The Food and Drug Administration has approved the first device to help reduce snoring and mild obstructive sleep apnea (OSA) that is used during the day while the patient is awake.

eXciteOSA (Signifier Medical Technologies) is a prescription-only, neuromuscular stimulation device designed to improve tongue muscle function, which, over time, can help prevent the tongue from collapsing backwards and obstructing the airway during sleep, the FDA said.

The eXciteOSA mouthpiece has four electrodes that deliver a series of electrical pulses with rest periods in between. Two electrodes are located above the tongue and two are located below the tongue.

The patient uses the device for 20 minutes once a day while awake for 6 weeks, and once a week thereafter. It is indicated for adults aged 18 and older with snoring and mild OSA.

OSA is marked by the recurring collapse of the upper airways during sleep, intermittently reducing or completely blocking airflow. Common symptoms include snoring, restless sleep and daytime sleepiness. Untreated OSA can lead to serious complications such as cardiovascular disease and cognitive and behavioral disorders.

Continuous positive airway pressure therapy, administered through a face mask that is worn while asleep, is a first-line treatment for OSA.

The eXciteOSA device “offers a new option for the thousands of individuals who experience snoring or mild sleep apnea,” Malvina Eydelman, MD, director, FDA Office of Ophthalmic, Anesthesia, Respiratory, ENT, and Dental Devices, said in a news release.

The FDA reviewed data on the safety and effectiveness of the eXciteOSA device in 115 patients with snoring, including 48 patients with snoring and mild OSA. All patients used the device for 20 minutes once a day for 6 weeks, then stopped using it for 2 weeks before they were reassessed.

Overall, the percentage of time spent snoring at levels louder than 40 decibels was reduced by more than 20% in 87 out of the 115 patients.

In the subset of patients with snoring and mild OSA, the average apnea-hypopnea index score was reduced by 48%, from 10.21 to 5.27, in 41 of 48 patients. Mild OSA is defined as an AHI score greater than 5 but less than 15.

The most common adverse events were excessive salivation, tongue or tooth discomfort, tongue tingling, dental filling sensitivity, metallic taste, gagging, and tight jaw.

Before using the eXciteOSA device, patients should receive a comprehensive dental examination, the FDA said. 

The device should not be used in patients with pacemakers or implanted pacing leads, or women who are pregnant. The device is also contraindicated in patients with temporary or permanent implants, dental braces, intraoral metal prosthesis/restorations, or ulcerations in or around the mouth.

The eXciteOSA device was approved under the de novo premarket review pathway for new low- to moderate-risk devices. More information on the device is available online.

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

The Food and Drug Administration has approved the first device to help reduce snoring and mild obstructive sleep apnea (OSA) that is used during the day while the patient is awake.

eXciteOSA (Signifier Medical Technologies) is a prescription-only, neuromuscular stimulation device designed to improve tongue muscle function, which, over time, can help prevent the tongue from collapsing backwards and obstructing the airway during sleep, the FDA said.

The eXciteOSA mouthpiece has four electrodes that deliver a series of electrical pulses with rest periods in between. Two electrodes are located above the tongue and two are located below the tongue.

The patient uses the device for 20 minutes once a day while awake for 6 weeks, and once a week thereafter. It is indicated for adults aged 18 and older with snoring and mild OSA.

OSA is marked by the recurring collapse of the upper airways during sleep, intermittently reducing or completely blocking airflow. Common symptoms include snoring, restless sleep and daytime sleepiness. Untreated OSA can lead to serious complications such as cardiovascular disease and cognitive and behavioral disorders.

Continuous positive airway pressure therapy, administered through a face mask that is worn while asleep, is a first-line treatment for OSA.

The eXciteOSA device “offers a new option for the thousands of individuals who experience snoring or mild sleep apnea,” Malvina Eydelman, MD, director, FDA Office of Ophthalmic, Anesthesia, Respiratory, ENT, and Dental Devices, said in a news release.

The FDA reviewed data on the safety and effectiveness of the eXciteOSA device in 115 patients with snoring, including 48 patients with snoring and mild OSA. All patients used the device for 20 minutes once a day for 6 weeks, then stopped using it for 2 weeks before they were reassessed.

Overall, the percentage of time spent snoring at levels louder than 40 decibels was reduced by more than 20% in 87 out of the 115 patients.

In the subset of patients with snoring and mild OSA, the average apnea-hypopnea index score was reduced by 48%, from 10.21 to 5.27, in 41 of 48 patients. Mild OSA is defined as an AHI score greater than 5 but less than 15.

The most common adverse events were excessive salivation, tongue or tooth discomfort, tongue tingling, dental filling sensitivity, metallic taste, gagging, and tight jaw.

Before using the eXciteOSA device, patients should receive a comprehensive dental examination, the FDA said. 

The device should not be used in patients with pacemakers or implanted pacing leads, or women who are pregnant. The device is also contraindicated in patients with temporary or permanent implants, dental braces, intraoral metal prosthesis/restorations, or ulcerations in or around the mouth.

The eXciteOSA device was approved under the de novo premarket review pathway for new low- to moderate-risk devices. More information on the device is available online.

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

The Food and Drug Administration has approved the first device to help reduce snoring and mild obstructive sleep apnea (OSA) that is used during the day while the patient is awake.

eXciteOSA (Signifier Medical Technologies) is a prescription-only, neuromuscular stimulation device designed to improve tongue muscle function, which, over time, can help prevent the tongue from collapsing backwards and obstructing the airway during sleep, the FDA said.

The eXciteOSA mouthpiece has four electrodes that deliver a series of electrical pulses with rest periods in between. Two electrodes are located above the tongue and two are located below the tongue.

The patient uses the device for 20 minutes once a day while awake for 6 weeks, and once a week thereafter. It is indicated for adults aged 18 and older with snoring and mild OSA.

OSA is marked by the recurring collapse of the upper airways during sleep, intermittently reducing or completely blocking airflow. Common symptoms include snoring, restless sleep and daytime sleepiness. Untreated OSA can lead to serious complications such as cardiovascular disease and cognitive and behavioral disorders.

Continuous positive airway pressure therapy, administered through a face mask that is worn while asleep, is a first-line treatment for OSA.

The eXciteOSA device “offers a new option for the thousands of individuals who experience snoring or mild sleep apnea,” Malvina Eydelman, MD, director, FDA Office of Ophthalmic, Anesthesia, Respiratory, ENT, and Dental Devices, said in a news release.

The FDA reviewed data on the safety and effectiveness of the eXciteOSA device in 115 patients with snoring, including 48 patients with snoring and mild OSA. All patients used the device for 20 minutes once a day for 6 weeks, then stopped using it for 2 weeks before they were reassessed.

Overall, the percentage of time spent snoring at levels louder than 40 decibels was reduced by more than 20% in 87 out of the 115 patients.

In the subset of patients with snoring and mild OSA, the average apnea-hypopnea index score was reduced by 48%, from 10.21 to 5.27, in 41 of 48 patients. Mild OSA is defined as an AHI score greater than 5 but less than 15.

The most common adverse events were excessive salivation, tongue or tooth discomfort, tongue tingling, dental filling sensitivity, metallic taste, gagging, and tight jaw.

Before using the eXciteOSA device, patients should receive a comprehensive dental examination, the FDA said. 

The device should not be used in patients with pacemakers or implanted pacing leads, or women who are pregnant. The device is also contraindicated in patients with temporary or permanent implants, dental braces, intraoral metal prosthesis/restorations, or ulcerations in or around the mouth.

The eXciteOSA device was approved under the de novo premarket review pathway for new low- to moderate-risk devices. More information on the device is available online.

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

The combination of lenvatinib and pembrolizumab outperforms sunitinib as first-line therapy for advanced clear-cell renal cell carcinoma (RCC), based on findings of the CLEAR trial.

Courtesy of Memorial Sloan Kettering Cancer Center

Results from the phase 3 trial were reported at the 2021 Genitourinary Cancers Symposium (Abstract 269) and simultaneously published in the New England Journal of Medicine.

Early-phase trials have shown the promise of targeting RCC from two angles, with both antiangiogenic therapy and immunotherapy, said presenter Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York.

The CLEAR trial was designed to compare monotherapy with sunitinib to treatment with lenvatinib plus either pembrolizumab or everolimus.

The risk of progression-free survival events was 61% lower with lenvatinib-pembrolizumab and 35% lower with lenvatinib-everolimus, compared with sunitinib. However, only the first combination significantly reduced the risk of death.

Treatment-related adverse events were more common with both combinations but manageable with dose modifications.

“These results support lenvatinib plus pembrolizumab as a potential first-line treatment for patients with advanced RCC,” Dr. Motzer said.

Oncologists will likely soon have a handful of first-line options from which to choose, he acknowledged.

“It is a great situation, that we have made such progress in RCC with IO [immuno-oncology] therapy in the first line with ipilimumab-nivolumab, and now with the IO-TKI [tyrosine kinase inhibitor] combinations,” Dr. Motzer said.

The choice will probably come down to personal preference, experience with the various combinations, and side effect profiles, he speculated.

“I will say, however, that the data with lenvatinib-pembrolizumab is very impressive in terms of the long progression-free survival, in terms of the doubling of response rate to over 70%, in terms of the 16% complete response rate,” he said.
 

Trial details

The CLEAR investigators evenly randomized 1,069 patients with advanced clear-cell RCC who had not received prior systemic therapy to treatment with lenvatinib-pembrolizumab, lenvatinib-everolimus, or sunitinib.

The primary analysis was conducted at a median follow-up of 27 months.

The median progression-free survival was 9.2 months with sunitinib, 23.9 months with lenvatinib-pembrolizumab (hazard ratio, 0.39; P < .001), and 14.7 months with lenvatinib-everolimus (HR for events, 0.65; P < .001).

Findings were similar across key subgroups, including International Metastatic RCC Database Consortium risk groups.

An interim analysis of overall survival showed that patients lived significantly longer with lenvatinib-pembrolizumab versus sunitinib (HR, 0.66; P = .005), with similar benefit across subgroups, except for the favorable risk group.

In contrast, lenvatinib-everolimus did not significantly improve overall survival (HR, 1.15; P = .3). The median overall survival was not reached in any treatment arm.

“To me, this emphasizes the role of IO therapy combinations in the first line. I think you need the IO in the first line to get the dramatic efficacy results that we saw in the CLEAR study,” Dr. Motzer said.

The confirmed objective response rate was 36.1% with sunitinib, 71.0% with lenvatinib-pembrolizumab (relative risk, 1.97; P < .001), and 53.5% with lenvatinib-everolimus (RR, 1.48; P <.001). The median duration of response was 14.6 months, 25.8 months, and 16.6 months, respectively.

Grade 3 or higher treatment-related adverse events occurred in 58.8% of patients in the sunitinib group, 71.6% of the lenvatinib-pembrolizumab group, and 73.0% of the lenvatinib-everolimus group. The higher rates with the combinations likely reflected longer treatment durations, according to Dr. Motzer.

The most common grade 3 or higher events with lenvatinib-pembrolizumab were hypertension (25.3%), diarrhea (8.2%), and proteinuria (7.4%). The most common grade 3 or higher events with lenvatinib-everolimus were hypertension (20.8%), hypertriglyceridemia (10.1%), and diarrhea (9.6%).

“The relatively low rates of hepatic toxicity, lack of myelosuppression, and low rate of high-grade hand-foot syndrome is an attractive feature for lenvatinib in combination,” Dr. Motzer said.
 

Which combination, which sequence?

“Lenvatinib plus pembrolizumab is another novel combination to have in our armamentarium now for first-line clear-cell RCC,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.

Courtesy of Loyola University

CLEAR is the fourth positive trial of combination tyrosine kinase inhibitor therapy and immunotherapy in this setting, although findings and study populations differ somewhat, and longer follow-up is needed, she said.

“None of these combinations have been directly compared to one another, and I don’t believe they will be compared head to head,” Dr. Berg said. “But other characteristics – for example, health-related quality of life, familiarity of the agents for clinicians, and high tumor burden versus slow-growing disease – may become important to choose the best first-line option for our patients.”

The emerging first-line options also raise some questions about the optimal sequencing of agents, according to Dr. Berg.

“If one starts with combination immunotherapy, it becomes an automatic choice to use a VEGF tyrosine kinase inhibitor second line,” she elaborated. “These trials establish that immuno-oncology–tyrosine kinase inhibitor combination therapy is now standard of care, but our second-line choice is less clear. Therefore, data is needed on the most suitable order of therapy for the entire population, as well as specific groups in the future.”

The CLEAR trial was sponsored by Eisai Inc. and Merck Sharp & Dohme Corp. Dr. Motzer disclosed relationships with Eisai, Merck, and many other companies. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.

The combination of lenvatinib and pembrolizumab outperforms sunitinib as first-line therapy for advanced clear-cell renal cell carcinoma (RCC), based on findings of the CLEAR trial.

Courtesy of Memorial Sloan Kettering Cancer Center

Results from the phase 3 trial were reported at the 2021 Genitourinary Cancers Symposium (Abstract 269) and simultaneously published in the New England Journal of Medicine.

Early-phase trials have shown the promise of targeting RCC from two angles, with both antiangiogenic therapy and immunotherapy, said presenter Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York.

The CLEAR trial was designed to compare monotherapy with sunitinib to treatment with lenvatinib plus either pembrolizumab or everolimus.

The risk of progression-free survival events was 61% lower with lenvatinib-pembrolizumab and 35% lower with lenvatinib-everolimus, compared with sunitinib. However, only the first combination significantly reduced the risk of death.

