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Atrial fibrillation is being seen with increasing frequency in patients admitted to U.S. hospitals for exacerbations of end-stage chronic obstructive pulmonary disease, based on a retrospective analysis of data from the Nationwide Inpatient Sample.

The prevalence of atrial fibrillation (AFib) among patients with end-stage chronic obstructive pulmonary disease (COPD) on home oxygen who were admitted with COPD exacerbations increased from 12.9% in 2003 to 21.3% in 2014, according to Xiaochun Xiao of the department of health statistics at Second Military Medical University in Shanghai and colleagues.

Additionally, “we found that comorbid [AFib] was associated with an increased risk of the need for mechanical ventilation, especially invasive mechanical ventilation. Moreover, comorbid [AFib] was associated with adverse clinical outcomes, including increased in-hospital death, acute respiratory failure, acute kidney injury, sepsis, and stroke,” the researchers wrote in the study published in the journal CHEST.

Patients included in the study were aged at least 18 years, were diagnosed with end-stage COPD and on home oxygen, and were hospitalized because of a COPD-related exacerbation. Based on 1,345,270 weighted hospital admissions of adults with end-stage COPD on home oxygen who met the inclusion criteria for the study, 18.2% (244,488 admissions) of patients had AFib, and the prevalence of AFib in COPD patients increased over time from 2003 (12.9%) to 2014 (21.3%; P less than .0001).

Patients with AFib, compared with patients without AFib, were older (75.5 years vs. 69.6 years; P less than .0001) and more likely to be male (50.7% vs. 59.1%; P less than .0001) and white (80.9% vs. 74.4%; P less than .0001). Patients with AFib also had higher stroke risk reflected in higher CHA₂DS₂-VASc scores (3.26 vs. 2.45; P less than .0001), and higher likelihood of in-hospital mortality and readmission reflected in Elixhauser scores greater than or equal to 4 (51.2% vs. 35.6%).

In addition, the prevalence of AFib increased with increasing income. Larger hospitals in terms of bed size, urban environment, and Medicare insurance status also were associated with a higher AFib prevalence.

AFib was associated with an increased cost of $1,415 and an increased length of stay of 0.6 days after adjustment for potential confounders. AFib also predicted risk for several adverse events, including stroke (odds ratio, 1.80; in-hospital death, [OR, 1.54]), invasive mechanical ventilation (OR, 1.37), sepsis (OR, 1.23), noninvasive mechanical ventilation (OR, 1.14), acute kidney injury (OR, 1.09), and acute respiratory failure (OR, 1.09).

The researchers noted the database could have potentially overinflated AFib prevalence, as they could not differentiate index admissions and readmissions. The database also does not contain information about secondary diagnoses codes present on admission, which could make it difficult to identify adverse events that occurred during hospitalization.

“Our findings should prompt further efforts to identify the reasons for increased [AFib] prevalence and provide better management strategies for end-stage COPD patients comorbid with [AFib],” the researchers concluded.

This study was funded by a grant from the Fourth Round of the Shanghai 3-year Action Plan on Public Health Discipline and Talent Program. The authors reported no relevant conflict of interest.

SOURCE: Xiao X et al. CHEST. 2019 Jan 23. doi: 10.1016/j.chest.2018.12.021.

Atrial fibrillation is being seen with increasing frequency in patients admitted to U.S. hospitals for exacerbations of end-stage chronic obstructive pulmonary disease, based on a retrospective analysis of data from the Nationwide Inpatient Sample.

The prevalence of atrial fibrillation (AFib) among patients with end-stage chronic obstructive pulmonary disease (COPD) on home oxygen who were admitted with COPD exacerbations increased from 12.9% in 2003 to 21.3% in 2014, according to Xiaochun Xiao of the department of health statistics at Second Military Medical University in Shanghai and colleagues.

Additionally, “we found that comorbid [AFib] was associated with an increased risk of the need for mechanical ventilation, especially invasive mechanical ventilation. Moreover, comorbid [AFib] was associated with adverse clinical outcomes, including increased in-hospital death, acute respiratory failure, acute kidney injury, sepsis, and stroke,” the researchers wrote in the study published in the journal CHEST.

Patients included in the study were aged at least 18 years, were diagnosed with end-stage COPD and on home oxygen, and were hospitalized because of a COPD-related exacerbation. Based on 1,345,270 weighted hospital admissions of adults with end-stage COPD on home oxygen who met the inclusion criteria for the study, 18.2% (244,488 admissions) of patients had AFib, and the prevalence of AFib in COPD patients increased over time from 2003 (12.9%) to 2014 (21.3%; P less than .0001).

Patients with AFib, compared with patients without AFib, were older (75.5 years vs. 69.6 years; P less than .0001) and more likely to be male (50.7% vs. 59.1%; P less than .0001) and white (80.9% vs. 74.4%; P less than .0001). Patients with AFib also had higher stroke risk reflected in higher CHA₂DS₂-VASc scores (3.26 vs. 2.45; P less than .0001), and higher likelihood of in-hospital mortality and readmission reflected in Elixhauser scores greater than or equal to 4 (51.2% vs. 35.6%).

In addition, the prevalence of AFib increased with increasing income. Larger hospitals in terms of bed size, urban environment, and Medicare insurance status also were associated with a higher AFib prevalence.

AFib was associated with an increased cost of $1,415 and an increased length of stay of 0.6 days after adjustment for potential confounders. AFib also predicted risk for several adverse events, including stroke (odds ratio, 1.80; in-hospital death, [OR, 1.54]), invasive mechanical ventilation (OR, 1.37), sepsis (OR, 1.23), noninvasive mechanical ventilation (OR, 1.14), acute kidney injury (OR, 1.09), and acute respiratory failure (OR, 1.09).

The researchers noted the database could have potentially overinflated AFib prevalence, as they could not differentiate index admissions and readmissions. The database also does not contain information about secondary diagnoses codes present on admission, which could make it difficult to identify adverse events that occurred during hospitalization.

“Our findings should prompt further efforts to identify the reasons for increased [AFib] prevalence and provide better management strategies for end-stage COPD patients comorbid with [AFib],” the researchers concluded.

This study was funded by a grant from the Fourth Round of the Shanghai 3-year Action Plan on Public Health Discipline and Talent Program. The authors reported no relevant conflict of interest.

SOURCE: Xiao X et al. CHEST. 2019 Jan 23. doi: 10.1016/j.chest.2018.12.021.

Atrial fibrillation is being seen with increasing frequency in patients admitted to U.S. hospitals for exacerbations of end-stage chronic obstructive pulmonary disease, based on a retrospective analysis of data from the Nationwide Inpatient Sample.

The prevalence of atrial fibrillation (AFib) among patients with end-stage chronic obstructive pulmonary disease (COPD) on home oxygen who were admitted with COPD exacerbations increased from 12.9% in 2003 to 21.3% in 2014, according to Xiaochun Xiao of the department of health statistics at Second Military Medical University in Shanghai and colleagues.

Additionally, “we found that comorbid [AFib] was associated with an increased risk of the need for mechanical ventilation, especially invasive mechanical ventilation. Moreover, comorbid [AFib] was associated with adverse clinical outcomes, including increased in-hospital death, acute respiratory failure, acute kidney injury, sepsis, and stroke,” the researchers wrote in the study published in the journal CHEST.

Patients included in the study were aged at least 18 years, were diagnosed with end-stage COPD and on home oxygen, and were hospitalized because of a COPD-related exacerbation. Based on 1,345,270 weighted hospital admissions of adults with end-stage COPD on home oxygen who met the inclusion criteria for the study, 18.2% (244,488 admissions) of patients had AFib, and the prevalence of AFib in COPD patients increased over time from 2003 (12.9%) to 2014 (21.3%; P less than .0001).

Patients with AFib, compared with patients without AFib, were older (75.5 years vs. 69.6 years; P less than .0001) and more likely to be male (50.7% vs. 59.1%; P less than .0001) and white (80.9% vs. 74.4%; P less than .0001). Patients with AFib also had higher stroke risk reflected in higher CHA₂DS₂-VASc scores (3.26 vs. 2.45; P less than .0001), and higher likelihood of in-hospital mortality and readmission reflected in Elixhauser scores greater than or equal to 4 (51.2% vs. 35.6%).

In addition, the prevalence of AFib increased with increasing income. Larger hospitals in terms of bed size, urban environment, and Medicare insurance status also were associated with a higher AFib prevalence.

AFib was associated with an increased cost of $1,415 and an increased length of stay of 0.6 days after adjustment for potential confounders. AFib also predicted risk for several adverse events, including stroke (odds ratio, 1.80; in-hospital death, [OR, 1.54]), invasive mechanical ventilation (OR, 1.37), sepsis (OR, 1.23), noninvasive mechanical ventilation (OR, 1.14), acute kidney injury (OR, 1.09), and acute respiratory failure (OR, 1.09).

The researchers noted the database could have potentially overinflated AFib prevalence, as they could not differentiate index admissions and readmissions. The database also does not contain information about secondary diagnoses codes present on admission, which could make it difficult to identify adverse events that occurred during hospitalization.

“Our findings should prompt further efforts to identify the reasons for increased [AFib] prevalence and provide better management strategies for end-stage COPD patients comorbid with [AFib],” the researchers concluded.

This study was funded by a grant from the Fourth Round of the Shanghai 3-year Action Plan on Public Health Discipline and Talent Program. The authors reported no relevant conflict of interest.

SOURCE: Xiao X et al. CHEST. 2019 Jan 23. doi: 10.1016/j.chest.2018.12.021.

While an increasing number of U.S. citizens are saying no to cigarettes, current smoking rates are holding steady among people who face multiple forms of socioeconomic or health-related disadvantages, a recent study shows.

Terroa/iStock/Getty Images

The odds of current smoking, versus never smoking, declined significantly during 2008-2017 for individuals with none of six disadvantages tied to cigarette use, including disability, unemployment, poverty, low education, psychological distress, and heavy alcohol intake, according to researchers.

Individuals with one or two of those disadvantages have also been cutting back, the data suggest. But, by contrast, odds of current versus never smoking did not significantly change for those with three or more disadvantages, according to Adam M. Leventhal, PhD, of the University of Southern California, Los Angeles, and coinvestigators.

“How this pattern can inform a cohesive policy agenda is unknown, but it is clear from these findings that the crux of the recently expanding tobacco-related health disparity problem in the United States is not tied to groups facing merely a single form of disadvantage,” Dr. Leventhal and coauthors wrote in a report on the study in JAMA Internal Medicine.

The cross-sectional analysis by Dr. Leventhal and colleagues was based on National Health Interview Survey (NHIS) data from 2008-2017 including more than 278,000 respondents aged 25 years or older.

A snapshot of that 10-year period showed that current smoking prevalence was successively higher depending on the number of socioeconomic or health-related disadvantages.

The mean prevalence of current smoking over that entire time period was just 13.8% for people with zero of the six disadvantages, 21.4% for those with one disadvantage, and so on, up to 58.2% for those with all six disadvantages, according to data in the published report.

Encouragingly, overall smoking prevalence fell from 20.8% in 2008-2009 to 15.8% in 2016-2017, the researchers found. However, the decreasing trend was not apparent for individuals with many disadvantages.

The odds ratio for change in odds of smoking per year was 0.951 (95% confidence interval, 0.944-0.958) for those with zero disadvantages, 0.96 (95% CI, 0.95-0.97) for one disadvantage, and 0.98 (95% CI, 0.97-0.99) for two, all representing significant annual reductions in current versus never smoking, investigators said. By contrast, no such significant changes were apparent for those with three, four, five, or six such disadvantages.

Tobacco control or regulatory policies that consider these disadvantages separately may be overlooking a “broader pattern” showing that the cumulative number of disadvantages correlates with the magnitude of disparity, wrote Dr. Leventhal and colleagues in their report.

“Successful prevention of smoking initiation and promotion of smoking cessation in multi-disadvantaged populations would substantially reduce the smoking-related public health burden in the United States,” they concluded.

Dr. Leventhal and colleagues reported no conflicts related to their research, which was supported in part by a Tobacco Centers of Regulatory Science award from the National Cancer Institute and the Food and Drug Administration, among other sources.

SOURCE: Leventhal AM et al. JAMA Intern Med. 2019 Apr 22. doi: 10.1001/jamainternmed.2019.0192.

While an increasing number of U.S. citizens are saying no to cigarettes, current smoking rates are holding steady among people who face multiple forms of socioeconomic or health-related disadvantages, a recent study shows.

Terroa/iStock/Getty Images

The odds of current smoking, versus never smoking, declined significantly during 2008-2017 for individuals with none of six disadvantages tied to cigarette use, including disability, unemployment, poverty, low education, psychological distress, and heavy alcohol intake, according to researchers.

