MDedge Dermatology

According to Iltefat H. Hamzavi, MD, the initial clinical assessment for hidradenitis suppurativa (HS) includes posing two questions to patients: Have you had outbreaks of boils during the past 6 months? Where and how many boils have you had?

If the answer to the first question is “yes” and the patient has had at least two boils in intertriginous areas, that person likely has HS, a disease of apocrine gland–bearing skin that occurs in 1%-4% of people, has a higher prevalence in Blacks, compared with Whites, and affects more women than men by a 3:1 ratio.

“Current treatments offer limited efficacy, and the disease is chronic and recurrent,” Dr. Hamzavi, of the department of dermatology at Henry Ford Health System, Detroit, said during MedscapeLive’s annual Las Vegas Dermatology Seminar. “You often see nodules, abscesses, fistulae, and scarring,” with all different skin types represented in the majority of patients.

Typical HS lesions appear as inflamed nodules, abscesses, draining fistulas, and scars as well as double-headed “tombstone” comedones, he said. These are typically located in the axilla, intermammary folds, in the groin, around the genitals, and on the buttocks. Atypical lesions can also occur – often folliculitis and open comedones in locations such as the waistline, the neck, and behind the ears.

The differential diagnosis is wide-ranging and includes bacterial abscess, inflamed cyst, folliculitis, pilonidal sinus, cellulitis, and cutaneous Crohn’s disease. Pain may appear out of proportion to the physical examination.

“There is a window of opportunity to treat HS, early in the disease process,” Dr. Hamzavi said. “There are no definitive cures for HS but lots of treatment options.”

According to clinical management guidelines published by the United States and Canadian Hidradenitis Suppurativa Foundations, options for moderate stage disease include antibiotics, antiandrogens, retinoids, immunosuppression/biologics, deroofing, and limited excision with primary closure. Options for severe disease include radical excision.

“HS requires a mix of medical and procedural treatments based on the number of nodules,” Dr. Hamzavi said. “Because the disease has so many different phases, there is no perfect outcome measure yet, but progress is being made.”

In 2018, an effort to develop a consensus core outcome set of domains regarding what to measure in clinical trials of HS was launched; it is known as the Hidradenitis Suppurativa Core Outcomes Set International Collaboration (HISTORIC). It was formed as a collaboration between the International Dermatology Outcome Measures (IDEOM) initiative, the Cochrane Skin Group – Core Outcome Set Initiative (CSG-COUSIN), and Zealand University Hospital, Roskilde.

HISTORIC is now part of the partnership with CSG-COUSIN and this work continues onward. Core domains as defined by the group include pain, physical signs, HS-specific quality of life, global assessment, and disease progression. “For now, we are mostly using some objective measures and some patient-reported outcomes with the addition of ultrasound in some centers,” Dr. Hamzavi said.

He underscored the importance of lifestyle modifications in patients with HS, including smoking cessation and weight loss, as well as decreasing pressure/friction on lesions, using warm compresses, and modifying diet. “This generally involves a low-inflammatory diet: Low carbohydrate, low dairy, and higher protein content, but there is much work needed to understand the role of diet in HS,” he said.

“This is a tough disease, but the compassion you offer these patients will be paid back to you a thousandfold. They tend to be some of the happiest and most appreciative patients you will ever have in your practice.”

Dr. Hamzavi disclosed that he has been a clinical investigator for Clinuvel, Incyte, Pfizer, Avita, and Ferndale Labs. He has also been a consultant for Pfizer, AbbVie, Novartis, and Aclaris, and has received a grant from Estee Lauder.

MedscapeLive and this news organization are owned by the same parent company.

[email protected]

According to Iltefat H. Hamzavi, MD, the initial clinical assessment for hidradenitis suppurativa (HS) includes posing two questions to patients: Have you had outbreaks of boils during the past 6 months? Where and how many boils have you had?

If the answer to the first question is “yes” and the patient has had at least two boils in intertriginous areas, that person likely has HS, a disease of apocrine gland–bearing skin that occurs in 1%-4% of people, has a higher prevalence in Blacks, compared with Whites, and affects more women than men by a 3:1 ratio.

“Current treatments offer limited efficacy, and the disease is chronic and recurrent,” Dr. Hamzavi, of the department of dermatology at Henry Ford Health System, Detroit, said during MedscapeLive’s annual Las Vegas Dermatology Seminar. “You often see nodules, abscesses, fistulae, and scarring,” with all different skin types represented in the majority of patients.

Typical HS lesions appear as inflamed nodules, abscesses, draining fistulas, and scars as well as double-headed “tombstone” comedones, he said. These are typically located in the axilla, intermammary folds, in the groin, around the genitals, and on the buttocks. Atypical lesions can also occur – often folliculitis and open comedones in locations such as the waistline, the neck, and behind the ears.

The differential diagnosis is wide-ranging and includes bacterial abscess, inflamed cyst, folliculitis, pilonidal sinus, cellulitis, and cutaneous Crohn’s disease. Pain may appear out of proportion to the physical examination.

“There is a window of opportunity to treat HS, early in the disease process,” Dr. Hamzavi said. “There are no definitive cures for HS but lots of treatment options.”

According to clinical management guidelines published by the United States and Canadian Hidradenitis Suppurativa Foundations, options for moderate stage disease include antibiotics, antiandrogens, retinoids, immunosuppression/biologics, deroofing, and limited excision with primary closure. Options for severe disease include radical excision.

“HS requires a mix of medical and procedural treatments based on the number of nodules,” Dr. Hamzavi said. “Because the disease has so many different phases, there is no perfect outcome measure yet, but progress is being made.”

In 2018, an effort to develop a consensus core outcome set of domains regarding what to measure in clinical trials of HS was launched; it is known as the Hidradenitis Suppurativa Core Outcomes Set International Collaboration (HISTORIC). It was formed as a collaboration between the International Dermatology Outcome Measures (IDEOM) initiative, the Cochrane Skin Group – Core Outcome Set Initiative (CSG-COUSIN), and Zealand University Hospital, Roskilde.

HISTORIC is now part of the partnership with CSG-COUSIN and this work continues onward. Core domains as defined by the group include pain, physical signs, HS-specific quality of life, global assessment, and disease progression. “For now, we are mostly using some objective measures and some patient-reported outcomes with the addition of ultrasound in some centers,” Dr. Hamzavi said.

He underscored the importance of lifestyle modifications in patients with HS, including smoking cessation and weight loss, as well as decreasing pressure/friction on lesions, using warm compresses, and modifying diet. “This generally involves a low-inflammatory diet: Low carbohydrate, low dairy, and higher protein content, but there is much work needed to understand the role of diet in HS,” he said.

“This is a tough disease, but the compassion you offer these patients will be paid back to you a thousandfold. They tend to be some of the happiest and most appreciative patients you will ever have in your practice.”

Dr. Hamzavi disclosed that he has been a clinical investigator for Clinuvel, Incyte, Pfizer, Avita, and Ferndale Labs. He has also been a consultant for Pfizer, AbbVie, Novartis, and Aclaris, and has received a grant from Estee Lauder.

MedscapeLive and this news organization are owned by the same parent company.

[email protected]

According to Iltefat H. Hamzavi, MD, the initial clinical assessment for hidradenitis suppurativa (HS) includes posing two questions to patients: Have you had outbreaks of boils during the past 6 months? Where and how many boils have you had?

If the answer to the first question is “yes” and the patient has had at least two boils in intertriginous areas, that person likely has HS, a disease of apocrine gland–bearing skin that occurs in 1%-4% of people, has a higher prevalence in Blacks, compared with Whites, and affects more women than men by a 3:1 ratio.

“Current treatments offer limited efficacy, and the disease is chronic and recurrent,” Dr. Hamzavi, of the department of dermatology at Henry Ford Health System, Detroit, said during MedscapeLive’s annual Las Vegas Dermatology Seminar. “You often see nodules, abscesses, fistulae, and scarring,” with all different skin types represented in the majority of patients.

Typical HS lesions appear as inflamed nodules, abscesses, draining fistulas, and scars as well as double-headed “tombstone” comedones, he said. These are typically located in the axilla, intermammary folds, in the groin, around the genitals, and on the buttocks. Atypical lesions can also occur – often folliculitis and open comedones in locations such as the waistline, the neck, and behind the ears.

The differential diagnosis is wide-ranging and includes bacterial abscess, inflamed cyst, folliculitis, pilonidal sinus, cellulitis, and cutaneous Crohn’s disease. Pain may appear out of proportion to the physical examination.

“There is a window of opportunity to treat HS, early in the disease process,” Dr. Hamzavi said. “There are no definitive cures for HS but lots of treatment options.”

According to clinical management guidelines published by the United States and Canadian Hidradenitis Suppurativa Foundations, options for moderate stage disease include antibiotics, antiandrogens, retinoids, immunosuppression/biologics, deroofing, and limited excision with primary closure. Options for severe disease include radical excision.

“HS requires a mix of medical and procedural treatments based on the number of nodules,” Dr. Hamzavi said. “Because the disease has so many different phases, there is no perfect outcome measure yet, but progress is being made.”

In 2018, an effort to develop a consensus core outcome set of domains regarding what to measure in clinical trials of HS was launched; it is known as the Hidradenitis Suppurativa Core Outcomes Set International Collaboration (HISTORIC). It was formed as a collaboration between the International Dermatology Outcome Measures (IDEOM) initiative, the Cochrane Skin Group – Core Outcome Set Initiative (CSG-COUSIN), and Zealand University Hospital, Roskilde.

HISTORIC is now part of the partnership with CSG-COUSIN and this work continues onward. Core domains as defined by the group include pain, physical signs, HS-specific quality of life, global assessment, and disease progression. “For now, we are mostly using some objective measures and some patient-reported outcomes with the addition of ultrasound in some centers,” Dr. Hamzavi said.

He underscored the importance of lifestyle modifications in patients with HS, including smoking cessation and weight loss, as well as decreasing pressure/friction on lesions, using warm compresses, and modifying diet. “This generally involves a low-inflammatory diet: Low carbohydrate, low dairy, and higher protein content, but there is much work needed to understand the role of diet in HS,” he said.

“This is a tough disease, but the compassion you offer these patients will be paid back to you a thousandfold. They tend to be some of the happiest and most appreciative patients you will ever have in your practice.”

Dr. Hamzavi disclosed that he has been a clinical investigator for Clinuvel, Incyte, Pfizer, Avita, and Ferndale Labs. He has also been a consultant for Pfizer, AbbVie, Novartis, and Aclaris, and has received a grant from Estee Lauder.

MedscapeLive and this news organization are owned by the same parent company.

[email protected]

Pediatric dermatologists who treat infantile hemangioma (IH) can consider nadolol as a noninferior – and possibly a better – alternative to the standard treatment propranolol, according to a study published in JAMA Pediatrics.

“In our experience, nadolol is preferable to propranolol given its observed efficacy and similar safety profile [and] its more predictable metabolism that does not involve the liver,” lead author Elena Pope, MD, told this news organization. “In addition, the fact that nadolol is less lipophilic than propranolol makes it less likely to cross the blood-brain barrier and potentially affect the central nervous system,” added Dr. Pope, who is head of the division of pediatric dermatology at the Hospital for Sick Children, Toronto, and professor of pediatric medicine at the University of Toronto.

The prospective double-blind, randomized noninferiority study was conducted between 2016 and 2020 at two tertiary academic pediatric dermatology clinics in Ontario, Canada. It included 71 infants with a corrected gestational age of 1-6 months whose hemangiomas were greater than 1.5 cm on the face or 3 cm or greater on another body part and had the potential to cause functional impairment or cosmetic disfigurement.

Patients were randomized to either nadolol (oral suspension, 10 mg/mL) or propranolol (oral suspension, 5 mg/mL) beginning at a dose of 0.5 mg/kg per day twice a day and titrated weekly by 0.5 mg/kg per day until the maximum dose of 2 mg/kg per day. The dose was then adjusted until week 24, based on patient weight and clinical response, after which parents could choose to continue the infant on the assigned medication or switch to the other one. Follow-up visits occurred every 2 months after that until week 52.

For the main study outcome, measured by visual analog scale (VAS) scores at week 24, the between-group differences of IH size and color from baseline were 8.8 and 17.1, respectively, in favor of the nadolol group, the researchers report, with similar results seen at week 52. Safety data were similar for both treatments, “demonstrating that nadolol was noninferior to propranolol,” they write.

Additionally, the mean size involution, compared with baseline was 97.9% in the nadolol group and 89.1% in the propranolol group, and the mean color fading was 94.5% in the nadolol group, compared with 80.5% in the propranolol group. During the study, nadolol was also “59% faster in achieving 75% shrinkage of IH, compared with propranolol (P = .02) and 105% faster in achieving 100% shrinkage (P = .07),” they add.

“A considerable portion of patients experienced at least one mild adverse event (77.1% vs. 94.4% at 0-24 weeks and 84.2% vs. 74.2% at 24-52 weeks in the nadolol group vs. the propranolol group, respectively), with a median of two in each intervention group,” they noted, adding that while these numbers are high, they are similar to those in previous clinical trials.

“The efficacy data coupled with a more predictable pharmacokinetic profile and lower chance of crossing the blood-brain barrier may make nadolol a favorable alternative intervention in patients with IHs,” the authors conclude. However, they add that “further studies are needed to prove superiority over propranolol.”

Asked to comment on the results, Ilona J. Frieden, MD, director of the Birthmarks & Vascular Anomalies Center at the University of California, San Francisco, said that while this is a “very interesting study and deserves further consideration,” the findings do not reach the level at which they would change guidelines. “The vast majority of patients being treated with a systemic medication for IH are in fact getting propranolol,” said Dr. Frieden, coauthor of the American Academy of Pediatrics Clinical Practice Guideline for the Management of Infantile Hemangiomas.

“Though this study – designed as a noninferiority study – does seem to show slightly better outcomes from nadolol versus propranolol … it is a relatively small study,” she told this news organization. “Infantile hemangiomas are a very heterogeneous group, and larger studies and longer-term outcome data would be needed to truly compare the two modalities of treatment.”

Concern over the safety of nadolol was raised in a case report published in Pediatrics, which described the death of a 10-week-old girl 7 weeks after starting nadolol for IH. The infant was found to have an elevated postmortem cardiac blood nadolol level of 0.94 mg/L. “Although we debated the conclusion of that report in terms of death attribution to nadolol, one practical pearl is to instruct the parents to discontinue nadolol if the baby has no bowel movements for more than 3 days,” Dr. Pope advised.

The author of that case report, Eric McGillis, MD, program director of clinical pharmacology and toxicology and an emergency physician at Alberta Health Services, in Calgary, Alt., said the conclusion of his report has been taken out of context. “We acknowledge that our case report, like any case report, cannot prove causation,” he told this news organization. “We hypothesized that nadolol may have contributed to the death of the infant based on the limited pharmacokinetic data currently available for nadolol in infants. Nadolol is largely eliminated in the feces and infants may have infrequent stooling based on diet and other factors; therefore, nadolol may accumulate,” he noted.

The infant in the case report did not have a bowel movement for 10 days “and had an elevated postmortem cardiac nadolol concentration in the absence of another obvious cause of death. More pharmacokinetic studies on nadolol in this population are needed to substantiate our hypothesis. However, in the meantime, we agree that having parents monitor stool output for dose adjustments makes practical sense and can potentially reduce harm.”

Dr. Pope presented the results of the study earlier this year at the annual meeting of the Society for Pediatric Dermatology.

The study was supported by Physician Services, Ont. Dr. Pope has reported serving as an advisory board member for Boehringer Ingelheim, Novartis, Sanofi Genzyme, and Timber. Other authors have reported receiving personal fees from Pierre Fabre during the conduct of the study, as well as personal fees from Amgen, Ipsen, Novartis, Pfizer, and Sanofi Genzyme; grants from AbbVie, Clementia, Mayne Pharma, and Sanofi Genzyme; and grants and personal fees from Venthera. One author has a patent for a new topical treatment of IH. Dr. Frieden has reported being a consultant for Pfizer (data safety board), Novartis, and Venthera. Dr. McGillis has reported no relevant financial relationships.

Commentary by Lawrence W. Eichenfield, MD

The treatment of functionally significant and deforming hemangiomas has been revolutionized by propranolol, developed after the observation by Christine Léauté-Labrèze, MD, that a child who developed hypertension as a side effect of systemic steroids for a nasal hemangioma and was prescribed propranolol for the hypertension had rapid shrinkage of the hemangioma. The study by Pope and colleagues assesses nadolol as an alternative to propranolol, showing noninferiority and in some parameters improved outcomes and speed of response. The drug appeared to be fairly well tolerated in the study, though there is a prior published case report of a death from nadolol use for hemangioma treatment from a different Canadian center. Nadolol may be an important alternative to propranolol; however, propranolol remains the only FDA-approved medication for infantile hemangiomas and the generally recommended medication in the American Academy of Pediatrics guidelines for management of infantile hemangiomas.

