Women with polycystic ovarian syndrome (PCOS) before menopause appear to have a greater risk of stroke, heart attack, and other cardiovascular events after menopause, according to findings presented at the virtual American Society for Reproductive Medicine (ASRM) 2020 Scientific Congress.

“We found a PCOS diagnosis prior to menopause was associated with a 64% increased risk of cardiovascular disease after menopause independent of age at enrollment, race, body mass index, and smoking status,” presenter Jacob Christ, MD, a resident at the University of Washington in Seattle, told attendees. “Taken together, our results suggest that women with PCOS have more risk factors for future cardiovascular disease at baseline, and a present PCOS diagnosis prior to menopause is associated with an increased risk of cardiovascular disease after menopause.”

The results are important to consider in women seeking care related to fertility, according to Amanda N. Kallen, MD, assistant professor of reproductive endocrinology and infertility at Yale Medicine in New Haven, Conn.

“As fertility specialists, we often see women with PCOS visit us when they are having trouble conceiving, but often [they] do not return to our care once they’ve built their family,” said Dr. Kallen, who was not involved in the research.

“This excellent talk emphasized how critical it is for us as reproductive endocrinologists to have ongoing discussions with PCOS patients about long-term cardiovascular risks at every opportunity, and to emphasize that these risks persist long after the reproductive years have ended,” Dr. Kallen said in an interview.
 

Identifying women at higher risk

Characteristics of PCOS in adolescence are already understood, including hyperandrogenism, acne, irregular bleeding, and variable ages of menarche, Dr. Christ explained. Similarly, in women’s reproductive years, PCOS is linked to abnormal uterine bleeding, hirsutism, dyslipidemia, infertility, impaired glucose tolerance, gestational diabetes, and preeclampsia.

“What is less clear is if baseline cardiometabolic dysfunction during reproductive years translates into cardiovascular disease after menopause,” Dr. Christ said. “Menopausal changes may reduce risk of cardiovascular disease among PCOS women, as it is known that overall, androgen levels decline during menopause. Furthermore, ovarian aging may be delayed in PCOS women, which may be protective against cardiovascular disease.”

To learn more, the researchers completed a secondary analysis of data from the Study of Women’s Health Across the Nation (SWAN), a prospective cohort study. Women enrolled in the study were aged 42-52 years at baseline, had a uterus and at least one ovary, and menstruated within the previous 3 months. Women were considered to have PCOS if they had both biochemical hyperandrogenism and a history of irregular menses.

The researchers included participants in the secondary analysis if they had complete data on the women’s baseline menstrual status and total testosterone and if the women had at least one follow-up visit after menopause. Menopause was approximated as 51 years old if not otherwise reported (or 1 year after study entry if age 51 at entry). At the follow-up visit, women self-reported any cardiovascular disease events since menopause.

The study’s primary outcome was the first postmenopausal cardiovascular event. These included any of the following: myocardial infarction, cerebrovascular accident or stroke, angina, percutaneous coronary intervention or angioplasty, coronary artery bypass graft, heart failure, carotid artery procedure, peripheral artery disease or lower extremity procedure, renal artery procedure, deep vein thrombosis, pulmonary embolism, and abdominal aortic aneurysm.

Among 1,340 women included in the analysis, 174 (13%) women had PCOS and 1,166 did not. The average age at screening and at menopause were not significantly different between the groups, but they did differ based on other baseline characteristics.

More women with PCOS frequently smoked cigarettes (22%) vs. those without PCOS (12.7%), and women with PCOS had an average body mass index of 31.3, vs. 26.7 among those without PCOS. Women with PCOS also had higher systolic blood pressure (120.7 vs. 115.8 mm Hg), higher total cholesterol (202 vs. 192 mg/dL), and higher fasting blood glucose (103.7 vs. 89.2 mg/dL; P < .01 for all).

After the researchers controlled for age at enrollment, race, BMI, and smoking status, women with PCOS had 1.6 times greater odds of a cardiovascular event after menopause compared with women without PCOS (odds ratio [OR], 1.6; P = .029). Those with PCOS also had a significantly higher Atherosclerotic Cardiovascular Disease risk scores (P = .024), but their Framingham 10-year risk score was not significantly different from those without PCOS.

Although the findings are not necessarily surprising, the study’s value particularly lay in its size, prospective data collection, and rigorous methods, said Ginny Ryan, MD, MA, professor and division chief of reproductive endocrinology and infertility at the University of Washington in Seattle.

“While this study’s criteria used to identify subjects with PCOS selected a population with a particularly severe phenotype of PCOS and thus a higher risk population for cardiovascular disease, it is vital for women’s health providers to truly understand the medium- and long-term life-threatening associations found more commonly in many with PCOS,” Dr. Ryan, who attended the talk and was not involved in the research, said in an interview.

“This study emphasizes the importance of identifying PCOS before menopause, not just for the patient’s immediate well-being, but also so that appropriate counseling and referral can take place to optimize primary, secondary, and tertiary prevention efforts against CVD and related morbidity and mortality,” Dr. Ryan said. “Providers who focus on reproductive health and reproductive-aged women have the opportunity to play a vital role in optimizing the long-term health of their patients.”

Aside from being a prospective cohort with more than 2 decades of follow-up, the study’s other strengths included the definition of PCOS before menopause and use of multiple markers of postmenopausal cardiovascular disease, Dr. Christ said. The study’s main weaknesses were the exclusion of mild PCOS, the self-reporting of cardiovascular events, and the multiple ways of defining menopause.

Dr. Kallen is a consultant for Gynaesight and a reviewer for Healthline. Dr. Christ and Dr. Ryan have disclosed no relevant financial relationships.

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

Women with polycystic ovarian syndrome (PCOS) before menopause appear to have a greater risk of stroke, heart attack, and other cardiovascular events after menopause, according to findings presented at the virtual American Society for Reproductive Medicine (ASRM) 2020 Scientific Congress.

“We found a PCOS diagnosis prior to menopause was associated with a 64% increased risk of cardiovascular disease after menopause independent of age at enrollment, race, body mass index, and smoking status,” presenter Jacob Christ, MD, a resident at the University of Washington in Seattle, told attendees. “Taken together, our results suggest that women with PCOS have more risk factors for future cardiovascular disease at baseline, and a present PCOS diagnosis prior to menopause is associated with an increased risk of cardiovascular disease after menopause.”

The results are important to consider in women seeking care related to fertility, according to Amanda N. Kallen, MD, assistant professor of reproductive endocrinology and infertility at Yale Medicine in New Haven, Conn.

“As fertility specialists, we often see women with PCOS visit us when they are having trouble conceiving, but often [they] do not return to our care once they’ve built their family,” said Dr. Kallen, who was not involved in the research.

“This excellent talk emphasized how critical it is for us as reproductive endocrinologists to have ongoing discussions with PCOS patients about long-term cardiovascular risks at every opportunity, and to emphasize that these risks persist long after the reproductive years have ended,” Dr. Kallen said in an interview.
 

Identifying women at higher risk

Characteristics of PCOS in adolescence are already understood, including hyperandrogenism, acne, irregular bleeding, and variable ages of menarche, Dr. Christ explained. Similarly, in women’s reproductive years, PCOS is linked to abnormal uterine bleeding, hirsutism, dyslipidemia, infertility, impaired glucose tolerance, gestational diabetes, and preeclampsia.

“What is less clear is if baseline cardiometabolic dysfunction during reproductive years translates into cardiovascular disease after menopause,” Dr. Christ said. “Menopausal changes may reduce risk of cardiovascular disease among PCOS women, as it is known that overall, androgen levels decline during menopause. Furthermore, ovarian aging may be delayed in PCOS women, which may be protective against cardiovascular disease.”