Individuals with one or two of those disadvantages have also been cutting back, the data suggest. But, by contrast, odds of current versus never smoking did not significantly change for those with three or more disadvantages, according to Adam M. Leventhal, PhD, of the University of Southern California, Los Angeles, and coinvestigators.

“How this pattern can inform a cohesive policy agenda is unknown, but it is clear from these findings that the crux of the recently expanding tobacco-related health disparity problem in the United States is not tied to groups facing merely a single form of disadvantage,” Dr. Leventhal and coauthors wrote in a report on the study in JAMA Internal Medicine.

The cross-sectional analysis by Dr. Leventhal and colleagues was based on National Health Interview Survey (NHIS) data from 2008-2017 including more than 278,000 respondents aged 25 years or older.

A snapshot of that 10-year period showed that current smoking prevalence was successively higher depending on the number of socioeconomic or health-related disadvantages.

The mean prevalence of current smoking over that entire time period was just 13.8% for people with zero of the six disadvantages, 21.4% for those with one disadvantage, and so on, up to 58.2% for those with all six disadvantages, according to data in the published report.

Encouragingly, overall smoking prevalence fell from 20.8% in 2008-2009 to 15.8% in 2016-2017, the researchers found. However, the decreasing trend was not apparent for individuals with many disadvantages.

The odds ratio for change in odds of smoking per year was 0.951 (95% confidence interval, 0.944-0.958) for those with zero disadvantages, 0.96 (95% CI, 0.95-0.97) for one disadvantage, and 0.98 (95% CI, 0.97-0.99) for two, all representing significant annual reductions in current versus never smoking, investigators said. By contrast, no such significant changes were apparent for those with three, four, five, or six such disadvantages.

Tobacco control or regulatory policies that consider these disadvantages separately may be overlooking a “broader pattern” showing that the cumulative number of disadvantages correlates with the magnitude of disparity, wrote Dr. Leventhal and colleagues in their report.

“Successful prevention of smoking initiation and promotion of smoking cessation in multi-disadvantaged populations would substantially reduce the smoking-related public health burden in the United States,” they concluded.

Dr. Leventhal and colleagues reported no conflicts related to their research, which was supported in part by a Tobacco Centers of Regulatory Science award from the National Cancer Institute and the Food and Drug Administration, among other sources.

SOURCE: Leventhal AM et al. JAMA Intern Med. 2019 Apr 22. doi: 10.1001/jamainternmed.2019.0192.

While an increasing number of U.S. citizens are saying no to cigarettes, current smoking rates are holding steady among people who face multiple forms of socioeconomic or health-related disadvantages, a recent study shows.

Terroa/iStock/Getty Images

The odds of current smoking, versus never smoking, declined significantly during 2008-2017 for individuals with none of six disadvantages tied to cigarette use, including disability, unemployment, poverty, low education, psychological distress, and heavy alcohol intake, according to researchers.

Individuals with one or two of those disadvantages have also been cutting back, the data suggest. But, by contrast, odds of current versus never smoking did not significantly change for those with three or more disadvantages, according to Adam M. Leventhal, PhD, of the University of Southern California, Los Angeles, and coinvestigators.

“How this pattern can inform a cohesive policy agenda is unknown, but it is clear from these findings that the crux of the recently expanding tobacco-related health disparity problem in the United States is not tied to groups facing merely a single form of disadvantage,” Dr. Leventhal and coauthors wrote in a report on the study in JAMA Internal Medicine.

The cross-sectional analysis by Dr. Leventhal and colleagues was based on National Health Interview Survey (NHIS) data from 2008-2017 including more than 278,000 respondents aged 25 years or older.

A snapshot of that 10-year period showed that current smoking prevalence was successively higher depending on the number of socioeconomic or health-related disadvantages.

The mean prevalence of current smoking over that entire time period was just 13.8% for people with zero of the six disadvantages, 21.4% for those with one disadvantage, and so on, up to 58.2% for those with all six disadvantages, according to data in the published report.

Encouragingly, overall smoking prevalence fell from 20.8% in 2008-2009 to 15.8% in 2016-2017, the researchers found. However, the decreasing trend was not apparent for individuals with many disadvantages.

The odds ratio for change in odds of smoking per year was 0.951 (95% confidence interval, 0.944-0.958) for those with zero disadvantages, 0.96 (95% CI, 0.95-0.97) for one disadvantage, and 0.98 (95% CI, 0.97-0.99) for two, all representing significant annual reductions in current versus never smoking, investigators said. By contrast, no such significant changes were apparent for those with three, four, five, or six such disadvantages.

Tobacco control or regulatory policies that consider these disadvantages separately may be overlooking a “broader pattern” showing that the cumulative number of disadvantages correlates with the magnitude of disparity, wrote Dr. Leventhal and colleagues in their report.

“Successful prevention of smoking initiation and promotion of smoking cessation in multi-disadvantaged populations would substantially reduce the smoking-related public health burden in the United States,” they concluded.

Dr. Leventhal and colleagues reported no conflicts related to their research, which was supported in part by a Tobacco Centers of Regulatory Science award from the National Cancer Institute and the Food and Drug Administration, among other sources.

SOURCE: Leventhal AM et al. JAMA Intern Med. 2019 Apr 22. doi: 10.1001/jamainternmed.2019.0192.

BIRMINGHAM, ENGLAND – Data from two early RA inception cohorts provide reassurance that methotrexate does not cause interstitial lung disease and suggest that treatment with methotrexate might even be protective.

Sara Freeman/MDedge News

In the Early RA Study (ERAS) and Early RA Network (ERAN), which together include 2,701 patients with RA, 101 (3.7%) had interstitial lung disease (ILD). There were 92 patients with RA-ILD who had information available on exposure to any conventional synthetic disease-modifying antirheumatic drug (csDMARD); of these, 39 (2.5%) had been exposed to methotrexate (n = 1,578) and 53 (4.8%) to other csDMARDs (n = 1,114).

Multivariate analysis showed that methotrexate exposure was associated with a reduced risk of developing ILD, with an odds ratio of 0.48 (P = .004). In a separate analysis that excluded 25 patients who had ILD before they received any csDMARD therapy (n = 67), there was no association between methotrexate use and ILD (OR, 0.85; P = .578). In fact, there was a nonsignificant trend for a delayed onset of ILD in patients who had been treated with methotrexate (OR, 0.54; P = .072).

Methotrexate use is associated with an acute hypersensitivity pneumonitis in patients with RA, explained Patrick Kiely, MBBS, PhD, of St. George’s University Hospitals NHS Foundation Trust in London at the British Society for Rheumatology annual conference. “This is well recognized, it’s very rare [0.43%-1.00%], it’s easy to spot, and usually goes away if you stop methotrexate,” said Dr. Kiely, adding that “it’s not benign, and severe cases can be life threatening.”

Because of the association between methotrexate and pneumonitis, there has been concern that methotrexate may exacerbate or even cause ILD in RA but there are sparse data available to confirm this. The bottom line is that you should not start someone on methotrexate if you think their existing lung capacity is not up to treatment with methotrexate, Dr. Kiely said.

ILD is not always symptomatic in RA, but when it is, it is associated with very poor survival. The lung disease can be present before joint symptoms, Dr. Kiely said. Although less than 10% of cases may be symptomatic, this “is a big deal, because it has a high mortality, with death within 5 years. It’s the second-commonest cause of excess mortality in RA after cardiovascular disease.”

To look at the association between incident RA-ILD and the use of methotrexate, Dr. Kiely and associates analyzed data from ERAS (1986-2001) and ERAN (2002-2013), that together have more than 25 years of follow-up data on patients who were recruited at the first sign of RA symptoms. Patients within these cohorts have been treated according to best practice, and a range of outcomes – including RA-ILD – have been assessed at annual intervals.

In the patients who developed ILD after any csDMARD exposure, older age at RA onset (OR, 1.04; P less than .001) and having ever smoked (OR, 1.91; P = .016) were associated with the development of the lung disease. Incident ILD was also associated with being positive for rheumatoid factor (OR, 2.02; P = .029) at baseline. Being male was also associated with a higher risk for developing ILD, Dr. Kiely reported, as was a longer duration of time between the onset of first RA symptoms and the first secondary care visit. Conversely, the presence of nonrespiratory, major comorbidities at baseline appeared to be protective (OR, 0.62; P = .027).

“We found no association between methotrexate treatment and incident RA-ILD and a possibility that it may be protective,” Dr. Kiely concluded, noting that these data were now published in BMJ Open (2019;9:e028466. doi: 10.1136/bmjopen-2018-028466).

Following Dr. Kiely’s presentation, an audience member asked if the protective effect seen with methotrexate could have been caused by better disease control overall.

Dr. Kiely answered that, up until 2001, the time when ERAS was ongoing, standard practice in the United Kingdom was to use sulfasalazine, but then methotrexate started to be used in higher and higher doses, as seen in ERAN.

The interesting thing is that in ERAN more methotrexate was used in higher doses, but less RA-ILD was seen, Dr. Kiely observed. The overall prevalence of RA-ILD in the later early RA cohort was 3.2% and the median dose of methotrexate used was 20 mg. In ERAS, the prevalence was 4.2% and the median dose of methotrexate used was 10 mg.

There was a suggestion that disease control was slightly better in ERAN than ERAS, but that wasn’t statistically significant, Dr. Kiely said.

So, should a patient with RA and ILD be given methotrexate? There’s no reason not to, Dr. Kiely suggested, based on the evidence shown. Part of the challenge will now be convincing chest physician colleagues that methotrexate is not problematic in terms of causing ILD.

These findings are completely on board with the ILD group’s findings that methotrexate doesn’t cause pulmonary fibrosis in patients with RA, commented Julie Dawson, MD, of St. Helens and Knowsley Teaching Hospitals NHS Trust, St. Helens, England. Her own research, which includes a 10-year follow-up of patients with inflammatory arthritis, has shown that methotrexate does not appear to increase the risk of pulmonary fibrosis.

The study had no specific outside funding. Dr. Kiely reported having no conflicts of interest.

SOURCE: Kiely P et al. Rheumatology. 2019;58(suppl 3), Abstract 009.

BIRMINGHAM, ENGLAND – Data from two early RA inception cohorts provide reassurance that methotrexate does not cause interstitial lung disease and suggest that treatment with methotrexate might even be protective.

Sara Freeman/MDedge News

In the Early RA Study (ERAS) and Early RA Network (ERAN), which together include 2,701 patients with RA, 101 (3.7%) had interstitial lung disease (ILD). There were 92 patients with RA-ILD who had information available on exposure to any conventional synthetic disease-modifying antirheumatic drug (csDMARD); of these, 39 (2.5%) had been exposed to methotrexate (n = 1,578) and 53 (4.8%) to other csDMARDs (n = 1,114).

Multivariate analysis showed that methotrexate exposure was associated with a reduced risk of developing ILD, with an odds ratio of 0.48 (P = .004). In a separate analysis that excluded 25 patients who had ILD before they received any csDMARD therapy (n = 67), there was no association between methotrexate use and ILD (OR, 0.85; P = .578). In fact, there was a nonsignificant trend for a delayed onset of ILD in patients who had been treated with methotrexate (OR, 0.54; P = .072).

Methotrexate use is associated with an acute hypersensitivity pneumonitis in patients with RA, explained Patrick Kiely, MBBS, PhD, of St. George’s University Hospitals NHS Foundation Trust in London at the British Society for Rheumatology annual conference. “This is well recognized, it’s very rare [0.43%-1.00%], it’s easy to spot, and usually goes away if you stop methotrexate,” said Dr. Kiely, adding that “it’s not benign, and severe cases can be life threatening.”

Because of the association between methotrexate and pneumonitis, there has been concern that methotrexate may exacerbate or even cause ILD in RA but there are sparse data available to confirm this. The bottom line is that you should not start someone on methotrexate if you think their existing lung capacity is not up to treatment with methotrexate, Dr. Kiely said.

ILD is not always symptomatic in RA, but when it is, it is associated with very poor survival. The lung disease can be present before joint symptoms, Dr. Kiely said. Although less than 10% of cases may be symptomatic, this “is a big deal, because it has a high mortality, with death within 5 years. It’s the second-commonest cause of excess mortality in RA after cardiovascular disease.”

To look at the association between incident RA-ILD and the use of methotrexate, Dr. Kiely and associates analyzed data from ERAS (1986-2001) and ERAN (2002-2013), that together have more than 25 years of follow-up data on patients who were recruited at the first sign of RA symptoms. Patients within these cohorts have been treated according to best practice, and a range of outcomes – including RA-ILD – have been assessed at annual intervals.

In the patients who developed ILD after any csDMARD exposure, older age at RA onset (OR, 1.04; P less than .001) and having ever smoked (OR, 1.91; P = .016) were associated with the development of the lung disease. Incident ILD was also associated with being positive for rheumatoid factor (OR, 2.02; P = .029) at baseline. Being male was also associated with a higher risk for developing ILD, Dr. Kiely reported, as was a longer duration of time between the onset of first RA symptoms and the first secondary care visit. Conversely, the presence of nonrespiratory, major comorbidities at baseline appeared to be protective (OR, 0.62; P = .027).

