Conference Coverage

Participants who had higher levels of fitness when beginning a behavioral weight-loss intervention kept off more weight over the course of an 18-month study, compared with those with lower levels of fitness at baseline.

Those with higher baseline fitness also were able to achieve higher levels of moderate to vigorous physical activity at the 18-month mark, Adnin Zaman, MD, said during a virtual news conference held by the Endocrine Society. The study had been slated for presentation during ENDO 2020, the society's annual meeting, which was canceled because of the COVID-19 pandemic.

“Our study really comes from an observation that we often see significant variability in how much weight participants lose during a behavioral weight-loss intervention study, said Dr. Zaman, an endocrinology research fellow at the University of Colorado at Denver, Aurora.

She and her colleagues wanted to look at baseline cardiovascular fitness as an individual-specific factor that could affect how much weight people lost when participating in a behavioral intervention.

“Very little is known about how cardiovascular fitness affects [people’s] ability to lose weight [or] to adhere to high levels of physical activity, which is a very common recommendation during a program for both weight loss and weight-loss maintenance,” she added.

Dr. Zaman and colleagues conducted a secondary analysis of data from an 18-month trial of behavioral interventions for weight loss. The trial randomized 170 participants 1:1 to receive either concurrent exercise and a dietary behavior modification intervention or sequential dietary and exercise interventions.

The 85 participants in the concurrent intervention arm received 18 months of combined dietary modifications (calorie-restricted diet and group-based behavioral support) and exercise (supervised for the first 6 months of the study, unsupervised for the final 12). Those participating in the sequential intervention arm received a diet-only intervention during the first 6 months of the study, after which supervised exercise was added to the dietary intervention for 6 months, followed by a final 6 months of unsupervised exercise.

Participants in both study arms worked up to 300 minutes a week of moderate to vigorous physical activity in the supervised exercise phase.

For the secondary analysis, Dr. Zaman and colleagues looked only at the 60 participants who received concurrent diet and exercise interventions and who completed the full 18-month study. The mean age in that group was 40 years, mean baseline body mass index (BMI) was 34.6 kg/m², and 80% of participants in the group were women.

Cardiovascular fitness as measured by VO_2max was assessed at baseline using a graded exercise test. Participants were designated as having either “very poor” or “poor or better” cardiovascular fitness (20 and 40 participants, respectively).

Participants in the original trial were inactive at baseline and had a BMI range of 27-42 kg/m². Among the subset of participants studied by Dr. Zaman and colleagues, those who were in the poor or better fitness category actually weighed less at baseline and had a lower BMI, compared with those in the very poor group (33.7 vs. 36.2, respectively), she said. Mean VO_2max for those with very poor fitness was 22.5 mL/kg per minute, compared with 25.6 mL/kg per minute for those with poor or better fitness.

“Despite those differences, it is interesting to note that, during the supervised exercise portion of the study ... everyone lost pretty much the same amount of weight in the first 6 months,” said Dr. Zaman. At the 6-month mark, those with very poor fitness had lost 9.2 kg (20.3 pounds), and those with poor or better fitness had lost 9.1 kg (20.1 pounds). However, weight regain was less likely in those with poor or better fitness, and those participants had a net loss of weight from baseline of 8.2 kg (18.1 pounds), compared with 4.4 kg (9.7 pounds) for those with very poor fitness.

Those with poor or better fitness were able to sustain a 33-minute bout of moderate to vigorous physical activity at baseline, whereas those with very poor fitness could achieve only about half of that. The difference in achievable physical activity between the two groups persisted throughout the study, with a peak at the 6-month mark, at about 60 minutes for the more fit participants and 38 minutes for those in the poor fitness group. By the end of the study, the less-fit participants achieved about 24 minutes of activity, whereas those who were more fit could sustain about 42 minutes of moderate to vigorous physical activity.

Physical activity levels were measured with a validated, wrist-worn device during a 1-week period at baseline and again at study months 6, 12, and 18.

Dr. Zaman noted that baseline weight may have confounded fitness categorization, because VO_2max includes body weight in its calculations. A newer method of calculating cardiorespiratory fitness that scales VO_2max to body weight may help minimize this potential confounder.

The investigators reported no outside sources of funding and reported that they had no financial conflicts of interest.

The research will be published in a special supplemental issue of the Journal of the Endocrine Society. In addition to a series of news conferences on March 30-31, the society will host ENDO Online 2020 during June 8-22, which will present programming for clinicians and researchers.

SOURCE: Zaman A et al. ENDO 2020, Abstract 575.

This article was updated on 4/17/2020.

Participants who had higher levels of fitness when beginning a behavioral weight-loss intervention kept off more weight over the course of an 18-month study, compared with those with lower levels of fitness at baseline.

Those with higher baseline fitness also were able to achieve higher levels of moderate to vigorous physical activity at the 18-month mark, Adnin Zaman, MD, said during a virtual news conference held by the Endocrine Society. The study had been slated for presentation during ENDO 2020, the society's annual meeting, which was canceled because of the COVID-19 pandemic.

“Our study really comes from an observation that we often see significant variability in how much weight participants lose during a behavioral weight-loss intervention study, said Dr. Zaman, an endocrinology research fellow at the University of Colorado at Denver, Aurora.

She and her colleagues wanted to look at baseline cardiovascular fitness as an individual-specific factor that could affect how much weight people lost when participating in a behavioral intervention.

“Very little is known about how cardiovascular fitness affects [people’s] ability to lose weight [or] to adhere to high levels of physical activity, which is a very common recommendation during a program for both weight loss and weight-loss maintenance,” she added.

Dr. Zaman and colleagues conducted a secondary analysis of data from an 18-month trial of behavioral interventions for weight loss. The trial randomized 170 participants 1:1 to receive either concurrent exercise and a dietary behavior modification intervention or sequential dietary and exercise interventions.

The 85 participants in the concurrent intervention arm received 18 months of combined dietary modifications (calorie-restricted diet and group-based behavioral support) and exercise (supervised for the first 6 months of the study, unsupervised for the final 12). Those participating in the sequential intervention arm received a diet-only intervention during the first 6 months of the study, after which supervised exercise was added to the dietary intervention for 6 months, followed by a final 6 months of unsupervised exercise.

Participants in both study arms worked up to 300 minutes a week of moderate to vigorous physical activity in the supervised exercise phase.

For the secondary analysis, Dr. Zaman and colleagues looked only at the 60 participants who received concurrent diet and exercise interventions and who completed the full 18-month study. The mean age in that group was 40 years, mean baseline body mass index (BMI) was 34.6 kg/m², and 80% of participants in the group were women.

Cardiovascular fitness as measured by VO_2max was assessed at baseline using a graded exercise test. Participants were designated as having either “very poor” or “poor or better” cardiovascular fitness (20 and 40 participants, respectively).

Participants in the original trial were inactive at baseline and had a BMI range of 27-42 kg/m². Among the subset of participants studied by Dr. Zaman and colleagues, those who were in the poor or better fitness category actually weighed less at baseline and had a lower BMI, compared with those in the very poor group (33.7 vs. 36.2, respectively), she said. Mean VO_2max for those with very poor fitness was 22.5 mL/kg per minute, compared with 25.6 mL/kg per minute for those with poor or better fitness.

“Despite those differences, it is interesting to note that, during the supervised exercise portion of the study ... everyone lost pretty much the same amount of weight in the first 6 months,” said Dr. Zaman. At the 6-month mark, those with very poor fitness had lost 9.2 kg (20.3 pounds), and those with poor or better fitness had lost 9.1 kg (20.1 pounds). However, weight regain was less likely in those with poor or better fitness, and those participants had a net loss of weight from baseline of 8.2 kg (18.1 pounds), compared with 4.4 kg (9.7 pounds) for those with very poor fitness.

Those with poor or better fitness were able to sustain a 33-minute bout of moderate to vigorous physical activity at baseline, whereas those with very poor fitness could achieve only about half of that. The difference in achievable physical activity between the two groups persisted throughout the study, with a peak at the 6-month mark, at about 60 minutes for the more fit participants and 38 minutes for those in the poor fitness group. By the end of the study, the less-fit participants achieved about 24 minutes of activity, whereas those who were more fit could sustain about 42 minutes of moderate to vigorous physical activity.

Physical activity levels were measured with a validated, wrist-worn device during a 1-week period at baseline and again at study months 6, 12, and 18.

Dr. Zaman noted that baseline weight may have confounded fitness categorization, because VO_2max includes body weight in its calculations. A newer method of calculating cardiorespiratory fitness that scales VO_2max to body weight may help minimize this potential confounder.

The investigators reported no outside sources of funding and reported that they had no financial conflicts of interest.

The research will be published in a special supplemental issue of the Journal of the Endocrine Society. In addition to a series of news conferences on March 30-31, the society will host ENDO Online 2020 during June 8-22, which will present programming for clinicians and researchers.

SOURCE: Zaman A et al. ENDO 2020, Abstract 575.

This article was updated on 4/17/2020.

Participants who had higher levels of fitness when beginning a behavioral weight-loss intervention kept off more weight over the course of an 18-month study, compared with those with lower levels of fitness at baseline.

Those with higher baseline fitness also were able to achieve higher levels of moderate to vigorous physical activity at the 18-month mark, Adnin Zaman, MD, said during a virtual news conference held by the Endocrine Society. The study had been slated for presentation during ENDO 2020, the society's annual meeting, which was canceled because of the COVID-19 pandemic.

“Our study really comes from an observation that we often see significant variability in how much weight participants lose during a behavioral weight-loss intervention study, said Dr. Zaman, an endocrinology research fellow at the University of Colorado at Denver, Aurora.

She and her colleagues wanted to look at baseline cardiovascular fitness as an individual-specific factor that could affect how much weight people lost when participating in a behavioral intervention.

“Very little is known about how cardiovascular fitness affects [people’s] ability to lose weight [or] to adhere to high levels of physical activity, which is a very common recommendation during a program for both weight loss and weight-loss maintenance,” she added.

Dr. Zaman and colleagues conducted a secondary analysis of data from an 18-month trial of behavioral interventions for weight loss. The trial randomized 170 participants 1:1 to receive either concurrent exercise and a dietary behavior modification intervention or sequential dietary and exercise interventions.

The 85 participants in the concurrent intervention arm received 18 months of combined dietary modifications (calorie-restricted diet and group-based behavioral support) and exercise (supervised for the first 6 months of the study, unsupervised for the final 12). Those participating in the sequential intervention arm received a diet-only intervention during the first 6 months of the study, after which supervised exercise was added to the dietary intervention for 6 months, followed by a final 6 months of unsupervised exercise.

Participants in both study arms worked up to 300 minutes a week of moderate to vigorous physical activity in the supervised exercise phase.

For the secondary analysis, Dr. Zaman and colleagues looked only at the 60 participants who received concurrent diet and exercise interventions and who completed the full 18-month study. The mean age in that group was 40 years, mean baseline body mass index (BMI) was 34.6 kg/m², and 80% of participants in the group were women.

Cardiovascular fitness as measured by VO_2max was assessed at baseline using a graded exercise test. Participants were designated as having either “very poor” or “poor or better” cardiovascular fitness (20 and 40 participants, respectively).

Participants in the original trial were inactive at baseline and had a BMI range of 27-42 kg/m². Among the subset of participants studied by Dr. Zaman and colleagues, those who were in the poor or better fitness category actually weighed less at baseline and had a lower BMI, compared with those in the very poor group (33.7 vs. 36.2, respectively), she said. Mean VO_2max for those with very poor fitness was 22.5 mL/kg per minute, compared with 25.6 mL/kg per minute for those with poor or better fitness.

“Despite those differences, it is interesting to note that, during the supervised exercise portion of the study ... everyone lost pretty much the same amount of weight in the first 6 months,” said Dr. Zaman. At the 6-month mark, those with very poor fitness had lost 9.2 kg (20.3 pounds), and those with poor or better fitness had lost 9.1 kg (20.1 pounds). However, weight regain was less likely in those with poor or better fitness, and those participants had a net loss of weight from baseline of 8.2 kg (18.1 pounds), compared with 4.4 kg (9.7 pounds) for those with very poor fitness.

Those with poor or better fitness were able to sustain a 33-minute bout of moderate to vigorous physical activity at baseline, whereas those with very poor fitness could achieve only about half of that. The difference in achievable physical activity between the two groups persisted throughout the study, with a peak at the 6-month mark, at about 60 minutes for the more fit participants and 38 minutes for those in the poor fitness group. By the end of the study, the less-fit participants achieved about 24 minutes of activity, whereas those who were more fit could sustain about 42 minutes of moderate to vigorous physical activity.

Physical activity levels were measured with a validated, wrist-worn device during a 1-week period at baseline and again at study months 6, 12, and 18.

Dr. Zaman noted that baseline weight may have confounded fitness categorization, because VO_2max includes body weight in its calculations. A newer method of calculating cardiorespiratory fitness that scales VO_2max to body weight may help minimize this potential confounder.

The investigators reported no outside sources of funding and reported that they had no financial conflicts of interest.

The research will be published in a special supplemental issue of the Journal of the Endocrine Society. In addition to a series of news conferences on March 30-31, the society will host ENDO Online 2020 during June 8-22, which will present programming for clinicians and researchers.

SOURCE: Zaman A et al. ENDO 2020, Abstract 575.

This article was updated on 4/17/2020.

In utero exposure to bisphenol-A (BPA) analogs led to hypertension in female rats, findings in a new study have shown.

Researchers tested exposures to BPA, as well as bisphenol-S (BPS) and bisphenol-F (BPF), which have been introduced in recent years as BPA alternatives and are now increasingly detectable in human and animal tissues. BPS and BPF are often found in products labeled as “BPA free.”

BPS and BPF have similar physiochemical properties to BPA, and there is concern over their effects.

But their physiological impact is not yet clear, according to Puliyur MohanKumar, DVM, PhD, of the University of Georgia Regenerative Bioscience Center, Athens. “We are exposed to BPA and related compounds on a regular basis, and the important thing is that BPA and related compounds easily cross the placental barrier,” Dr. MohanKumar said during a virtual news conference held by the Endocrine Society. The study had been slated for presentation during ENDO 2020, the society's annual meeting, which was canceled because of the COVID-19 pandemic.

Dr. MohanKumar and colleagues exposed pregnant rats to BPA, BPS, or BPF. When the offspring reached adulthood, the researchers implanted them with radiotelemetry devices to track systolic and diastolic blood pressure, which they measured every 10 minutes over a 24-hour period. This was repeated once a week for 11 weeks.

“The female offspring had elevated systolic as well as diastolic blood pressure, and this was an increase of about 8 mm [Hg] higher than the control animals. That was pretty significant. Keeping these animals at such a prehypertensive state for such a long period of time is going to [lead to] lots of cardiovascular issues later on,” said Dr. MohanKumar.

Robert Sargis, MD, PhD, professor of endocrinology, diabetes, and metabolism at the University of Illinois at Chicago, noted that, although animal studies don’t necessarily translate to similar outcomes in humans, the results are cause for concern.

“What’s particularly interesting, is that there is whole area of essential hypertension, where people develop hypertension and we don’t really know why. We just treat it,” he said in an interview. “But thinking about biological origins [of hypertension] is potentially interesting for a couple of reasons. These bisphenol compounds are really common. Most Americans are exposed to bisphenol A, and it’s been associated with other adverse metabolic effects, including alterations to body weight and glucose homeostasis.

“[These findings] feed into a whole series of studies that have begun to look at the BPA replacements and the fact that they may be, at best, as bad as BPA, and at worst, possibly slightly worse, depending on which outcomes you’re looking at,” Dr. Sargis added.

In the study, seven pregnant rats were orally exposed to saline, four pregnant rats to 5 mcg/kg BPA, four to 5 mcg/kg BPS, and five to 1 mcg/kg BPF during days 6-21 of pregnancy. The lower dose of BPF was used because a dose of 5 mcg/kg proved too toxic. When the offspring reached adulthood, the researchers implanted radiotelemetry devices in the offspring’s femoral artery.

Mean daytime systolic BP was highest in the BPA group (133.3 mg Hg; P < .05), followed by BPS (132.5 mm Hg; P < .05) and BPF (129.2 mm Hg; nonsignificant), compared with 125.2 mm Hg in controls. Nighttime systolic BP was again highest in the BPA group (134.2 mm Hg; P < .01), followed by BPS (133.2 mm Hg; P < .05) and BPF (129.6 mm Hg; nonsignificant), compared with 125.1 mm Hg in controls.

During the day, diastolic BP was highest in the BPS group (91.3 mm Hg; P < .01), followed by BPA (88.8 mm Hg; nonsignificant) and BPF (88.6 mm Hg; nonsignificant), compared with 84.1 mm Hg in controls. At night, diastolic BP was highest in the BPS group (89.7 mm Hg; P < .01), followed by BPA (89.6 mm Hg; P < .01) and BPF (88.6 mm Hg; P < .01), compared with 83.3 mm Hg in controls.

During the day, mean arterial pressure was highest in the BPA group (110.5 mm Hg; P < .01), followed by BPS (108.9 mm Hg; P < .01) and BPF (105.2 mm Hg; nonsignificant), compared with 102.6 mm Hg in controls. At night, mean arterial pressure was highest in BPS (108.6 mm Hg; P < .05), followed by BPA (107.5 mm Hg; nonsignificant) and BPF (105.7 mm Hg; nonsignificant), compared with 101.8 mm Hg in controls.

“These results indicate that prenatal exposure to low levels of BPA analogs has a profound effect on hypertension” in the offspring of pregnant rats exposed to bisphenols, Dr. MohanKumar and colleagues wrote in the abstract.

He noted during his presentation that he and his colleagues plan to repeat the study in male offspring to determine if there are sex differences.