To learn more, the researchers completed a secondary analysis of data from the Study of Women’s Health Across the Nation (SWAN), a prospective cohort study. Women enrolled in the study were aged 42-52 years at baseline, had a uterus and at least one ovary, and menstruated within the previous 3 months. Women were considered to have PCOS if they had both biochemical hyperandrogenism and a history of irregular menses.

The researchers included participants in the secondary analysis if they had complete data on the women’s baseline menstrual status and total testosterone and if the women had at least one follow-up visit after menopause. Menopause was approximated as 51 years old if not otherwise reported (or 1 year after study entry if age 51 at entry). At the follow-up visit, women self-reported any cardiovascular disease events since menopause.

The study’s primary outcome was the first postmenopausal cardiovascular event. These included any of the following: myocardial infarction, cerebrovascular accident or stroke, angina, percutaneous coronary intervention or angioplasty, coronary artery bypass graft, heart failure, carotid artery procedure, peripheral artery disease or lower extremity procedure, renal artery procedure, deep vein thrombosis, pulmonary embolism, and abdominal aortic aneurysm.

Among 1,340 women included in the analysis, 174 (13%) women had PCOS and 1,166 did not. The average age at screening and at menopause were not significantly different between the groups, but they did differ based on other baseline characteristics.

More women with PCOS frequently smoked cigarettes (22%) vs. those without PCOS (12.7%), and women with PCOS had an average body mass index of 31.3, vs. 26.7 among those without PCOS. Women with PCOS also had higher systolic blood pressure (120.7 vs. 115.8 mm Hg), higher total cholesterol (202 vs. 192 mg/dL), and higher fasting blood glucose (103.7 vs. 89.2 mg/dL; P < .01 for all).

After the researchers controlled for age at enrollment, race, BMI, and smoking status, women with PCOS had 1.6 times greater odds of a cardiovascular event after menopause compared with women without PCOS (odds ratio [OR], 1.6; P = .029). Those with PCOS also had a significantly higher Atherosclerotic Cardiovascular Disease risk scores (P = .024), but their Framingham 10-year risk score was not significantly different from those without PCOS.

Although the findings are not necessarily surprising, the study’s value particularly lay in its size, prospective data collection, and rigorous methods, said Ginny Ryan, MD, MA, professor and division chief of reproductive endocrinology and infertility at the University of Washington in Seattle.

“While this study’s criteria used to identify subjects with PCOS selected a population with a particularly severe phenotype of PCOS and thus a higher risk population for cardiovascular disease, it is vital for women’s health providers to truly understand the medium- and long-term life-threatening associations found more commonly in many with PCOS,” Dr. Ryan, who attended the talk and was not involved in the research, said in an interview.

“This study emphasizes the importance of identifying PCOS before menopause, not just for the patient’s immediate well-being, but also so that appropriate counseling and referral can take place to optimize primary, secondary, and tertiary prevention efforts against CVD and related morbidity and mortality,” Dr. Ryan said. “Providers who focus on reproductive health and reproductive-aged women have the opportunity to play a vital role in optimizing the long-term health of their patients.”

Aside from being a prospective cohort with more than 2 decades of follow-up, the study’s other strengths included the definition of PCOS before menopause and use of multiple markers of postmenopausal cardiovascular disease, Dr. Christ said. The study’s main weaknesses were the exclusion of mild PCOS, the self-reporting of cardiovascular events, and the multiple ways of defining menopause.

Dr. Kallen is a consultant for Gynaesight and a reviewer for Healthline. Dr. Christ and Dr. Ryan have disclosed no relevant financial relationships.

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

Women with polycystic ovarian syndrome (PCOS) before menopause appear to have a greater risk of stroke, heart attack, and other cardiovascular events after menopause, according to findings presented at the virtual American Society for Reproductive Medicine (ASRM) 2020 Scientific Congress.

“We found a PCOS diagnosis prior to menopause was associated with a 64% increased risk of cardiovascular disease after menopause independent of age at enrollment, race, body mass index, and smoking status,” presenter Jacob Christ, MD, a resident at the University of Washington in Seattle, told attendees. “Taken together, our results suggest that women with PCOS have more risk factors for future cardiovascular disease at baseline, and a present PCOS diagnosis prior to menopause is associated with an increased risk of cardiovascular disease after menopause.”

The results are important to consider in women seeking care related to fertility, according to Amanda N. Kallen, MD, assistant professor of reproductive endocrinology and infertility at Yale Medicine in New Haven, Conn.

“As fertility specialists, we often see women with PCOS visit us when they are having trouble conceiving, but often [they] do not return to our care once they’ve built their family,” said Dr. Kallen, who was not involved in the research.

“This excellent talk emphasized how critical it is for us as reproductive endocrinologists to have ongoing discussions with PCOS patients about long-term cardiovascular risks at every opportunity, and to emphasize that these risks persist long after the reproductive years have ended,” Dr. Kallen said in an interview.
 

Identifying women at higher risk

Characteristics of PCOS in adolescence are already understood, including hyperandrogenism, acne, irregular bleeding, and variable ages of menarche, Dr. Christ explained. Similarly, in women’s reproductive years, PCOS is linked to abnormal uterine bleeding, hirsutism, dyslipidemia, infertility, impaired glucose tolerance, gestational diabetes, and preeclampsia.

“What is less clear is if baseline cardiometabolic dysfunction during reproductive years translates into cardiovascular disease after menopause,” Dr. Christ said. “Menopausal changes may reduce risk of cardiovascular disease among PCOS women, as it is known that overall, androgen levels decline during menopause. Furthermore, ovarian aging may be delayed in PCOS women, which may be protective against cardiovascular disease.”

To learn more, the researchers completed a secondary analysis of data from the Study of Women’s Health Across the Nation (SWAN), a prospective cohort study. Women enrolled in the study were aged 42-52 years at baseline, had a uterus and at least one ovary, and menstruated within the previous 3 months. Women were considered to have PCOS if they had both biochemical hyperandrogenism and a history of irregular menses.

The researchers included participants in the secondary analysis if they had complete data on the women’s baseline menstrual status and total testosterone and if the women had at least one follow-up visit after menopause. Menopause was approximated as 51 years old if not otherwise reported (or 1 year after study entry if age 51 at entry). At the follow-up visit, women self-reported any cardiovascular disease events since menopause.

The study’s primary outcome was the first postmenopausal cardiovascular event. These included any of the following: myocardial infarction, cerebrovascular accident or stroke, angina, percutaneous coronary intervention or angioplasty, coronary artery bypass graft, heart failure, carotid artery procedure, peripheral artery disease or lower extremity procedure, renal artery procedure, deep vein thrombosis, pulmonary embolism, and abdominal aortic aneurysm.

Among 1,340 women included in the analysis, 174 (13%) women had PCOS and 1,166 did not. The average age at screening and at menopause were not significantly different between the groups, but they did differ based on other baseline characteristics.

More women with PCOS frequently smoked cigarettes (22%) vs. those without PCOS (12.7%), and women with PCOS had an average body mass index of 31.3, vs. 26.7 among those without PCOS. Women with PCOS also had higher systolic blood pressure (120.7 vs. 115.8 mm Hg), higher total cholesterol (202 vs. 192 mg/dL), and higher fasting blood glucose (103.7 vs. 89.2 mg/dL; P < .01 for all).

After the researchers controlled for age at enrollment, race, BMI, and smoking status, women with PCOS had 1.6 times greater odds of a cardiovascular event after menopause compared with women without PCOS (odds ratio [OR], 1.6; P = .029). Those with PCOS also had a significantly higher Atherosclerotic Cardiovascular Disease risk scores (P = .024), but their Framingham 10-year risk score was not significantly different from those without PCOS.

Although the findings are not necessarily surprising, the study’s value particularly lay in its size, prospective data collection, and rigorous methods, said Ginny Ryan, MD, MA, professor and division chief of reproductive endocrinology and infertility at the University of Washington in Seattle.