Treatment-related adverse events were more common with both combinations but manageable with dose modifications.

“These results support lenvatinib plus pembrolizumab as a potential first-line treatment for patients with advanced RCC,” Dr. Motzer said.

Oncologists will likely soon have a handful of first-line options from which to choose, he acknowledged.

“It is a great situation, that we have made such progress in RCC with IO [immuno-oncology] therapy in the first line with ipilimumab-nivolumab, and now with the IO-TKI [tyrosine kinase inhibitor] combinations,” Dr. Motzer said.

The choice will probably come down to personal preference, experience with the various combinations, and side effect profiles, he speculated.

“I will say, however, that the data with lenvatinib-pembrolizumab is very impressive in terms of the long progression-free survival, in terms of the doubling of response rate to over 70%, in terms of the 16% complete response rate,” he said.
 

Trial details

The CLEAR investigators evenly randomized 1,069 patients with advanced clear-cell RCC who had not received prior systemic therapy to treatment with lenvatinib-pembrolizumab, lenvatinib-everolimus, or sunitinib.

The primary analysis was conducted at a median follow-up of 27 months.

The median progression-free survival was 9.2 months with sunitinib, 23.9 months with lenvatinib-pembrolizumab (hazard ratio, 0.39; P < .001), and 14.7 months with lenvatinib-everolimus (HR for events, 0.65; P < .001).

Findings were similar across key subgroups, including International Metastatic RCC Database Consortium risk groups.

An interim analysis of overall survival showed that patients lived significantly longer with lenvatinib-pembrolizumab versus sunitinib (HR, 0.66; P = .005), with similar benefit across subgroups, except for the favorable risk group.

In contrast, lenvatinib-everolimus did not significantly improve overall survival (HR, 1.15; P = .3). The median overall survival was not reached in any treatment arm.

“To me, this emphasizes the role of IO therapy combinations in the first line. I think you need the IO in the first line to get the dramatic efficacy results that we saw in the CLEAR study,” Dr. Motzer said.

The confirmed objective response rate was 36.1% with sunitinib, 71.0% with lenvatinib-pembrolizumab (relative risk, 1.97; P < .001), and 53.5% with lenvatinib-everolimus (RR, 1.48; P <.001). The median duration of response was 14.6 months, 25.8 months, and 16.6 months, respectively.

Grade 3 or higher treatment-related adverse events occurred in 58.8% of patients in the sunitinib group, 71.6% of the lenvatinib-pembrolizumab group, and 73.0% of the lenvatinib-everolimus group. The higher rates with the combinations likely reflected longer treatment durations, according to Dr. Motzer.

The most common grade 3 or higher events with lenvatinib-pembrolizumab were hypertension (25.3%), diarrhea (8.2%), and proteinuria (7.4%). The most common grade 3 or higher events with lenvatinib-everolimus were hypertension (20.8%), hypertriglyceridemia (10.1%), and diarrhea (9.6%).

“The relatively low rates of hepatic toxicity, lack of myelosuppression, and low rate of high-grade hand-foot syndrome is an attractive feature for lenvatinib in combination,” Dr. Motzer said.
 

Which combination, which sequence?

“Lenvatinib plus pembrolizumab is another novel combination to have in our armamentarium now for first-line clear-cell RCC,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.

Courtesy of Loyola University

CLEAR is the fourth positive trial of combination tyrosine kinase inhibitor therapy and immunotherapy in this setting, although findings and study populations differ somewhat, and longer follow-up is needed, she said.

“None of these combinations have been directly compared to one another, and I don’t believe they will be compared head to head,” Dr. Berg said. “But other characteristics – for example, health-related quality of life, familiarity of the agents for clinicians, and high tumor burden versus slow-growing disease – may become important to choose the best first-line option for our patients.”

The emerging first-line options also raise some questions about the optimal sequencing of agents, according to Dr. Berg.

“If one starts with combination immunotherapy, it becomes an automatic choice to use a VEGF tyrosine kinase inhibitor second line,” she elaborated. “These trials establish that immuno-oncology–tyrosine kinase inhibitor combination therapy is now standard of care, but our second-line choice is less clear. Therefore, data is needed on the most suitable order of therapy for the entire population, as well as specific groups in the future.”

The CLEAR trial was sponsored by Eisai Inc. and Merck Sharp & Dohme Corp. Dr. Motzer disclosed relationships with Eisai, Merck, and many other companies. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.

The combination of lenvatinib and pembrolizumab outperforms sunitinib as first-line therapy for advanced clear-cell renal cell carcinoma (RCC), based on findings of the CLEAR trial.

Courtesy of Memorial Sloan Kettering Cancer Center

Results from the phase 3 trial were reported at the 2021 Genitourinary Cancers Symposium (Abstract 269) and simultaneously published in the New England Journal of Medicine.

Early-phase trials have shown the promise of targeting RCC from two angles, with both antiangiogenic therapy and immunotherapy, said presenter Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York.

The CLEAR trial was designed to compare monotherapy with sunitinib to treatment with lenvatinib plus either pembrolizumab or everolimus.

The risk of progression-free survival events was 61% lower with lenvatinib-pembrolizumab and 35% lower with lenvatinib-everolimus, compared with sunitinib. However, only the first combination significantly reduced the risk of death.

Treatment-related adverse events were more common with both combinations but manageable with dose modifications.

“These results support lenvatinib plus pembrolizumab as a potential first-line treatment for patients with advanced RCC,” Dr. Motzer said.

Oncologists will likely soon have a handful of first-line options from which to choose, he acknowledged.

“It is a great situation, that we have made such progress in RCC with IO [immuno-oncology] therapy in the first line with ipilimumab-nivolumab, and now with the IO-TKI [tyrosine kinase inhibitor] combinations,” Dr. Motzer said.

The choice will probably come down to personal preference, experience with the various combinations, and side effect profiles, he speculated.

“I will say, however, that the data with lenvatinib-pembrolizumab is very impressive in terms of the long progression-free survival, in terms of the doubling of response rate to over 70%, in terms of the 16% complete response rate,” he said.
 

Trial details

The CLEAR investigators evenly randomized 1,069 patients with advanced clear-cell RCC who had not received prior systemic therapy to treatment with lenvatinib-pembrolizumab, lenvatinib-everolimus, or sunitinib.

The primary analysis was conducted at a median follow-up of 27 months.

The median progression-free survival was 9.2 months with sunitinib, 23.9 months with lenvatinib-pembrolizumab (hazard ratio, 0.39; P < .001), and 14.7 months with lenvatinib-everolimus (HR for events, 0.65; P < .001).

Findings were similar across key subgroups, including International Metastatic RCC Database Consortium risk groups.

An interim analysis of overall survival showed that patients lived significantly longer with lenvatinib-pembrolizumab versus sunitinib (HR, 0.66; P = .005), with similar benefit across subgroups, except for the favorable risk group.

In contrast, lenvatinib-everolimus did not significantly improve overall survival (HR, 1.15; P = .3). The median overall survival was not reached in any treatment arm.

“To me, this emphasizes the role of IO therapy combinations in the first line. I think you need the IO in the first line to get the dramatic efficacy results that we saw in the CLEAR study,” Dr. Motzer said.

The confirmed objective response rate was 36.1% with sunitinib, 71.0% with lenvatinib-pembrolizumab (relative risk, 1.97; P < .001), and 53.5% with lenvatinib-everolimus (RR, 1.48; P <.001). The median duration of response was 14.6 months, 25.8 months, and 16.6 months, respectively.

Grade 3 or higher treatment-related adverse events occurred in 58.8% of patients in the sunitinib group, 71.6% of the lenvatinib-pembrolizumab group, and 73.0% of the lenvatinib-everolimus group. The higher rates with the combinations likely reflected longer treatment durations, according to Dr. Motzer.

The most common grade 3 or higher events with lenvatinib-pembrolizumab were hypertension (25.3%), diarrhea (8.2%), and proteinuria (7.4%). The most common grade 3 or higher events with lenvatinib-everolimus were hypertension (20.8%), hypertriglyceridemia (10.1%), and diarrhea (9.6%).

“The relatively low rates of hepatic toxicity, lack of myelosuppression, and low rate of high-grade hand-foot syndrome is an attractive feature for lenvatinib in combination,” Dr. Motzer said.
 

Which combination, which sequence?

“Lenvatinib plus pembrolizumab is another novel combination to have in our armamentarium now for first-line clear-cell RCC,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.

Courtesy of Loyola University

CLEAR is the fourth positive trial of combination tyrosine kinase inhibitor therapy and immunotherapy in this setting, although findings and study populations differ somewhat, and longer follow-up is needed, she said.

“None of these combinations have been directly compared to one another, and I don’t believe they will be compared head to head,” Dr. Berg said. “But other characteristics – for example, health-related quality of life, familiarity of the agents for clinicians, and high tumor burden versus slow-growing disease – may become important to choose the best first-line option for our patients.”

The emerging first-line options also raise some questions about the optimal sequencing of agents, according to Dr. Berg.

“If one starts with combination immunotherapy, it becomes an automatic choice to use a VEGF tyrosine kinase inhibitor second line,” she elaborated. “These trials establish that immuno-oncology–tyrosine kinase inhibitor combination therapy is now standard of care, but our second-line choice is less clear. Therefore, data is needed on the most suitable order of therapy for the entire population, as well as specific groups in the future.”

The CLEAR trial was sponsored by Eisai Inc. and Merck Sharp & Dohme Corp. Dr. Motzer disclosed relationships with Eisai, Merck, and many other companies. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.

The proportion of family physicians providing care to children from 2017 to 2018 has dropped again, according to new research.

This the latest sign of a long-term decline, and it “poses a broader concern for a specialty that defines itself by its comprehensive scope of practice,” said the study investigators of the Robert Graham Center in Washington, D.C., in a written statement. “This is consistent with previous Robert Graham Center research that reported a similar steady decline from 1992 to 2002.”

Self-reported data from family physicians indicate that 84.3% cared for children aged 18 years and under in 2017, compared with 83.0% in 2018, based on a cross-sectional analysis of data gathered from 11,674 family physicians who completed the practice demographic questionnaire attached to the American Board of Family Medicine’s certification exam in 2017 and 2018.

“This current trend is unsettling, because family physicians provide the majority of pediatric care in rural and pediatrically underserved areas of the United States,” study author Anuradha Jetty, MPH, and coauthors said in the statement.

The analysis also offers a snapshot of the current state of pediatric care offered by family physicians. In 2017 and 2018, FPs were more likely to see patients aged 5-18 years than those under age 5 (83.0% vs. 67.0%), with variation by age, location, and race/ethnicity, said Ms. Jetty and colleagues, in their new paper.

FPs aged 60 years and older were much less likely to see pediatric patients, compared with those under age 40: odds ratios were 0.52 for children under 5 and 0.56 for children 5-18. Regional variation was even more pronounced: Compared with their colleagues in the Southern states, Midwestern FPs were 1.52 times as likely to treat children aged 5-18 and 2.52 times as likely to treat children under age 5, the investigators reported.

Non-Hispanic Asian and Hispanic family physicians had significantly lower odds of seeing pediatric patients, relative to non-Hispanic White family physicians, as did FPs who were international medical graduates (OR, 0.74), compared with those who trained in the United States, they said.

“Female gender was associated with seeing pediatric patients in a prior study using 2006-2009 [American Board of Family Medicine] data; however, we found no such association in 2017-2018,” Ms. Jetty and associates noted.

“Many diverse drivers likely influence the findings we observed, including organizational, personal, social, and economic factors,” they wrote, suggesting that the policies of some HMOs “may limit scope of practice for employed physicians,” while those who practice in areas of low pediatrician density might “capitalize on a market opportunity ... more than physicians in pediatrician-saturated areas with greater competition for young patients.”

The overall shortage of primary pediatric care may be a matter of debate, the investigators said, but “there is undoubtedly significant variability in the regional supply of pediatric primary care physicians and thus areas where family physicians are needed to meet current pediatric workforce demand.”

The authors reported no conflicts.

[email protected]

The proportion of family physicians providing care to children from 2017 to 2018 has dropped again, according to new research.

This the latest sign of a long-term decline, and it “poses a broader concern for a specialty that defines itself by its comprehensive scope of practice,” said the study investigators of the Robert Graham Center in Washington, D.C., in a written statement. “This is consistent with previous Robert Graham Center research that reported a similar steady decline from 1992 to 2002.”

Self-reported data from family physicians indicate that 84.3% cared for children aged 18 years and under in 2017, compared with 83.0% in 2018, based on a cross-sectional analysis of data gathered from 11,674 family physicians who completed the practice demographic questionnaire attached to the American Board of Family Medicine’s certification exam in 2017 and 2018.

“This current trend is unsettling, because family physicians provide the majority of pediatric care in rural and pediatrically underserved areas of the United States,” study author Anuradha Jetty, MPH, and coauthors said in the statement.

The analysis also offers a snapshot of the current state of pediatric care offered by family physicians. In 2017 and 2018, FPs were more likely to see patients aged 5-18 years than those under age 5 (83.0% vs. 67.0%), with variation by age, location, and race/ethnicity, said Ms. Jetty and colleagues, in their new paper.

FPs aged 60 years and older were much less likely to see pediatric patients, compared with those under age 40: odds ratios were 0.52 for children under 5 and 0.56 for children 5-18. Regional variation was even more pronounced: Compared with their colleagues in the Southern states, Midwestern FPs were 1.52 times as likely to treat children aged 5-18 and 2.52 times as likely to treat children under age 5, the investigators reported.