Dr. MohanKumar and colleagues reported having no relevant financial disclosures. Dr. Sargis also reported no conflicts of interest.

The research will be published in a special supplemental issue of the Journal of the Endocrine Society. In addition to a series of news conferences on March 30-31, the society will host ENDO Online 2020 during June 8-22, which will present programming for clinicians and researchers.

SOURCE: MohanKumar P et al. ENDO 2020, Abstract 719.

This article was updated on 4/17/2020.

In utero exposure to bisphenol-A (BPA) analogs led to hypertension in female rats, findings in a new study have shown.

Researchers tested exposures to BPA, as well as bisphenol-S (BPS) and bisphenol-F (BPF), which have been introduced in recent years as BPA alternatives and are now increasingly detectable in human and animal tissues. BPS and BPF are often found in products labeled as “BPA free.”

BPS and BPF have similar physiochemical properties to BPA, and there is concern over their effects.

But their physiological impact is not yet clear, according to Puliyur MohanKumar, DVM, PhD, of the University of Georgia Regenerative Bioscience Center, Athens. “We are exposed to BPA and related compounds on a regular basis, and the important thing is that BPA and related compounds easily cross the placental barrier,” Dr. MohanKumar said during a virtual news conference held by the Endocrine Society. The study had been slated for presentation during ENDO 2020, the society's annual meeting, which was canceled because of the COVID-19 pandemic.

Dr. MohanKumar and colleagues exposed pregnant rats to BPA, BPS, or BPF. When the offspring reached adulthood, the researchers implanted them with radiotelemetry devices to track systolic and diastolic blood pressure, which they measured every 10 minutes over a 24-hour period. This was repeated once a week for 11 weeks.

“The female offspring had elevated systolic as well as diastolic blood pressure, and this was an increase of about 8 mm [Hg] higher than the control animals. That was pretty significant. Keeping these animals at such a prehypertensive state for such a long period of time is going to [lead to] lots of cardiovascular issues later on,” said Dr. MohanKumar.

Robert Sargis, MD, PhD, professor of endocrinology, diabetes, and metabolism at the University of Illinois at Chicago, noted that, although animal studies don’t necessarily translate to similar outcomes in humans, the results are cause for concern.

“What’s particularly interesting, is that there is whole area of essential hypertension, where people develop hypertension and we don’t really know why. We just treat it,” he said in an interview. “But thinking about biological origins [of hypertension] is potentially interesting for a couple of reasons. These bisphenol compounds are really common. Most Americans are exposed to bisphenol A, and it’s been associated with other adverse metabolic effects, including alterations to body weight and glucose homeostasis.

“[These findings] feed into a whole series of studies that have begun to look at the BPA replacements and the fact that they may be, at best, as bad as BPA, and at worst, possibly slightly worse, depending on which outcomes you’re looking at,” Dr. Sargis added.

In the study, seven pregnant rats were orally exposed to saline, four pregnant rats to 5 mcg/kg BPA, four to 5 mcg/kg BPS, and five to 1 mcg/kg BPF during days 6-21 of pregnancy. The lower dose of BPF was used because a dose of 5 mcg/kg proved too toxic. When the offspring reached adulthood, the researchers implanted radiotelemetry devices in the offspring’s femoral artery.

Mean daytime systolic BP was highest in the BPA group (133.3 mg Hg; P < .05), followed by BPS (132.5 mm Hg; P < .05) and BPF (129.2 mm Hg; nonsignificant), compared with 125.2 mm Hg in controls. Nighttime systolic BP was again highest in the BPA group (134.2 mm Hg; P < .01), followed by BPS (133.2 mm Hg; P < .05) and BPF (129.6 mm Hg; nonsignificant), compared with 125.1 mm Hg in controls.

During the day, diastolic BP was highest in the BPS group (91.3 mm Hg; P < .01), followed by BPA (88.8 mm Hg; nonsignificant) and BPF (88.6 mm Hg; nonsignificant), compared with 84.1 mm Hg in controls. At night, diastolic BP was highest in the BPS group (89.7 mm Hg; P < .01), followed by BPA (89.6 mm Hg; P < .01) and BPF (88.6 mm Hg; P < .01), compared with 83.3 mm Hg in controls.

During the day, mean arterial pressure was highest in the BPA group (110.5 mm Hg; P < .01), followed by BPS (108.9 mm Hg; P < .01) and BPF (105.2 mm Hg; nonsignificant), compared with 102.6 mm Hg in controls. At night, mean arterial pressure was highest in BPS (108.6 mm Hg; P < .05), followed by BPA (107.5 mm Hg; nonsignificant) and BPF (105.7 mm Hg; nonsignificant), compared with 101.8 mm Hg in controls.

“These results indicate that prenatal exposure to low levels of BPA analogs has a profound effect on hypertension” in the offspring of pregnant rats exposed to bisphenols, Dr. MohanKumar and colleagues wrote in the abstract.

He noted during his presentation that he and his colleagues plan to repeat the study in male offspring to determine if there are sex differences.

Dr. MohanKumar and colleagues reported having no relevant financial disclosures. Dr. Sargis also reported no conflicts of interest.

The research will be published in a special supplemental issue of the Journal of the Endocrine Society. In addition to a series of news conferences on March 30-31, the society will host ENDO Online 2020 during June 8-22, which will present programming for clinicians and researchers.

SOURCE: MohanKumar P et al. ENDO 2020, Abstract 719.

This article was updated on 4/17/2020.

In utero exposure to bisphenol-A (BPA) analogs led to hypertension in female rats, findings in a new study have shown.

Researchers tested exposures to BPA, as well as bisphenol-S (BPS) and bisphenol-F (BPF), which have been introduced in recent years as BPA alternatives and are now increasingly detectable in human and animal tissues. BPS and BPF are often found in products labeled as “BPA free.”

BPS and BPF have similar physiochemical properties to BPA, and there is concern over their effects.

But their physiological impact is not yet clear, according to Puliyur MohanKumar, DVM, PhD, of the University of Georgia Regenerative Bioscience Center, Athens. “We are exposed to BPA and related compounds on a regular basis, and the important thing is that BPA and related compounds easily cross the placental barrier,” Dr. MohanKumar said during a virtual news conference held by the Endocrine Society. The study had been slated for presentation during ENDO 2020, the society's annual meeting, which was canceled because of the COVID-19 pandemic.

Dr. MohanKumar and colleagues exposed pregnant rats to BPA, BPS, or BPF. When the offspring reached adulthood, the researchers implanted them with radiotelemetry devices to track systolic and diastolic blood pressure, which they measured every 10 minutes over a 24-hour period. This was repeated once a week for 11 weeks.

“The female offspring had elevated systolic as well as diastolic blood pressure, and this was an increase of about 8 mm [Hg] higher than the control animals. That was pretty significant. Keeping these animals at such a prehypertensive state for such a long period of time is going to [lead to] lots of cardiovascular issues later on,” said Dr. MohanKumar.

Robert Sargis, MD, PhD, professor of endocrinology, diabetes, and metabolism at the University of Illinois at Chicago, noted that, although animal studies don’t necessarily translate to similar outcomes in humans, the results are cause for concern.

“What’s particularly interesting, is that there is whole area of essential hypertension, where people develop hypertension and we don’t really know why. We just treat it,” he said in an interview. “But thinking about biological origins [of hypertension] is potentially interesting for a couple of reasons. These bisphenol compounds are really common. Most Americans are exposed to bisphenol A, and it’s been associated with other adverse metabolic effects, including alterations to body weight and glucose homeostasis.

“[These findings] feed into a whole series of studies that have begun to look at the BPA replacements and the fact that they may be, at best, as bad as BPA, and at worst, possibly slightly worse, depending on which outcomes you’re looking at,” Dr. Sargis added.

In the study, seven pregnant rats were orally exposed to saline, four pregnant rats to 5 mcg/kg BPA, four to 5 mcg/kg BPS, and five to 1 mcg/kg BPF during days 6-21 of pregnancy. The lower dose of BPF was used because a dose of 5 mcg/kg proved too toxic. When the offspring reached adulthood, the researchers implanted radiotelemetry devices in the offspring’s femoral artery.

Mean daytime systolic BP was highest in the BPA group (133.3 mg Hg; P < .05), followed by BPS (132.5 mm Hg; P < .05) and BPF (129.2 mm Hg; nonsignificant), compared with 125.2 mm Hg in controls. Nighttime systolic BP was again highest in the BPA group (134.2 mm Hg; P < .01), followed by BPS (133.2 mm Hg; P < .05) and BPF (129.6 mm Hg; nonsignificant), compared with 125.1 mm Hg in controls.

During the day, diastolic BP was highest in the BPS group (91.3 mm Hg; P < .01), followed by BPA (88.8 mm Hg; nonsignificant) and BPF (88.6 mm Hg; nonsignificant), compared with 84.1 mm Hg in controls. At night, diastolic BP was highest in the BPS group (89.7 mm Hg; P < .01), followed by BPA (89.6 mm Hg; P < .01) and BPF (88.6 mm Hg; P < .01), compared with 83.3 mm Hg in controls.

During the day, mean arterial pressure was highest in the BPA group (110.5 mm Hg; P < .01), followed by BPS (108.9 mm Hg; P < .01) and BPF (105.2 mm Hg; nonsignificant), compared with 102.6 mm Hg in controls. At night, mean arterial pressure was highest in BPS (108.6 mm Hg; P < .05), followed by BPA (107.5 mm Hg; nonsignificant) and BPF (105.7 mm Hg; nonsignificant), compared with 101.8 mm Hg in controls.

“These results indicate that prenatal exposure to low levels of BPA analogs has a profound effect on hypertension” in the offspring of pregnant rats exposed to bisphenols, Dr. MohanKumar and colleagues wrote in the abstract.

He noted during his presentation that he and his colleagues plan to repeat the study in male offspring to determine if there are sex differences.

Dr. MohanKumar and colleagues reported having no relevant financial disclosures. Dr. Sargis also reported no conflicts of interest.

The research will be published in a special supplemental issue of the Journal of the Endocrine Society. In addition to a series of news conferences on March 30-31, the society will host ENDO Online 2020 during June 8-22, which will present programming for clinicians and researchers.

SOURCE: MohanKumar P et al. ENDO 2020, Abstract 719.

This article was updated on 4/17/2020.

LONDON – The larger the wound caused by epidermolysis bullosa (EB), the worse someone’s quality of life (QoL) is likely to be, according to the results of a global survey.

Of 85 patients with the recessive dystrophic type of EB (RDEB) who were surveyed through the EBCare Registry, 39 had available data from the validated quality of life in EB (QOLEB) questionnaire. Those with the largest wounds (7.5 cm or greater) had an average QOLEB score of 27, compared with 22.5 for those with wounds ranging from 2.5 to 7.5 cm in size, and a score of 14 for those with wounds less than 2.5 cm in size. The maximum score on the 17-item questionnaire is 51, with the higher the number, the greater the impact on quality of life.

“Large wound areas were seen more frequently in chronic open wounds, similar to findings in separate studies,” Emily S. Gorell, DO, a postdoctoral clinical research fellow in dermatology at Stanford (Calif.) University, and associates reported in a poster presentation at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association.

“Larger wounds correlate with self-reported disease severity and key clinical manifestations,” they said, which includes history of squamous cell carcinoma (P = .04), anemia (P less than.01), osteoporosis (P = .03), and gastrostomy tube use (P = .02).

In total, 28 adults and 37 children and adolescents were surveyed; the majority (59%) were from North America, with the remainder from Europe (26%) or other countries (15%). Just over half of respondents were female (53%), and about 38% of surveys were completed by the individual rather than a parent or care giver (62%).

Dr. Gorell is working with Jean Y. Tang, MD, PhD, professor of dermatology at Stanford. During an oral presentation at the meeting, Dr. Tang observed that wounds could be defined as being recurrent or chronic open wounds. These two types of wounds behave differently, she said, with the latter never fully healing.

Indeed, in the survey, data on 1,226 wounds were collated, with 937 (76%) classified as recurrent – and healing within 12 weeks – but 289 (24%) remaining chronic open wounds, which did not heal for 12 weeks or longer. Some patients have had open wounds for more than 6 years, Dr. Tang noted.

“In our natural history study … you can see that chronic open wounds never reached 100% closure, they hardly ever reached 50% closure,” she said. In contrast, recurrent wounds have a more dynamic nature, healing completely, then reopening time after time. This is important when considering suitable endpoints for clinical trials, she said, as it could make or break some of the novel treatment approaches currently being tested. For instance, the placebo response in phase 3 trials of the topical therapy allantoin might have been high because recurrent wounds were being studied and were more likely to heal with or without active treatment.

“We’ve done a lot of work, it’s been 2 years, and we have benefited tremendously from these data in our negotiations with the FDA [Food and Drug Administration],” Dr. Tang said. “I am glad we did our homework … we were able to convince the FDA that, for a chronic open wound, a meaningful outcome is 50% healing, not 100%.”

Dr. Tang and Dr. Gorell are part of a team looking at gene-corrected autologous cell therapy (EB-101) to help heal large wounds caused by RDEB. The premise is that by replacing the faulty COL7A1 gene in keratinocytes taken from an individual, these skin cells will be able to produce collagen type VII (COL7). After being grown in culture to form epidermal sheets that look like a plastic film, the sheets can then be grafted over an individuals’ wounds.

Dr. Tang noted that the work was the culmination of 17 years’ of hard work by a small group of committed scientists. Preclinical studies started in 2003, when, she said, “the only funding we could get was through the NIH and thankfully some of the patient organizations.”

Initial results with the EB-101 therapy have been promising. Data on the first four subjects included in a seven-patient phase 1/2 study were published 4 years ago (JAMA. 2016;316[17]:1808-17), and the complete data were recently released (JCI Insight. 2019;4. doi: 10.1172/jci.insight.130554). Each trial subject had an EB-101 graft of approximately 35 cm² (5 cm x 7 cm) transplanted onto three wounds, with three similar wounds used as controls.

At 6 months, 95% of treated wounds had healed by 50% or more, compared with none of the untreated control wounds (P less than .0001). Healing rates at 1 year and 2 years, respectively, were 68% vs. 17% (P = .025) and 71% vs. 17% (P = .019). All grafts were well tolerated and molecular correction was seen to last for up to 2 years in two patients.

EB-101 therapy will be evaluated in a phase 3 study, the VIITAL study, a multicenter, randomized trial involving 10-15 individuals with RDEB; 50% wound healing at 3 months is the trial’s primary endpoint. The trial, funded by Abeona Therapeutics, was given the go ahead by the FDA in December 2019 and has an estimated completion date of March 2021.

Dr. Gorell did not provide a conflict of interest statement. Dr. Tang disclosed receipt of honoraria or consultation fees from Abeona and Menlo Therapeutics and being a stock shareholder in PellePharm and BridgeBio. Dr. Tang also acknowledged receiving research grants from the EB Research Partnership, the Epidermolysis Medical Research Foundation, and the California Institute for Regenerative Medicine.

SOURCES: Gorell ES et al. EB World Congress, poster 29. Tang JYl. EB World Congress, oral presentation.

LONDON – The larger the wound caused by epidermolysis bullosa (EB), the worse someone’s quality of life (QoL) is likely to be, according to the results of a global survey.

Of 85 patients with the recessive dystrophic type of EB (RDEB) who were surveyed through the EBCare Registry, 39 had available data from the validated quality of life in EB (QOLEB) questionnaire. Those with the largest wounds (7.5 cm or greater) had an average QOLEB score of 27, compared with 22.5 for those with wounds ranging from 2.5 to 7.5 cm in size, and a score of 14 for those with wounds less than 2.5 cm in size. The maximum score on the 17-item questionnaire is 51, with the higher the number, the greater the impact on quality of life.

“Large wound areas were seen more frequently in chronic open wounds, similar to findings in separate studies,” Emily S. Gorell, DO, a postdoctoral clinical research fellow in dermatology at Stanford (Calif.) University, and associates reported in a poster presentation at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association.

“Larger wounds correlate with self-reported disease severity and key clinical manifestations,” they said, which includes history of squamous cell carcinoma (P = .04), anemia (P less than.01), osteoporosis (P = .03), and gastrostomy tube use (P = .02).

In total, 28 adults and 37 children and adolescents were surveyed; the majority (59%) were from North America, with the remainder from Europe (26%) or other countries (15%). Just over half of respondents were female (53%), and about 38% of surveys were completed by the individual rather than a parent or care giver (62%).

Dr. Gorell is working with Jean Y. Tang, MD, PhD, professor of dermatology at Stanford. During an oral presentation at the meeting, Dr. Tang observed that wounds could be defined as being recurrent or chronic open wounds. These two types of wounds behave differently, she said, with the latter never fully healing.

Indeed, in the survey, data on 1,226 wounds were collated, with 937 (76%) classified as recurrent – and healing within 12 weeks – but 289 (24%) remaining chronic open wounds, which did not heal for 12 weeks or longer. Some patients have had open wounds for more than 6 years, Dr. Tang noted.

“In our natural history study … you can see that chronic open wounds never reached 100% closure, they hardly ever reached 50% closure,” she said. In contrast, recurrent wounds have a more dynamic nature, healing completely, then reopening time after time. This is important when considering suitable endpoints for clinical trials, she said, as it could make or break some of the novel treatment approaches currently being tested. For instance, the placebo response in phase 3 trials of the topical therapy allantoin might have been high because recurrent wounds were being studied and were more likely to heal with or without active treatment.

“We’ve done a lot of work, it’s been 2 years, and we have benefited tremendously from these data in our negotiations with the FDA [Food and Drug Administration],” Dr. Tang said. “I am glad we did our homework … we were able to convince the FDA that, for a chronic open wound, a meaningful outcome is 50% healing, not 100%.”

