “was changed in a pragmatic way because of recruitment challenges.”

Something for the future would be to select patients for such trials based on the tumor biology rather than risk status, Dr. Schmid suggested. “That is something we may have to take into consideration with our increasing knowledge around primary and secondary resistance and what treatments we want to introduce to target-resistant clones,” he said.

The UNIRAD study was sponsored by UNICANCER, with funding and support from the French Ministry of Health, Cancer Research UK, Myriad Genetics (which provided Endopredict tests), and Novartis (which provided everolimus and placebo). Dr. Bachelot, Dr. Schmid, and Dr. Dent disclosed relationships with Novartis and several other pharmaceutical companies.

Adding everolimus to adjuvant hormone therapy for early ER+, HER2- breast cancer does not offer any benefit over hormone therapy alone, according to results of the phase 3 UNIRAD study.

At a median follow-up of almost 3 years, rates of disease-free survival, distant metastasis-free survival, and overall survival were similar in the everolimus and hormone therapy-alone arms.

These findings were presented at the inaugural ESMO Virtual Plenary and published in Annals of Oncology.

The UNIRAD results contrast results from prior studies of everolimus in the advanced breast cancer setting. In the BOLERO-2 and BOLERO-4 studies, the mTOR inhibitor provided a progression-free survival benefit when added to hormone therapy.

“There clearly is rationale for targeted therapy in early ER+, HER2- breast cancer,” said Rebecca Dent, MD, of the National Cancer Center in Singapore, who chaired the ESMO Virtual Plenary in which the UNIRAD findings were presented.

“Patients with high-risk luminal breast cancer clearly have an unmet need. We probably still underestimate the risk of early and late recurrences, and chemotherapy is not necessarily the answer,” Dr. Dent said.

She observed that a lot has been learned about the mTOR pathway, including how complicated it is and its role in endocrine resistance. Since mTOR inhibition was standard care in the metastatic setting, “it really is appropriate now to test in early breast cancer,” she added.

Study details

The aim of the UNIRAD study was to compare the efficacy and safety of everolimus plus standard adjuvant hormone therapy to hormone therapy alone in women with ER+, HER2- early breast cancer who had a high risk of recurrence. High risk was defined as having more than four positive nodes, having one or more positive nodes after neoadjuvant chemotherapy or hormone therapy, or having one or more positive nodes and an EPclin score of 3.3 or higher.

The trial enrolled 1,278 patients. At baseline, their median age was 54 years (range, 48-63), 65.8% were postmenopausal, and 52.7% had four or more positive nodes.

The patients were randomized 1:1 to receive 2 years of everolimus plus hormone therapy or placebo plus hormone therapy. The type of hormone therapy was investigor’s choice.

Investigator Thomas Bachelot, MD, PhD, of Centre Leon Berard in Lyon, France, noted that the study started in 2013 and underwent several protocol amendments, first for accrual problems and then because of toxicity. This led to dropping the starting dose of everolimus from 10 mg to 5 mg.

“Acceptability was a concern; 50% of our patients stopped everolimus before study completion for toxicity or personal decision,” Dr. Bachelot acknowledged.

Grade 3 or higher adverse events were more frequent in patients taking everolimus (29.9%) than placebo (15.9%) in combination with hormone therapy. The rates of serious adverse events were a respective 11.8% and 9.3%.

Mucositis was one of the main adverse events, occurring in more than half of all patients treated with everolimus (33.8% grade 1, 25.4% grade 2, and 7.4% grade 3/4). The success of managing this side effect with a dexamethasone mouthwash was not known at the time of the UNIRAD trial design.

The study also showed no benefit of everolimus over placebo for the following efficacy outcomes:

• Disease-free survival – 88% and 89%, respectively (hazard ratio, 0.95; 95% confidence interval, 0.69-1.32; P = .78)
• Distant metastasis-free survival – 91% and 90%, respectively (HR, 0.88; 95% CI, 0.62-1.25)
• Overall survival – both 96% (HR, 1.09; 95% CI, 0.62-1.92).

With the exception of patients who had received tamoxifen rather than an aromatase inhibitor, a preplanned subgroup analysis suggested there was no population of patients who benefited from the addition of everolimus.
 

Problems interpreting data

There are several problems in interpreting the UNIRAD data, observed study discussant Peter Schmid, MD, PhD, of St. Bartholomew’s Hospital & Barts Cancer Institute in London.

For one, “whether we like it or not,” the trial was underpowered, he said. This was because the trial had been halted early for futility at the first interim analysis when about two-thirds of the intended study cohort had been accrued.

In addition, Dr. Schmid said, this is clearly not a trial that included patients with primary endocrine resistance. In all, 43% of patients had received less than 1 year of endocrine treatment, 42% had received 2-3 years, and 15% had received more than 3 years of endocrine treatment.

Dr. Schmid said that the starting dose of everolimus had to be lowered because of toxicity or poor acceptance. “As a result, two-thirds of patients received a 5-mg dose, and we don’t know whether that had an impact on efficacy,” he said.

Furthermore, the median time on treatment was less than half of what was initially planned, and 53% of patients had to stop everolimus before the end of the study.

Dr. Schmid noted that this discontinuation rate is higher than that seen in trials of CDK4/6 inhibitors added to endocrine treatment. Dropout rates were 19% in the negative Penelope-B trial with palbociclib, 42% in the negative PALLAS trial with palbociclib, and 27% in the positive monarchE trial with abemaciclib.

With such a high discontinuation rate in the UNIRAD trial, “we’re not sure whether we can ultimately evaluate really whether this trial did work,” Dr. Schmid said.

“Could the results change over time?” he asked. “I personally think it is unlikely, as the trial clearly has already an adequate follow-up for what it was supposed to show.”

Looking at whether the trial’s hypothesis is still valid, he added: “I think that is unclear to all of us, and we need to work out whether these compounds are cytostatic in nature, or cytotoxic. And that is something we need to learn over time.”

Commending the study overall, Dr. Schmid observed: “I think it was an excellent trial design based on what we knew at that time,” and the design “was changed in a pragmatic way because of recruitment challenges.”

Something for the future would be to select patients for such trials based on the tumor biology rather than risk status, Dr. Schmid suggested. “That is something we may have to take into consideration with our increasing knowledge around primary and secondary resistance and what treatments we want to introduce to target-resistant clones,” he said.

The UNIRAD study was sponsored by UNICANCER, with funding and support from the French Ministry of Health, Cancer Research UK, Myriad Genetics (which provided Endopredict tests), and Novartis (which provided everolimus and placebo). Dr. Bachelot, Dr. Schmid, and Dr. Dent disclosed relationships with Novartis and several other pharmaceutical companies.

Adding everolimus to adjuvant hormone therapy for early ER+, HER2- breast cancer does not offer any benefit over hormone therapy alone, according to results of the phase 3 UNIRAD study.

At a median follow-up of almost 3 years, rates of disease-free survival, distant metastasis-free survival, and overall survival were similar in the everolimus and hormone therapy-alone arms.

These findings were presented at the inaugural ESMO Virtual Plenary and published in Annals of Oncology.

The UNIRAD results contrast results from prior studies of everolimus in the advanced breast cancer setting. In the BOLERO-2 and BOLERO-4 studies, the mTOR inhibitor provided a progression-free survival benefit when added to hormone therapy.

“There clearly is rationale for targeted therapy in early ER+, HER2- breast cancer,” said Rebecca Dent, MD, of the National Cancer Center in Singapore, who chaired the ESMO Virtual Plenary in which the UNIRAD findings were presented.

“Patients with high-risk luminal breast cancer clearly have an unmet need. We probably still underestimate the risk of early and late recurrences, and chemotherapy is not necessarily the answer,” Dr. Dent said.

She observed that a lot has been learned about the mTOR pathway, including how complicated it is and its role in endocrine resistance. Since mTOR inhibition was standard care in the metastatic setting, “it really is appropriate now to test in early breast cancer,” she added.

Study details

The aim of the UNIRAD study was to compare the efficacy and safety of everolimus plus standard adjuvant hormone therapy to hormone therapy alone in women with ER+, HER2- early breast cancer who had a high risk of recurrence. High risk was defined as having more than four positive nodes, having one or more positive nodes after neoadjuvant chemotherapy or hormone therapy, or having one or more positive nodes and an EPclin score of 3.3 or higher.

The trial enrolled 1,278 patients. At baseline, their median age was 54 years (range, 48-63), 65.8% were postmenopausal, and 52.7% had four or more positive nodes.

The patients were randomized 1:1 to receive 2 years of everolimus plus hormone therapy or placebo plus hormone therapy. The type of hormone therapy was investigor’s choice.

Investigator Thomas Bachelot, MD, PhD, of Centre Leon Berard in Lyon, France, noted that the study started in 2013 and underwent several protocol amendments, first for accrual problems and then because of toxicity. This led to dropping the starting dose of everolimus from 10 mg to 5 mg.

“Acceptability was a concern; 50% of our patients stopped everolimus before study completion for toxicity or personal decision,” Dr. Bachelot acknowledged.

Grade 3 or higher adverse events were more frequent in patients taking everolimus (29.9%) than placebo (15.9%) in combination with hormone therapy. The rates of serious adverse events were a respective 11.8% and 9.3%.

Mucositis was one of the main adverse events, occurring in more than half of all patients treated with everolimus (33.8% grade 1, 25.4% grade 2, and 7.4% grade 3/4). The success of managing this side effect with a dexamethasone mouthwash was not known at the time of the UNIRAD trial design.

The study also showed no benefit of everolimus over placebo for the following efficacy outcomes:

• Disease-free survival – 88% and 89%, respectively (hazard ratio, 0.95; 95% confidence interval, 0.69-1.32; P = .78)
• Distant metastasis-free survival – 91% and 90%, respectively (HR, 0.88; 95% CI, 0.62-1.25)
• Overall survival – both 96% (HR, 1.09; 95% CI, 0.62-1.92).

With the exception of patients who had received tamoxifen rather than an aromatase inhibitor, a preplanned subgroup analysis suggested there was no population of patients who benefited from the addition of everolimus.
 

Problems interpreting data

There are several problems in interpreting the UNIRAD data, observed study discussant Peter Schmid, MD, PhD, of St. Bartholomew’s Hospital & Barts Cancer Institute in London.

For one, “whether we like it or not,” the trial was underpowered, he said. This was because the trial had been halted early for futility at the first interim analysis when about two-thirds of the intended study cohort had been accrued.

In addition, Dr. Schmid said, this is clearly not a trial that included patients with primary endocrine resistance. In all, 43% of patients had received less than 1 year of endocrine treatment, 42% had received 2-3 years, and 15% had received more than 3 years of endocrine treatment.

Dr. Schmid said that the starting dose of everolimus had to be lowered because of toxicity or poor acceptance. “As a result, two-thirds of patients received a 5-mg dose, and we don’t know whether that had an impact on efficacy,” he said.

Furthermore, the median time on treatment was less than half of what was initially planned, and 53% of patients had to stop everolimus before the end of the study.

Dr. Schmid noted that this discontinuation rate is higher than that seen in trials of CDK4/6 inhibitors added to endocrine treatment. Dropout rates were 19% in the negative Penelope-B trial with palbociclib, 42% in the negative PALLAS trial with palbociclib, and 27% in the positive monarchE trial with abemaciclib.

With such a high discontinuation rate in the UNIRAD trial, “we’re not sure whether we can ultimately evaluate really whether this trial did work,” Dr. Schmid said.

“Could the results change over time?” he asked. “I personally think it is unlikely, as the trial clearly has already an adequate follow-up for what it was supposed to show.”

Looking at whether the trial’s hypothesis is still valid, he added: “I think that is unclear to all of us, and we need to work out whether these compounds are cytostatic in nature, or cytotoxic. And that is something we need to learn over time.”

Commending the study overall, Dr. Schmid observed: “I think it was an excellent trial design based on what we knew at that time,” and the design “was changed in a pragmatic way because of recruitment challenges.”

Something for the future would be to select patients for such trials based on the tumor biology rather than risk status, Dr. Schmid suggested. “That is something we may have to take into consideration with our increasing knowledge around primary and secondary resistance and what treatments we want to introduce to target-resistant clones,” he said.

The UNIRAD study was sponsored by UNICANCER, with funding and support from the French Ministry of Health, Cancer Research UK, Myriad Genetics (which provided Endopredict tests), and Novartis (which provided everolimus and placebo). Dr. Bachelot, Dr. Schmid, and Dr. Dent disclosed relationships with Novartis and several other pharmaceutical companies.

A casual survey of my dermatology co-residents yielded overwhelmingly unanimous results: A complete skin check goes from head to toe but does not routinely include an examination of the genital area. This observation contrasts starkly with the American Academy of Dermatology’s Basic Dermatology Curriculum, which recommends inspection of the entire skin surface including the mucous membranes (ie, eyes, mouth, anus, genital area) as part of the total-body skin examination (TBSE).¹ It even draws attention to so-called hidden areas where lesions easily can be missed, such as the perianal skin. My observation seems far from anecdotal; even a recent attempt at optimizing movements in the TBSE neglected to include examination of the genitalia in the proposed method,^2-4 and many practicing dermatologists seem to agree. A survey of international dermatologists at high-risk skin cancer clinics found male and female genitalia were the least frequently examined anatomy sites during the TBSE. Additionally, female genitalia were examined less frequently than male genitalia (labia majora, 28%; penis, 52%; P=.003).⁵ Another survey of US academic dermatologists (23 dermatologists, 1 nurse practitioner) found that only 4% always visually inspected the vulva during routine annual examinations, and 50% did not think that vulvar examination was the dermatologist’s responsibility.⁶ Similar findings were reported in a survey of US dermatology residents.⁷

Why is the genital area routinely omitted from the dermatologic TBSE? Based on the surveys of dermatologists and dermatology residents, the most common reason cited for not examining these sites was patient discomfort, but there also was a dominant belief that other specialties, such as gynecologists, urologists, or primary care providers, routinely examine these areas.^5,7 Time constraints also were a concern.

Although examination of sensitive areas can be uncomfortable,⁸ most patients still expect these locations to be examined during the TBSE. In a survey of 500 adults presenting for TBSE at an academic dermatology clinic, 84% of respondents expected the dermatologist to examine the genital area.⁹ Similarly, another survey of patient preferences (N=443) for the TBSE found that only 31.3% of women and 12.5% of men preferred not to have their genital area examined.¹⁰ As providers, we may be uncomfortable examining the genital area; however, our patients mostly expect it as part of routine practice. There are a number of barriers that may prevent incorporating the genital examination into daily dermatologic practice.

Training in Genital Examinations

Adequate training may be an issue for provider comfort when examining the genital skin. In a survey of dermatology residency program directors (n=38) and residents (n=91), 61.7% reported receiving formal instruction on TBSE technique and 38.3% reported being self-taught. Examination of the genital skin was included only 40% of the time.¹¹ Even vulvar disorder experts have admitted to receiving their training by self-teaching, with only 19% receiving vulvar training during residency and 11% during fellowship.¹² Improving this training appears to be an ongoing effort.²

Passing the Buck

It may be easier to think that another provider is routinely examining genital skin based on the relative absence of this area in dermatologic training; however, that does not appear to be the case. In a 1999 survey of primary care providers, only 31% reported performing skin cancer screenings on their adult patients, citing lack of confidence in this clinical skill as the biggest hurdle.¹³ Similarly, changes in recommendations for the utility of the screening pelvic examination in asymptomatic, average-risk, nonpregnant adult women have decreased the performance of this examination in actual practice.¹⁴ Reviews of resident training in vulvovaginal disease also have shown that although dermatology residents receive slightly less formal training hours on vulvar skin disease, they see more than double the number of patients with vulvar disease per year when compared to obstetrics and gynecology residents.¹⁵ In practice, dermatologists generally are more confident when evaluating vulvar pigmented lesions than gynecologists.⁶

The Importance of the Genital Examination

Looking past these barriers seems essential to providing the best dermatologic care, as there are a multitude of neoplastic and inflammatory dermatoses that can affect the genital skin. Furthermore, early diagnosis and treatment of these conditions potentially can limit morbidity and mortality as well as improve quality of life. Genital melanomas are a good example. Although they may be rare, it is well known that genital melanomas are associated with an aggressive disease course and have worse outcomes than melanomas found elsewhere on the body.^16,17 Increasing rates of genital and perianal keratinocyte carcinomas make including this as part of the TBSE even more important.¹⁸

We also should not forget that inflammatory conditions can routinely involve the genitals.^19-21 Although robust data are lacking, chronic vulvar concerns frequently are seen in the primary care setting. In one study in the United Kingdom, 52% of general practitioners surveyed saw more than 3 patients per month with vulvar concerns.²² Even in common dermatologic conditions such as psoriasis and lichen planus, genital involvement often is overlooked despite its relative frequency.^23-27 In one study, 60% of psoriasis patients with genital involvement had not had these lesions examined by a physician.²⁸

Theoretically, TBSEs that include genital examination would yield higher and earlier detection rates of neoplasms as well as inflammatory dermatoses.^29-32 Thus, there is real value in diagnosing ailments of the genital skin, and dermatologists are well prepared to manage these conditions. Consistently incorporating a genital examination within the TBSE is the first step.