“We found no association between methotrexate treatment and incident RA-ILD and a possibility that it may be protective,” Dr. Kiely concluded, noting that these data were now published in BMJ Open (2019;9:e028466. doi: 10.1136/bmjopen-2018-028466).

Following Dr. Kiely’s presentation, an audience member asked if the protective effect seen with methotrexate could have been caused by better disease control overall.

Dr. Kiely answered that, up until 2001, the time when ERAS was ongoing, standard practice in the United Kingdom was to use sulfasalazine, but then methotrexate started to be used in higher and higher doses, as seen in ERAN.

The interesting thing is that in ERAN more methotrexate was used in higher doses, but less RA-ILD was seen, Dr. Kiely observed. The overall prevalence of RA-ILD in the later early RA cohort was 3.2% and the median dose of methotrexate used was 20 mg. In ERAS, the prevalence was 4.2% and the median dose of methotrexate used was 10 mg.

There was a suggestion that disease control was slightly better in ERAN than ERAS, but that wasn’t statistically significant, Dr. Kiely said.

So, should a patient with RA and ILD be given methotrexate? There’s no reason not to, Dr. Kiely suggested, based on the evidence shown. Part of the challenge will now be convincing chest physician colleagues that methotrexate is not problematic in terms of causing ILD.

These findings are completely on board with the ILD group’s findings that methotrexate doesn’t cause pulmonary fibrosis in patients with RA, commented Julie Dawson, MD, of St. Helens and Knowsley Teaching Hospitals NHS Trust, St. Helens, England. Her own research, which includes a 10-year follow-up of patients with inflammatory arthritis, has shown that methotrexate does not appear to increase the risk of pulmonary fibrosis.

The study had no specific outside funding. Dr. Kiely reported having no conflicts of interest.

SOURCE: Kiely P et al. Rheumatology. 2019;58(suppl 3), Abstract 009.

BIRMINGHAM, ENGLAND – Data from two early RA inception cohorts provide reassurance that methotrexate does not cause interstitial lung disease and suggest that treatment with methotrexate might even be protective.

Sara Freeman/MDedge News

In the Early RA Study (ERAS) and Early RA Network (ERAN), which together include 2,701 patients with RA, 101 (3.7%) had interstitial lung disease (ILD). There were 92 patients with RA-ILD who had information available on exposure to any conventional synthetic disease-modifying antirheumatic drug (csDMARD); of these, 39 (2.5%) had been exposed to methotrexate (n = 1,578) and 53 (4.8%) to other csDMARDs (n = 1,114).

Multivariate analysis showed that methotrexate exposure was associated with a reduced risk of developing ILD, with an odds ratio of 0.48 (P = .004). In a separate analysis that excluded 25 patients who had ILD before they received any csDMARD therapy (n = 67), there was no association between methotrexate use and ILD (OR, 0.85; P = .578). In fact, there was a nonsignificant trend for a delayed onset of ILD in patients who had been treated with methotrexate (OR, 0.54; P = .072).

Methotrexate use is associated with an acute hypersensitivity pneumonitis in patients with RA, explained Patrick Kiely, MBBS, PhD, of St. George’s University Hospitals NHS Foundation Trust in London at the British Society for Rheumatology annual conference. “This is well recognized, it’s very rare [0.43%-1.00%], it’s easy to spot, and usually goes away if you stop methotrexate,” said Dr. Kiely, adding that “it’s not benign, and severe cases can be life threatening.”

Because of the association between methotrexate and pneumonitis, there has been concern that methotrexate may exacerbate or even cause ILD in RA but there are sparse data available to confirm this. The bottom line is that you should not start someone on methotrexate if you think their existing lung capacity is not up to treatment with methotrexate, Dr. Kiely said.

ILD is not always symptomatic in RA, but when it is, it is associated with very poor survival. The lung disease can be present before joint symptoms, Dr. Kiely said. Although less than 10% of cases may be symptomatic, this “is a big deal, because it has a high mortality, with death within 5 years. It’s the second-commonest cause of excess mortality in RA after cardiovascular disease.”

To look at the association between incident RA-ILD and the use of methotrexate, Dr. Kiely and associates analyzed data from ERAS (1986-2001) and ERAN (2002-2013), that together have more than 25 years of follow-up data on patients who were recruited at the first sign of RA symptoms. Patients within these cohorts have been treated according to best practice, and a range of outcomes – including RA-ILD – have been assessed at annual intervals.

In the patients who developed ILD after any csDMARD exposure, older age at RA onset (OR, 1.04; P less than .001) and having ever smoked (OR, 1.91; P = .016) were associated with the development of the lung disease. Incident ILD was also associated with being positive for rheumatoid factor (OR, 2.02; P = .029) at baseline. Being male was also associated with a higher risk for developing ILD, Dr. Kiely reported, as was a longer duration of time between the onset of first RA symptoms and the first secondary care visit. Conversely, the presence of nonrespiratory, major comorbidities at baseline appeared to be protective (OR, 0.62; P = .027).

“We found no association between methotrexate treatment and incident RA-ILD and a possibility that it may be protective,” Dr. Kiely concluded, noting that these data were now published in BMJ Open (2019;9:e028466. doi: 10.1136/bmjopen-2018-028466).

Following Dr. Kiely’s presentation, an audience member asked if the protective effect seen with methotrexate could have been caused by better disease control overall.

Dr. Kiely answered that, up until 2001, the time when ERAS was ongoing, standard practice in the United Kingdom was to use sulfasalazine, but then methotrexate started to be used in higher and higher doses, as seen in ERAN.

The interesting thing is that in ERAN more methotrexate was used in higher doses, but less RA-ILD was seen, Dr. Kiely observed. The overall prevalence of RA-ILD in the later early RA cohort was 3.2% and the median dose of methotrexate used was 20 mg. In ERAS, the prevalence was 4.2% and the median dose of methotrexate used was 10 mg.

There was a suggestion that disease control was slightly better in ERAN than ERAS, but that wasn’t statistically significant, Dr. Kiely said.

So, should a patient with RA and ILD be given methotrexate? There’s no reason not to, Dr. Kiely suggested, based on the evidence shown. Part of the challenge will now be convincing chest physician colleagues that methotrexate is not problematic in terms of causing ILD.

These findings are completely on board with the ILD group’s findings that methotrexate doesn’t cause pulmonary fibrosis in patients with RA, commented Julie Dawson, MD, of St. Helens and Knowsley Teaching Hospitals NHS Trust, St. Helens, England. Her own research, which includes a 10-year follow-up of patients with inflammatory arthritis, has shown that methotrexate does not appear to increase the risk of pulmonary fibrosis.

The study had no specific outside funding. Dr. Kiely reported having no conflicts of interest.

SOURCE: Kiely P et al. Rheumatology. 2019;58(suppl 3), Abstract 009.

To provide better “culturally responsive” care, the IHS and American College of Obstetricians and Gynecologists (ACOG) have announced new clinical recommendations for health care providers (HCPs) who treat Native American pregnant woman and women of childbearing age with opioid use disorder (OUD).

There are no current comprehensive guidelines to manage the care of pregnant women with opioid dependence who live in rural or remote communities, ACOG acknowledges. That absence, in addition to a lack of resources, lack of training in treating substance use disorder in pregnancy, and providers’ discomfort with opioid agonist therapy in pregnancy, has contributed to “wide variation in the quality of care these women receive.”

Disparities are particularly extreme for American Indian and Alaska Native women (AI/AN), ACOG notes. They have the highest risk of dying of prescription opioid overdose, and they face specific barriers to accessing treatment. For instance, there are few opioid treatment programs offering methadone treatment on tribal lands.

The new recommendations were developed in partnership with tribes and ACOG’s Committee on American Indian and Alaska Native Women’s Health, based on critical feedback from listening sessions and tribal consultations in the past year. The specific guidelines are tailored for Native women.

 The committee recognizes, it says, the “necessary wide-ranging scope of treatment for OUD, especially among AI/AN childbearing women.” Key recommendations include strategies to avoid or minimize the use of opioids for pain management and encourage alternative pain therapies, such as physical therapy, acupuncture, and mindfulness-based therapy. In pregnancy, ACOG recommends that obstetric providers perform universal screening and brief intervention using a validated tool as early in prenatal care as possible.

Treatment may require management of co-occurring polysubstance use disorders; concomitant alcohol and methamphetamine use predominate in many tribal areas. HCPs also may need to offer personalized care that “acknowledges the contributions of intergenerational and personal trauma,” the guidelines say. Trauma-informed interdisciplinary approaches to posttraumatic stress disorder that engage tribal resources, social structures, and assets are “crucial to impactful care of opioid use disorder.”

The postpartum period is associated with a high rate of relapse, ACOG says. Histories of trauma, for instance, can exacerbate mood disorders. Moreover, substance use and overdose are increasingly being recognized as key contributors to pregnancy-associated death in the US; a disproportionate share of deaths are postpartum. Infants of untreated, depressed mothers demonstrate poor outcomes, including impaired motor adaptation and self-regulation, developmental delay, and higher arousal scores. The guidelines advise treating mothers and infants as dyads to improve the course of neonatal opioid withdrawal syndrome (NOWS). The proportion of infants with NOWS who need pharmacologic treatment has risen dramatically, the committee notes.

 “[I]t is clear from our site visits and clinical experience,” the committee members note, “that adaptation of systems for integration and reach in rural settings is necessary, with potentially different needs and assets in Native and rural populations.” Native culture and traditions, they add, offer opportunities for community engagement and support that can be integrated into medical care for the women and their infants.

To provide better “culturally responsive” care, the IHS and American College of Obstetricians and Gynecologists (ACOG) have announced new clinical recommendations for health care providers (HCPs) who treat Native American pregnant woman and women of childbearing age with opioid use disorder (OUD).

There are no current comprehensive guidelines to manage the care of pregnant women with opioid dependence who live in rural or remote communities, ACOG acknowledges. That absence, in addition to a lack of resources, lack of training in treating substance use disorder in pregnancy, and providers’ discomfort with opioid agonist therapy in pregnancy, has contributed to “wide variation in the quality of care these women receive.”

Disparities are particularly extreme for American Indian and Alaska Native women (AI/AN), ACOG notes. They have the highest risk of dying of prescription opioid overdose, and they face specific barriers to accessing treatment. For instance, there are few opioid treatment programs offering methadone treatment on tribal lands.

The new recommendations were developed in partnership with tribes and ACOG’s Committee on American Indian and Alaska Native Women’s Health, based on critical feedback from listening sessions and tribal consultations in the past year. The specific guidelines are tailored for Native women.

 The committee recognizes, it says, the “necessary wide-ranging scope of treatment for OUD, especially among AI/AN childbearing women.” Key recommendations include strategies to avoid or minimize the use of opioids for pain management and encourage alternative pain therapies, such as physical therapy, acupuncture, and mindfulness-based therapy. In pregnancy, ACOG recommends that obstetric providers perform universal screening and brief intervention using a validated tool as early in prenatal care as possible.

Treatment may require management of co-occurring polysubstance use disorders; concomitant alcohol and methamphetamine use predominate in many tribal areas. HCPs also may need to offer personalized care that “acknowledges the contributions of intergenerational and personal trauma,” the guidelines say. Trauma-informed interdisciplinary approaches to posttraumatic stress disorder that engage tribal resources, social structures, and assets are “crucial to impactful care of opioid use disorder.”

The postpartum period is associated with a high rate of relapse, ACOG says. Histories of trauma, for instance, can exacerbate mood disorders. Moreover, substance use and overdose are increasingly being recognized as key contributors to pregnancy-associated death in the US; a disproportionate share of deaths are postpartum. Infants of untreated, depressed mothers demonstrate poor outcomes, including impaired motor adaptation and self-regulation, developmental delay, and higher arousal scores. The guidelines advise treating mothers and infants as dyads to improve the course of neonatal opioid withdrawal syndrome (NOWS). The proportion of infants with NOWS who need pharmacologic treatment has risen dramatically, the committee notes.

 “[I]t is clear from our site visits and clinical experience,” the committee members note, “that adaptation of systems for integration and reach in rural settings is necessary, with potentially different needs and assets in Native and rural populations.” Native culture and traditions, they add, offer opportunities for community engagement and support that can be integrated into medical care for the women and their infants.

To provide better “culturally responsive” care, the IHS and American College of Obstetricians and Gynecologists (ACOG) have announced new clinical recommendations for health care providers (HCPs) who treat Native American pregnant woman and women of childbearing age with opioid use disorder (OUD).