Non-Hispanic Asian and Hispanic family physicians had significantly lower odds of seeing pediatric patients, relative to non-Hispanic White family physicians, as did FPs who were international medical graduates (OR, 0.74), compared with those who trained in the United States, they said.

“Female gender was associated with seeing pediatric patients in a prior study using 2006-2009 [American Board of Family Medicine] data; however, we found no such association in 2017-2018,” Ms. Jetty and associates noted.

“Many diverse drivers likely influence the findings we observed, including organizational, personal, social, and economic factors,” they wrote, suggesting that the policies of some HMOs “may limit scope of practice for employed physicians,” while those who practice in areas of low pediatrician density might “capitalize on a market opportunity ... more than physicians in pediatrician-saturated areas with greater competition for young patients.”

The overall shortage of primary pediatric care may be a matter of debate, the investigators said, but “there is undoubtedly significant variability in the regional supply of pediatric primary care physicians and thus areas where family physicians are needed to meet current pediatric workforce demand.”

The authors reported no conflicts.

[email protected]

The proportion of family physicians providing care to children from 2017 to 2018 has dropped again, according to new research.

This the latest sign of a long-term decline, and it “poses a broader concern for a specialty that defines itself by its comprehensive scope of practice,” said the study investigators of the Robert Graham Center in Washington, D.C., in a written statement. “This is consistent with previous Robert Graham Center research that reported a similar steady decline from 1992 to 2002.”

Self-reported data from family physicians indicate that 84.3% cared for children aged 18 years and under in 2017, compared with 83.0% in 2018, based on a cross-sectional analysis of data gathered from 11,674 family physicians who completed the practice demographic questionnaire attached to the American Board of Family Medicine’s certification exam in 2017 and 2018.

“This current trend is unsettling, because family physicians provide the majority of pediatric care in rural and pediatrically underserved areas of the United States,” study author Anuradha Jetty, MPH, and coauthors said in the statement.

The analysis also offers a snapshot of the current state of pediatric care offered by family physicians. In 2017 and 2018, FPs were more likely to see patients aged 5-18 years than those under age 5 (83.0% vs. 67.0%), with variation by age, location, and race/ethnicity, said Ms. Jetty and colleagues, in their new paper.

FPs aged 60 years and older were much less likely to see pediatric patients, compared with those under age 40: odds ratios were 0.52 for children under 5 and 0.56 for children 5-18. Regional variation was even more pronounced: Compared with their colleagues in the Southern states, Midwestern FPs were 1.52 times as likely to treat children aged 5-18 and 2.52 times as likely to treat children under age 5, the investigators reported.

Non-Hispanic Asian and Hispanic family physicians had significantly lower odds of seeing pediatric patients, relative to non-Hispanic White family physicians, as did FPs who were international medical graduates (OR, 0.74), compared with those who trained in the United States, they said.

“Female gender was associated with seeing pediatric patients in a prior study using 2006-2009 [American Board of Family Medicine] data; however, we found no such association in 2017-2018,” Ms. Jetty and associates noted.

“Many diverse drivers likely influence the findings we observed, including organizational, personal, social, and economic factors,” they wrote, suggesting that the policies of some HMOs “may limit scope of practice for employed physicians,” while those who practice in areas of low pediatrician density might “capitalize on a market opportunity ... more than physicians in pediatrician-saturated areas with greater competition for young patients.”

The overall shortage of primary pediatric care may be a matter of debate, the investigators said, but “there is undoubtedly significant variability in the regional supply of pediatric primary care physicians and thus areas where family physicians are needed to meet current pediatric workforce demand.”

The authors reported no conflicts.

[email protected]

New COVID-19 cases in children continue to drop each week, but the total number of cases has now surpassed 3 million since the start of the pandemic, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

There were just over 99,000 new cases reported during the week of Feb. 5-11, the lowest number since early November and the fourth consecutive week with a decline. It was still enough, though, to bring the total to 3.03 million children infected with SARS-CoV-19 in the United States, the AAP and the CHA said in their weekly report.

The nation also hit a couple of other ignominious milestones. The cumulative rate of COVID-19 infection now stands at 4,030 per 100,000, so 4% of all children have been infected. Also, children represented 16.9% of all new cases for the week, which equals the highest proportion seen throughout the pandemic, based on data from health departments in 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.

There have been 241 COVID-19–related deaths in children so far, with 14 reported during the week of Feb. 5-11. Kansas just recorded its first pediatric death, which leaves 10 states that have had no fatalities. Texas, with 39 deaths, has had more than any other state, among the 43 that are reporting mortality by age, the AAP/CHA report showed.

[email protected]

New COVID-19 cases in children continue to drop each week, but the total number of cases has now surpassed 3 million since the start of the pandemic, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

There were just over 99,000 new cases reported during the week of Feb. 5-11, the lowest number since early November and the fourth consecutive week with a decline. It was still enough, though, to bring the total to 3.03 million children infected with SARS-CoV-19 in the United States, the AAP and the CHA said in their weekly report.

The nation also hit a couple of other ignominious milestones. The cumulative rate of COVID-19 infection now stands at 4,030 per 100,000, so 4% of all children have been infected. Also, children represented 16.9% of all new cases for the week, which equals the highest proportion seen throughout the pandemic, based on data from health departments in 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.

There have been 241 COVID-19–related deaths in children so far, with 14 reported during the week of Feb. 5-11. Kansas just recorded its first pediatric death, which leaves 10 states that have had no fatalities. Texas, with 39 deaths, has had more than any other state, among the 43 that are reporting mortality by age, the AAP/CHA report showed.

[email protected]

New COVID-19 cases in children continue to drop each week, but the total number of cases has now surpassed 3 million since the start of the pandemic, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

There were just over 99,000 new cases reported during the week of Feb. 5-11, the lowest number since early November and the fourth consecutive week with a decline. It was still enough, though, to bring the total to 3.03 million children infected with SARS-CoV-19 in the United States, the AAP and the CHA said in their weekly report.

The nation also hit a couple of other ignominious milestones. The cumulative rate of COVID-19 infection now stands at 4,030 per 100,000, so 4% of all children have been infected. Also, children represented 16.9% of all new cases for the week, which equals the highest proportion seen throughout the pandemic, based on data from health departments in 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.

There have been 241 COVID-19–related deaths in children so far, with 14 reported during the week of Feb. 5-11. Kansas just recorded its first pediatric death, which leaves 10 states that have had no fatalities. Texas, with 39 deaths, has had more than any other state, among the 43 that are reporting mortality by age, the AAP/CHA report showed.

[email protected]

The Food and Drug Administration has approved a groundbreaking expanded indication for sacubitril/valsartan (Entresto), making it the first drug in the United States indicated for chronic heart failure not specifically characterized by ejection fraction.

The new labeling, as provided by Novartis, grants physicians a good deal of discretion in prescribing sacubitril/valsartan for patients with HF beyond those with HF and reduced ejection fraction (HFrEF), for which the drug was approved in 2015 primarily on the basis of the PARADIGM-HF trial.

The indication now reads, “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.”

Of note, the labeling cautions that “LVEF is a variable measure, so use clinical judgment in deciding whom to treat.”

The expanded indication essentially extends the sacubitril/valsartan option to many patients with HF and preserved LVEF (HFpEF), who in practice are most likely to have an LVEF in the range adjacent to “reduced,” long defined as “preserved” but lately categorized as “mid-range.”

But the FDA did not get so specific. In granting the expanded indication, which Novartis announced Feb. 16 in a press release, the agency accommodated the Dec. 15 majority recommendation of its Cardiovascular and Renal Drugs Advisory Committee that the PARAGON-HF trial “provided sufficient evidence to support” an indication beyond HFrEF.

The nature of the PARAGON-HF trial, along with detailed discussion among committee members after their vote tally, made it clear that the 12-to-1 majority favored an indication that would include clinically appropriate patients with “below normal” LVEF.

PARAGON-HF had assigned more than 4,800 patients whose LVEF was 45% or higher and were in NYHA class 2-4 to receive sacubitril/valsartan or valsartan only. Those taking the combo drug showed a 13% drop in risk for HF hospitalization or cardiovascular deaths over an average of 3 years, which narrowly missed significance (P = .059).

But a subgroup analysis garnered attention for its hint of benefit for patients with “mid-range” LVEF, in this case, below the median of 57%. The finding was supported by a later PARAGON-HF and PARADIGM-HF meta-analysis that pointed to a significant benefit for patients with HFpEF at its lowest LVEF levels, especially in women.

The expanded approval “is a significant advancement, providing a treatment to many patients who were not eligible for treatment before, because their ejection fraction was above the region we normally considered reduced,” Scott Solomon, MD, of Brigham and Women’s Hospital, Boston, said in the Novartis press release. “We can now offer a treatment to a wider range of patients who have an LVEF below normal,” added Dr. Solomon, PARAGON-HF executive committee cochair.

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

The Food and Drug Administration has approved a groundbreaking expanded indication for sacubitril/valsartan (Entresto), making it the first drug in the United States indicated for chronic heart failure not specifically characterized by ejection fraction.

The new labeling, as provided by Novartis, grants physicians a good deal of discretion in prescribing sacubitril/valsartan for patients with HF beyond those with HF and reduced ejection fraction (HFrEF), for which the drug was approved in 2015 primarily on the basis of the PARADIGM-HF trial.

The indication now reads, “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.”

Of note, the labeling cautions that “LVEF is a variable measure, so use clinical judgment in deciding whom to treat.”

The expanded indication essentially extends the sacubitril/valsartan option to many patients with HF and preserved LVEF (HFpEF), who in practice are most likely to have an LVEF in the range adjacent to “reduced,” long defined as “preserved” but lately categorized as “mid-range.”

But the FDA did not get so specific. In granting the expanded indication, which Novartis announced Feb. 16 in a press release, the agency accommodated the Dec. 15 majority recommendation of its Cardiovascular and Renal Drugs Advisory Committee that the PARAGON-HF trial “provided sufficient evidence to support” an indication beyond HFrEF.

The nature of the PARAGON-HF trial, along with detailed discussion among committee members after their vote tally, made it clear that the 12-to-1 majority favored an indication that would include clinically appropriate patients with “below normal” LVEF.

PARAGON-HF had assigned more than 4,800 patients whose LVEF was 45% or higher and were in NYHA class 2-4 to receive sacubitril/valsartan or valsartan only. Those taking the combo drug showed a 13% drop in risk for HF hospitalization or cardiovascular deaths over an average of 3 years, which narrowly missed significance (P = .059).

But a subgroup analysis garnered attention for its hint of benefit for patients with “mid-range” LVEF, in this case, below the median of 57%. The finding was supported by a later PARAGON-HF and PARADIGM-HF meta-analysis that pointed to a significant benefit for patients with HFpEF at its lowest LVEF levels, especially in women.

The expanded approval “is a significant advancement, providing a treatment to many patients who were not eligible for treatment before, because their ejection fraction was above the region we normally considered reduced,” Scott Solomon, MD, of Brigham and Women’s Hospital, Boston, said in the Novartis press release. “We can now offer a treatment to a wider range of patients who have an LVEF below normal,” added Dr. Solomon, PARAGON-HF executive committee cochair.

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

The Food and Drug Administration has approved a groundbreaking expanded indication for sacubitril/valsartan (Entresto), making it the first drug in the United States indicated for chronic heart failure not specifically characterized by ejection fraction.

The new labeling, as provided by Novartis, grants physicians a good deal of discretion in prescribing sacubitril/valsartan for patients with HF beyond those with HF and reduced ejection fraction (HFrEF), for which the drug was approved in 2015 primarily on the basis of the PARADIGM-HF trial.

The indication now reads, “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.”

Of note, the labeling cautions that “LVEF is a variable measure, so use clinical judgment in deciding whom to treat.”

The expanded indication essentially extends the sacubitril/valsartan option to many patients with HF and preserved LVEF (HFpEF), who in practice are most likely to have an LVEF in the range adjacent to “reduced,” long defined as “preserved” but lately categorized as “mid-range.”

But the FDA did not get so specific. In granting the expanded indication, which Novartis announced Feb. 16 in a press release, the agency accommodated the Dec. 15 majority recommendation of its Cardiovascular and Renal Drugs Advisory Committee that the PARAGON-HF trial “provided sufficient evidence to support” an indication beyond HFrEF.

The nature of the PARAGON-HF trial, along with detailed discussion among committee members after their vote tally, made it clear that the 12-to-1 majority favored an indication that would include clinically appropriate patients with “below normal” LVEF.

PARAGON-HF had assigned more than 4,800 patients whose LVEF was 45% or higher and were in NYHA class 2-4 to receive sacubitril/valsartan or valsartan only. Those taking the combo drug showed a 13% drop in risk for HF hospitalization or cardiovascular deaths over an average of 3 years, which narrowly missed significance (P = .059).

But a subgroup analysis garnered attention for its hint of benefit for patients with “mid-range” LVEF, in this case, below the median of 57%. The finding was supported by a later PARAGON-HF and PARADIGM-HF meta-analysis that pointed to a significant benefit for patients with HFpEF at its lowest LVEF levels, especially in women.

The expanded approval “is a significant advancement, providing a treatment to many patients who were not eligible for treatment before, because their ejection fraction was above the region we normally considered reduced,” Scott Solomon, MD, of Brigham and Women’s Hospital, Boston, said in the Novartis press release. “We can now offer a treatment to a wider range of patients who have an LVEF below normal,” added Dr. Solomon, PARAGON-HF executive committee cochair.