An Approach to the Genital Skin Examination

As with the TBSE, no standardized protocol for the genital skin examination exists, and there is no consensus for how best to perform this evaluation. Ideally, both male and female patients should remove all clothing, including undergarments, though one study found patients preferred to keep undergarments on during the genital examination.^10,33,34

In general, adult female genital anatomy is best viewed with the patient in the supine position.^6,33,35 There is no clear agreement on the use of stirrups, and the decision to use these may be left to the discretion of the patient. One randomized clinical trial found that women undergoing routine gynecologic examination without stirrups reported less physical discomfort and had a reduced sense of vulnerability than women examined in stirrups.³⁶ During the female genital examination, the head of the bed ideally should be positioned at a 30° to 45° angle to allow the provider to maintain eye contact and face-to-face communication with the patient.³³ This positioning also facilitates the use of a handheld mirror to instruct patients on techniques for medication application as well as to point out sites of disease.

For adult males, the genital examination can be performed with the patient standing facing a seated examiner.³⁵ The patient’s gown should be raised to the level of the umbilicus to expose the entire genital region. Good lighting is essential. These recommendations apply mainly to adults, but helpful tips on how to approach evaluating prepubertal children in the dermatology clinic are available.³⁷

The presence of a chaperone also is optional for maximizing patient comfort but also may be helpful for providing medicolegal protection for the provider. It always should be offered regardless of patient gender. A dermatology study found that when patients were examined by a same-gender physician, women and men were more comfortable without a chaperone than with a chaperone, and patients generally preferred fewer bodies in the room during sensitive examinations.⁹

Educating Patients About the TBSE

The most helpful recommendation for successfully incorporating and performing the genital skin examination as part of the TBSE appears to be patient education. In a randomized double-arm study, patients who received pre-education consisting of written information explaining the need for a TBSE were less likely to be concerned about a genital examination compared to patients who received no information.³⁸ Discussing that skin diseases, including melanoma, can arise in all areas of the body including the genital skin and encouraging patients to perform genital self-examinations is critical.³⁵ In the age of the electronic health record and virtual communication, disseminating this information has become even easier.³⁹ It may be beneficial to explore patients’ TBSE expectations at the outset through these varied avenues to help establish a trusted physician-patient relationship.⁴⁰

Final Thoughts

Dermatologists should consistently offer a genital examination to all patients who present for a routine TBSE. Patients should be provided with adequate education to assess their comfort level for the skin examination. If a patient declines this examination, the dermatologist should ensure that another physician—be it a gynecologist, primary care provider, or other specialist—is routinely examining the area.^6,7

A casual survey of my dermatology co-residents yielded overwhelmingly unanimous results: A complete skin check goes from head to toe but does not routinely include an examination of the genital area. This observation contrasts starkly with the American Academy of Dermatology’s Basic Dermatology Curriculum, which recommends inspection of the entire skin surface including the mucous membranes (ie, eyes, mouth, anus, genital area) as part of the total-body skin examination (TBSE).¹ It even draws attention to so-called hidden areas where lesions easily can be missed, such as the perianal skin. My observation seems far from anecdotal; even a recent attempt at optimizing movements in the TBSE neglected to include examination of the genitalia in the proposed method,^2-4 and many practicing dermatologists seem to agree. A survey of international dermatologists at high-risk skin cancer clinics found male and female genitalia were the least frequently examined anatomy sites during the TBSE. Additionally, female genitalia were examined less frequently than male genitalia (labia majora, 28%; penis, 52%; P=.003).⁵ Another survey of US academic dermatologists (23 dermatologists, 1 nurse practitioner) found that only 4% always visually inspected the vulva during routine annual examinations, and 50% did not think that vulvar examination was the dermatologist’s responsibility.⁶ Similar findings were reported in a survey of US dermatology residents.⁷

Why is the genital area routinely omitted from the dermatologic TBSE? Based on the surveys of dermatologists and dermatology residents, the most common reason cited for not examining these sites was patient discomfort, but there also was a dominant belief that other specialties, such as gynecologists, urologists, or primary care providers, routinely examine these areas.^5,7 Time constraints also were a concern.

Although examination of sensitive areas can be uncomfortable,⁸ most patients still expect these locations to be examined during the TBSE. In a survey of 500 adults presenting for TBSE at an academic dermatology clinic, 84% of respondents expected the dermatologist to examine the genital area.⁹ Similarly, another survey of patient preferences (N=443) for the TBSE found that only 31.3% of women and 12.5% of men preferred not to have their genital area examined.¹⁰ As providers, we may be uncomfortable examining the genital area; however, our patients mostly expect it as part of routine practice. There are a number of barriers that may prevent incorporating the genital examination into daily dermatologic practice.

Training in Genital Examinations

Adequate training may be an issue for provider comfort when examining the genital skin. In a survey of dermatology residency program directors (n=38) and residents (n=91), 61.7% reported receiving formal instruction on TBSE technique and 38.3% reported being self-taught. Examination of the genital skin was included only 40% of the time.¹¹ Even vulvar disorder experts have admitted to receiving their training by self-teaching, with only 19% receiving vulvar training during residency and 11% during fellowship.¹² Improving this training appears to be an ongoing effort.²

Passing the Buck

It may be easier to think that another provider is routinely examining genital skin based on the relative absence of this area in dermatologic training; however, that does not appear to be the case. In a 1999 survey of primary care providers, only 31% reported performing skin cancer screenings on their adult patients, citing lack of confidence in this clinical skill as the biggest hurdle.¹³ Similarly, changes in recommendations for the utility of the screening pelvic examination in asymptomatic, average-risk, nonpregnant adult women have decreased the performance of this examination in actual practice.¹⁴ Reviews of resident training in vulvovaginal disease also have shown that although dermatology residents receive slightly less formal training hours on vulvar skin disease, they see more than double the number of patients with vulvar disease per year when compared to obstetrics and gynecology residents.¹⁵ In practice, dermatologists generally are more confident when evaluating vulvar pigmented lesions than gynecologists.⁶

The Importance of the Genital Examination

Looking past these barriers seems essential to providing the best dermatologic care, as there are a multitude of neoplastic and inflammatory dermatoses that can affect the genital skin. Furthermore, early diagnosis and treatment of these conditions potentially can limit morbidity and mortality as well as improve quality of life. Genital melanomas are a good example. Although they may be rare, it is well known that genital melanomas are associated with an aggressive disease course and have worse outcomes than melanomas found elsewhere on the body.^16,17 Increasing rates of genital and perianal keratinocyte carcinomas make including this as part of the TBSE even more important.¹⁸

We also should not forget that inflammatory conditions can routinely involve the genitals.^19-21 Although robust data are lacking, chronic vulvar concerns frequently are seen in the primary care setting. In one study in the United Kingdom, 52% of general practitioners surveyed saw more than 3 patients per month with vulvar concerns.²² Even in common dermatologic conditions such as psoriasis and lichen planus, genital involvement often is overlooked despite its relative frequency.^23-27 In one study, 60% of psoriasis patients with genital involvement had not had these lesions examined by a physician.²⁸

Theoretically, TBSEs that include genital examination would yield higher and earlier detection rates of neoplasms as well as inflammatory dermatoses.^29-32 Thus, there is real value in diagnosing ailments of the genital skin, and dermatologists are well prepared to manage these conditions. Consistently incorporating a genital examination within the TBSE is the first step.

An Approach to the Genital Skin Examination

As with the TBSE, no standardized protocol for the genital skin examination exists, and there is no consensus for how best to perform this evaluation. Ideally, both male and female patients should remove all clothing, including undergarments, though one study found patients preferred to keep undergarments on during the genital examination.^10,33,34

In general, adult female genital anatomy is best viewed with the patient in the supine position.^6,33,35 There is no clear agreement on the use of stirrups, and the decision to use these may be left to the discretion of the patient. One randomized clinical trial found that women undergoing routine gynecologic examination without stirrups reported less physical discomfort and had a reduced sense of vulnerability than women examined in stirrups.³⁶ During the female genital examination, the head of the bed ideally should be positioned at a 30° to 45° angle to allow the provider to maintain eye contact and face-to-face communication with the patient.³³ This positioning also facilitates the use of a handheld mirror to instruct patients on techniques for medication application as well as to point out sites of disease.

For adult males, the genital examination can be performed with the patient standing facing a seated examiner.³⁵ The patient’s gown should be raised to the level of the umbilicus to expose the entire genital region. Good lighting is essential. These recommendations apply mainly to adults, but helpful tips on how to approach evaluating prepubertal children in the dermatology clinic are available.³⁷

The presence of a chaperone also is optional for maximizing patient comfort but also may be helpful for providing medicolegal protection for the provider. It always should be offered regardless of patient gender. A dermatology study found that when patients were examined by a same-gender physician, women and men were more comfortable without a chaperone than with a chaperone, and patients generally preferred fewer bodies in the room during sensitive examinations.⁹

Educating Patients About the TBSE

The most helpful recommendation for successfully incorporating and performing the genital skin examination as part of the TBSE appears to be patient education. In a randomized double-arm study, patients who received pre-education consisting of written information explaining the need for a TBSE were less likely to be concerned about a genital examination compared to patients who received no information.³⁸ Discussing that skin diseases, including melanoma, can arise in all areas of the body including the genital skin and encouraging patients to perform genital self-examinations is critical.³⁵ In the age of the electronic health record and virtual communication, disseminating this information has become even easier.³⁹ It may be beneficial to explore patients’ TBSE expectations at the outset through these varied avenues to help establish a trusted physician-patient relationship.⁴⁰

Final Thoughts

Dermatologists should consistently offer a genital examination to all patients who present for a routine TBSE. Patients should be provided with adequate education to assess their comfort level for the skin examination. If a patient declines this examination, the dermatologist should ensure that another physician—be it a gynecologist, primary care provider, or other specialist—is routinely examining the area.^6,7

A casual survey of my dermatology co-residents yielded overwhelmingly unanimous results: A complete skin check goes from head to toe but does not routinely include an examination of the genital area. This observation contrasts starkly with the American Academy of Dermatology’s Basic Dermatology Curriculum, which recommends inspection of the entire skin surface including the mucous membranes (ie, eyes, mouth, anus, genital area) as part of the total-body skin examination (TBSE).¹ It even draws attention to so-called hidden areas where lesions easily can be missed, such as the perianal skin. My observation seems far from anecdotal; even a recent attempt at optimizing movements in the TBSE neglected to include examination of the genitalia in the proposed method,^2-4 and many practicing dermatologists seem to agree. A survey of international dermatologists at high-risk skin cancer clinics found male and female genitalia were the least frequently examined anatomy sites during the TBSE. Additionally, female genitalia were examined less frequently than male genitalia (labia majora, 28%; penis, 52%; P=.003).⁵ Another survey of US academic dermatologists (23 dermatologists, 1 nurse practitioner) found that only 4% always visually inspected the vulva during routine annual examinations, and 50% did not think that vulvar examination was the dermatologist’s responsibility.⁶ Similar findings were reported in a survey of US dermatology residents.⁷

Why is the genital area routinely omitted from the dermatologic TBSE? Based on the surveys of dermatologists and dermatology residents, the most common reason cited for not examining these sites was patient discomfort, but there also was a dominant belief that other specialties, such as gynecologists, urologists, or primary care providers, routinely examine these areas.^5,7 Time constraints also were a concern.

Although examination of sensitive areas can be uncomfortable,⁸ most patients still expect these locations to be examined during the TBSE. In a survey of 500 adults presenting for TBSE at an academic dermatology clinic, 84% of respondents expected the dermatologist to examine the genital area.⁹ Similarly, another survey of patient preferences (N=443) for the TBSE found that only 31.3% of women and 12.5% of men preferred not to have their genital area examined.¹⁰ As providers, we may be uncomfortable examining the genital area; however, our patients mostly expect it as part of routine practice. There are a number of barriers that may prevent incorporating the genital examination into daily dermatologic practice.

Training in Genital Examinations

Adequate training may be an issue for provider comfort when examining the genital skin. In a survey of dermatology residency program directors (n=38) and residents (n=91), 61.7% reported receiving formal instruction on TBSE technique and 38.3% reported being self-taught. Examination of the genital skin was included only 40% of the time.¹¹ Even vulvar disorder experts have admitted to receiving their training by self-teaching, with only 19% receiving vulvar training during residency and 11% during fellowship.¹² Improving this training appears to be an ongoing effort.²

Passing the Buck

It may be easier to think that another provider is routinely examining genital skin based on the relative absence of this area in dermatologic training; however, that does not appear to be the case. In a 1999 survey of primary care providers, only 31% reported performing skin cancer screenings on their adult patients, citing lack of confidence in this clinical skill as the biggest hurdle.¹³ Similarly, changes in recommendations for the utility of the screening pelvic examination in asymptomatic, average-risk, nonpregnant adult women have decreased the performance of this examination in actual practice.¹⁴ Reviews of resident training in vulvovaginal disease also have shown that although dermatology residents receive slightly less formal training hours on vulvar skin disease, they see more than double the number of patients with vulvar disease per year when compared to obstetrics and gynecology residents.¹⁵ In practice, dermatologists generally are more confident when evaluating vulvar pigmented lesions than gynecologists.⁶

The Importance of the Genital Examination

Looking past these barriers seems essential to providing the best dermatologic care, as there are a multitude of neoplastic and inflammatory dermatoses that can affect the genital skin. Furthermore, early diagnosis and treatment of these conditions potentially can limit morbidity and mortality as well as improve quality of life. Genital melanomas are a good example. Although they may be rare, it is well known that genital melanomas are associated with an aggressive disease course and have worse outcomes than melanomas found elsewhere on the body.^16,17 Increasing rates of genital and perianal keratinocyte carcinomas make including this as part of the TBSE even more important.¹⁸

We also should not forget that inflammatory conditions can routinely involve the genitals.^19-21 Although robust data are lacking, chronic vulvar concerns frequently are seen in the primary care setting. In one study in the United Kingdom, 52% of general practitioners surveyed saw more than 3 patients per month with vulvar concerns.²² Even in common dermatologic conditions such as psoriasis and lichen planus, genital involvement often is overlooked despite its relative frequency.^23-27 In one study, 60% of psoriasis patients with genital involvement had not had these lesions examined by a physician.²⁸

Theoretically, TBSEs that include genital examination would yield higher and earlier detection rates of neoplasms as well as inflammatory dermatoses.^29-32 Thus, there is real value in diagnosing ailments of the genital skin, and dermatologists are well prepared to manage these conditions. Consistently incorporating a genital examination within the TBSE is the first step.

An Approach to the Genital Skin Examination

As with the TBSE, no standardized protocol for the genital skin examination exists, and there is no consensus for how best to perform this evaluation. Ideally, both male and female patients should remove all clothing, including undergarments, though one study found patients preferred to keep undergarments on during the genital examination.^10,33,34

In general, adult female genital anatomy is best viewed with the patient in the supine position.^6,33,35 There is no clear agreement on the use of stirrups, and the decision to use these may be left to the discretion of the patient. One randomized clinical trial found that women undergoing routine gynecologic examination without stirrups reported less physical discomfort and had a reduced sense of vulnerability than women examined in stirrups.³⁶ During the female genital examination, the head of the bed ideally should be positioned at a 30° to 45° angle to allow the provider to maintain eye contact and face-to-face communication with the patient.³³ This positioning also facilitates the use of a handheld mirror to instruct patients on techniques for medication application as well as to point out sites of disease.