There are no current comprehensive guidelines to manage the care of pregnant women with opioid dependence who live in rural or remote communities, ACOG acknowledges. That absence, in addition to a lack of resources, lack of training in treating substance use disorder in pregnancy, and providers’ discomfort with opioid agonist therapy in pregnancy, has contributed to “wide variation in the quality of care these women receive.”

Disparities are particularly extreme for American Indian and Alaska Native women (AI/AN), ACOG notes. They have the highest risk of dying of prescription opioid overdose, and they face specific barriers to accessing treatment. For instance, there are few opioid treatment programs offering methadone treatment on tribal lands.

The new recommendations were developed in partnership with tribes and ACOG’s Committee on American Indian and Alaska Native Women’s Health, based on critical feedback from listening sessions and tribal consultations in the past year. The specific guidelines are tailored for Native women.

 The committee recognizes, it says, the “necessary wide-ranging scope of treatment for OUD, especially among AI/AN childbearing women.” Key recommendations include strategies to avoid or minimize the use of opioids for pain management and encourage alternative pain therapies, such as physical therapy, acupuncture, and mindfulness-based therapy. In pregnancy, ACOG recommends that obstetric providers perform universal screening and brief intervention using a validated tool as early in prenatal care as possible.

Treatment may require management of co-occurring polysubstance use disorders; concomitant alcohol and methamphetamine use predominate in many tribal areas. HCPs also may need to offer personalized care that “acknowledges the contributions of intergenerational and personal trauma,” the guidelines say. Trauma-informed interdisciplinary approaches to posttraumatic stress disorder that engage tribal resources, social structures, and assets are “crucial to impactful care of opioid use disorder.”

The postpartum period is associated with a high rate of relapse, ACOG says. Histories of trauma, for instance, can exacerbate mood disorders. Moreover, substance use and overdose are increasingly being recognized as key contributors to pregnancy-associated death in the US; a disproportionate share of deaths are postpartum. Infants of untreated, depressed mothers demonstrate poor outcomes, including impaired motor adaptation and self-regulation, developmental delay, and higher arousal scores. The guidelines advise treating mothers and infants as dyads to improve the course of neonatal opioid withdrawal syndrome (NOWS). The proportion of infants with NOWS who need pharmacologic treatment has risen dramatically, the committee notes.

 “[I]t is clear from our site visits and clinical experience,” the committee members note, “that adaptation of systems for integration and reach in rural settings is necessary, with potentially different needs and assets in Native and rural populations.” Native culture and traditions, they add, offer opportunities for community engagement and support that can be integrated into medical care for the women and their infants.

U.S. health care personnel no longer need to undergo routine tuberculosis testing in the absence of known exposure, according to new screening guidelines from the National Tuberculosis Controllers Association and CDC.

The revised guidelines on tuberculosis screening, testing, and treatment of U.S. health care personnel, published in Morbidity and Mortality Weekly Report, are the first update since 2005. The new recommendations reflect a reduction in concern about U.S. health care personnel’s risk of occupational exposure to latent and active tuberculosis infection.

Lynn E. Sosa, MD, from the Connecticut Department of Public Health and National Tuberculosis Controllers Association, and coauthors wrote that rates of tuberculosis infection in the United States have declined by 73% since 1991, from 10.4/100,000 population in 1991 to 2.8/100,000 in 2017. This has been matched by similar declines among health care workers, which the authors said raised questions about the cost-effectiveness of the previously recommended routine serial occupational testing.

“In addition, a recent retrospective cohort study of approximately 40,000 health care personnel at a tertiary U.S. medical center in a low TB-incidence state found an extremely low rate of TST conversion (0.3%) during 1998-2014, with a limited proportion attributable to occupational exposure,” they wrote.

The new guidelines recommend health care personnel undergo baseline or preplacement tuberculosis testing with an interferon-gamma release assay (IGRA) or a tuberculin skin test (TST), as well as individual risk assessment and symptom evaluation.

The individual risk assessment considers whether the person has lived in a country with a high tuberculosis rate, whether they are immunosuppressed, or whether they have had close contact with someone with infectious tuberculosis.

This risk assessment can help decide how to interpret an initial positive test result, the authors said.

“For example, health care personnel with a positive test who are asymptomatic, unlikely to be infected with M. [Mycobacterium] tuberculosis, and at low risk for progression on the basis of their risk assessment should have a second test (either an IGRA or a TST) as recommended in the 2017 TB diagnostic guidelines of the American Thoracic Society, Infectious Diseases Society of America, and CDC,” they wrote. “In this example, the health care personnel should be considered infected with M. tuberculosis only if both the first and second tests are positive.”

After that baseline testing, personnel do not need to undergo routine serial testing except in the case of known exposure or ongoing transmission. The guideline authors suggested serial screening might be considered for health care workers whose work puts them at greater risk – for example, pulmonologists or respiratory therapists – or for those working in settings in which transmission has happened in the past.

For personnel with latent tuberculosis infection, the guidelines recommend “encouragement of treatment” unless it is contraindicated, and annual symptom screening in those not undergoing treatment.

The guideline committee also advocated for annual tuberculosis education for all health care workers.

The new recommendations were based on a systematic review of 36 studies of tuberculosis screening and testing among health care per­sonnel, 16 of which were performed in the United States, and all but two of which were conducted in a hospital setting.

The authors stressed that recommendations from the 2005 CDC guidelines – which do not pertain to health care personnel screening, testing, treatment and education – remain unchanged.

One author declared personal fees from the National Tuberculosis Controllers Association during the conduct of the study. Two others reported unrelated grants and personal fees from private industry. No other conflicts of interest were disclosed.

SOURCE: Sosa L et al. MMWR. 2019;68:439-43.

U.S. health care personnel no longer need to undergo routine tuberculosis testing in the absence of known exposure, according to new screening guidelines from the National Tuberculosis Controllers Association and CDC.

The revised guidelines on tuberculosis screening, testing, and treatment of U.S. health care personnel, published in Morbidity and Mortality Weekly Report, are the first update since 2005. The new recommendations reflect a reduction in concern about U.S. health care personnel’s risk of occupational exposure to latent and active tuberculosis infection.

Lynn E. Sosa, MD, from the Connecticut Department of Public Health and National Tuberculosis Controllers Association, and coauthors wrote that rates of tuberculosis infection in the United States have declined by 73% since 1991, from 10.4/100,000 population in 1991 to 2.8/100,000 in 2017. This has been matched by similar declines among health care workers, which the authors said raised questions about the cost-effectiveness of the previously recommended routine serial occupational testing.

“In addition, a recent retrospective cohort study of approximately 40,000 health care personnel at a tertiary U.S. medical center in a low TB-incidence state found an extremely low rate of TST conversion (0.3%) during 1998-2014, with a limited proportion attributable to occupational exposure,” they wrote.

The new guidelines recommend health care personnel undergo baseline or preplacement tuberculosis testing with an interferon-gamma release assay (IGRA) or a tuberculin skin test (TST), as well as individual risk assessment and symptom evaluation.

The individual risk assessment considers whether the person has lived in a country with a high tuberculosis rate, whether they are immunosuppressed, or whether they have had close contact with someone with infectious tuberculosis.

This risk assessment can help decide how to interpret an initial positive test result, the authors said.

“For example, health care personnel with a positive test who are asymptomatic, unlikely to be infected with M. [Mycobacterium] tuberculosis, and at low risk for progression on the basis of their risk assessment should have a second test (either an IGRA or a TST) as recommended in the 2017 TB diagnostic guidelines of the American Thoracic Society, Infectious Diseases Society of America, and CDC,” they wrote. “In this example, the health care personnel should be considered infected with M. tuberculosis only if both the first and second tests are positive.”

After that baseline testing, personnel do not need to undergo routine serial testing except in the case of known exposure or ongoing transmission. The guideline authors suggested serial screening might be considered for health care workers whose work puts them at greater risk – for example, pulmonologists or respiratory therapists – or for those working in settings in which transmission has happened in the past.

For personnel with latent tuberculosis infection, the guidelines recommend “encouragement of treatment” unless it is contraindicated, and annual symptom screening in those not undergoing treatment.

The guideline committee also advocated for annual tuberculosis education for all health care workers.

The new recommendations were based on a systematic review of 36 studies of tuberculosis screening and testing among health care per­sonnel, 16 of which were performed in the United States, and all but two of which were conducted in a hospital setting.

The authors stressed that recommendations from the 2005 CDC guidelines – which do not pertain to health care personnel screening, testing, treatment and education – remain unchanged.

One author declared personal fees from the National Tuberculosis Controllers Association during the conduct of the study. Two others reported unrelated grants and personal fees from private industry. No other conflicts of interest were disclosed.

SOURCE: Sosa L et al. MMWR. 2019;68:439-43.

U.S. health care personnel no longer need to undergo routine tuberculosis testing in the absence of known exposure, according to new screening guidelines from the National Tuberculosis Controllers Association and CDC.

The revised guidelines on tuberculosis screening, testing, and treatment of U.S. health care personnel, published in Morbidity and Mortality Weekly Report, are the first update since 2005. The new recommendations reflect a reduction in concern about U.S. health care personnel’s risk of occupational exposure to latent and active tuberculosis infection.

Lynn E. Sosa, MD, from the Connecticut Department of Public Health and National Tuberculosis Controllers Association, and coauthors wrote that rates of tuberculosis infection in the United States have declined by 73% since 1991, from 10.4/100,000 population in 1991 to 2.8/100,000 in 2017. This has been matched by similar declines among health care workers, which the authors said raised questions about the cost-effectiveness of the previously recommended routine serial occupational testing.

“In addition, a recent retrospective cohort study of approximately 40,000 health care personnel at a tertiary U.S. medical center in a low TB-incidence state found an extremely low rate of TST conversion (0.3%) during 1998-2014, with a limited proportion attributable to occupational exposure,” they wrote.

The new guidelines recommend health care personnel undergo baseline or preplacement tuberculosis testing with an interferon-gamma release assay (IGRA) or a tuberculin skin test (TST), as well as individual risk assessment and symptom evaluation.

The individual risk assessment considers whether the person has lived in a country with a high tuberculosis rate, whether they are immunosuppressed, or whether they have had close contact with someone with infectious tuberculosis.

This risk assessment can help decide how to interpret an initial positive test result, the authors said.

“For example, health care personnel with a positive test who are asymptomatic, unlikely to be infected with M. [Mycobacterium] tuberculosis, and at low risk for progression on the basis of their risk assessment should have a second test (either an IGRA or a TST) as recommended in the 2017 TB diagnostic guidelines of the American Thoracic Society, Infectious Diseases Society of America, and CDC,” they wrote. “In this example, the health care personnel should be considered infected with M. tuberculosis only if both the first and second tests are positive.”

After that baseline testing, personnel do not need to undergo routine serial testing except in the case of known exposure or ongoing transmission. The guideline authors suggested serial screening might be considered for health care workers whose work puts them at greater risk – for example, pulmonologists or respiratory therapists – or for those working in settings in which transmission has happened in the past.

For personnel with latent tuberculosis infection, the guidelines recommend “encouragement of treatment” unless it is contraindicated, and annual symptom screening in those not undergoing treatment.

The guideline committee also advocated for annual tuberculosis education for all health care workers.

The new recommendations were based on a systematic review of 36 studies of tuberculosis screening and testing among health care per­sonnel, 16 of which were performed in the United States, and all but two of which were conducted in a hospital setting.

The authors stressed that recommendations from the 2005 CDC guidelines – which do not pertain to health care personnel screening, testing, treatment and education – remain unchanged.

One author declared personal fees from the National Tuberculosis Controllers Association during the conduct of the study. Two others reported unrelated grants and personal fees from private industry. No other conflicts of interest were disclosed.

SOURCE: Sosa L et al. MMWR. 2019;68:439-43.

The Oncologic Drugs Advisory Committee (ODAC) of the Food and Drug Administration voted to support approval of the small molecule kinase inhibitor pexidartinib for the treatment of adults with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and is not amenable to improvement with surgery.

The drug was favored by a 12-3 margin (no abstentions), with the majority of panel members agreeing that it offers clinical benefits that outweigh significant risk for elevated liver enzymes and small but real potential for serious or even fatal liver injury.

The FDA usually follows the recommendation of advisory committees in deciding final approval. Daiichi Sankyo plans to market the drug under the trade name Turalio.

Final approval and marketing of the drug will hinge on a mandatory Risk Evaluation and Mitigation Strategy that will require certification of prescribers, patient participation in education about the need for frequent liver function testing and the signs and symptoms of liver injury, and distribution of the drug only to certified pharmacies.

Both the ODAC panel members and pexidartinib’s manufacturer, Daiichi Sankyo, agreed that the drug is effective, but opinions about the degree of clinical benefit and the risk-benefit ratio differed.

TGCT is a rare, nonmalignant, and nonlethal tumor of the synovium, bursae, or tendon sheath that can be locally aggressive, and for some patients completely disabling. Surgery is the primary mode of treatment, but less than 10% of patients have disease that is not amenable to resection; for these patients treatment options are limited, because there are no approved systemic therapies for the disease.