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

The potent anabolic, antiosteoporosis agent romosozumab has been saddled with an Food and Drug Administration–mandated black-box warning for increased cardiovascular risk that may not be warranted, Glenn Haugeberg, MD, PhD, asserted at the 2021 Rheumatology Winter Clinical Symposium.

ogichobanov/iStock/Getty Images Plus

The black-box warning states that romosozumab (Evenity), a monoclonal antibody approved in 2019 for fracture prevention in patients with osteoporosis, may increase the risk of MI, stroke, and cardiovascular death. The warning arose from FDA concerns raised by the results of the phase 3 ARCH trial in which 4,093 postmenopausal women at high fracture risk were randomized to monthly subcutaneous injections of romosozumab or weekly dosing of the oral bisphosphonate alendronate (Fosamax) for 1 year, followed by 12 months of open-label alendronate for all. Alarm bells went off at the FDA because during year 1, the incidence of adjudicated major adverse cardiovascular events was 2.5% in the romosozumab arm, compared with 1.9% with alendronate.
 

Could a cardioprotective effect of bisphosphonates explain cardiovascular concerns?

However, evidence from multiple animal and human studies suggests that bisphosphonates actually have a cardioprotective effect. For example, a Taiwanese population-based cohort study of 1,548 patients on bisphosphonate therapy for osteoporotic fractures and 4,644 individuals with hip or vertebral fractures who were not on a bisphosphonate showed a 65% reduction in the risk of acute MI during 2 years of follow-up in those who received a bisphosphonate.

“That may explain the ARCH finding. It may – I say may – be that this concern in the ARCH study can be explained by the positive effect of the bisphosphonates on cardiovascular events,” according to Dr. Haugeberg, head of the division of rheumatology at the Southern Norway Hospital Trust, Kristiansand, and professor of medicine at the Norwegian University of Science and Technology, Trondheim.

He noted that, in the FRAME trial, another pivotal phase 3 trial of romosozumab, there was no signal of increased cardiovascular risk, compared with placebo. In FRAME, which included 7,180 osteoporotic postmenopausal women, rates of major adverse cardiovascular events and other adverse events were balanced between the two study arms at 12 months. Indeed, the incidence of adjudicated serious cardiovascular events was 0.5% with romosozumab and 0.4% with placebo injections. After 12 months, all participants were transitioned to denosumab (Prolia) for another 12 months. At 24 months, there remained no significant between-group difference in cardiovascular events, cancer, osteoarthritis, hyperostosis, or other major adverse events.
 

Potency of romosozumab

Romosozumab’s efficacy for fracture prevention in these two pivotal trials was striking. The risk of new vertebral fractures was reduced by 73% with romosozumab, compared with placebo at 12 months in FRAME, and by 75% at 24 months in the romosozumab-to-denosumab group.

“FRAME was a 12-month study for the primary endpoint. The bisphosphonate studies typically had a 3-year design in order to show benefit, but here you see only 12-month follow-up. This illustrates the potency of this drug. We saw rapid increase in bone density and a huge decrease in new vertebral fractures versus placebo in the first 12 months, then during follow-up with denosumab the reduction in fractures was maintained,” the rheumatologist commented.

In the ARCH trial, where romosozumab went head to head with a very effective oral bisphosphonate, the risk of new vertebral fractures was 48% lower at 24 months in the romosozumab-to-alendronate group than in women on alendronate for the full 24 months, while the risk of hip fractures was reduced by 38%.

Romosozumab is a humanized monoclonal antibody with a novel mechanism of anabolic action: This agent binds to sclerostin, which is produced in osteocytes. When sclerostin binds to receptors on osteoblasts it reduces their activity, thereby inhibiting bone formation. Romosozumab takes away this inhibition of osteoblasts, boosting their activity. The result is increased bone formation accompanied by decreased bone resorption. This allows for a logical treatment approach: first using an anabolic agent – in this instance, subcutaneously injected romosozumab at 210 mg once monthly for 12 months – then switching to an antiresorptive agent in order to maintain the gain in bone mineral density and decrease fracture risk. This is the same treatment strategy recommended when using the anabolic agents teriparatide (Forteo) and abaloparatide (Tymlos); however, those parathyroid hormone and parathyroid hormone–related protein analogs are seldom used in Norway because their cost is substantially greater than for romosozumab, he explained.

Updated Endocrine Society guidelines

Dr. Haugeberg called romosozumab “a new and wonderful drug.” The Endocrine Society also considers romosozumab an important new drug, as evidenced by the release of an 8-page update of the group’s clinical practice guideline on the pharmacologic management of osteoporosis in postmenopausal women; the update was devoted specifically to the use of romosozumab. The update, published in response to the biologic’s recent approval by U.S., Canadian, and European regulatory agencies, came just 10 months after release of the Endocrine Society’s comprehensive 28-page clinical practice guideline.

Dr. Haugeberg is a fan of the Endocrine Society guideline, which recommends romosozumab as a first-line therapy in postmenopausal women at very high risk of osteoporotic fracture, defined as those with a history of multiple vertebral fractures or severe osteoporosis with a T score of –2.5 or less at the hip or spine plus fractures. The updated guideline also recommends consideration of the antisclerostin biologic in high-risk patients who have failed on antiresorptive treatments.

The practice guideline states that the issue of a possible cardioprotective effect of alendronate in the ARCH trial “remains uncertain at this time.”

“Women at high risk of cardiovascular disease and stroke should not be considered for romosozumab pending further studies on cardiovascular risk associated with this treatment,” according to the Endocrine Society.

Dr. Haugeberg reported receiving research grants from Pfizer and Biogen and serving as a consultant to and/or on speakers’ bureaus for Amgen, which markets romosozumab, and more than a dozen other pharmaceutical companies.

[email protected]

The potent anabolic, antiosteoporosis agent romosozumab has been saddled with an Food and Drug Administration–mandated black-box warning for increased cardiovascular risk that may not be warranted, Glenn Haugeberg, MD, PhD, asserted at the 2021 Rheumatology Winter Clinical Symposium.

ogichobanov/iStock/Getty Images Plus

The black-box warning states that romosozumab (Evenity), a monoclonal antibody approved in 2019 for fracture prevention in patients with osteoporosis, may increase the risk of MI, stroke, and cardiovascular death. The warning arose from FDA concerns raised by the results of the phase 3 ARCH trial in which 4,093 postmenopausal women at high fracture risk were randomized to monthly subcutaneous injections of romosozumab or weekly dosing of the oral bisphosphonate alendronate (Fosamax) for 1 year, followed by 12 months of open-label alendronate for all. Alarm bells went off at the FDA because during year 1, the incidence of adjudicated major adverse cardiovascular events was 2.5% in the romosozumab arm, compared with 1.9% with alendronate.
 

Could a cardioprotective effect of bisphosphonates explain cardiovascular concerns?

However, evidence from multiple animal and human studies suggests that bisphosphonates actually have a cardioprotective effect. For example, a Taiwanese population-based cohort study of 1,548 patients on bisphosphonate therapy for osteoporotic fractures and 4,644 individuals with hip or vertebral fractures who were not on a bisphosphonate showed a 65% reduction in the risk of acute MI during 2 years of follow-up in those who received a bisphosphonate.

“That may explain the ARCH finding. It may – I say may – be that this concern in the ARCH study can be explained by the positive effect of the bisphosphonates on cardiovascular events,” according to Dr. Haugeberg, head of the division of rheumatology at the Southern Norway Hospital Trust, Kristiansand, and professor of medicine at the Norwegian University of Science and Technology, Trondheim.

He noted that, in the FRAME trial, another pivotal phase 3 trial of romosozumab, there was no signal of increased cardiovascular risk, compared with placebo. In FRAME, which included 7,180 osteoporotic postmenopausal women, rates of major adverse cardiovascular events and other adverse events were balanced between the two study arms at 12 months. Indeed, the incidence of adjudicated serious cardiovascular events was 0.5% with romosozumab and 0.4% with placebo injections. After 12 months, all participants were transitioned to denosumab (Prolia) for another 12 months. At 24 months, there remained no significant between-group difference in cardiovascular events, cancer, osteoarthritis, hyperostosis, or other major adverse events.
 

Potency of romosozumab

Romosozumab’s efficacy for fracture prevention in these two pivotal trials was striking. The risk of new vertebral fractures was reduced by 73% with romosozumab, compared with placebo at 12 months in FRAME, and by 75% at 24 months in the romosozumab-to-denosumab group.

“FRAME was a 12-month study for the primary endpoint. The bisphosphonate studies typically had a 3-year design in order to show benefit, but here you see only 12-month follow-up. This illustrates the potency of this drug. We saw rapid increase in bone density and a huge decrease in new vertebral fractures versus placebo in the first 12 months, then during follow-up with denosumab the reduction in fractures was maintained,” the rheumatologist commented.

In the ARCH trial, where romosozumab went head to head with a very effective oral bisphosphonate, the risk of new vertebral fractures was 48% lower at 24 months in the romosozumab-to-alendronate group than in women on alendronate for the full 24 months, while the risk of hip fractures was reduced by 38%.

Romosozumab is a humanized monoclonal antibody with a novel mechanism of anabolic action: This agent binds to sclerostin, which is produced in osteocytes. When sclerostin binds to receptors on osteoblasts it reduces their activity, thereby inhibiting bone formation. Romosozumab takes away this inhibition of osteoblasts, boosting their activity. The result is increased bone formation accompanied by decreased bone resorption. This allows for a logical treatment approach: first using an anabolic agent – in this instance, subcutaneously injected romosozumab at 210 mg once monthly for 12 months – then switching to an antiresorptive agent in order to maintain the gain in bone mineral density and decrease fracture risk. This is the same treatment strategy recommended when using the anabolic agents teriparatide (Forteo) and abaloparatide (Tymlos); however, those parathyroid hormone and parathyroid hormone–related protein analogs are seldom used in Norway because their cost is substantially greater than for romosozumab, he explained.

Updated Endocrine Society guidelines

Dr. Haugeberg called romosozumab “a new and wonderful drug.” The Endocrine Society also considers romosozumab an important new drug, as evidenced by the release of an 8-page update of the group’s clinical practice guideline on the pharmacologic management of osteoporosis in postmenopausal women; the update was devoted specifically to the use of romosozumab. The update, published in response to the biologic’s recent approval by U.S., Canadian, and European regulatory agencies, came just 10 months after release of the Endocrine Society’s comprehensive 28-page clinical practice guideline.

Dr. Haugeberg is a fan of the Endocrine Society guideline, which recommends romosozumab as a first-line therapy in postmenopausal women at very high risk of osteoporotic fracture, defined as those with a history of multiple vertebral fractures or severe osteoporosis with a T score of –2.5 or less at the hip or spine plus fractures. The updated guideline also recommends consideration of the antisclerostin biologic in high-risk patients who have failed on antiresorptive treatments.

The practice guideline states that the issue of a possible cardioprotective effect of alendronate in the ARCH trial “remains uncertain at this time.”

“Women at high risk of cardiovascular disease and stroke should not be considered for romosozumab pending further studies on cardiovascular risk associated with this treatment,” according to the Endocrine Society.

Dr. Haugeberg reported receiving research grants from Pfizer and Biogen and serving as a consultant to and/or on speakers’ bureaus for Amgen, which markets romosozumab, and more than a dozen other pharmaceutical companies.

[email protected]

The potent anabolic, antiosteoporosis agent romosozumab has been saddled with an Food and Drug Administration–mandated black-box warning for increased cardiovascular risk that may not be warranted, Glenn Haugeberg, MD, PhD, asserted at the 2021 Rheumatology Winter Clinical Symposium.

ogichobanov/iStock/Getty Images Plus

The black-box warning states that romosozumab (Evenity), a monoclonal antibody approved in 2019 for fracture prevention in patients with osteoporosis, may increase the risk of MI, stroke, and cardiovascular death. The warning arose from FDA concerns raised by the results of the phase 3 ARCH trial in which 4,093 postmenopausal women at high fracture risk were randomized to monthly subcutaneous injections of romosozumab or weekly dosing of the oral bisphosphonate alendronate (Fosamax) for 1 year, followed by 12 months of open-label alendronate for all. Alarm bells went off at the FDA because during year 1, the incidence of adjudicated major adverse cardiovascular events was 2.5% in the romosozumab arm, compared with 1.9% with alendronate.
 

Could a cardioprotective effect of bisphosphonates explain cardiovascular concerns?

However, evidence from multiple animal and human studies suggests that bisphosphonates actually have a cardioprotective effect. For example, a Taiwanese population-based cohort study of 1,548 patients on bisphosphonate therapy for osteoporotic fractures and 4,644 individuals with hip or vertebral fractures who were not on a bisphosphonate showed a 65% reduction in the risk of acute MI during 2 years of follow-up in those who received a bisphosphonate.

“That may explain the ARCH finding. It may – I say may – be that this concern in the ARCH study can be explained by the positive effect of the bisphosphonates on cardiovascular events,” according to Dr. Haugeberg, head of the division of rheumatology at the Southern Norway Hospital Trust, Kristiansand, and professor of medicine at the Norwegian University of Science and Technology, Trondheim.

He noted that, in the FRAME trial, another pivotal phase 3 trial of romosozumab, there was no signal of increased cardiovascular risk, compared with placebo. In FRAME, which included 7,180 osteoporotic postmenopausal women, rates of major adverse cardiovascular events and other adverse events were balanced between the two study arms at 12 months. Indeed, the incidence of adjudicated serious cardiovascular events was 0.5% with romosozumab and 0.4% with placebo injections. After 12 months, all participants were transitioned to denosumab (Prolia) for another 12 months. At 24 months, there remained no significant between-group difference in cardiovascular events, cancer, osteoarthritis, hyperostosis, or other major adverse events.
 