For adult males, the genital examination can be performed with the patient standing facing a seated examiner.³⁵ The patient’s gown should be raised to the level of the umbilicus to expose the entire genital region. Good lighting is essential. These recommendations apply mainly to adults, but helpful tips on how to approach evaluating prepubertal children in the dermatology clinic are available.³⁷

The presence of a chaperone also is optional for maximizing patient comfort but also may be helpful for providing medicolegal protection for the provider. It always should be offered regardless of patient gender. A dermatology study found that when patients were examined by a same-gender physician, women and men were more comfortable without a chaperone than with a chaperone, and patients generally preferred fewer bodies in the room during sensitive examinations.⁹

Educating Patients About the TBSE

The most helpful recommendation for successfully incorporating and performing the genital skin examination as part of the TBSE appears to be patient education. In a randomized double-arm study, patients who received pre-education consisting of written information explaining the need for a TBSE were less likely to be concerned about a genital examination compared to patients who received no information.³⁸ Discussing that skin diseases, including melanoma, can arise in all areas of the body including the genital skin and encouraging patients to perform genital self-examinations is critical.³⁵ In the age of the electronic health record and virtual communication, disseminating this information has become even easier.³⁹ It may be beneficial to explore patients’ TBSE expectations at the outset through these varied avenues to help establish a trusted physician-patient relationship.⁴⁰

Final Thoughts

Dermatologists should consistently offer a genital examination to all patients who present for a routine TBSE. Patients should be provided with adequate education to assess their comfort level for the skin examination. If a patient declines this examination, the dermatologist should ensure that another physician—be it a gynecologist, primary care provider, or other specialist—is routinely examining the area.^6,7

To the Editor:

Unilateral nevoid telangiectasia (UNT) is a rare cutaneous disease characterized by superficial telangiectases arranged in a unilateral linear pattern. First described by Alfred Blaschko in 1899, this rare disease has been reported in higher frequency in recent years, with approximately 100 cases published in the literature according to a PubMed search of articles indexed for MEDLINE using the term unilateral nevoid telangiectasia.¹ Unilateral nevoid telangiectasia can be congenital or acquired; occurs more commonly in women; and typically involves the dermatomal distributions of the trigeminal, cervical, and upper thoracic nerves. Although the pathogenesis of the disease remains unknown, the currently proposed etiology involves hyperestrogenic states, including puberty, pregnancy, and chronic liver disease.² We report a case of progressively worsening, pruritic, unilateral telangiectases of unknown etiology.

A 55-year-old woman presented to our dermatology clinic with progressive red spots involving the right side of the upper body of 3 years’ duration. She noted pruritus, and the rash was otherwise asymptomatic. Her medical history was notable for hypertension, dyspepsia, sciatica, uterine fibroids, and a hysterectomy. Her medications included lisinopril, hydrochlorothiazide, tramadol, aspirin, and a multivitamin. The patient did not report the use of oral contraceptive pills or hormone replacement therapy. She also denied the use of cigarettes or illicit drugs but reported occasional alcohol consumption. A review of systems was negative for any constitutional symptoms or symptoms of liver disease. Her family history also was noncontributory.

Physical examination revealed multiple, 1- to 3-mm, telangiectatic macules and patches in a blaschkoid distribution on the right side of the upper chest, back, shoulder, and arm (Figure, A–C). Darier sign was negative. There was no evidence of palmar erythema, hepatosplenomegaly, ascites, thyromegaly, or thyroid nodules. Dermoscopy confirmed the presence of telangiectasia (Figure, D). More specifically, dermoscopy revealed plump telangiectasia with faint pigment in the background, consistent with UNT. Additionally, there was no pink-white, shiny, scarlike background, and vessels were not thin or arborized, further supporting our diagnosis vs other entities included in the differential diagnosis.

Our case provides another unique presentation of UNT. Our patient was a healthy adult woman with no hyperestrogen-based etiology for disease. Importantly, our patient also represented a rare instance of UNT presenting with symptoms such as pruritus, though UNT classically is described as an asymptomatic phenomenon. In our patient, treatment with PDL was suggested and believed to be warranted not only for cosmetic improvement but also in light of the fact that her lesions were symptomatic.

To the Editor:

Unilateral nevoid telangiectasia (UNT) is a rare cutaneous disease characterized by superficial telangiectases arranged in a unilateral linear pattern. First described by Alfred Blaschko in 1899, this rare disease has been reported in higher frequency in recent years, with approximately 100 cases published in the literature according to a PubMed search of articles indexed for MEDLINE using the term unilateral nevoid telangiectasia.¹ Unilateral nevoid telangiectasia can be congenital or acquired; occurs more commonly in women; and typically involves the dermatomal distributions of the trigeminal, cervical, and upper thoracic nerves. Although the pathogenesis of the disease remains unknown, the currently proposed etiology involves hyperestrogenic states, including puberty, pregnancy, and chronic liver disease.² We report a case of progressively worsening, pruritic, unilateral telangiectases of unknown etiology.

A 55-year-old woman presented to our dermatology clinic with progressive red spots involving the right side of the upper body of 3 years’ duration. She noted pruritus, and the rash was otherwise asymptomatic. Her medical history was notable for hypertension, dyspepsia, sciatica, uterine fibroids, and a hysterectomy. Her medications included lisinopril, hydrochlorothiazide, tramadol, aspirin, and a multivitamin. The patient did not report the use of oral contraceptive pills or hormone replacement therapy. She also denied the use of cigarettes or illicit drugs but reported occasional alcohol consumption. A review of systems was negative for any constitutional symptoms or symptoms of liver disease. Her family history also was noncontributory.

Physical examination revealed multiple, 1- to 3-mm, telangiectatic macules and patches in a blaschkoid distribution on the right side of the upper chest, back, shoulder, and arm (Figure, A–C). Darier sign was negative. There was no evidence of palmar erythema, hepatosplenomegaly, ascites, thyromegaly, or thyroid nodules. Dermoscopy confirmed the presence of telangiectasia (Figure, D). More specifically, dermoscopy revealed plump telangiectasia with faint pigment in the background, consistent with UNT. Additionally, there was no pink-white, shiny, scarlike background, and vessels were not thin or arborized, further supporting our diagnosis vs other entities included in the differential diagnosis.

Our case provides another unique presentation of UNT. Our patient was a healthy adult woman with no hyperestrogen-based etiology for disease. Importantly, our patient also represented a rare instance of UNT presenting with symptoms such as pruritus, though UNT classically is described as an asymptomatic phenomenon. In our patient, treatment with PDL was suggested and believed to be warranted not only for cosmetic improvement but also in light of the fact that her lesions were symptomatic.

To the Editor:

Unilateral nevoid telangiectasia (UNT) is a rare cutaneous disease characterized by superficial telangiectases arranged in a unilateral linear pattern. First described by Alfred Blaschko in 1899, this rare disease has been reported in higher frequency in recent years, with approximately 100 cases published in the literature according to a PubMed search of articles indexed for MEDLINE using the term unilateral nevoid telangiectasia.¹ Unilateral nevoid telangiectasia can be congenital or acquired; occurs more commonly in women; and typically involves the dermatomal distributions of the trigeminal, cervical, and upper thoracic nerves. Although the pathogenesis of the disease remains unknown, the currently proposed etiology involves hyperestrogenic states, including puberty, pregnancy, and chronic liver disease.² We report a case of progressively worsening, pruritic, unilateral telangiectases of unknown etiology.

A 55-year-old woman presented to our dermatology clinic with progressive red spots involving the right side of the upper body of 3 years’ duration. She noted pruritus, and the rash was otherwise asymptomatic. Her medical history was notable for hypertension, dyspepsia, sciatica, uterine fibroids, and a hysterectomy. Her medications included lisinopril, hydrochlorothiazide, tramadol, aspirin, and a multivitamin. The patient did not report the use of oral contraceptive pills or hormone replacement therapy. She also denied the use of cigarettes or illicit drugs but reported occasional alcohol consumption. A review of systems was negative for any constitutional symptoms or symptoms of liver disease. Her family history also was noncontributory.

Physical examination revealed multiple, 1- to 3-mm, telangiectatic macules and patches in a blaschkoid distribution on the right side of the upper chest, back, shoulder, and arm (Figure, A–C). Darier sign was negative. There was no evidence of palmar erythema, hepatosplenomegaly, ascites, thyromegaly, or thyroid nodules. Dermoscopy confirmed the presence of telangiectasia (Figure, D). More specifically, dermoscopy revealed plump telangiectasia with faint pigment in the background, consistent with UNT. Additionally, there was no pink-white, shiny, scarlike background, and vessels were not thin or arborized, further supporting our diagnosis vs other entities included in the differential diagnosis.

Our case provides another unique presentation of UNT. Our patient was a healthy adult woman with no hyperestrogen-based etiology for disease. Importantly, our patient also represented a rare instance of UNT presenting with symptoms such as pruritus, though UNT classically is described as an asymptomatic phenomenon. In our patient, treatment with PDL was suggested and believed to be warranted not only for cosmetic improvement but also in light of the fact that her lesions were symptomatic.

Several maternal chronic conditions increase the risk of giving birth to a child with cerebral palsy, based on data from more than 1.3 million Norwegian children.

Mothers with autoimmune disorders, such as diabetes and lupus, had the greatest risks, reported lead author Marianne S. Strøm, MD, of the University of Bergen (Norway) and colleagues.

“The etiologies of cerebral palsy are complex, and only a few prenatal risk factors have been identified,” the investigators wrote in Pediatrics. “Among these possible risk factors are maternal chronic conditions, although studies are typically underpowered and limited to one or two conditions.”

According to Dr. Strøm and colleagues, several components of maternal chronic conditions have been linked with cerebral palsy, including placental abnormalities, altered thrombotic state, and inflammation. Furthermore, mothers with chronic conditions are more likely to give birth prematurely and have children with congenital malformations, both of which have also been associated with cerebral palsy.

To date, however, “there has been no systematic description of maternal chronic conditions and risk of cerebral palsy in offspring,” the investigators noted.

The present, prospective cohort study aimed to meet this need with a population of 1,360,149 children born in Norway from 1990 to 2012, among whom 3,575 had cerebral palsy. Case data were extracted from the Norwegian Patient Registry and the National Insurance Scheme. Information about maternal chronic conditions was extracted from the Medical Birth Registry of Norway and the Norwegian Patient Registry, with the latter also providing information about paternal chronic conditions.

Using log binomial regression models, the investigators determined relative risks of having children with cerebral palsy among parents with chronic conditions versus parents from the general population. This revealed that chronic conditions in fathers had no correlation with cerebral palsy. In contrast, mothers with chronic conditions had a 30% increased risk (relative risk, 1.3; 95% confidence interval, 1.2-1.5), which could be further stratified by number of chronic conditions; mothers with one chronic condition, for instance, had a 20% increased risk (RR, 1.2; 95% CI, 1.1-1.4), while those with two chronic conditions had a 60% increased risk (RR, 1.6; 95% CI, 1.1-2.2), and those with more than two chronic conditions had triple the risk (RR, 3.1; 95% CI, 1.4-6.8)

“The lack of associations between the father’s chronic illness and cerebral palsy risk supports the interpretation that cerebral palsy risk in offspring is the direct result of the mother’s condition and not genetic predisposition or unmeasured situational factors,” the investigators wrote.

Maternal autoimmune conditions were particularly relevant, as they were associated with a 40% increased risk of cerebral palsy (RR, 1.4; 95% CI, 1.1-1.7), a rate that climbed dramatically, to 270%, among mothers with more than one autoimmune condition (RR, 2.7; 95% CI, 1.1-6.6).

“The role of autoimmune diseases in cerebral palsy risk (and maternal inflammation specifically) deserves closer attention,” the investigators wrote. “Using studies with larger sample sizes and a more clinical focus, including measures of placental structure and perinatal blood assays, researchers may be able to explore these possible connections between maternal autoimmune diseases and fetal neurodevelopment.”

Specifically, cerebral palsy in offspring was most strongly associated with maternal Crohn’s disease (RR, 2.1; 95% CI, 1.0-4.1), type 1 diabetes (RR, 2.2; 95% CI, 1.4-3.4), lupus erythematosus (RR, 2.7; 95% CI, 0.9-8.3), and type 2 diabetes (RR, 3.2; 95% CI, 1.8-5.4). Associations were also found for migraine (RR, 1.6; 95% CI, 1.2-2.2), multiple sclerosis (RR, 1.8; 95% CI, 0.8-4.4), and rheumatoid arthritis (RR, 2.0; 95% CI, 1.3-2.9). Several “weaker and less convincing associations” were detected for ulcerative colitis, thyroid disorder, epilepsy, asthma, anemia, and hypertension. Adjusting for parental education level, age, smoking status, and single-mother status did not significantly alter findings. Poisson and logistic regression models generated similar results.

In an accompanying editorial, Sandra Julsen Hollung, PhD, of the Cerebral Palsy Registry of Norway, Vestfold Hospital Trust, Tønsberg, and colleagues, advised that clinicians maintain perspective when discussing these findings with the general public.

“As the authors state, the absolute risk of cerebral palsy associated with at least one chronic maternal condition is low,” wrote Dr. Hollung and colleagues. “Among 1,000 pregnant women with any chronic and/or autoimmune disorder, more than 990 will deliver an infant who will not be diagnosed with cerebral palsy.”

They went on to emphasize that the study findings should not be viewed as firm evidence of causal relationships.

“Thus, the study cannot give clues to any specific preventive treatment,” wrote Dr. Hollung and colleagues. “However, if these disorders are part of a causal pathway, optimal treatment might reduce the risk of cerebral palsy.”

Although Dr. Hollung and colleagues advised that such efforts “would hardly affect the birth prevalence of cerebral palsy,” they also cited the Royal College of Obstetricians and Gynaecologists in the United Kingdom, noting that “each baby counts.”

Emeritus Professor Alastair MacLennan, AO, MB ChB, FRCOG, FRANZCOG, head of the Australian Collaborative Cerebral Palsy Research Group at the University of Adelaide (Australia) suggested that the findings may guide future research.

“An increasing proportion of cerebral palsy cases are being diagnosed by genome sequencing and other genetic techniques to have causative genetic variations,” Dr. MacLennan said. “The possibility of epigenetic interactions are also likely and are still to be investigated. Maternal disorders such as diabetes, lupus, or Crohn’s disease are possible epigenetic factors and this study helps to target these in future genetic and environmental studies of cerebral palsy causation. The days of attributing cerebral palsy to ‘birth asphyxia’ are over.”

The study was supported by the National Institutes of Health and the Western Norwegian Regional Health Authorities. The investigators reported no conflicts of interest.

Several maternal chronic conditions increase the risk of giving birth to a child with cerebral palsy, based on data from more than 1.3 million Norwegian children.

Mothers with autoimmune disorders, such as diabetes and lupus, had the greatest risks, reported lead author Marianne S. Strøm, MD, of the University of Bergen (Norway) and colleagues.

“The etiologies of cerebral palsy are complex, and only a few prenatal risk factors have been identified,” the investigators wrote in Pediatrics. “Among these possible risk factors are maternal chronic conditions, although studies are typically underpowered and limited to one or two conditions.”

According to Dr. Strøm and colleagues, several components of maternal chronic conditions have been linked with cerebral palsy, including placental abnormalities, altered thrombotic state, and inflammation. Furthermore, mothers with chronic conditions are more likely to give birth prematurely and have children with congenital malformations, both of which have also been associated with cerebral palsy.

To date, however, “there has been no systematic description of maternal chronic conditions and risk of cerebral palsy in offspring,” the investigators noted.

The present, prospective cohort study aimed to meet this need with a population of 1,360,149 children born in Norway from 1990 to 2012, among whom 3,575 had cerebral palsy. Case data were extracted from the Norwegian Patient Registry and the National Insurance Scheme. Information about maternal chronic conditions was extracted from the Medical Birth Registry of Norway and the Norwegian Patient Registry, with the latter also providing information about paternal chronic conditions.

Using log binomial regression models, the investigators determined relative risks of having children with cerebral palsy among parents with chronic conditions versus parents from the general population. This revealed that chronic conditions in fathers had no correlation with cerebral palsy. In contrast, mothers with chronic conditions had a 30% increased risk (relative risk, 1.3; 95% confidence interval, 1.2-1.5), which could be further stratified by number of chronic conditions; mothers with one chronic condition, for instance, had a 20% increased risk (RR, 1.2; 95% CI, 1.1-1.4), while those with two chronic conditions had a 60% increased risk (RR, 1.6; 95% CI, 1.1-2.2), and those with more than two chronic conditions had triple the risk (RR, 3.1; 95% CI, 1.4-6.8)

“The lack of associations between the father’s chronic illness and cerebral palsy risk supports the interpretation that cerebral palsy risk in offspring is the direct result of the mother’s condition and not genetic predisposition or unmeasured situational factors,” the investigators wrote.

Maternal autoimmune conditions were particularly relevant, as they were associated with a 40% increased risk of cerebral palsy (RR, 1.4; 95% CI, 1.1-1.7), a rate that climbed dramatically, to 270%, among mothers with more than one autoimmune condition (RR, 2.7; 95% CI, 1.1-6.6).

“The role of autoimmune diseases in cerebral palsy risk (and maternal inflammation specifically) deserves closer attention,” the investigators wrote. “Using studies with larger sample sizes and a more clinical focus, including measures of placental structure and perinatal blood assays, researchers may be able to explore these possible connections between maternal autoimmune diseases and fetal neurodevelopment.”