ENLIVEN

Evidence submitted to support the application comes from the phase 3 ENLIVEN trial, in which patients with TGCT not amenable to surgery were randomly assigned to receive pexidartinib or placebo. The trial was designed to enroll 126 patients to provide 90% power to detect a difference in objective response rate at a two-sided alpha level of 0.05, assuming an overall response rate of 10% with placebo, and 35% with pexidartinib.

The actual trial enrollment, however, fell a little short, with a total of 120 patients randomized.

The ORR at week 25 as assessed by blinded independent central reviewers, the primary endpoint, was 39% for the 61 patients in the pexidartinib group, compared with 0% for the 59 patients in the placebo group (P less than .0001).

There were also statistically significant improvements in the pexidartinib arm at week 25 in the secondary endpoints of mean change in range of motion (ROM), ORR by tumor-volume score at week 25, mean change from baseline in the Patient-Reported Outcomes Measurement Information physical function scale, and mean change in the Worst Stiffness numeric rating scale item. There were no significant differences between the groups for worst pain, however.

The FDA briefing document notes that “interpretation of the results of the secondary endpoints should be viewed with caution as there was a high proportion of missing data at week 25 for ROM, physical function, and worst stiffness (27%, 43% 43%, respectively); the proportion of patients with missing data was similar across study arms.”

Risk and benefits

The major issues before the ODAC included the validity of clinical outcome assessment given the large chunks of missing data and the major adverse event of liver injury, with a majority of patients on pexidartinib experiencing transaminase elevations. The potential for liver injury may be exacerbated by chronic use of the drug or by drugs used to treat comorbidities such as diabetes or cardiovascular disease, several panel members noted.

During the clinical development program for the drug, 2 of 768 patients who received the drug developed irreversible liver injury leading to liver transplant in 1 patient and death in the other.

Many of the panelists who voted to support approval did so with some reluctance about the adverse events. For example, Karin Anton Calis, PharmD, of the National Institutes of Health voted yes because of the efficacy of the drug in a disabling condition.

“Hopefully it will be used in a restricted system so that there can be adequate monitoring, but I’m still concerned about those patients that may have this unpredictable liver toxicity, “ he said.

Victor M. Villalobos MD, PhD, from the University of Colorado at Denver, Aurora, also voted yes.

“This is an ultra-rare disease with no good therapies available to patients and it can be highly morbid, and I feel that getting real-world data on how we can use this drug in a safe and effective manner will be really important to the academic community going forward,” he said.

Other panel members who also voted to support approval expressed concerns about the hepatotoxicity, but noted that the drug has the potential to change lives, as attested by TCGT patients who spoke during the public comment portion of the meeting.

However, panelist Doris Strader, MD, from the University of Vermont, Burlington, said that she voted no because, while she was sensitive to the potential benefits of the drug for some patients, “I was concerned about the missing data and was not convinced that there was clinically meaningful benefit. Likewise, while I understand that the hepatic injury is not liver failure, I am concerned that this may be persistent for a long time, and I worry that there is not enough to suggest that there is going to be rigorous monitoring of patients over their lifetimes.”

The Oncologic Drugs Advisory Committee (ODAC) of the Food and Drug Administration voted to support approval of the small molecule kinase inhibitor pexidartinib for the treatment of adults with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and is not amenable to improvement with surgery.

The drug was favored by a 12-3 margin (no abstentions), with the majority of panel members agreeing that it offers clinical benefits that outweigh significant risk for elevated liver enzymes and small but real potential for serious or even fatal liver injury.

The FDA usually follows the recommendation of advisory committees in deciding final approval. Daiichi Sankyo plans to market the drug under the trade name Turalio.

Final approval and marketing of the drug will hinge on a mandatory Risk Evaluation and Mitigation Strategy that will require certification of prescribers, patient participation in education about the need for frequent liver function testing and the signs and symptoms of liver injury, and distribution of the drug only to certified pharmacies.

Both the ODAC panel members and pexidartinib’s manufacturer, Daiichi Sankyo, agreed that the drug is effective, but opinions about the degree of clinical benefit and the risk-benefit ratio differed.

TGCT is a rare, nonmalignant, and nonlethal tumor of the synovium, bursae, or tendon sheath that can be locally aggressive, and for some patients completely disabling. Surgery is the primary mode of treatment, but less than 10% of patients have disease that is not amenable to resection; for these patients treatment options are limited, because there are no approved systemic therapies for the disease.

ENLIVEN

Evidence submitted to support the application comes from the phase 3 ENLIVEN trial, in which patients with TGCT not amenable to surgery were randomly assigned to receive pexidartinib or placebo. The trial was designed to enroll 126 patients to provide 90% power to detect a difference in objective response rate at a two-sided alpha level of 0.05, assuming an overall response rate of 10% with placebo, and 35% with pexidartinib.

The actual trial enrollment, however, fell a little short, with a total of 120 patients randomized.

The ORR at week 25 as assessed by blinded independent central reviewers, the primary endpoint, was 39% for the 61 patients in the pexidartinib group, compared with 0% for the 59 patients in the placebo group (P less than .0001).

There were also statistically significant improvements in the pexidartinib arm at week 25 in the secondary endpoints of mean change in range of motion (ROM), ORR by tumor-volume score at week 25, mean change from baseline in the Patient-Reported Outcomes Measurement Information physical function scale, and mean change in the Worst Stiffness numeric rating scale item. There were no significant differences between the groups for worst pain, however.

The FDA briefing document notes that “interpretation of the results of the secondary endpoints should be viewed with caution as there was a high proportion of missing data at week 25 for ROM, physical function, and worst stiffness (27%, 43% 43%, respectively); the proportion of patients with missing data was similar across study arms.”

Risk and benefits

The major issues before the ODAC included the validity of clinical outcome assessment given the large chunks of missing data and the major adverse event of liver injury, with a majority of patients on pexidartinib experiencing transaminase elevations. The potential for liver injury may be exacerbated by chronic use of the drug or by drugs used to treat comorbidities such as diabetes or cardiovascular disease, several panel members noted.

During the clinical development program for the drug, 2 of 768 patients who received the drug developed irreversible liver injury leading to liver transplant in 1 patient and death in the other.

Many of the panelists who voted to support approval did so with some reluctance about the adverse events. For example, Karin Anton Calis, PharmD, of the National Institutes of Health voted yes because of the efficacy of the drug in a disabling condition.

“Hopefully it will be used in a restricted system so that there can be adequate monitoring, but I’m still concerned about those patients that may have this unpredictable liver toxicity, “ he said.

Victor M. Villalobos MD, PhD, from the University of Colorado at Denver, Aurora, also voted yes.

“This is an ultra-rare disease with no good therapies available to patients and it can be highly morbid, and I feel that getting real-world data on how we can use this drug in a safe and effective manner will be really important to the academic community going forward,” he said.

Other panel members who also voted to support approval expressed concerns about the hepatotoxicity, but noted that the drug has the potential to change lives, as attested by TCGT patients who spoke during the public comment portion of the meeting.

However, panelist Doris Strader, MD, from the University of Vermont, Burlington, said that she voted no because, while she was sensitive to the potential benefits of the drug for some patients, “I was concerned about the missing data and was not convinced that there was clinically meaningful benefit. Likewise, while I understand that the hepatic injury is not liver failure, I am concerned that this may be persistent for a long time, and I worry that there is not enough to suggest that there is going to be rigorous monitoring of patients over their lifetimes.”

The Oncologic Drugs Advisory Committee (ODAC) of the Food and Drug Administration voted to support approval of the small molecule kinase inhibitor pexidartinib for the treatment of adults with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and is not amenable to improvement with surgery.

The drug was favored by a 12-3 margin (no abstentions), with the majority of panel members agreeing that it offers clinical benefits that outweigh significant risk for elevated liver enzymes and small but real potential for serious or even fatal liver injury.

The FDA usually follows the recommendation of advisory committees in deciding final approval. Daiichi Sankyo plans to market the drug under the trade name Turalio.

Final approval and marketing of the drug will hinge on a mandatory Risk Evaluation and Mitigation Strategy that will require certification of prescribers, patient participation in education about the need for frequent liver function testing and the signs and symptoms of liver injury, and distribution of the drug only to certified pharmacies.

Both the ODAC panel members and pexidartinib’s manufacturer, Daiichi Sankyo, agreed that the drug is effective, but opinions about the degree of clinical benefit and the risk-benefit ratio differed.

TGCT is a rare, nonmalignant, and nonlethal tumor of the synovium, bursae, or tendon sheath that can be locally aggressive, and for some patients completely disabling. Surgery is the primary mode of treatment, but less than 10% of patients have disease that is not amenable to resection; for these patients treatment options are limited, because there are no approved systemic therapies for the disease.

ENLIVEN

Evidence submitted to support the application comes from the phase 3 ENLIVEN trial, in which patients with TGCT not amenable to surgery were randomly assigned to receive pexidartinib or placebo. The trial was designed to enroll 126 patients to provide 90% power to detect a difference in objective response rate at a two-sided alpha level of 0.05, assuming an overall response rate of 10% with placebo, and 35% with pexidartinib.

The actual trial enrollment, however, fell a little short, with a total of 120 patients randomized.

The ORR at week 25 as assessed by blinded independent central reviewers, the primary endpoint, was 39% for the 61 patients in the pexidartinib group, compared with 0% for the 59 patients in the placebo group (P less than .0001).

There were also statistically significant improvements in the pexidartinib arm at week 25 in the secondary endpoints of mean change in range of motion (ROM), ORR by tumor-volume score at week 25, mean change from baseline in the Patient-Reported Outcomes Measurement Information physical function scale, and mean change in the Worst Stiffness numeric rating scale item. There were no significant differences between the groups for worst pain, however.

The FDA briefing document notes that “interpretation of the results of the secondary endpoints should be viewed with caution as there was a high proportion of missing data at week 25 for ROM, physical function, and worst stiffness (27%, 43% 43%, respectively); the proportion of patients with missing data was similar across study arms.”

Risk and benefits

The major issues before the ODAC included the validity of clinical outcome assessment given the large chunks of missing data and the major adverse event of liver injury, with a majority of patients on pexidartinib experiencing transaminase elevations. The potential for liver injury may be exacerbated by chronic use of the drug or by drugs used to treat comorbidities such as diabetes or cardiovascular disease, several panel members noted.

During the clinical development program for the drug, 2 of 768 patients who received the drug developed irreversible liver injury leading to liver transplant in 1 patient and death in the other.

Many of the panelists who voted to support approval did so with some reluctance about the adverse events. For example, Karin Anton Calis, PharmD, of the National Institutes of Health voted yes because of the efficacy of the drug in a disabling condition.

“Hopefully it will be used in a restricted system so that there can be adequate monitoring, but I’m still concerned about those patients that may have this unpredictable liver toxicity, “ he said.

Victor M. Villalobos MD, PhD, from the University of Colorado at Denver, Aurora, also voted yes.

“This is an ultra-rare disease with no good therapies available to patients and it can be highly morbid, and I feel that getting real-world data on how we can use this drug in a safe and effective manner will be really important to the academic community going forward,” he said.

Other panel members who also voted to support approval expressed concerns about the hepatotoxicity, but noted that the drug has the potential to change lives, as attested by TCGT patients who spoke during the public comment portion of the meeting.

However, panelist Doris Strader, MD, from the University of Vermont, Burlington, said that she voted no because, while she was sensitive to the potential benefits of the drug for some patients, “I was concerned about the missing data and was not convinced that there was clinically meaningful benefit. Likewise, while I understand that the hepatic injury is not liver failure, I am concerned that this may be persistent for a long time, and I worry that there is not enough to suggest that there is going to be rigorous monitoring of patients over their lifetimes.”

The mother of an 8-month-old calls your office and is hysterical. Her daughter has had cough for a few days with high fevers and now has developed a full body rash. She is worried about measles and is on her way to your office.

CDC/Molly Kurnit, M.P.H.

We are in the middle of a measles epidemic, there’s no denying it. Measles was declared eliminated in 2000, but reported cases in the United States have been on the rise, and are now at the highest number since 2014. Five months into 2019, there have been 839 reported cases as of May 13). Measles outbreaks (defined by the Centers for Disease Control and Prevention as three or more cases) have been reported in California, Georgia, Maryland, Michigan, New Jersey, New York, and Pennsylvania. When vaccination rates fall, it is easy for measles to spread. The virus is highly contagious in nonimmune people, because of its airborne spread and its persistence in the environment for hours.
 

First – is it really measles?

When there is a measles outbreak, there is a heightened concern to “rule out” measles in any febrile child with a rash. It can be difficult to distinguish the maculopapular rash of measles from similar rashes that occur with more benign viral illnesses. Adding to the challenge, the last major measles outbreak in the United States was over 2 decades ago, and many practicing pediatricians have never seen a single case. So, what clinical features can help distinguish measles from other febrile illnesses?