Dr. Eichenfield is chief of pediatric and adolescent dermatology at Rady Children's Hospital-San Diego. He is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego. He disclosed that he has served as an investigator and/or consultant to AbbVie, Lilly, Pfizer, Regeneron, Sanofi-Genzyme, and Verrica.

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

This article was updated 6/18/22.

Pediatric dermatologists who treat infantile hemangioma (IH) can consider nadolol as a noninferior – and possibly a better – alternative to the standard treatment propranolol, according to a study published in JAMA Pediatrics.

“In our experience, nadolol is preferable to propranolol given its observed efficacy and similar safety profile [and] its more predictable metabolism that does not involve the liver,” lead author Elena Pope, MD, told this news organization. “In addition, the fact that nadolol is less lipophilic than propranolol makes it less likely to cross the blood-brain barrier and potentially affect the central nervous system,” added Dr. Pope, who is head of the division of pediatric dermatology at the Hospital for Sick Children, Toronto, and professor of pediatric medicine at the University of Toronto.

The prospective double-blind, randomized noninferiority study was conducted between 2016 and 2020 at two tertiary academic pediatric dermatology clinics in Ontario, Canada. It included 71 infants with a corrected gestational age of 1-6 months whose hemangiomas were greater than 1.5 cm on the face or 3 cm or greater on another body part and had the potential to cause functional impairment or cosmetic disfigurement.

Patients were randomized to either nadolol (oral suspension, 10 mg/mL) or propranolol (oral suspension, 5 mg/mL) beginning at a dose of 0.5 mg/kg per day twice a day and titrated weekly by 0.5 mg/kg per day until the maximum dose of 2 mg/kg per day. The dose was then adjusted until week 24, based on patient weight and clinical response, after which parents could choose to continue the infant on the assigned medication or switch to the other one. Follow-up visits occurred every 2 months after that until week 52.

For the main study outcome, measured by visual analog scale (VAS) scores at week 24, the between-group differences of IH size and color from baseline were 8.8 and 17.1, respectively, in favor of the nadolol group, the researchers report, with similar results seen at week 52. Safety data were similar for both treatments, “demonstrating that nadolol was noninferior to propranolol,” they write.

Additionally, the mean size involution, compared with baseline was 97.9% in the nadolol group and 89.1% in the propranolol group, and the mean color fading was 94.5% in the nadolol group, compared with 80.5% in the propranolol group. During the study, nadolol was also “59% faster in achieving 75% shrinkage of IH, compared with propranolol (P = .02) and 105% faster in achieving 100% shrinkage (P = .07),” they add.

“A considerable portion of patients experienced at least one mild adverse event (77.1% vs. 94.4% at 0-24 weeks and 84.2% vs. 74.2% at 24-52 weeks in the nadolol group vs. the propranolol group, respectively), with a median of two in each intervention group,” they noted, adding that while these numbers are high, they are similar to those in previous clinical trials.

“The efficacy data coupled with a more predictable pharmacokinetic profile and lower chance of crossing the blood-brain barrier may make nadolol a favorable alternative intervention in patients with IHs,” the authors conclude. However, they add that “further studies are needed to prove superiority over propranolol.”

Asked to comment on the results, Ilona J. Frieden, MD, director of the Birthmarks & Vascular Anomalies Center at the University of California, San Francisco, said that while this is a “very interesting study and deserves further consideration,” the findings do not reach the level at which they would change guidelines. “The vast majority of patients being treated with a systemic medication for IH are in fact getting propranolol,” said Dr. Frieden, coauthor of the American Academy of Pediatrics Clinical Practice Guideline for the Management of Infantile Hemangiomas.

“Though this study – designed as a noninferiority study – does seem to show slightly better outcomes from nadolol versus propranolol … it is a relatively small study,” she told this news organization. “Infantile hemangiomas are a very heterogeneous group, and larger studies and longer-term outcome data would be needed to truly compare the two modalities of treatment.”

Concern over the safety of nadolol was raised in a case report published in Pediatrics, which described the death of a 10-week-old girl 7 weeks after starting nadolol for IH. The infant was found to have an elevated postmortem cardiac blood nadolol level of 0.94 mg/L. “Although we debated the conclusion of that report in terms of death attribution to nadolol, one practical pearl is to instruct the parents to discontinue nadolol if the baby has no bowel movements for more than 3 days,” Dr. Pope advised.

The author of that case report, Eric McGillis, MD, program director of clinical pharmacology and toxicology and an emergency physician at Alberta Health Services, in Calgary, Alt., said the conclusion of his report has been taken out of context. “We acknowledge that our case report, like any case report, cannot prove causation,” he told this news organization. “We hypothesized that nadolol may have contributed to the death of the infant based on the limited pharmacokinetic data currently available for nadolol in infants. Nadolol is largely eliminated in the feces and infants may have infrequent stooling based on diet and other factors; therefore, nadolol may accumulate,” he noted.

The infant in the case report did not have a bowel movement for 10 days “and had an elevated postmortem cardiac nadolol concentration in the absence of another obvious cause of death. More pharmacokinetic studies on nadolol in this population are needed to substantiate our hypothesis. However, in the meantime, we agree that having parents monitor stool output for dose adjustments makes practical sense and can potentially reduce harm.”

Dr. Pope presented the results of the study earlier this year at the annual meeting of the Society for Pediatric Dermatology.

The study was supported by Physician Services, Ont. Dr. Pope has reported serving as an advisory board member for Boehringer Ingelheim, Novartis, Sanofi Genzyme, and Timber. Other authors have reported receiving personal fees from Pierre Fabre during the conduct of the study, as well as personal fees from Amgen, Ipsen, Novartis, Pfizer, and Sanofi Genzyme; grants from AbbVie, Clementia, Mayne Pharma, and Sanofi Genzyme; and grants and personal fees from Venthera. One author has a patent for a new topical treatment of IH. Dr. Frieden has reported being a consultant for Pfizer (data safety board), Novartis, and Venthera. Dr. McGillis has reported no relevant financial relationships.

Commentary by Lawrence W. Eichenfield, MD

The treatment of functionally significant and deforming hemangiomas has been revolutionized by propranolol, developed after the observation by Christine Léauté-Labrèze, MD, that a child who developed hypertension as a side effect of systemic steroids for a nasal hemangioma and was prescribed propranolol for the hypertension had rapid shrinkage of the hemangioma. The study by Pope and colleagues assesses nadolol as an alternative to propranolol, showing noninferiority and in some parameters improved outcomes and speed of response. The drug appeared to be fairly well tolerated in the study, though there is a prior published case report of a death from nadolol use for hemangioma treatment from a different Canadian center. Nadolol may be an important alternative to propranolol; however, propranolol remains the only FDA-approved medication for infantile hemangiomas and the generally recommended medication in the American Academy of Pediatrics guidelines for management of infantile hemangiomas.

Dr. Eichenfield is chief of pediatric and adolescent dermatology at Rady Children's Hospital-San Diego. He is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego. He disclosed that he has served as an investigator and/or consultant to AbbVie, Lilly, Pfizer, Regeneron, Sanofi-Genzyme, and Verrica.

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

This article was updated 6/18/22.

Pediatric dermatologists who treat infantile hemangioma (IH) can consider nadolol as a noninferior – and possibly a better – alternative to the standard treatment propranolol, according to a study published in JAMA Pediatrics.

“In our experience, nadolol is preferable to propranolol given its observed efficacy and similar safety profile [and] its more predictable metabolism that does not involve the liver,” lead author Elena Pope, MD, told this news organization. “In addition, the fact that nadolol is less lipophilic than propranolol makes it less likely to cross the blood-brain barrier and potentially affect the central nervous system,” added Dr. Pope, who is head of the division of pediatric dermatology at the Hospital for Sick Children, Toronto, and professor of pediatric medicine at the University of Toronto.

The prospective double-blind, randomized noninferiority study was conducted between 2016 and 2020 at two tertiary academic pediatric dermatology clinics in Ontario, Canada. It included 71 infants with a corrected gestational age of 1-6 months whose hemangiomas were greater than 1.5 cm on the face or 3 cm or greater on another body part and had the potential to cause functional impairment or cosmetic disfigurement.

Patients were randomized to either nadolol (oral suspension, 10 mg/mL) or propranolol (oral suspension, 5 mg/mL) beginning at a dose of 0.5 mg/kg per day twice a day and titrated weekly by 0.5 mg/kg per day until the maximum dose of 2 mg/kg per day. The dose was then adjusted until week 24, based on patient weight and clinical response, after which parents could choose to continue the infant on the assigned medication or switch to the other one. Follow-up visits occurred every 2 months after that until week 52.

For the main study outcome, measured by visual analog scale (VAS) scores at week 24, the between-group differences of IH size and color from baseline were 8.8 and 17.1, respectively, in favor of the nadolol group, the researchers report, with similar results seen at week 52. Safety data were similar for both treatments, “demonstrating that nadolol was noninferior to propranolol,” they write.

Additionally, the mean size involution, compared with baseline was 97.9% in the nadolol group and 89.1% in the propranolol group, and the mean color fading was 94.5% in the nadolol group, compared with 80.5% in the propranolol group. During the study, nadolol was also “59% faster in achieving 75% shrinkage of IH, compared with propranolol (P = .02) and 105% faster in achieving 100% shrinkage (P = .07),” they add.

“A considerable portion of patients experienced at least one mild adverse event (77.1% vs. 94.4% at 0-24 weeks and 84.2% vs. 74.2% at 24-52 weeks in the nadolol group vs. the propranolol group, respectively), with a median of two in each intervention group,” they noted, adding that while these numbers are high, they are similar to those in previous clinical trials.

“The efficacy data coupled with a more predictable pharmacokinetic profile and lower chance of crossing the blood-brain barrier may make nadolol a favorable alternative intervention in patients with IHs,” the authors conclude. However, they add that “further studies are needed to prove superiority over propranolol.”

Asked to comment on the results, Ilona J. Frieden, MD, director of the Birthmarks & Vascular Anomalies Center at the University of California, San Francisco, said that while this is a “very interesting study and deserves further consideration,” the findings do not reach the level at which they would change guidelines. “The vast majority of patients being treated with a systemic medication for IH are in fact getting propranolol,” said Dr. Frieden, coauthor of the American Academy of Pediatrics Clinical Practice Guideline for the Management of Infantile Hemangiomas.

“Though this study – designed as a noninferiority study – does seem to show slightly better outcomes from nadolol versus propranolol … it is a relatively small study,” she told this news organization. “Infantile hemangiomas are a very heterogeneous group, and larger studies and longer-term outcome data would be needed to truly compare the two modalities of treatment.”

Concern over the safety of nadolol was raised in a case report published in Pediatrics, which described the death of a 10-week-old girl 7 weeks after starting nadolol for IH. The infant was found to have an elevated postmortem cardiac blood nadolol level of 0.94 mg/L. “Although we debated the conclusion of that report in terms of death attribution to nadolol, one practical pearl is to instruct the parents to discontinue nadolol if the baby has no bowel movements for more than 3 days,” Dr. Pope advised.

The author of that case report, Eric McGillis, MD, program director of clinical pharmacology and toxicology and an emergency physician at Alberta Health Services, in Calgary, Alt., said the conclusion of his report has been taken out of context. “We acknowledge that our case report, like any case report, cannot prove causation,” he told this news organization. “We hypothesized that nadolol may have contributed to the death of the infant based on the limited pharmacokinetic data currently available for nadolol in infants. Nadolol is largely eliminated in the feces and infants may have infrequent stooling based on diet and other factors; therefore, nadolol may accumulate,” he noted.

The infant in the case report did not have a bowel movement for 10 days “and had an elevated postmortem cardiac nadolol concentration in the absence of another obvious cause of death. More pharmacokinetic studies on nadolol in this population are needed to substantiate our hypothesis. However, in the meantime, we agree that having parents monitor stool output for dose adjustments makes practical sense and can potentially reduce harm.”

Dr. Pope presented the results of the study earlier this year at the annual meeting of the Society for Pediatric Dermatology.

The study was supported by Physician Services, Ont. Dr. Pope has reported serving as an advisory board member for Boehringer Ingelheim, Novartis, Sanofi Genzyme, and Timber. Other authors have reported receiving personal fees from Pierre Fabre during the conduct of the study, as well as personal fees from Amgen, Ipsen, Novartis, Pfizer, and Sanofi Genzyme; grants from AbbVie, Clementia, Mayne Pharma, and Sanofi Genzyme; and grants and personal fees from Venthera. One author has a patent for a new topical treatment of IH. Dr. Frieden has reported being a consultant for Pfizer (data safety board), Novartis, and Venthera. Dr. McGillis has reported no relevant financial relationships.

Commentary by Lawrence W. Eichenfield, MD

The treatment of functionally significant and deforming hemangiomas has been revolutionized by propranolol, developed after the observation by Christine Léauté-Labrèze, MD, that a child who developed hypertension as a side effect of systemic steroids for a nasal hemangioma and was prescribed propranolol for the hypertension had rapid shrinkage of the hemangioma. The study by Pope and colleagues assesses nadolol as an alternative to propranolol, showing noninferiority and in some parameters improved outcomes and speed of response. The drug appeared to be fairly well tolerated in the study, though there is a prior published case report of a death from nadolol use for hemangioma treatment from a different Canadian center. Nadolol may be an important alternative to propranolol; however, propranolol remains the only FDA-approved medication for infantile hemangiomas and the generally recommended medication in the American Academy of Pediatrics guidelines for management of infantile hemangiomas.

Dr. Eichenfield is chief of pediatric and adolescent dermatology at Rady Children's Hospital-San Diego. He is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego. He disclosed that he has served as an investigator and/or consultant to AbbVie, Lilly, Pfizer, Regeneron, Sanofi-Genzyme, and Verrica.

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

This article was updated 6/18/22.

Merck’s antiviral pill for COVID-19, molnupiravir, appears to be far less effective than early results from the clinical trial first suggested.

According to an analysis by scientists at the Food and Drug Administration, the experimental pill cut the risk of hospitalization or death from COVID-19 by about 30%, compared to a placebo, and the pill showed no benefit for people with antibodies against COVID-19 from prior infection.

The updated analysis showed 48 hospitalizations or deaths among study participants who were randomly assigned to take the antiviral drug, compared to 68 among those who took a placebo.

Those results come from the full set of 1,433 patients who were randomized in the clinical trial, which just became available last week.

Initial results from the first 775 patients enrolled in the clinical trial, which were issued in a company news release in October, had said the drug cut the risk of hospitalization or death for patients at high risk of severe disease by about 50%.

Merck has been producing millions of doses of molnupiravir, which is the first antiviral pill to treat COVID-19 infections. The United Kingdom’s drug regulator authorized use of the medication in early November. The company said it expected to distribute the medication globally by the end of 2021.

In October, two Indian drug companies halted late-stage clinical trials of a generic version of molnupiravir after the studies failed to find any benefit to patients with moderate COVID-19. Trials in patients with milder symptoms are still ongoing.

On Nov. 27, the New England Journal of Medicine postponed its planned early release of the molnupiravir study results, citing “new information.”

The medication is designed to be given as four pills taken every 12 hours for 5 days. It’s most effective when taken within the first few days of new symptoms, something that requires convenient and affordable testing.

The new results seem to put molnupiravir far below the effectiveness of existing treatments.

The infused monoclonal antibody cocktail REGEN-COV, which the FDA has already authorized for emergency use, is about 85% effective at preventing hospitalization or death in patients who are at risk for severe COVID-19 outcomes, and it appears to be just as effective in people who already have antibodies against COVID-19, which is why it is being given to both vaccinated and unvaccinated patients, the FDA said.

In early November, Pfizer said its experimental antiviral pill Paxlovid cut the risk of hospitalization or death by 89%.

In briefing documents posted ahead of an advisory committee meeting Nov. 30, the FDA highlights other potential safety issues with the Merck drug, which works by causing the virus to make mistakes as it copies itself, eventually causing the virus to mutate itself to death.

The agency has asked the advisory committee to weigh in on the right patient population for the drug: Should pregnant women get it? Could the drug harm a developing fetus?

Should vaccinated people with breakthrough infections get it? Would it work for them? People with reduced immune function are more likely to get a breakthrough infection. They’re also more likely to shed virus for a longer period of time, making them perfect incubators for variants. What could happen if we give this type of patient a drug that increases mutations?

And what about mutations caused by the medication? Could they increase the potential for more variants? The agency concluded the risk of this happening was low.