Dr. Tang and Dr. Gorell are part of a team looking at gene-corrected autologous cell therapy (EB-101) to help heal large wounds caused by RDEB. The premise is that by replacing the faulty COL7A1 gene in keratinocytes taken from an individual, these skin cells will be able to produce collagen type VII (COL7). After being grown in culture to form epidermal sheets that look like a plastic film, the sheets can then be grafted over an individuals’ wounds.

Dr. Tang noted that the work was the culmination of 17 years’ of hard work by a small group of committed scientists. Preclinical studies started in 2003, when, she said, “the only funding we could get was through the NIH and thankfully some of the patient organizations.”

Initial results with the EB-101 therapy have been promising. Data on the first four subjects included in a seven-patient phase 1/2 study were published 4 years ago (JAMA. 2016;316[17]:1808-17), and the complete data were recently released (JCI Insight. 2019;4. doi: 10.1172/jci.insight.130554). Each trial subject had an EB-101 graft of approximately 35 cm² (5 cm x 7 cm) transplanted onto three wounds, with three similar wounds used as controls.

At 6 months, 95% of treated wounds had healed by 50% or more, compared with none of the untreated control wounds (P less than .0001). Healing rates at 1 year and 2 years, respectively, were 68% vs. 17% (P = .025) and 71% vs. 17% (P = .019). All grafts were well tolerated and molecular correction was seen to last for up to 2 years in two patients.

EB-101 therapy will be evaluated in a phase 3 study, the VIITAL study, a multicenter, randomized trial involving 10-15 individuals with RDEB; 50% wound healing at 3 months is the trial’s primary endpoint. The trial, funded by Abeona Therapeutics, was given the go ahead by the FDA in December 2019 and has an estimated completion date of March 2021.

Dr. Gorell did not provide a conflict of interest statement. Dr. Tang disclosed receipt of honoraria or consultation fees from Abeona and Menlo Therapeutics and being a stock shareholder in PellePharm and BridgeBio. Dr. Tang also acknowledged receiving research grants from the EB Research Partnership, the Epidermolysis Medical Research Foundation, and the California Institute for Regenerative Medicine.

SOURCES: Gorell ES et al. EB World Congress, poster 29. Tang JYl. EB World Congress, oral presentation.

LONDON – The larger the wound caused by epidermolysis bullosa (EB), the worse someone’s quality of life (QoL) is likely to be, according to the results of a global survey.

Of 85 patients with the recessive dystrophic type of EB (RDEB) who were surveyed through the EBCare Registry, 39 had available data from the validated quality of life in EB (QOLEB) questionnaire. Those with the largest wounds (7.5 cm or greater) had an average QOLEB score of 27, compared with 22.5 for those with wounds ranging from 2.5 to 7.5 cm in size, and a score of 14 for those with wounds less than 2.5 cm in size. The maximum score on the 17-item questionnaire is 51, with the higher the number, the greater the impact on quality of life.

“Large wound areas were seen more frequently in chronic open wounds, similar to findings in separate studies,” Emily S. Gorell, DO, a postdoctoral clinical research fellow in dermatology at Stanford (Calif.) University, and associates reported in a poster presentation at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association.

“Larger wounds correlate with self-reported disease severity and key clinical manifestations,” they said, which includes history of squamous cell carcinoma (P = .04), anemia (P less than.01), osteoporosis (P = .03), and gastrostomy tube use (P = .02).

In total, 28 adults and 37 children and adolescents were surveyed; the majority (59%) were from North America, with the remainder from Europe (26%) or other countries (15%). Just over half of respondents were female (53%), and about 38% of surveys were completed by the individual rather than a parent or care giver (62%).

Dr. Gorell is working with Jean Y. Tang, MD, PhD, professor of dermatology at Stanford. During an oral presentation at the meeting, Dr. Tang observed that wounds could be defined as being recurrent or chronic open wounds. These two types of wounds behave differently, she said, with the latter never fully healing.

Indeed, in the survey, data on 1,226 wounds were collated, with 937 (76%) classified as recurrent – and healing within 12 weeks – but 289 (24%) remaining chronic open wounds, which did not heal for 12 weeks or longer. Some patients have had open wounds for more than 6 years, Dr. Tang noted.

“In our natural history study … you can see that chronic open wounds never reached 100% closure, they hardly ever reached 50% closure,” she said. In contrast, recurrent wounds have a more dynamic nature, healing completely, then reopening time after time. This is important when considering suitable endpoints for clinical trials, she said, as it could make or break some of the novel treatment approaches currently being tested. For instance, the placebo response in phase 3 trials of the topical therapy allantoin might have been high because recurrent wounds were being studied and were more likely to heal with or without active treatment.

“We’ve done a lot of work, it’s been 2 years, and we have benefited tremendously from these data in our negotiations with the FDA [Food and Drug Administration],” Dr. Tang said. “I am glad we did our homework … we were able to convince the FDA that, for a chronic open wound, a meaningful outcome is 50% healing, not 100%.”

Dr. Tang and Dr. Gorell are part of a team looking at gene-corrected autologous cell therapy (EB-101) to help heal large wounds caused by RDEB. The premise is that by replacing the faulty COL7A1 gene in keratinocytes taken from an individual, these skin cells will be able to produce collagen type VII (COL7). After being grown in culture to form epidermal sheets that look like a plastic film, the sheets can then be grafted over an individuals’ wounds.

Dr. Tang noted that the work was the culmination of 17 years’ of hard work by a small group of committed scientists. Preclinical studies started in 2003, when, she said, “the only funding we could get was through the NIH and thankfully some of the patient organizations.”

Initial results with the EB-101 therapy have been promising. Data on the first four subjects included in a seven-patient phase 1/2 study were published 4 years ago (JAMA. 2016;316[17]:1808-17), and the complete data were recently released (JCI Insight. 2019;4. doi: 10.1172/jci.insight.130554). Each trial subject had an EB-101 graft of approximately 35 cm² (5 cm x 7 cm) transplanted onto three wounds, with three similar wounds used as controls.

At 6 months, 95% of treated wounds had healed by 50% or more, compared with none of the untreated control wounds (P less than .0001). Healing rates at 1 year and 2 years, respectively, were 68% vs. 17% (P = .025) and 71% vs. 17% (P = .019). All grafts were well tolerated and molecular correction was seen to last for up to 2 years in two patients.

EB-101 therapy will be evaluated in a phase 3 study, the VIITAL study, a multicenter, randomized trial involving 10-15 individuals with RDEB; 50% wound healing at 3 months is the trial’s primary endpoint. The trial, funded by Abeona Therapeutics, was given the go ahead by the FDA in December 2019 and has an estimated completion date of March 2021.

Dr. Gorell did not provide a conflict of interest statement. Dr. Tang disclosed receipt of honoraria or consultation fees from Abeona and Menlo Therapeutics and being a stock shareholder in PellePharm and BridgeBio. Dr. Tang also acknowledged receiving research grants from the EB Research Partnership, the Epidermolysis Medical Research Foundation, and the California Institute for Regenerative Medicine.

SOURCES: Gorell ES et al. EB World Congress, poster 29. Tang JYl. EB World Congress, oral presentation.

MAUI, HAWAII – When a rheumatologist gets a call from an ophthalmologist regarding a patient with an inflamed eye and elevated intraocular pressure unresponsive to the eye specialist’s customary array of topical, systemic, and intraocular implanted corticosteroids, that’s a patient who needs to be seen immediately, Alvin F. Wells, MD, PhD, said at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

Elevated intraocular pressure due to uveitis or scleritis can result in blindness. Eye specialists call upon rheumatologists here because of their expertise in step-up therapy with methotrexate and other traditional oral disease-modifying antirheumatic drugs as well as biologic agents.

“Here’s my treatment approach to inflammatory eye disease: We’re pulling out all the guns,” declared Dr. Wells, a rheumatologist with a special interest in eye disease. He is director of the Rheumatology and Immunotherapy Center in Franklin, Wisc., with academic appointments to the Karolinska Institute in Stockholm, Duke University, and Marquette University.

Uveitis involves inflammation of the iris, choroid, and ciliary body. A straightforward case of noninfectious anterior uveitis will typically respond to 2 weeks of topical steroid drops, or sometimes even topical NSAID drops.

However, noninfectious posterior, intermediate, or panuveitis is another matter. In those circumstances, he gives the patient 125 mg of methylprednisolone by intramuscular injection and a 20-mg dose of oral methotrexate at that first clinic visit. The patient is sent home with a prescription for oral prednisone, tapering over 2-3 weeks, and another for methotrexate at 15-25 mg/week plus 1-2 mg/day of folic acid. Dr. Wells also gives consideration to add-on azathioprine or mycophenolate mofetil. He views multidrug therapy as having a sound rationale because multiple inflammatory pathways are involved in noninfectious uveitis.

“Ophthalmologists like to push for cyclophosphamide, but there’s no controlled data out there showing it’s effective in inflammatory eye disorders. It’s a pretty toxic regimen, and when you think about all the complications we see in using this drug to treat patients with lupus, I’d rather hold it in reserve for severe cases where we can go to it if we need to,” the rheumatologist explained.

He conducted a literature review to rank rheumatologic medications in terms of their evidence base for treatment of inflammatory ocular disorders. Among oral agents, at the top of the heap is methotrexate, whose efficacy for both noninfectious uveitis and scleritis is supported by multiple randomized, controlled studies. But mycophenolate mofetil is a reasonable alternative first-line corticosteroid-sparing agent, as demonstrated in the 265-patient multicenter FAST (First-line Antimetabolites as Steroid-sparing Treatment) trial sponsored by the National Eye Institute. That trial demonstrated no significant difference in treatment success at 6 months between methotrexate and mycophenolate mofetil.

Oral apremilast (Otezla) is approved for treatment of the oral ulcers of Behçet’s disease, but not for Behçet’s eye disease, where the experience is anecdotal.

Dr. Wells is quick to turn to adalimumab (Humira) when he deems a biologic to be warranted; indeed, it’s the only biologic approved for noninfectious uveitis. Of course, not everyone is a responder.

“Can we extrapolate that high-quality evidence of benefit for adalimumab to other drugs? Probably yes, and if you did that it would be for the IgG monoclonal antibodies that can cross the blood/aqueous barrier,” he said.

Infliximab (Remicade) is the biologic with the second-strongest supporting evidence in noninfectious uveitis. For the uveitis of Behçet’s disease, one of the most common rheumatic causes of inflammatory eye disease, Spanish investigators who conducted a nationwide nonrandomized study reported that both adalimumab and infliximab were effective, although adalimumab had superior outcomes at 1 year.

Uveitis is the most common extra-articular expression of axial spondyloarthritis (axSpA). In the open-label extension of the randomized RAPID-axSpA trial, patients randomized to certolizumab pegol (Cimzia) had a significantly lower incidence of uveitis flares than with placebo through 204 weeks of follow-up.

“The take-home message is we have some post hoc data here to say, ‘Hey, this could work in those patients who have inflammatory eye diseases in the setting of axSpA,’ ” Dr. Wells said.

The interleukin-6 receptor inhibitor tocilizumab (Actemra) “definitely works” for noninfectious uveitis, according to Dr. Wells, pointing to the positive results of the multicenter U.S. STOP-Uveitis study.

“The caveat here is tocilizumab has only been studied in the IV formulation. It’s too bad they didn’t use the [subcutaneous formulation]; you can’t get IV tocilizumab approved by payers in the U.S.,” according to the rheumatologist.

Based upon positive anecdotal case reports, Dr. Wells has a few patients on rituximab (Rituxan) for uveitis, with favorable results. The same for abatacept (Orencia).

It’s imperative that a patient on a biologic for uveitis undergo weekly ophthalmologic examinations. Only after the intraocular pressure is normal and inflammatory cells in the anterior chamber have waned is it appropriate to discontinue the biologic and slowly taper the methotrexate and any other oral disease-modifying antirheumatic drugs. Some experts argue for lifelong therapy in patients who’ve experienced uveitis. Dr. Wells disagrees, preferring to treat acute uveitis flares as they arise, although if underlying disease such as psoriatic arthritis or axSpA is present, some form of background therapy will probably be necessary.
 

Get to know teprotumumab

Rheumatologists who operate an infusion center are likely to increasingly be called upon by endocrinologists and ophthalmologists to administer intravenous teprotumumab-trbw (Tepezza), a human monoclonal antibody directed against the insulin-like growth factor 1 receptor that was approved earlier this year by the Food and Drug Administration as the first-ever drug for thyroid eye disease, a disfiguring and potentially blinding condition.

“This is really exciting,” Dr. Wells said. “The disease has an acute inflammatory stage, and that’s when you’ll be called on to give this drug. It makes a dramatic difference. Once a patient gets to the scarring phase there’s not a whole lot they can do other than surgery.”

In the pivotal phase 3 randomized trial, 83% of the teprotumumab group achieved the primary endpoint, a reduction in proptosis, or eye bulging, of at least 2 mm at week 24, compared with 10% of placebo-treated controls. The number needed to treat was 1.4. The chief side effects were muscle spasms, hair loss, fatigue, and nausea.

“You might say, ‘two millimeters, that’s nothing.’ But the primary drug used before teprotumumab was IV steroids, and there a 0.6-mm reduction in proptosis was considered improvement,” Dr. Wells observed.

Obtaining payer approval

“I’ve found over the last 10 years that when it comes to eye disease, insurance companies have a little more wiggle room,” he said. “They’re not going to let somebody go blind. You can get the references I’ve mentioned and show them the data. After all, we only have one biologic drug that’s been approved, and not everybody responds to it.

“Titrate your therapy based upon the intraocular pressure, the number of inflammatory cells in the anterior chamber, and any visual changes. You’ve got to be very aggressive with therapy, and don’t take no for an answer from the insurance companies,” he advised.

Dr. Wells reported serving as a member of an advisory board and/or speakers bureau for more than a dozen pharmaceutical companies.

bjancin@mdedge.com

MAUI, HAWAII – When a rheumatologist gets a call from an ophthalmologist regarding a patient with an inflamed eye and elevated intraocular pressure unresponsive to the eye specialist’s customary array of topical, systemic, and intraocular implanted corticosteroids, that’s a patient who needs to be seen immediately, Alvin F. Wells, MD, PhD, said at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

Elevated intraocular pressure due to uveitis or scleritis can result in blindness. Eye specialists call upon rheumatologists here because of their expertise in step-up therapy with methotrexate and other traditional oral disease-modifying antirheumatic drugs as well as biologic agents.

“Here’s my treatment approach to inflammatory eye disease: We’re pulling out all the guns,” declared Dr. Wells, a rheumatologist with a special interest in eye disease. He is director of the Rheumatology and Immunotherapy Center in Franklin, Wisc., with academic appointments to the Karolinska Institute in Stockholm, Duke University, and Marquette University.

Uveitis involves inflammation of the iris, choroid, and ciliary body. A straightforward case of noninfectious anterior uveitis will typically respond to 2 weeks of topical steroid drops, or sometimes even topical NSAID drops.

However, noninfectious posterior, intermediate, or panuveitis is another matter. In those circumstances, he gives the patient 125 mg of methylprednisolone by intramuscular injection and a 20-mg dose of oral methotrexate at that first clinic visit. The patient is sent home with a prescription for oral prednisone, tapering over 2-3 weeks, and another for methotrexate at 15-25 mg/week plus 1-2 mg/day of folic acid. Dr. Wells also gives consideration to add-on azathioprine or mycophenolate mofetil. He views multidrug therapy as having a sound rationale because multiple inflammatory pathways are involved in noninfectious uveitis.

“Ophthalmologists like to push for cyclophosphamide, but there’s no controlled data out there showing it’s effective in inflammatory eye disorders. It’s a pretty toxic regimen, and when you think about all the complications we see in using this drug to treat patients with lupus, I’d rather hold it in reserve for severe cases where we can go to it if we need to,” the rheumatologist explained.

He conducted a literature review to rank rheumatologic medications in terms of their evidence base for treatment of inflammatory ocular disorders. Among oral agents, at the top of the heap is methotrexate, whose efficacy for both noninfectious uveitis and scleritis is supported by multiple randomized, controlled studies. But mycophenolate mofetil is a reasonable alternative first-line corticosteroid-sparing agent, as demonstrated in the 265-patient multicenter FAST (First-line Antimetabolites as Steroid-sparing Treatment) trial sponsored by the National Eye Institute. That trial demonstrated no significant difference in treatment success at 6 months between methotrexate and mycophenolate mofetil.

Oral apremilast (Otezla) is approved for treatment of the oral ulcers of Behçet’s disease, but not for Behçet’s eye disease, where the experience is anecdotal.

Dr. Wells is quick to turn to adalimumab (Humira) when he deems a biologic to be warranted; indeed, it’s the only biologic approved for noninfectious uveitis. Of course, not everyone is a responder.

“Can we extrapolate that high-quality evidence of benefit for adalimumab to other drugs? Probably yes, and if you did that it would be for the IgG monoclonal antibodies that can cross the blood/aqueous barrier,” he said.

Infliximab (Remicade) is the biologic with the second-strongest supporting evidence in noninfectious uveitis. For the uveitis of Behçet’s disease, one of the most common rheumatic causes of inflammatory eye disease, Spanish investigators who conducted a nationwide nonrandomized study reported that both adalimumab and infliximab were effective, although adalimumab had superior outcomes at 1 year.

Uveitis is the most common extra-articular expression of axial spondyloarthritis (axSpA). In the open-label extension of the randomized RAPID-axSpA trial, patients randomized to certolizumab pegol (Cimzia) had a significantly lower incidence of uveitis flares than with placebo through 204 weeks of follow-up.

“The take-home message is we have some post hoc data here to say, ‘Hey, this could work in those patients who have inflammatory eye diseases in the setting of axSpA,’ ” Dr. Wells said.