The prodromal phase of measles lasts approximately 2-4 days and children have high fevers (103°-105° F), anorexia, and malaise. Conjunctivitis, coryza, and cough develop during this phase, and precede any rash. Koplik spots appear during the prodromal phase, but are not seen in all cases. These spots are 1- to 3-mm blue-white lesions on an erythematous base on the buccal mucosa, classically opposite the first molar. The spots often slough once the rash appears. The rash appears 2-4 days after the onset of fever, and is initially maculopapular and blanching. The first lesions appear on the face and neck, and the rash spreads cranial to caudal, typically sparing palms and soles. After days 3-4, the rash will no longer blanch. High fevers persist for 2-4 more days with rash, ongoing respiratory symptoms, conjunctivitis, and pharyngitis. Note that the fever will persist even with development of the rash, unlike in roseola.

It is not only important to diagnosis measles from a public health standpoint, but also because measles can have severe complications, especially in infants and children under 5 years. During the 1989-1991 outbreak, the mortality rate was 2.2 deaths per 1,000 cases (J Infect Dis. 2004 May 1. doi: 10.1086/377694).

Six percent of patients develop pneumonia, which in infants and toddlers can lead to respiratory distress or failure requiring hospitalization. Pneumonia is responsible for 60% of measles deaths, according to the CDC “Pink Book,” Epidemiology and Prevention of Vaccine-Preventable Diseases, chapter 13 on measles, 13th Ed., 2015. Ocular complications include keratitis and corneal ulceration. Measles also can cause serious neurologic complications. Encephalitis, seen in 1 per 1,000 cases, usually arises several days after the rash and may present with seizure or encephalopathy. Acute disseminated encephalomyelitis (ADEM), an inflammatory demyelinating disease of the central nervous system, occurs in approximately 1 per 1,000 cases, typically presents during the recovery phase (1-2 weeks after rash), and can have long-term sequelae. Subacute sclerosing panencephalitis (SSPE) is a progressive and fatal neurodegenerative disorder, and presents 7-10 years after measles infection.
 

Should you transfer the patient to a hospital?

Unless there is a medical need for the child to be admitted, sending a patient with potential measles to the hospital is not necessary, and can cause exposure to a large group of medical personnel, and patients who cannot be vaccinated (such as infants, immunocompromised patients, and pregnant women). However, if there is concern for complications such as seizures, encephalitis, or pneumonia, then transfer is indicated. Call the accepting hospital in advance so the staff can prepare for the patient. During transfer, place a standard face mask on the patient and instruct the patient not to remove it.

For hospitals accepting a suspected measles case, meet the patient outside of the facility and ensure that the patient is wearing a standard face mask. All staff interacting with the patient should practice contact and airborne precautions (N95 respirator mask). Take the patient directly to an isolation room with negative airflow. Caution pregnant staff that they should not have contact with the patient.
 

Which diagnostic tests should you use?

Diagnosis can be made based on serum antibody tests (measles IgM and IgG), throat or urine viral cultures, and nasopharyngeal and throat specimen polymerase chain reaction (PCR) testing. The CDC recommends obtaining a serum sample for measles IgM testing and a throat swab for PCR in all suspected cases, but local health departments vary in their specific testing recommendations. Familiarize yourself with the tests recommended by your local department of health, and where they prefer testing on outpatients to be done. Confirmed measles should be reported to your department of health.

What are considerations for community pediatric offices?

Update families in emails to call ahead if they suspect measles. This way the office can prepare a room for the family, and have the family immediately brought back without exposing staff and other families in the waiting area. It may be more prudent to examine these children at the end of the clinic day as the virus can persist for up to 2 hours on fomites and in the air. Therefore, all waiting areas and shared air spaces (including those with shared air ducts) should be cleared for 2 hours after the patient leaves.

When should you provide prophylaxis after exposure?

A patient with suspected measles does not require immediate vaccination. If it is measles, it is already too late to vaccinate. If measles is ruled out, the child should follow the standard measles vaccination guidelines.

Individuals are contagious from 4 days before to 4 days after the rash appears.

If measles is confirmed, all people who are unvaccinated or undervaccinated and were exposed to the confirmed case during the contagious period should be vaccinated within 72 hours of exposure. Infants 6 months or older may safely receive the MMR vaccine. However, infants vaccinated with MMR before their first birthday must be vaccinated again at age 12-15 months (greater than 28 days after prior vaccine) and at 4-6 years. Immunoglobulin prophylaxis should be given intramuscularly in exposed infants ages birth to less than 6 months, and in those ages 6-12 months who present beyond the 72-hour window. Unvaccinated or undervaccinated, exposed individuals at high risk for complications from measles (immunocompromised, pregnant) also should receive immunoglobulin.
 

What should you tell traveling families?

Several countries have large, ongoing measles outbreaks, including Israel, Ukraine, and the Philippines. Before international travel, infants 6-11 months should receive one dose of MMR vaccine, and children 12 months and older need two doses separated by at least 28 days. For unvaccinated or undervaccinated children, consider advising families to hold off travel to high-risk countries, or understand the indications to vaccinate a child upon return.
 

Dr. Angelica DesPain is a pediatric emergency medicine fellow at Children’s National Medical Center in Washington. She said she has no relevant financial disclosures. Dr. Emily Willner is a pediatric emergency medicine attending at Children’s National Medical Center, and an assistant professor of pediatrics and emergency medicine at George Washington University, Washington. She has no relevant financial disclosures.

The mother of an 8-month-old calls your office and is hysterical. Her daughter has had cough for a few days with high fevers and now has developed a full body rash. She is worried about measles and is on her way to your office.

CDC/Molly Kurnit, M.P.H.

We are in the middle of a measles epidemic, there’s no denying it. Measles was declared eliminated in 2000, but reported cases in the United States have been on the rise, and are now at the highest number since 2014. Five months into 2019, there have been 839 reported cases as of May 13). Measles outbreaks (defined by the Centers for Disease Control and Prevention as three or more cases) have been reported in California, Georgia, Maryland, Michigan, New Jersey, New York, and Pennsylvania. When vaccination rates fall, it is easy for measles to spread. The virus is highly contagious in nonimmune people, because of its airborne spread and its persistence in the environment for hours.
 

First – is it really measles?

When there is a measles outbreak, there is a heightened concern to “rule out” measles in any febrile child with a rash. It can be difficult to distinguish the maculopapular rash of measles from similar rashes that occur with more benign viral illnesses. Adding to the challenge, the last major measles outbreak in the United States was over 2 decades ago, and many practicing pediatricians have never seen a single case. So, what clinical features can help distinguish measles from other febrile illnesses?

The prodromal phase of measles lasts approximately 2-4 days and children have high fevers (103°-105° F), anorexia, and malaise. Conjunctivitis, coryza, and cough develop during this phase, and precede any rash. Koplik spots appear during the prodromal phase, but are not seen in all cases. These spots are 1- to 3-mm blue-white lesions on an erythematous base on the buccal mucosa, classically opposite the first molar. The spots often slough once the rash appears. The rash appears 2-4 days after the onset of fever, and is initially maculopapular and blanching. The first lesions appear on the face and neck, and the rash spreads cranial to caudal, typically sparing palms and soles. After days 3-4, the rash will no longer blanch. High fevers persist for 2-4 more days with rash, ongoing respiratory symptoms, conjunctivitis, and pharyngitis. Note that the fever will persist even with development of the rash, unlike in roseola.

It is not only important to diagnosis measles from a public health standpoint, but also because measles can have severe complications, especially in infants and children under 5 years. During the 1989-1991 outbreak, the mortality rate was 2.2 deaths per 1,000 cases (J Infect Dis. 2004 May 1. doi: 10.1086/377694).

Six percent of patients develop pneumonia, which in infants and toddlers can lead to respiratory distress or failure requiring hospitalization. Pneumonia is responsible for 60% of measles deaths, according to the CDC “Pink Book,” Epidemiology and Prevention of Vaccine-Preventable Diseases, chapter 13 on measles, 13th Ed., 2015. Ocular complications include keratitis and corneal ulceration. Measles also can cause serious neurologic complications. Encephalitis, seen in 1 per 1,000 cases, usually arises several days after the rash and may present with seizure or encephalopathy. Acute disseminated encephalomyelitis (ADEM), an inflammatory demyelinating disease of the central nervous system, occurs in approximately 1 per 1,000 cases, typically presents during the recovery phase (1-2 weeks after rash), and can have long-term sequelae. Subacute sclerosing panencephalitis (SSPE) is a progressive and fatal neurodegenerative disorder, and presents 7-10 years after measles infection.
 

Should you transfer the patient to a hospital?

Unless there is a medical need for the child to be admitted, sending a patient with potential measles to the hospital is not necessary, and can cause exposure to a large group of medical personnel, and patients who cannot be vaccinated (such as infants, immunocompromised patients, and pregnant women). However, if there is concern for complications such as seizures, encephalitis, or pneumonia, then transfer is indicated. Call the accepting hospital in advance so the staff can prepare for the patient. During transfer, place a standard face mask on the patient and instruct the patient not to remove it.

For hospitals accepting a suspected measles case, meet the patient outside of the facility and ensure that the patient is wearing a standard face mask. All staff interacting with the patient should practice contact and airborne precautions (N95 respirator mask). Take the patient directly to an isolation room with negative airflow. Caution pregnant staff that they should not have contact with the patient.
 

Which diagnostic tests should you use?

Diagnosis can be made based on serum antibody tests (measles IgM and IgG), throat or urine viral cultures, and nasopharyngeal and throat specimen polymerase chain reaction (PCR) testing. The CDC recommends obtaining a serum sample for measles IgM testing and a throat swab for PCR in all suspected cases, but local health departments vary in their specific testing recommendations. Familiarize yourself with the tests recommended by your local department of health, and where they prefer testing on outpatients to be done. Confirmed measles should be reported to your department of health.

What are considerations for community pediatric offices?

Update families in emails to call ahead if they suspect measles. This way the office can prepare a room for the family, and have the family immediately brought back without exposing staff and other families in the waiting area. It may be more prudent to examine these children at the end of the clinic day as the virus can persist for up to 2 hours on fomites and in the air. Therefore, all waiting areas and shared air spaces (including those with shared air ducts) should be cleared for 2 hours after the patient leaves.

When should you provide prophylaxis after exposure?

A patient with suspected measles does not require immediate vaccination. If it is measles, it is already too late to vaccinate. If measles is ruled out, the child should follow the standard measles vaccination guidelines.

Individuals are contagious from 4 days before to 4 days after the rash appears.

If measles is confirmed, all people who are unvaccinated or undervaccinated and were exposed to the confirmed case during the contagious period should be vaccinated within 72 hours of exposure. Infants 6 months or older may safely receive the MMR vaccine. However, infants vaccinated with MMR before their first birthday must be vaccinated again at age 12-15 months (greater than 28 days after prior vaccine) and at 4-6 years. Immunoglobulin prophylaxis should be given intramuscularly in exposed infants ages birth to less than 6 months, and in those ages 6-12 months who present beyond the 72-hour window. Unvaccinated or undervaccinated, exposed individuals at high risk for complications from measles (immunocompromised, pregnant) also should receive immunoglobulin.
 

What should you tell traveling families?

Several countries have large, ongoing measles outbreaks, including Israel, Ukraine, and the Philippines. Before international travel, infants 6-11 months should receive one dose of MMR vaccine, and children 12 months and older need two doses separated by at least 28 days. For unvaccinated or undervaccinated children, consider advising families to hold off travel to high-risk countries, or understand the indications to vaccinate a child upon return.
 

Dr. Angelica DesPain is a pediatric emergency medicine fellow at Children’s National Medical Center in Washington. She said she has no relevant financial disclosures. Dr. Emily Willner is a pediatric emergency medicine attending at Children’s National Medical Center, and an assistant professor of pediatrics and emergency medicine at George Washington University, Washington. She has no relevant financial disclosures.

The mother of an 8-month-old calls your office and is hysterical. Her daughter has had cough for a few days with high fevers and now has developed a full body rash. She is worried about measles and is on her way to your office.

CDC/Molly Kurnit, M.P.H.

We are in the middle of a measles epidemic, there’s no denying it. Measles was declared eliminated in 2000, but reported cases in the United States have been on the rise, and are now at the highest number since 2014. Five months into 2019, there have been 839 reported cases as of May 13). Measles outbreaks (defined by the Centers for Disease Control and Prevention as three or more cases) have been reported in California, Georgia, Maryland, Michigan, New Jersey, New York, and Pennsylvania. When vaccination rates fall, it is easy for measles to spread. The virus is highly contagious in nonimmune people, because of its airborne spread and its persistence in the environment for hours.
 