Potency of romosozumab

Romosozumab’s efficacy for fracture prevention in these two pivotal trials was striking. The risk of new vertebral fractures was reduced by 73% with romosozumab, compared with placebo at 12 months in FRAME, and by 75% at 24 months in the romosozumab-to-denosumab group.

“FRAME was a 12-month study for the primary endpoint. The bisphosphonate studies typically had a 3-year design in order to show benefit, but here you see only 12-month follow-up. This illustrates the potency of this drug. We saw rapid increase in bone density and a huge decrease in new vertebral fractures versus placebo in the first 12 months, then during follow-up with denosumab the reduction in fractures was maintained,” the rheumatologist commented.

In the ARCH trial, where romosozumab went head to head with a very effective oral bisphosphonate, the risk of new vertebral fractures was 48% lower at 24 months in the romosozumab-to-alendronate group than in women on alendronate for the full 24 months, while the risk of hip fractures was reduced by 38%.

Romosozumab is a humanized monoclonal antibody with a novel mechanism of anabolic action: This agent binds to sclerostin, which is produced in osteocytes. When sclerostin binds to receptors on osteoblasts it reduces their activity, thereby inhibiting bone formation. Romosozumab takes away this inhibition of osteoblasts, boosting their activity. The result is increased bone formation accompanied by decreased bone resorption. This allows for a logical treatment approach: first using an anabolic agent – in this instance, subcutaneously injected romosozumab at 210 mg once monthly for 12 months – then switching to an antiresorptive agent in order to maintain the gain in bone mineral density and decrease fracture risk. This is the same treatment strategy recommended when using the anabolic agents teriparatide (Forteo) and abaloparatide (Tymlos); however, those parathyroid hormone and parathyroid hormone–related protein analogs are seldom used in Norway because their cost is substantially greater than for romosozumab, he explained.

Updated Endocrine Society guidelines

Dr. Haugeberg called romosozumab “a new and wonderful drug.” The Endocrine Society also considers romosozumab an important new drug, as evidenced by the release of an 8-page update of the group’s clinical practice guideline on the pharmacologic management of osteoporosis in postmenopausal women; the update was devoted specifically to the use of romosozumab. The update, published in response to the biologic’s recent approval by U.S., Canadian, and European regulatory agencies, came just 10 months after release of the Endocrine Society’s comprehensive 28-page clinical practice guideline.

Dr. Haugeberg is a fan of the Endocrine Society guideline, which recommends romosozumab as a first-line therapy in postmenopausal women at very high risk of osteoporotic fracture, defined as those with a history of multiple vertebral fractures or severe osteoporosis with a T score of –2.5 or less at the hip or spine plus fractures. The updated guideline also recommends consideration of the antisclerostin biologic in high-risk patients who have failed on antiresorptive treatments.

The practice guideline states that the issue of a possible cardioprotective effect of alendronate in the ARCH trial “remains uncertain at this time.”

“Women at high risk of cardiovascular disease and stroke should not be considered for romosozumab pending further studies on cardiovascular risk associated with this treatment,” according to the Endocrine Society.

Dr. Haugeberg reported receiving research grants from Pfizer and Biogen and serving as a consultant to and/or on speakers’ bureaus for Amgen, which markets romosozumab, and more than a dozen other pharmaceutical companies.

[email protected]

The American Academy of Dermatology has announced a 3-year, multifaceted initiative to improve diversity, equity, and inclusion not only within the academy itself, but also in the profession of dermatology overall.

“Last year’s events surrounding social justice issues and the disproportionate impact of COVID-19 on minority communities underscored an urgent need for the academy to outline a strategy to address gaps in diversity, equity, and inclusion across the academy’s programs, provide better access to dermatologic care, and expand the pipeline for prospective dermatologists,” according to an AAD statement introducing the plan.

“The AAD has long recognized the importance of fostering diversity in the dermatology specialty and increasing dermatologic services to underserved populations as a key strategic goal,” Kanya Ferguson, MD, chair of the AAD’s diversity committee, said in an interview.

“The importance and urgency of furthering these goals have been underscored by the social justice events of 2020 and the disproportionate impact that COVID-19 has had, specifically on Black and Latino communities,” added Dr. Ferguson, of the department of dermatology, at the University of Iowa, Iowa City. “The 3-year plan comprehensively expands current diversity, equity, and inclusion initiatives in an effort to accelerate the Academy’s progress toward its strategic goals.”

“Numerous barriers persist that contribute to the narrowing pipeline in medicine and ultimately in dermatology,” Dr. Ferguson noted. “The AAD’s diversity, equity, and inclusion initiatives, toolkits, and resources aim to address some of these barriers through early exposure, pipeline programming, and mentorship.”

As for the next steps, “the diversity committee will be working hard over the next few years to coordinate the integration and adoption of initiatives throughout the Academy’s activities,” she added. “This work will take a significant amount of collaboration and the committee is excited to move this forward in a meaningful and sustainable way.”

The AAD’s diversity committee headed the development of the plan, unanimously approved by the AAD’s board of directors, which outlines four key goals for the next 3 years, presented in the Diversity in Dermatology plan as follows:

“Promote and facilitate diversity, equity, and inclusion within the AAD.” Steps toward this goal include facilitating diverse representation on AAD committees, councils, and task forces, increasing representation of skin of color session speakers and lecture topics at Academy meetings, and ensuring equity in the selection process for awards including the Leadership Forum, Academic Dermatology Leadership Program, Advanced Leadership Forum, Journal of the AAD Editorial Mentorship Program, and other leadership activities.

• “Ensure dermatologic education and research encompasses health disparities and skin of color, and advocate for Black and Latino patient representation in research.” Steps toward this goal include increasing use of images reflecting the full spectrum of skin types, ensuring that skin of color populations receive information about dermatologic diseases, and supporting underrepresented minority (URM) dermatology physician scientists in leadership and professional development.
• “Expand Academy’s Advocacy Priorities to prioritize addressing health inequities.” Steps toward this goal include prioritizing issues that affect minority and marginalized populations, establishing relationships with relevant congressional leadership, and advocating for patient support groups for diseases that disproportionately impact skin of color patients.
• “Increase the number of practicing dermatologists who are underrepresented minorities and provide leadership and professional development programming.” Steps toward this goal include expanding the AAD mentorship program to include physician scientists, expanding diversity champion programs, expanding outreach to URM college students in STEM majors, and launching an AAD Summer Diversity & Inclusion camp for younger students to promote interest in a medical career.

The AAD diversity committee also has assembled a toolkit of resources designed to help its members learn how to talk about race, be an effective ally, and achieve cultural competency. Additional updated resources include guidelines on mentorship and outreach.

The American Academy of Dermatology has announced a 3-year, multifaceted initiative to improve diversity, equity, and inclusion not only within the academy itself, but also in the profession of dermatology overall.

“Last year’s events surrounding social justice issues and the disproportionate impact of COVID-19 on minority communities underscored an urgent need for the academy to outline a strategy to address gaps in diversity, equity, and inclusion across the academy’s programs, provide better access to dermatologic care, and expand the pipeline for prospective dermatologists,” according to an AAD statement introducing the plan.

“The AAD has long recognized the importance of fostering diversity in the dermatology specialty and increasing dermatologic services to underserved populations as a key strategic goal,” Kanya Ferguson, MD, chair of the AAD’s diversity committee, said in an interview.

“The importance and urgency of furthering these goals have been underscored by the social justice events of 2020 and the disproportionate impact that COVID-19 has had, specifically on Black and Latino communities,” added Dr. Ferguson, of the department of dermatology, at the University of Iowa, Iowa City. “The 3-year plan comprehensively expands current diversity, equity, and inclusion initiatives in an effort to accelerate the Academy’s progress toward its strategic goals.”

“Numerous barriers persist that contribute to the narrowing pipeline in medicine and ultimately in dermatology,” Dr. Ferguson noted. “The AAD’s diversity, equity, and inclusion initiatives, toolkits, and resources aim to address some of these barriers through early exposure, pipeline programming, and mentorship.”

As for the next steps, “the diversity committee will be working hard over the next few years to coordinate the integration and adoption of initiatives throughout the Academy’s activities,” she added. “This work will take a significant amount of collaboration and the committee is excited to move this forward in a meaningful and sustainable way.”

The AAD’s diversity committee headed the development of the plan, unanimously approved by the AAD’s board of directors, which outlines four key goals for the next 3 years, presented in the Diversity in Dermatology plan as follows:

“Promote and facilitate diversity, equity, and inclusion within the AAD.” Steps toward this goal include facilitating diverse representation on AAD committees, councils, and task forces, increasing representation of skin of color session speakers and lecture topics at Academy meetings, and ensuring equity in the selection process for awards including the Leadership Forum, Academic Dermatology Leadership Program, Advanced Leadership Forum, Journal of the AAD Editorial Mentorship Program, and other leadership activities.

• “Ensure dermatologic education and research encompasses health disparities and skin of color, and advocate for Black and Latino patient representation in research.” Steps toward this goal include increasing use of images reflecting the full spectrum of skin types, ensuring that skin of color populations receive information about dermatologic diseases, and supporting underrepresented minority (URM) dermatology physician scientists in leadership and professional development.
• “Expand Academy’s Advocacy Priorities to prioritize addressing health inequities.” Steps toward this goal include prioritizing issues that affect minority and marginalized populations, establishing relationships with relevant congressional leadership, and advocating for patient support groups for diseases that disproportionately impact skin of color patients.
• “Increase the number of practicing dermatologists who are underrepresented minorities and provide leadership and professional development programming.” Steps toward this goal include expanding the AAD mentorship program to include physician scientists, expanding diversity champion programs, expanding outreach to URM college students in STEM majors, and launching an AAD Summer Diversity & Inclusion camp for younger students to promote interest in a medical career.

The AAD diversity committee also has assembled a toolkit of resources designed to help its members learn how to talk about race, be an effective ally, and achieve cultural competency. Additional updated resources include guidelines on mentorship and outreach.

The American Academy of Dermatology has announced a 3-year, multifaceted initiative to improve diversity, equity, and inclusion not only within the academy itself, but also in the profession of dermatology overall.

“Last year’s events surrounding social justice issues and the disproportionate impact of COVID-19 on minority communities underscored an urgent need for the academy to outline a strategy to address gaps in diversity, equity, and inclusion across the academy’s programs, provide better access to dermatologic care, and expand the pipeline for prospective dermatologists,” according to an AAD statement introducing the plan.

“The AAD has long recognized the importance of fostering diversity in the dermatology specialty and increasing dermatologic services to underserved populations as a key strategic goal,” Kanya Ferguson, MD, chair of the AAD’s diversity committee, said in an interview.

“The importance and urgency of furthering these goals have been underscored by the social justice events of 2020 and the disproportionate impact that COVID-19 has had, specifically on Black and Latino communities,” added Dr. Ferguson, of the department of dermatology, at the University of Iowa, Iowa City. “The 3-year plan comprehensively expands current diversity, equity, and inclusion initiatives in an effort to accelerate the Academy’s progress toward its strategic goals.”

“Numerous barriers persist that contribute to the narrowing pipeline in medicine and ultimately in dermatology,” Dr. Ferguson noted. “The AAD’s diversity, equity, and inclusion initiatives, toolkits, and resources aim to address some of these barriers through early exposure, pipeline programming, and mentorship.”

As for the next steps, “the diversity committee will be working hard over the next few years to coordinate the integration and adoption of initiatives throughout the Academy’s activities,” she added. “This work will take a significant amount of collaboration and the committee is excited to move this forward in a meaningful and sustainable way.”

The AAD’s diversity committee headed the development of the plan, unanimously approved by the AAD’s board of directors, which outlines four key goals for the next 3 years, presented in the Diversity in Dermatology plan as follows:

“Promote and facilitate diversity, equity, and inclusion within the AAD.” Steps toward this goal include facilitating diverse representation on AAD committees, councils, and task forces, increasing representation of skin of color session speakers and lecture topics at Academy meetings, and ensuring equity in the selection process for awards including the Leadership Forum, Academic Dermatology Leadership Program, Advanced Leadership Forum, Journal of the AAD Editorial Mentorship Program, and other leadership activities.

• “Ensure dermatologic education and research encompasses health disparities and skin of color, and advocate for Black and Latino patient representation in research.” Steps toward this goal include increasing use of images reflecting the full spectrum of skin types, ensuring that skin of color populations receive information about dermatologic diseases, and supporting underrepresented minority (URM) dermatology physician scientists in leadership and professional development.
• “Expand Academy’s Advocacy Priorities to prioritize addressing health inequities.” Steps toward this goal include prioritizing issues that affect minority and marginalized populations, establishing relationships with relevant congressional leadership, and advocating for patient support groups for diseases that disproportionately impact skin of color patients.
• “Increase the number of practicing dermatologists who are underrepresented minorities and provide leadership and professional development programming.” Steps toward this goal include expanding the AAD mentorship program to include physician scientists, expanding diversity champion programs, expanding outreach to URM college students in STEM majors, and launching an AAD Summer Diversity & Inclusion camp for younger students to promote interest in a medical career.

The AAD diversity committee also has assembled a toolkit of resources designed to help its members learn how to talk about race, be an effective ally, and achieve cultural competency. Additional updated resources include guidelines on mentorship and outreach.

Although coronavirus 19 disease (COVID-19), caused by severe acute respiratory coronavirus 2, is characterized by symptoms that primarily impact the respiratory system, many patients experience neurological manifestations, with headache among leading complaints. Moreover, headache symptoms, including migraine-like headache, can last long after patients recover from COVID-19. 