In animal studies, the drug impacted bone formation. For this reason, the agency has agreed with the drug company that molnupiravir should not be given to anyone under the age of 18.

Aside from these concerns, the FDA says there were no major safety issues among people who took part in the clinical trial, though they acknowledge that number is small.

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

Merck’s antiviral pill for COVID-19, molnupiravir, appears to be far less effective than early results from the clinical trial first suggested.

According to an analysis by scientists at the Food and Drug Administration, the experimental pill cut the risk of hospitalization or death from COVID-19 by about 30%, compared to a placebo, and the pill showed no benefit for people with antibodies against COVID-19 from prior infection.

The updated analysis showed 48 hospitalizations or deaths among study participants who were randomly assigned to take the antiviral drug, compared to 68 among those who took a placebo.

Those results come from the full set of 1,433 patients who were randomized in the clinical trial, which just became available last week.

Initial results from the first 775 patients enrolled in the clinical trial, which were issued in a company news release in October, had said the drug cut the risk of hospitalization or death for patients at high risk of severe disease by about 50%.

Merck has been producing millions of doses of molnupiravir, which is the first antiviral pill to treat COVID-19 infections. The United Kingdom’s drug regulator authorized use of the medication in early November. The company said it expected to distribute the medication globally by the end of 2021.

In October, two Indian drug companies halted late-stage clinical trials of a generic version of molnupiravir after the studies failed to find any benefit to patients with moderate COVID-19. Trials in patients with milder symptoms are still ongoing.

On Nov. 27, the New England Journal of Medicine postponed its planned early release of the molnupiravir study results, citing “new information.”

The medication is designed to be given as four pills taken every 12 hours for 5 days. It’s most effective when taken within the first few days of new symptoms, something that requires convenient and affordable testing.

The new results seem to put molnupiravir far below the effectiveness of existing treatments.

The infused monoclonal antibody cocktail REGEN-COV, which the FDA has already authorized for emergency use, is about 85% effective at preventing hospitalization or death in patients who are at risk for severe COVID-19 outcomes, and it appears to be just as effective in people who already have antibodies against COVID-19, which is why it is being given to both vaccinated and unvaccinated patients, the FDA said.

In early November, Pfizer said its experimental antiviral pill Paxlovid cut the risk of hospitalization or death by 89%.

In briefing documents posted ahead of an advisory committee meeting Nov. 30, the FDA highlights other potential safety issues with the Merck drug, which works by causing the virus to make mistakes as it copies itself, eventually causing the virus to mutate itself to death.

The agency has asked the advisory committee to weigh in on the right patient population for the drug: Should pregnant women get it? Could the drug harm a developing fetus?

Should vaccinated people with breakthrough infections get it? Would it work for them? People with reduced immune function are more likely to get a breakthrough infection. They’re also more likely to shed virus for a longer period of time, making them perfect incubators for variants. What could happen if we give this type of patient a drug that increases mutations?

And what about mutations caused by the medication? Could they increase the potential for more variants? The agency concluded the risk of this happening was low.

In animal studies, the drug impacted bone formation. For this reason, the agency has agreed with the drug company that molnupiravir should not be given to anyone under the age of 18.

Aside from these concerns, the FDA says there were no major safety issues among people who took part in the clinical trial, though they acknowledge that number is small.

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

Merck’s antiviral pill for COVID-19, molnupiravir, appears to be far less effective than early results from the clinical trial first suggested.

According to an analysis by scientists at the Food and Drug Administration, the experimental pill cut the risk of hospitalization or death from COVID-19 by about 30%, compared to a placebo, and the pill showed no benefit for people with antibodies against COVID-19 from prior infection.

The updated analysis showed 48 hospitalizations or deaths among study participants who were randomly assigned to take the antiviral drug, compared to 68 among those who took a placebo.

Those results come from the full set of 1,433 patients who were randomized in the clinical trial, which just became available last week.

Initial results from the first 775 patients enrolled in the clinical trial, which were issued in a company news release in October, had said the drug cut the risk of hospitalization or death for patients at high risk of severe disease by about 50%.

Merck has been producing millions of doses of molnupiravir, which is the first antiviral pill to treat COVID-19 infections. The United Kingdom’s drug regulator authorized use of the medication in early November. The company said it expected to distribute the medication globally by the end of 2021.

In October, two Indian drug companies halted late-stage clinical trials of a generic version of molnupiravir after the studies failed to find any benefit to patients with moderate COVID-19. Trials in patients with milder symptoms are still ongoing.

On Nov. 27, the New England Journal of Medicine postponed its planned early release of the molnupiravir study results, citing “new information.”

The medication is designed to be given as four pills taken every 12 hours for 5 days. It’s most effective when taken within the first few days of new symptoms, something that requires convenient and affordable testing.

The new results seem to put molnupiravir far below the effectiveness of existing treatments.

The infused monoclonal antibody cocktail REGEN-COV, which the FDA has already authorized for emergency use, is about 85% effective at preventing hospitalization or death in patients who are at risk for severe COVID-19 outcomes, and it appears to be just as effective in people who already have antibodies against COVID-19, which is why it is being given to both vaccinated and unvaccinated patients, the FDA said.

In early November, Pfizer said its experimental antiviral pill Paxlovid cut the risk of hospitalization or death by 89%.

In briefing documents posted ahead of an advisory committee meeting Nov. 30, the FDA highlights other potential safety issues with the Merck drug, which works by causing the virus to make mistakes as it copies itself, eventually causing the virus to mutate itself to death.

The agency has asked the advisory committee to weigh in on the right patient population for the drug: Should pregnant women get it? Could the drug harm a developing fetus?

Should vaccinated people with breakthrough infections get it? Would it work for them? People with reduced immune function are more likely to get a breakthrough infection. They’re also more likely to shed virus for a longer period of time, making them perfect incubators for variants. What could happen if we give this type of patient a drug that increases mutations?

And what about mutations caused by the medication? Could they increase the potential for more variants? The agency concluded the risk of this happening was low.

In animal studies, the drug impacted bone formation. For this reason, the agency has agreed with the drug company that molnupiravir should not be given to anyone under the age of 18.

Aside from these concerns, the FDA says there were no major safety issues among people who took part in the clinical trial, though they acknowledge that number is small.

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

Ramy Sedhom, MD, a medical oncologist and a palliative care physician at Penn Medicine Princeton Health in Plainsboro, N.J., will always wonder if prior authorization refusals led to his patient’s death.

The patient had advanced gastric cancer and the insurer initially denied a PET scan to rule out metastatic disease. When the scan was eventually allowed, it revealed that the cancer had spread.

Standard treatment would have been difficult for the patient, an older individual with comorbidities. But Dr. Sedhom knew that a European study had reported equal efficacy and fewer side effects with a reduced chemotherapy regimen, and he thought that was the best approach in this situation.

The insurer disagreed with Dr. Sedhom’s decision and, while the two argued, the patient’s symptoms worsened. He was admitted to the hospital, where he experienced a decline in function, common for older patients. “Long story short, he was never able to seek treatment and then transitioned to hospice,” Dr. Sedhom said. “It was one of those situations where there was a 3- to 4-week delay in what should have been standard care.”

That course of events is not an outlier but everyday life for physicians trying to navigate insurers’ prior authorization rules before they can treat their patients. Nearly 4 years after major organizations — American Hospital Association, America’s Health Insurance Plans, American Medical Association, Blue Cross Blue Shield Association, and others — signed a consensus statement agreeing to improve the prior authorization process, physicians say little progress has been made.

Indeed, 83% of physicians say that the number of prior authorizations required for prescription medications and medical services has increased over the last 5 years, according to survey results released earlier this year.

“It’s decidedly worse — there’s no question about it,” said Andrew R. Spector, MD, a neurologist and sleep medicine specialist at Duke Health in Durham, N.C. “Drugs that I used to get without prior authorizations now require them.”

When Vignesh I. Doraiswamy, MD, an internal medicine hospitalist at the Ohio State University Wexner Medical Center in Columbus, discharged a patient with Clostridioides difficile infection, he followed clinical guidelines to prescribe vancomycin for 10 to 14 days. “And the insurance company said, ‘Well, yeah, we only authorize about 5 days,’ which just makes no sense,” Dr. Doraiswamy said. “There’s nowhere in any literature that says 5 days is sufficient. What worries me is that is the standard of care we are supposed to give and yet we are unable to.”

Yash B. Jobanputra, MD, a cardiology fellow at Saint Vincent Hospital in Worcester, Mass., laments that prior authorization is used in situations that simply do not make common sense. During his residency, a woman who had tested positive for the BRCA gene mutation with a strong family history of breast cancer needed a breast ultrasound and an MRI scan every 6 months to 1 year. Despite the documentation that she was at extremely high risk for developing breast cancer, he had to go through prior authorization every time she was due for new images.

“I had to call the insurance company, they would put me on hold, I would wait to speak to a physician — and the end response would be, ‘Yeah, this is what needs to be done,’” he said. “But having established her positive status once should be enough really. I shouldn’t have to go through the circus all over again.”

Prior authorization is also being used for routine diagnostics, such as a Holter monitor for patients complaining of heart palpitations. “Depending on the insurance, for some patients we can give it to them in the clinic right away,” Dr. Jobanputra said. “Whereas some others we have to wait until we get prior authorization from the insurance company and the patient has to come back again to the hospital to get the monitor. That is a delay in patient care.”

The delays also extend to emergency care, Dr. Doraiswamy said. He cites the example of a heart attack patient who needed an emergency heart catheterization but ran into a prior authorization delay. “I just said, ‘Try your best not to get stressed’ which is not easy for a patient finding out their stay wasn’t covered when they had just been through a heart attack,” he said. “Then I spent 20 to 30 minutes — most of it on hold — to answer the question ‘Why did this patient need to get admitted?’ “

Physicians feel disrespected because that type of prior authorization hassle is just busywork. “Rarely is a valid stay that was initially denied, not eventually accepted,” Dr. Doraiswamy said. “But why couldn’t they have just seen that the guy had a heart attack and he obviously needed to be in the hospital?”

For Dr. Spector, the Duke Health sleep medicine specialist, prior authorization is not just a speed bump, it’s a full stop. Insurers have started mandating a multiple sleep latency test (MSLT) to confirm narcolepsy before covering medication to treat the condition. “We know that the MSLT is very often wrong,” he said. “There are a lot of times we’re dealing with patients with narcolepsy who simply don’t meet the testing criteria that the insurance requires, and payers will not accept our clinical judgment.”

In his view, the prior authorization landscape is worsening — and not only because a “faulty test” is being used to deny treatment. “The appeal process is worse,” Dr. Spector said. “I used to be able to get on the phone and do a peer-to-peer review with a physician who I could reason with… but that doesn’t happen anymore. There is virtually no way to bypass these blanket rules.”

Other survey findings also stand in direct contradiction of the 2018 consensus agreement:

A large majority (87%) of physicians report that prior authorization interferes with continuity of care, even though the industry groups agreed that patients should be protected from treatment disruption when there is a formulary or treatment-coverage change.

Despite a consensus to encourage transparency and easy accessibility of prior authorization requirements, 68% of physicians reported that it is difficult to determine whether a prescription medication requires prior authorization, and 58% report that it’s difficult for medical services.

Phone and fax are the most commonly used methods for completing prior authorizations, despite agreement that electronic prior authorization, using existing national standard transactions, should be accelerated. Fewer than one quarter of physicians said that their electronic health record system supports electronic prior authorization for prescription medications.

Dr. Spector wants to see legislation that forces insurers to live up to some of the tenets of the 2018 consensus statement. In September, a new Texas law went into effect, exempting physicians from prior authorization if, during the previous six months, 90% of their treatments met an insurer›s medical necessity criteria. In January, the recently approved Prior Authorization Reform Act in Illinois will reduce the number of services subject to prior authorization, mandate a prior authorization decision within 5 days, and set disciplinary measures for health plans that do not comply, among other things.

“What gives me hope is that at least somewhere in the country, somebody is doing something,” Dr. Spector said. “And if it goes well, maybe other insurers will adopt it. I’m really hoping they demonstrate that the money they can save on the administration of all the appeals and prior authorization paperwork can actually go into caring for patients.”

In addition to state-level action, reform may also be advancing at the federal level. In October, a bill was introduced in the U.S. Senate that mirrors a prior authorization reform bill introduced in the House of Representatives last May. Both bills have broad bipartisan support; the House bill has more than 235 co-sponsors.

In an interview with this news organization, Rep. Ami Bera, MD, (D-CA) said it is “very realistic” that the bill will become law during this session of Congress. “We do think this bill will get marked up in committee and hopefully we can get it to the floor either as a stand-alone bill where we know we have the votes to pass it or as part of a larger legislative package,” he said.

If approved, the Improving Seniors’ Timely Access to Care Act of 2021 would require that Medicare Advantage plans minimize the use of prior authorization for routinely approved services; require real-time decisions for certain requests; report the extent of their use of prior authorization and their rate of approvals or denials, among other things; and establish an electronic prior authorization system.

Medicare Advantage plans are private insurers that are regulated by the Centers for Medicare & Medicaid Services (CMS), which will create the specific rules and penalties associated with the reforms, if they become law. “One would presume that a condition of being a Medicare Advantage plan is that you’re going to have to comply with these new regulations,” said Katie Orrico, senior vice president of health policy and advocacy for the American Association of Neurological Surgeons and Congress of Neurological Surgeons (AANS/CNS). “So they will have some amount of teeth in the form of a mandate.”

The AANS and CNS are part of the Regulatory Relief Coalition, a group of 14 national physician specialty organizations. Winning prior authorization reform in the Medicare Advantage plans is part of its bigger strategy. “If those commercial plans have to follow a set of rules and processes for Medicare, then why not just expand those same processes to all other parts of their business?” Ms. Orrico said. 

Despite his frustration with their prior authorization processes, Dr. Doraiswamy, the Ohio State hospitalist, agrees that working to improve insurers’ practices is the best way forward. “It’s so easy to make them look like these evil, giant conglomerations that exist solely to suck money and not care about anyone’s health, but I don’t know if that’s necessarily the case,” he said. “We really have to figure out how best to work with insurance companies to make sure that, while they are profit-generating institutions, that [profit] shouldn’t come at the cost of patient care.”

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

Ramy Sedhom, MD, a medical oncologist and a palliative care physician at Penn Medicine Princeton Health in Plainsboro, N.J., will always wonder if prior authorization refusals led to his patient’s death.

The patient had advanced gastric cancer and the insurer initially denied a PET scan to rule out metastatic disease. When the scan was eventually allowed, it revealed that the cancer had spread.

Standard treatment would have been difficult for the patient, an older individual with comorbidities. But Dr. Sedhom knew that a European study had reported equal efficacy and fewer side effects with a reduced chemotherapy regimen, and he thought that was the best approach in this situation.

The insurer disagreed with Dr. Sedhom’s decision and, while the two argued, the patient’s symptoms worsened. He was admitted to the hospital, where he experienced a decline in function, common for older patients. “Long story short, he was never able to seek treatment and then transitioned to hospice,” Dr. Sedhom said. “It was one of those situations where there was a 3- to 4-week delay in what should have been standard care.”

That course of events is not an outlier but everyday life for physicians trying to navigate insurers’ prior authorization rules before they can treat their patients. Nearly 4 years after major organizations — American Hospital Association, America’s Health Insurance Plans, American Medical Association, Blue Cross Blue Shield Association, and others — signed a consensus statement agreeing to improve the prior authorization process, physicians say little progress has been made.

Indeed, 83% of physicians say that the number of prior authorizations required for prescription medications and medical services has increased over the last 5 years, according to survey results released earlier this year.

“It’s decidedly worse — there’s no question about it,” said Andrew R. Spector, MD, a neurologist and sleep medicine specialist at Duke Health in Durham, N.C. “Drugs that I used to get without prior authorizations now require them.”

When Vignesh I. Doraiswamy, MD, an internal medicine hospitalist at the Ohio State University Wexner Medical Center in Columbus, discharged a patient with Clostridioides difficile infection, he followed clinical guidelines to prescribe vancomycin for 10 to 14 days. “And the insurance company said, ‘Well, yeah, we only authorize about 5 days,’ which just makes no sense,” Dr. Doraiswamy said. “There’s nowhere in any literature that says 5 days is sufficient. What worries me is that is the standard of care we are supposed to give and yet we are unable to.”

Yash B. Jobanputra, MD, a cardiology fellow at Saint Vincent Hospital in Worcester, Mass., laments that prior authorization is used in situations that simply do not make common sense. During his residency, a woman who had tested positive for the BRCA gene mutation with a strong family history of breast cancer needed a breast ultrasound and an MRI scan every 6 months to 1 year. Despite the documentation that she was at extremely high risk for developing breast cancer, he had to go through prior authorization every time she was due for new images.