Specifically, cerebral palsy in offspring was most strongly associated with maternal Crohn’s disease (RR, 2.1; 95% CI, 1.0-4.1), type 1 diabetes (RR, 2.2; 95% CI, 1.4-3.4), lupus erythematosus (RR, 2.7; 95% CI, 0.9-8.3), and type 2 diabetes (RR, 3.2; 95% CI, 1.8-5.4). Associations were also found for migraine (RR, 1.6; 95% CI, 1.2-2.2), multiple sclerosis (RR, 1.8; 95% CI, 0.8-4.4), and rheumatoid arthritis (RR, 2.0; 95% CI, 1.3-2.9). Several “weaker and less convincing associations” were detected for ulcerative colitis, thyroid disorder, epilepsy, asthma, anemia, and hypertension. Adjusting for parental education level, age, smoking status, and single-mother status did not significantly alter findings. Poisson and logistic regression models generated similar results.

In an accompanying editorial, Sandra Julsen Hollung, PhD, of the Cerebral Palsy Registry of Norway, Vestfold Hospital Trust, Tønsberg, and colleagues, advised that clinicians maintain perspective when discussing these findings with the general public.

“As the authors state, the absolute risk of cerebral palsy associated with at least one chronic maternal condition is low,” wrote Dr. Hollung and colleagues. “Among 1,000 pregnant women with any chronic and/or autoimmune disorder, more than 990 will deliver an infant who will not be diagnosed with cerebral palsy.”

They went on to emphasize that the study findings should not be viewed as firm evidence of causal relationships.

“Thus, the study cannot give clues to any specific preventive treatment,” wrote Dr. Hollung and colleagues. “However, if these disorders are part of a causal pathway, optimal treatment might reduce the risk of cerebral palsy.”

Although Dr. Hollung and colleagues advised that such efforts “would hardly affect the birth prevalence of cerebral palsy,” they also cited the Royal College of Obstetricians and Gynaecologists in the United Kingdom, noting that “each baby counts.”

Emeritus Professor Alastair MacLennan, AO, MB ChB, FRCOG, FRANZCOG, head of the Australian Collaborative Cerebral Palsy Research Group at the University of Adelaide (Australia) suggested that the findings may guide future research.

“An increasing proportion of cerebral palsy cases are being diagnosed by genome sequencing and other genetic techniques to have causative genetic variations,” Dr. MacLennan said. “The possibility of epigenetic interactions are also likely and are still to be investigated. Maternal disorders such as diabetes, lupus, or Crohn’s disease are possible epigenetic factors and this study helps to target these in future genetic and environmental studies of cerebral palsy causation. The days of attributing cerebral palsy to ‘birth asphyxia’ are over.”

The study was supported by the National Institutes of Health and the Western Norwegian Regional Health Authorities. The investigators reported no conflicts of interest.

Several maternal chronic conditions increase the risk of giving birth to a child with cerebral palsy, based on data from more than 1.3 million Norwegian children.

Mothers with autoimmune disorders, such as diabetes and lupus, had the greatest risks, reported lead author Marianne S. Strøm, MD, of the University of Bergen (Norway) and colleagues.

“The etiologies of cerebral palsy are complex, and only a few prenatal risk factors have been identified,” the investigators wrote in Pediatrics. “Among these possible risk factors are maternal chronic conditions, although studies are typically underpowered and limited to one or two conditions.”

According to Dr. Strøm and colleagues, several components of maternal chronic conditions have been linked with cerebral palsy, including placental abnormalities, altered thrombotic state, and inflammation. Furthermore, mothers with chronic conditions are more likely to give birth prematurely and have children with congenital malformations, both of which have also been associated with cerebral palsy.

To date, however, “there has been no systematic description of maternal chronic conditions and risk of cerebral palsy in offspring,” the investigators noted.

The present, prospective cohort study aimed to meet this need with a population of 1,360,149 children born in Norway from 1990 to 2012, among whom 3,575 had cerebral palsy. Case data were extracted from the Norwegian Patient Registry and the National Insurance Scheme. Information about maternal chronic conditions was extracted from the Medical Birth Registry of Norway and the Norwegian Patient Registry, with the latter also providing information about paternal chronic conditions.

Using log binomial regression models, the investigators determined relative risks of having children with cerebral palsy among parents with chronic conditions versus parents from the general population. This revealed that chronic conditions in fathers had no correlation with cerebral palsy. In contrast, mothers with chronic conditions had a 30% increased risk (relative risk, 1.3; 95% confidence interval, 1.2-1.5), which could be further stratified by number of chronic conditions; mothers with one chronic condition, for instance, had a 20% increased risk (RR, 1.2; 95% CI, 1.1-1.4), while those with two chronic conditions had a 60% increased risk (RR, 1.6; 95% CI, 1.1-2.2), and those with more than two chronic conditions had triple the risk (RR, 3.1; 95% CI, 1.4-6.8)

“The lack of associations between the father’s chronic illness and cerebral palsy risk supports the interpretation that cerebral palsy risk in offspring is the direct result of the mother’s condition and not genetic predisposition or unmeasured situational factors,” the investigators wrote.

Maternal autoimmune conditions were particularly relevant, as they were associated with a 40% increased risk of cerebral palsy (RR, 1.4; 95% CI, 1.1-1.7), a rate that climbed dramatically, to 270%, among mothers with more than one autoimmune condition (RR, 2.7; 95% CI, 1.1-6.6).

“The role of autoimmune diseases in cerebral palsy risk (and maternal inflammation specifically) deserves closer attention,” the investigators wrote. “Using studies with larger sample sizes and a more clinical focus, including measures of placental structure and perinatal blood assays, researchers may be able to explore these possible connections between maternal autoimmune diseases and fetal neurodevelopment.”

Specifically, cerebral palsy in offspring was most strongly associated with maternal Crohn’s disease (RR, 2.1; 95% CI, 1.0-4.1), type 1 diabetes (RR, 2.2; 95% CI, 1.4-3.4), lupus erythematosus (RR, 2.7; 95% CI, 0.9-8.3), and type 2 diabetes (RR, 3.2; 95% CI, 1.8-5.4). Associations were also found for migraine (RR, 1.6; 95% CI, 1.2-2.2), multiple sclerosis (RR, 1.8; 95% CI, 0.8-4.4), and rheumatoid arthritis (RR, 2.0; 95% CI, 1.3-2.9). Several “weaker and less convincing associations” were detected for ulcerative colitis, thyroid disorder, epilepsy, asthma, anemia, and hypertension. Adjusting for parental education level, age, smoking status, and single-mother status did not significantly alter findings. Poisson and logistic regression models generated similar results.

In an accompanying editorial, Sandra Julsen Hollung, PhD, of the Cerebral Palsy Registry of Norway, Vestfold Hospital Trust, Tønsberg, and colleagues, advised that clinicians maintain perspective when discussing these findings with the general public.

“As the authors state, the absolute risk of cerebral palsy associated with at least one chronic maternal condition is low,” wrote Dr. Hollung and colleagues. “Among 1,000 pregnant women with any chronic and/or autoimmune disorder, more than 990 will deliver an infant who will not be diagnosed with cerebral palsy.”

They went on to emphasize that the study findings should not be viewed as firm evidence of causal relationships.

“Thus, the study cannot give clues to any specific preventive treatment,” wrote Dr. Hollung and colleagues. “However, if these disorders are part of a causal pathway, optimal treatment might reduce the risk of cerebral palsy.”

Although Dr. Hollung and colleagues advised that such efforts “would hardly affect the birth prevalence of cerebral palsy,” they also cited the Royal College of Obstetricians and Gynaecologists in the United Kingdom, noting that “each baby counts.”

Emeritus Professor Alastair MacLennan, AO, MB ChB, FRCOG, FRANZCOG, head of the Australian Collaborative Cerebral Palsy Research Group at the University of Adelaide (Australia) suggested that the findings may guide future research.

“An increasing proportion of cerebral palsy cases are being diagnosed by genome sequencing and other genetic techniques to have causative genetic variations,” Dr. MacLennan said. “The possibility of epigenetic interactions are also likely and are still to be investigated. Maternal disorders such as diabetes, lupus, or Crohn’s disease are possible epigenetic factors and this study helps to target these in future genetic and environmental studies of cerebral palsy causation. The days of attributing cerebral palsy to ‘birth asphyxia’ are over.”

The study was supported by the National Institutes of Health and the Western Norwegian Regional Health Authorities. The investigators reported no conflicts of interest.

In his role as head of the division of pediatric behavioral health at National Jewish Health, Denver, Bruce G. Bender, PhD, helps children and adults navigate the adverse effects of severe atopic dermatitis (AD) on their quality of life.

“There have been many surveys of adults with AD who report impairment of their sleep, reduced activity level, increased work absence, financial burden, emotional distress, and social avoidance,” he said at the Revolutionizing Atopic Dermatitis virtual symposium. “Similarly, children with AD or their parents report emotional distress, reduced activity, and increased school absence, social avoidance, and sleep disturbance. Families report financial burdens, conflict, particularly among the adults, social avoidance, sleep disturbance in the parents, and reduction of well-being in the siblings.”

Getting adequate sleep is especially challenging for patients with AD, and loss of sleep can have serious daytime consequences. In an effort to objectively measure sleep change in this population, Dr. Bender and colleagues recruited 14 adults with AD and 14 healthy controls who wore an ActiGraph for 1 week and completed questionnaires about sleep, itch, and quality of life. Patients with AD were awake almost twice as many minutes each night as the healthy controls (a mean of 57.3 vs. 32.3 minutes, respectively; P = .0480). Consequently, their sleep efficiency was significantly reduced based on the Pittsburgh sleep quality index (a mean of 90.6 vs. 95; P = .0305).

In another study, Dr. Bender and colleagues enrolled 20 adults with AD who underwent 2 nights of polysomnography and actigraphy. The lab was set up to measure a scratching event, which was recorded when a burst of electromyographic activity of at least 3 seconds was accompanied by a visible scratching motion. “We learned that sleep efficiency as measured by both PSG and actigraphy correlated with total body surface area and scratching index,” he said. “As we might assume, the more skin involved, the more patients scratch, the less well they sleep.”
 

Behavioral, neurocognitive effects

In a separate study of AD, sleep, and behavior, the researchers studied 1,041 children with asthma who were enrolled in the Childhood Asthma Management Program at eight North American sites. They used baseline parent ratings on standardized sleep and behavior rating scales and found that increased awakenings were associated with increased school absence and daytime behavior problems. “So, not only do children with AD sleep less well, but this shows up to impair their functioning during the day,” said Dr. Bender, professor of psychiatry at the University of Colorado, Denver.

In a report from Australia, researchers set out to explore the association between sleep and neurocognitive function in 21 children with eczema and 20 healthy controls. Participants underwent cognitive testing and polysomnography. The authors found that the children with eczema demonstrated lower test scores. Reduced scores were correlated with parental reports of sleep problems but not polysomnography.

In a much larger study funded by the Agency for Healthcare Research and Quality, investigators analyzed data on 354,416 children and 34,613 adults from 19 U.S. population surveys including the National Health Interview Survey 1997-2013 and the National Survey of Children’s Health 2003/4 and 2007/8. They found that AD was associated with ADHD in children (adjusted odds ratio, 1.14) and adults (aOR, 1.61). Higher odds of ADHD were found in children who had significant sleep disturbance (aOR, 16.83) and other allergic disease and asthma (aOR, 1.61).

“All of these findings show that AD can impact quality of life, especially sleep, with the result of poorer daytime functioning,” Dr. Bender said. “But those studies don’t answer this question: Are patients with AD at increased risk for psychological disorders such as depression and anxiety?”
 

Impact on depression, anxiety

Two systematic reviews on the topic suggest that patients with AD are twice as likely to experience depression. One was published in 2018 and the other in 2019. The 2018 review reported a little more than a twofold increase (OR, 2.19), the 2019 review a little bit less (OR, 1.71).

“At the more severe end of the depression continuum, we sometimes see suicidal ideation and suicide attempts,” Dr. Bender said. “A number of studies have asked whether these are increased in patients with AD. Quite a few studies collectively show an increased incidence of suicidal ideation. The question of suicide attempts is reflected in fewer studies. And while the result is small, it is significant. There is a significant increase reported of suicide attempts in AD patients.”

The 2018 review also found an increased incidence of anxiety in AD patients: a little more than twofold in adults (OR, 2.19) and a little less than twofold in children (OR, 1.81).

“It’s a two-way relationship between AD and psychological factors,” Dr. Bender said. “We generally think about AD – the stress that it brings, the burden that it puts on children, adults, and families. But it can work the other way around,” he said, referring to patients who have psychological problems, experience a great deal of stress, have trouble being adherent to their treatment regimen, and find it difficult to resist scratching. “The behavioral/psychological characteristics of the patient also drive the AD. It is well established that acute and chronic stress can result in a worsening of skin conditions in AD patients.”

Behavioral health interventions that have been described in the literature include cognitive therapy, stress management, biofeedback, hypnotherapy, relaxation training, mindfulness, habit reversal, and patient education – some of which have been tested in randomized trials. “All of them report a decrease in scratching as a consequence of the behavioral intervention,” Dr. Bender said.

“Other studies have been reported that look at the impact of behavioral interventions on the severity of the skin condition. Most report an improvement in the skin condition from these behavioral interventions but it’s not a perfect literature.” Critiques of these studies include the fact that there is often not enough detail about the intervention or the framework for the intervention that would allow a clinician to test an intervention in another study or actually pull that intervention into clinical practice (Cochrane Database Syst Rev. 2014 Jan 7;2014[1]:CD004054), (Int Arch Allergy Immunol.2007;144[1]:1-9).

“Some of the studies lack rigorous designs, some have sampling bias, and some have inadequate outcome measurements,” he said. “We really need additional, high-quality studies to look at what is helpful for patients with AD.”

Dr. Bender reported having no financial disclosures.

[email protected]

In his role as head of the division of pediatric behavioral health at National Jewish Health, Denver, Bruce G. Bender, PhD, helps children and adults navigate the adverse effects of severe atopic dermatitis (AD) on their quality of life.

“There have been many surveys of adults with AD who report impairment of their sleep, reduced activity level, increased work absence, financial burden, emotional distress, and social avoidance,” he said at the Revolutionizing Atopic Dermatitis virtual symposium. “Similarly, children with AD or their parents report emotional distress, reduced activity, and increased school absence, social avoidance, and sleep disturbance. Families report financial burdens, conflict, particularly among the adults, social avoidance, sleep disturbance in the parents, and reduction of well-being in the siblings.”

Getting adequate sleep is especially challenging for patients with AD, and loss of sleep can have serious daytime consequences. In an effort to objectively measure sleep change in this population, Dr. Bender and colleagues recruited 14 adults with AD and 14 healthy controls who wore an ActiGraph for 1 week and completed questionnaires about sleep, itch, and quality of life. Patients with AD were awake almost twice as many minutes each night as the healthy controls (a mean of 57.3 vs. 32.3 minutes, respectively; P = .0480). Consequently, their sleep efficiency was significantly reduced based on the Pittsburgh sleep quality index (a mean of 90.6 vs. 95; P = .0305).

In another study, Dr. Bender and colleagues enrolled 20 adults with AD who underwent 2 nights of polysomnography and actigraphy. The lab was set up to measure a scratching event, which was recorded when a burst of electromyographic activity of at least 3 seconds was accompanied by a visible scratching motion. “We learned that sleep efficiency as measured by both PSG and actigraphy correlated with total body surface area and scratching index,” he said. “As we might assume, the more skin involved, the more patients scratch, the less well they sleep.”
 

Behavioral, neurocognitive effects

In a separate study of AD, sleep, and behavior, the researchers studied 1,041 children with asthma who were enrolled in the Childhood Asthma Management Program at eight North American sites. They used baseline parent ratings on standardized sleep and behavior rating scales and found that increased awakenings were associated with increased school absence and daytime behavior problems. “So, not only do children with AD sleep less well, but this shows up to impair their functioning during the day,” said Dr. Bender, professor of psychiatry at the University of Colorado, Denver.

In a report from Australia, researchers set out to explore the association between sleep and neurocognitive function in 21 children with eczema and 20 healthy controls. Participants underwent cognitive testing and polysomnography. The authors found that the children with eczema demonstrated lower test scores. Reduced scores were correlated with parental reports of sleep problems but not polysomnography.