“While this study’s criteria used to identify subjects with PCOS selected a population with a particularly severe phenotype of PCOS and thus a higher risk population for cardiovascular disease, it is vital for women’s health providers to truly understand the medium- and long-term life-threatening associations found more commonly in many with PCOS,” Dr. Ryan, who attended the talk and was not involved in the research, said in an interview.

“This study emphasizes the importance of identifying PCOS before menopause, not just for the patient’s immediate well-being, but also so that appropriate counseling and referral can take place to optimize primary, secondary, and tertiary prevention efforts against CVD and related morbidity and mortality,” Dr. Ryan said. “Providers who focus on reproductive health and reproductive-aged women have the opportunity to play a vital role in optimizing the long-term health of their patients.”

Aside from being a prospective cohort with more than 2 decades of follow-up, the study’s other strengths included the definition of PCOS before menopause and use of multiple markers of postmenopausal cardiovascular disease, Dr. Christ said. The study’s main weaknesses were the exclusion of mild PCOS, the self-reporting of cardiovascular events, and the multiple ways of defining menopause.

Dr. Kallen is a consultant for Gynaesight and a reviewer for Healthline. Dr. Christ and Dr. Ryan have disclosed no relevant financial relationships.

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

A combination therapy using the experimental drug relugolix was effective in treating pain and heavy bleeding from uterine fibroids for a full year, according to findings from a long-term extension study of the phase 3, open-label LIBERTY trials.

The drug was also well tolerated, with retention of bone mineral density and no new adverse events, said Ayman Al-Hendy, MD, PhD, who presented the results Oct. 17 at the virtual American Society for Reproductive Medicine 2020 Scientific Congress.

“Relugolix combination therapy represents a potential long-term treatment for women with heavy menstrual bleeding associated with uterine fibroids,” said Al-Hendy, a gynecologist and endoscopic surgeon at the University of Chicago.

Dr. Al-Hendy, who consults for the company that makes the drug, on Oct. 20 presented results showing improvement in quality of life with relugolix therapy.

“The fact that this longer-term study shows continued, persistent results at a year really gives us confidence that we’ll be able to use these drugs as a long-term therapy to treat fibroids,” Hugh S. Taylor, MD, president-elect of ASRM, said in an interview. Dr. Taylor, a professor and chair of ob.gyn. and reproductive sciences at Yale University, New Haven, Conn., was not involved in the study.

“A drug like this is so necessary,” Dr. Taylor continued. “We don’t have any other drugs on the market approved for long-term use.”

Relugolix is an oral gonadotropin-releasing hormone (GnRH) receptor antagonist under investigation for long-term management of uterine fibroids. The once-daily combination therapy includes 40 mg relugolix, 1 mg estradiol, and 0.5 mg norethindrone acetate.
 

Extension study shows prolonged benefits

The extension trial enrolled women aged 18-50 years who were experiencing heavy menstrual bleeding from uterine fibroids and who completed the 24-week phase 3, double-blind, placebo-controlled LIBERTY 1 or 2 trials. Heavy menstrual bleeding was defined as bleeding in which at least 80 mL of blood was lost per cycle for two cycles or 160 mL was lost during one cycle. Ultrasound imaging was used to confirm the presence of fibroids.

In LIBERTY 1 and 2, women were randomly assigned to receive relugolix combination therapy, placebo, or relugolix alone for 12 weeks followed by combination therapy for the remaining 12 weeks (delayed group). Those trials found that relugolix combination therapy was effective through 6 months in reducing menstrual blood loss and pain in women with uterine fibroids without loss of bone mineral density.

LIBERTY 3 extended the trial to 52 weeks, with all participants receiving relugolix combination therapy.

As in the earlier trials, the primary endpoint was reduced menstrual blood loss. By the end of the study, women needed to have at least a 50% reduction in blood loss from the initial study’s baseline while maintaining a blood loss of <80 mL. The investigators also evaluated the mean percentage of menstrual blood loss reduction, amenorrhea rate, and improvements in anemia as secondary endpoints and assessed changes in bone mineral density.

The extension study enrolled 78% (n = 477) of the 610 women who completed the initial study; of those, 363 women completed the extension study.

Among the 163 women who began with relugolix combination therapy in the first two trials, 87.7% met the primary endpoint in a per-protocol analysis through week 52. The proportion of responders in the extension study was 75.6% among the group that formerly received placebo (n = 164) and 79.9% in the delayed group (n = 149).

The overall average reduction in menstrual blood volume was 89.9%. Most of the women experienced amenorrhea at the end of the year: 70.6% in the relugolix group, 57.9% in the group that formerly received placebo, and 68.5% in the delayed group.

Reductions in uterine volume and uterine fibroid volume were also sustained from week 24 to week 52. For the relugolix combination therapy group, the mean loss of uterine fibroid volume from baseline was 13.5% at week 24 and 18.3% at week 52. Similarly, the delayed group’s average loss in fibroid volume was 28.1% at week 24 and 33.9% at week 52. The placebo group, which only had a 7% loss in fibroid volume at week 24, had an 18.4% loss in volume from baseline at week 52.

Among patients with anemia, defined as hemoglobin concentrations of <10.5 g/dL at baseline, 59% of those in the original relugolix group saw an improvement of at least 2 g/dL hemoglobin. The women’s improvement in pain symptoms also continued through week 52, with a 51.3-point reduction in scores on the bleeding pain and discomfort scale from baseline to the end of the study.

Adverse events were the same in the extension study and in the initial study. Those most commonly reported were headache and hot flashes. No serious safety signals occurred. The average reduction in bone mineral density was 0.80% at week 52, indicating no concerning loss.
 

A new drug class to treat uterine fibroids

Relugolix is one of three GnRH antagonists being studied for the long-term treatment of fibroids. The Food and Drug Administration approved the combination of elagolix, estradiol, and norethindrone acetate (Oriahnn) in May. Linzagolix, another GnRH antagonist, is currently in clinical trials.

“We’ll have a whole class of new drugs that are likely to fulfill this long sought-after goal of reducing the need for surgery for fibroids and doing it without a lot of side effects,” Dr. Taylor said. “The quality-of-life improvements seen here, the lack of significant adverse effects – none that were surprising in long term – the relatively low reduction in bone mineral density in a year are all very exciting [and suggest] that this will be a safe and effective long-term treatment.”
 

Significant improvement in quality of life

In the presentation on quality of life with relugolix therapy, Dr. Al-Hendy shared results regarding the severity of women’s symptoms as well as health-related quality of life, as determined on the basis of the Uterine Fibroid Symptom and Health-Related Quality of Life (UFS-QoL) questionnaire at baseline, week 12, and week 24 in LIBERTY 1 and 2. Higher UFS-QoL scores correlate with more severe symptoms. With the subscale of health-related quality of life, higher scores indicate a better quality of life.

The substudy enrolled 253 patients who received relugolix combination therapy and 256 patients who received placebo. The average menstrual blood loss was 243 mL in the relugolix group and 215 mL in the placebo group at baseline. Mean fibroid volume was the same in both groups at baseline, 73 cm³.

The proportion of Black patients was similar in both groups: 48% of the relugolix group and 54% of the placebo group.

The severity of women’s symptoms dropped from a baseline UFS-QoL score of 57 to 22.4 at 6 months among those who received relugolix combination therapy. In the placebo group, the initial score of 59.6 only dropped to 46.9 (P < .0001, for –21.4 difference in change).

Health-related quality of life increased from 38.3 to 76.6 among those who received relugolix. In the placebo group, it increased from 35.7 to 48.2 (P < .0001, for 24.5 difference). Subscales of health-related quality of life – including concern, control, activities, energy/mood, self-consciousness, and sexual function – also all improved significantly in the relugolix group, compared with the placebo group (P < .0001).