“I had to call the insurance company, they would put me on hold, I would wait to speak to a physician — and the end response would be, ‘Yeah, this is what needs to be done,’” he said. “But having established her positive status once should be enough really. I shouldn’t have to go through the circus all over again.”

Prior authorization is also being used for routine diagnostics, such as a Holter monitor for patients complaining of heart palpitations. “Depending on the insurance, for some patients we can give it to them in the clinic right away,” Dr. Jobanputra said. “Whereas some others we have to wait until we get prior authorization from the insurance company and the patient has to come back again to the hospital to get the monitor. That is a delay in patient care.”

The delays also extend to emergency care, Dr. Doraiswamy said. He cites the example of a heart attack patient who needed an emergency heart catheterization but ran into a prior authorization delay. “I just said, ‘Try your best not to get stressed’ which is not easy for a patient finding out their stay wasn’t covered when they had just been through a heart attack,” he said. “Then I spent 20 to 30 minutes — most of it on hold — to answer the question ‘Why did this patient need to get admitted?’ “

Physicians feel disrespected because that type of prior authorization hassle is just busywork. “Rarely is a valid stay that was initially denied, not eventually accepted,” Dr. Doraiswamy said. “But why couldn’t they have just seen that the guy had a heart attack and he obviously needed to be in the hospital?”

For Dr. Spector, the Duke Health sleep medicine specialist, prior authorization is not just a speed bump, it’s a full stop. Insurers have started mandating a multiple sleep latency test (MSLT) to confirm narcolepsy before covering medication to treat the condition. “We know that the MSLT is very often wrong,” he said. “There are a lot of times we’re dealing with patients with narcolepsy who simply don’t meet the testing criteria that the insurance requires, and payers will not accept our clinical judgment.”

In his view, the prior authorization landscape is worsening — and not only because a “faulty test” is being used to deny treatment. “The appeal process is worse,” Dr. Spector said. “I used to be able to get on the phone and do a peer-to-peer review with a physician who I could reason with… but that doesn’t happen anymore. There is virtually no way to bypass these blanket rules.”

Other survey findings also stand in direct contradiction of the 2018 consensus agreement:

A large majority (87%) of physicians report that prior authorization interferes with continuity of care, even though the industry groups agreed that patients should be protected from treatment disruption when there is a formulary or treatment-coverage change.

Despite a consensus to encourage transparency and easy accessibility of prior authorization requirements, 68% of physicians reported that it is difficult to determine whether a prescription medication requires prior authorization, and 58% report that it’s difficult for medical services.

Phone and fax are the most commonly used methods for completing prior authorizations, despite agreement that electronic prior authorization, using existing national standard transactions, should be accelerated. Fewer than one quarter of physicians said that their electronic health record system supports electronic prior authorization for prescription medications.

Dr. Spector wants to see legislation that forces insurers to live up to some of the tenets of the 2018 consensus statement. In September, a new Texas law went into effect, exempting physicians from prior authorization if, during the previous six months, 90% of their treatments met an insurer›s medical necessity criteria. In January, the recently approved Prior Authorization Reform Act in Illinois will reduce the number of services subject to prior authorization, mandate a prior authorization decision within 5 days, and set disciplinary measures for health plans that do not comply, among other things.

“What gives me hope is that at least somewhere in the country, somebody is doing something,” Dr. Spector said. “And if it goes well, maybe other insurers will adopt it. I’m really hoping they demonstrate that the money they can save on the administration of all the appeals and prior authorization paperwork can actually go into caring for patients.”

In addition to state-level action, reform may also be advancing at the federal level. In October, a bill was introduced in the U.S. Senate that mirrors a prior authorization reform bill introduced in the House of Representatives last May. Both bills have broad bipartisan support; the House bill has more than 235 co-sponsors.

In an interview with this news organization, Rep. Ami Bera, MD, (D-CA) said it is “very realistic” that the bill will become law during this session of Congress. “We do think this bill will get marked up in committee and hopefully we can get it to the floor either as a stand-alone bill where we know we have the votes to pass it or as part of a larger legislative package,” he said.

If approved, the Improving Seniors’ Timely Access to Care Act of 2021 would require that Medicare Advantage plans minimize the use of prior authorization for routinely approved services; require real-time decisions for certain requests; report the extent of their use of prior authorization and their rate of approvals or denials, among other things; and establish an electronic prior authorization system.

Medicare Advantage plans are private insurers that are regulated by the Centers for Medicare & Medicaid Services (CMS), which will create the specific rules and penalties associated with the reforms, if they become law. “One would presume that a condition of being a Medicare Advantage plan is that you’re going to have to comply with these new regulations,” said Katie Orrico, senior vice president of health policy and advocacy for the American Association of Neurological Surgeons and Congress of Neurological Surgeons (AANS/CNS). “So they will have some amount of teeth in the form of a mandate.”

The AANS and CNS are part of the Regulatory Relief Coalition, a group of 14 national physician specialty organizations. Winning prior authorization reform in the Medicare Advantage plans is part of its bigger strategy. “If those commercial plans have to follow a set of rules and processes for Medicare, then why not just expand those same processes to all other parts of their business?” Ms. Orrico said. 

Despite his frustration with their prior authorization processes, Dr. Doraiswamy, the Ohio State hospitalist, agrees that working to improve insurers’ practices is the best way forward. “It’s so easy to make them look like these evil, giant conglomerations that exist solely to suck money and not care about anyone’s health, but I don’t know if that’s necessarily the case,” he said. “We really have to figure out how best to work with insurance companies to make sure that, while they are profit-generating institutions, that [profit] shouldn’t come at the cost of patient care.”

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

Ramy Sedhom, MD, a medical oncologist and a palliative care physician at Penn Medicine Princeton Health in Plainsboro, N.J., will always wonder if prior authorization refusals led to his patient’s death.

The patient had advanced gastric cancer and the insurer initially denied a PET scan to rule out metastatic disease. When the scan was eventually allowed, it revealed that the cancer had spread.

Standard treatment would have been difficult for the patient, an older individual with comorbidities. But Dr. Sedhom knew that a European study had reported equal efficacy and fewer side effects with a reduced chemotherapy regimen, and he thought that was the best approach in this situation.

The insurer disagreed with Dr. Sedhom’s decision and, while the two argued, the patient’s symptoms worsened. He was admitted to the hospital, where he experienced a decline in function, common for older patients. “Long story short, he was never able to seek treatment and then transitioned to hospice,” Dr. Sedhom said. “It was one of those situations where there was a 3- to 4-week delay in what should have been standard care.”

That course of events is not an outlier but everyday life for physicians trying to navigate insurers’ prior authorization rules before they can treat their patients. Nearly 4 years after major organizations — American Hospital Association, America’s Health Insurance Plans, American Medical Association, Blue Cross Blue Shield Association, and others — signed a consensus statement agreeing to improve the prior authorization process, physicians say little progress has been made.

Indeed, 83% of physicians say that the number of prior authorizations required for prescription medications and medical services has increased over the last 5 years, according to survey results released earlier this year.

“It’s decidedly worse — there’s no question about it,” said Andrew R. Spector, MD, a neurologist and sleep medicine specialist at Duke Health in Durham, N.C. “Drugs that I used to get without prior authorizations now require them.”

When Vignesh I. Doraiswamy, MD, an internal medicine hospitalist at the Ohio State University Wexner Medical Center in Columbus, discharged a patient with Clostridioides difficile infection, he followed clinical guidelines to prescribe vancomycin for 10 to 14 days. “And the insurance company said, ‘Well, yeah, we only authorize about 5 days,’ which just makes no sense,” Dr. Doraiswamy said. “There’s nowhere in any literature that says 5 days is sufficient. What worries me is that is the standard of care we are supposed to give and yet we are unable to.”

Yash B. Jobanputra, MD, a cardiology fellow at Saint Vincent Hospital in Worcester, Mass., laments that prior authorization is used in situations that simply do not make common sense. During his residency, a woman who had tested positive for the BRCA gene mutation with a strong family history of breast cancer needed a breast ultrasound and an MRI scan every 6 months to 1 year. Despite the documentation that she was at extremely high risk for developing breast cancer, he had to go through prior authorization every time she was due for new images.

“I had to call the insurance company, they would put me on hold, I would wait to speak to a physician — and the end response would be, ‘Yeah, this is what needs to be done,’” he said. “But having established her positive status once should be enough really. I shouldn’t have to go through the circus all over again.”

Prior authorization is also being used for routine diagnostics, such as a Holter monitor for patients complaining of heart palpitations. “Depending on the insurance, for some patients we can give it to them in the clinic right away,” Dr. Jobanputra said. “Whereas some others we have to wait until we get prior authorization from the insurance company and the patient has to come back again to the hospital to get the monitor. That is a delay in patient care.”

The delays also extend to emergency care, Dr. Doraiswamy said. He cites the example of a heart attack patient who needed an emergency heart catheterization but ran into a prior authorization delay. “I just said, ‘Try your best not to get stressed’ which is not easy for a patient finding out their stay wasn’t covered when they had just been through a heart attack,” he said. “Then I spent 20 to 30 minutes — most of it on hold — to answer the question ‘Why did this patient need to get admitted?’ “

Physicians feel disrespected because that type of prior authorization hassle is just busywork. “Rarely is a valid stay that was initially denied, not eventually accepted,” Dr. Doraiswamy said. “But why couldn’t they have just seen that the guy had a heart attack and he obviously needed to be in the hospital?”

For Dr. Spector, the Duke Health sleep medicine specialist, prior authorization is not just a speed bump, it’s a full stop. Insurers have started mandating a multiple sleep latency test (MSLT) to confirm narcolepsy before covering medication to treat the condition. “We know that the MSLT is very often wrong,” he said. “There are a lot of times we’re dealing with patients with narcolepsy who simply don’t meet the testing criteria that the insurance requires, and payers will not accept our clinical judgment.”

In his view, the prior authorization landscape is worsening — and not only because a “faulty test” is being used to deny treatment. “The appeal process is worse,” Dr. Spector said. “I used to be able to get on the phone and do a peer-to-peer review with a physician who I could reason with… but that doesn’t happen anymore. There is virtually no way to bypass these blanket rules.”

Other survey findings also stand in direct contradiction of the 2018 consensus agreement:

A large majority (87%) of physicians report that prior authorization interferes with continuity of care, even though the industry groups agreed that patients should be protected from treatment disruption when there is a formulary or treatment-coverage change.

Despite a consensus to encourage transparency and easy accessibility of prior authorization requirements, 68% of physicians reported that it is difficult to determine whether a prescription medication requires prior authorization, and 58% report that it’s difficult for medical services.

Phone and fax are the most commonly used methods for completing prior authorizations, despite agreement that electronic prior authorization, using existing national standard transactions, should be accelerated. Fewer than one quarter of physicians said that their electronic health record system supports electronic prior authorization for prescription medications.

Dr. Spector wants to see legislation that forces insurers to live up to some of the tenets of the 2018 consensus statement. In September, a new Texas law went into effect, exempting physicians from prior authorization if, during the previous six months, 90% of their treatments met an insurer›s medical necessity criteria. In January, the recently approved Prior Authorization Reform Act in Illinois will reduce the number of services subject to prior authorization, mandate a prior authorization decision within 5 days, and set disciplinary measures for health plans that do not comply, among other things.

“What gives me hope is that at least somewhere in the country, somebody is doing something,” Dr. Spector said. “And if it goes well, maybe other insurers will adopt it. I’m really hoping they demonstrate that the money they can save on the administration of all the appeals and prior authorization paperwork can actually go into caring for patients.”

In addition to state-level action, reform may also be advancing at the federal level. In October, a bill was introduced in the U.S. Senate that mirrors a prior authorization reform bill introduced in the House of Representatives last May. Both bills have broad bipartisan support; the House bill has more than 235 co-sponsors.

In an interview with this news organization, Rep. Ami Bera, MD, (D-CA) said it is “very realistic” that the bill will become law during this session of Congress. “We do think this bill will get marked up in committee and hopefully we can get it to the floor either as a stand-alone bill where we know we have the votes to pass it or as part of a larger legislative package,” he said.

If approved, the Improving Seniors’ Timely Access to Care Act of 2021 would require that Medicare Advantage plans minimize the use of prior authorization for routinely approved services; require real-time decisions for certain requests; report the extent of their use of prior authorization and their rate of approvals or denials, among other things; and establish an electronic prior authorization system.

Medicare Advantage plans are private insurers that are regulated by the Centers for Medicare & Medicaid Services (CMS), which will create the specific rules and penalties associated with the reforms, if they become law. “One would presume that a condition of being a Medicare Advantage plan is that you’re going to have to comply with these new regulations,” said Katie Orrico, senior vice president of health policy and advocacy for the American Association of Neurological Surgeons and Congress of Neurological Surgeons (AANS/CNS). “So they will have some amount of teeth in the form of a mandate.”

The AANS and CNS are part of the Regulatory Relief Coalition, a group of 14 national physician specialty organizations. Winning prior authorization reform in the Medicare Advantage plans is part of its bigger strategy. “If those commercial plans have to follow a set of rules and processes for Medicare, then why not just expand those same processes to all other parts of their business?” Ms. Orrico said. 

Despite his frustration with their prior authorization processes, Dr. Doraiswamy, the Ohio State hospitalist, agrees that working to improve insurers’ practices is the best way forward. “It’s so easy to make them look like these evil, giant conglomerations that exist solely to suck money and not care about anyone’s health, but I don’t know if that’s necessarily the case,” he said. “We really have to figure out how best to work with insurance companies to make sure that, while they are profit-generating institutions, that [profit] shouldn’t come at the cost of patient care.”

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

There is a significant inverse relationship between concentrations of circulating 25-hydroxy-vitamin D (25[OH]D) and all-cause mortality, but only in people with vitamin D deficiency, suggests a new large-scale analysis.

Data on more than 380,000 participants gathered from 35 studies showed that, overall, there is no significant relationship between 25(OH)D concentrations, a clinical indicator of vitamin D status, and the incidence of coronary heart disease (CHD), stroke, or all-cause death, in a Mendelian randomization analysis.

However, Stephen Burgess, PhD, and colleagues showed that, in vitamin D–deficient individuals, each 10 nmol/L increase in 25(OH)D concentrations reduced the risk of all-cause mortality by 31%.

The research, published in The Lancet Diabetes & Endocrinology, also suggests there was a nonsignificant link between 25(OH)D concentrations and stroke and CHD, but again, only in vitamin D deficient individuals.

In an accompanying editorial, Guillaume Butler-Laporte, MD, and J. Brent Richards, MD, praise the researchers on their study methodology.

They add that the results “could have important public health and clinical consequences” and will “allow clinicians to better weigh the potential benefits of supplementation against its risk,” such as financial cost, “for better patient care – particularly among those with frank vitamin D deficiency.”

They continue: “Given that vitamin D deficiency is relatively common and vitamin D supplementation is safe, the rationale exists to test the effect of vitamin D supplementation in those with deficiency in large-scale randomized controlled trials.”

However, Dr. Butler-Laporte and Dr. Richards, of the Lady Davis Institute, Jewish General Hospital, Montreal, also note the study has several limitations, including the fact that the lifetime exposure to lower vitamin D levels captured by Mendelian randomization may result in larger effect sizes than in conventional trials.
 

Prior RCTS underpowered to detect effects of vitamin D supplements

“There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality, including mechanisms linking low vitamin D status with hyperparathyroidism and low serum calcium and phosphate,” write Dr. Burgess of the MRC Biostatistics Unit, University of Cambridge (England), and coauthors.

They also highlight that vitamin D is “further implicated in endothelial cell function” and affects the transcription of genes linked to cell division and apoptosis, providing “potential mechanisms implicating vitamin D for cancer.”

The researchers note that, while epidemiologic studies have “consistently” found a link between 25(OH)D levels and increased risk of cardiovascular disease, all-cause mortality, and other chronic diseases, several large trials of vitamin D supplementation have reported “null results.”

They argue, however, that many of these trials have recruited individuals “irrespective of baseline 25(OH)D concentration” and have been underpowered to detect the effects of supplementation.

To overcome these limitations, the team gathered data from the UK Biobank, the European Prospective Investigation Into Cancer and Nutrition Cardiovascular Disease (EPIC-CVD) study, 31 studies from the Vitamin D Studies Collaboration (VitDSC), and two Copenhagen population-based studies.

They first performed an observational study that included 384,721 individuals from the UK Biobank and 26,336 from EPIC-CVD who had a valid 25(OH)D measurement and no previously known cardiovascular disease at baseline.

Researchers also included 67,992 participants from the VitDSC studies who did not have previously known cardiovascular disease. They analyzed 25(OH)D concentrations, conventional cardiovascular risk factors, and major incident cardiovascular morbidity and mortality using individual participant data.