The interleukin-6 receptor inhibitor tocilizumab (Actemra) “definitely works” for noninfectious uveitis, according to Dr. Wells, pointing to the positive results of the multicenter U.S. STOP-Uveitis study.

“The caveat here is tocilizumab has only been studied in the IV formulation. It’s too bad they didn’t use the [subcutaneous formulation]; you can’t get IV tocilizumab approved by payers in the U.S.,” according to the rheumatologist.

Based upon positive anecdotal case reports, Dr. Wells has a few patients on rituximab (Rituxan) for uveitis, with favorable results. The same for abatacept (Orencia).

It’s imperative that a patient on a biologic for uveitis undergo weekly ophthalmologic examinations. Only after the intraocular pressure is normal and inflammatory cells in the anterior chamber have waned is it appropriate to discontinue the biologic and slowly taper the methotrexate and any other oral disease-modifying antirheumatic drugs. Some experts argue for lifelong therapy in patients who’ve experienced uveitis. Dr. Wells disagrees, preferring to treat acute uveitis flares as they arise, although if underlying disease such as psoriatic arthritis or axSpA is present, some form of background therapy will probably be necessary.
 

Get to know teprotumumab

Rheumatologists who operate an infusion center are likely to increasingly be called upon by endocrinologists and ophthalmologists to administer intravenous teprotumumab-trbw (Tepezza), a human monoclonal antibody directed against the insulin-like growth factor 1 receptor that was approved earlier this year by the Food and Drug Administration as the first-ever drug for thyroid eye disease, a disfiguring and potentially blinding condition.

“This is really exciting,” Dr. Wells said. “The disease has an acute inflammatory stage, and that’s when you’ll be called on to give this drug. It makes a dramatic difference. Once a patient gets to the scarring phase there’s not a whole lot they can do other than surgery.”

In the pivotal phase 3 randomized trial, 83% of the teprotumumab group achieved the primary endpoint, a reduction in proptosis, or eye bulging, of at least 2 mm at week 24, compared with 10% of placebo-treated controls. The number needed to treat was 1.4. The chief side effects were muscle spasms, hair loss, fatigue, and nausea.

“You might say, ‘two millimeters, that’s nothing.’ But the primary drug used before teprotumumab was IV steroids, and there a 0.6-mm reduction in proptosis was considered improvement,” Dr. Wells observed.

Obtaining payer approval

“I’ve found over the last 10 years that when it comes to eye disease, insurance companies have a little more wiggle room,” he said. “They’re not going to let somebody go blind. You can get the references I’ve mentioned and show them the data. After all, we only have one biologic drug that’s been approved, and not everybody responds to it.

“Titrate your therapy based upon the intraocular pressure, the number of inflammatory cells in the anterior chamber, and any visual changes. You’ve got to be very aggressive with therapy, and don’t take no for an answer from the insurance companies,” he advised.

Dr. Wells reported serving as a member of an advisory board and/or speakers bureau for more than a dozen pharmaceutical companies.

bjancin@mdedge.com

MAUI, HAWAII – When a rheumatologist gets a call from an ophthalmologist regarding a patient with an inflamed eye and elevated intraocular pressure unresponsive to the eye specialist’s customary array of topical, systemic, and intraocular implanted corticosteroids, that’s a patient who needs to be seen immediately, Alvin F. Wells, MD, PhD, said at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

Elevated intraocular pressure due to uveitis or scleritis can result in blindness. Eye specialists call upon rheumatologists here because of their expertise in step-up therapy with methotrexate and other traditional oral disease-modifying antirheumatic drugs as well as biologic agents.

“Here’s my treatment approach to inflammatory eye disease: We’re pulling out all the guns,” declared Dr. Wells, a rheumatologist with a special interest in eye disease. He is director of the Rheumatology and Immunotherapy Center in Franklin, Wisc., with academic appointments to the Karolinska Institute in Stockholm, Duke University, and Marquette University.

Uveitis involves inflammation of the iris, choroid, and ciliary body. A straightforward case of noninfectious anterior uveitis will typically respond to 2 weeks of topical steroid drops, or sometimes even topical NSAID drops.

However, noninfectious posterior, intermediate, or panuveitis is another matter. In those circumstances, he gives the patient 125 mg of methylprednisolone by intramuscular injection and a 20-mg dose of oral methotrexate at that first clinic visit. The patient is sent home with a prescription for oral prednisone, tapering over 2-3 weeks, and another for methotrexate at 15-25 mg/week plus 1-2 mg/day of folic acid. Dr. Wells also gives consideration to add-on azathioprine or mycophenolate mofetil. He views multidrug therapy as having a sound rationale because multiple inflammatory pathways are involved in noninfectious uveitis.

“Ophthalmologists like to push for cyclophosphamide, but there’s no controlled data out there showing it’s effective in inflammatory eye disorders. It’s a pretty toxic regimen, and when you think about all the complications we see in using this drug to treat patients with lupus, I’d rather hold it in reserve for severe cases where we can go to it if we need to,” the rheumatologist explained.

He conducted a literature review to rank rheumatologic medications in terms of their evidence base for treatment of inflammatory ocular disorders. Among oral agents, at the top of the heap is methotrexate, whose efficacy for both noninfectious uveitis and scleritis is supported by multiple randomized, controlled studies. But mycophenolate mofetil is a reasonable alternative first-line corticosteroid-sparing agent, as demonstrated in the 265-patient multicenter FAST (First-line Antimetabolites as Steroid-sparing Treatment) trial sponsored by the National Eye Institute. That trial demonstrated no significant difference in treatment success at 6 months between methotrexate and mycophenolate mofetil.

Oral apremilast (Otezla) is approved for treatment of the oral ulcers of Behçet’s disease, but not for Behçet’s eye disease, where the experience is anecdotal.

Dr. Wells is quick to turn to adalimumab (Humira) when he deems a biologic to be warranted; indeed, it’s the only biologic approved for noninfectious uveitis. Of course, not everyone is a responder.

“Can we extrapolate that high-quality evidence of benefit for adalimumab to other drugs? Probably yes, and if you did that it would be for the IgG monoclonal antibodies that can cross the blood/aqueous barrier,” he said.

Infliximab (Remicade) is the biologic with the second-strongest supporting evidence in noninfectious uveitis. For the uveitis of Behçet’s disease, one of the most common rheumatic causes of inflammatory eye disease, Spanish investigators who conducted a nationwide nonrandomized study reported that both adalimumab and infliximab were effective, although adalimumab had superior outcomes at 1 year.

Uveitis is the most common extra-articular expression of axial spondyloarthritis (axSpA). In the open-label extension of the randomized RAPID-axSpA trial, patients randomized to certolizumab pegol (Cimzia) had a significantly lower incidence of uveitis flares than with placebo through 204 weeks of follow-up.

“The take-home message is we have some post hoc data here to say, ‘Hey, this could work in those patients who have inflammatory eye diseases in the setting of axSpA,’ ” Dr. Wells said.

The interleukin-6 receptor inhibitor tocilizumab (Actemra) “definitely works” for noninfectious uveitis, according to Dr. Wells, pointing to the positive results of the multicenter U.S. STOP-Uveitis study.

“The caveat here is tocilizumab has only been studied in the IV formulation. It’s too bad they didn’t use the [subcutaneous formulation]; you can’t get IV tocilizumab approved by payers in the U.S.,” according to the rheumatologist.

Based upon positive anecdotal case reports, Dr. Wells has a few patients on rituximab (Rituxan) for uveitis, with favorable results. The same for abatacept (Orencia).

It’s imperative that a patient on a biologic for uveitis undergo weekly ophthalmologic examinations. Only after the intraocular pressure is normal and inflammatory cells in the anterior chamber have waned is it appropriate to discontinue the biologic and slowly taper the methotrexate and any other oral disease-modifying antirheumatic drugs. Some experts argue for lifelong therapy in patients who’ve experienced uveitis. Dr. Wells disagrees, preferring to treat acute uveitis flares as they arise, although if underlying disease such as psoriatic arthritis or axSpA is present, some form of background therapy will probably be necessary.
 

Get to know teprotumumab

Rheumatologists who operate an infusion center are likely to increasingly be called upon by endocrinologists and ophthalmologists to administer intravenous teprotumumab-trbw (Tepezza), a human monoclonal antibody directed against the insulin-like growth factor 1 receptor that was approved earlier this year by the Food and Drug Administration as the first-ever drug for thyroid eye disease, a disfiguring and potentially blinding condition.

“This is really exciting,” Dr. Wells said. “The disease has an acute inflammatory stage, and that’s when you’ll be called on to give this drug. It makes a dramatic difference. Once a patient gets to the scarring phase there’s not a whole lot they can do other than surgery.”

In the pivotal phase 3 randomized trial, 83% of the teprotumumab group achieved the primary endpoint, a reduction in proptosis, or eye bulging, of at least 2 mm at week 24, compared with 10% of placebo-treated controls. The number needed to treat was 1.4. The chief side effects were muscle spasms, hair loss, fatigue, and nausea.

“You might say, ‘two millimeters, that’s nothing.’ But the primary drug used before teprotumumab was IV steroids, and there a 0.6-mm reduction in proptosis was considered improvement,” Dr. Wells observed.

Obtaining payer approval

“I’ve found over the last 10 years that when it comes to eye disease, insurance companies have a little more wiggle room,” he said. “They’re not going to let somebody go blind. You can get the references I’ve mentioned and show them the data. After all, we only have one biologic drug that’s been approved, and not everybody responds to it.

“Titrate your therapy based upon the intraocular pressure, the number of inflammatory cells in the anterior chamber, and any visual changes. You’ve got to be very aggressive with therapy, and don’t take no for an answer from the insurance companies,” he advised.

Dr. Wells reported serving as a member of an advisory board and/or speakers bureau for more than a dozen pharmaceutical companies.

bjancin@mdedge.com

Combination therapy with apatinib and camrelizumab shows promising antitumor activity in patients with advanced cervical cancer, regardless of programmed death–ligand 1 (PD-L1) expression, according to preliminary findings from a phase 2 study.

Dr. Chunyan Lan

Apatinib, an inhibitor of vascular endothelial growth factor receptor-2, and camrelizumab, an anti-PD-1 monoclonal antibody, produced an objective response rate of 60% in evaluable patients.

Chunyan Lan, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China, and colleagues reported these results in an abstract that had been slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic. The following data differ somewhat from the abstract.

Dr. Lan and colleagues reported results in 45 patients who had progressed after at least one line of systemic chemotherapy for metastatic, recurrent, or persistent cervical cancer, and had measurable disease. Patients had a median age of 51 years and an Eastern Cooperative Oncology Group performance status of 0-1. They were enrolled at four centers in China between Jan. 21 and Aug. 1, 2019.

Treatment consisted of oral apatinib at a dose of 250 mg once daily and intravenous camrelizumab at a dose of 200 mg every 2 weeks until disease progression, unacceptable toxicity, or consent withdrawal.

As of Jan. 22, 2020, 25 of 42 efficacy-evaluable patients had achieved a response. Two patients had a complete response, 23 had a partial response, and 12 had stable disease.

“We saw responses in patients regardless of PD-L1 expression,” Dr. Lan said. “In our study, 34% were PD-L1 negative, and the response rate is 65% in PD-L1-positive and 50% in PD-L1-negative [patients].”

The median duration of response was not reached, she added.

The median follow-up was 9.2 months, with the last patient enrolled having 6 months of follow-up. At the data cutoff, 19 patients had disease progression, and 8 had died of their disease.

The median overall survival also was not reached, Dr. Lan said, but overall survival at 9 months was 80%. The median progression-free survival was 7.6 months, and the 6-month progression-free survival rate was 58%.

Grade 3 or greater treatment-related adverse events occurred in 68.9% of patients; adverse events occurring in at least 5% of patients included hypertension (22.2%), fatigue (15.6%), anemia (13.3%), and thrombocytopenia (6.7%).

“Nineteen patients were still on treatment at the data cutoff date, and 26 patients discontinued the study,” Dr. Lan said. “The most common reason to discontinue was disease progression, and three patients discontinued the study due to adverse events.”

“These preliminary results are very encouraging,” Dr. Lan said. “As we know, pembrolizumab is approved as the second-line therapy in recurrent cervical cancer [in] PD-L1-positive patients, and the objective response rate with pembrolizumab monotherapy for recurrent cervical cancer is only 17%, as reported in KEYNOTE-028 [J Clin Oncol. 2017 Dec 20;35(36):4035-41].”

Furthermore, apatinib monotherapy has been studied with only modest results.

“But in our study, this combination is really effective in recurrent cervical cancer, and we see a very durable response,” she said, again emphasizing that those responses occurred regardless of PD-L1 expression. “So this is important. ... We think our findings expand the opportunity of patients with recurrent cervical cancer to receive immune therapy.”

Study participants will be followed for 2 years, Dr. Lan noted.

She reported having no disclosures. The study is sponsored by Sun Yat-sen University.

sworcester@mdedge.com

SOURCE: Lan C et al. SGO 2020, Abstract 55.

Combination therapy with apatinib and camrelizumab shows promising antitumor activity in patients with advanced cervical cancer, regardless of programmed death–ligand 1 (PD-L1) expression, according to preliminary findings from a phase 2 study.

Dr. Chunyan Lan

Apatinib, an inhibitor of vascular endothelial growth factor receptor-2, and camrelizumab, an anti-PD-1 monoclonal antibody, produced an objective response rate of 60% in evaluable patients.

Chunyan Lan, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China, and colleagues reported these results in an abstract that had been slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic. The following data differ somewhat from the abstract.

Dr. Lan and colleagues reported results in 45 patients who had progressed after at least one line of systemic chemotherapy for metastatic, recurrent, or persistent cervical cancer, and had measurable disease. Patients had a median age of 51 years and an Eastern Cooperative Oncology Group performance status of 0-1. They were enrolled at four centers in China between Jan. 21 and Aug. 1, 2019.

Treatment consisted of oral apatinib at a dose of 250 mg once daily and intravenous camrelizumab at a dose of 200 mg every 2 weeks until disease progression, unacceptable toxicity, or consent withdrawal.

As of Jan. 22, 2020, 25 of 42 efficacy-evaluable patients had achieved a response. Two patients had a complete response, 23 had a partial response, and 12 had stable disease.

“We saw responses in patients regardless of PD-L1 expression,” Dr. Lan said. “In our study, 34% were PD-L1 negative, and the response rate is 65% in PD-L1-positive and 50% in PD-L1-negative [patients].”

The median duration of response was not reached, she added.

The median follow-up was 9.2 months, with the last patient enrolled having 6 months of follow-up. At the data cutoff, 19 patients had disease progression, and 8 had died of their disease.

The median overall survival also was not reached, Dr. Lan said, but overall survival at 9 months was 80%. The median progression-free survival was 7.6 months, and the 6-month progression-free survival rate was 58%.

Grade 3 or greater treatment-related adverse events occurred in 68.9% of patients; adverse events occurring in at least 5% of patients included hypertension (22.2%), fatigue (15.6%), anemia (13.3%), and thrombocytopenia (6.7%).

“Nineteen patients were still on treatment at the data cutoff date, and 26 patients discontinued the study,” Dr. Lan said. “The most common reason to discontinue was disease progression, and three patients discontinued the study due to adverse events.”

“These preliminary results are very encouraging,” Dr. Lan said. “As we know, pembrolizumab is approved as the second-line therapy in recurrent cervical cancer [in] PD-L1-positive patients, and the objective response rate with pembrolizumab monotherapy for recurrent cervical cancer is only 17%, as reported in KEYNOTE-028 [J Clin Oncol. 2017 Dec 20;35(36):4035-41].”

Furthermore, apatinib monotherapy has been studied with only modest results.

“But in our study, this combination is really effective in recurrent cervical cancer, and we see a very durable response,” she said, again emphasizing that those responses occurred regardless of PD-L1 expression. “So this is important. ... We think our findings expand the opportunity of patients with recurrent cervical cancer to receive immune therapy.”

Study participants will be followed for 2 years, Dr. Lan noted.

She reported having no disclosures. The study is sponsored by Sun Yat-sen University.

sworcester@mdedge.com

SOURCE: Lan C et al. SGO 2020, Abstract 55.

Combination therapy with apatinib and camrelizumab shows promising antitumor activity in patients with advanced cervical cancer, regardless of programmed death–ligand 1 (PD-L1) expression, according to preliminary findings from a phase 2 study.

Dr. Chunyan Lan

Apatinib, an inhibitor of vascular endothelial growth factor receptor-2, and camrelizumab, an anti-PD-1 monoclonal antibody, produced an objective response rate of 60% in evaluable patients.

Chunyan Lan, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China, and colleagues reported these results in an abstract that had been slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic. The following data differ somewhat from the abstract.

Dr. Lan and colleagues reported results in 45 patients who had progressed after at least one line of systemic chemotherapy for metastatic, recurrent, or persistent cervical cancer, and had measurable disease. Patients had a median age of 51 years and an Eastern Cooperative Oncology Group performance status of 0-1. They were enrolled at four centers in China between Jan. 21 and Aug. 1, 2019.

Treatment consisted of oral apatinib at a dose of 250 mg once daily and intravenous camrelizumab at a dose of 200 mg every 2 weeks until disease progression, unacceptable toxicity, or consent withdrawal.

As of Jan. 22, 2020, 25 of 42 efficacy-evaluable patients had achieved a response. Two patients had a complete response, 23 had a partial response, and 12 had stable disease.

“We saw responses in patients regardless of PD-L1 expression,” Dr. Lan said. “In our study, 34% were PD-L1 negative, and the response rate is 65% in PD-L1-positive and 50% in PD-L1-negative [patients].”

The median duration of response was not reached, she added.