“This is a condition we see all the time that’s easily diagnosed, and we have first-line drugs we’ve been using to treat them, but none are good long-term fixes,” Dr. Taylor said. The current first-line treatments, oral contraceptives, can stabilize bleeding, “but they don’t make the fibroids shrink, they don’t stop the bleeding, women continue to have breakthrough bleeding, and the fibroids can continue to grow.”

He said most of the estimated 600,000 hysterectomies performed in the United States each year are for uterine fibroids.

“It’s a major surgery that no one wants to go through if they don’t have to,” Dr. Taylor said. “Here we have a drug that really has potential to stop the growth of the fibroids, that can stop the bleeding or dramatically improve it, and, really, for the first time, directly impact the fibroids and give us a long-term alternative.”

The studies were funded by Myovant Sciences. Dr. Al-Hendy reported consulting for AbbVie, Bayer, and Myovant Sciences, and he owns a patent for novel diagnostics and therapeutics for uterine sarcoma. Dr. Taylor has disclosed no relevant financial relationships.

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

A combination therapy using the experimental drug relugolix was effective in treating pain and heavy bleeding from uterine fibroids for a full year, according to findings from a long-term extension study of the phase 3, open-label LIBERTY trials.

The drug was also well tolerated, with retention of bone mineral density and no new adverse events, said Ayman Al-Hendy, MD, PhD, who presented the results Oct. 17 at the virtual American Society for Reproductive Medicine 2020 Scientific Congress.

“Relugolix combination therapy represents a potential long-term treatment for women with heavy menstrual bleeding associated with uterine fibroids,” said Al-Hendy, a gynecologist and endoscopic surgeon at the University of Chicago.

Dr. Al-Hendy, who consults for the company that makes the drug, on Oct. 20 presented results showing improvement in quality of life with relugolix therapy.

“The fact that this longer-term study shows continued, persistent results at a year really gives us confidence that we’ll be able to use these drugs as a long-term therapy to treat fibroids,” Hugh S. Taylor, MD, president-elect of ASRM, said in an interview. Dr. Taylor, a professor and chair of ob.gyn. and reproductive sciences at Yale University, New Haven, Conn., was not involved in the study.

“A drug like this is so necessary,” Dr. Taylor continued. “We don’t have any other drugs on the market approved for long-term use.”

Relugolix is an oral gonadotropin-releasing hormone (GnRH) receptor antagonist under investigation for long-term management of uterine fibroids. The once-daily combination therapy includes 40 mg relugolix, 1 mg estradiol, and 0.5 mg norethindrone acetate.
 

Extension study shows prolonged benefits

The extension trial enrolled women aged 18-50 years who were experiencing heavy menstrual bleeding from uterine fibroids and who completed the 24-week phase 3, double-blind, placebo-controlled LIBERTY 1 or 2 trials. Heavy menstrual bleeding was defined as bleeding in which at least 80 mL of blood was lost per cycle for two cycles or 160 mL was lost during one cycle. Ultrasound imaging was used to confirm the presence of fibroids.

In LIBERTY 1 and 2, women were randomly assigned to receive relugolix combination therapy, placebo, or relugolix alone for 12 weeks followed by combination therapy for the remaining 12 weeks (delayed group). Those trials found that relugolix combination therapy was effective through 6 months in reducing menstrual blood loss and pain in women with uterine fibroids without loss of bone mineral density.

LIBERTY 3 extended the trial to 52 weeks, with all participants receiving relugolix combination therapy.

As in the earlier trials, the primary endpoint was reduced menstrual blood loss. By the end of the study, women needed to have at least a 50% reduction in blood loss from the initial study’s baseline while maintaining a blood loss of <80 mL. The investigators also evaluated the mean percentage of menstrual blood loss reduction, amenorrhea rate, and improvements in anemia as secondary endpoints and assessed changes in bone mineral density.

The extension study enrolled 78% (n = 477) of the 610 women who completed the initial study; of those, 363 women completed the extension study.

Among the 163 women who began with relugolix combination therapy in the first two trials, 87.7% met the primary endpoint in a per-protocol analysis through week 52. The proportion of responders in the extension study was 75.6% among the group that formerly received placebo (n = 164) and 79.9% in the delayed group (n = 149).

The overall average reduction in menstrual blood volume was 89.9%. Most of the women experienced amenorrhea at the end of the year: 70.6% in the relugolix group, 57.9% in the group that formerly received placebo, and 68.5% in the delayed group.

Reductions in uterine volume and uterine fibroid volume were also sustained from week 24 to week 52. For the relugolix combination therapy group, the mean loss of uterine fibroid volume from baseline was 13.5% at week 24 and 18.3% at week 52. Similarly, the delayed group’s average loss in fibroid volume was 28.1% at week 24 and 33.9% at week 52. The placebo group, which only had a 7% loss in fibroid volume at week 24, had an 18.4% loss in volume from baseline at week 52.

Among patients with anemia, defined as hemoglobin concentrations of <10.5 g/dL at baseline, 59% of those in the original relugolix group saw an improvement of at least 2 g/dL hemoglobin. The women’s improvement in pain symptoms also continued through week 52, with a 51.3-point reduction in scores on the bleeding pain and discomfort scale from baseline to the end of the study.

Adverse events were the same in the extension study and in the initial study. Those most commonly reported were headache and hot flashes. No serious safety signals occurred. The average reduction in bone mineral density was 0.80% at week 52, indicating no concerning loss.
 

A new drug class to treat uterine fibroids

Relugolix is one of three GnRH antagonists being studied for the long-term treatment of fibroids. The Food and Drug Administration approved the combination of elagolix, estradiol, and norethindrone acetate (Oriahnn) in May. Linzagolix, another GnRH antagonist, is currently in clinical trials.

“We’ll have a whole class of new drugs that are likely to fulfill this long sought-after goal of reducing the need for surgery for fibroids and doing it without a lot of side effects,” Dr. Taylor said. “The quality-of-life improvements seen here, the lack of significant adverse effects – none that were surprising in long term – the relatively low reduction in bone mineral density in a year are all very exciting [and suggest] that this will be a safe and effective long-term treatment.”
 

Significant improvement in quality of life

In the presentation on quality of life with relugolix therapy, Dr. Al-Hendy shared results regarding the severity of women’s symptoms as well as health-related quality of life, as determined on the basis of the Uterine Fibroid Symptom and Health-Related Quality of Life (UFS-QoL) questionnaire at baseline, week 12, and week 24 in LIBERTY 1 and 2. Higher UFS-QoL scores correlate with more severe symptoms. With the subscale of health-related quality of life, higher scores indicate a better quality of life.

The substudy enrolled 253 patients who received relugolix combination therapy and 256 patients who received placebo. The average menstrual blood loss was 243 mL in the relugolix group and 215 mL in the placebo group at baseline. Mean fibroid volume was the same in both groups at baseline, 73 cm³.

The proportion of Black patients was similar in both groups: 48% of the relugolix group and 54% of the placebo group.

The severity of women’s symptoms dropped from a baseline UFS-QoL score of 57 to 22.4 at 6 months among those who received relugolix combination therapy. In the placebo group, the initial score of 59.6 only dropped to 46.9 (P < .0001, for –21.4 difference in change).

Health-related quality of life increased from 38.3 to 76.6 among those who received relugolix. In the placebo group, it increased from 35.7 to 48.2 (P < .0001, for 24.5 difference). Subscales of health-related quality of life – including concern, control, activities, energy/mood, self-consciousness, and sexual function – also all improved significantly in the relugolix group, compared with the placebo group (P < .0001).

“This is a condition we see all the time that’s easily diagnosed, and we have first-line drugs we’ve been using to treat them, but none are good long-term fixes,” Dr. Taylor said. The current first-line treatments, oral contraceptives, can stabilize bleeding, “but they don’t make the fibroids shrink, they don’t stop the bleeding, women continue to have breakthrough bleeding, and the fibroids can continue to grow.”