The results showed that, at low 25(OH)D concentrations, there was an inverse association between 25(OH)D and incident CHD, stroke, and all-cause mortality.

Next, the team conducted a Mendelian randomization analysis on 333,002 individuals from the UK Biobank and 26,336 from EPIC-CVD who were of European ancestry and had both a valid 25(OH)D measurement and genetic data that passed quality-control steps.

Information on 31,362 participants in the Copenhagen population-based studies was also included, giving a total of 386,406 individuals, of whom 33,546 had CHD, 18,166 had a stroke, and 27,885 died.

The mean age of participants ranged from 54.8 to 57.5 years, and between 53.4% and 55.4% were female.
 

Up to 7% of study participants were vitamin D deficient

The 25(OH)D analysis indicated that 3.9% of UK Biobank and 3.7% of Copenhagen study participants were deficient, compared with 6.9% in EPIC-CVD.

Across the full range of 25(OH)D concentrations, there was no significant association between genetically predicted 25(OH)D levels and CHD, stroke, or all-cause mortality.

However, restricting the analysis to individuals deemed vitamin D deficient (25[OH]D concentration < 25 nmol/L) revealed there was “strong evidence” for an inverse association with all-cause mortality, at an odds ratio per 10 nmol/L increase in genetically predicted 25(OH)D concentration of 0.69 (P < .0001), the team notes.

There were also nonsignificant associations between being in the deficient stratum and CHD, at an odds ratio of 0.89 (P = .14), and stroke, at an odds ratio of 0.85 (P = .09).

Further analysis suggests the association between 25(OH)D concentrations and all-cause mortality has a “clear threshold shape,” the researchers say, with evidence of an inverse association at concentrations below 40 nmol/L and null associations above that threshold.

They acknowledge, however, that their study has several potential limitations, including the assumption in their Mendelian randomization that the “only causal pathway from the genetic variants to the outcome is via 25(OH)D concentrations.”

Moreover, the genetic variants may affect 25(OH)D concentrations in a different way from “dietary supplementation or other clinical interventions.”

They also concede that their study was limited to middle-aged participants of European ancestries, which means the findings “might not be applicable to other populations.”

The study was funded by the British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. Dr. Burgess has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

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

There is a significant inverse relationship between concentrations of circulating 25-hydroxy-vitamin D (25[OH]D) and all-cause mortality, but only in people with vitamin D deficiency, suggests a new large-scale analysis.

Data on more than 380,000 participants gathered from 35 studies showed that, overall, there is no significant relationship between 25(OH)D concentrations, a clinical indicator of vitamin D status, and the incidence of coronary heart disease (CHD), stroke, or all-cause death, in a Mendelian randomization analysis.

However, Stephen Burgess, PhD, and colleagues showed that, in vitamin D–deficient individuals, each 10 nmol/L increase in 25(OH)D concentrations reduced the risk of all-cause mortality by 31%.

The research, published in The Lancet Diabetes & Endocrinology, also suggests there was a nonsignificant link between 25(OH)D concentrations and stroke and CHD, but again, only in vitamin D deficient individuals.

In an accompanying editorial, Guillaume Butler-Laporte, MD, and J. Brent Richards, MD, praise the researchers on their study methodology.

They add that the results “could have important public health and clinical consequences” and will “allow clinicians to better weigh the potential benefits of supplementation against its risk,” such as financial cost, “for better patient care – particularly among those with frank vitamin D deficiency.”

They continue: “Given that vitamin D deficiency is relatively common and vitamin D supplementation is safe, the rationale exists to test the effect of vitamin D supplementation in those with deficiency in large-scale randomized controlled trials.”

However, Dr. Butler-Laporte and Dr. Richards, of the Lady Davis Institute, Jewish General Hospital, Montreal, also note the study has several limitations, including the fact that the lifetime exposure to lower vitamin D levels captured by Mendelian randomization may result in larger effect sizes than in conventional trials.
 

Prior RCTS underpowered to detect effects of vitamin D supplements

“There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality, including mechanisms linking low vitamin D status with hyperparathyroidism and low serum calcium and phosphate,” write Dr. Burgess of the MRC Biostatistics Unit, University of Cambridge (England), and coauthors.

They also highlight that vitamin D is “further implicated in endothelial cell function” and affects the transcription of genes linked to cell division and apoptosis, providing “potential mechanisms implicating vitamin D for cancer.”

The researchers note that, while epidemiologic studies have “consistently” found a link between 25(OH)D levels and increased risk of cardiovascular disease, all-cause mortality, and other chronic diseases, several large trials of vitamin D supplementation have reported “null results.”

They argue, however, that many of these trials have recruited individuals “irrespective of baseline 25(OH)D concentration” and have been underpowered to detect the effects of supplementation.

To overcome these limitations, the team gathered data from the UK Biobank, the European Prospective Investigation Into Cancer and Nutrition Cardiovascular Disease (EPIC-CVD) study, 31 studies from the Vitamin D Studies Collaboration (VitDSC), and two Copenhagen population-based studies.

They first performed an observational study that included 384,721 individuals from the UK Biobank and 26,336 from EPIC-CVD who had a valid 25(OH)D measurement and no previously known cardiovascular disease at baseline.

Researchers also included 67,992 participants from the VitDSC studies who did not have previously known cardiovascular disease. They analyzed 25(OH)D concentrations, conventional cardiovascular risk factors, and major incident cardiovascular morbidity and mortality using individual participant data.

The results showed that, at low 25(OH)D concentrations, there was an inverse association between 25(OH)D and incident CHD, stroke, and all-cause mortality.

Next, the team conducted a Mendelian randomization analysis on 333,002 individuals from the UK Biobank and 26,336 from EPIC-CVD who were of European ancestry and had both a valid 25(OH)D measurement and genetic data that passed quality-control steps.

Information on 31,362 participants in the Copenhagen population-based studies was also included, giving a total of 386,406 individuals, of whom 33,546 had CHD, 18,166 had a stroke, and 27,885 died.

The mean age of participants ranged from 54.8 to 57.5 years, and between 53.4% and 55.4% were female.
 

Up to 7% of study participants were vitamin D deficient

The 25(OH)D analysis indicated that 3.9% of UK Biobank and 3.7% of Copenhagen study participants were deficient, compared with 6.9% in EPIC-CVD.

Across the full range of 25(OH)D concentrations, there was no significant association between genetically predicted 25(OH)D levels and CHD, stroke, or all-cause mortality.

However, restricting the analysis to individuals deemed vitamin D deficient (25[OH]D concentration < 25 nmol/L) revealed there was “strong evidence” for an inverse association with all-cause mortality, at an odds ratio per 10 nmol/L increase in genetically predicted 25(OH)D concentration of 0.69 (P < .0001), the team notes.

There were also nonsignificant associations between being in the deficient stratum and CHD, at an odds ratio of 0.89 (P = .14), and stroke, at an odds ratio of 0.85 (P = .09).

Further analysis suggests the association between 25(OH)D concentrations and all-cause mortality has a “clear threshold shape,” the researchers say, with evidence of an inverse association at concentrations below 40 nmol/L and null associations above that threshold.

They acknowledge, however, that their study has several potential limitations, including the assumption in their Mendelian randomization that the “only causal pathway from the genetic variants to the outcome is via 25(OH)D concentrations.”

Moreover, the genetic variants may affect 25(OH)D concentrations in a different way from “dietary supplementation or other clinical interventions.”

They also concede that their study was limited to middle-aged participants of European ancestries, which means the findings “might not be applicable to other populations.”

The study was funded by the British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. Dr. Burgess has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

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

There is a significant inverse relationship between concentrations of circulating 25-hydroxy-vitamin D (25[OH]D) and all-cause mortality, but only in people with vitamin D deficiency, suggests a new large-scale analysis.

Data on more than 380,000 participants gathered from 35 studies showed that, overall, there is no significant relationship between 25(OH)D concentrations, a clinical indicator of vitamin D status, and the incidence of coronary heart disease (CHD), stroke, or all-cause death, in a Mendelian randomization analysis.

However, Stephen Burgess, PhD, and colleagues showed that, in vitamin D–deficient individuals, each 10 nmol/L increase in 25(OH)D concentrations reduced the risk of all-cause mortality by 31%.

The research, published in The Lancet Diabetes & Endocrinology, also suggests there was a nonsignificant link between 25(OH)D concentrations and stroke and CHD, but again, only in vitamin D deficient individuals.

In an accompanying editorial, Guillaume Butler-Laporte, MD, and J. Brent Richards, MD, praise the researchers on their study methodology.

They add that the results “could have important public health and clinical consequences” and will “allow clinicians to better weigh the potential benefits of supplementation against its risk,” such as financial cost, “for better patient care – particularly among those with frank vitamin D deficiency.”

They continue: “Given that vitamin D deficiency is relatively common and vitamin D supplementation is safe, the rationale exists to test the effect of vitamin D supplementation in those with deficiency in large-scale randomized controlled trials.”

However, Dr. Butler-Laporte and Dr. Richards, of the Lady Davis Institute, Jewish General Hospital, Montreal, also note the study has several limitations, including the fact that the lifetime exposure to lower vitamin D levels captured by Mendelian randomization may result in larger effect sizes than in conventional trials.
 

Prior RCTS underpowered to detect effects of vitamin D supplements

“There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality, including mechanisms linking low vitamin D status with hyperparathyroidism and low serum calcium and phosphate,” write Dr. Burgess of the MRC Biostatistics Unit, University of Cambridge (England), and coauthors.

They also highlight that vitamin D is “further implicated in endothelial cell function” and affects the transcription of genes linked to cell division and apoptosis, providing “potential mechanisms implicating vitamin D for cancer.”

The researchers note that, while epidemiologic studies have “consistently” found a link between 25(OH)D levels and increased risk of cardiovascular disease, all-cause mortality, and other chronic diseases, several large trials of vitamin D supplementation have reported “null results.”

They argue, however, that many of these trials have recruited individuals “irrespective of baseline 25(OH)D concentration” and have been underpowered to detect the effects of supplementation.

To overcome these limitations, the team gathered data from the UK Biobank, the European Prospective Investigation Into Cancer and Nutrition Cardiovascular Disease (EPIC-CVD) study, 31 studies from the Vitamin D Studies Collaboration (VitDSC), and two Copenhagen population-based studies.

They first performed an observational study that included 384,721 individuals from the UK Biobank and 26,336 from EPIC-CVD who had a valid 25(OH)D measurement and no previously known cardiovascular disease at baseline.

Researchers also included 67,992 participants from the VitDSC studies who did not have previously known cardiovascular disease. They analyzed 25(OH)D concentrations, conventional cardiovascular risk factors, and major incident cardiovascular morbidity and mortality using individual participant data.

The results showed that, at low 25(OH)D concentrations, there was an inverse association between 25(OH)D and incident CHD, stroke, and all-cause mortality.

Next, the team conducted a Mendelian randomization analysis on 333,002 individuals from the UK Biobank and 26,336 from EPIC-CVD who were of European ancestry and had both a valid 25(OH)D measurement and genetic data that passed quality-control steps.

Information on 31,362 participants in the Copenhagen population-based studies was also included, giving a total of 386,406 individuals, of whom 33,546 had CHD, 18,166 had a stroke, and 27,885 died.

The mean age of participants ranged from 54.8 to 57.5 years, and between 53.4% and 55.4% were female.
 

Up to 7% of study participants were vitamin D deficient

The 25(OH)D analysis indicated that 3.9% of UK Biobank and 3.7% of Copenhagen study participants were deficient, compared with 6.9% in EPIC-CVD.

Across the full range of 25(OH)D concentrations, there was no significant association between genetically predicted 25(OH)D levels and CHD, stroke, or all-cause mortality.

However, restricting the analysis to individuals deemed vitamin D deficient (25[OH]D concentration < 25 nmol/L) revealed there was “strong evidence” for an inverse association with all-cause mortality, at an odds ratio per 10 nmol/L increase in genetically predicted 25(OH)D concentration of 0.69 (P < .0001), the team notes.

There were also nonsignificant associations between being in the deficient stratum and CHD, at an odds ratio of 0.89 (P = .14), and stroke, at an odds ratio of 0.85 (P = .09).

Further analysis suggests the association between 25(OH)D concentrations and all-cause mortality has a “clear threshold shape,” the researchers say, with evidence of an inverse association at concentrations below 40 nmol/L and null associations above that threshold.

They acknowledge, however, that their study has several potential limitations, including the assumption in their Mendelian randomization that the “only causal pathway from the genetic variants to the outcome is via 25(OH)D concentrations.”

Moreover, the genetic variants may affect 25(OH)D concentrations in a different way from “dietary supplementation or other clinical interventions.”

They also concede that their study was limited to middle-aged participants of European ancestries, which means the findings “might not be applicable to other populations.”

The study was funded by the British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. Dr. Burgess has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

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

The Diagnosis: Nevoid Basal Cell Carcinoma Syndrome

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a rare autosomal-dominant disorder that increases the risk for developing various carcinomas and affects multiple organ systems. Nevoid basal cell carcinoma syndrome is estimated at 1 per 40,000 to 60,000 individuals with no sexual predilection.^1,2 Pathogenesis of NBCCS occurs through molecular alterations in the dormant hedgehog signaling pathway, causing constitutive signaling activity and a loss of function in the tumor suppressor patched 1 gene, PTCH1. As a result, the inhibition of smoothened oncogenes is released, Gli proteins are activated, and the hedgehog signaling pathway is no longer quiescent.² Additional loss of function in the suppressor of fused homolog protein, a negative regulator of the hedgehog pathway, allows for further tumor proliferation. The crucial role these genes play in the hedgehog signaling pathway and their mutation association with NBCCS allows for molecular confirmation in the diagnosis of NBCCS. Allelic losses at the PTCH1 gene site are thought to occur in approximately 70% of NBCCS patients.²

Diagnosis of NBCCS is based on genetic testing to examine pathogenic gene variants, notably in the PTCH1 gene, and identification of characteristic clinical findings.² Diagnosis of NBCCS requires either 2 minor suggestive criteria and 1 major suggestive criterion, 2 major suggestive criteria and 1 minor suggestive criterion, or 1 major suggestive criterion with molecular confirmation. The presence of basal cell carcinomas (BCCs) before 20 years of age or an excessive numbers of BCCs, keratocystic odontogenic tumors (KOTs), palmar or plantar pitting, and first-degree relatives with NBCCS are classified as major suggestive criteria.² Nevoid basal cell carcinoma syndrome patients typically have BCCs that crust, ulcerate, or bleed. Minor suggestive criteria for NBCCS are rib abnormalities, skeletal malformations, macrocephaly, cleft lip or palate, and desmoplastic medulloblastoma.^2-4 Suppressor of fused homolog protein mutations may increase the risk for desmoplastic medulloblastoma in NBCCS patients. Our patient had 4 of the major suggestive criteria, including a history of KOTs, multiple BCCs, first-degree relatives with NBCCS, and palmar or plantar pitting (bottom quiz image), while having 1 minor suggestive criterion of frontal bossing.