Last November, in an interview with 60 Minutes,  Sadie Nagamootoo described her experience. “There are days when I do nothing and cannot get out of bed. The migraines are 10 times worse than a flu headache.”

To help individuals like Nagamootoo and others who experience headache as a result of COVID-19, it is important to understand the data that are emerging and how to incorporate them into practice. Following are answers to important questions that can guide front-line neurologists and other clinicians who are practicing during the pandemic.

Why is headache a symptom of COVID-19? It should come as no surprise that patients with COVID-19 can experience headache. Peng reminds us, in a November 2020 editorial in Cephalalgia, that headache is a common symptom in individuals with acute respiratory disease, representing a physiological response to acute infection. Headache is often the primary reason patients seek treatment. 

How is headache associated with COVID-19? It is too early to know with certainty the mechanisms underlying COVID-19 headache, but a possible explanation—according to Uygun and colleagues, writing in the The Journal of Headache and Pain—is that the virus directly invades trigeminal nerve endings in the nasal and oral cavities. 

How does headache tend to present in COVID-19? Patricia Pozo-Rosich, MD, PhD, presented on this topic at the American Headache Society’s 2020 Virtual Annual Scientific Meeting in June. In a recent interview with Neurology Reviews,  Dr. Pozo-Rosich, head of the Headache & Craniofacial Pain Unit at Vall d’Hebron University Hospital, Barcelona, Spain, noted that “headache seems to have 2 different presentations: 1) migraine-like characteristics that are severe, disabling, and usually start before other COVID symptoms and 2) tension-type headache characteristics, which usually start together with the rest of COVID symptoms.”

Are there symptoms that tend to occur more frequently in patients with COVID-19 and headache? Caronna and colleagues recently published an analysis in Cephalalgia of 130 individuals with COVID-19, showing that loss of smell and/or taste occurred in more than half of patients with headache, compared with fewer than 20% of those without headache. This finding is notable because it has been frequently reported in case reports of patients with COVID-19 and headache.

What does the presence of headache indicate about COVID-19 prognosis? The good news for individuals with COVID-19 who experience headache is that the duration of their COVID-19 illness might very well be shorter. In the Caronna study, COVID-19 duration in individuals with headache was, on average, 1 week shorter (24 days) than in those without headache symptoms (31 days).  “We don’t know why,” said Dr. Pozo-Rosich, who is one of the study’s authors. She hypothesizes that it is because of a balance between neuroinflammation and systemic inflammation. “Having an extraordinary initial reaction at the nasal cavity might protect us from having greater systemic inflammation.”

What is the cause of headache from COVID-19? Bolay and colleagues reported in Headache in Spring 2020 that patients developed new-onset, moderate-to-severe, bilateral pulsating or pressing headache toward the frontal area and forehead during the viral phase of disease. The virus activates peripheral trigeminal nerve endings directly or through vasculopathy and/or increased circulating pro-inflammatory cytokines.

What else is important to be aware of regarding headache evolution in individuals with COVID-19? The bad news for many of these individuals is that, although their COVID-19 illness might dissipate more quickly, headaches could linger. Moreover, many will be experiencing chronic headache for the first time in their life. Caronna reported that that one third of follow-up patients who reported headache were experiencing persistent disabling headache daily after 6 weeks, and more than half had no history of recurrent headache.

What is the recommended treatment for headache associated with COVID-19? Dr. Pozo-Rosich recommends starting with a nonsteroidal anti-inflammatory medication. Eventually, steroids might be indicated, “especially if the disease progresses.”

It is important for neurologists to be aware of new-onset headache associated with anosmia early in the disease. Test for the virus in such a patient; hopefully, their course will be shorter, milder, and non-respiratory.

Although coronavirus 19 disease (COVID-19), caused by severe acute respiratory coronavirus 2, is characterized by symptoms that primarily impact the respiratory system, many patients experience neurological manifestations, with headache among leading complaints. Moreover, headache symptoms, including migraine-like headache, can last long after patients recover from COVID-19. 

Last November, in an interview with 60 Minutes,  Sadie Nagamootoo described her experience. “There are days when I do nothing and cannot get out of bed. The migraines are 10 times worse than a flu headache.”

To help individuals like Nagamootoo and others who experience headache as a result of COVID-19, it is important to understand the data that are emerging and how to incorporate them into practice. Following are answers to important questions that can guide front-line neurologists and other clinicians who are practicing during the pandemic.

Why is headache a symptom of COVID-19? It should come as no surprise that patients with COVID-19 can experience headache. Peng reminds us, in a November 2020 editorial in Cephalalgia, that headache is a common symptom in individuals with acute respiratory disease, representing a physiological response to acute infection. Headache is often the primary reason patients seek treatment. 

How is headache associated with COVID-19? It is too early to know with certainty the mechanisms underlying COVID-19 headache, but a possible explanation—according to Uygun and colleagues, writing in the The Journal of Headache and Pain—is that the virus directly invades trigeminal nerve endings in the nasal and oral cavities. 

How does headache tend to present in COVID-19? Patricia Pozo-Rosich, MD, PhD, presented on this topic at the American Headache Society’s 2020 Virtual Annual Scientific Meeting in June. In a recent interview with Neurology Reviews,  Dr. Pozo-Rosich, head of the Headache & Craniofacial Pain Unit at Vall d’Hebron University Hospital, Barcelona, Spain, noted that “headache seems to have 2 different presentations: 1) migraine-like characteristics that are severe, disabling, and usually start before other COVID symptoms and 2) tension-type headache characteristics, which usually start together with the rest of COVID symptoms.”

Are there symptoms that tend to occur more frequently in patients with COVID-19 and headache? Caronna and colleagues recently published an analysis in Cephalalgia of 130 individuals with COVID-19, showing that loss of smell and/or taste occurred in more than half of patients with headache, compared with fewer than 20% of those without headache. This finding is notable because it has been frequently reported in case reports of patients with COVID-19 and headache.

What does the presence of headache indicate about COVID-19 prognosis? The good news for individuals with COVID-19 who experience headache is that the duration of their COVID-19 illness might very well be shorter. In the Caronna study, COVID-19 duration in individuals with headache was, on average, 1 week shorter (24 days) than in those without headache symptoms (31 days).  “We don’t know why,” said Dr. Pozo-Rosich, who is one of the study’s authors. She hypothesizes that it is because of a balance between neuroinflammation and systemic inflammation. “Having an extraordinary initial reaction at the nasal cavity might protect us from having greater systemic inflammation.”

What is the cause of headache from COVID-19? Bolay and colleagues reported in Headache in Spring 2020 that patients developed new-onset, moderate-to-severe, bilateral pulsating or pressing headache toward the frontal area and forehead during the viral phase of disease. The virus activates peripheral trigeminal nerve endings directly or through vasculopathy and/or increased circulating pro-inflammatory cytokines.

What else is important to be aware of regarding headache evolution in individuals with COVID-19? The bad news for many of these individuals is that, although their COVID-19 illness might dissipate more quickly, headaches could linger. Moreover, many will be experiencing chronic headache for the first time in their life. Caronna reported that that one third of follow-up patients who reported headache were experiencing persistent disabling headache daily after 6 weeks, and more than half had no history of recurrent headache.

What is the recommended treatment for headache associated with COVID-19? Dr. Pozo-Rosich recommends starting with a nonsteroidal anti-inflammatory medication. Eventually, steroids might be indicated, “especially if the disease progresses.”

It is important for neurologists to be aware of new-onset headache associated with anosmia early in the disease. Test for the virus in such a patient; hopefully, their course will be shorter, milder, and non-respiratory.

Although coronavirus 19 disease (COVID-19), caused by severe acute respiratory coronavirus 2, is characterized by symptoms that primarily impact the respiratory system, many patients experience neurological manifestations, with headache among leading complaints. Moreover, headache symptoms, including migraine-like headache, can last long after patients recover from COVID-19. 

Last November, in an interview with 60 Minutes,  Sadie Nagamootoo described her experience. “There are days when I do nothing and cannot get out of bed. The migraines are 10 times worse than a flu headache.”

To help individuals like Nagamootoo and others who experience headache as a result of COVID-19, it is important to understand the data that are emerging and how to incorporate them into practice. Following are answers to important questions that can guide front-line neurologists and other clinicians who are practicing during the pandemic.

Why is headache a symptom of COVID-19? It should come as no surprise that patients with COVID-19 can experience headache. Peng reminds us, in a November 2020 editorial in Cephalalgia, that headache is a common symptom in individuals with acute respiratory disease, representing a physiological response to acute infection. Headache is often the primary reason patients seek treatment. 

How is headache associated with COVID-19? It is too early to know with certainty the mechanisms underlying COVID-19 headache, but a possible explanation—according to Uygun and colleagues, writing in the The Journal of Headache and Pain—is that the virus directly invades trigeminal nerve endings in the nasal and oral cavities. 

How does headache tend to present in COVID-19? Patricia Pozo-Rosich, MD, PhD, presented on this topic at the American Headache Society’s 2020 Virtual Annual Scientific Meeting in June. In a recent interview with Neurology Reviews,  Dr. Pozo-Rosich, head of the Headache & Craniofacial Pain Unit at Vall d’Hebron University Hospital, Barcelona, Spain, noted that “headache seems to have 2 different presentations: 1) migraine-like characteristics that are severe, disabling, and usually start before other COVID symptoms and 2) tension-type headache characteristics, which usually start together with the rest of COVID symptoms.”

Are there symptoms that tend to occur more frequently in patients with COVID-19 and headache? Caronna and colleagues recently published an analysis in Cephalalgia of 130 individuals with COVID-19, showing that loss of smell and/or taste occurred in more than half of patients with headache, compared with fewer than 20% of those without headache. This finding is notable because it has been frequently reported in case reports of patients with COVID-19 and headache.

What does the presence of headache indicate about COVID-19 prognosis? The good news for individuals with COVID-19 who experience headache is that the duration of their COVID-19 illness might very well be shorter. In the Caronna study, COVID-19 duration in individuals with headache was, on average, 1 week shorter (24 days) than in those without headache symptoms (31 days).  “We don’t know why,” said Dr. Pozo-Rosich, who is one of the study’s authors. She hypothesizes that it is because of a balance between neuroinflammation and systemic inflammation. “Having an extraordinary initial reaction at the nasal cavity might protect us from having greater systemic inflammation.”

What is the cause of headache from COVID-19? Bolay and colleagues reported in Headache in Spring 2020 that patients developed new-onset, moderate-to-severe, bilateral pulsating or pressing headache toward the frontal area and forehead during the viral phase of disease. The virus activates peripheral trigeminal nerve endings directly or through vasculopathy and/or increased circulating pro-inflammatory cytokines.

What else is important to be aware of regarding headache evolution in individuals with COVID-19? The bad news for many of these individuals is that, although their COVID-19 illness might dissipate more quickly, headaches could linger. Moreover, many will be experiencing chronic headache for the first time in their life. Caronna reported that that one third of follow-up patients who reported headache were experiencing persistent disabling headache daily after 6 weeks, and more than half had no history of recurrent headache.

What is the recommended treatment for headache associated with COVID-19? Dr. Pozo-Rosich recommends starting with a nonsteroidal anti-inflammatory medication. Eventually, steroids might be indicated, “especially if the disease progresses.”

It is important for neurologists to be aware of new-onset headache associated with anosmia early in the disease. Test for the virus in such a patient; hopefully, their course will be shorter, milder, and non-respiratory.

Survival rates for patients with pulmonary arterial hypertension associated with connective tissue diseases have improved significantly in recent years, and there is growing evidence that treatments for idiopathic pulmonary arterial hypertension can also benefit this group.

In an article published online Feb. 3, 2021, in Arthritis & Rheumatology, researchers report the outcomes of a meta-analysis to explore the effect of more modern pulmonary arterial hypertension treatments on patients with conditions such as systemic sclerosis.

First author Dinesh Khanna, MBBS, MSc, of the division of rheumatology at the University of Michigan, Ann Arbor, said in an interview that connective tissue disease–associated pulmonary arterial hypertension (CTD-PAH) was a leading cause of death, but earlier clinical trials had found poor outcomes in patients with CTD, compared with those with idiopathic PAH.

“Recent clinical trial data show that aggressive, up-front PAH treatments have better outcomes in those with CTD-PAH, and we wanted to explore these observations carefully in a systematic review and meta-analysis,” Dr. Khanna said.

The analysis included 11 randomized, controlled trials, involving 4,329 patients with PAH (1,267 with CTD), and 19 registries with a total of 9,739 patients with PAH, including 4,008 with CTD. Trials were required to report long-term clinical outcomes with a median enrollment time of greater than 6 months, and outcomes measured between 3-6 months after the patients started treatment.

Patients with CTDs had an older mean age and a lower 6-minute walk distance than did those with idiopathic PAH.

Five randomized, controlled trials – involving 3,172 patients, 941 of whom had a CTD – found that additional PAH treatment was associated with a 36% reduction in the risk of morbidity or mortality events, compared with controls both in the overall PAH group and in those with CTD.

Additional therapy was also associated with a 34.6-meter increase in 6-minute walk distance in the general PAH population, and a 20.4-meter increase in those with CTD.

The authors commented that the smaller improvement in 6-minute walk distance among patients with CTD may be influenced by comorbidities such as musculoskeletal involvement that would be independent of their cardiopulmonary function.
 

Differential patient survival among PAH etiologies

“Our meta-analysis of RCTs demonstrated that patients with CTD-PAH derive a clinically significant benefit from currently available PAH therapies which, in many patients, comprised the addition of a drug targeting a second or third pathway involved in the pathophysiology of PAH,” the authors wrote.