He said most of the estimated 600,000 hysterectomies performed in the United States each year are for uterine fibroids.

“It’s a major surgery that no one wants to go through if they don’t have to,” Dr. Taylor said. “Here we have a drug that really has potential to stop the growth of the fibroids, that can stop the bleeding or dramatically improve it, and, really, for the first time, directly impact the fibroids and give us a long-term alternative.”

The studies were funded by Myovant Sciences. Dr. Al-Hendy reported consulting for AbbVie, Bayer, and Myovant Sciences, and he owns a patent for novel diagnostics and therapeutics for uterine sarcoma. Dr. Taylor has disclosed no relevant financial relationships.

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

A combination therapy using the experimental drug relugolix was effective in treating pain and heavy bleeding from uterine fibroids for a full year, according to findings from a long-term extension study of the phase 3, open-label LIBERTY trials.

The drug was also well tolerated, with retention of bone mineral density and no new adverse events, said Ayman Al-Hendy, MD, PhD, who presented the results Oct. 17 at the virtual American Society for Reproductive Medicine 2020 Scientific Congress.

“Relugolix combination therapy represents a potential long-term treatment for women with heavy menstrual bleeding associated with uterine fibroids,” said Al-Hendy, a gynecologist and endoscopic surgeon at the University of Chicago.

Dr. Al-Hendy, who consults for the company that makes the drug, on Oct. 20 presented results showing improvement in quality of life with relugolix therapy.

“The fact that this longer-term study shows continued, persistent results at a year really gives us confidence that we’ll be able to use these drugs as a long-term therapy to treat fibroids,” Hugh S. Taylor, MD, president-elect of ASRM, said in an interview. Dr. Taylor, a professor and chair of ob.gyn. and reproductive sciences at Yale University, New Haven, Conn., was not involved in the study.

“A drug like this is so necessary,” Dr. Taylor continued. “We don’t have any other drugs on the market approved for long-term use.”

Relugolix is an oral gonadotropin-releasing hormone (GnRH) receptor antagonist under investigation for long-term management of uterine fibroids. The once-daily combination therapy includes 40 mg relugolix, 1 mg estradiol, and 0.5 mg norethindrone acetate.
 

Extension study shows prolonged benefits

The extension trial enrolled women aged 18-50 years who were experiencing heavy menstrual bleeding from uterine fibroids and who completed the 24-week phase 3, double-blind, placebo-controlled LIBERTY 1 or 2 trials. Heavy menstrual bleeding was defined as bleeding in which at least 80 mL of blood was lost per cycle for two cycles or 160 mL was lost during one cycle. Ultrasound imaging was used to confirm the presence of fibroids.

In LIBERTY 1 and 2, women were randomly assigned to receive relugolix combination therapy, placebo, or relugolix alone for 12 weeks followed by combination therapy for the remaining 12 weeks (delayed group). Those trials found that relugolix combination therapy was effective through 6 months in reducing menstrual blood loss and pain in women with uterine fibroids without loss of bone mineral density.

LIBERTY 3 extended the trial to 52 weeks, with all participants receiving relugolix combination therapy.

As in the earlier trials, the primary endpoint was reduced menstrual blood loss. By the end of the study, women needed to have at least a 50% reduction in blood loss from the initial study’s baseline while maintaining a blood loss of <80 mL. The investigators also evaluated the mean percentage of menstrual blood loss reduction, amenorrhea rate, and improvements in anemia as secondary endpoints and assessed changes in bone mineral density.

The extension study enrolled 78% (n = 477) of the 610 women who completed the initial study; of those, 363 women completed the extension study.

Among the 163 women who began with relugolix combination therapy in the first two trials, 87.7% met the primary endpoint in a per-protocol analysis through week 52. The proportion of responders in the extension study was 75.6% among the group that formerly received placebo (n = 164) and 79.9% in the delayed group (n = 149).

The overall average reduction in menstrual blood volume was 89.9%. Most of the women experienced amenorrhea at the end of the year: 70.6% in the relugolix group, 57.9% in the group that formerly received placebo, and 68.5% in the delayed group.

Reductions in uterine volume and uterine fibroid volume were also sustained from week 24 to week 52. For the relugolix combination therapy group, the mean loss of uterine fibroid volume from baseline was 13.5% at week 24 and 18.3% at week 52. Similarly, the delayed group’s average loss in fibroid volume was 28.1% at week 24 and 33.9% at week 52. The placebo group, which only had a 7% loss in fibroid volume at week 24, had an 18.4% loss in volume from baseline at week 52.

Among patients with anemia, defined as hemoglobin concentrations of <10.5 g/dL at baseline, 59% of those in the original relugolix group saw an improvement of at least 2 g/dL hemoglobin. The women’s improvement in pain symptoms also continued through week 52, with a 51.3-point reduction in scores on the bleeding pain and discomfort scale from baseline to the end of the study.

Adverse events were the same in the extension study and in the initial study. Those most commonly reported were headache and hot flashes. No serious safety signals occurred. The average reduction in bone mineral density was 0.80% at week 52, indicating no concerning loss.
 

A new drug class to treat uterine fibroids

Relugolix is one of three GnRH antagonists being studied for the long-term treatment of fibroids. The Food and Drug Administration approved the combination of elagolix, estradiol, and norethindrone acetate (Oriahnn) in May. Linzagolix, another GnRH antagonist, is currently in clinical trials.

“We’ll have a whole class of new drugs that are likely to fulfill this long sought-after goal of reducing the need for surgery for fibroids and doing it without a lot of side effects,” Dr. Taylor said. “The quality-of-life improvements seen here, the lack of significant adverse effects – none that were surprising in long term – the relatively low reduction in bone mineral density in a year are all very exciting [and suggest] that this will be a safe and effective long-term treatment.”
 

Significant improvement in quality of life

In the presentation on quality of life with relugolix therapy, Dr. Al-Hendy shared results regarding the severity of women’s symptoms as well as health-related quality of life, as determined on the basis of the Uterine Fibroid Symptom and Health-Related Quality of Life (UFS-QoL) questionnaire at baseline, week 12, and week 24 in LIBERTY 1 and 2. Higher UFS-QoL scores correlate with more severe symptoms. With the subscale of health-related quality of life, higher scores indicate a better quality of life.

The substudy enrolled 253 patients who received relugolix combination therapy and 256 patients who received placebo. The average menstrual blood loss was 243 mL in the relugolix group and 215 mL in the placebo group at baseline. Mean fibroid volume was the same in both groups at baseline, 73 cm³.

The proportion of Black patients was similar in both groups: 48% of the relugolix group and 54% of the placebo group.

The severity of women’s symptoms dropped from a baseline UFS-QoL score of 57 to 22.4 at 6 months among those who received relugolix combination therapy. In the placebo group, the initial score of 59.6 only dropped to 46.9 (P < .0001, for –21.4 difference in change).

Health-related quality of life increased from 38.3 to 76.6 among those who received relugolix. In the placebo group, it increased from 35.7 to 48.2 (P < .0001, for 24.5 difference). Subscales of health-related quality of life – including concern, control, activities, energy/mood, self-consciousness, and sexual function – also all improved significantly in the relugolix group, compared with the placebo group (P < .0001).

“This is a condition we see all the time that’s easily diagnosed, and we have first-line drugs we’ve been using to treat them, but none are good long-term fixes,” Dr. Taylor said. The current first-line treatments, oral contraceptives, can stabilize bleeding, “but they don’t make the fibroids shrink, they don’t stop the bleeding, women continue to have breakthrough bleeding, and the fibroids can continue to grow.”

He said most of the estimated 600,000 hysterectomies performed in the United States each year are for uterine fibroids.