Patients with NBCCS have high phenotypic variability, as their skin carcinomas do not have the classic features of pearly surfaces or corkscrew telangiectasia that typically are associated with BCCs.¹ Basal cell carcinomas in NBCCS-affected individuals usually are indistinguishable from sporadic lesions that arise in sun-exposed areas, making NBCCS difficult to diagnose. These sporadic lesions often are misdiagnosed as psoriatic or eczematous lesions, and additional subsequent examination is required. The findings of multiple papules and plaques spanning the body as well as lesions with rolled borders and ulcerated bases, indicative of BCCs, aid dermatologists in distinguishing benign lesions from those of NBCCS.¹

Additional differential diagnoses are required to distinguish NBCCS from other similar inherited skin disorders that are characterized by BCCs. The presence of multiple incidental BCCs early in life remains a histopathologic clue for NBCCS diagnosis, as opposed to Rombo syndrome, in which BCCs often develop in adulthood.^2,4 In addition, although both Bazex syndrome and Muir-Torre syndrome are characterized by the early onset of BCCs, the lack of skeletal abnormalities and palmar and plantar pitting distinguish these entities from NBCCS.^2,4 Furthermore, though psoriasis also can present on the scalp, clinical presentation often includes well-demarcated and symmetric plaques that are erythematous and silvery, all of which were not present in our patient and typically are not seen in NBCCS.⁵

The recommended treatment of NBCCS is vismodegib, a specific oncogene inhibitor. This medication suppresses the hedgehog signaling pathway by inhibiting smoothened oncogenes and downstream target molecules, thereby decreasing tumor proliferation.⁶ In doing so, vismodegib inhibits the development of new BCCs while reducing the burden of present ones. Additionally, vismodegib appears to effectively treat KOTs. If successful, this medication may be able to suppress KOTs in patients with NBCCS and thus facilitate surgery.⁶ Additional hedgehog inhibitors include patidegib, sonidegib, and itraconazole. Patidegib gel 2% currently is in phase 3 clinical trials for evaluation of efficacy and safety in treatment of NBCCS. Sonidegib is approved for the treatment of locally advanced BCCs in the United States and the European Union and for both locally advanced BCCs and metastatic BCCs in Switzerland and Australia.⁷ Further research is needed before recommending antifungal itraconazole for NBCCS clinical use.8 Other medications for localized areas include topical application of 5-fluorouracil and imiquimod.²

The Diagnosis: Nevoid Basal Cell Carcinoma Syndrome

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a rare autosomal-dominant disorder that increases the risk for developing various carcinomas and affects multiple organ systems. Nevoid basal cell carcinoma syndrome is estimated at 1 per 40,000 to 60,000 individuals with no sexual predilection.^1,2 Pathogenesis of NBCCS occurs through molecular alterations in the dormant hedgehog signaling pathway, causing constitutive signaling activity and a loss of function in the tumor suppressor patched 1 gene, PTCH1. As a result, the inhibition of smoothened oncogenes is released, Gli proteins are activated, and the hedgehog signaling pathway is no longer quiescent.² Additional loss of function in the suppressor of fused homolog protein, a negative regulator of the hedgehog pathway, allows for further tumor proliferation. The crucial role these genes play in the hedgehog signaling pathway and their mutation association with NBCCS allows for molecular confirmation in the diagnosis of NBCCS. Allelic losses at the PTCH1 gene site are thought to occur in approximately 70% of NBCCS patients.²

Diagnosis of NBCCS is based on genetic testing to examine pathogenic gene variants, notably in the PTCH1 gene, and identification of characteristic clinical findings.² Diagnosis of NBCCS requires either 2 minor suggestive criteria and 1 major suggestive criterion, 2 major suggestive criteria and 1 minor suggestive criterion, or 1 major suggestive criterion with molecular confirmation. The presence of basal cell carcinomas (BCCs) before 20 years of age or an excessive numbers of BCCs, keratocystic odontogenic tumors (KOTs), palmar or plantar pitting, and first-degree relatives with NBCCS are classified as major suggestive criteria.² Nevoid basal cell carcinoma syndrome patients typically have BCCs that crust, ulcerate, or bleed. Minor suggestive criteria for NBCCS are rib abnormalities, skeletal malformations, macrocephaly, cleft lip or palate, and desmoplastic medulloblastoma.^2-4 Suppressor of fused homolog protein mutations may increase the risk for desmoplastic medulloblastoma in NBCCS patients. Our patient had 4 of the major suggestive criteria, including a history of KOTs, multiple BCCs, first-degree relatives with NBCCS, and palmar or plantar pitting (bottom quiz image), while having 1 minor suggestive criterion of frontal bossing.

Patients with NBCCS have high phenotypic variability, as their skin carcinomas do not have the classic features of pearly surfaces or corkscrew telangiectasia that typically are associated with BCCs.¹ Basal cell carcinomas in NBCCS-affected individuals usually are indistinguishable from sporadic lesions that arise in sun-exposed areas, making NBCCS difficult to diagnose. These sporadic lesions often are misdiagnosed as psoriatic or eczematous lesions, and additional subsequent examination is required. The findings of multiple papules and plaques spanning the body as well as lesions with rolled borders and ulcerated bases, indicative of BCCs, aid dermatologists in distinguishing benign lesions from those of NBCCS.¹

Additional differential diagnoses are required to distinguish NBCCS from other similar inherited skin disorders that are characterized by BCCs. The presence of multiple incidental BCCs early in life remains a histopathologic clue for NBCCS diagnosis, as opposed to Rombo syndrome, in which BCCs often develop in adulthood.^2,4 In addition, although both Bazex syndrome and Muir-Torre syndrome are characterized by the early onset of BCCs, the lack of skeletal abnormalities and palmar and plantar pitting distinguish these entities from NBCCS.^2,4 Furthermore, though psoriasis also can present on the scalp, clinical presentation often includes well-demarcated and symmetric plaques that are erythematous and silvery, all of which were not present in our patient and typically are not seen in NBCCS.⁵

The recommended treatment of NBCCS is vismodegib, a specific oncogene inhibitor. This medication suppresses the hedgehog signaling pathway by inhibiting smoothened oncogenes and downstream target molecules, thereby decreasing tumor proliferation.⁶ In doing so, vismodegib inhibits the development of new BCCs while reducing the burden of present ones. Additionally, vismodegib appears to effectively treat KOTs. If successful, this medication may be able to suppress KOTs in patients with NBCCS and thus facilitate surgery.⁶ Additional hedgehog inhibitors include patidegib, sonidegib, and itraconazole. Patidegib gel 2% currently is in phase 3 clinical trials for evaluation of efficacy and safety in treatment of NBCCS. Sonidegib is approved for the treatment of locally advanced BCCs in the United States and the European Union and for both locally advanced BCCs and metastatic BCCs in Switzerland and Australia.⁷ Further research is needed before recommending antifungal itraconazole for NBCCS clinical use.8 Other medications for localized areas include topical application of 5-fluorouracil and imiquimod.²

The Diagnosis: Nevoid Basal Cell Carcinoma Syndrome

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a rare autosomal-dominant disorder that increases the risk for developing various carcinomas and affects multiple organ systems. Nevoid basal cell carcinoma syndrome is estimated at 1 per 40,000 to 60,000 individuals with no sexual predilection.^1,2 Pathogenesis of NBCCS occurs through molecular alterations in the dormant hedgehog signaling pathway, causing constitutive signaling activity and a loss of function in the tumor suppressor patched 1 gene, PTCH1. As a result, the inhibition of smoothened oncogenes is released, Gli proteins are activated, and the hedgehog signaling pathway is no longer quiescent.² Additional loss of function in the suppressor of fused homolog protein, a negative regulator of the hedgehog pathway, allows for further tumor proliferation. The crucial role these genes play in the hedgehog signaling pathway and their mutation association with NBCCS allows for molecular confirmation in the diagnosis of NBCCS. Allelic losses at the PTCH1 gene site are thought to occur in approximately 70% of NBCCS patients.²

Diagnosis of NBCCS is based on genetic testing to examine pathogenic gene variants, notably in the PTCH1 gene, and identification of characteristic clinical findings.² Diagnosis of NBCCS requires either 2 minor suggestive criteria and 1 major suggestive criterion, 2 major suggestive criteria and 1 minor suggestive criterion, or 1 major suggestive criterion with molecular confirmation. The presence of basal cell carcinomas (BCCs) before 20 years of age or an excessive numbers of BCCs, keratocystic odontogenic tumors (KOTs), palmar or plantar pitting, and first-degree relatives with NBCCS are classified as major suggestive criteria.² Nevoid basal cell carcinoma syndrome patients typically have BCCs that crust, ulcerate, or bleed. Minor suggestive criteria for NBCCS are rib abnormalities, skeletal malformations, macrocephaly, cleft lip or palate, and desmoplastic medulloblastoma.^2-4 Suppressor of fused homolog protein mutations may increase the risk for desmoplastic medulloblastoma in NBCCS patients. Our patient had 4 of the major suggestive criteria, including a history of KOTs, multiple BCCs, first-degree relatives with NBCCS, and palmar or plantar pitting (bottom quiz image), while having 1 minor suggestive criterion of frontal bossing.

Patients with NBCCS have high phenotypic variability, as their skin carcinomas do not have the classic features of pearly surfaces or corkscrew telangiectasia that typically are associated with BCCs.¹ Basal cell carcinomas in NBCCS-affected individuals usually are indistinguishable from sporadic lesions that arise in sun-exposed areas, making NBCCS difficult to diagnose. These sporadic lesions often are misdiagnosed as psoriatic or eczematous lesions, and additional subsequent examination is required. The findings of multiple papules and plaques spanning the body as well as lesions with rolled borders and ulcerated bases, indicative of BCCs, aid dermatologists in distinguishing benign lesions from those of NBCCS.¹

Additional differential diagnoses are required to distinguish NBCCS from other similar inherited skin disorders that are characterized by BCCs. The presence of multiple incidental BCCs early in life remains a histopathologic clue for NBCCS diagnosis, as opposed to Rombo syndrome, in which BCCs often develop in adulthood.^2,4 In addition, although both Bazex syndrome and Muir-Torre syndrome are characterized by the early onset of BCCs, the lack of skeletal abnormalities and palmar and plantar pitting distinguish these entities from NBCCS.^2,4 Furthermore, though psoriasis also can present on the scalp, clinical presentation often includes well-demarcated and symmetric plaques that are erythematous and silvery, all of which were not present in our patient and typically are not seen in NBCCS.⁵

The recommended treatment of NBCCS is vismodegib, a specific oncogene inhibitor. This medication suppresses the hedgehog signaling pathway by inhibiting smoothened oncogenes and downstream target molecules, thereby decreasing tumor proliferation.⁶ In doing so, vismodegib inhibits the development of new BCCs while reducing the burden of present ones. Additionally, vismodegib appears to effectively treat KOTs. If successful, this medication may be able to suppress KOTs in patients with NBCCS and thus facilitate surgery.⁶ Additional hedgehog inhibitors include patidegib, sonidegib, and itraconazole. Patidegib gel 2% currently is in phase 3 clinical trials for evaluation of efficacy and safety in treatment of NBCCS. Sonidegib is approved for the treatment of locally advanced BCCs in the United States and the European Union and for both locally advanced BCCs and metastatic BCCs in Switzerland and Australia.⁷ Further research is needed before recommending antifungal itraconazole for NBCCS clinical use.8 Other medications for localized areas include topical application of 5-fluorouracil and imiquimod.²

Human papillomavirus (HPV) vaccination helps prevent cervical cancer and saves lives, new nationwide data suggest.

The analysis adds to a growing body of evidence demonstrating vaccine-associated changes in cervical cancer incidence and mortality.

Previous data from the United Kingdom, published earlier in November, showed that cervical cancer rates were 87% lower among girls who received the HPV vaccine compared to previously unvaccinated generations. Based on the analysis, the authors concluded that the UK’s HPV immunization program “almost eliminated cervical cancer” in women born since September 1995.

The latest study, published Nov. 29 in JAMA Pediatrics , reports a 38% drop in cervical cancer incidence and a 43% decline in mortality among young women and girls after HPV vaccination was introduced in the United States.

“These results are encouraging,” Peter Sasieni, MD, of King’s College London, and senior author on the U.K. study, told this news organization in an email.

The difference in incidence rates between the U.K. and U.S. studies, Dr. Sasieni explained, is likely due to HPV vaccine coverage not expanding as significantly in the United States as it has in the United Kingdom, and “thus one would anticipate a lower impact on the population in the U.S.”

In the U.S. analysis, Justin Barnes, MD, a radiation oncology resident at Washington University, St. Louis, and colleagues examined cervical cancer incidence between January 2001 and December 2017 using Surveillance, Epidemiology, and End Results and National Program of Cancer Registries data as well as mortality data from the National Center for Health Statistics.

Dr. Barnes and colleagues then compared changes in cervical cancer incidence and mortality between prevaccination years (January 2001 to December 2005) and postvaccination years (January 2010 to December 2017) among three age cohorts – 15-24 years, 25-29 years, and 30-39 years.

“The older 2 groups were included as comparison, given their low vaccination rates,” Dr. Barnes and colleagues explained.

Results show that between the prevaccination and postvaccination periods, the incidence of cervical cancer dropped by 38% in the youngest cohort and by only 16% in the middle-aged group and 8% in the oldest cohort.

Women and girls in the youngest group saw a striking drop in mortality: a 43% decline, which translated to a mortality rate of 0.6 per 100,000.

On the other hand, the authors report a 4.7% decline in mortality in the oldest group and a 4.3% increase in mortality in the middle-aged group – translating to a mortality rate of 1.89 per 100,000 and 0.57 per 100,000, respectively.

Overall, “these nationwide data showed decreased cervical cancer incidence and mortality among women and girls aged 15-24 years after HPV vaccine introduction,” Dr. Barnes and colleagues wrote. The changes in cervical cancer incidence and mortality observed in the youngest age group “were greater than changes in those aged 25 to 29 years and 30 to 39 years, suggesting possible associations with HPV vaccination.”

This analysis lines up with previous evidence from U.S. epidemiologic data, which “have shown decreased cervical cancer incidence after vaccine implementation in women and girls aged 15 to 24 years but not older women.”

Although “the number of deaths and hence the number of potentially averted deaths in young women and girls was small,” the study adds to the current literature by “providing suggestive evidence for vaccine-associated decreases in cervical cancer mortality,” investigators concluded.

The authors have disclosed no relevant financial relationships.

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

Human papillomavirus (HPV) vaccination helps prevent cervical cancer and saves lives, new nationwide data suggest.

The analysis adds to a growing body of evidence demonstrating vaccine-associated changes in cervical cancer incidence and mortality.

Previous data from the United Kingdom, published earlier in November, showed that cervical cancer rates were 87% lower among girls who received the HPV vaccine compared to previously unvaccinated generations. Based on the analysis, the authors concluded that the UK’s HPV immunization program “almost eliminated cervical cancer” in women born since September 1995.

The latest study, published Nov. 29 in JAMA Pediatrics , reports a 38% drop in cervical cancer incidence and a 43% decline in mortality among young women and girls after HPV vaccination was introduced in the United States.

“These results are encouraging,” Peter Sasieni, MD, of King’s College London, and senior author on the U.K. study, told this news organization in an email.

The difference in incidence rates between the U.K. and U.S. studies, Dr. Sasieni explained, is likely due to HPV vaccine coverage not expanding as significantly in the United States as it has in the United Kingdom, and “thus one would anticipate a lower impact on the population in the U.S.”

In the U.S. analysis, Justin Barnes, MD, a radiation oncology resident at Washington University, St. Louis, and colleagues examined cervical cancer incidence between January 2001 and December 2017 using Surveillance, Epidemiology, and End Results and National Program of Cancer Registries data as well as mortality data from the National Center for Health Statistics.

Dr. Barnes and colleagues then compared changes in cervical cancer incidence and mortality between prevaccination years (January 2001 to December 2005) and postvaccination years (January 2010 to December 2017) among three age cohorts – 15-24 years, 25-29 years, and 30-39 years.

“The older 2 groups were included as comparison, given their low vaccination rates,” Dr. Barnes and colleagues explained.

Results show that between the prevaccination and postvaccination periods, the incidence of cervical cancer dropped by 38% in the youngest cohort and by only 16% in the middle-aged group and 8% in the oldest cohort.

Women and girls in the youngest group saw a striking drop in mortality: a 43% decline, which translated to a mortality rate of 0.6 per 100,000.

On the other hand, the authors report a 4.7% decline in mortality in the oldest group and a 4.3% increase in mortality in the middle-aged group – translating to a mortality rate of 1.89 per 100,000 and 0.57 per 100,000, respectively.

Overall, “these nationwide data showed decreased cervical cancer incidence and mortality among women and girls aged 15-24 years after HPV vaccine introduction,” Dr. Barnes and colleagues wrote. The changes in cervical cancer incidence and mortality observed in the youngest age group “were greater than changes in those aged 25 to 29 years and 30 to 39 years, suggesting possible associations with HPV vaccination.”

This analysis lines up with previous evidence from U.S. epidemiologic data, which “have shown decreased cervical cancer incidence after vaccine implementation in women and girls aged 15 to 24 years but not older women.”

Although “the number of deaths and hence the number of potentially averted deaths in young women and girls was small,” the study adds to the current literature by “providing suggestive evidence for vaccine-associated decreases in cervical cancer mortality,” investigators concluded.

The authors have disclosed no relevant financial relationships.

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

Human papillomavirus (HPV) vaccination helps prevent cervical cancer and saves lives, new nationwide data suggest.

The analysis adds to a growing body of evidence demonstrating vaccine-associated changes in cervical cancer incidence and mortality.

Previous data from the United Kingdom, published earlier in November, showed that cervical cancer rates were 87% lower among girls who received the HPV vaccine compared to previously unvaccinated generations. Based on the analysis, the authors concluded that the UK’s HPV immunization program “almost eliminated cervical cancer” in women born since September 1995.

The latest study, published Nov. 29 in JAMA Pediatrics , reports a 38% drop in cervical cancer incidence and a 43% decline in mortality among young women and girls after HPV vaccination was introduced in the United States.

“These results are encouraging,” Peter Sasieni, MD, of King’s College London, and senior author on the U.K. study, told this news organization in an email.

The difference in incidence rates between the U.K. and U.S. studies, Dr. Sasieni explained, is likely due to HPV vaccine coverage not expanding as significantly in the United States as it has in the United Kingdom, and “thus one would anticipate a lower impact on the population in the U.S.”