First – is it really measles?

When there is a measles outbreak, there is a heightened concern to “rule out” measles in any febrile child with a rash. It can be difficult to distinguish the maculopapular rash of measles from similar rashes that occur with more benign viral illnesses. Adding to the challenge, the last major measles outbreak in the United States was over 2 decades ago, and many practicing pediatricians have never seen a single case. So, what clinical features can help distinguish measles from other febrile illnesses?

The prodromal phase of measles lasts approximately 2-4 days and children have high fevers (103°-105° F), anorexia, and malaise. Conjunctivitis, coryza, and cough develop during this phase, and precede any rash. Koplik spots appear during the prodromal phase, but are not seen in all cases. These spots are 1- to 3-mm blue-white lesions on an erythematous base on the buccal mucosa, classically opposite the first molar. The spots often slough once the rash appears. The rash appears 2-4 days after the onset of fever, and is initially maculopapular and blanching. The first lesions appear on the face and neck, and the rash spreads cranial to caudal, typically sparing palms and soles. After days 3-4, the rash will no longer blanch. High fevers persist for 2-4 more days with rash, ongoing respiratory symptoms, conjunctivitis, and pharyngitis. Note that the fever will persist even with development of the rash, unlike in roseola.

It is not only important to diagnosis measles from a public health standpoint, but also because measles can have severe complications, especially in infants and children under 5 years. During the 1989-1991 outbreak, the mortality rate was 2.2 deaths per 1,000 cases (J Infect Dis. 2004 May 1. doi: 10.1086/377694).

Six percent of patients develop pneumonia, which in infants and toddlers can lead to respiratory distress or failure requiring hospitalization. Pneumonia is responsible for 60% of measles deaths, according to the CDC “Pink Book,” Epidemiology and Prevention of Vaccine-Preventable Diseases, chapter 13 on measles, 13th Ed., 2015. Ocular complications include keratitis and corneal ulceration. Measles also can cause serious neurologic complications. Encephalitis, seen in 1 per 1,000 cases, usually arises several days after the rash and may present with seizure or encephalopathy. Acute disseminated encephalomyelitis (ADEM), an inflammatory demyelinating disease of the central nervous system, occurs in approximately 1 per 1,000 cases, typically presents during the recovery phase (1-2 weeks after rash), and can have long-term sequelae. Subacute sclerosing panencephalitis (SSPE) is a progressive and fatal neurodegenerative disorder, and presents 7-10 years after measles infection.
 

Should you transfer the patient to a hospital?

Unless there is a medical need for the child to be admitted, sending a patient with potential measles to the hospital is not necessary, and can cause exposure to a large group of medical personnel, and patients who cannot be vaccinated (such as infants, immunocompromised patients, and pregnant women). However, if there is concern for complications such as seizures, encephalitis, or pneumonia, then transfer is indicated. Call the accepting hospital in advance so the staff can prepare for the patient. During transfer, place a standard face mask on the patient and instruct the patient not to remove it.

For hospitals accepting a suspected measles case, meet the patient outside of the facility and ensure that the patient is wearing a standard face mask. All staff interacting with the patient should practice contact and airborne precautions (N95 respirator mask). Take the patient directly to an isolation room with negative airflow. Caution pregnant staff that they should not have contact with the patient.
 

Which diagnostic tests should you use?

Diagnosis can be made based on serum antibody tests (measles IgM and IgG), throat or urine viral cultures, and nasopharyngeal and throat specimen polymerase chain reaction (PCR) testing. The CDC recommends obtaining a serum sample for measles IgM testing and a throat swab for PCR in all suspected cases, but local health departments vary in their specific testing recommendations. Familiarize yourself with the tests recommended by your local department of health, and where they prefer testing on outpatients to be done. Confirmed measles should be reported to your department of health.

What are considerations for community pediatric offices?

Update families in emails to call ahead if they suspect measles. This way the office can prepare a room for the family, and have the family immediately brought back without exposing staff and other families in the waiting area. It may be more prudent to examine these children at the end of the clinic day as the virus can persist for up to 2 hours on fomites and in the air. Therefore, all waiting areas and shared air spaces (including those with shared air ducts) should be cleared for 2 hours after the patient leaves.

When should you provide prophylaxis after exposure?

A patient with suspected measles does not require immediate vaccination. If it is measles, it is already too late to vaccinate. If measles is ruled out, the child should follow the standard measles vaccination guidelines.

Individuals are contagious from 4 days before to 4 days after the rash appears.

If measles is confirmed, all people who are unvaccinated or undervaccinated and were exposed to the confirmed case during the contagious period should be vaccinated within 72 hours of exposure. Infants 6 months or older may safely receive the MMR vaccine. However, infants vaccinated with MMR before their first birthday must be vaccinated again at age 12-15 months (greater than 28 days after prior vaccine) and at 4-6 years. Immunoglobulin prophylaxis should be given intramuscularly in exposed infants ages birth to less than 6 months, and in those ages 6-12 months who present beyond the 72-hour window. Unvaccinated or undervaccinated, exposed individuals at high risk for complications from measles (immunocompromised, pregnant) also should receive immunoglobulin.
 

What should you tell traveling families?

Several countries have large, ongoing measles outbreaks, including Israel, Ukraine, and the Philippines. Before international travel, infants 6-11 months should receive one dose of MMR vaccine, and children 12 months and older need two doses separated by at least 28 days. For unvaccinated or undervaccinated children, consider advising families to hold off travel to high-risk countries, or understand the indications to vaccinate a child upon return.
 

Dr. Angelica DesPain is a pediatric emergency medicine fellow at Children’s National Medical Center in Washington. She said she has no relevant financial disclosures. Dr. Emily Willner is a pediatric emergency medicine attending at Children’s National Medical Center, and an assistant professor of pediatrics and emergency medicine at George Washington University, Washington. She has no relevant financial disclosures.

Younger patients with non–small cell lung cancer (NSCLC) may have better survival, despite higher rates of brain metastasis and driver mutations, according to results from a retrospective analysis.

“We carried out a comprehensive analysis of patient clinicopathologic features and clinical outcomes in both young (age ≤ 50 years) and older (age > 60 years) patients with NSCLC,” wrote Anna May Suidan of Tel Aviv University, and colleagues. The findings were published in the Journal of Global Oncology.

The researchers reviewed medical records of patients who were diagnosed with lung cancer at a large cancer treatment facility in Israel from 2010 to 2015. Patients were categorized into two groups according to age at cancer diagnosis, which was established based on tumor pathology.

Various clinical data were collected, including demographic information, history of malignancy, smoking history, histologic subtype, and survival data.

In all, 62 patients were included in the younger cohort (median age, 44.5 years) and 124 patients in the older cohort (median age, 68.0 years).

After analysis, the researchers found that younger patients had a higher incidence of brain metastasis (39% vs. 25%, respectively; P = .04), and increased rates of EGFR mutations (23% vs. 18%, respectively; P = .4) and ALK translocations (13% vs. 2%, respectively; P = .002) versus older patients.

“Our cohort, which was [composed] of white patients, demonstrated that younger patients harbored more targetable driver mutations compared with older patients (34% vs. 18%; P = .01),” the researchers wrote.

In addition, among those with a driver mutation, younger patients showed a trend toward better survival (median survival, 33 vs. 25 months, respectively; P = .4).

Two key limitations of the study were the small sample size and retrospective design.

“[These results] highlight the importance of genetic background assessments and considering lung cancer as a possible diagnosis in young symptomatic patients in clinical settings,” the researchers concluded.

No funding sources were reported. The authors reported financial affiliations with Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Novartis, Roche, Teva Pharmaceuticals, and several others.

SOURCE: Suidan AM et al. J Glob Oncol. 2019 May 8. doi: 10.1200/JGO.18.00216.

Younger patients with non–small cell lung cancer (NSCLC) may have better survival, despite higher rates of brain metastasis and driver mutations, according to results from a retrospective analysis.

“We carried out a comprehensive analysis of patient clinicopathologic features and clinical outcomes in both young (age ≤ 50 years) and older (age > 60 years) patients with NSCLC,” wrote Anna May Suidan of Tel Aviv University, and colleagues. The findings were published in the Journal of Global Oncology.

The researchers reviewed medical records of patients who were diagnosed with lung cancer at a large cancer treatment facility in Israel from 2010 to 2015. Patients were categorized into two groups according to age at cancer diagnosis, which was established based on tumor pathology.

Various clinical data were collected, including demographic information, history of malignancy, smoking history, histologic subtype, and survival data.

In all, 62 patients were included in the younger cohort (median age, 44.5 years) and 124 patients in the older cohort (median age, 68.0 years).

After analysis, the researchers found that younger patients had a higher incidence of brain metastasis (39% vs. 25%, respectively; P = .04), and increased rates of EGFR mutations (23% vs. 18%, respectively; P = .4) and ALK translocations (13% vs. 2%, respectively; P = .002) versus older patients.

“Our cohort, which was [composed] of white patients, demonstrated that younger patients harbored more targetable driver mutations compared with older patients (34% vs. 18%; P = .01),” the researchers wrote.

In addition, among those with a driver mutation, younger patients showed a trend toward better survival (median survival, 33 vs. 25 months, respectively; P = .4).

Two key limitations of the study were the small sample size and retrospective design.

“[These results] highlight the importance of genetic background assessments and considering lung cancer as a possible diagnosis in young symptomatic patients in clinical settings,” the researchers concluded.

No funding sources were reported. The authors reported financial affiliations with Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Novartis, Roche, Teva Pharmaceuticals, and several others.

SOURCE: Suidan AM et al. J Glob Oncol. 2019 May 8. doi: 10.1200/JGO.18.00216.

Younger patients with non–small cell lung cancer (NSCLC) may have better survival, despite higher rates of brain metastasis and driver mutations, according to results from a retrospective analysis.

“We carried out a comprehensive analysis of patient clinicopathologic features and clinical outcomes in both young (age ≤ 50 years) and older (age > 60 years) patients with NSCLC,” wrote Anna May Suidan of Tel Aviv University, and colleagues. The findings were published in the Journal of Global Oncology.

The researchers reviewed medical records of patients who were diagnosed with lung cancer at a large cancer treatment facility in Israel from 2010 to 2015. Patients were categorized into two groups according to age at cancer diagnosis, which was established based on tumor pathology.

Various clinical data were collected, including demographic information, history of malignancy, smoking history, histologic subtype, and survival data.

In all, 62 patients were included in the younger cohort (median age, 44.5 years) and 124 patients in the older cohort (median age, 68.0 years).

After analysis, the researchers found that younger patients had a higher incidence of brain metastasis (39% vs. 25%, respectively; P = .04), and increased rates of EGFR mutations (23% vs. 18%, respectively; P = .4) and ALK translocations (13% vs. 2%, respectively; P = .002) versus older patients.

“Our cohort, which was [composed] of white patients, demonstrated that younger patients harbored more targetable driver mutations compared with older patients (34% vs. 18%; P = .01),” the researchers wrote.

In addition, among those with a driver mutation, younger patients showed a trend toward better survival (median survival, 33 vs. 25 months, respectively; P = .4).

Two key limitations of the study were the small sample size and retrospective design.

“[These results] highlight the importance of genetic background assessments and considering lung cancer as a possible diagnosis in young symptomatic patients in clinical settings,” the researchers concluded.

No funding sources were reported. The authors reported financial affiliations with Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Novartis, Roche, Teva Pharmaceuticals, and several others.

SOURCE: Suidan AM et al. J Glob Oncol. 2019 May 8. doi: 10.1200/JGO.18.00216.

African American men with diabetes may be at risk for significantly low levels of oxytocin (OT), according to a study of 92 veterans by researchers from the Jesse Brown Veterans Administration Medical Center in Chicago, Illinois. Research has recently been revealing oxytocin’s role in energy homeostasis; OT derangements have also been implicated in a variety of diseases, including schizophrenia, autism, dysthymia, and attention-deficit/hyperactivity disorder.

The researchers note that their study participants represent a “unique population” of African American male veterans for whom no data on OT levels exist in the literature. The population has a disproportionately high rate of obesity and dysglycemia, as well as high rates of comorbid psychiatric disease.

In the study, urinary oxytocin was higher in men with lower weight, body mass index (BMI), and hemoglobin A_1c and better renal function. Men with the highest levels of oxytocin were about 80% less likely to have type 2 diabetes. The researchers say several studies have appeared to show that intranasal OT may reduce reward-driven food intake, and that OT administration may result in weight reduction.

Men with high oxytocin levels were 4 times more likely to be using psychiatric medications. Although there was no difference in psychiatric conditions based on OT levels, the use of psychiatric medications remained significant after adjustment for BMI. The influence of psychiatric medications on oxytocinergic systems is not well understood, the researchers say. However, they add that medication-related improved psychological health outcome might result in OT changes.