“It’s a major surgery that no one wants to go through if they don’t have to,” Dr. Taylor said. “Here we have a drug that really has potential to stop the growth of the fibroids, that can stop the bleeding or dramatically improve it, and, really, for the first time, directly impact the fibroids and give us a long-term alternative.”

The studies were funded by Myovant Sciences. Dr. Al-Hendy reported consulting for AbbVie, Bayer, and Myovant Sciences, and he owns a patent for novel diagnostics and therapeutics for uterine sarcoma. Dr. Taylor has disclosed no relevant financial relationships.

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

Researchers and several medical groups on Oct. 23 pressed for changes to the US Food and Drug Administration’s (FDA) current plans for deciding how to eventually clear vaccines for COVID-19, arguing tougher standards would help bolster confidence in these critical medicines.

The FDA’s Vaccines and Related Biological Products Advisory Committee met for a wide-ranging discussion beginning around 10 am. The FDA did not ask the panel to weigh in on any particular vaccine. Instead, the FDA asked for the panel’s feedback on a series of questions, including considerations for continuing phase 3 trials if a product were to get an interim clearance known as an emergency use authorization (EUA).

Speakers at the hearing made a variety of requests, including asking for data showing COVID-19 vaccines can prevent serious illness and urging transparency about the agency’s deliberations for each product to be considered.

FDA staff are closely tracking the crop of experimental vaccines that have made it into advanced stages of testing, including products from Pfizer Inc, AstraZeneca, Johnson & Johnson, and Moderna.
 

‘Time for a reset’

Among the speakers at the public hearing was Peter Lurie, MD, who served as an FDA associate commissioner from 2014 to 2017. Now the president of the Center for Science in the Public Interest, Lurie was among the speakers who asked the agency to make its independence clear.

President Donald Trump has for months been making predictions about COVID-19 vaccine approvals that have been overly optimistic. In one example, the president, who is seeking re-election on November 3, last month spoke about being able to begin distributing a vaccine in October.

“Until now the process of developing candidate vaccines has been inappropriately politicized with an eye on the election calendar, rather than the deliberate timeframe science requires,” Lurie told the FDA advisory panel. “Now is the time for a reset. This committee has a unique opportunity to set a new tone for vaccine deliberations going forward.”

Lurie asked the panel to press the FDA to commit to hold an advisory committee meeting on requests by drugmakers for EUAs. He also asked the panel to demand that informed consent forms and minutes from institutional review board (IRB) discussions of COVID-19 vaccines trials be made public.

Also among the speakers at the public hearing was Peter Doshi, PhD, an associate professor at the University of Maryland School of Pharmacy, who argued that the current trials won’t answer the right questions about the COVID-19 vaccines.

“We could end up with approved vaccines that reduce the risk of mild infection, but do not decrease the risk of hospitalization, ICU use, or death — either at all or by a clinically relevant amount,” Doshi told the panel.

In his presentation, he reiterated points he had made previously, including in an October 21 article in the BMJ, for which he is an associate editor. Doshi also raised these concerns in a September opinion article in The New York Times, co-authored with Eric Topol, MD, director of the Scripps Research Translational Institute and editor-in-chief of Medscape.
 

Risks of a ‘rushed vaccine’

Other complaints about the FDA’s approach included criticism of a 2-month follow-up time after vaccination, which was seen as too short. ECRI, a nonprofit organization that seeks to improve the safety, quality, and cost-effectiveness of medicines, has argued that approving a weak COVID-19 vaccine might worsen the pandemic.

In an October 21 statement, ECRI noted the risk of a partially effective vaccine, which could be welcomed as a means of slowing transmission of the virus. But public response and attitudes over the past 9 months in the United States suggest that people would relax their precautions as soon as a vaccine is available.

“Resulting infections may offset the vaccine’s impact and end up increasing the mortality and morbidity burden,” ECRI said in the brief.

“The risks and consequences of a rushed vaccine could be very severe if the review is anything shy of thorough,” ECRI Chief Executive Officer Marcus Schabacker, MD, PhD, said in a statement prepared for the hearing.

This article first appeared on Medscape.com.

Researchers and several medical groups on Oct. 23 pressed for changes to the US Food and Drug Administration’s (FDA) current plans for deciding how to eventually clear vaccines for COVID-19, arguing tougher standards would help bolster confidence in these critical medicines.

The FDA’s Vaccines and Related Biological Products Advisory Committee met for a wide-ranging discussion beginning around 10 am. The FDA did not ask the panel to weigh in on any particular vaccine. Instead, the FDA asked for the panel’s feedback on a series of questions, including considerations for continuing phase 3 trials if a product were to get an interim clearance known as an emergency use authorization (EUA).

Speakers at the hearing made a variety of requests, including asking for data showing COVID-19 vaccines can prevent serious illness and urging transparency about the agency’s deliberations for each product to be considered.

FDA staff are closely tracking the crop of experimental vaccines that have made it into advanced stages of testing, including products from Pfizer Inc, AstraZeneca, Johnson & Johnson, and Moderna.
 

‘Time for a reset’

Among the speakers at the public hearing was Peter Lurie, MD, who served as an FDA associate commissioner from 2014 to 2017. Now the president of the Center for Science in the Public Interest, Lurie was among the speakers who asked the agency to make its independence clear.

President Donald Trump has for months been making predictions about COVID-19 vaccine approvals that have been overly optimistic. In one example, the president, who is seeking re-election on November 3, last month spoke about being able to begin distributing a vaccine in October.

“Until now the process of developing candidate vaccines has been inappropriately politicized with an eye on the election calendar, rather than the deliberate timeframe science requires,” Lurie told the FDA advisory panel. “Now is the time for a reset. This committee has a unique opportunity to set a new tone for vaccine deliberations going forward.”

Lurie asked the panel to press the FDA to commit to hold an advisory committee meeting on requests by drugmakers for EUAs. He also asked the panel to demand that informed consent forms and minutes from institutional review board (IRB) discussions of COVID-19 vaccines trials be made public.

Also among the speakers at the public hearing was Peter Doshi, PhD, an associate professor at the University of Maryland School of Pharmacy, who argued that the current trials won’t answer the right questions about the COVID-19 vaccines.

“We could end up with approved vaccines that reduce the risk of mild infection, but do not decrease the risk of hospitalization, ICU use, or death — either at all or by a clinically relevant amount,” Doshi told the panel.

In his presentation, he reiterated points he had made previously, including in an October 21 article in the BMJ, for which he is an associate editor. Doshi also raised these concerns in a September opinion article in The New York Times, co-authored with Eric Topol, MD, director of the Scripps Research Translational Institute and editor-in-chief of Medscape.
 

Risks of a ‘rushed vaccine’

Other complaints about the FDA’s approach included criticism of a 2-month follow-up time after vaccination, which was seen as too short. ECRI, a nonprofit organization that seeks to improve the safety, quality, and cost-effectiveness of medicines, has argued that approving a weak COVID-19 vaccine might worsen the pandemic.

In an October 21 statement, ECRI noted the risk of a partially effective vaccine, which could be welcomed as a means of slowing transmission of the virus. But public response and attitudes over the past 9 months in the United States suggest that people would relax their precautions as soon as a vaccine is available.

“Resulting infections may offset the vaccine’s impact and end up increasing the mortality and morbidity burden,” ECRI said in the brief.

“The risks and consequences of a rushed vaccine could be very severe if the review is anything shy of thorough,” ECRI Chief Executive Officer Marcus Schabacker, MD, PhD, said in a statement prepared for the hearing.

This article first appeared on Medscape.com.

Researchers and several medical groups on Oct. 23 pressed for changes to the US Food and Drug Administration’s (FDA) current plans for deciding how to eventually clear vaccines for COVID-19, arguing tougher standards would help bolster confidence in these critical medicines.