In a much larger study funded by the Agency for Healthcare Research and Quality, investigators analyzed data on 354,416 children and 34,613 adults from 19 U.S. population surveys including the National Health Interview Survey 1997-2013 and the National Survey of Children’s Health 2003/4 and 2007/8. They found that AD was associated with ADHD in children (adjusted odds ratio, 1.14) and adults (aOR, 1.61). Higher odds of ADHD were found in children who had significant sleep disturbance (aOR, 16.83) and other allergic disease and asthma (aOR, 1.61).

“All of these findings show that AD can impact quality of life, especially sleep, with the result of poorer daytime functioning,” Dr. Bender said. “But those studies don’t answer this question: Are patients with AD at increased risk for psychological disorders such as depression and anxiety?”
 

Impact on depression, anxiety

Two systematic reviews on the topic suggest that patients with AD are twice as likely to experience depression. One was published in 2018 and the other in 2019. The 2018 review reported a little more than a twofold increase (OR, 2.19), the 2019 review a little bit less (OR, 1.71).

“At the more severe end of the depression continuum, we sometimes see suicidal ideation and suicide attempts,” Dr. Bender said. “A number of studies have asked whether these are increased in patients with AD. Quite a few studies collectively show an increased incidence of suicidal ideation. The question of suicide attempts is reflected in fewer studies. And while the result is small, it is significant. There is a significant increase reported of suicide attempts in AD patients.”

The 2018 review also found an increased incidence of anxiety in AD patients: a little more than twofold in adults (OR, 2.19) and a little less than twofold in children (OR, 1.81).

“It’s a two-way relationship between AD and psychological factors,” Dr. Bender said. “We generally think about AD – the stress that it brings, the burden that it puts on children, adults, and families. But it can work the other way around,” he said, referring to patients who have psychological problems, experience a great deal of stress, have trouble being adherent to their treatment regimen, and find it difficult to resist scratching. “The behavioral/psychological characteristics of the patient also drive the AD. It is well established that acute and chronic stress can result in a worsening of skin conditions in AD patients.”

Behavioral health interventions that have been described in the literature include cognitive therapy, stress management, biofeedback, hypnotherapy, relaxation training, mindfulness, habit reversal, and patient education – some of which have been tested in randomized trials. “All of them report a decrease in scratching as a consequence of the behavioral intervention,” Dr. Bender said.

“Other studies have been reported that look at the impact of behavioral interventions on the severity of the skin condition. Most report an improvement in the skin condition from these behavioral interventions but it’s not a perfect literature.” Critiques of these studies include the fact that there is often not enough detail about the intervention or the framework for the intervention that would allow a clinician to test an intervention in another study or actually pull that intervention into clinical practice (Cochrane Database Syst Rev. 2014 Jan 7;2014[1]:CD004054), (Int Arch Allergy Immunol.2007;144[1]:1-9).

“Some of the studies lack rigorous designs, some have sampling bias, and some have inadequate outcome measurements,” he said. “We really need additional, high-quality studies to look at what is helpful for patients with AD.”

Dr. Bender reported having no financial disclosures.

[email protected]

In his role as head of the division of pediatric behavioral health at National Jewish Health, Denver, Bruce G. Bender, PhD, helps children and adults navigate the adverse effects of severe atopic dermatitis (AD) on their quality of life.

“There have been many surveys of adults with AD who report impairment of their sleep, reduced activity level, increased work absence, financial burden, emotional distress, and social avoidance,” he said at the Revolutionizing Atopic Dermatitis virtual symposium. “Similarly, children with AD or their parents report emotional distress, reduced activity, and increased school absence, social avoidance, and sleep disturbance. Families report financial burdens, conflict, particularly among the adults, social avoidance, sleep disturbance in the parents, and reduction of well-being in the siblings.”

Getting adequate sleep is especially challenging for patients with AD, and loss of sleep can have serious daytime consequences. In an effort to objectively measure sleep change in this population, Dr. Bender and colleagues recruited 14 adults with AD and 14 healthy controls who wore an ActiGraph for 1 week and completed questionnaires about sleep, itch, and quality of life. Patients with AD were awake almost twice as many minutes each night as the healthy controls (a mean of 57.3 vs. 32.3 minutes, respectively; P = .0480). Consequently, their sleep efficiency was significantly reduced based on the Pittsburgh sleep quality index (a mean of 90.6 vs. 95; P = .0305).

In another study, Dr. Bender and colleagues enrolled 20 adults with AD who underwent 2 nights of polysomnography and actigraphy. The lab was set up to measure a scratching event, which was recorded when a burst of electromyographic activity of at least 3 seconds was accompanied by a visible scratching motion. “We learned that sleep efficiency as measured by both PSG and actigraphy correlated with total body surface area and scratching index,” he said. “As we might assume, the more skin involved, the more patients scratch, the less well they sleep.”
 

Behavioral, neurocognitive effects

In a separate study of AD, sleep, and behavior, the researchers studied 1,041 children with asthma who were enrolled in the Childhood Asthma Management Program at eight North American sites. They used baseline parent ratings on standardized sleep and behavior rating scales and found that increased awakenings were associated with increased school absence and daytime behavior problems. “So, not only do children with AD sleep less well, but this shows up to impair their functioning during the day,” said Dr. Bender, professor of psychiatry at the University of Colorado, Denver.

In a report from Australia, researchers set out to explore the association between sleep and neurocognitive function in 21 children with eczema and 20 healthy controls. Participants underwent cognitive testing and polysomnography. The authors found that the children with eczema demonstrated lower test scores. Reduced scores were correlated with parental reports of sleep problems but not polysomnography.

In a much larger study funded by the Agency for Healthcare Research and Quality, investigators analyzed data on 354,416 children and 34,613 adults from 19 U.S. population surveys including the National Health Interview Survey 1997-2013 and the National Survey of Children’s Health 2003/4 and 2007/8. They found that AD was associated with ADHD in children (adjusted odds ratio, 1.14) and adults (aOR, 1.61). Higher odds of ADHD were found in children who had significant sleep disturbance (aOR, 16.83) and other allergic disease and asthma (aOR, 1.61).

“All of these findings show that AD can impact quality of life, especially sleep, with the result of poorer daytime functioning,” Dr. Bender said. “But those studies don’t answer this question: Are patients with AD at increased risk for psychological disorders such as depression and anxiety?”
 

Impact on depression, anxiety

Two systematic reviews on the topic suggest that patients with AD are twice as likely to experience depression. One was published in 2018 and the other in 2019. The 2018 review reported a little more than a twofold increase (OR, 2.19), the 2019 review a little bit less (OR, 1.71).

“At the more severe end of the depression continuum, we sometimes see suicidal ideation and suicide attempts,” Dr. Bender said. “A number of studies have asked whether these are increased in patients with AD. Quite a few studies collectively show an increased incidence of suicidal ideation. The question of suicide attempts is reflected in fewer studies. And while the result is small, it is significant. There is a significant increase reported of suicide attempts in AD patients.”

The 2018 review also found an increased incidence of anxiety in AD patients: a little more than twofold in adults (OR, 2.19) and a little less than twofold in children (OR, 1.81).

“It’s a two-way relationship between AD and psychological factors,” Dr. Bender said. “We generally think about AD – the stress that it brings, the burden that it puts on children, adults, and families. But it can work the other way around,” he said, referring to patients who have psychological problems, experience a great deal of stress, have trouble being adherent to their treatment regimen, and find it difficult to resist scratching. “The behavioral/psychological characteristics of the patient also drive the AD. It is well established that acute and chronic stress can result in a worsening of skin conditions in AD patients.”

Behavioral health interventions that have been described in the literature include cognitive therapy, stress management, biofeedback, hypnotherapy, relaxation training, mindfulness, habit reversal, and patient education – some of which have been tested in randomized trials. “All of them report a decrease in scratching as a consequence of the behavioral intervention,” Dr. Bender said.

“Other studies have been reported that look at the impact of behavioral interventions on the severity of the skin condition. Most report an improvement in the skin condition from these behavioral interventions but it’s not a perfect literature.” Critiques of these studies include the fact that there is often not enough detail about the intervention or the framework for the intervention that would allow a clinician to test an intervention in another study or actually pull that intervention into clinical practice (Cochrane Database Syst Rev. 2014 Jan 7;2014[1]:CD004054), (Int Arch Allergy Immunol.2007;144[1]:1-9).

“Some of the studies lack rigorous designs, some have sampling bias, and some have inadequate outcome measurements,” he said. “We really need additional, high-quality studies to look at what is helpful for patients with AD.”

Dr. Bender reported having no financial disclosures.

[email protected]

Elevations in serum neurofilament light chain levels in people with multiple sclerosis (MS) are significantly linked to worse neurologic function, clinical disability, and lower brain volumes, according to new findings from a large, diverse population of patients with MS. “This is one of the largest studies to evaluate serum neurofilament light chain levels in people with MS,” said lead author Elias S. Sotirchos, MD, an assistant professor of neurology at Johns Hopkins University, Baltimore.

“An important strength of this cohort is that it is a real-world cohort of patients followed in U.S. and European MS centers,” he said. “The study captures the diversity of the MS population, including demographics, comorbidities, lifestyle factors, and clinical characteristics that may otherwise not be captured in a clinical trial population.”

The research was presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
 

Scrutinizing serum neurofilament light chain levels in a real-world cohort

Neurofilaments – neuron-specific proteins that release in response to neuroaxonal injury – have been observed to be elevated in a variety of neurologic disorders, and with a need for biomarkers in MS, there is high interest of their role in the disease. But studies involving real-world, heterogeneous MS populations are lacking, the researchers noted.

To take a broader look at the issue, Dr. Sotirchos and colleagues conducted a cross-sectional evaluation of 6,968 people with MS in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS), a large network of MS centers in the United States and Europe.

Participants’ baseline serum neurofilament light chain levels were compared with those of 201 healthy controls in the cohort using a novel, high-throughput immunoassay (Siemens Healthineers).

Of those with MS, 1,202 (17.2%) showed elevated serum neurofilament light chain levels, above the age-specific 97.5th percentile derived from the healthy controls.

A look at key factors associated with elevations showed significant links to having progressive MS (odds ratio, 1.63), non-White race (OR, 1.43), type 2 diabetes (OR, 1.89), and smoking (current vs. never smoker; OR, 1.49).

Associations with age and symptom duration were somewhat complex, but overall, younger patients and those with shorter disease duration had the highest frequency of elevated serum neurofilament light chain levels.

Interestingly, those with a higher body mass index (BMI) showed a reduced odds of having elevated serum neurofilament light chain levels (OR, 0.83 per 5 kg/m² increase in BMI).

Evaluation of neuroperformance measures – including walking speed, manual dexterity and processing speed, and MRI data – showed that those with elevated serum neurofilament light chain levels had worse neurologic function, lower brain parenchymal fraction, lower thalamic volume, and higher T2 lesion volume (P < .001 for all).

Dr. Sotirchos noted that the higher rates of elevations in younger people, also observed in previous clinical trials, may reflect higher early-stage disease activity. “Generally, people who are younger and earlier in the course of disease tend to have more inflammatory disease activity in MS, and that could be what we’re capturing here, but we need to better understand the pathologic correlates of elevated serum neurofilament light chain levels.”

The lower levels of neurofilament light chain with higher BMI, also recently reported in another study, likewise need further investigation, including in healthy controls, Dr. Sotirchos added. “Having lower serum neurofilament light chain levels with increasing BMI could have to do with effects of blood volume and how the serum neurofilament light chain levels is distributed in the body,” he explained.

The findings suggest that interpretation of serum neurofilament light chain levels without accounting for BMI could result in false-negative or false-positive results, Dr. Sotirchos noted. “It will be important to further evaluate this observation in control populations and account for BMI in neurofilament light chain reference ranges.”

Dr. Sotirchos added that the 17% rate of elevated serum neurofilament light chain levels seen in people with MS in the study is likely an underestimate.

“This is a cross-sectional study and represents one sample per patient, so it is a snapshot in time,” he said. “With the nature of MS, we know that people’s levels fluctuate over time.” In addition, most patients were on disease-modifying therapy for MS, so serum neurofilament light chain elevations could have been suppressed.
 

Applying the findings to individual patients

Commenting on the findings, Jennifer Graves, MD, PhD, director of the neuroimmunology research program at the University of California, San Diego, said the study is an important addition to the ongoing evidence on serum neurofilament light chain in MS.

“The current presented research importantly addresses the gaps we have in understanding how best to apply serum filament light chain levels to individual patients and not just using them to assess group level means of outcome measures,” she said.

“The MS PATHS collaborative is looking at multiple factors (in addition to MS activity) that drive serum neurofilament light chain levels so meaningful and practical cutoffs for what’s abnormal can be created,” said Dr. Graves, who also directs the Rady Children’s Pediatric MS Clinic in San Diego.

Dr. Graves noted that the findings on BMI were unexpected. “Elevated BMI has been shown to be associated with greater brain atrophy and greater relapses and disability in MS participants, so to have an opposite effect with serum neurofilament light chain is interesting.

“My thoughts would be that obesity is somehow affecting measurable blood levels of this marker. I think it less likely BMI has a protective effect against neurodegeneration given the observations with other MS outcome measures,” she added. 
 

Future research

In terms of future directions, Dr. Sotirchos noted that the researchers are following the group longitudinally to further assess changes in neurofilament light chain over time, and will be looking at associations with longitudinal, clinical, and radiologic outcomes.

The current research, meanwhile, offers important insights in terms of developing precision reference ranges, he noted.

“It appears that reference ranges may need to account for sex, race, BMI, and comorbid/lifestyle factors,” Dr. Sotirchos said, “in order to potentially improve the performance of serum neurofilament light chain as a biomarker in MS and other neurological diseases.”

The study received funding from Biogen and the MS PATHS network receives funding from Biogen. Dr. Sotirchos has served on scientific advisory boards for Alexion, Viela Bio, and Genentech, and has received speaker honoraria from Viela Bio and Biogen. Dr. Graves has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Elevations in serum neurofilament light chain levels in people with multiple sclerosis (MS) are significantly linked to worse neurologic function, clinical disability, and lower brain volumes, according to new findings from a large, diverse population of patients with MS. “This is one of the largest studies to evaluate serum neurofilament light chain levels in people with MS,” said lead author Elias S. Sotirchos, MD, an assistant professor of neurology at Johns Hopkins University, Baltimore.

“An important strength of this cohort is that it is a real-world cohort of patients followed in U.S. and European MS centers,” he said. “The study captures the diversity of the MS population, including demographics, comorbidities, lifestyle factors, and clinical characteristics that may otherwise not be captured in a clinical trial population.”

The research was presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
 

Scrutinizing serum neurofilament light chain levels in a real-world cohort

Neurofilaments – neuron-specific proteins that release in response to neuroaxonal injury – have been observed to be elevated in a variety of neurologic disorders, and with a need for biomarkers in MS, there is high interest of their role in the disease. But studies involving real-world, heterogeneous MS populations are lacking, the researchers noted.

To take a broader look at the issue, Dr. Sotirchos and colleagues conducted a cross-sectional evaluation of 6,968 people with MS in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS), a large network of MS centers in the United States and Europe.

Participants’ baseline serum neurofilament light chain levels were compared with those of 201 healthy controls in the cohort using a novel, high-throughput immunoassay (Siemens Healthineers).

Of those with MS, 1,202 (17.2%) showed elevated serum neurofilament light chain levels, above the age-specific 97.5th percentile derived from the healthy controls.

A look at key factors associated with elevations showed significant links to having progressive MS (odds ratio, 1.63), non-White race (OR, 1.43), type 2 diabetes (OR, 1.89), and smoking (current vs. never smoker; OR, 1.49).

Associations with age and symptom duration were somewhat complex, but overall, younger patients and those with shorter disease duration had the highest frequency of elevated serum neurofilament light chain levels.

Interestingly, those with a higher body mass index (BMI) showed a reduced odds of having elevated serum neurofilament light chain levels (OR, 0.83 per 5 kg/m² increase in BMI).

Evaluation of neuroperformance measures – including walking speed, manual dexterity and processing speed, and MRI data – showed that those with elevated serum neurofilament light chain levels had worse neurologic function, lower brain parenchymal fraction, lower thalamic volume, and higher T2 lesion volume (P < .001 for all).

Dr. Sotirchos noted that the higher rates of elevations in younger people, also observed in previous clinical trials, may reflect higher early-stage disease activity. “Generally, people who are younger and earlier in the course of disease tend to have more inflammatory disease activity in MS, and that could be what we’re capturing here, but we need to better understand the pathologic correlates of elevated serum neurofilament light chain levels.”

The lower levels of neurofilament light chain with higher BMI, also recently reported in another study, likewise need further investigation, including in healthy controls, Dr. Sotirchos added. “Having lower serum neurofilament light chain levels with increasing BMI could have to do with effects of blood volume and how the serum neurofilament light chain levels is distributed in the body,” he explained.