When researchers analyzed data from nine registries that included a wide range of PAH etiologies, they found the overall survival rates were lower among patients with CTD, compared with the overall population. The analysis also suggested that patients with systemic sclerosis and PAH had lower survival rates than did those with systemic lupus erythematosus.

Dr. Khanna said this may relate to different pathophysiology of PAH in patients with CTDs, but could also be a reflection of other differences, such as older age and the involvement of other comorbidities, including lung fibrosis and heart involvement.

Data across all 19 registries also showed that survival rates among those with CTD were higher in registries where more than 50% of the registry study period was during or after 2010, compared with registries where 50% or more of the study period was before 2010.

The authors suggested the differences in survival rates may relate to increased screening for PAH, particularly among people with CTDs. They noted that increased screening leads to earlier diagnosis, which could introduce a lead-time bias such that later registries would have younger participants with less severe disease. However, their analysis found that the later registries had older patients but also with less severe disease, and they suggested that it wasn’t possible to determine if lead-time bias was playing a role in their results.

Improvements in treatment options could also account for differences in survival over time, although the authors commented that only six registries in the study included patients from 2015 or later, when currently available treatments came into use and early combination therapy was used more.

“These data also support the 2018 World Symposium on Pulmonary Hypertension recommendations to initiate up-front combination pulmonary arterial hypertension therapy in majority of cases with CTD-PAH,” Dr. Khanna said.

‘Still have to be aggressive at identifying the high-risk patients’

Commenting on the findings, Virginia Steen, MD, of the division of rheumatology at Georgetown University, Washington, said clinicians were finally seeing some significant changes over time in scleroderma-associated PAH.

“Although some of it may be just early diagnosis, I think that the combination of early diagnosis and more aggressive treatment with combination medication is definitely making a difference,” Dr. Steen said in an interview. “The bottom line is that we as rheumatologists still have to be aggressive at identifying the high-risk patients, making an early diagnosis, and working with our pulmonary hypertension colleagues and aggressively treating these patients so we can make a long-term difference.”

The authors of an accompanying editorial said the meta-analysis’ findings showed the positive impact of early combination therapy and early diagnosis through proactive screening.

“It is notable because the present analysis again confirms that outcomes are worse in CTD-PAH than in idiopathic or familial forms of PAH, the impact of treatments should no longer be regarded as insignificant,” the editorial’s authors wrote. “This is a practice changing observation, especially now that many of the drugs are available in generic formulations and so the cost of modern PAH treatment has fallen at the same time as its true value is convincingly demonstrated.”

They also argued there was strong evidence for the value of combination therapies, both for PAH-targeted drugs used in combination and concurrent use of immunosuppression and drugs specifically for PAH in some patients with CTD-PAH.

However, they pointed out that not all treatments for idiopathic PAH were suitable for patients with CTDs, highlighting the example of anticoagulation that can improve survival in the first but worsen it in the second.

The study was funded by Actelion. Six authors declared funding and grants from the pharmaceutical sector, including the study sponsor, and three authors were employees of Actelion.

Survival rates for patients with pulmonary arterial hypertension associated with connective tissue diseases have improved significantly in recent years, and there is growing evidence that treatments for idiopathic pulmonary arterial hypertension can also benefit this group.

In an article published online Feb. 3, 2021, in Arthritis & Rheumatology, researchers report the outcomes of a meta-analysis to explore the effect of more modern pulmonary arterial hypertension treatments on patients with conditions such as systemic sclerosis.

First author Dinesh Khanna, MBBS, MSc, of the division of rheumatology at the University of Michigan, Ann Arbor, said in an interview that connective tissue disease–associated pulmonary arterial hypertension (CTD-PAH) was a leading cause of death, but earlier clinical trials had found poor outcomes in patients with CTD, compared with those with idiopathic PAH.

“Recent clinical trial data show that aggressive, up-front PAH treatments have better outcomes in those with CTD-PAH, and we wanted to explore these observations carefully in a systematic review and meta-analysis,” Dr. Khanna said.

The analysis included 11 randomized, controlled trials, involving 4,329 patients with PAH (1,267 with CTD), and 19 registries with a total of 9,739 patients with PAH, including 4,008 with CTD. Trials were required to report long-term clinical outcomes with a median enrollment time of greater than 6 months, and outcomes measured between 3-6 months after the patients started treatment.

Patients with CTDs had an older mean age and a lower 6-minute walk distance than did those with idiopathic PAH.

Five randomized, controlled trials – involving 3,172 patients, 941 of whom had a CTD – found that additional PAH treatment was associated with a 36% reduction in the risk of morbidity or mortality events, compared with controls both in the overall PAH group and in those with CTD.

Additional therapy was also associated with a 34.6-meter increase in 6-minute walk distance in the general PAH population, and a 20.4-meter increase in those with CTD.

The authors commented that the smaller improvement in 6-minute walk distance among patients with CTD may be influenced by comorbidities such as musculoskeletal involvement that would be independent of their cardiopulmonary function.
 

Differential patient survival among PAH etiologies

“Our meta-analysis of RCTs demonstrated that patients with CTD-PAH derive a clinically significant benefit from currently available PAH therapies which, in many patients, comprised the addition of a drug targeting a second or third pathway involved in the pathophysiology of PAH,” the authors wrote.

When researchers analyzed data from nine registries that included a wide range of PAH etiologies, they found the overall survival rates were lower among patients with CTD, compared with the overall population. The analysis also suggested that patients with systemic sclerosis and PAH had lower survival rates than did those with systemic lupus erythematosus.

Dr. Khanna said this may relate to different pathophysiology of PAH in patients with CTDs, but could also be a reflection of other differences, such as older age and the involvement of other comorbidities, including lung fibrosis and heart involvement.

Data across all 19 registries also showed that survival rates among those with CTD were higher in registries where more than 50% of the registry study period was during or after 2010, compared with registries where 50% or more of the study period was before 2010.

The authors suggested the differences in survival rates may relate to increased screening for PAH, particularly among people with CTDs. They noted that increased screening leads to earlier diagnosis, which could introduce a lead-time bias such that later registries would have younger participants with less severe disease. However, their analysis found that the later registries had older patients but also with less severe disease, and they suggested that it wasn’t possible to determine if lead-time bias was playing a role in their results.

Improvements in treatment options could also account for differences in survival over time, although the authors commented that only six registries in the study included patients from 2015 or later, when currently available treatments came into use and early combination therapy was used more.

“These data also support the 2018 World Symposium on Pulmonary Hypertension recommendations to initiate up-front combination pulmonary arterial hypertension therapy in majority of cases with CTD-PAH,” Dr. Khanna said.

‘Still have to be aggressive at identifying the high-risk patients’

Commenting on the findings, Virginia Steen, MD, of the division of rheumatology at Georgetown University, Washington, said clinicians were finally seeing some significant changes over time in scleroderma-associated PAH.

“Although some of it may be just early diagnosis, I think that the combination of early diagnosis and more aggressive treatment with combination medication is definitely making a difference,” Dr. Steen said in an interview. “The bottom line is that we as rheumatologists still have to be aggressive at identifying the high-risk patients, making an early diagnosis, and working with our pulmonary hypertension colleagues and aggressively treating these patients so we can make a long-term difference.”

The authors of an accompanying editorial said the meta-analysis’ findings showed the positive impact of early combination therapy and early diagnosis through proactive screening.

“It is notable because the present analysis again confirms that outcomes are worse in CTD-PAH than in idiopathic or familial forms of PAH, the impact of treatments should no longer be regarded as insignificant,” the editorial’s authors wrote. “This is a practice changing observation, especially now that many of the drugs are available in generic formulations and so the cost of modern PAH treatment has fallen at the same time as its true value is convincingly demonstrated.”

They also argued there was strong evidence for the value of combination therapies, both for PAH-targeted drugs used in combination and concurrent use of immunosuppression and drugs specifically for PAH in some patients with CTD-PAH.

However, they pointed out that not all treatments for idiopathic PAH were suitable for patients with CTDs, highlighting the example of anticoagulation that can improve survival in the first but worsen it in the second.

The study was funded by Actelion. Six authors declared funding and grants from the pharmaceutical sector, including the study sponsor, and three authors were employees of Actelion.

Survival rates for patients with pulmonary arterial hypertension associated with connective tissue diseases have improved significantly in recent years, and there is growing evidence that treatments for idiopathic pulmonary arterial hypertension can also benefit this group.

In an article published online Feb. 3, 2021, in Arthritis & Rheumatology, researchers report the outcomes of a meta-analysis to explore the effect of more modern pulmonary arterial hypertension treatments on patients with conditions such as systemic sclerosis.

First author Dinesh Khanna, MBBS, MSc, of the division of rheumatology at the University of Michigan, Ann Arbor, said in an interview that connective tissue disease–associated pulmonary arterial hypertension (CTD-PAH) was a leading cause of death, but earlier clinical trials had found poor outcomes in patients with CTD, compared with those with idiopathic PAH.

“Recent clinical trial data show that aggressive, up-front PAH treatments have better outcomes in those with CTD-PAH, and we wanted to explore these observations carefully in a systematic review and meta-analysis,” Dr. Khanna said.

The analysis included 11 randomized, controlled trials, involving 4,329 patients with PAH (1,267 with CTD), and 19 registries with a total of 9,739 patients with PAH, including 4,008 with CTD. Trials were required to report long-term clinical outcomes with a median enrollment time of greater than 6 months, and outcomes measured between 3-6 months after the patients started treatment.

Patients with CTDs had an older mean age and a lower 6-minute walk distance than did those with idiopathic PAH.

Five randomized, controlled trials – involving 3,172 patients, 941 of whom had a CTD – found that additional PAH treatment was associated with a 36% reduction in the risk of morbidity or mortality events, compared with controls both in the overall PAH group and in those with CTD.

Additional therapy was also associated with a 34.6-meter increase in 6-minute walk distance in the general PAH population, and a 20.4-meter increase in those with CTD.

The authors commented that the smaller improvement in 6-minute walk distance among patients with CTD may be influenced by comorbidities such as musculoskeletal involvement that would be independent of their cardiopulmonary function.
 

Differential patient survival among PAH etiologies

“Our meta-analysis of RCTs demonstrated that patients with CTD-PAH derive a clinically significant benefit from currently available PAH therapies which, in many patients, comprised the addition of a drug targeting a second or third pathway involved in the pathophysiology of PAH,” the authors wrote.

When researchers analyzed data from nine registries that included a wide range of PAH etiologies, they found the overall survival rates were lower among patients with CTD, compared with the overall population. The analysis also suggested that patients with systemic sclerosis and PAH had lower survival rates than did those with systemic lupus erythematosus.

Dr. Khanna said this may relate to different pathophysiology of PAH in patients with CTDs, but could also be a reflection of other differences, such as older age and the involvement of other comorbidities, including lung fibrosis and heart involvement.

Data across all 19 registries also showed that survival rates among those with CTD were higher in registries where more than 50% of the registry study period was during or after 2010, compared with registries where 50% or more of the study period was before 2010.

The authors suggested the differences in survival rates may relate to increased screening for PAH, particularly among people with CTDs. They noted that increased screening leads to earlier diagnosis, which could introduce a lead-time bias such that later registries would have younger participants with less severe disease. However, their analysis found that the later registries had older patients but also with less severe disease, and they suggested that it wasn’t possible to determine if lead-time bias was playing a role in their results.

Improvements in treatment options could also account for differences in survival over time, although the authors commented that only six registries in the study included patients from 2015 or later, when currently available treatments came into use and early combination therapy was used more.

“These data also support the 2018 World Symposium on Pulmonary Hypertension recommendations to initiate up-front combination pulmonary arterial hypertension therapy in majority of cases with CTD-PAH,” Dr. Khanna said.

‘Still have to be aggressive at identifying the high-risk patients’

Commenting on the findings, Virginia Steen, MD, of the division of rheumatology at Georgetown University, Washington, said clinicians were finally seeing some significant changes over time in scleroderma-associated PAH.

“Although some of it may be just early diagnosis, I think that the combination of early diagnosis and more aggressive treatment with combination medication is definitely making a difference,” Dr. Steen said in an interview. “The bottom line is that we as rheumatologists still have to be aggressive at identifying the high-risk patients, making an early diagnosis, and working with our pulmonary hypertension colleagues and aggressively treating these patients so we can make a long-term difference.”

The authors of an accompanying editorial said the meta-analysis’ findings showed the positive impact of early combination therapy and early diagnosis through proactive screening.

“It is notable because the present analysis again confirms that outcomes are worse in CTD-PAH than in idiopathic or familial forms of PAH, the impact of treatments should no longer be regarded as insignificant,” the editorial’s authors wrote. “This is a practice changing observation, especially now that many of the drugs are available in generic formulations and so the cost of modern PAH treatment has fallen at the same time as its true value is convincingly demonstrated.”

They also argued there was strong evidence for the value of combination therapies, both for PAH-targeted drugs used in combination and concurrent use of immunosuppression and drugs specifically for PAH in some patients with CTD-PAH.

However, they pointed out that not all treatments for idiopathic PAH were suitable for patients with CTDs, highlighting the example of anticoagulation that can improve survival in the first but worsen it in the second.

The study was funded by Actelion. Six authors declared funding and grants from the pharmaceutical sector, including the study sponsor, and three authors were employees of Actelion.