The median follow-up was 9.2 months, with the last patient enrolled having 6 months of follow-up. At the data cutoff, 19 patients had disease progression, and 8 had died of their disease.

The median overall survival also was not reached, Dr. Lan said, but overall survival at 9 months was 80%. The median progression-free survival was 7.6 months, and the 6-month progression-free survival rate was 58%.

Grade 3 or greater treatment-related adverse events occurred in 68.9% of patients; adverse events occurring in at least 5% of patients included hypertension (22.2%), fatigue (15.6%), anemia (13.3%), and thrombocytopenia (6.7%).

“Nineteen patients were still on treatment at the data cutoff date, and 26 patients discontinued the study,” Dr. Lan said. “The most common reason to discontinue was disease progression, and three patients discontinued the study due to adverse events.”

“These preliminary results are very encouraging,” Dr. Lan said. “As we know, pembrolizumab is approved as the second-line therapy in recurrent cervical cancer [in] PD-L1-positive patients, and the objective response rate with pembrolizumab monotherapy for recurrent cervical cancer is only 17%, as reported in KEYNOTE-028 [J Clin Oncol. 2017 Dec 20;35(36):4035-41].”

Furthermore, apatinib monotherapy has been studied with only modest results.

“But in our study, this combination is really effective in recurrent cervical cancer, and we see a very durable response,” she said, again emphasizing that those responses occurred regardless of PD-L1 expression. “So this is important. ... We think our findings expand the opportunity of patients with recurrent cervical cancer to receive immune therapy.”

Study participants will be followed for 2 years, Dr. Lan noted.

She reported having no disclosures. The study is sponsored by Sun Yat-sen University.

sworcester@mdedge.com

SOURCE: Lan C et al. SGO 2020, Abstract 55.

If the shoe fits a presumptive clinical diagnosis of calciphylaxis, wear it – and don’t assume that ordering imaging studies or histology will make for a better fit or is even necessary.

That was the key message of Karl M. Saardi, MD, during his video presentation at a virtual meeting held by the George Washington University department of dermatology. The virtual meeting included presentations that had been slated for the annual meeting of the American Academy of Dermatology, which was canceled because of the COVID-19 pandemic.

“You may not need imaging studies or biopsy to diagnose calciphylaxis,” said Dr. Saardi, a dermatology resident at Georgetown University in Washington, D.C.

He presented a single-center, retrospective study that underscored the diagnostic challenges posed by calciphylaxis, a condition for which there are no generally accepted clinical, radiographic, or histologic diagnostic criteria.

The rare skin condition is characterized by calcium deposition in small arterioles and capillaries in the skin and subcutaneous tissue. It’s most common in patients with end-stage renal disease who are on dialysis; however, there is also an increasingly recognized nonuremic variant that’s associated with the use of warfarin, chronic steroids, obesity, and possibly with being antiphospholipid antibody positive.

Calciphylaxis is an extremely painful condition – the pain is ischemic in nature – and it’s associated with substantial morbidity as well as a mortality rate that in many series exceeds 50%. Affected individuals typically present with progressive, painful retiform purpura on the legs, belly, buttocks, and other fatty body sites.

Dr. Saardi’s study entailed a retrospective look at the medical records and pathologic reports of 57 patients who underwent skin biopsy for suspected calciphylaxis. Of the 57, 18 had no antecedent imaging studies done during the preceding 3 months; 8 of those 18 (40%), had a confirmatory positive biopsy. A total of 39 patients did have imaging studies, deemed positive for calciphylaxis in 11 cases, which in only 5 of the 11 imaging-positive cases (45%) were subsequently confirmed by positive biopsy.

And finally, of the 28 patients with negative imaging studies, 10 (36%), had a positive biopsy. Those positive biopsy rates, ranging from 36% to 45%, did not differ statistically. Thus, whether an imaging study was positive or negative, or wasn’t even done, made no difference in terms of the ultimate diagnosis.

“You may not need imaging studies, because imaging has often been done before the consultation is requested because people are looking for things like arterial thrombus, cellulitis, [deep vein thrombosis] or something like that,” Dr. Saardi noted. “In our series, the indication was never calciphylaxis, it was always something like pain, infection, swelling, suspected [deep vein thrombosis], things like that.”

The classic signature of calciphylaxis on plain x-ray is net-like calcifications in skin and subcutaneous tissue. In one study, this often-subtle finding was associated with a 830% increased likelihood of a positive biopsy, with a specificity of 90%; however, these x-ray changes were only found in 13 of 29 patients with biopsy-confirmed calciphylaxis.

“It’s really important when you request plain films in these patients to review the images yourself or together with the radiologist because oftentimes the indication for imaging will be very different from what we’re looking for. Radiologists often won’t know to look for this specifically,” Dr. Saardi said.

The classic histopathologic finding is calcification of the small- and medium-sized vessels in the dermis and subcutaneous soft tissue. However, sometimes all that’s present are small intravascular inflammatory thrombi with intimal hyperplasia.

Skin biopsies are not infrequently falsely negative or nondiagnostic. To maximize the utility of the procedure, it’s important to go deep and gather a tissue sample that extends into subcutaneous tissue.

“You need to do a very deep punch or double-punch biopsy,” he said. “Another key is to avoid biopsy if the pretest probability of calciphylaxis is high because a negative biopsy shouldn’t necessarily reassure you or cause you to withhold treatment. And with the concern about pathergy or Koebnerization of the area causing a wound that’s never going to heal, sometimes a biopsy is not needed if the pretest suspicion is high enough.”

Other investigators have shown that the likelihood of an informative biopsy is enhanced by using a calcium stain on the specimen and having an experienced dermatopathologist do the evaluation. Also, the use of a radiographically guided core needle biopsy to ensure that the physician is getting sufficiently deep into subcutaneous fat is now under evaluation.

In addition to plain radiographs, other imaging methods that are sometimes used to evaluate soft-tissue sites for suspected calciphylaxis included CT and ultrasound. Dr. Saardi is particularly intrigued by reports from investigators at Harvard University regarding the utility of nuclear bone scintigraphy; in one study, this form of imaging was positive in 16 of 18 patients with clinically diagnosed calciphylaxis, versus just 1 of 31 controls with end-stage renal disease.

“We’ve started doing this in situations where biopsy is not desirable or feasible at that moment,” he said.

Dr. Saardi reported having no financial conflicts regarding his presentation.
 

bjancin@mdedge.com

If the shoe fits a presumptive clinical diagnosis of calciphylaxis, wear it – and don’t assume that ordering imaging studies or histology will make for a better fit or is even necessary.

That was the key message of Karl M. Saardi, MD, during his video presentation at a virtual meeting held by the George Washington University department of dermatology. The virtual meeting included presentations that had been slated for the annual meeting of the American Academy of Dermatology, which was canceled because of the COVID-19 pandemic.

“You may not need imaging studies or biopsy to diagnose calciphylaxis,” said Dr. Saardi, a dermatology resident at Georgetown University in Washington, D.C.

He presented a single-center, retrospective study that underscored the diagnostic challenges posed by calciphylaxis, a condition for which there are no generally accepted clinical, radiographic, or histologic diagnostic criteria.

The rare skin condition is characterized by calcium deposition in small arterioles and capillaries in the skin and subcutaneous tissue. It’s most common in patients with end-stage renal disease who are on dialysis; however, there is also an increasingly recognized nonuremic variant that’s associated with the use of warfarin, chronic steroids, obesity, and possibly with being antiphospholipid antibody positive.

Calciphylaxis is an extremely painful condition – the pain is ischemic in nature – and it’s associated with substantial morbidity as well as a mortality rate that in many series exceeds 50%. Affected individuals typically present with progressive, painful retiform purpura on the legs, belly, buttocks, and other fatty body sites.

Dr. Saardi’s study entailed a retrospective look at the medical records and pathologic reports of 57 patients who underwent skin biopsy for suspected calciphylaxis. Of the 57, 18 had no antecedent imaging studies done during the preceding 3 months; 8 of those 18 (40%), had a confirmatory positive biopsy. A total of 39 patients did have imaging studies, deemed positive for calciphylaxis in 11 cases, which in only 5 of the 11 imaging-positive cases (45%) were subsequently confirmed by positive biopsy.

And finally, of the 28 patients with negative imaging studies, 10 (36%), had a positive biopsy. Those positive biopsy rates, ranging from 36% to 45%, did not differ statistically. Thus, whether an imaging study was positive or negative, or wasn’t even done, made no difference in terms of the ultimate diagnosis.

“You may not need imaging studies, because imaging has often been done before the consultation is requested because people are looking for things like arterial thrombus, cellulitis, [deep vein thrombosis] or something like that,” Dr. Saardi noted. “In our series, the indication was never calciphylaxis, it was always something like pain, infection, swelling, suspected [deep vein thrombosis], things like that.”

The classic signature of calciphylaxis on plain x-ray is net-like calcifications in skin and subcutaneous tissue. In one study, this often-subtle finding was associated with a 830% increased likelihood of a positive biopsy, with a specificity of 90%; however, these x-ray changes were only found in 13 of 29 patients with biopsy-confirmed calciphylaxis.

“It’s really important when you request plain films in these patients to review the images yourself or together with the radiologist because oftentimes the indication for imaging will be very different from what we’re looking for. Radiologists often won’t know to look for this specifically,” Dr. Saardi said.

The classic histopathologic finding is calcification of the small- and medium-sized vessels in the dermis and subcutaneous soft tissue. However, sometimes all that’s present are small intravascular inflammatory thrombi with intimal hyperplasia.

Skin biopsies are not infrequently falsely negative or nondiagnostic. To maximize the utility of the procedure, it’s important to go deep and gather a tissue sample that extends into subcutaneous tissue.

“You need to do a very deep punch or double-punch biopsy,” he said. “Another key is to avoid biopsy if the pretest probability of calciphylaxis is high because a negative biopsy shouldn’t necessarily reassure you or cause you to withhold treatment. And with the concern about pathergy or Koebnerization of the area causing a wound that’s never going to heal, sometimes a biopsy is not needed if the pretest suspicion is high enough.”

Other investigators have shown that the likelihood of an informative biopsy is enhanced by using a calcium stain on the specimen and having an experienced dermatopathologist do the evaluation. Also, the use of a radiographically guided core needle biopsy to ensure that the physician is getting sufficiently deep into subcutaneous fat is now under evaluation.

In addition to plain radiographs, other imaging methods that are sometimes used to evaluate soft-tissue sites for suspected calciphylaxis included CT and ultrasound. Dr. Saardi is particularly intrigued by reports from investigators at Harvard University regarding the utility of nuclear bone scintigraphy; in one study, this form of imaging was positive in 16 of 18 patients with clinically diagnosed calciphylaxis, versus just 1 of 31 controls with end-stage renal disease.

“We’ve started doing this in situations where biopsy is not desirable or feasible at that moment,” he said.

Dr. Saardi reported having no financial conflicts regarding his presentation.
 

bjancin@mdedge.com

If the shoe fits a presumptive clinical diagnosis of calciphylaxis, wear it – and don’t assume that ordering imaging studies or histology will make for a better fit or is even necessary.

That was the key message of Karl M. Saardi, MD, during his video presentation at a virtual meeting held by the George Washington University department of dermatology. The virtual meeting included presentations that had been slated for the annual meeting of the American Academy of Dermatology, which was canceled because of the COVID-19 pandemic.

“You may not need imaging studies or biopsy to diagnose calciphylaxis,” said Dr. Saardi, a dermatology resident at Georgetown University in Washington, D.C.

He presented a single-center, retrospective study that underscored the diagnostic challenges posed by calciphylaxis, a condition for which there are no generally accepted clinical, radiographic, or histologic diagnostic criteria.

The rare skin condition is characterized by calcium deposition in small arterioles and capillaries in the skin and subcutaneous tissue. It’s most common in patients with end-stage renal disease who are on dialysis; however, there is also an increasingly recognized nonuremic variant that’s associated with the use of warfarin, chronic steroids, obesity, and possibly with being antiphospholipid antibody positive.

Calciphylaxis is an extremely painful condition – the pain is ischemic in nature – and it’s associated with substantial morbidity as well as a mortality rate that in many series exceeds 50%. Affected individuals typically present with progressive, painful retiform purpura on the legs, belly, buttocks, and other fatty body sites.

Dr. Saardi’s study entailed a retrospective look at the medical records and pathologic reports of 57 patients who underwent skin biopsy for suspected calciphylaxis. Of the 57, 18 had no antecedent imaging studies done during the preceding 3 months; 8 of those 18 (40%), had a confirmatory positive biopsy. A total of 39 patients did have imaging studies, deemed positive for calciphylaxis in 11 cases, which in only 5 of the 11 imaging-positive cases (45%) were subsequently confirmed by positive biopsy.

And finally, of the 28 patients with negative imaging studies, 10 (36%), had a positive biopsy. Those positive biopsy rates, ranging from 36% to 45%, did not differ statistically. Thus, whether an imaging study was positive or negative, or wasn’t even done, made no difference in terms of the ultimate diagnosis.

“You may not need imaging studies, because imaging has often been done before the consultation is requested because people are looking for things like arterial thrombus, cellulitis, [deep vein thrombosis] or something like that,” Dr. Saardi noted. “In our series, the indication was never calciphylaxis, it was always something like pain, infection, swelling, suspected [deep vein thrombosis], things like that.”

The classic signature of calciphylaxis on plain x-ray is net-like calcifications in skin and subcutaneous tissue. In one study, this often-subtle finding was associated with a 830% increased likelihood of a positive biopsy, with a specificity of 90%; however, these x-ray changes were only found in 13 of 29 patients with biopsy-confirmed calciphylaxis.

“It’s really important when you request plain films in these patients to review the images yourself or together with the radiologist because oftentimes the indication for imaging will be very different from what we’re looking for. Radiologists often won’t know to look for this specifically,” Dr. Saardi said.

The classic histopathologic finding is calcification of the small- and medium-sized vessels in the dermis and subcutaneous soft tissue. However, sometimes all that’s present are small intravascular inflammatory thrombi with intimal hyperplasia.

Skin biopsies are not infrequently falsely negative or nondiagnostic. To maximize the utility of the procedure, it’s important to go deep and gather a tissue sample that extends into subcutaneous tissue.

“You need to do a very deep punch or double-punch biopsy,” he said. “Another key is to avoid biopsy if the pretest probability of calciphylaxis is high because a negative biopsy shouldn’t necessarily reassure you or cause you to withhold treatment. And with the concern about pathergy or Koebnerization of the area causing a wound that’s never going to heal, sometimes a biopsy is not needed if the pretest suspicion is high enough.”

Other investigators have shown that the likelihood of an informative biopsy is enhanced by using a calcium stain on the specimen and having an experienced dermatopathologist do the evaluation. Also, the use of a radiographically guided core needle biopsy to ensure that the physician is getting sufficiently deep into subcutaneous fat is now under evaluation.

In addition to plain radiographs, other imaging methods that are sometimes used to evaluate soft-tissue sites for suspected calciphylaxis included CT and ultrasound. Dr. Saardi is particularly intrigued by reports from investigators at Harvard University regarding the utility of nuclear bone scintigraphy; in one study, this form of imaging was positive in 16 of 18 patients with clinically diagnosed calciphylaxis, versus just 1 of 31 controls with end-stage renal disease.

“We’ve started doing this in situations where biopsy is not desirable or feasible at that moment,” he said.

Dr. Saardi reported having no financial conflicts regarding his presentation.
 

bjancin@mdedge.com

The monoclonal antibody dupilumab significantly improved symptoms of atopic dermatitis (AD) in grade school-aged children, according to new clinical trial results.

In a cohort of children with severe AD, 33% achieved clear or nearly clear skin after 16 weeks of treatment with every 4-week dosing of the injectable medication, while 30% also achieved that mark when receiving a weight-based dose every 2 weeks. Both groups had results that were significantly better than those receiving placebo, with 11% of these children had clear or nearly clear skin by 16 weeks of dupilumab (Dupixent) therapy (P less than .0001 for both therapy arms versus placebo).

“Dupilumab with a topical corticosteroid showed clinically meaningful and statistically significant improvement in the atopic dermatitis signs and symptoms in children aged 6 to less than 12 years of age with severe atopic dermatitis,” said Amy Paller, MD, the Walter J. Hamlin professor and chair of the department of dermatology at Northwestern University, Chicago, presenting the results at the Revolutionizing Atopic Dermatitis virtual symposium. Portions of the conference, which has been rescheduled to December 2020, in Chicago, were presented virtually because of the COVID-19 pandemic.

The phase 3 trial of subcutaneously injected dupilumab for atopic dermatitis, dubbed LIBERTY AD PEDS, included children aged 6-11 years with severe AD. The study’s primary endpoint was the proportion of patients achieving a score of 0 or 1 (clear or almost clear skin) on the Investigator’s Global Assessment (IGA) scale by study week 16.

For the purposes of reporting results to the European Medicines Agency, the investigators added a coprimary endpoint of patients reaching 75% clearing on the Eczema Area and Severity Index (EASI-75) by week 16.

The randomized, double-blind, placebo-controlled trial enrolled 367 children with IGA scores of 4, denoting severe AD. The EASI score had to be at least 21 and patients had to endorse peak pruritus of at least 4 on a 0-10 numeric rating scale; body surface involvement had to be at least 15%. Patients went through a washout period of any systemic therapies before beginning the trial, which randomized patients 1:1:1 to receive placebo, dupilumab 300 mg every 4 weeks, or dupilumab every 2 weeks with weight-dependent dosing. All participants were also permitted topical corticosteroids.

Patients were an average of aged 8 years, about half were female, and about two-thirds were white. Most participants had developed AD within their first year of life. Patients were about evenly divided between weighing over and under 30 kg, which was the cutoff for 100 mcg versus 200 mcg dupilumab for the every-2-week dosing group.