The findings suggest that interpretation of serum neurofilament light chain levels without accounting for BMI could result in false-negative or false-positive results, Dr. Sotirchos noted. “It will be important to further evaluate this observation in control populations and account for BMI in neurofilament light chain reference ranges.”

Dr. Sotirchos added that the 17% rate of elevated serum neurofilament light chain levels seen in people with MS in the study is likely an underestimate.

“This is a cross-sectional study and represents one sample per patient, so it is a snapshot in time,” he said. “With the nature of MS, we know that people’s levels fluctuate over time.” In addition, most patients were on disease-modifying therapy for MS, so serum neurofilament light chain elevations could have been suppressed.
 

Applying the findings to individual patients

Commenting on the findings, Jennifer Graves, MD, PhD, director of the neuroimmunology research program at the University of California, San Diego, said the study is an important addition to the ongoing evidence on serum neurofilament light chain in MS.

“The current presented research importantly addresses the gaps we have in understanding how best to apply serum filament light chain levels to individual patients and not just using them to assess group level means of outcome measures,” she said.

“The MS PATHS collaborative is looking at multiple factors (in addition to MS activity) that drive serum neurofilament light chain levels so meaningful and practical cutoffs for what’s abnormal can be created,” said Dr. Graves, who also directs the Rady Children’s Pediatric MS Clinic in San Diego.

Dr. Graves noted that the findings on BMI were unexpected. “Elevated BMI has been shown to be associated with greater brain atrophy and greater relapses and disability in MS participants, so to have an opposite effect with serum neurofilament light chain is interesting.

“My thoughts would be that obesity is somehow affecting measurable blood levels of this marker. I think it less likely BMI has a protective effect against neurodegeneration given the observations with other MS outcome measures,” she added. 
 

Future research

In terms of future directions, Dr. Sotirchos noted that the researchers are following the group longitudinally to further assess changes in neurofilament light chain over time, and will be looking at associations with longitudinal, clinical, and radiologic outcomes.

The current research, meanwhile, offers important insights in terms of developing precision reference ranges, he noted.

“It appears that reference ranges may need to account for sex, race, BMI, and comorbid/lifestyle factors,” Dr. Sotirchos said, “in order to potentially improve the performance of serum neurofilament light chain as a biomarker in MS and other neurological diseases.”

The study received funding from Biogen and the MS PATHS network receives funding from Biogen. Dr. Sotirchos has served on scientific advisory boards for Alexion, Viela Bio, and Genentech, and has received speaker honoraria from Viela Bio and Biogen. Dr. Graves has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Elevations in serum neurofilament light chain levels in people with multiple sclerosis (MS) are significantly linked to worse neurologic function, clinical disability, and lower brain volumes, according to new findings from a large, diverse population of patients with MS. “This is one of the largest studies to evaluate serum neurofilament light chain levels in people with MS,” said lead author Elias S. Sotirchos, MD, an assistant professor of neurology at Johns Hopkins University, Baltimore.

“An important strength of this cohort is that it is a real-world cohort of patients followed in U.S. and European MS centers,” he said. “The study captures the diversity of the MS population, including demographics, comorbidities, lifestyle factors, and clinical characteristics that may otherwise not be captured in a clinical trial population.”

The research was presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
 

Scrutinizing serum neurofilament light chain levels in a real-world cohort

Neurofilaments – neuron-specific proteins that release in response to neuroaxonal injury – have been observed to be elevated in a variety of neurologic disorders, and with a need for biomarkers in MS, there is high interest of their role in the disease. But studies involving real-world, heterogeneous MS populations are lacking, the researchers noted.

To take a broader look at the issue, Dr. Sotirchos and colleagues conducted a cross-sectional evaluation of 6,968 people with MS in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS), a large network of MS centers in the United States and Europe.

Participants’ baseline serum neurofilament light chain levels were compared with those of 201 healthy controls in the cohort using a novel, high-throughput immunoassay (Siemens Healthineers).

Of those with MS, 1,202 (17.2%) showed elevated serum neurofilament light chain levels, above the age-specific 97.5th percentile derived from the healthy controls.

A look at key factors associated with elevations showed significant links to having progressive MS (odds ratio, 1.63), non-White race (OR, 1.43), type 2 diabetes (OR, 1.89), and smoking (current vs. never smoker; OR, 1.49).

Associations with age and symptom duration were somewhat complex, but overall, younger patients and those with shorter disease duration had the highest frequency of elevated serum neurofilament light chain levels.

Interestingly, those with a higher body mass index (BMI) showed a reduced odds of having elevated serum neurofilament light chain levels (OR, 0.83 per 5 kg/m² increase in BMI).

Evaluation of neuroperformance measures – including walking speed, manual dexterity and processing speed, and MRI data – showed that those with elevated serum neurofilament light chain levels had worse neurologic function, lower brain parenchymal fraction, lower thalamic volume, and higher T2 lesion volume (P < .001 for all).

Dr. Sotirchos noted that the higher rates of elevations in younger people, also observed in previous clinical trials, may reflect higher early-stage disease activity. “Generally, people who are younger and earlier in the course of disease tend to have more inflammatory disease activity in MS, and that could be what we’re capturing here, but we need to better understand the pathologic correlates of elevated serum neurofilament light chain levels.”

The lower levels of neurofilament light chain with higher BMI, also recently reported in another study, likewise need further investigation, including in healthy controls, Dr. Sotirchos added. “Having lower serum neurofilament light chain levels with increasing BMI could have to do with effects of blood volume and how the serum neurofilament light chain levels is distributed in the body,” he explained.

The findings suggest that interpretation of serum neurofilament light chain levels without accounting for BMI could result in false-negative or false-positive results, Dr. Sotirchos noted. “It will be important to further evaluate this observation in control populations and account for BMI in neurofilament light chain reference ranges.”

Dr. Sotirchos added that the 17% rate of elevated serum neurofilament light chain levels seen in people with MS in the study is likely an underestimate.

“This is a cross-sectional study and represents one sample per patient, so it is a snapshot in time,” he said. “With the nature of MS, we know that people’s levels fluctuate over time.” In addition, most patients were on disease-modifying therapy for MS, so serum neurofilament light chain elevations could have been suppressed.
 

Applying the findings to individual patients

Commenting on the findings, Jennifer Graves, MD, PhD, director of the neuroimmunology research program at the University of California, San Diego, said the study is an important addition to the ongoing evidence on serum neurofilament light chain in MS.

“The current presented research importantly addresses the gaps we have in understanding how best to apply serum filament light chain levels to individual patients and not just using them to assess group level means of outcome measures,” she said.

“The MS PATHS collaborative is looking at multiple factors (in addition to MS activity) that drive serum neurofilament light chain levels so meaningful and practical cutoffs for what’s abnormal can be created,” said Dr. Graves, who also directs the Rady Children’s Pediatric MS Clinic in San Diego.

Dr. Graves noted that the findings on BMI were unexpected. “Elevated BMI has been shown to be associated with greater brain atrophy and greater relapses and disability in MS participants, so to have an opposite effect with serum neurofilament light chain is interesting.

“My thoughts would be that obesity is somehow affecting measurable blood levels of this marker. I think it less likely BMI has a protective effect against neurodegeneration given the observations with other MS outcome measures,” she added. 
 

Future research

In terms of future directions, Dr. Sotirchos noted that the researchers are following the group longitudinally to further assess changes in neurofilament light chain over time, and will be looking at associations with longitudinal, clinical, and radiologic outcomes.

The current research, meanwhile, offers important insights in terms of developing precision reference ranges, he noted.

“It appears that reference ranges may need to account for sex, race, BMI, and comorbid/lifestyle factors,” Dr. Sotirchos said, “in order to potentially improve the performance of serum neurofilament light chain as a biomarker in MS and other neurological diseases.”

The study received funding from Biogen and the MS PATHS network receives funding from Biogen. Dr. Sotirchos has served on scientific advisory boards for Alexion, Viela Bio, and Genentech, and has received speaker honoraria from Viela Bio and Biogen. Dr. Graves has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

There has been a marked increase in the time to antibiotic administration for ICU patients with sepsis across Veterans Affairs (VA) hospitals, but there is no evidence that they are being given inappropriately, according to new findings.

Accelerating time-to-antibiotics in sepsis means that patients will be treated earlier, but it could also result in more patients receiving antibiotics, including those without infection. This in turn may contribute to antimicrobial resistance.

“The time to antibiotics for sepsis accelerated across VA hospitals, and declined from 5.8 to 4.8 hours between 2013 and 2018,” said lead study author Sarah Seelye, PhD, data scientist at the U.S. Department of Veterans Affairs, Ann Arbor, Mich. “Despite this, there was no evidence between hospital level antibiotic acceleration in sepsis and antibiotic use among all patients with potential sepsis.”

The results were presented at the Critical Care Congress sponsored by the Society of Critical Care Medicine, which was held virtually this year.

“Many hospitals have initiated programs like this to accelerate the use of antibiotics in patients with severe sepsis, but at the same time, there is growing concern that earlier antibiotic initiation may result in increased antibiotic treatment overall, including those without infection,” said Dr. Seelye. “However, to date, there is little evidence to support this claim.”

The goal of their study was to investigate whether hospital-level acceleration in antibiotic timing for sepsis was associated with increasing antibiotic use among patients hospitalized with potential infection.

They identified 1,101,239 hospitalizations for potential infection in 132 VA hospitals during the period from 2013 to 2018. Of these patients, 608,128 (55.2%) received antibiotics within 48 hours of presentation to the emergency department. A total of 117,435 (10.7%) met the criteria for sepsis.

Hospitals were classified into tertiles of antibiotic acceleration for sepsis: rapid, slow, and flat.

In the VA system, patients with severe sepsis began receiving faster antibiotic treatment in 2017, compared with earlier years. In 2017-2018 more than 20% of sepsis patients had received their first treatment within 2 hours, compared with 14% in 2013-1014.

In 2017-2018, more than 20% of sepsis patients had received their first treatment within 2 hours, compared with 14% in 2013-1014.

Hospitals categorized as rapid accelerators decreased their time to antibiotic initiation from 6.4 hours to 4.5 hours, while slow accelerators went from 5.6 to 4.6 hours from 2013 to 2018, and flat accelerators remained stable during the time period (5.3 hours down to 5.2 hours).

However, statistical analysis showed no real difference between the three groups in antibiotic prescribing.

“Despite this, there was no evidence between hospital-level antibiotic acceleration in sepsis and antibiotic use among all patients with potential sepsis,” said Dr. Seelye.

Weighing in on the study results, Craig M. Coopersmith, MD, professor of surgery at Emory University, Atlanta, noted that these results are very convincing, considering the size of the study and that it encompassed 132 different facilities.

“It’s difficult to say how generalizable these results are but they are definitely generalizable to all hospitals in the VA system,” he said. “In general, there are similarities between large health care systems, and it would be surprising if we found the opposite to be true in non-VA health systems.”

However, he emphasized that there is some possibility that the results would not be identical because different health care systems have different methods of providing care.

“This paper does show that you can get antibiotics into patients faster, which can be life saving, without inappropriately using them on everybody,” Dr. Coopersmith said.

He explained that there is more attention being paid now to antibiotic stewardship, compared with 10 or 15 years ago. “Given the choice of giving someone a single dose of antibiotics who may not need it, as opposed to withholding them from someone who is septic which is life threatening, the risk benefit ratio weighs heavily towards starting them early,” he said. “And then escalate rapidly.”

There has been a marked increase in the time to antibiotic administration for ICU patients with sepsis across Veterans Affairs (VA) hospitals, but there is no evidence that they are being given inappropriately, according to new findings.

Accelerating time-to-antibiotics in sepsis means that patients will be treated earlier, but it could also result in more patients receiving antibiotics, including those without infection. This in turn may contribute to antimicrobial resistance.

“The time to antibiotics for sepsis accelerated across VA hospitals, and declined from 5.8 to 4.8 hours between 2013 and 2018,” said lead study author Sarah Seelye, PhD, data scientist at the U.S. Department of Veterans Affairs, Ann Arbor, Mich. “Despite this, there was no evidence between hospital level antibiotic acceleration in sepsis and antibiotic use among all patients with potential sepsis.”

The results were presented at the Critical Care Congress sponsored by the Society of Critical Care Medicine, which was held virtually this year.

“Many hospitals have initiated programs like this to accelerate the use of antibiotics in patients with severe sepsis, but at the same time, there is growing concern that earlier antibiotic initiation may result in increased antibiotic treatment overall, including those without infection,” said Dr. Seelye. “However, to date, there is little evidence to support this claim.”

The goal of their study was to investigate whether hospital-level acceleration in antibiotic timing for sepsis was associated with increasing antibiotic use among patients hospitalized with potential infection.

They identified 1,101,239 hospitalizations for potential infection in 132 VA hospitals during the period from 2013 to 2018. Of these patients, 608,128 (55.2%) received antibiotics within 48 hours of presentation to the emergency department. A total of 117,435 (10.7%) met the criteria for sepsis.

Hospitals were classified into tertiles of antibiotic acceleration for sepsis: rapid, slow, and flat.

In the VA system, patients with severe sepsis began receiving faster antibiotic treatment in 2017, compared with earlier years. In 2017-2018 more than 20% of sepsis patients had received their first treatment within 2 hours, compared with 14% in 2013-1014.

In 2017-2018, more than 20% of sepsis patients had received their first treatment within 2 hours, compared with 14% in 2013-1014.

Hospitals categorized as rapid accelerators decreased their time to antibiotic initiation from 6.4 hours to 4.5 hours, while slow accelerators went from 5.6 to 4.6 hours from 2013 to 2018, and flat accelerators remained stable during the time period (5.3 hours down to 5.2 hours).

However, statistical analysis showed no real difference between the three groups in antibiotic prescribing.

“Despite this, there was no evidence between hospital-level antibiotic acceleration in sepsis and antibiotic use among all patients with potential sepsis,” said Dr. Seelye.

Weighing in on the study results, Craig M. Coopersmith, MD, professor of surgery at Emory University, Atlanta, noted that these results are very convincing, considering the size of the study and that it encompassed 132 different facilities.

“It’s difficult to say how generalizable these results are but they are definitely generalizable to all hospitals in the VA system,” he said. “In general, there are similarities between large health care systems, and it would be surprising if we found the opposite to be true in non-VA health systems.”

However, he emphasized that there is some possibility that the results would not be identical because different health care systems have different methods of providing care.

“This paper does show that you can get antibiotics into patients faster, which can be life saving, without inappropriately using them on everybody,” Dr. Coopersmith said.

He explained that there is more attention being paid now to antibiotic stewardship, compared with 10 or 15 years ago. “Given the choice of giving someone a single dose of antibiotics who may not need it, as opposed to withholding them from someone who is septic which is life threatening, the risk benefit ratio weighs heavily towards starting them early,” he said. “And then escalate rapidly.”

There has been a marked increase in the time to antibiotic administration for ICU patients with sepsis across Veterans Affairs (VA) hospitals, but there is no evidence that they are being given inappropriately, according to new findings.

Accelerating time-to-antibiotics in sepsis means that patients will be treated earlier, but it could also result in more patients receiving antibiotics, including those without infection. This in turn may contribute to antimicrobial resistance.

“The time to antibiotics for sepsis accelerated across VA hospitals, and declined from 5.8 to 4.8 hours between 2013 and 2018,” said lead study author Sarah Seelye, PhD, data scientist at the U.S. Department of Veterans Affairs, Ann Arbor, Mich. “Despite this, there was no evidence between hospital level antibiotic acceleration in sepsis and antibiotic use among all patients with potential sepsis.”

The results were presented at the Critical Care Congress sponsored by the Society of Critical Care Medicine, which was held virtually this year.

“Many hospitals have initiated programs like this to accelerate the use of antibiotics in patients with severe sepsis, but at the same time, there is growing concern that earlier antibiotic initiation may result in increased antibiotic treatment overall, including those without infection,” said Dr. Seelye. “However, to date, there is little evidence to support this claim.”

The goal of their study was to investigate whether hospital-level acceleration in antibiotic timing for sepsis was associated with increasing antibiotic use among patients hospitalized with potential infection.

They identified 1,101,239 hospitalizations for potential infection in 132 VA hospitals during the period from 2013 to 2018. Of these patients, 608,128 (55.2%) received antibiotics within 48 hours of presentation to the emergency department. A total of 117,435 (10.7%) met the criteria for sepsis.

Hospitals were classified into tertiles of antibiotic acceleration for sepsis: rapid, slow, and flat.