Home-based subcutaneous immune globulin therapy is a promising alternative to intravenous immune globulin therapy for patients with refractory dermatomyositis or polymyositis, Anna Postolova, MD, MPH, declared at the 2021 Rheumatology Winter Clinical Symposium.

“This is really exciting. I think in the years to come we may see a change to having our patients be able to do immune globulin therapy at home,” said Dr. Postolova, a rheumatologist and allergist/immunologist at Stanford (Calif.) Health Care.

“The technology is there. I think our patients might feel more comfortable getting immune globulin at home,” she said. “I would love to switch more patients from IVIg to SCIg [subcutaneous immune globulin] in my practice.”

A few caveats: SCIg remains off label for treatment of dermatomyositis (DM) or polymyositis (PM). Its approved indication is as replacement therapy in patients with primary or secondary immunodeficiency diseases. IVIg is approved for this indication, but is also approved for DM/PM refractory to high-dose corticosteroids and immunosuppressants. Yet SCIg is clearly effective for these autoimmune inflammatory diseases, albeit to date the supporting evidence comes chiefly from observational studies and anecdotal experience.

“I don’t know if insurers will cover it, but they should because it’s obviously a lot cheaper to do it at home,” she noted.
 

SCIg advantages

SCIg offers compelling advantages over IVIg in addition to its substantially lower cost. These include far fewer systemic side effects, shorter infusion time, greater bioavailability, and better quality of life. Patients self-administer SCIg at home, avoiding the inconvenience of IVIg therapy, which entails travel time for once-monthly hospitalization or long hours spent in an infusion center, she explained.

French investigators recently documented a previously unappreciated further advantage of home-based SCIg. They convened a focus group of patients with DM or PM experienced with both IVIg and home SCIg and determined that participants uniformly preferred home SCIg. The patients cited a new and welcome feeling of autonomy and control.

“All patients with experience of IVIg and SCIg expressed a clear preference for SCIg, which was described to be easy, less disruptive for daily life, well tolerated, and less time-consuming. Preference was mainly related to a restoration of autonomy. Home-based self-administration reinforced the feeling of independence,” according to the investigators.
 

Available products

Six preparations of SCIg are commercially available. Most are in 10% concentration, as are all IVIg products. However, a 20% formulation of SCIg known as Hizentra allows for a smaller infusion volume and quicker completion of a treatment session. And one SCIg product, HyQvia, uses recombinant human hyaluronidase-facilitated 10% immune globulin, allowing home infusion of large volumes of sustained-release immune globulin on a once-monthly basis.

The relatively recent introduction of home SCIg for treatment of autoimmune inflammatory diseases, including DM, PM, and chronic inflammatory demyelinating polyneuropathy, has been pioneered mainly by European investigators. The treatment is often given by programmable mechanical pump once weekly. Italian investigators have reported efficacy in DM using 0.2 g/kg per week, which is about half the monthly total dose of IVIg employed. The infusion rate is 10-40 mL/hour, with a volume of around 35 mL per injection site.

Alternatively, SCIg can be delivered by rapid push infusions of smaller volumes with a syringe two or three times per week; that’s the regimen that was used at 2 g/kg over the course of a month by patients in the French focus group study, who didn’t mind the more frequent dosing.

“As they have had severe long-lasting symptoms, SCIg was perceived as a curative rather than a preventive therapy,” according to the French investigators.

More than 40% of patients experience adverse reactions to IVIg. These often involve headaches, nausea, back or abdominal pain, arthralgias, and/or difficulty breathing. Thromboembolic events and acute renal failure occur occasionally. For this reason, many physicians give a prophylactic dose of corticosteroids an hour before a patient’s first dose of IVIg. These systemic side effects are so rare with SCIg that Dr. Postolova has never pretreated with steroids, even though the main reason she resorts to the home therapy is a patient’s track record of poor tolerance of IVIg. The lower abdomen and thigh are the most commonly used subcutaneous infusion sites. Mild local infusion site reactions are fairly common.

Formulating IVIg and SCIg is a complex process that entails plasma procurement and pooling, fractionation, and purification. It takes 10,000-60,000 plasma donations to make one lot of IVIg. Donations are accepted only from repeated donors. Samples are held for 6 months and tested for infectious agents. However, efforts are underway to develop bioengineered recombinant immune globulin products that don’t require donated plasma. These products are being designed to capture and enhance the most important mechanisms of benefit of plasma-derived immunoglobulins using Fc fragments that target key receptors, rather than relying on full-length immune globulin. The goal is enhanced efficacy at much lower doses than with IVIg or SCIg.

Dr. Postolova reported having no financial conflicts regarding her presentation.

[email protected]

Home-based subcutaneous immune globulin therapy is a promising alternative to intravenous immune globulin therapy for patients with refractory dermatomyositis or polymyositis, Anna Postolova, MD, MPH, declared at the 2021 Rheumatology Winter Clinical Symposium.

“This is really exciting. I think in the years to come we may see a change to having our patients be able to do immune globulin therapy at home,” said Dr. Postolova, a rheumatologist and allergist/immunologist at Stanford (Calif.) Health Care.

“The technology is there. I think our patients might feel more comfortable getting immune globulin at home,” she said. “I would love to switch more patients from IVIg to SCIg [subcutaneous immune globulin] in my practice.”

A few caveats: SCIg remains off label for treatment of dermatomyositis (DM) or polymyositis (PM). Its approved indication is as replacement therapy in patients with primary or secondary immunodeficiency diseases. IVIg is approved for this indication, but is also approved for DM/PM refractory to high-dose corticosteroids and immunosuppressants. Yet SCIg is clearly effective for these autoimmune inflammatory diseases, albeit to date the supporting evidence comes chiefly from observational studies and anecdotal experience.

“I don’t know if insurers will cover it, but they should because it’s obviously a lot cheaper to do it at home,” she noted.
 

SCIg advantages

SCIg offers compelling advantages over IVIg in addition to its substantially lower cost. These include far fewer systemic side effects, shorter infusion time, greater bioavailability, and better quality of life. Patients self-administer SCIg at home, avoiding the inconvenience of IVIg therapy, which entails travel time for once-monthly hospitalization or long hours spent in an infusion center, she explained.

French investigators recently documented a previously unappreciated further advantage of home-based SCIg. They convened a focus group of patients with DM or PM experienced with both IVIg and home SCIg and determined that participants uniformly preferred home SCIg. The patients cited a new and welcome feeling of autonomy and control.

“All patients with experience of IVIg and SCIg expressed a clear preference for SCIg, which was described to be easy, less disruptive for daily life, well tolerated, and less time-consuming. Preference was mainly related to a restoration of autonomy. Home-based self-administration reinforced the feeling of independence,” according to the investigators.
 

Available products

Six preparations of SCIg are commercially available. Most are in 10% concentration, as are all IVIg products. However, a 20% formulation of SCIg known as Hizentra allows for a smaller infusion volume and quicker completion of a treatment session. And one SCIg product, HyQvia, uses recombinant human hyaluronidase-facilitated 10% immune globulin, allowing home infusion of large volumes of sustained-release immune globulin on a once-monthly basis.

The relatively recent introduction of home SCIg for treatment of autoimmune inflammatory diseases, including DM, PM, and chronic inflammatory demyelinating polyneuropathy, has been pioneered mainly by European investigators. The treatment is often given by programmable mechanical pump once weekly. Italian investigators have reported efficacy in DM using 0.2 g/kg per week, which is about half the monthly total dose of IVIg employed. The infusion rate is 10-40 mL/hour, with a volume of around 35 mL per injection site.

Alternatively, SCIg can be delivered by rapid push infusions of smaller volumes with a syringe two or three times per week; that’s the regimen that was used at 2 g/kg over the course of a month by patients in the French focus group study, who didn’t mind the more frequent dosing.

“As they have had severe long-lasting symptoms, SCIg was perceived as a curative rather than a preventive therapy,” according to the French investigators.

More than 40% of patients experience adverse reactions to IVIg. These often involve headaches, nausea, back or abdominal pain, arthralgias, and/or difficulty breathing. Thromboembolic events and acute renal failure occur occasionally. For this reason, many physicians give a prophylactic dose of corticosteroids an hour before a patient’s first dose of IVIg. These systemic side effects are so rare with SCIg that Dr. Postolova has never pretreated with steroids, even though the main reason she resorts to the home therapy is a patient’s track record of poor tolerance of IVIg. The lower abdomen and thigh are the most commonly used subcutaneous infusion sites. Mild local infusion site reactions are fairly common.

Formulating IVIg and SCIg is a complex process that entails plasma procurement and pooling, fractionation, and purification. It takes 10,000-60,000 plasma donations to make one lot of IVIg. Donations are accepted only from repeated donors. Samples are held for 6 months and tested for infectious agents. However, efforts are underway to develop bioengineered recombinant immune globulin products that don’t require donated plasma. These products are being designed to capture and enhance the most important mechanisms of benefit of plasma-derived immunoglobulins using Fc fragments that target key receptors, rather than relying on full-length immune globulin. The goal is enhanced efficacy at much lower doses than with IVIg or SCIg.

Dr. Postolova reported having no financial conflicts regarding her presentation.

[email protected]

Home-based subcutaneous immune globulin therapy is a promising alternative to intravenous immune globulin therapy for patients with refractory dermatomyositis or polymyositis, Anna Postolova, MD, MPH, declared at the 2021 Rheumatology Winter Clinical Symposium.

“This is really exciting. I think in the years to come we may see a change to having our patients be able to do immune globulin therapy at home,” said Dr. Postolova, a rheumatologist and allergist/immunologist at Stanford (Calif.) Health Care.

“The technology is there. I think our patients might feel more comfortable getting immune globulin at home,” she said. “I would love to switch more patients from IVIg to SCIg [subcutaneous immune globulin] in my practice.”

A few caveats: SCIg remains off label for treatment of dermatomyositis (DM) or polymyositis (PM). Its approved indication is as replacement therapy in patients with primary or secondary immunodeficiency diseases. IVIg is approved for this indication, but is also approved for DM/PM refractory to high-dose corticosteroids and immunosuppressants. Yet SCIg is clearly effective for these autoimmune inflammatory diseases, albeit to date the supporting evidence comes chiefly from observational studies and anecdotal experience.

“I don’t know if insurers will cover it, but they should because it’s obviously a lot cheaper to do it at home,” she noted.
 

SCIg advantages

SCIg offers compelling advantages over IVIg in addition to its substantially lower cost. These include far fewer systemic side effects, shorter infusion time, greater bioavailability, and better quality of life. Patients self-administer SCIg at home, avoiding the inconvenience of IVIg therapy, which entails travel time for once-monthly hospitalization or long hours spent in an infusion center, she explained.

French investigators recently documented a previously unappreciated further advantage of home-based SCIg. They convened a focus group of patients with DM or PM experienced with both IVIg and home SCIg and determined that participants uniformly preferred home SCIg. The patients cited a new and welcome feeling of autonomy and control.

“All patients with experience of IVIg and SCIg expressed a clear preference for SCIg, which was described to be easy, less disruptive for daily life, well tolerated, and less time-consuming. Preference was mainly related to a restoration of autonomy. Home-based self-administration reinforced the feeling of independence,” according to the investigators.
 

Available products

Six preparations of SCIg are commercially available. Most are in 10% concentration, as are all IVIg products. However, a 20% formulation of SCIg known as Hizentra allows for a smaller infusion volume and quicker completion of a treatment session. And one SCIg product, HyQvia, uses recombinant human hyaluronidase-facilitated 10% immune globulin, allowing home infusion of large volumes of sustained-release immune globulin on a once-monthly basis.

The relatively recent introduction of home SCIg for treatment of autoimmune inflammatory diseases, including DM, PM, and chronic inflammatory demyelinating polyneuropathy, has been pioneered mainly by European investigators. The treatment is often given by programmable mechanical pump once weekly. Italian investigators have reported efficacy in DM using 0.2 g/kg per week, which is about half the monthly total dose of IVIg employed. The infusion rate is 10-40 mL/hour, with a volume of around 35 mL per injection site.

Alternatively, SCIg can be delivered by rapid push infusions of smaller volumes with a syringe two or three times per week; that’s the regimen that was used at 2 g/kg over the course of a month by patients in the French focus group study, who didn’t mind the more frequent dosing.

“As they have had severe long-lasting symptoms, SCIg was perceived as a curative rather than a preventive therapy,” according to the French investigators.

More than 40% of patients experience adverse reactions to IVIg. These often involve headaches, nausea, back or abdominal pain, arthralgias, and/or difficulty breathing. Thromboembolic events and acute renal failure occur occasionally. For this reason, many physicians give a prophylactic dose of corticosteroids an hour before a patient’s first dose of IVIg. These systemic side effects are so rare with SCIg that Dr. Postolova has never pretreated with steroids, even though the main reason she resorts to the home therapy is a patient’s track record of poor tolerance of IVIg. The lower abdomen and thigh are the most commonly used subcutaneous infusion sites. Mild local infusion site reactions are fairly common.

Formulating IVIg and SCIg is a complex process that entails plasma procurement and pooling, fractionation, and purification. It takes 10,000-60,000 plasma donations to make one lot of IVIg. Donations are accepted only from repeated donors. Samples are held for 6 months and tested for infectious agents. However, efforts are underway to develop bioengineered recombinant immune globulin products that don’t require donated plasma. These products are being designed to capture and enhance the most important mechanisms of benefit of plasma-derived immunoglobulins using Fc fragments that target key receptors, rather than relying on full-length immune globulin. The goal is enhanced efficacy at much lower doses than with IVIg or SCIg.

Dr. Postolova reported having no financial conflicts regarding her presentation.

[email protected]