The FDA’s Vaccines and Related Biological Products Advisory Committee met for a wide-ranging discussion beginning around 10 am. The FDA did not ask the panel to weigh in on any particular vaccine. Instead, the FDA asked for the panel’s feedback on a series of questions, including considerations for continuing phase 3 trials if a product were to get an interim clearance known as an emergency use authorization (EUA).

Speakers at the hearing made a variety of requests, including asking for data showing COVID-19 vaccines can prevent serious illness and urging transparency about the agency’s deliberations for each product to be considered.

FDA staff are closely tracking the crop of experimental vaccines that have made it into advanced stages of testing, including products from Pfizer Inc, AstraZeneca, Johnson & Johnson, and Moderna.
 

‘Time for a reset’

Among the speakers at the public hearing was Peter Lurie, MD, who served as an FDA associate commissioner from 2014 to 2017. Now the president of the Center for Science in the Public Interest, Lurie was among the speakers who asked the agency to make its independence clear.

President Donald Trump has for months been making predictions about COVID-19 vaccine approvals that have been overly optimistic. In one example, the president, who is seeking re-election on November 3, last month spoke about being able to begin distributing a vaccine in October.

“Until now the process of developing candidate vaccines has been inappropriately politicized with an eye on the election calendar, rather than the deliberate timeframe science requires,” Lurie told the FDA advisory panel. “Now is the time for a reset. This committee has a unique opportunity to set a new tone for vaccine deliberations going forward.”

Lurie asked the panel to press the FDA to commit to hold an advisory committee meeting on requests by drugmakers for EUAs. He also asked the panel to demand that informed consent forms and minutes from institutional review board (IRB) discussions of COVID-19 vaccines trials be made public.

Also among the speakers at the public hearing was Peter Doshi, PhD, an associate professor at the University of Maryland School of Pharmacy, who argued that the current trials won’t answer the right questions about the COVID-19 vaccines.

“We could end up with approved vaccines that reduce the risk of mild infection, but do not decrease the risk of hospitalization, ICU use, or death — either at all or by a clinically relevant amount,” Doshi told the panel.

In his presentation, he reiterated points he had made previously, including in an October 21 article in the BMJ, for which he is an associate editor. Doshi also raised these concerns in a September opinion article in The New York Times, co-authored with Eric Topol, MD, director of the Scripps Research Translational Institute and editor-in-chief of Medscape.
 

Risks of a ‘rushed vaccine’

Other complaints about the FDA’s approach included criticism of a 2-month follow-up time after vaccination, which was seen as too short. ECRI, a nonprofit organization that seeks to improve the safety, quality, and cost-effectiveness of medicines, has argued that approving a weak COVID-19 vaccine might worsen the pandemic.

In an October 21 statement, ECRI noted the risk of a partially effective vaccine, which could be welcomed as a means of slowing transmission of the virus. But public response and attitudes over the past 9 months in the United States suggest that people would relax their precautions as soon as a vaccine is available.

“Resulting infections may offset the vaccine’s impact and end up increasing the mortality and morbidity burden,” ECRI said in the brief.

“The risks and consequences of a rushed vaccine could be very severe if the review is anything shy of thorough,” ECRI Chief Executive Officer Marcus Schabacker, MD, PhD, said in a statement prepared for the hearing.

This article first appeared on Medscape.com.

The available data suggest that the risks posed by COVID-19 infection to patients with psoriasis, including those on therapies that affect immune function, are modest at most, according to a summary of published studies and expert opinions summarized at the annual Coastal Dermatology Symposium, held virtually.

For patients with psoriasis concerned about their outcome if infected with COVID-19, “there is no evidence to support stopping biologics or systemic agents, so I am asking my patients to continue,” Kristina C. Duffin, MD, professor and chair of dermatology at the University of Utah, Salt Lake City, said at the meeting.

The National Psoriasis Foundation, which created a COVID-19 task force and maintains a COVID-19 Resource Center on its website, has provided similar advice. Many statements are phrased cautiously and clinicians are encouraged to practice shared decision-making, but the NPF guidance supports continuing effective therapy – or, in newly diagnosed patients, starting effective therapy – among those who are not infected with SARS-CoV2.

Patients with a new diagnosis of psoriasis “should be aware that untreated psoriatic disease is associated with serious impact on physical and emotional health, and in the case of psoriatic arthritis, can lead to permanent joint damage and disability,” according to the NPF guidance.

Overall, the “existing data generally suggest” that most treatments for psoriasis and psoriatic arthritis “do not meaningfully alter the risks of contracting SARS-CoV2 or having a worse course of COVID-19 illness,” the current guidance states. Yet, because of limited data this “is not known with certainty.”

Chronic systemic steroids are an exception. In a review of recently published studies evaluating whether psoriasis or its therapies increase risk of adverse outcomes in patients with COVID-19 infection, Dr. Duffin pointed to several that associated systemic steroids with hospitalization or other markers of severe disease.

The NPF guidance also recommends avoiding chronic systemic steroids in patients with psoriasis during the current COVID-19 era “if possible.” In patients with psoriatic arthritis who require systemic steroids, the guidance recommends “the lowest dose necessary to achieve the desired therapeutic effect.”

This is not necessarily true in patients with psoriasis and COVID-19 infection. Based on the potential for systemic steroids to improve outcomes in hospitalized COVID-19 patients requiring oxygen, steroids “should not be withheld” even when the justification is concern about the potential risk of flares with withdrawal, according to the NPF guidance statement.

The NPF guidance specifically cautions against use of hydroxychloroquine or chloroquine for prevention or treatment of COVID-19. In addition to an uncertain benefit, these antimalarial drugs have been associated previously with flares of psoriasis.

Dr. Duffin agreed and went on to warn that COVID-19 infection itself is a potential trigger for flares. She cited two published case reports of flares associated with psoriasis. Although one patient had also been exposed to hydroxychloroquine, she said the risk of psoriasis-induced flare “makes sense” based on previous associations made between flares and other viral infections and stress.

In patients with psoriasis who contract COVID-19 infection, Dr. Duffin concurred with the NPF guidance that management decisions should be made on a “case-by-case basis.” Although the NPF guidance states that “most patients can restart psoriasis and/or psoriatic arthritis treatments after complete resolution of COVID-19 symptoms,” no specific advice was offered on the decision to stop treatments.

For protecting psoriasis patients from infection and managing COVID-19 in those who become infected, much of the NPF advice is consistent with that offered to patients without psoriasis. This involves practicing infection control that reduces risk of transmission. Both the NPF guidance and Dr. Duffin suggested telemedicine is appropriate for limiting in-patient visits under pandemic conditions.

Although patients with psoriasis are more likely than the general population to have the comorbidities associated with bad COVID-19 infection outcomes, according to the NPF guidance, Dr. Duffin called the overall data evaluating susceptibility among psoriasis patients “reassuring.” She cautioned that the data are still limited, but the evidence so far suggests that neither psoriasis nor biologics are independent risk factors for acquiring COVID-19 or having a worse outcome if infected.

Yet, more definitive data are needed, and Dr. Duffin advised clinicians and patients to consult the NPF website for updates. “More up-to-date information will certainly be added as we go forward,” she said at the meeting, jointly presented by the University of Louisville and Global Academy for Medical Education.

This NPF task force on COVID-19 is meeting every 2 weeks, according to Joel M. Gelfand, MD, professor of dermatology, University of Pennsylvania, Philadelphia, and cochair of the task force. Dr. Gelfand reported that updates are based on a discussion of the available data.

“We will be releasing additional recommendations as necessary based on the developments,” he said in an interview. Updates are not necessarily required at this frequency but can be if appropriate. The goal is to keep recommendations current and evidence-based.