In the VA system, patients with severe sepsis began receiving faster antibiotic treatment in 2017, compared with earlier years. In 2017-2018 more than 20% of sepsis patients had received their first treatment within 2 hours, compared with 14% in 2013-1014.

In 2017-2018, more than 20% of sepsis patients had received their first treatment within 2 hours, compared with 14% in 2013-1014.

Hospitals categorized as rapid accelerators decreased their time to antibiotic initiation from 6.4 hours to 4.5 hours, while slow accelerators went from 5.6 to 4.6 hours from 2013 to 2018, and flat accelerators remained stable during the time period (5.3 hours down to 5.2 hours).

However, statistical analysis showed no real difference between the three groups in antibiotic prescribing.

“Despite this, there was no evidence between hospital-level antibiotic acceleration in sepsis and antibiotic use among all patients with potential sepsis,” said Dr. Seelye.

Weighing in on the study results, Craig M. Coopersmith, MD, professor of surgery at Emory University, Atlanta, noted that these results are very convincing, considering the size of the study and that it encompassed 132 different facilities.

“It’s difficult to say how generalizable these results are but they are definitely generalizable to all hospitals in the VA system,” he said. “In general, there are similarities between large health care systems, and it would be surprising if we found the opposite to be true in non-VA health systems.”

However, he emphasized that there is some possibility that the results would not be identical because different health care systems have different methods of providing care.

“This paper does show that you can get antibiotics into patients faster, which can be life saving, without inappropriately using them on everybody,” Dr. Coopersmith said.

He explained that there is more attention being paid now to antibiotic stewardship, compared with 10 or 15 years ago. “Given the choice of giving someone a single dose of antibiotics who may not need it, as opposed to withholding them from someone who is septic which is life threatening, the risk benefit ratio weighs heavily towards starting them early,” he said. “And then escalate rapidly.”

Vitamin D deficiency detected at the time of multiple sclerosis (MS) diagnosis is associated with cognitive impairment and may also impact disability, according to new research that adds to the known adverse relationship between low vitamin D and MS.

“We confirmed that low vitamin D may affect not only early disability but also cognition in newly MS diagnosed patients,” said lead author Eleonora Virgilio, MD, of the MS Center, neurology unit, at the University of Eastern Piedmont, Novara, Italy.

“The possible effects of vitamin D on both cognition (in particular, information processing speed) and early disability in newly diagnosed MS patients needs to be further investigated because this association might represent a marker of future disability, supporting the need for prompt supplementation,” she said.

The findings were presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
 

Low vitamin D and MS

Previous studies have linked insufficient serum vitamin D with everything from the development of MS to activity and disease progression, but less has been reported on a specific link to the impairment of cognitive function, an important complication of MS.

“Cognitive impairment, and, in particular, slowed information processing speed, is very frequent in the MS population from the early stages of disease, and frequently underestimated,” Dr. Virgilio noted. “It has yet to be completely elucidated what the exact underlying mechanisms are.”

To evaluate the relationship, Dr. Virgilio and colleagues enrolled 60 patients in Italy with MS who were newly diagnosed and had serum vitamin D levels collected upon diagnosis. The participants were also tested at diagnosis with the Symbol Digit Modalities Test (SDMT) for information processing speed, which is a hallmark of the cognitive impairment that can occur in MS and is typically the first cognitive domain to show effects of the disease.

Among the patients, 40 were female and the mean age at diagnosis was 39.5 years; 90% had relapsing remitting MS at baseline and 10% had progressive MS. Their median Expanded Disability Status Scale score at diagnosis was 1.5.

At baseline, as many as 85% of the participants (51) had low serum vitamin D levels, defined as below 30 ng/mL, which Dr. Virgilio noted is consistent with other rates reported among people with MS in the Lombardy region of Italy, where the study was conducted.

The patients had a mean vitamin D level of 21.17 ng/mL (± 10.02), with 51.7% considered to have a deficiency (less than 20 ng/mL) and 33.3% with an insufficiency (20-30 ng/mL).

Of the patients, 16 (27%) had cognitive impairment, defined as a z score of 1.5 or less. Their mean raw SDMT score was 46.50 (± 14.73) and mean z score was –0.62 (± 1.29).

Importantly, those with cognitive impairment were significantly more likely to have severe hypovitaminosis D, compared with those with sufficient vitamin D levels, none of whom showed cognitive impairment (P = .02).

Furthermore, vitamin D levels positively correlated with SDMT raw values (P = .001) and z score (P = .008).

Over a mean follow-up of 2 years, a significant correlation was observed between serum vitamin D levels at diagnosis and early disability on the MS severity score (MSSS; P = .02) and a weak correlation with age-related MSSS (ARMSS; P = .08) at the last clinical follow-up.

Dr. Virgilio noted that factors including disease treatment effects or other factors could have played a role in the weaker results. “It is possible that the linear correlation we found was not as strong as expected [because of] an effect of treatment with disease-modifying therapies or vitamin D supplementation, or because of the short follow-up available at the moment for our population – only for a mean period of 2 years after MS diagnosis.”

The mechanisms for vitamin D deficiency in the MS population are likely multifactorial, with genetic as well as environmental links, she noted.

“The immunomodulatory effects of vitamin D are well known,” Dr. Virgilio said.

“Vitamin D was already linked to cognitive function in other neurodegenerative diseases, [including] Alzheimer’s disease, but more importantly, also in other autoimmune diseases, such as systemic lupus erythematosus,” she explained.
 

Vitamin D also linked to long-term cognitive function

The study adds to recent research showing longer-term effects of vitamin D deficiency and cognitive impairment in MS: In the longitudinal BENEFIT trial published in 2020, researchers following 278 patients with MS over the course of 11 years found that a 50 ng/L higher mean vitamin D level in the first 2 years of the study was associated with a 65% lower odds of a poor performance on Paced Auditory Serial Addition Test scores at the 11-year follow-up.

That study also looked at neurofilament light chain concentrations, which are associated with MS disease activity, and found they were 20% lower among those with higher vitamin D at baseline. Smokers also had lower cognitive scores.

“Lower vitamin D and smoking after clinical onset predicted worse long-term cognitive function and neuronal integrity in patients with MS,” the authors concluded.

The authors disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Vitamin D deficiency detected at the time of multiple sclerosis (MS) diagnosis is associated with cognitive impairment and may also impact disability, according to new research that adds to the known adverse relationship between low vitamin D and MS.

“We confirmed that low vitamin D may affect not only early disability but also cognition in newly MS diagnosed patients,” said lead author Eleonora Virgilio, MD, of the MS Center, neurology unit, at the University of Eastern Piedmont, Novara, Italy.

“The possible effects of vitamin D on both cognition (in particular, information processing speed) and early disability in newly diagnosed MS patients needs to be further investigated because this association might represent a marker of future disability, supporting the need for prompt supplementation,” she said.

The findings were presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
 

Low vitamin D and MS

Previous studies have linked insufficient serum vitamin D with everything from the development of MS to activity and disease progression, but less has been reported on a specific link to the impairment of cognitive function, an important complication of MS.

“Cognitive impairment, and, in particular, slowed information processing speed, is very frequent in the MS population from the early stages of disease, and frequently underestimated,” Dr. Virgilio noted. “It has yet to be completely elucidated what the exact underlying mechanisms are.”

To evaluate the relationship, Dr. Virgilio and colleagues enrolled 60 patients in Italy with MS who were newly diagnosed and had serum vitamin D levels collected upon diagnosis. The participants were also tested at diagnosis with the Symbol Digit Modalities Test (SDMT) for information processing speed, which is a hallmark of the cognitive impairment that can occur in MS and is typically the first cognitive domain to show effects of the disease.

Among the patients, 40 were female and the mean age at diagnosis was 39.5 years; 90% had relapsing remitting MS at baseline and 10% had progressive MS. Their median Expanded Disability Status Scale score at diagnosis was 1.5.

At baseline, as many as 85% of the participants (51) had low serum vitamin D levels, defined as below 30 ng/mL, which Dr. Virgilio noted is consistent with other rates reported among people with MS in the Lombardy region of Italy, where the study was conducted.

The patients had a mean vitamin D level of 21.17 ng/mL (± 10.02), with 51.7% considered to have a deficiency (less than 20 ng/mL) and 33.3% with an insufficiency (20-30 ng/mL).

Of the patients, 16 (27%) had cognitive impairment, defined as a z score of 1.5 or less. Their mean raw SDMT score was 46.50 (± 14.73) and mean z score was –0.62 (± 1.29).

Importantly, those with cognitive impairment were significantly more likely to have severe hypovitaminosis D, compared with those with sufficient vitamin D levels, none of whom showed cognitive impairment (P = .02).

Furthermore, vitamin D levels positively correlated with SDMT raw values (P = .001) and z score (P = .008).

Over a mean follow-up of 2 years, a significant correlation was observed between serum vitamin D levels at diagnosis and early disability on the MS severity score (MSSS; P = .02) and a weak correlation with age-related MSSS (ARMSS; P = .08) at the last clinical follow-up.

Dr. Virgilio noted that factors including disease treatment effects or other factors could have played a role in the weaker results. “It is possible that the linear correlation we found was not as strong as expected [because of] an effect of treatment with disease-modifying therapies or vitamin D supplementation, or because of the short follow-up available at the moment for our population – only for a mean period of 2 years after MS diagnosis.”

The mechanisms for vitamin D deficiency in the MS population are likely multifactorial, with genetic as well as environmental links, she noted.

“The immunomodulatory effects of vitamin D are well known,” Dr. Virgilio said.

“Vitamin D was already linked to cognitive function in other neurodegenerative diseases, [including] Alzheimer’s disease, but more importantly, also in other autoimmune diseases, such as systemic lupus erythematosus,” she explained.
 

Vitamin D also linked to long-term cognitive function

The study adds to recent research showing longer-term effects of vitamin D deficiency and cognitive impairment in MS: In the longitudinal BENEFIT trial published in 2020, researchers following 278 patients with MS over the course of 11 years found that a 50 ng/L higher mean vitamin D level in the first 2 years of the study was associated with a 65% lower odds of a poor performance on Paced Auditory Serial Addition Test scores at the 11-year follow-up.

That study also looked at neurofilament light chain concentrations, which are associated with MS disease activity, and found they were 20% lower among those with higher vitamin D at baseline. Smokers also had lower cognitive scores.

“Lower vitamin D and smoking after clinical onset predicted worse long-term cognitive function and neuronal integrity in patients with MS,” the authors concluded.

The authors disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Vitamin D deficiency detected at the time of multiple sclerosis (MS) diagnosis is associated with cognitive impairment and may also impact disability, according to new research that adds to the known adverse relationship between low vitamin D and MS.

“We confirmed that low vitamin D may affect not only early disability but also cognition in newly MS diagnosed patients,” said lead author Eleonora Virgilio, MD, of the MS Center, neurology unit, at the University of Eastern Piedmont, Novara, Italy.

“The possible effects of vitamin D on both cognition (in particular, information processing speed) and early disability in newly diagnosed MS patients needs to be further investigated because this association might represent a marker of future disability, supporting the need for prompt supplementation,” she said.

The findings were presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
 

Low vitamin D and MS

Previous studies have linked insufficient serum vitamin D with everything from the development of MS to activity and disease progression, but less has been reported on a specific link to the impairment of cognitive function, an important complication of MS.

“Cognitive impairment, and, in particular, slowed information processing speed, is very frequent in the MS population from the early stages of disease, and frequently underestimated,” Dr. Virgilio noted. “It has yet to be completely elucidated what the exact underlying mechanisms are.”

To evaluate the relationship, Dr. Virgilio and colleagues enrolled 60 patients in Italy with MS who were newly diagnosed and had serum vitamin D levels collected upon diagnosis. The participants were also tested at diagnosis with the Symbol Digit Modalities Test (SDMT) for information processing speed, which is a hallmark of the cognitive impairment that can occur in MS and is typically the first cognitive domain to show effects of the disease.

Among the patients, 40 were female and the mean age at diagnosis was 39.5 years; 90% had relapsing remitting MS at baseline and 10% had progressive MS. Their median Expanded Disability Status Scale score at diagnosis was 1.5.

At baseline, as many as 85% of the participants (51) had low serum vitamin D levels, defined as below 30 ng/mL, which Dr. Virgilio noted is consistent with other rates reported among people with MS in the Lombardy region of Italy, where the study was conducted.

The patients had a mean vitamin D level of 21.17 ng/mL (± 10.02), with 51.7% considered to have a deficiency (less than 20 ng/mL) and 33.3% with an insufficiency (20-30 ng/mL).

Of the patients, 16 (27%) had cognitive impairment, defined as a z score of 1.5 or less. Their mean raw SDMT score was 46.50 (± 14.73) and mean z score was –0.62 (± 1.29).

Importantly, those with cognitive impairment were significantly more likely to have severe hypovitaminosis D, compared with those with sufficient vitamin D levels, none of whom showed cognitive impairment (P = .02).

Furthermore, vitamin D levels positively correlated with SDMT raw values (P = .001) and z score (P = .008).

Over a mean follow-up of 2 years, a significant correlation was observed between serum vitamin D levels at diagnosis and early disability on the MS severity score (MSSS; P = .02) and a weak correlation with age-related MSSS (ARMSS; P = .08) at the last clinical follow-up.

Dr. Virgilio noted that factors including disease treatment effects or other factors could have played a role in the weaker results. “It is possible that the linear correlation we found was not as strong as expected [because of] an effect of treatment with disease-modifying therapies or vitamin D supplementation, or because of the short follow-up available at the moment for our population – only for a mean period of 2 years after MS diagnosis.”

The mechanisms for vitamin D deficiency in the MS population are likely multifactorial, with genetic as well as environmental links, she noted.

“The immunomodulatory effects of vitamin D are well known,” Dr. Virgilio said.

“Vitamin D was already linked to cognitive function in other neurodegenerative diseases, [including] Alzheimer’s disease, but more importantly, also in other autoimmune diseases, such as systemic lupus erythematosus,” she explained.
 

Vitamin D also linked to long-term cognitive function

The study adds to recent research showing longer-term effects of vitamin D deficiency and cognitive impairment in MS: In the longitudinal BENEFIT trial published in 2020, researchers following 278 patients with MS over the course of 11 years found that a 50 ng/L higher mean vitamin D level in the first 2 years of the study was associated with a 65% lower odds of a poor performance on Paced Auditory Serial Addition Test scores at the 11-year follow-up.

That study also looked at neurofilament light chain concentrations, which are associated with MS disease activity, and found they were 20% lower among those with higher vitamin D at baseline. Smokers also had lower cognitive scores.

“Lower vitamin D and smoking after clinical onset predicted worse long-term cognitive function and neuronal integrity in patients with MS,” the authors concluded.

The authors disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Metformin has a modest favorable effect on body mass index z score and insulin resistance in children and adolescents with obesity, compared with placebo, according to a systematic review of trial data.

moodboard/thinkstockphotos

“The available evidence is of varying quality,” however, and the drug increases the likelihood of gastrointestinal adverse effects, reported Reem Masarwa, PharmD, PhD, and colleagues in Pediatrics. “Nonetheless, metformin may be considered for use as a pharmacologic therapy in this pediatric population because of its modest efficacy, availability, cost, and safety profile.”

The Food and Drug Administration has approved metformin for the treatment of type 2 diabetes in children and adolescents. Doctors have used the drug off label for weight loss in children with obesity, but this use “remains controversial,” the review authors said.

To assess the efficacy and safety of metformin plus lifestyle interventions compared with placebo plus lifestyle interventions in children and adolescents with obesity, Dr. Masarwa, with the Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, and the department of epidemiology, biostatistics, and occupational health, McGill University, Montreal, and colleagues systematically reviewed data from randomized controlled trials (RCTs). Their review was published online in Pediatrics.

The investigators focused on studies that examined outcomes such as body mass index, BMI z score, insulin resistance, and gastrointestinal adverse effects. They excluded studies of children with type 2 diabetes.

The researchers included 24 RCTs in their review. The studies included 1,623 children and adolescents who received metformin (861 participants) or placebo (762 participants). Indications included uncomplicated obesity in 10 studies, obesity with insulin resistance in 9 studies, prediabetes in 3 studies, and nonalcoholic fatty liver disease in 2 studies. One of the trials did not incorporate a lifestyle cointervention.

Participants ranged in age from 4 years to 19 years, and trial durations ranged from 2 months to 2 years. The total daily dose of metformin ranged from 500 mg to 2,000 mg.

In 14 RCTs that reported BMI, metformin generally decreased BMI (range of mean changes: –2.70 to 1.30), compared with placebo (range of mean changes: –1.12 to 1.90), although three trials suggested that metformin increased BMI. The average difference in the treatment effect between the metformin and placebo groups ranged from –2.72 to 0.70. “Importantly, the authors of many RCTs reported variable treatment effects, preventing definitive conclusions from being drawn from individual trials,” Dr. Masarwa and coauthors wrote.