Over 90% of patients had other atopic comorbidities, and the mean EASI score was about 38 with average weekly peak pruritus averaging 7.8 on the numeric rating scale.

“When we’re talking about how severe this population is, it’s interesting to note that about 30 to 35% were all that had been previously treated with either systemic steroids or some systemic nonsteroidal immunosuppressants,” Dr. Paller pointed out. “I think that reflects the fact that so many of these very severely affected children are not put on a systemic therapy, but are still staying on topical therapies to try to control their disease.”

Looking at the proportion of patients reaching EASI-75, both dosing strategies for dupilumab out-performed placebo, with 70% of the every 4-week group and 67% of the every 2-week group reaching EASI-75 at 16 weeks, compared with 27% of those on placebo (P less than .0001 for both active arms). “These differences were seen very early on; by 2 weeks already, we can see that we’re starting to see a difference in both of these arms,” noted Dr. Paller, adding that the difference was statistically significant by 4 weeks into the study.

The overall group of dupilumab participants saw their EASI scores drop by about 80%, while those taking placebo saw a 49% drop in EASI scores.

For the group of participants weighing less than 30 kg, the every 4-week strategy resulted in better clearing as measured by both IGA and EASI-75. This effect wasn’t seen for heavier patients. Trough dupilumab concentrations at 16 weeks were higher for lighter patients with every 4-week dosing and for heavier patients with the biweekly strategy, noted Dr. Paller.

In terms of itch, 60% to 68% of participants receiving dupilumab had a drop of at least 3 points in peak pruritus on the numeric rating scale, compared with 21% of those receiving placebo (P less than .001), while about half of the dupilumab groups and 12% of the placebo group saw pruritus improvements of 4 points or more (P less than .001). Pruritus improved early in the active arms of the study, becoming statistically significant at the 2 to 4 week range.

Treatment-emergent adverse events were numerically higher in patients in the placebo group, including infections and adjudicated skin infections. Conjunctivitis occurred more frequently in the dupilumab group, as did injection-site reactions.

“Overall, dupilumab was well tolerated, and data were consistent with the known dupilumab safety profile observed in adults and adolescents,” Dr. Paller said.

Dupilumab has been approved by the Food and Drug Administration to treat moderate to severe AD in those aged 12 years and older whose disease can’t be adequately controlled with topical prescription medications, or when those treatments are not advisable.

The fully human monoclonal antibody blocks a shared receptor component for interleukin-4 and interleukin-13, which contribute to inflammation in AD, as well as asthma, chronic rhinosinusitis with nasal polyps, and eosinophilic esophagitis.

Dr. Paller reported receiving support from multiple pharmaceutical companies including Sanofi and Regeneron Pharmaceuticals, which sponsored the study.

koakes@mdedge.com

The monoclonal antibody dupilumab significantly improved symptoms of atopic dermatitis (AD) in grade school-aged children, according to new clinical trial results.

In a cohort of children with severe AD, 33% achieved clear or nearly clear skin after 16 weeks of treatment with every 4-week dosing of the injectable medication, while 30% also achieved that mark when receiving a weight-based dose every 2 weeks. Both groups had results that were significantly better than those receiving placebo, with 11% of these children had clear or nearly clear skin by 16 weeks of dupilumab (Dupixent) therapy (P less than .0001 for both therapy arms versus placebo).

“Dupilumab with a topical corticosteroid showed clinically meaningful and statistically significant improvement in the atopic dermatitis signs and symptoms in children aged 6 to less than 12 years of age with severe atopic dermatitis,” said Amy Paller, MD, the Walter J. Hamlin professor and chair of the department of dermatology at Northwestern University, Chicago, presenting the results at the Revolutionizing Atopic Dermatitis virtual symposium. Portions of the conference, which has been rescheduled to December 2020, in Chicago, were presented virtually because of the COVID-19 pandemic.

The phase 3 trial of subcutaneously injected dupilumab for atopic dermatitis, dubbed LIBERTY AD PEDS, included children aged 6-11 years with severe AD. The study’s primary endpoint was the proportion of patients achieving a score of 0 or 1 (clear or almost clear skin) on the Investigator’s Global Assessment (IGA) scale by study week 16.

For the purposes of reporting results to the European Medicines Agency, the investigators added a coprimary endpoint of patients reaching 75% clearing on the Eczema Area and Severity Index (EASI-75) by week 16.

The randomized, double-blind, placebo-controlled trial enrolled 367 children with IGA scores of 4, denoting severe AD. The EASI score had to be at least 21 and patients had to endorse peak pruritus of at least 4 on a 0-10 numeric rating scale; body surface involvement had to be at least 15%. Patients went through a washout period of any systemic therapies before beginning the trial, which randomized patients 1:1:1 to receive placebo, dupilumab 300 mg every 4 weeks, or dupilumab every 2 weeks with weight-dependent dosing. All participants were also permitted topical corticosteroids.

Patients were an average of aged 8 years, about half were female, and about two-thirds were white. Most participants had developed AD within their first year of life. Patients were about evenly divided between weighing over and under 30 kg, which was the cutoff for 100 mcg versus 200 mcg dupilumab for the every-2-week dosing group.

Over 90% of patients had other atopic comorbidities, and the mean EASI score was about 38 with average weekly peak pruritus averaging 7.8 on the numeric rating scale.

“When we’re talking about how severe this population is, it’s interesting to note that about 30 to 35% were all that had been previously treated with either systemic steroids or some systemic nonsteroidal immunosuppressants,” Dr. Paller pointed out. “I think that reflects the fact that so many of these very severely affected children are not put on a systemic therapy, but are still staying on topical therapies to try to control their disease.”

Looking at the proportion of patients reaching EASI-75, both dosing strategies for dupilumab out-performed placebo, with 70% of the every 4-week group and 67% of the every 2-week group reaching EASI-75 at 16 weeks, compared with 27% of those on placebo (P less than .0001 for both active arms). “These differences were seen very early on; by 2 weeks already, we can see that we’re starting to see a difference in both of these arms,” noted Dr. Paller, adding that the difference was statistically significant by 4 weeks into the study.

The overall group of dupilumab participants saw their EASI scores drop by about 80%, while those taking placebo saw a 49% drop in EASI scores.

For the group of participants weighing less than 30 kg, the every 4-week strategy resulted in better clearing as measured by both IGA and EASI-75. This effect wasn’t seen for heavier patients. Trough dupilumab concentrations at 16 weeks were higher for lighter patients with every 4-week dosing and for heavier patients with the biweekly strategy, noted Dr. Paller.

In terms of itch, 60% to 68% of participants receiving dupilumab had a drop of at least 3 points in peak pruritus on the numeric rating scale, compared with 21% of those receiving placebo (P less than .001), while about half of the dupilumab groups and 12% of the placebo group saw pruritus improvements of 4 points or more (P less than .001). Pruritus improved early in the active arms of the study, becoming statistically significant at the 2 to 4 week range.

Treatment-emergent adverse events were numerically higher in patients in the placebo group, including infections and adjudicated skin infections. Conjunctivitis occurred more frequently in the dupilumab group, as did injection-site reactions.

“Overall, dupilumab was well tolerated, and data were consistent with the known dupilumab safety profile observed in adults and adolescents,” Dr. Paller said.

Dupilumab has been approved by the Food and Drug Administration to treat moderate to severe AD in those aged 12 years and older whose disease can’t be adequately controlled with topical prescription medications, or when those treatments are not advisable.

The fully human monoclonal antibody blocks a shared receptor component for interleukin-4 and interleukin-13, which contribute to inflammation in AD, as well as asthma, chronic rhinosinusitis with nasal polyps, and eosinophilic esophagitis.

Dr. Paller reported receiving support from multiple pharmaceutical companies including Sanofi and Regeneron Pharmaceuticals, which sponsored the study.

koakes@mdedge.com

The monoclonal antibody dupilumab significantly improved symptoms of atopic dermatitis (AD) in grade school-aged children, according to new clinical trial results.

In a cohort of children with severe AD, 33% achieved clear or nearly clear skin after 16 weeks of treatment with every 4-week dosing of the injectable medication, while 30% also achieved that mark when receiving a weight-based dose every 2 weeks. Both groups had results that were significantly better than those receiving placebo, with 11% of these children had clear or nearly clear skin by 16 weeks of dupilumab (Dupixent) therapy (P less than .0001 for both therapy arms versus placebo).

“Dupilumab with a topical corticosteroid showed clinically meaningful and statistically significant improvement in the atopic dermatitis signs and symptoms in children aged 6 to less than 12 years of age with severe atopic dermatitis,” said Amy Paller, MD, the Walter J. Hamlin professor and chair of the department of dermatology at Northwestern University, Chicago, presenting the results at the Revolutionizing Atopic Dermatitis virtual symposium. Portions of the conference, which has been rescheduled to December 2020, in Chicago, were presented virtually because of the COVID-19 pandemic.

The phase 3 trial of subcutaneously injected dupilumab for atopic dermatitis, dubbed LIBERTY AD PEDS, included children aged 6-11 years with severe AD. The study’s primary endpoint was the proportion of patients achieving a score of 0 or 1 (clear or almost clear skin) on the Investigator’s Global Assessment (IGA) scale by study week 16.

For the purposes of reporting results to the European Medicines Agency, the investigators added a coprimary endpoint of patients reaching 75% clearing on the Eczema Area and Severity Index (EASI-75) by week 16.

The randomized, double-blind, placebo-controlled trial enrolled 367 children with IGA scores of 4, denoting severe AD. The EASI score had to be at least 21 and patients had to endorse peak pruritus of at least 4 on a 0-10 numeric rating scale; body surface involvement had to be at least 15%. Patients went through a washout period of any systemic therapies before beginning the trial, which randomized patients 1:1:1 to receive placebo, dupilumab 300 mg every 4 weeks, or dupilumab every 2 weeks with weight-dependent dosing. All participants were also permitted topical corticosteroids.

Patients were an average of aged 8 years, about half were female, and about two-thirds were white. Most participants had developed AD within their first year of life. Patients were about evenly divided between weighing over and under 30 kg, which was the cutoff for 100 mcg versus 200 mcg dupilumab for the every-2-week dosing group.

Over 90% of patients had other atopic comorbidities, and the mean EASI score was about 38 with average weekly peak pruritus averaging 7.8 on the numeric rating scale.

“When we’re talking about how severe this population is, it’s interesting to note that about 30 to 35% were all that had been previously treated with either systemic steroids or some systemic nonsteroidal immunosuppressants,” Dr. Paller pointed out. “I think that reflects the fact that so many of these very severely affected children are not put on a systemic therapy, but are still staying on topical therapies to try to control their disease.”

Looking at the proportion of patients reaching EASI-75, both dosing strategies for dupilumab out-performed placebo, with 70% of the every 4-week group and 67% of the every 2-week group reaching EASI-75 at 16 weeks, compared with 27% of those on placebo (P less than .0001 for both active arms). “These differences were seen very early on; by 2 weeks already, we can see that we’re starting to see a difference in both of these arms,” noted Dr. Paller, adding that the difference was statistically significant by 4 weeks into the study.

The overall group of dupilumab participants saw their EASI scores drop by about 80%, while those taking placebo saw a 49% drop in EASI scores.

For the group of participants weighing less than 30 kg, the every 4-week strategy resulted in better clearing as measured by both IGA and EASI-75. This effect wasn’t seen for heavier patients. Trough dupilumab concentrations at 16 weeks were higher for lighter patients with every 4-week dosing and for heavier patients with the biweekly strategy, noted Dr. Paller.

In terms of itch, 60% to 68% of participants receiving dupilumab had a drop of at least 3 points in peak pruritus on the numeric rating scale, compared with 21% of those receiving placebo (P less than .001), while about half of the dupilumab groups and 12% of the placebo group saw pruritus improvements of 4 points or more (P less than .001). Pruritus improved early in the active arms of the study, becoming statistically significant at the 2 to 4 week range.

Treatment-emergent adverse events were numerically higher in patients in the placebo group, including infections and adjudicated skin infections. Conjunctivitis occurred more frequently in the dupilumab group, as did injection-site reactions.

“Overall, dupilumab was well tolerated, and data were consistent with the known dupilumab safety profile observed in adults and adolescents,” Dr. Paller said.

Dupilumab has been approved by the Food and Drug Administration to treat moderate to severe AD in those aged 12 years and older whose disease can’t be adequately controlled with topical prescription medications, or when those treatments are not advisable.

The fully human monoclonal antibody blocks a shared receptor component for interleukin-4 and interleukin-13, which contribute to inflammation in AD, as well as asthma, chronic rhinosinusitis with nasal polyps, and eosinophilic esophagitis.

Dr. Paller reported receiving support from multiple pharmaceutical companies including Sanofi and Regeneron Pharmaceuticals, which sponsored the study.

koakes@mdedge.com

Black patients in the Washington, D.C., area face an increased risk of mortality from Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), compared with nonblack patients, results from a single-center study showed.

Adam Swigost, MD, presented data on behalf of the study’s principal investigator, Helena B. Pasieka, MD, and associates at MedStar Health Georgetown University in Washington in a video presentation during a virtual meeting held by the George Washington University department of dermatology. The virtual meeting included presentations slated for the annual meeting of the American Academy of Dermatology, which was canceled because of the COVID-19 pandemic.

According to the 2009-2012 Nationwide Inpatient Survey, there were 12,195 cases of SJS, 2,373 cases of SJS/TEN overlap, and 2,675 cases of TEN. In 2016, researchers led by Derek Y. Hsu, MD, of Northwestern University, Chicago, found that SJS/TEN was associated with nonwhite race, particularly Asians (odds ratio, 3.27) and blacks (OR, 2.01) (J Invest Dermatol. 2016;136[7]:1387-97).

“This led Dr. Pasieka and our team to ask the question: Are there differences in SJS/TEN outcomes in self-reported blacks in the U.S.?” said Dr. Swigost, a resident in the department of dermatology at MedStar Health Georgetown University.

To find out, he and his colleagues retrospectively analyzed records from 74 patients with SJS/TEN who were treated at Washington Hospital Center in Washington, D.C., from 2009 to 2019. They drew data from clinical diagnoses with histopathologic evaluation, when available, and performed a multivariate analysis adjusted for age, HIV status, black race, and offending drug category.

Of the 75 patients, 43 were female, 45 were black, 16 were white, 6 were Asian, 5 were Indian, 1 was Native American, and 1 was South Asian. Multivariate analysis revealed that black race was the only significant variable associated with an elevated risk of mortality from SJS/TEN (OR, 4.81; P = .04).

Of the 45 black patients in the study, 33 were HIV negative and 12 were HIV positive. “While this variable was not statistically significant, it did seem to have an elevated risk for mortality in HIV-positive patients [4 of 12; 33%], compared with 8 of 33 HIV-negative patients [25%],” Dr. Swigost said.

Next, the researchers investigated the culprit medications in the black patients. As a reference, they compared their data with a 2015 study that set out to document the clinical profile, etiologies, and outcomes of SJS and TEN in hospitals in four sub-Saharan African countries (Int J Dermatol. 2013 May;52[5]:575-9). In the 2015 study, sulfonamides were the most-used drugs (38%) followed by the antiretroviral drug nevirapine (20%) and tuberculosis drugs (6%). In the study by Dr. Swigost and colleagues, the most frequently implicated drugs were sulfonamides (24%), followed by other antibiotics (24%), and anticonvulsants (17%).

“Our patients at MedStar Washington Hospital Center are going to have different comorbidities and medical problems that dictate different medications being used in different proportions,” Dr. Swigost explained.

Delayed detection is one possible reason for the increased mortality observed in black patients. “Dermatology education on a national level is biased most commonly toward white skin,” he said. “Often, diseases can be missed in skin of color. It’s possible that the diagnoses are being delayed and so treatment is being delayed.”

Socioeconomics and access to health care could also play a role in the poor outcome we observed. “Those are variables we want to further analyze in this data,” Dr. Swigost said. “Other things to consider are genetic variations between African and American black patient populations, because in the U.S. our black population is likely more heterogeneous than African patient populations are. It’s possible that there are HLA [human leukocyte antigen] differences that are contributing. Lastly, further characterization and stratification of SJS/TEN risk factors are required.”

Dr. Swigost and Dr. Pasieka reported having no disclosures.

dbrunk@mdedge.com

Black patients in the Washington, D.C., area face an increased risk of mortality from Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), compared with nonblack patients, results from a single-center study showed.

Adam Swigost, MD, presented data on behalf of the study’s principal investigator, Helena B. Pasieka, MD, and associates at MedStar Health Georgetown University in Washington in a video presentation during a virtual meeting held by the George Washington University department of dermatology. The virtual meeting included presentations slated for the annual meeting of the American Academy of Dermatology, which was canceled because of the COVID-19 pandemic.

According to the 2009-2012 Nationwide Inpatient Survey, there were 12,195 cases of SJS, 2,373 cases of SJS/TEN overlap, and 2,675 cases of TEN. In 2016, researchers led by Derek Y. Hsu, MD, of Northwestern University, Chicago, found that SJS/TEN was associated with nonwhite race, particularly Asians (odds ratio, 3.27) and blacks (OR, 2.01) (J Invest Dermatol. 2016;136[7]:1387-97).

“This led Dr. Pasieka and our team to ask the question: Are there differences in SJS/TEN outcomes in self-reported blacks in the U.S.?” said Dr. Swigost, a resident in the department of dermatology at MedStar Health Georgetown University.

To find out, he and his colleagues retrospectively analyzed records from 74 patients with SJS/TEN who were treated at Washington Hospital Center in Washington, D.C., from 2009 to 2019. They drew data from clinical diagnoses with histopathologic evaluation, when available, and performed a multivariate analysis adjusted for age, HIV status, black race, and offending drug category.