Men with high oxytocin levels were also 4 times more likely to be smokers. The researchers note that chronic administration of nicotine seems to upregulate OT receptor binding in regions of the brain involved in stress and emotion regulation, and these neuro-adaptations likely influence nicotine-seeking behavior. Intranasal OT is being investigated for smoking cessation.

African American men with diabetes may be at risk for significantly low levels of oxytocin (OT), according to a study of 92 veterans by researchers from the Jesse Brown Veterans Administration Medical Center in Chicago, Illinois. Research has recently been revealing oxytocin’s role in energy homeostasis; OT derangements have also been implicated in a variety of diseases, including schizophrenia, autism, dysthymia, and attention-deficit/hyperactivity disorder.

The researchers note that their study participants represent a “unique population” of African American male veterans for whom no data on OT levels exist in the literature. The population has a disproportionately high rate of obesity and dysglycemia, as well as high rates of comorbid psychiatric disease.

In the study, urinary oxytocin was higher in men with lower weight, body mass index (BMI), and hemoglobin A_1c and better renal function. Men with the highest levels of oxytocin were about 80% less likely to have type 2 diabetes. The researchers say several studies have appeared to show that intranasal OT may reduce reward-driven food intake, and that OT administration may result in weight reduction.

Men with high oxytocin levels were 4 times more likely to be using psychiatric medications. Although there was no difference in psychiatric conditions based on OT levels, the use of psychiatric medications remained significant after adjustment for BMI. The influence of psychiatric medications on oxytocinergic systems is not well understood, the researchers say. However, they add that medication-related improved psychological health outcome might result in OT changes.

Men with high oxytocin levels were also 4 times more likely to be smokers. The researchers note that chronic administration of nicotine seems to upregulate OT receptor binding in regions of the brain involved in stress and emotion regulation, and these neuro-adaptations likely influence nicotine-seeking behavior. Intranasal OT is being investigated for smoking cessation.

African American men with diabetes may be at risk for significantly low levels of oxytocin (OT), according to a study of 92 veterans by researchers from the Jesse Brown Veterans Administration Medical Center in Chicago, Illinois. Research has recently been revealing oxytocin’s role in energy homeostasis; OT derangements have also been implicated in a variety of diseases, including schizophrenia, autism, dysthymia, and attention-deficit/hyperactivity disorder.

The researchers note that their study participants represent a “unique population” of African American male veterans for whom no data on OT levels exist in the literature. The population has a disproportionately high rate of obesity and dysglycemia, as well as high rates of comorbid psychiatric disease.

In the study, urinary oxytocin was higher in men with lower weight, body mass index (BMI), and hemoglobin A_1c and better renal function. Men with the highest levels of oxytocin were about 80% less likely to have type 2 diabetes. The researchers say several studies have appeared to show that intranasal OT may reduce reward-driven food intake, and that OT administration may result in weight reduction.

Men with high oxytocin levels were 4 times more likely to be using psychiatric medications. Although there was no difference in psychiatric conditions based on OT levels, the use of psychiatric medications remained significant after adjustment for BMI. The influence of psychiatric medications on oxytocinergic systems is not well understood, the researchers say. However, they add that medication-related improved psychological health outcome might result in OT changes.

Men with high oxytocin levels were also 4 times more likely to be smokers. The researchers note that chronic administration of nicotine seems to upregulate OT receptor binding in regions of the brain involved in stress and emotion regulation, and these neuro-adaptations likely influence nicotine-seeking behavior. Intranasal OT is being investigated for smoking cessation.

A 5-member panel of experts in primary care, geriatrics, and behavioral sciences, among others, convened by the  National Institutes of Health (NIH), sought to answer that question. In the Pathways to Prevention (P2P) Workshop: Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention, the panel discussed the available evidence on long-term drug therapies, in hopes of identifying research gaps and ways to “advance the field.” Then they published a report that summarizes their findings, along with recommendations for “new strengthened research.”

Trials have found 3 to 5 years of ODT is safe and effective, the panel notes, and that some ODTs reduce the incidence of nonvertebral fractures. But those studies have been done mainly in white postmenopausal women. Men, people of other race and ethnicity, residents in facilities, people with advanced and multiple comorbid conditions, and other populations are absent or underrepresented. Thus, estimates on benefits and harms may differ in practice. Moreover, the trial results presented no data on nonfracture patient outcomes or sequelae, such as mobility, hospitalizations, and nursing home placement. The studies also offered limited or no evidence on whether patient characteristics would result in different fracture outcomes.

The panel also noted that few trials extended beyond 5 years, although some observational studies provided “limited evidence” on potential benefits and harms from longer term use. Gaps exist in how to use information on bone biomarkers and other patient characteristics, such as concurrent medication use, that might modify the effects of ODT, the panel concluded.

 One of the main issues the panel investigated was how to make sure that the people at highest risk of fracture get the medicine they need. Only about one-third of women at high risk have reported treatment with osteoporosis medication. And among older adults with a hip fracture, only 11% to 13% filled any prescription for osteoporosis medication within 3 months of the fracture.

Information about ODT use and adherence was not included in the systematic evidence review, so the report relies on material provided by the workshop speakers, who say low rates of diagnosis and treatment probably stem from multiple clinician and patient factors. For instance, they said, with regard to clinicians, the problems may be lack of time, knowledge gaps, and lack of appropriate systems in primary care.

The panelists also cited another gap: in communication between clinicians about treatment as patients transition from one setting to another. One solution could be a hospital-based fracture liaison service to coordinate care, they suggest.

Patient factors include perceptions that osteoporosis is a normal part of aging, or that drugs do not work or that they are harmful and risky. Studies about decision making have found that people often overestimate their risk for rare adverse effects (AEs) and underestimate the likelihood of having a fracture.

In their assessment of studies, the workshop panelists found education-based interventions sometimes increase rates of filled prescriptions but not adherence 6 or 10 months down the road. They also found coaching and counseling have been “largely ineffective.”

“We need to identify the reasons why,” the panelists concluded, and made a number of recommendations about how to do the research. For instance, they suggest using a broader array of trial designs, such as innovative platform trials as used in cancer research, where the target of the investigation is the disease and not the drug. Studies also should focus on fracture sequelae, and include diverse populations that “more closely match” the characteristics of people who actually have fractures.

Gaps in knowledge about the uncommon AEs reported with bisphosphonates and other questions mean questions to be answered include which class of drugs should be used first, when treatment should start and how long it should last, and which doses are preferable.

Knowing how to treat can help clinicians and their patients decide whom to treat, the report suggests. Addressing the research gaps will improve the shared decision making needed for answering those questions.

The report was published in Annals of Internal Medicine on April 23, 2019.

A 5-member panel of experts in primary care, geriatrics, and behavioral sciences, among others, convened by the  National Institutes of Health (NIH), sought to answer that question. In the Pathways to Prevention (P2P) Workshop: Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention, the panel discussed the available evidence on long-term drug therapies, in hopes of identifying research gaps and ways to “advance the field.” Then they published a report that summarizes their findings, along with recommendations for “new strengthened research.”

Trials have found 3 to 5 years of ODT is safe and effective, the panel notes, and that some ODTs reduce the incidence of nonvertebral fractures. But those studies have been done mainly in white postmenopausal women. Men, people of other race and ethnicity, residents in facilities, people with advanced and multiple comorbid conditions, and other populations are absent or underrepresented. Thus, estimates on benefits and harms may differ in practice. Moreover, the trial results presented no data on nonfracture patient outcomes or sequelae, such as mobility, hospitalizations, and nursing home placement. The studies also offered limited or no evidence on whether patient characteristics would result in different fracture outcomes.

The panel also noted that few trials extended beyond 5 years, although some observational studies provided “limited evidence” on potential benefits and harms from longer term use. Gaps exist in how to use information on bone biomarkers and other patient characteristics, such as concurrent medication use, that might modify the effects of ODT, the panel concluded.

 One of the main issues the panel investigated was how to make sure that the people at highest risk of fracture get the medicine they need. Only about one-third of women at high risk have reported treatment with osteoporosis medication. And among older adults with a hip fracture, only 11% to 13% filled any prescription for osteoporosis medication within 3 months of the fracture.

Information about ODT use and adherence was not included in the systematic evidence review, so the report relies on material provided by the workshop speakers, who say low rates of diagnosis and treatment probably stem from multiple clinician and patient factors. For instance, they said, with regard to clinicians, the problems may be lack of time, knowledge gaps, and lack of appropriate systems in primary care.

The panelists also cited another gap: in communication between clinicians about treatment as patients transition from one setting to another. One solution could be a hospital-based fracture liaison service to coordinate care, they suggest.

Patient factors include perceptions that osteoporosis is a normal part of aging, or that drugs do not work or that they are harmful and risky. Studies about decision making have found that people often overestimate their risk for rare adverse effects (AEs) and underestimate the likelihood of having a fracture.

In their assessment of studies, the workshop panelists found education-based interventions sometimes increase rates of filled prescriptions but not adherence 6 or 10 months down the road. They also found coaching and counseling have been “largely ineffective.”

“We need to identify the reasons why,” the panelists concluded, and made a number of recommendations about how to do the research. For instance, they suggest using a broader array of trial designs, such as innovative platform trials as used in cancer research, where the target of the investigation is the disease and not the drug. Studies also should focus on fracture sequelae, and include diverse populations that “more closely match” the characteristics of people who actually have fractures.

Gaps in knowledge about the uncommon AEs reported with bisphosphonates and other questions mean questions to be answered include which class of drugs should be used first, when treatment should start and how long it should last, and which doses are preferable.

Knowing how to treat can help clinicians and their patients decide whom to treat, the report suggests. Addressing the research gaps will improve the shared decision making needed for answering those questions.

The report was published in Annals of Internal Medicine on April 23, 2019.

A 5-member panel of experts in primary care, geriatrics, and behavioral sciences, among others, convened by the  National Institutes of Health (NIH), sought to answer that question. In the Pathways to Prevention (P2P) Workshop: Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention, the panel discussed the available evidence on long-term drug therapies, in hopes of identifying research gaps and ways to “advance the field.” Then they published a report that summarizes their findings, along with recommendations for “new strengthened research.”

Trials have found 3 to 5 years of ODT is safe and effective, the panel notes, and that some ODTs reduce the incidence of nonvertebral fractures. But those studies have been done mainly in white postmenopausal women. Men, people of other race and ethnicity, residents in facilities, people with advanced and multiple comorbid conditions, and other populations are absent or underrepresented. Thus, estimates on benefits and harms may differ in practice. Moreover, the trial results presented no data on nonfracture patient outcomes or sequelae, such as mobility, hospitalizations, and nursing home placement. The studies also offered limited or no evidence on whether patient characteristics would result in different fracture outcomes.

The panel also noted that few trials extended beyond 5 years, although some observational studies provided “limited evidence” on potential benefits and harms from longer term use. Gaps exist in how to use information on bone biomarkers and other patient characteristics, such as concurrent medication use, that might modify the effects of ODT, the panel concluded.

 One of the main issues the panel investigated was how to make sure that the people at highest risk of fracture get the medicine they need. Only about one-third of women at high risk have reported treatment with osteoporosis medication. And among older adults with a hip fracture, only 11% to 13% filled any prescription for osteoporosis medication within 3 months of the fracture.

Information about ODT use and adherence was not included in the systematic evidence review, so the report relies on material provided by the workshop speakers, who say low rates of diagnosis and treatment probably stem from multiple clinician and patient factors. For instance, they said, with regard to clinicians, the problems may be lack of time, knowledge gaps, and lack of appropriate systems in primary care.

The panelists also cited another gap: in communication between clinicians about treatment as patients transition from one setting to another. One solution could be a hospital-based fracture liaison service to coordinate care, they suggest.

Patient factors include perceptions that osteoporosis is a normal part of aging, or that drugs do not work or that they are harmful and risky. Studies about decision making have found that people often overestimate their risk for rare adverse effects (AEs) and underestimate the likelihood of having a fracture.

In their assessment of studies, the workshop panelists found education-based interventions sometimes increase rates of filled prescriptions but not adherence 6 or 10 months down the road. They also found coaching and counseling have been “largely ineffective.”

“We need to identify the reasons why,” the panelists concluded, and made a number of recommendations about how to do the research. For instance, they suggest using a broader array of trial designs, such as innovative platform trials as used in cancer research, where the target of the investigation is the disease and not the drug. Studies also should focus on fracture sequelae, and include diverse populations that “more closely match” the characteristics of people who actually have fractures.

Gaps in knowledge about the uncommon AEs reported with bisphosphonates and other questions mean questions to be answered include which class of drugs should be used first, when treatment should start and how long it should last, and which doses are preferable.

Knowing how to treat can help clinicians and their patients decide whom to treat, the report suggests. Addressing the research gaps will improve the shared decision making needed for answering those questions.

The report was published in Annals of Internal Medicine on April 23, 2019.