In the U.S. analysis, Justin Barnes, MD, a radiation oncology resident at Washington University, St. Louis, and colleagues examined cervical cancer incidence between January 2001 and December 2017 using Surveillance, Epidemiology, and End Results and National Program of Cancer Registries data as well as mortality data from the National Center for Health Statistics.

Dr. Barnes and colleagues then compared changes in cervical cancer incidence and mortality between prevaccination years (January 2001 to December 2005) and postvaccination years (January 2010 to December 2017) among three age cohorts – 15-24 years, 25-29 years, and 30-39 years.

“The older 2 groups were included as comparison, given their low vaccination rates,” Dr. Barnes and colleagues explained.

Results show that between the prevaccination and postvaccination periods, the incidence of cervical cancer dropped by 38% in the youngest cohort and by only 16% in the middle-aged group and 8% in the oldest cohort.

Women and girls in the youngest group saw a striking drop in mortality: a 43% decline, which translated to a mortality rate of 0.6 per 100,000.

On the other hand, the authors report a 4.7% decline in mortality in the oldest group and a 4.3% increase in mortality in the middle-aged group – translating to a mortality rate of 1.89 per 100,000 and 0.57 per 100,000, respectively.

Overall, “these nationwide data showed decreased cervical cancer incidence and mortality among women and girls aged 15-24 years after HPV vaccine introduction,” Dr. Barnes and colleagues wrote. The changes in cervical cancer incidence and mortality observed in the youngest age group “were greater than changes in those aged 25 to 29 years and 30 to 39 years, suggesting possible associations with HPV vaccination.”

This analysis lines up with previous evidence from U.S. epidemiologic data, which “have shown decreased cervical cancer incidence after vaccine implementation in women and girls aged 15 to 24 years but not older women.”

Although “the number of deaths and hence the number of potentially averted deaths in young women and girls was small,” the study adds to the current literature by “providing suggestive evidence for vaccine-associated decreases in cervical cancer mortality,” investigators concluded.

The authors have disclosed no relevant financial relationships.

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

Although the estimated annual number of measles deaths decreased 94% from 2000 to 2020, the COVID-19 pandemic took a toll on both measles vaccination and surveillance, according to a recent report in Morbidity and Mortality Weekly Report.

The number of World Health Organization member states that achieved more than 90% coverage with the first dose of the measles vaccine (MCV1) declined 37% from 2019 to 2020. In 2020, 23 million infants did not receive MCV1 through routine immunization services, and another 93 million were affected by the postponement of mass immunizations or supplementary immunization activities because of the pandemic. Also, endemic transmission was reestablished in nine countries that had previously eliminated measles.

But perhaps the most overlooked aspect of COVID-19 is its effect on surveillance.

“The entire COVID pandemic really put a lot of strain on the surveillance systems, not only for measles but for all vaccine-preventable disease, because there’s a lot of overlap in the staff who work for surveillance,” said Katrina Kretsinger, MD, a medical epidemiologist at the Centers for Disease Control and Prevention, who contributed to the MMWR report.

Because of the stress on the systems, a lot fewer specimens were tested, she said in an interview. And it’s not just measles that is at risk. This has had an impact on the Global Polio Eradication Initiative, which lost staff.

In addition, many vaccination campaigns “were postponed and curtailed throughout 2020,” Dr. Kretsinger said. The strengthening of surveillance systems – and immunization systems, more broadly – needs to be a priority.

“It’s not clear that the children who were missed during that year were subsequently caught up,” she explained. Having a “cohort of children who have missed measles vaccine creates the reservoir of susceptibility that will provide the nidus for the next big outbreak.”

Measles is the indicator disease. That could mean a resurgence of other vaccine-preventable diseases as well.

This report “was written by some of the world’s experts in measles, and it raises concerns about potential resurgence of measles,” said Walter Orenstein, MD, professor of medicine, epidemiology, global health, and pediatrics at Emory University, Atlanta. “Measles is sort of a canary in the coal mine. If you look at vaccine-preventable diseases, measles is probably the most contagious, so the herd-immunity threshold is highest. Usually on the order of 92%-94% immunity is needed to stop transmission.”

“Measles is the indicator disease,” he said in an interview. “That could mean a resurgence of other vaccine-preventable diseases as well.” Outbreaks don’t just affect the countries where infections are occurring, they “also affect our own domestic health security.”

“Some sort of periodic intensified routine immunization” would be helpful, said Dr. Kretsinger, who recommends “going through and selectively doing some sort of intensified efforts to catch children up early for the entire range of vaccines that they may have missed.”

“Some of these capture campaigns in areas that are thought to have the major problem would be very, very important,” agreed Dr. Orenstein. “A school entry check is one way of trying to look at kids, let’s say at 4-6 years of age, in schools around the world,” offering doses if they’re unvaccinated or inadequately vaccinated. “Another is to try to improve surveillance and try to understand if the cases are vaccine failure or failure to vaccinate.”

“Where the health systems are the most fragile is where those gaps will be the last to be filled, if they are at all, and where we have the basic concerns,” Dr. Kretsinger explained.

“Years ago, WHO recognized that vaccine hesitancy is a top global health threat,” said Dr. Orenstein. “People may not see these diseases so they don’t mean much to them. Since vaccines, we’re victims of our own success.” There’s also a lot of incorrect information circulating.

“We need to realize – and it’s been shown with COVID – that a decision not to vaccinate is not just a decision for your own child. It’s a community decision,” he pointed out. “It’s not my freedom to drive drunk, because not only do I put myself at risk, but others can’t control the car. We have speed limits and other examples where we restrict personal choice because it can adversely affect individuals.”

“My favorite line is vaccines don’t save lives, vaccinations save lives,” Dr. Orenstein said. “The vaccine dose that remains in the vial is 0% effective, no matter what the clinical trials show. And the issue, I think, is that we need to determine how to convince the hesitant to get confident enough to accept vaccination. For that, there is behavioral research; there’s a whole bunch of things that need to be supported. Just purchasing the vaccine doesn’t get it into the bodies.”

Dr. Kretsinger and Dr. Orenstein disclosed no relevant financial relationships .

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

Although the estimated annual number of measles deaths decreased 94% from 2000 to 2020, the COVID-19 pandemic took a toll on both measles vaccination and surveillance, according to a recent report in Morbidity and Mortality Weekly Report.

The number of World Health Organization member states that achieved more than 90% coverage with the first dose of the measles vaccine (MCV1) declined 37% from 2019 to 2020. In 2020, 23 million infants did not receive MCV1 through routine immunization services, and another 93 million were affected by the postponement of mass immunizations or supplementary immunization activities because of the pandemic. Also, endemic transmission was reestablished in nine countries that had previously eliminated measles.

But perhaps the most overlooked aspect of COVID-19 is its effect on surveillance.

“The entire COVID pandemic really put a lot of strain on the surveillance systems, not only for measles but for all vaccine-preventable disease, because there’s a lot of overlap in the staff who work for surveillance,” said Katrina Kretsinger, MD, a medical epidemiologist at the Centers for Disease Control and Prevention, who contributed to the MMWR report.

Because of the stress on the systems, a lot fewer specimens were tested, she said in an interview. And it’s not just measles that is at risk. This has had an impact on the Global Polio Eradication Initiative, which lost staff.

In addition, many vaccination campaigns “were postponed and curtailed throughout 2020,” Dr. Kretsinger said. The strengthening of surveillance systems – and immunization systems, more broadly – needs to be a priority.

“It’s not clear that the children who were missed during that year were subsequently caught up,” she explained. Having a “cohort of children who have missed measles vaccine creates the reservoir of susceptibility that will provide the nidus for the next big outbreak.”

Measles is the indicator disease. That could mean a resurgence of other vaccine-preventable diseases as well.

This report “was written by some of the world’s experts in measles, and it raises concerns about potential resurgence of measles,” said Walter Orenstein, MD, professor of medicine, epidemiology, global health, and pediatrics at Emory University, Atlanta. “Measles is sort of a canary in the coal mine. If you look at vaccine-preventable diseases, measles is probably the most contagious, so the herd-immunity threshold is highest. Usually on the order of 92%-94% immunity is needed to stop transmission.”

“Measles is the indicator disease,” he said in an interview. “That could mean a resurgence of other vaccine-preventable diseases as well.” Outbreaks don’t just affect the countries where infections are occurring, they “also affect our own domestic health security.”

“Some sort of periodic intensified routine immunization” would be helpful, said Dr. Kretsinger, who recommends “going through and selectively doing some sort of intensified efforts to catch children up early for the entire range of vaccines that they may have missed.”

“Some of these capture campaigns in areas that are thought to have the major problem would be very, very important,” agreed Dr. Orenstein. “A school entry check is one way of trying to look at kids, let’s say at 4-6 years of age, in schools around the world,” offering doses if they’re unvaccinated or inadequately vaccinated. “Another is to try to improve surveillance and try to understand if the cases are vaccine failure or failure to vaccinate.”

“Where the health systems are the most fragile is where those gaps will be the last to be filled, if they are at all, and where we have the basic concerns,” Dr. Kretsinger explained.

“Years ago, WHO recognized that vaccine hesitancy is a top global health threat,” said Dr. Orenstein. “People may not see these diseases so they don’t mean much to them. Since vaccines, we’re victims of our own success.” There’s also a lot of incorrect information circulating.

“We need to realize – and it’s been shown with COVID – that a decision not to vaccinate is not just a decision for your own child. It’s a community decision,” he pointed out. “It’s not my freedom to drive drunk, because not only do I put myself at risk, but others can’t control the car. We have speed limits and other examples where we restrict personal choice because it can adversely affect individuals.”

“My favorite line is vaccines don’t save lives, vaccinations save lives,” Dr. Orenstein said. “The vaccine dose that remains in the vial is 0% effective, no matter what the clinical trials show. And the issue, I think, is that we need to determine how to convince the hesitant to get confident enough to accept vaccination. For that, there is behavioral research; there’s a whole bunch of things that need to be supported. Just purchasing the vaccine doesn’t get it into the bodies.”

Dr. Kretsinger and Dr. Orenstein disclosed no relevant financial relationships .

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

Although the estimated annual number of measles deaths decreased 94% from 2000 to 2020, the COVID-19 pandemic took a toll on both measles vaccination and surveillance, according to a recent report in Morbidity and Mortality Weekly Report.

The number of World Health Organization member states that achieved more than 90% coverage with the first dose of the measles vaccine (MCV1) declined 37% from 2019 to 2020. In 2020, 23 million infants did not receive MCV1 through routine immunization services, and another 93 million were affected by the postponement of mass immunizations or supplementary immunization activities because of the pandemic. Also, endemic transmission was reestablished in nine countries that had previously eliminated measles.

But perhaps the most overlooked aspect of COVID-19 is its effect on surveillance.

“The entire COVID pandemic really put a lot of strain on the surveillance systems, not only for measles but for all vaccine-preventable disease, because there’s a lot of overlap in the staff who work for surveillance,” said Katrina Kretsinger, MD, a medical epidemiologist at the Centers for Disease Control and Prevention, who contributed to the MMWR report.

Because of the stress on the systems, a lot fewer specimens were tested, she said in an interview. And it’s not just measles that is at risk. This has had an impact on the Global Polio Eradication Initiative, which lost staff.

In addition, many vaccination campaigns “were postponed and curtailed throughout 2020,” Dr. Kretsinger said. The strengthening of surveillance systems – and immunization systems, more broadly – needs to be a priority.

“It’s not clear that the children who were missed during that year were subsequently caught up,” she explained. Having a “cohort of children who have missed measles vaccine creates the reservoir of susceptibility that will provide the nidus for the next big outbreak.”

Measles is the indicator disease. That could mean a resurgence of other vaccine-preventable diseases as well.

This report “was written by some of the world’s experts in measles, and it raises concerns about potential resurgence of measles,” said Walter Orenstein, MD, professor of medicine, epidemiology, global health, and pediatrics at Emory University, Atlanta. “Measles is sort of a canary in the coal mine. If you look at vaccine-preventable diseases, measles is probably the most contagious, so the herd-immunity threshold is highest. Usually on the order of 92%-94% immunity is needed to stop transmission.”

“Measles is the indicator disease,” he said in an interview. “That could mean a resurgence of other vaccine-preventable diseases as well.” Outbreaks don’t just affect the countries where infections are occurring, they “also affect our own domestic health security.”

“Some sort of periodic intensified routine immunization” would be helpful, said Dr. Kretsinger, who recommends “going through and selectively doing some sort of intensified efforts to catch children up early for the entire range of vaccines that they may have missed.”

“Some of these capture campaigns in areas that are thought to have the major problem would be very, very important,” agreed Dr. Orenstein. “A school entry check is one way of trying to look at kids, let’s say at 4-6 years of age, in schools around the world,” offering doses if they’re unvaccinated or inadequately vaccinated. “Another is to try to improve surveillance and try to understand if the cases are vaccine failure or failure to vaccinate.”

“Where the health systems are the most fragile is where those gaps will be the last to be filled, if they are at all, and where we have the basic concerns,” Dr. Kretsinger explained.

“Years ago, WHO recognized that vaccine hesitancy is a top global health threat,” said Dr. Orenstein. “People may not see these diseases so they don’t mean much to them. Since vaccines, we’re victims of our own success.” There’s also a lot of incorrect information circulating.

“We need to realize – and it’s been shown with COVID – that a decision not to vaccinate is not just a decision for your own child. It’s a community decision,” he pointed out. “It’s not my freedom to drive drunk, because not only do I put myself at risk, but others can’t control the car. We have speed limits and other examples where we restrict personal choice because it can adversely affect individuals.”

“My favorite line is vaccines don’t save lives, vaccinations save lives,” Dr. Orenstein said. “The vaccine dose that remains in the vial is 0% effective, no matter what the clinical trials show. And the issue, I think, is that we need to determine how to convince the hesitant to get confident enough to accept vaccination. For that, there is behavioral research; there’s a whole bunch of things that need to be supported. Just purchasing the vaccine doesn’t get it into the bodies.”

Dr. Kretsinger and Dr. Orenstein disclosed no relevant financial relationships .

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

Certain opioids are proving to be effective in treating a variety of itch conditions, according to Brian S. Kim, MD.

“We know that opioids or opiates do cause itch in a significant number of patients,” Dr. Kim, a dermatologist who is codirector of the Center for the Study of Itch & Sensory Disorders at Washington University, St. Louis, said during MedscapeLive’s annual Las Vegas Dermatology Seminar. “It’s thought to do this by way of acting as a pruritogen at times and stimulating sensory neurons [that] then activate the itch cascade. But it’s also been well known that endogenous kappa opioids can activate sensory neurons that can then suppress itch and gate out signals from these opiates, but perhaps other pruritogens as well.”

Multiple drugs differentially target kappa-opioid receptor (KOR) and mu-opioid receptor (MOR) pathways, he continued. For example, oral naltrexone is a MOR antagonist, oral nalfurafine and intravenous difelikefalin are KOR agonists, while intranasal butorphanol and oral nalbuphine have a dual mechanism.

Difelikefalin is the first Food and Drug Administration–approved treatment for uremic pruritus associated with dialysis, approved in August 2021 for moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis; it is administered intravenously. During the 2021 annual congress of the European Academy of Dermatology and Venereology, Dr. Kim and colleagues presented findings from a phase 2 trial of 401 people with atopic dermatitis (AD) and moderate to severe pruritus, who were randomized to receive oral difelikefalin at a dose of 0.25 mg, 0.5 mg, or 1.0 mg, or placebo over a 12-week treatment period. The primary endpoint, change from baseline in Itch Numerical Rating Scale score, was not met in any of the difelikefalin dose groups in the overall study population, but patients with a body surface area of less than 10% experienced a significant improvement in itch at week 12 in the combined difelikefalin dose group in (P = .039). A significant reduction in itch with difelikefalin was seen in this group of patients with itch-dominant AD, as early as the second day of treatment.

In another trial, 373 hemodialysis patients with moderate or severe uremic pruritus were randomized in a 1: 1:1 ratio to nalbuphine extended-release tablets 120 mg, 60 mg, or placebo and treated for 8 weeks. The researchers found that nalbuphine 120 mg significantly reduced the itching intensity. Specifically, from a baseline numerical rate scale (NRS) of 6.9, the mean NRS declined by 3.5 and by 2.8 in the nalbuphine 120-mg and the placebo groups, respectively (P = .017).

In a separate, unpublished multicenter, randomized, phase 2/3 trial, researchers evaluated the safety and antipruritic efficacy of nalbuphine extended-release tablets dosed twice daily at 90 mg and 180 mg in 62 patients in the United States and Europe. The proportion of patients in the nalbuphine 180-mg arm who met 50% responder criteria at week 10 or last observed visit approached statistical significance (P = .083), and this arm met statistical significance for patients who completed treatment (P = .028).