Of the 75 patients, 43 were female, 45 were black, 16 were white, 6 were Asian, 5 were Indian, 1 was Native American, and 1 was South Asian. Multivariate analysis revealed that black race was the only significant variable associated with an elevated risk of mortality from SJS/TEN (OR, 4.81; P = .04).

Of the 45 black patients in the study, 33 were HIV negative and 12 were HIV positive. “While this variable was not statistically significant, it did seem to have an elevated risk for mortality in HIV-positive patients [4 of 12; 33%], compared with 8 of 33 HIV-negative patients [25%],” Dr. Swigost said.

Next, the researchers investigated the culprit medications in the black patients. As a reference, they compared their data with a 2015 study that set out to document the clinical profile, etiologies, and outcomes of SJS and TEN in hospitals in four sub-Saharan African countries (Int J Dermatol. 2013 May;52[5]:575-9). In the 2015 study, sulfonamides were the most-used drugs (38%) followed by the antiretroviral drug nevirapine (20%) and tuberculosis drugs (6%). In the study by Dr. Swigost and colleagues, the most frequently implicated drugs were sulfonamides (24%), followed by other antibiotics (24%), and anticonvulsants (17%).

“Our patients at MedStar Washington Hospital Center are going to have different comorbidities and medical problems that dictate different medications being used in different proportions,” Dr. Swigost explained.

Delayed detection is one possible reason for the increased mortality observed in black patients. “Dermatology education on a national level is biased most commonly toward white skin,” he said. “Often, diseases can be missed in skin of color. It’s possible that the diagnoses are being delayed and so treatment is being delayed.”

Socioeconomics and access to health care could also play a role in the poor outcome we observed. “Those are variables we want to further analyze in this data,” Dr. Swigost said. “Other things to consider are genetic variations between African and American black patient populations, because in the U.S. our black population is likely more heterogeneous than African patient populations are. It’s possible that there are HLA [human leukocyte antigen] differences that are contributing. Lastly, further characterization and stratification of SJS/TEN risk factors are required.”

Dr. Swigost and Dr. Pasieka reported having no disclosures.

dbrunk@mdedge.com

Black patients in the Washington, D.C., area face an increased risk of mortality from Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), compared with nonblack patients, results from a single-center study showed.

Adam Swigost, MD, presented data on behalf of the study’s principal investigator, Helena B. Pasieka, MD, and associates at MedStar Health Georgetown University in Washington in a video presentation during a virtual meeting held by the George Washington University department of dermatology. The virtual meeting included presentations slated for the annual meeting of the American Academy of Dermatology, which was canceled because of the COVID-19 pandemic.

According to the 2009-2012 Nationwide Inpatient Survey, there were 12,195 cases of SJS, 2,373 cases of SJS/TEN overlap, and 2,675 cases of TEN. In 2016, researchers led by Derek Y. Hsu, MD, of Northwestern University, Chicago, found that SJS/TEN was associated with nonwhite race, particularly Asians (odds ratio, 3.27) and blacks (OR, 2.01) (J Invest Dermatol. 2016;136[7]:1387-97).

“This led Dr. Pasieka and our team to ask the question: Are there differences in SJS/TEN outcomes in self-reported blacks in the U.S.?” said Dr. Swigost, a resident in the department of dermatology at MedStar Health Georgetown University.

To find out, he and his colleagues retrospectively analyzed records from 74 patients with SJS/TEN who were treated at Washington Hospital Center in Washington, D.C., from 2009 to 2019. They drew data from clinical diagnoses with histopathologic evaluation, when available, and performed a multivariate analysis adjusted for age, HIV status, black race, and offending drug category.

Of the 75 patients, 43 were female, 45 were black, 16 were white, 6 were Asian, 5 were Indian, 1 was Native American, and 1 was South Asian. Multivariate analysis revealed that black race was the only significant variable associated with an elevated risk of mortality from SJS/TEN (OR, 4.81; P = .04).

Of the 45 black patients in the study, 33 were HIV negative and 12 were HIV positive. “While this variable was not statistically significant, it did seem to have an elevated risk for mortality in HIV-positive patients [4 of 12; 33%], compared with 8 of 33 HIV-negative patients [25%],” Dr. Swigost said.

Next, the researchers investigated the culprit medications in the black patients. As a reference, they compared their data with a 2015 study that set out to document the clinical profile, etiologies, and outcomes of SJS and TEN in hospitals in four sub-Saharan African countries (Int J Dermatol. 2013 May;52[5]:575-9). In the 2015 study, sulfonamides were the most-used drugs (38%) followed by the antiretroviral drug nevirapine (20%) and tuberculosis drugs (6%). In the study by Dr. Swigost and colleagues, the most frequently implicated drugs were sulfonamides (24%), followed by other antibiotics (24%), and anticonvulsants (17%).

“Our patients at MedStar Washington Hospital Center are going to have different comorbidities and medical problems that dictate different medications being used in different proportions,” Dr. Swigost explained.

Delayed detection is one possible reason for the increased mortality observed in black patients. “Dermatology education on a national level is biased most commonly toward white skin,” he said. “Often, diseases can be missed in skin of color. It’s possible that the diagnoses are being delayed and so treatment is being delayed.”

Socioeconomics and access to health care could also play a role in the poor outcome we observed. “Those are variables we want to further analyze in this data,” Dr. Swigost said. “Other things to consider are genetic variations between African and American black patient populations, because in the U.S. our black population is likely more heterogeneous than African patient populations are. It’s possible that there are HLA [human leukocyte antigen] differences that are contributing. Lastly, further characterization and stratification of SJS/TEN risk factors are required.”

Dr. Swigost and Dr. Pasieka reported having no disclosures.

dbrunk@mdedge.com

STOWE, VT – The preventive treatment of migraine has the potential to change patients’ lives and modify the trajectory of the disease, said Rebecca Burch, MD, staff attending neurologist at Brigham and Women’s Hospital in Boston. Clinical observation suggests that preventive treatment provides benefits for appropriately selected migraineurs, although few data confirm a modifying effect on disease course, she said at the Stowe Headache Symposium sponsored by the Headache Cooperative of New England. In her overview, Dr. Burch discussed when preventive treatment is appropriate, which patients are candidates for preventive therapy, and what the levels of evidence are for the preventive therapies.

Identifying candidates for preventive treatment

Migraine is the second most disabling condition worldwide and imposes a large social and economic burden, said Dr. Burch. Preventive therapy reduces the disability associated with migraine. It reduces headache frequency and, thus, the risk that episodic migraine will transform into chronic migraine. By reducing the number of headache days, preventive treatment also may reduce the overuse of acute medication, which is a risk factor for migraine chronification.

Neurologists can consider preventive therapy for migraineurs with frequent headaches, but the term “frequent” is not clearly defined. Common definitions include one headache per week and two headaches per month with significant disability. These definitions are based on expert consensus and do not have strong evidential support, said Dr. Burch. Preventive therapy also may be appropriate for migraineurs who overuse acute medication or who have failed acute medications. Special cases, such as patients with exceptional anxiety or disability, may also call for preventive treatment, said Dr. Burch.

Data suggest that preventive treatment for migraine is underused. The American Migraine Prevalence and Prevention study of 2007 found that half of patients who should be offered preventive treatment are currently receiving it. In 2016, the Chronic Migraine Epidemiology and Outcomes study found that 4.5% of chronic migraineurs take both acute and preventive treatment.

Other data published in Cephalalgia in 2015 indicate that adherence to migraine preventive treatment is approximately 20%. About 45% of patients discontinue medication because of side effects, and 45% cite lack of efficacy as their reason for discontinuation. Patients also mentioned cost, interactions with other medications, and the inconvenience of daily medication as other reasons for discontinuation.

Neurologists can take several steps to increase adherence to preventive treatment, said Dr. Burch. First, neurologists should confirm that patients want preventive medication. A clear discussion of the goals of preventive treatment is helpful as well. Furthermore, neurologists should explain that they are offering patients a trial, said Dr. Burch. The medication can be titrated slowly from a low dose to minimize side effects. Patients can be reassured that ineffective medications will be stopped. Neurologists can emphasize that their relationship with the patient is a partnership and that the treatment strategy will be improved over time.
 

Examining the evidence on treatments’ efficacy

Many drug classes, such as antiepileptics, antidepressants, beta blockers, neurotoxins, and calcitonin gene-related peptide (CGRP) antibodies, include therapies that are used as preventive treatments for migraine. When selecting a medication, a neurologist should start with one that is supported by Level A or Level B evidence, said Dr. Burch. Medications with Level A evidence include divalproex, topiramate, metoprolol, propranolol, erenumab, galcanezumab, fremanezumab, eptinezumab, and onabotulinumtoxinA. Medications with Level B evidence include amitriptyline, venlafaxine, memantine, lisinopril, and candesartan. Neurologists sometimes prescribe gabapentin and verapamil, although the evidence for them is Level U. Duloxetine, nortriptyline, and pregabalin also are used, but the evidence for them has not been evaluated. “We need more evidence in these areas,” said Dr. Burch.

Neurologists should consider access (e.g., cost and insurance coverage), efficacy, side effects, and comorbidities and contraindications when choosing a preventive therapy, she added. Verapamil and memantine are well tolerated and appropriate choices if the goal is to avoid side effects in general. If weight gain or fatigue is a concern, then topiramate and venlafaxine should be considered. Neurologists should avoid prescribing antiepileptic drugs if cognitive symptoms are a concern, said Dr. Burch. Beta blockers and venlafaxine would be better options in this case.

In clinical trials of CGRP therapies, the rates of adverse events were similar between the active and control arms. “But it’s become fairly clear that the clinical trials did not fully capture the side-effect profile that we are seeing in clinical practice,” said Dr. Burch. In a paper currently in review, she and her colleagues retrospectively studied 241 patients that they had treated with CGRP monoclonal antibodies at their headache center. The most common adverse events were constipation (43%), injection-site reaction (24%), muscle or joint pain (17%), and fatigue (15%). Furthermore, CGRP antagonists were associated with maternal hypertension, fetal growth restriction, and fetal mortality in animal studies. The current recommendation is to avoid CGRP monoclonal antibodies during pregnancy or in any patient who is at risk of becoming pregnant, said Dr. Burch.
 

How should neurologists assess preventive efficacy?

The assessment of a medication’s preventive efficacy “is a moving target in the headache world,” said Dr. Burch. “Historically, we have used headache days per month, and that is still, according to the International Headache Society clinical trials guidelines, how we should be judging whether a medication is working or not. But that doesn’t necessarily tell us what’s going to happen to an individual patient in front of us.”

In 2017, the Institute for Clinical Effectiveness Research compared data for old and new migraine treatments in a network meta-analysis. They all tended to reduce the number of monthly migraine days by one to two, compared with placebo. When one analyzes clinical trials of the drugs using this criterion, “most of these treatments come out about the same,” said Dr. Burch.

More recently, investigators have examined responder rates. They commonly report the proportions of patients who had a reduction in headache days of 50%, 75%, or 100%, for example. To extrapolate responder rates from the trial participants to the general population, a neurologist must know which groups of patients got worse on treatment, said Dr. Burch. Furthermore, the responder rates for older medications are unknown, because they were not examined. This situation makes comparisons of newer and older therapies more complicated.

Phase 3 trials of the CGRP drugs included analyses of the therapies’ 50% responder rates. This rate was about 42% for the 70-mg dose of erenumab and 50% for the 140-mg dose. The 50% responder rates for fremanezumab were 47.7% for the 225-mg dose and 44.4% for the 675-mg dose. In two trials of galcanezumab, the 50% responder rate for the 120-mg dose was approximately 60%, and the rate for the 240-mg dose was about 59%. The 50% responder rates for eptinezumab were 50% for the 100-mg dose and 56% for the 300-mg dose. The 50% responder rate across all trials was around 50%-60% in the active group, which is roughly 25% over the placebo group, said Dr. Burch.

Another measurement of efficacy is the efficacy-to-harm ratio, which is derived from the number needed to treat and the number needed to harm. To calculate this ratio, however, harm needs to be assessed adequately during a clinical trial. Although the ratio can provide a clinically relevant overview of a drug’s effects, patients may differ from each other in the way they evaluate efficacy and harm.

In addition, many questions about preventive treatment of migraine have no clear answers yet. It is uncertain, for example, how long a patient should receive preventive treatment and when treatment should be withdrawn, said Dr. Burch. “Can we expect that a lot of people are going to need to be on it for life, or is there a subpopulation who will get better and [for whom] we can withdraw [treatment]?” she asked. “How do we identify them?” Also, more data are needed before neurologists can understand why a given patient responds to one treatment, but not to another. It is difficult to predict which patients will respond to which treatments. Finally, it remains unclear how much of patients’ improvement can be attributed to regression to the mean, rather than preventive treatment.

egreb@mdedge.com

STOWE, VT – The preventive treatment of migraine has the potential to change patients’ lives and modify the trajectory of the disease, said Rebecca Burch, MD, staff attending neurologist at Brigham and Women’s Hospital in Boston. Clinical observation suggests that preventive treatment provides benefits for appropriately selected migraineurs, although few data confirm a modifying effect on disease course, she said at the Stowe Headache Symposium sponsored by the Headache Cooperative of New England. In her overview, Dr. Burch discussed when preventive treatment is appropriate, which patients are candidates for preventive therapy, and what the levels of evidence are for the preventive therapies.

Identifying candidates for preventive treatment

Migraine is the second most disabling condition worldwide and imposes a large social and economic burden, said Dr. Burch. Preventive therapy reduces the disability associated with migraine. It reduces headache frequency and, thus, the risk that episodic migraine will transform into chronic migraine. By reducing the number of headache days, preventive treatment also may reduce the overuse of acute medication, which is a risk factor for migraine chronification.

Neurologists can consider preventive therapy for migraineurs with frequent headaches, but the term “frequent” is not clearly defined. Common definitions include one headache per week and two headaches per month with significant disability. These definitions are based on expert consensus and do not have strong evidential support, said Dr. Burch. Preventive therapy also may be appropriate for migraineurs who overuse acute medication or who have failed acute medications. Special cases, such as patients with exceptional anxiety or disability, may also call for preventive treatment, said Dr. Burch.

Data suggest that preventive treatment for migraine is underused. The American Migraine Prevalence and Prevention study of 2007 found that half of patients who should be offered preventive treatment are currently receiving it. In 2016, the Chronic Migraine Epidemiology and Outcomes study found that 4.5% of chronic migraineurs take both acute and preventive treatment.

Other data published in Cephalalgia in 2015 indicate that adherence to migraine preventive treatment is approximately 20%. About 45% of patients discontinue medication because of side effects, and 45% cite lack of efficacy as their reason for discontinuation. Patients also mentioned cost, interactions with other medications, and the inconvenience of daily medication as other reasons for discontinuation.

Neurologists can take several steps to increase adherence to preventive treatment, said Dr. Burch. First, neurologists should confirm that patients want preventive medication. A clear discussion of the goals of preventive treatment is helpful as well. Furthermore, neurologists should explain that they are offering patients a trial, said Dr. Burch. The medication can be titrated slowly from a low dose to minimize side effects. Patients can be reassured that ineffective medications will be stopped. Neurologists can emphasize that their relationship with the patient is a partnership and that the treatment strategy will be improved over time.
 

Examining the evidence on treatments’ efficacy

Many drug classes, such as antiepileptics, antidepressants, beta blockers, neurotoxins, and calcitonin gene-related peptide (CGRP) antibodies, include therapies that are used as preventive treatments for migraine. When selecting a medication, a neurologist should start with one that is supported by Level A or Level B evidence, said Dr. Burch. Medications with Level A evidence include divalproex, topiramate, metoprolol, propranolol, erenumab, galcanezumab, fremanezumab, eptinezumab, and onabotulinumtoxinA. Medications with Level B evidence include amitriptyline, venlafaxine, memantine, lisinopril, and candesartan. Neurologists sometimes prescribe gabapentin and verapamil, although the evidence for them is Level U. Duloxetine, nortriptyline, and pregabalin also are used, but the evidence for them has not been evaluated. “We need more evidence in these areas,” said Dr. Burch.

Neurologists should consider access (e.g., cost and insurance coverage), efficacy, side effects, and comorbidities and contraindications when choosing a preventive therapy, she added. Verapamil and memantine are well tolerated and appropriate choices if the goal is to avoid side effects in general. If weight gain or fatigue is a concern, then topiramate and venlafaxine should be considered. Neurologists should avoid prescribing antiepileptic drugs if cognitive symptoms are a concern, said Dr. Burch. Beta blockers and venlafaxine would be better options in this case.

In clinical trials of CGRP therapies, the rates of adverse events were similar between the active and control arms. “But it’s become fairly clear that the clinical trials did not fully capture the side-effect profile that we are seeing in clinical practice,” said Dr. Burch. In a paper currently in review, she and her colleagues retrospectively studied 241 patients that they had treated with CGRP monoclonal antibodies at their headache center. The most common adverse events were constipation (43%), injection-site reaction (24%), muscle or joint pain (17%), and fatigue (15%). Furthermore, CGRP antagonists were associated with maternal hypertension, fetal growth restriction, and fetal mortality in animal studies. The current recommendation is to avoid CGRP monoclonal antibodies during pregnancy or in any patient who is at risk of becoming pregnant, said Dr. Burch.
 

How should neurologists assess preventive efficacy?

The assessment of a medication’s preventive efficacy “is a moving target in the headache world,” said Dr. Burch. “Historically, we have used headache days per month, and that is still, according to the International Headache Society clinical trials guidelines, how we should be judging whether a medication is working or not. But that doesn’t necessarily tell us what’s going to happen to an individual patient in front of us.”