In seven RCTs that reported BMI z score, metformin consistently decreased BMI z score (range of mean changes: –0.37 to –0.03), compared with placebo (range of mean changes: –0.22 to 0.15). The mean difference in the treatment effect between treatment groups ranged from –0.15 to –0.07. The largest decrease occurred in patients with nonalcoholic fatty liver disease.

The rate of gastrointestinal adverse events nearly doubled with metformin treatment, relative to placebo (rate range: 2%-74% for metformin vs. 0%-42% for placebo).

Metformin adherence rates ranged from 60% to 90%, and lifestyle cointerventions varied substantially across the trials, the researchers noted. The clinical significance and long-term effects of metformin treatment in this population “remain uncertain,” they said.
 

Off-label use may not be ideal

“Ideally, children with obesity should be entered into a clinical trial rather than placed on an off-label medication,” Vandana Raman, MD, and Carol M. Foster, MD, said in a related commentary. Still, treatment with metformin may be reasonable in certain cases, said Dr. Raman and Dr. Foster of the division of endocrinology in the department of pediatrics at the University of Utah in Salt Lake City. “Metformin is a low-cost option and may provide modest clinical benefit for weight loss with minimal side effects. If lifestyle modification has been pursued but has achieved minimal weight loss, it may be reasonable to try an agent such as metformin as adjunctive therapy,” they said.

Lifestyle modification therapy – including nutritional changes, physical activity, and behavior modification – has been the “mainstay of management” for patients with obesity, and this approach underpins successful weight loss, they said. But durable weight loss with lifestyle modification may be challenging, and pharmacologic treatments “are attractive options before proceeding to bariatric surgery,” they said.

For younger patients, FDA-approved medications for obesity include orlistat and liraglutide for patients aged 12 years and older, and phentermine for patients aged 16 years and older.

“Orlistat has been associated with modest BMI reduction but may cause intolerable gastrointestinal side effects and possible fat-soluble vitamin deficiency,” they said. “Phentermine is approved for short-term therapy only and may increase heart rate and blood pressure and cause irritability and insomnia.”

Liraglutide, which was approved for the treatment of pediatric obesity in December 2020, reduced BMI in a trial that included adolescents with obesity. About 43% of the participants who received liraglutide, compared with 18% who received placebo, had a 5% reduction in BMI. In addition, 26% and 8%, respectively, had a 10% reduction in BMI. The use of liraglutide “is limited by the need for daily subcutaneous injections and high frequency of gastrointestinal side effects and high cost,” however, the commentary authors noted.

In addition, the FDA has approved setmelanotide for children older than 6 years with obesity caused by three rare genetic conditions.

Some small studies have suggested that topiramate may lead to meaningful weight loss in children, but the medication has been associated with cognitive dysfunction, they said.
 

Considering surgery

“This is an important review of the efficacy of metformin as a tool for weight loss in children with obesity,” said Suzanne C. Boulter, MD, adjunct professor emeritus of pediatrics and community and family medicine at the Geisel School of Medicine at Dartmouth in Hanover, N.H. “Results showed modest decreases in BMI z scores compared to placebo but there were a significant percentage of GI side effects and dropouts from the trials.”

“Tools other than lifestyle changes are needed to address” pediatric obesity, Dr. Boulter said. “Another tool is gastric bypass which is now a recommended intervention in selected clinical sites for adolescents 14 years of age and older with BMIs greater than 35.”

Dr. Boulter highlighted a recent study in Pediatrics that examined data from more than 200 adolescents who underwent bariatric surgery. The researchers found that outcomes were similar for older and younger patients.

“It would be interesting to pediatricians in practice to see a comparison study between metformin and bariatric surgery long-term results,” Dr. Boulter added.

Dr. Masarwa and coauthors received support from the Quebec Foundation for Health Research and the Canadian Institutes of Health Research Drug Safety and Effectiveness Cross-Disciplinary Training Program. One coauthor also is supported by an award from McGill University.

The authors of the systematic review and the accompanying commentary had no relevant financial disclosures. Dr. Boulter is a member of the editorial advisory board for Pediatric News and had no relevant financial disclosures.

[email protected]

Metformin has a modest favorable effect on body mass index z score and insulin resistance in children and adolescents with obesity, compared with placebo, according to a systematic review of trial data.

moodboard/thinkstockphotos

“The available evidence is of varying quality,” however, and the drug increases the likelihood of gastrointestinal adverse effects, reported Reem Masarwa, PharmD, PhD, and colleagues in Pediatrics. “Nonetheless, metformin may be considered for use as a pharmacologic therapy in this pediatric population because of its modest efficacy, availability, cost, and safety profile.”

The Food and Drug Administration has approved metformin for the treatment of type 2 diabetes in children and adolescents. Doctors have used the drug off label for weight loss in children with obesity, but this use “remains controversial,” the review authors said.

To assess the efficacy and safety of metformin plus lifestyle interventions compared with placebo plus lifestyle interventions in children and adolescents with obesity, Dr. Masarwa, with the Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, and the department of epidemiology, biostatistics, and occupational health, McGill University, Montreal, and colleagues systematically reviewed data from randomized controlled trials (RCTs). Their review was published online in Pediatrics.

The investigators focused on studies that examined outcomes such as body mass index, BMI z score, insulin resistance, and gastrointestinal adverse effects. They excluded studies of children with type 2 diabetes.

The researchers included 24 RCTs in their review. The studies included 1,623 children and adolescents who received metformin (861 participants) or placebo (762 participants). Indications included uncomplicated obesity in 10 studies, obesity with insulin resistance in 9 studies, prediabetes in 3 studies, and nonalcoholic fatty liver disease in 2 studies. One of the trials did not incorporate a lifestyle cointervention.

Participants ranged in age from 4 years to 19 years, and trial durations ranged from 2 months to 2 years. The total daily dose of metformin ranged from 500 mg to 2,000 mg.

In 14 RCTs that reported BMI, metformin generally decreased BMI (range of mean changes: –2.70 to 1.30), compared with placebo (range of mean changes: –1.12 to 1.90), although three trials suggested that metformin increased BMI. The average difference in the treatment effect between the metformin and placebo groups ranged from –2.72 to 0.70. “Importantly, the authors of many RCTs reported variable treatment effects, preventing definitive conclusions from being drawn from individual trials,” Dr. Masarwa and coauthors wrote.

In seven RCTs that reported BMI z score, metformin consistently decreased BMI z score (range of mean changes: –0.37 to –0.03), compared with placebo (range of mean changes: –0.22 to 0.15). The mean difference in the treatment effect between treatment groups ranged from –0.15 to –0.07. The largest decrease occurred in patients with nonalcoholic fatty liver disease.

The rate of gastrointestinal adverse events nearly doubled with metformin treatment, relative to placebo (rate range: 2%-74% for metformin vs. 0%-42% for placebo).

Metformin adherence rates ranged from 60% to 90%, and lifestyle cointerventions varied substantially across the trials, the researchers noted. The clinical significance and long-term effects of metformin treatment in this population “remain uncertain,” they said.
 

Off-label use may not be ideal

“Ideally, children with obesity should be entered into a clinical trial rather than placed on an off-label medication,” Vandana Raman, MD, and Carol M. Foster, MD, said in a related commentary. Still, treatment with metformin may be reasonable in certain cases, said Dr. Raman and Dr. Foster of the division of endocrinology in the department of pediatrics at the University of Utah in Salt Lake City. “Metformin is a low-cost option and may provide modest clinical benefit for weight loss with minimal side effects. If lifestyle modification has been pursued but has achieved minimal weight loss, it may be reasonable to try an agent such as metformin as adjunctive therapy,” they said.

Lifestyle modification therapy – including nutritional changes, physical activity, and behavior modification – has been the “mainstay of management” for patients with obesity, and this approach underpins successful weight loss, they said. But durable weight loss with lifestyle modification may be challenging, and pharmacologic treatments “are attractive options before proceeding to bariatric surgery,” they said.

For younger patients, FDA-approved medications for obesity include orlistat and liraglutide for patients aged 12 years and older, and phentermine for patients aged 16 years and older.

“Orlistat has been associated with modest BMI reduction but may cause intolerable gastrointestinal side effects and possible fat-soluble vitamin deficiency,” they said. “Phentermine is approved for short-term therapy only and may increase heart rate and blood pressure and cause irritability and insomnia.”

Liraglutide, which was approved for the treatment of pediatric obesity in December 2020, reduced BMI in a trial that included adolescents with obesity. About 43% of the participants who received liraglutide, compared with 18% who received placebo, had a 5% reduction in BMI. In addition, 26% and 8%, respectively, had a 10% reduction in BMI. The use of liraglutide “is limited by the need for daily subcutaneous injections and high frequency of gastrointestinal side effects and high cost,” however, the commentary authors noted.

In addition, the FDA has approved setmelanotide for children older than 6 years with obesity caused by three rare genetic conditions.

Some small studies have suggested that topiramate may lead to meaningful weight loss in children, but the medication has been associated with cognitive dysfunction, they said.
 

Considering surgery

“This is an important review of the efficacy of metformin as a tool for weight loss in children with obesity,” said Suzanne C. Boulter, MD, adjunct professor emeritus of pediatrics and community and family medicine at the Geisel School of Medicine at Dartmouth in Hanover, N.H. “Results showed modest decreases in BMI z scores compared to placebo but there were a significant percentage of GI side effects and dropouts from the trials.”

“Tools other than lifestyle changes are needed to address” pediatric obesity, Dr. Boulter said. “Another tool is gastric bypass which is now a recommended intervention in selected clinical sites for adolescents 14 years of age and older with BMIs greater than 35.”

Dr. Boulter highlighted a recent study in Pediatrics that examined data from more than 200 adolescents who underwent bariatric surgery. The researchers found that outcomes were similar for older and younger patients.

“It would be interesting to pediatricians in practice to see a comparison study between metformin and bariatric surgery long-term results,” Dr. Boulter added.

Dr. Masarwa and coauthors received support from the Quebec Foundation for Health Research and the Canadian Institutes of Health Research Drug Safety and Effectiveness Cross-Disciplinary Training Program. One coauthor also is supported by an award from McGill University.

The authors of the systematic review and the accompanying commentary had no relevant financial disclosures. Dr. Boulter is a member of the editorial advisory board for Pediatric News and had no relevant financial disclosures.

[email protected]

Metformin has a modest favorable effect on body mass index z score and insulin resistance in children and adolescents with obesity, compared with placebo, according to a systematic review of trial data.

moodboard/thinkstockphotos

“The available evidence is of varying quality,” however, and the drug increases the likelihood of gastrointestinal adverse effects, reported Reem Masarwa, PharmD, PhD, and colleagues in Pediatrics. “Nonetheless, metformin may be considered for use as a pharmacologic therapy in this pediatric population because of its modest efficacy, availability, cost, and safety profile.”

The Food and Drug Administration has approved metformin for the treatment of type 2 diabetes in children and adolescents. Doctors have used the drug off label for weight loss in children with obesity, but this use “remains controversial,” the review authors said.

To assess the efficacy and safety of metformin plus lifestyle interventions compared with placebo plus lifestyle interventions in children and adolescents with obesity, Dr. Masarwa, with the Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, and the department of epidemiology, biostatistics, and occupational health, McGill University, Montreal, and colleagues systematically reviewed data from randomized controlled trials (RCTs). Their review was published online in Pediatrics.

The investigators focused on studies that examined outcomes such as body mass index, BMI z score, insulin resistance, and gastrointestinal adverse effects. They excluded studies of children with type 2 diabetes.

The researchers included 24 RCTs in their review. The studies included 1,623 children and adolescents who received metformin (861 participants) or placebo (762 participants). Indications included uncomplicated obesity in 10 studies, obesity with insulin resistance in 9 studies, prediabetes in 3 studies, and nonalcoholic fatty liver disease in 2 studies. One of the trials did not incorporate a lifestyle cointervention.

Participants ranged in age from 4 years to 19 years, and trial durations ranged from 2 months to 2 years. The total daily dose of metformin ranged from 500 mg to 2,000 mg.

In 14 RCTs that reported BMI, metformin generally decreased BMI (range of mean changes: –2.70 to 1.30), compared with placebo (range of mean changes: –1.12 to 1.90), although three trials suggested that metformin increased BMI. The average difference in the treatment effect between the metformin and placebo groups ranged from –2.72 to 0.70. “Importantly, the authors of many RCTs reported variable treatment effects, preventing definitive conclusions from being drawn from individual trials,” Dr. Masarwa and coauthors wrote.

In seven RCTs that reported BMI z score, metformin consistently decreased BMI z score (range of mean changes: –0.37 to –0.03), compared with placebo (range of mean changes: –0.22 to 0.15). The mean difference in the treatment effect between treatment groups ranged from –0.15 to –0.07. The largest decrease occurred in patients with nonalcoholic fatty liver disease.

The rate of gastrointestinal adverse events nearly doubled with metformin treatment, relative to placebo (rate range: 2%-74% for metformin vs. 0%-42% for placebo).

Metformin adherence rates ranged from 60% to 90%, and lifestyle cointerventions varied substantially across the trials, the researchers noted. The clinical significance and long-term effects of metformin treatment in this population “remain uncertain,” they said.
 

Off-label use may not be ideal

“Ideally, children with obesity should be entered into a clinical trial rather than placed on an off-label medication,” Vandana Raman, MD, and Carol M. Foster, MD, said in a related commentary. Still, treatment with metformin may be reasonable in certain cases, said Dr. Raman and Dr. Foster of the division of endocrinology in the department of pediatrics at the University of Utah in Salt Lake City. “Metformin is a low-cost option and may provide modest clinical benefit for weight loss with minimal side effects. If lifestyle modification has been pursued but has achieved minimal weight loss, it may be reasonable to try an agent such as metformin as adjunctive therapy,” they said.

Lifestyle modification therapy – including nutritional changes, physical activity, and behavior modification – has been the “mainstay of management” for patients with obesity, and this approach underpins successful weight loss, they said. But durable weight loss with lifestyle modification may be challenging, and pharmacologic treatments “are attractive options before proceeding to bariatric surgery,” they said.

For younger patients, FDA-approved medications for obesity include orlistat and liraglutide for patients aged 12 years and older, and phentermine for patients aged 16 years and older.

“Orlistat has been associated with modest BMI reduction but may cause intolerable gastrointestinal side effects and possible fat-soluble vitamin deficiency,” they said. “Phentermine is approved for short-term therapy only and may increase heart rate and blood pressure and cause irritability and insomnia.”

Liraglutide, which was approved for the treatment of pediatric obesity in December 2020, reduced BMI in a trial that included adolescents with obesity. About 43% of the participants who received liraglutide, compared with 18% who received placebo, had a 5% reduction in BMI. In addition, 26% and 8%, respectively, had a 10% reduction in BMI. The use of liraglutide “is limited by the need for daily subcutaneous injections and high frequency of gastrointestinal side effects and high cost,” however, the commentary authors noted.

In addition, the FDA has approved setmelanotide for children older than 6 years with obesity caused by three rare genetic conditions.

Some small studies have suggested that topiramate may lead to meaningful weight loss in children, but the medication has been associated with cognitive dysfunction, they said.
 

Considering surgery

“This is an important review of the efficacy of metformin as a tool for weight loss in children with obesity,” said Suzanne C. Boulter, MD, adjunct professor emeritus of pediatrics and community and family medicine at the Geisel School of Medicine at Dartmouth in Hanover, N.H. “Results showed modest decreases in BMI z scores compared to placebo but there were a significant percentage of GI side effects and dropouts from the trials.”

“Tools other than lifestyle changes are needed to address” pediatric obesity, Dr. Boulter said. “Another tool is gastric bypass which is now a recommended intervention in selected clinical sites for adolescents 14 years of age and older with BMIs greater than 35.”

Dr. Boulter highlighted a recent study in Pediatrics that examined data from more than 200 adolescents who underwent bariatric surgery. The researchers found that outcomes were similar for older and younger patients.

“It would be interesting to pediatricians in practice to see a comparison study between metformin and bariatric surgery long-term results,” Dr. Boulter added.

Dr. Masarwa and coauthors received support from the Quebec Foundation for Health Research and the Canadian Institutes of Health Research Drug Safety and Effectiveness Cross-Disciplinary Training Program. One coauthor also is supported by an award from McGill University.

The authors of the systematic review and the accompanying commentary had no relevant financial disclosures. Dr. Boulter is a member of the editorial advisory board for Pediatric News and had no relevant financial disclosures.

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