Dr. Kim disclosed that he has served as a consultant for AbbVie, AstraZeneca, Cara Therapeutics, Galderma, GlaxoSmithKline, LEO Pharma, Lilly, Pfizer, Regeneron, Sanofi, Trevi Therapeutics. He also has conducted contracted research for Cara Therapeutics and LEO Pharma.

MedscapeLive and this news organization are owned by the same parent company.

[email protected]

Certain opioids are proving to be effective in treating a variety of itch conditions, according to Brian S. Kim, MD.

“We know that opioids or opiates do cause itch in a significant number of patients,” Dr. Kim, a dermatologist who is codirector of the Center for the Study of Itch & Sensory Disorders at Washington University, St. Louis, said during MedscapeLive’s annual Las Vegas Dermatology Seminar. “It’s thought to do this by way of acting as a pruritogen at times and stimulating sensory neurons [that] then activate the itch cascade. But it’s also been well known that endogenous kappa opioids can activate sensory neurons that can then suppress itch and gate out signals from these opiates, but perhaps other pruritogens as well.”

Multiple drugs differentially target kappa-opioid receptor (KOR) and mu-opioid receptor (MOR) pathways, he continued. For example, oral naltrexone is a MOR antagonist, oral nalfurafine and intravenous difelikefalin are KOR agonists, while intranasal butorphanol and oral nalbuphine have a dual mechanism.

Difelikefalin is the first Food and Drug Administration–approved treatment for uremic pruritus associated with dialysis, approved in August 2021 for moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis; it is administered intravenously. During the 2021 annual congress of the European Academy of Dermatology and Venereology, Dr. Kim and colleagues presented findings from a phase 2 trial of 401 people with atopic dermatitis (AD) and moderate to severe pruritus, who were randomized to receive oral difelikefalin at a dose of 0.25 mg, 0.5 mg, or 1.0 mg, or placebo over a 12-week treatment period. The primary endpoint, change from baseline in Itch Numerical Rating Scale score, was not met in any of the difelikefalin dose groups in the overall study population, but patients with a body surface area of less than 10% experienced a significant improvement in itch at week 12 in the combined difelikefalin dose group in (P = .039). A significant reduction in itch with difelikefalin was seen in this group of patients with itch-dominant AD, as early as the second day of treatment.

In another trial, 373 hemodialysis patients with moderate or severe uremic pruritus were randomized in a 1: 1:1 ratio to nalbuphine extended-release tablets 120 mg, 60 mg, or placebo and treated for 8 weeks. The researchers found that nalbuphine 120 mg significantly reduced the itching intensity. Specifically, from a baseline numerical rate scale (NRS) of 6.9, the mean NRS declined by 3.5 and by 2.8 in the nalbuphine 120-mg and the placebo groups, respectively (P = .017).

In a separate, unpublished multicenter, randomized, phase 2/3 trial, researchers evaluated the safety and antipruritic efficacy of nalbuphine extended-release tablets dosed twice daily at 90 mg and 180 mg in 62 patients in the United States and Europe. The proportion of patients in the nalbuphine 180-mg arm who met 50% responder criteria at week 10 or last observed visit approached statistical significance (P = .083), and this arm met statistical significance for patients who completed treatment (P = .028).

Dr. Kim disclosed that he has served as a consultant for AbbVie, AstraZeneca, Cara Therapeutics, Galderma, GlaxoSmithKline, LEO Pharma, Lilly, Pfizer, Regeneron, Sanofi, Trevi Therapeutics. He also has conducted contracted research for Cara Therapeutics and LEO Pharma.

MedscapeLive and this news organization are owned by the same parent company.

[email protected]

Certain opioids are proving to be effective in treating a variety of itch conditions, according to Brian S. Kim, MD.

“We know that opioids or opiates do cause itch in a significant number of patients,” Dr. Kim, a dermatologist who is codirector of the Center for the Study of Itch & Sensory Disorders at Washington University, St. Louis, said during MedscapeLive’s annual Las Vegas Dermatology Seminar. “It’s thought to do this by way of acting as a pruritogen at times and stimulating sensory neurons [that] then activate the itch cascade. But it’s also been well known that endogenous kappa opioids can activate sensory neurons that can then suppress itch and gate out signals from these opiates, but perhaps other pruritogens as well.”

Multiple drugs differentially target kappa-opioid receptor (KOR) and mu-opioid receptor (MOR) pathways, he continued. For example, oral naltrexone is a MOR antagonist, oral nalfurafine and intravenous difelikefalin are KOR agonists, while intranasal butorphanol and oral nalbuphine have a dual mechanism.

Difelikefalin is the first Food and Drug Administration–approved treatment for uremic pruritus associated with dialysis, approved in August 2021 for moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis; it is administered intravenously. During the 2021 annual congress of the European Academy of Dermatology and Venereology, Dr. Kim and colleagues presented findings from a phase 2 trial of 401 people with atopic dermatitis (AD) and moderate to severe pruritus, who were randomized to receive oral difelikefalin at a dose of 0.25 mg, 0.5 mg, or 1.0 mg, or placebo over a 12-week treatment period. The primary endpoint, change from baseline in Itch Numerical Rating Scale score, was not met in any of the difelikefalin dose groups in the overall study population, but patients with a body surface area of less than 10% experienced a significant improvement in itch at week 12 in the combined difelikefalin dose group in (P = .039). A significant reduction in itch with difelikefalin was seen in this group of patients with itch-dominant AD, as early as the second day of treatment.

In another trial, 373 hemodialysis patients with moderate or severe uremic pruritus were randomized in a 1: 1:1 ratio to nalbuphine extended-release tablets 120 mg, 60 mg, or placebo and treated for 8 weeks. The researchers found that nalbuphine 120 mg significantly reduced the itching intensity. Specifically, from a baseline numerical rate scale (NRS) of 6.9, the mean NRS declined by 3.5 and by 2.8 in the nalbuphine 120-mg and the placebo groups, respectively (P = .017).

In a separate, unpublished multicenter, randomized, phase 2/3 trial, researchers evaluated the safety and antipruritic efficacy of nalbuphine extended-release tablets dosed twice daily at 90 mg and 180 mg in 62 patients in the United States and Europe. The proportion of patients in the nalbuphine 180-mg arm who met 50% responder criteria at week 10 or last observed visit approached statistical significance (P = .083), and this arm met statistical significance for patients who completed treatment (P = .028).

Dr. Kim disclosed that he has served as a consultant for AbbVie, AstraZeneca, Cara Therapeutics, Galderma, GlaxoSmithKline, LEO Pharma, Lilly, Pfizer, Regeneron, Sanofi, Trevi Therapeutics. He also has conducted contracted research for Cara Therapeutics and LEO Pharma.

MedscapeLive and this news organization are owned by the same parent company.

[email protected]

COVID-19 cases are rising across 40 states and territories, setting the United States up for a rough fifth surge of the pandemic.

“A significant rise in cases just before Thanksgiving is not what we want to be seeing,” said Stephen Kissler, PhD, a postdoctoral researcher and data modeler at the Harvard TH Chan School of Public Health in Boston.

Dr. Kissler said he’d rather see increases in daily cases coming 2 weeks after busy travel periods, as that would mean they could come back down as people returned to their routines.

Seeing big increases in cases ahead of the holidays, he said, “is sort of like adding fuel to an already raging fire.”

Last winter, vaccines hadn’t been rolled out as the nation prepared for Thanksgiving. COVID-19 was burning through family gatherings.

But now that two-thirds of Americans over age 5 are fully vaccinated and booster doses are approved for all adults, will a rise in cases translate, once again, into a strain on our still thinly stretched healthcare system?

Experts say the vaccines are keeping people out of the hospital, which will help. And new antiviral pills are coming that seem to be able to cut a COVID-19 infection off at the knees, at least according to early data. A U.S. Food and Drug Administration panel meets next week to discuss the first application for a pill by Merck.

But experts caution that the coming surge will almost certainly tax hospitals again, especially in areas with lower vaccination rates.

And even states where blood testing shows that significant numbers of people have antibodies after a COVID-19 infection aren’t out of the woods, in part because we still don’t know how long the immunity generated by infection may last.
 

“Erosion of immunity”

“It’s hard to know how much risk is out there,” said Jeffrey Shaman, PhD, professor of environmental health sciences at Columbia University’s Mailman School of Public Health in New York City, who has been modeling the trajectory of the pandemic.

“We’re estimating, unfortunately, and we have for many weeks now, that there is an erosion of immunity,” Dr. Shaman said. “I think it could get bad. How bad? I’m not sure.”

Ali Mokdad, PhD, a professor of health metrics sciences at the University of Washington’s Institute for Health Metrics and Evaluation in Seattle, agrees.

Because there are so few studies on how long immunity from natural infection lasts, Dr. Mokdad and his colleagues are assuming that waning immunity after infection happens at least as quickly as it does after vaccination.

Their model is predicting that the average number of daily cases will peak at around 100,000, with another 100,000 going undetected, and will stay at that level until the end of January, as some states recover from their surges and others pick up steam.

While the number of daily deaths won’t climb to the heights seen during the summer surge, Dr. Mokdad said their model is predicting that daily deaths will climb again to about 1,200 a day.

“We are almost there right now, and it will be with us for a while,” he said. “We are predicting 881,000 deaths by March 1.”

The United States has currently recorded 773,000 COVID-19 deaths, so Dr. Mokdad is predicting about 120,000 more deaths between now and then.

He said his model shows that more than half of those deaths could be prevented if 95% of Americans wore their masks while in close proximity to strangers.

Currently, only about 36% of Americans are consistently wearing masks, according to surveys. While people are moving around more now, mobility is at prepandemic levels in some states.

“The rise that you are seeing right now is high mobility and low mask wearing in the United States,” Dr. Mokdad said.

The solution, he said, is for all adults to get another dose of vaccine — he doesn’t like calling it a booster.

“Because they’re vaccinated and they have two doses they have a false sense of security that they are protected. We needed to come ahead of it immediately and say you need a third dose, and we were late to do so,” Dr. Mokdad said.

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

COVID-19 cases are rising across 40 states and territories, setting the United States up for a rough fifth surge of the pandemic.

“A significant rise in cases just before Thanksgiving is not what we want to be seeing,” said Stephen Kissler, PhD, a postdoctoral researcher and data modeler at the Harvard TH Chan School of Public Health in Boston.

Dr. Kissler said he’d rather see increases in daily cases coming 2 weeks after busy travel periods, as that would mean they could come back down as people returned to their routines.

Seeing big increases in cases ahead of the holidays, he said, “is sort of like adding fuel to an already raging fire.”

Last winter, vaccines hadn’t been rolled out as the nation prepared for Thanksgiving. COVID-19 was burning through family gatherings.

But now that two-thirds of Americans over age 5 are fully vaccinated and booster doses are approved for all adults, will a rise in cases translate, once again, into a strain on our still thinly stretched healthcare system?

Experts say the vaccines are keeping people out of the hospital, which will help. And new antiviral pills are coming that seem to be able to cut a COVID-19 infection off at the knees, at least according to early data. A U.S. Food and Drug Administration panel meets next week to discuss the first application for a pill by Merck.

But experts caution that the coming surge will almost certainly tax hospitals again, especially in areas with lower vaccination rates.

And even states where blood testing shows that significant numbers of people have antibodies after a COVID-19 infection aren’t out of the woods, in part because we still don’t know how long the immunity generated by infection may last.
 

“Erosion of immunity”

“It’s hard to know how much risk is out there,” said Jeffrey Shaman, PhD, professor of environmental health sciences at Columbia University’s Mailman School of Public Health in New York City, who has been modeling the trajectory of the pandemic.

“We’re estimating, unfortunately, and we have for many weeks now, that there is an erosion of immunity,” Dr. Shaman said. “I think it could get bad. How bad? I’m not sure.”

Ali Mokdad, PhD, a professor of health metrics sciences at the University of Washington’s Institute for Health Metrics and Evaluation in Seattle, agrees.

Because there are so few studies on how long immunity from natural infection lasts, Dr. Mokdad and his colleagues are assuming that waning immunity after infection happens at least as quickly as it does after vaccination.

Their model is predicting that the average number of daily cases will peak at around 100,000, with another 100,000 going undetected, and will stay at that level until the end of January, as some states recover from their surges and others pick up steam.

While the number of daily deaths won’t climb to the heights seen during the summer surge, Dr. Mokdad said their model is predicting that daily deaths will climb again to about 1,200 a day.

“We are almost there right now, and it will be with us for a while,” he said. “We are predicting 881,000 deaths by March 1.”

The United States has currently recorded 773,000 COVID-19 deaths, so Dr. Mokdad is predicting about 120,000 more deaths between now and then.

He said his model shows that more than half of those deaths could be prevented if 95% of Americans wore their masks while in close proximity to strangers.

Currently, only about 36% of Americans are consistently wearing masks, according to surveys. While people are moving around more now, mobility is at prepandemic levels in some states.

“The rise that you are seeing right now is high mobility and low mask wearing in the United States,” Dr. Mokdad said.

The solution, he said, is for all adults to get another dose of vaccine — he doesn’t like calling it a booster.

“Because they’re vaccinated and they have two doses they have a false sense of security that they are protected. We needed to come ahead of it immediately and say you need a third dose, and we were late to do so,” Dr. Mokdad said.

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

COVID-19 cases are rising across 40 states and territories, setting the United States up for a rough fifth surge of the pandemic.

“A significant rise in cases just before Thanksgiving is not what we want to be seeing,” said Stephen Kissler, PhD, a postdoctoral researcher and data modeler at the Harvard TH Chan School of Public Health in Boston.

Dr. Kissler said he’d rather see increases in daily cases coming 2 weeks after busy travel periods, as that would mean they could come back down as people returned to their routines.

Seeing big increases in cases ahead of the holidays, he said, “is sort of like adding fuel to an already raging fire.”

Last winter, vaccines hadn’t been rolled out as the nation prepared for Thanksgiving. COVID-19 was burning through family gatherings.

But now that two-thirds of Americans over age 5 are fully vaccinated and booster doses are approved for all adults, will a rise in cases translate, once again, into a strain on our still thinly stretched healthcare system?

Experts say the vaccines are keeping people out of the hospital, which will help. And new antiviral pills are coming that seem to be able to cut a COVID-19 infection off at the knees, at least according to early data. A U.S. Food and Drug Administration panel meets next week to discuss the first application for a pill by Merck.

But experts caution that the coming surge will almost certainly tax hospitals again, especially in areas with lower vaccination rates.

And even states where blood testing shows that significant numbers of people have antibodies after a COVID-19 infection aren’t out of the woods, in part because we still don’t know how long the immunity generated by infection may last.
 

“Erosion of immunity”

“It’s hard to know how much risk is out there,” said Jeffrey Shaman, PhD, professor of environmental health sciences at Columbia University’s Mailman School of Public Health in New York City, who has been modeling the trajectory of the pandemic.

“We’re estimating, unfortunately, and we have for many weeks now, that there is an erosion of immunity,” Dr. Shaman said. “I think it could get bad. How bad? I’m not sure.”

Ali Mokdad, PhD, a professor of health metrics sciences at the University of Washington’s Institute for Health Metrics and Evaluation in Seattle, agrees.

Because there are so few studies on how long immunity from natural infection lasts, Dr. Mokdad and his colleagues are assuming that waning immunity after infection happens at least as quickly as it does after vaccination.

Their model is predicting that the average number of daily cases will peak at around 100,000, with another 100,000 going undetected, and will stay at that level until the end of January, as some states recover from their surges and others pick up steam.

While the number of daily deaths won’t climb to the heights seen during the summer surge, Dr. Mokdad said their model is predicting that daily deaths will climb again to about 1,200 a day.

“We are almost there right now, and it will be with us for a while,” he said. “We are predicting 881,000 deaths by March 1.”

The United States has currently recorded 773,000 COVID-19 deaths, so Dr. Mokdad is predicting about 120,000 more deaths between now and then.

He said his model shows that more than half of those deaths could be prevented if 95% of Americans wore their masks while in close proximity to strangers.

Currently, only about 36% of Americans are consistently wearing masks, according to surveys. While people are moving around more now, mobility is at prepandemic levels in some states.

“The rise that you are seeing right now is high mobility and low mask wearing in the United States,” Dr. Mokdad said.

The solution, he said, is for all adults to get another dose of vaccine — he doesn’t like calling it a booster.

“Because they’re vaccinated and they have two doses they have a false sense of security that they are protected. We needed to come ahead of it immediately and say you need a third dose, and we were late to do so,” Dr. Mokdad said.

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