In 2017, the Institute for Clinical Effectiveness Research compared data for old and new migraine treatments in a network meta-analysis. They all tended to reduce the number of monthly migraine days by one to two, compared with placebo. When one analyzes clinical trials of the drugs using this criterion, “most of these treatments come out about the same,” said Dr. Burch.

More recently, investigators have examined responder rates. They commonly report the proportions of patients who had a reduction in headache days of 50%, 75%, or 100%, for example. To extrapolate responder rates from the trial participants to the general population, a neurologist must know which groups of patients got worse on treatment, said Dr. Burch. Furthermore, the responder rates for older medications are unknown, because they were not examined. This situation makes comparisons of newer and older therapies more complicated.

Phase 3 trials of the CGRP drugs included analyses of the therapies’ 50% responder rates. This rate was about 42% for the 70-mg dose of erenumab and 50% for the 140-mg dose. The 50% responder rates for fremanezumab were 47.7% for the 225-mg dose and 44.4% for the 675-mg dose. In two trials of galcanezumab, the 50% responder rate for the 120-mg dose was approximately 60%, and the rate for the 240-mg dose was about 59%. The 50% responder rates for eptinezumab were 50% for the 100-mg dose and 56% for the 300-mg dose. The 50% responder rate across all trials was around 50%-60% in the active group, which is roughly 25% over the placebo group, said Dr. Burch.

Another measurement of efficacy is the efficacy-to-harm ratio, which is derived from the number needed to treat and the number needed to harm. To calculate this ratio, however, harm needs to be assessed adequately during a clinical trial. Although the ratio can provide a clinically relevant overview of a drug’s effects, patients may differ from each other in the way they evaluate efficacy and harm.

In addition, many questions about preventive treatment of migraine have no clear answers yet. It is uncertain, for example, how long a patient should receive preventive treatment and when treatment should be withdrawn, said Dr. Burch. “Can we expect that a lot of people are going to need to be on it for life, or is there a subpopulation who will get better and [for whom] we can withdraw [treatment]?” she asked. “How do we identify them?” Also, more data are needed before neurologists can understand why a given patient responds to one treatment, but not to another. It is difficult to predict which patients will respond to which treatments. Finally, it remains unclear how much of patients’ improvement can be attributed to regression to the mean, rather than preventive treatment.

egreb@mdedge.com

STOWE, VT – The preventive treatment of migraine has the potential to change patients’ lives and modify the trajectory of the disease, said Rebecca Burch, MD, staff attending neurologist at Brigham and Women’s Hospital in Boston. Clinical observation suggests that preventive treatment provides benefits for appropriately selected migraineurs, although few data confirm a modifying effect on disease course, she said at the Stowe Headache Symposium sponsored by the Headache Cooperative of New England. In her overview, Dr. Burch discussed when preventive treatment is appropriate, which patients are candidates for preventive therapy, and what the levels of evidence are for the preventive therapies.

Identifying candidates for preventive treatment

Migraine is the second most disabling condition worldwide and imposes a large social and economic burden, said Dr. Burch. Preventive therapy reduces the disability associated with migraine. It reduces headache frequency and, thus, the risk that episodic migraine will transform into chronic migraine. By reducing the number of headache days, preventive treatment also may reduce the overuse of acute medication, which is a risk factor for migraine chronification.

Neurologists can consider preventive therapy for migraineurs with frequent headaches, but the term “frequent” is not clearly defined. Common definitions include one headache per week and two headaches per month with significant disability. These definitions are based on expert consensus and do not have strong evidential support, said Dr. Burch. Preventive therapy also may be appropriate for migraineurs who overuse acute medication or who have failed acute medications. Special cases, such as patients with exceptional anxiety or disability, may also call for preventive treatment, said Dr. Burch.

Data suggest that preventive treatment for migraine is underused. The American Migraine Prevalence and Prevention study of 2007 found that half of patients who should be offered preventive treatment are currently receiving it. In 2016, the Chronic Migraine Epidemiology and Outcomes study found that 4.5% of chronic migraineurs take both acute and preventive treatment.

Other data published in Cephalalgia in 2015 indicate that adherence to migraine preventive treatment is approximately 20%. About 45% of patients discontinue medication because of side effects, and 45% cite lack of efficacy as their reason for discontinuation. Patients also mentioned cost, interactions with other medications, and the inconvenience of daily medication as other reasons for discontinuation.

Neurologists can take several steps to increase adherence to preventive treatment, said Dr. Burch. First, neurologists should confirm that patients want preventive medication. A clear discussion of the goals of preventive treatment is helpful as well. Furthermore, neurologists should explain that they are offering patients a trial, said Dr. Burch. The medication can be titrated slowly from a low dose to minimize side effects. Patients can be reassured that ineffective medications will be stopped. Neurologists can emphasize that their relationship with the patient is a partnership and that the treatment strategy will be improved over time.
 

Examining the evidence on treatments’ efficacy

Many drug classes, such as antiepileptics, antidepressants, beta blockers, neurotoxins, and calcitonin gene-related peptide (CGRP) antibodies, include therapies that are used as preventive treatments for migraine. When selecting a medication, a neurologist should start with one that is supported by Level A or Level B evidence, said Dr. Burch. Medications with Level A evidence include divalproex, topiramate, metoprolol, propranolol, erenumab, galcanezumab, fremanezumab, eptinezumab, and onabotulinumtoxinA. Medications with Level B evidence include amitriptyline, venlafaxine, memantine, lisinopril, and candesartan. Neurologists sometimes prescribe gabapentin and verapamil, although the evidence for them is Level U. Duloxetine, nortriptyline, and pregabalin also are used, but the evidence for them has not been evaluated. “We need more evidence in these areas,” said Dr. Burch.

Neurologists should consider access (e.g., cost and insurance coverage), efficacy, side effects, and comorbidities and contraindications when choosing a preventive therapy, she added. Verapamil and memantine are well tolerated and appropriate choices if the goal is to avoid side effects in general. If weight gain or fatigue is a concern, then topiramate and venlafaxine should be considered. Neurologists should avoid prescribing antiepileptic drugs if cognitive symptoms are a concern, said Dr. Burch. Beta blockers and venlafaxine would be better options in this case.

In clinical trials of CGRP therapies, the rates of adverse events were similar between the active and control arms. “But it’s become fairly clear that the clinical trials did not fully capture the side-effect profile that we are seeing in clinical practice,” said Dr. Burch. In a paper currently in review, she and her colleagues retrospectively studied 241 patients that they had treated with CGRP monoclonal antibodies at their headache center. The most common adverse events were constipation (43%), injection-site reaction (24%), muscle or joint pain (17%), and fatigue (15%). Furthermore, CGRP antagonists were associated with maternal hypertension, fetal growth restriction, and fetal mortality in animal studies. The current recommendation is to avoid CGRP monoclonal antibodies during pregnancy or in any patient who is at risk of becoming pregnant, said Dr. Burch.
 

How should neurologists assess preventive efficacy?

The assessment of a medication’s preventive efficacy “is a moving target in the headache world,” said Dr. Burch. “Historically, we have used headache days per month, and that is still, according to the International Headache Society clinical trials guidelines, how we should be judging whether a medication is working or not. But that doesn’t necessarily tell us what’s going to happen to an individual patient in front of us.”

In 2017, the Institute for Clinical Effectiveness Research compared data for old and new migraine treatments in a network meta-analysis. They all tended to reduce the number of monthly migraine days by one to two, compared with placebo. When one analyzes clinical trials of the drugs using this criterion, “most of these treatments come out about the same,” said Dr. Burch.

More recently, investigators have examined responder rates. They commonly report the proportions of patients who had a reduction in headache days of 50%, 75%, or 100%, for example. To extrapolate responder rates from the trial participants to the general population, a neurologist must know which groups of patients got worse on treatment, said Dr. Burch. Furthermore, the responder rates for older medications are unknown, because they were not examined. This situation makes comparisons of newer and older therapies more complicated.

Phase 3 trials of the CGRP drugs included analyses of the therapies’ 50% responder rates. This rate was about 42% for the 70-mg dose of erenumab and 50% for the 140-mg dose. The 50% responder rates for fremanezumab were 47.7% for the 225-mg dose and 44.4% for the 675-mg dose. In two trials of galcanezumab, the 50% responder rate for the 120-mg dose was approximately 60%, and the rate for the 240-mg dose was about 59%. The 50% responder rates for eptinezumab were 50% for the 100-mg dose and 56% for the 300-mg dose. The 50% responder rate across all trials was around 50%-60% in the active group, which is roughly 25% over the placebo group, said Dr. Burch.

Another measurement of efficacy is the efficacy-to-harm ratio, which is derived from the number needed to treat and the number needed to harm. To calculate this ratio, however, harm needs to be assessed adequately during a clinical trial. Although the ratio can provide a clinically relevant overview of a drug’s effects, patients may differ from each other in the way they evaluate efficacy and harm.

In addition, many questions about preventive treatment of migraine have no clear answers yet. It is uncertain, for example, how long a patient should receive preventive treatment and when treatment should be withdrawn, said Dr. Burch. “Can we expect that a lot of people are going to need to be on it for life, or is there a subpopulation who will get better and [for whom] we can withdraw [treatment]?” she asked. “How do we identify them?” Also, more data are needed before neurologists can understand why a given patient responds to one treatment, but not to another. It is difficult to predict which patients will respond to which treatments. Finally, it remains unclear how much of patients’ improvement can be attributed to regression to the mean, rather than preventive treatment.

egreb@mdedge.com

Strict adherence to pathology guidelines for interpreting immumohistochemical (IHC) staining in endometrial cancer samples may miss the opportunity to identify patients with Lynch syndrome, investigators cautioned.

Current College of American Pathologists recommendations say that any partial, indeterminate, or “heterogeneous” IHC staining for DNA mismatch repair proteins (MMRP) should be considered as intact expression staining.

However, a retrospective review of patients with endometrial cancer showed that 3 of 13 patients with Lynch syndrome had a small proportion of staining and would have been considered at low risk for Lynch syndrome if the reporting rules were followed to the letter, according to Courtney J. Riedinger, MD, and colleagues from the University of Tennessee Medical Center in Knoxville.

“IHC staining for mismatch repair proteins is a way to screen for who should get genetic testing [for Lynch syndrome],” Dr. Riedinger said in an interview. “The pathology guidelines say that any expression is intact staining, but we found some tumor specimens that have about only 20% staining, and we found that 3 of 27 patients with a range of 20%-60% expression had Lynch syndrome.”

The findings suggest that genetic testing for Lynch syndrome should be considered in patients with heterogeneous staining for MMRP, Dr. Riedinger and colleagues wrote in an abstract that had been slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled due to the COVID-19 pandemic.A recent systematic review estimated the prevalence of Lynch syndrome in women with endometrial cancer to be 3%. The authors of the review recommended universal screening for Lynch syndrome in women with endometrial cancer (Genet Med. 2019 Oct;21[10]:2167-2180).

As Dr. Riedinger and colleagues noted, screening for Lynch syndrome can be performed clinically with microsatellite instability testing or IHC staining for MMRP.

To determine the frequency of Lynch syndrome in women with endometrial cancer whose samples exhibited heterogeneous staining for MMRP, the investigators conducted a retrospective review.

They identified 455 women who underwent hysterectomy for endometrial cancer during 2012-2017. Of this group, samples from 315 patients had no MMRP loss, 92 had complete loss, and 48 had heterogeneous MMRP staining. Of the latter group, 21 samples were reported as intact, and 27 were reported as heterogeneous.

A total of 13 patients were identified as having Lynch syndrome, including 3 of the 27 patients with reported heterogeneous staining and 10 with reported complete loss of MMRP.

The investigators found the frequency of Lynch syndrome among patients with reported heterogeneous staining was not significantly different than that for patients with complete MMRP loss. In addition, there were no significant differences between samples with heterogeneous or complete loss of staining by type of MMRP.

“Our data suggest genetic testing for Lynch syndrome in patients with heterogeneous IHC staining for MMRP should be considered. Current reporting guidelines regarding MMRP expression in endometrial cancer patients need to be reevaluated,” Dr. Riedinger and colleagues concluded.

Dr. Riedinger reported no conflicts of interest. The study was internally funded.

SOURCE: Riedinger CJ et al. SGO 2020, Abstract 104.

Strict adherence to pathology guidelines for interpreting immumohistochemical (IHC) staining in endometrial cancer samples may miss the opportunity to identify patients with Lynch syndrome, investigators cautioned.

Current College of American Pathologists recommendations say that any partial, indeterminate, or “heterogeneous” IHC staining for DNA mismatch repair proteins (MMRP) should be considered as intact expression staining.

However, a retrospective review of patients with endometrial cancer showed that 3 of 13 patients with Lynch syndrome had a small proportion of staining and would have been considered at low risk for Lynch syndrome if the reporting rules were followed to the letter, according to Courtney J. Riedinger, MD, and colleagues from the University of Tennessee Medical Center in Knoxville.

“IHC staining for mismatch repair proteins is a way to screen for who should get genetic testing [for Lynch syndrome],” Dr. Riedinger said in an interview. “The pathology guidelines say that any expression is intact staining, but we found some tumor specimens that have about only 20% staining, and we found that 3 of 27 patients with a range of 20%-60% expression had Lynch syndrome.”

The findings suggest that genetic testing for Lynch syndrome should be considered in patients with heterogeneous staining for MMRP, Dr. Riedinger and colleagues wrote in an abstract that had been slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled due to the COVID-19 pandemic.A recent systematic review estimated the prevalence of Lynch syndrome in women with endometrial cancer to be 3%. The authors of the review recommended universal screening for Lynch syndrome in women with endometrial cancer (Genet Med. 2019 Oct;21[10]:2167-2180).

As Dr. Riedinger and colleagues noted, screening for Lynch syndrome can be performed clinically with microsatellite instability testing or IHC staining for MMRP.

To determine the frequency of Lynch syndrome in women with endometrial cancer whose samples exhibited heterogeneous staining for MMRP, the investigators conducted a retrospective review.

They identified 455 women who underwent hysterectomy for endometrial cancer during 2012-2017. Of this group, samples from 315 patients had no MMRP loss, 92 had complete loss, and 48 had heterogeneous MMRP staining. Of the latter group, 21 samples were reported as intact, and 27 were reported as heterogeneous.

A total of 13 patients were identified as having Lynch syndrome, including 3 of the 27 patients with reported heterogeneous staining and 10 with reported complete loss of MMRP.

The investigators found the frequency of Lynch syndrome among patients with reported heterogeneous staining was not significantly different than that for patients with complete MMRP loss. In addition, there were no significant differences between samples with heterogeneous or complete loss of staining by type of MMRP.

“Our data suggest genetic testing for Lynch syndrome in patients with heterogeneous IHC staining for MMRP should be considered. Current reporting guidelines regarding MMRP expression in endometrial cancer patients need to be reevaluated,” Dr. Riedinger and colleagues concluded.

Dr. Riedinger reported no conflicts of interest. The study was internally funded.

SOURCE: Riedinger CJ et al. SGO 2020, Abstract 104.

Strict adherence to pathology guidelines for interpreting immumohistochemical (IHC) staining in endometrial cancer samples may miss the opportunity to identify patients with Lynch syndrome, investigators cautioned.

Current College of American Pathologists recommendations say that any partial, indeterminate, or “heterogeneous” IHC staining for DNA mismatch repair proteins (MMRP) should be considered as intact expression staining.

However, a retrospective review of patients with endometrial cancer showed that 3 of 13 patients with Lynch syndrome had a small proportion of staining and would have been considered at low risk for Lynch syndrome if the reporting rules were followed to the letter, according to Courtney J. Riedinger, MD, and colleagues from the University of Tennessee Medical Center in Knoxville.

“IHC staining for mismatch repair proteins is a way to screen for who should get genetic testing [for Lynch syndrome],” Dr. Riedinger said in an interview. “The pathology guidelines say that any expression is intact staining, but we found some tumor specimens that have about only 20% staining, and we found that 3 of 27 patients with a range of 20%-60% expression had Lynch syndrome.”

The findings suggest that genetic testing for Lynch syndrome should be considered in patients with heterogeneous staining for MMRP, Dr. Riedinger and colleagues wrote in an abstract that had been slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled due to the COVID-19 pandemic.A recent systematic review estimated the prevalence of Lynch syndrome in women with endometrial cancer to be 3%. The authors of the review recommended universal screening for Lynch syndrome in women with endometrial cancer (Genet Med. 2019 Oct;21[10]:2167-2180).

As Dr. Riedinger and colleagues noted, screening for Lynch syndrome can be performed clinically with microsatellite instability testing or IHC staining for MMRP.

To determine the frequency of Lynch syndrome in women with endometrial cancer whose samples exhibited heterogeneous staining for MMRP, the investigators conducted a retrospective review.

They identified 455 women who underwent hysterectomy for endometrial cancer during 2012-2017. Of this group, samples from 315 patients had no MMRP loss, 92 had complete loss, and 48 had heterogeneous MMRP staining. Of the latter group, 21 samples were reported as intact, and 27 were reported as heterogeneous.

A total of 13 patients were identified as having Lynch syndrome, including 3 of the 27 patients with reported heterogeneous staining and 10 with reported complete loss of MMRP.

The investigators found the frequency of Lynch syndrome among patients with reported heterogeneous staining was not significantly different than that for patients with complete MMRP loss. In addition, there were no significant differences between samples with heterogeneous or complete loss of staining by type of MMRP.

“Our data suggest genetic testing for Lynch syndrome in patients with heterogeneous IHC staining for MMRP should be considered. Current reporting guidelines regarding MMRP expression in endometrial cancer patients need to be reevaluated,” Dr. Riedinger and colleagues concluded.

Dr. Riedinger reported no conflicts of interest. The study was internally funded.

SOURCE: Riedinger CJ et al. SGO 2020, Abstract 104.