Dr. Duffin reported financial relationships with Amgen, AbbVie, Bristol-Myers Squibb, Boehringer-Ingelheim, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Siena, and UCB. Dr. Gelfand reported financial relationships with AbbVie, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Pfizer, Roche, and UCB.

This publication and Global Academy for Medical Education are owned by the same parent company.
 

The available data suggest that the risks posed by COVID-19 infection to patients with psoriasis, including those on therapies that affect immune function, are modest at most, according to a summary of published studies and expert opinions summarized at the annual Coastal Dermatology Symposium, held virtually.

For patients with psoriasis concerned about their outcome if infected with COVID-19, “there is no evidence to support stopping biologics or systemic agents, so I am asking my patients to continue,” Kristina C. Duffin, MD, professor and chair of dermatology at the University of Utah, Salt Lake City, said at the meeting.

The National Psoriasis Foundation, which created a COVID-19 task force and maintains a COVID-19 Resource Center on its website, has provided similar advice. Many statements are phrased cautiously and clinicians are encouraged to practice shared decision-making, but the NPF guidance supports continuing effective therapy – or, in newly diagnosed patients, starting effective therapy – among those who are not infected with SARS-CoV2.

Patients with a new diagnosis of psoriasis “should be aware that untreated psoriatic disease is associated with serious impact on physical and emotional health, and in the case of psoriatic arthritis, can lead to permanent joint damage and disability,” according to the NPF guidance.

Overall, the “existing data generally suggest” that most treatments for psoriasis and psoriatic arthritis “do not meaningfully alter the risks of contracting SARS-CoV2 or having a worse course of COVID-19 illness,” the current guidance states. Yet, because of limited data this “is not known with certainty.”

Chronic systemic steroids are an exception. In a review of recently published studies evaluating whether psoriasis or its therapies increase risk of adverse outcomes in patients with COVID-19 infection, Dr. Duffin pointed to several that associated systemic steroids with hospitalization or other markers of severe disease.

The NPF guidance also recommends avoiding chronic systemic steroids in patients with psoriasis during the current COVID-19 era “if possible.” In patients with psoriatic arthritis who require systemic steroids, the guidance recommends “the lowest dose necessary to achieve the desired therapeutic effect.”

This is not necessarily true in patients with psoriasis and COVID-19 infection. Based on the potential for systemic steroids to improve outcomes in hospitalized COVID-19 patients requiring oxygen, steroids “should not be withheld” even when the justification is concern about the potential risk of flares with withdrawal, according to the NPF guidance statement.

The NPF guidance specifically cautions against use of hydroxychloroquine or chloroquine for prevention or treatment of COVID-19. In addition to an uncertain benefit, these antimalarial drugs have been associated previously with flares of psoriasis.

Dr. Duffin agreed and went on to warn that COVID-19 infection itself is a potential trigger for flares. She cited two published case reports of flares associated with psoriasis. Although one patient had also been exposed to hydroxychloroquine, she said the risk of psoriasis-induced flare “makes sense” based on previous associations made between flares and other viral infections and stress.

In patients with psoriasis who contract COVID-19 infection, Dr. Duffin concurred with the NPF guidance that management decisions should be made on a “case-by-case basis.” Although the NPF guidance states that “most patients can restart psoriasis and/or psoriatic arthritis treatments after complete resolution of COVID-19 symptoms,” no specific advice was offered on the decision to stop treatments.

For protecting psoriasis patients from infection and managing COVID-19 in those who become infected, much of the NPF advice is consistent with that offered to patients without psoriasis. This involves practicing infection control that reduces risk of transmission. Both the NPF guidance and Dr. Duffin suggested telemedicine is appropriate for limiting in-patient visits under pandemic conditions.

Although patients with psoriasis are more likely than the general population to have the comorbidities associated with bad COVID-19 infection outcomes, according to the NPF guidance, Dr. Duffin called the overall data evaluating susceptibility among psoriasis patients “reassuring.” She cautioned that the data are still limited, but the evidence so far suggests that neither psoriasis nor biologics are independent risk factors for acquiring COVID-19 or having a worse outcome if infected.

Yet, more definitive data are needed, and Dr. Duffin advised clinicians and patients to consult the NPF website for updates. “More up-to-date information will certainly be added as we go forward,” she said at the meeting, jointly presented by the University of Louisville and Global Academy for Medical Education.

This NPF task force on COVID-19 is meeting every 2 weeks, according to Joel M. Gelfand, MD, professor of dermatology, University of Pennsylvania, Philadelphia, and cochair of the task force. Dr. Gelfand reported that updates are based on a discussion of the available data.

“We will be releasing additional recommendations as necessary based on the developments,” he said in an interview. Updates are not necessarily required at this frequency but can be if appropriate. The goal is to keep recommendations current and evidence-based.

Dr. Duffin reported financial relationships with Amgen, AbbVie, Bristol-Myers Squibb, Boehringer-Ingelheim, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Siena, and UCB. Dr. Gelfand reported financial relationships with AbbVie, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Pfizer, Roche, and UCB.

This publication and Global Academy for Medical Education are owned by the same parent company.
 

The available data suggest that the risks posed by COVID-19 infection to patients with psoriasis, including those on therapies that affect immune function, are modest at most, according to a summary of published studies and expert opinions summarized at the annual Coastal Dermatology Symposium, held virtually.

For patients with psoriasis concerned about their outcome if infected with COVID-19, “there is no evidence to support stopping biologics or systemic agents, so I am asking my patients to continue,” Kristina C. Duffin, MD, professor and chair of dermatology at the University of Utah, Salt Lake City, said at the meeting.

The National Psoriasis Foundation, which created a COVID-19 task force and maintains a COVID-19 Resource Center on its website, has provided similar advice. Many statements are phrased cautiously and clinicians are encouraged to practice shared decision-making, but the NPF guidance supports continuing effective therapy – or, in newly diagnosed patients, starting effective therapy – among those who are not infected with SARS-CoV2.

Patients with a new diagnosis of psoriasis “should be aware that untreated psoriatic disease is associated with serious impact on physical and emotional health, and in the case of psoriatic arthritis, can lead to permanent joint damage and disability,” according to the NPF guidance.

Overall, the “existing data generally suggest” that most treatments for psoriasis and psoriatic arthritis “do not meaningfully alter the risks of contracting SARS-CoV2 or having a worse course of COVID-19 illness,” the current guidance states. Yet, because of limited data this “is not known with certainty.”

Chronic systemic steroids are an exception. In a review of recently published studies evaluating whether psoriasis or its therapies increase risk of adverse outcomes in patients with COVID-19 infection, Dr. Duffin pointed to several that associated systemic steroids with hospitalization or other markers of severe disease.

The NPF guidance also recommends avoiding chronic systemic steroids in patients with psoriasis during the current COVID-19 era “if possible.” In patients with psoriatic arthritis who require systemic steroids, the guidance recommends “the lowest dose necessary to achieve the desired therapeutic effect.”

This is not necessarily true in patients with psoriasis and COVID-19 infection. Based on the potential for systemic steroids to improve outcomes in hospitalized COVID-19 patients requiring oxygen, steroids “should not be withheld” even when the justification is concern about the potential risk of flares with withdrawal, according to the NPF guidance statement.

The NPF guidance specifically cautions against use of hydroxychloroquine or chloroquine for prevention or treatment of COVID-19. In addition to an uncertain benefit, these antimalarial drugs have been associated previously with flares of psoriasis.

Dr. Duffin agreed and went on to warn that COVID-19 infection itself is a potential trigger for flares. She cited two published case reports of flares associated with psoriasis. Although one patient had also been exposed to hydroxychloroquine, she said the risk of psoriasis-induced flare “makes sense” based on previous associations made between flares and other viral infections and stress.

In patients with psoriasis who contract COVID-19 infection, Dr. Duffin concurred with the NPF guidance that management decisions should be made on a “case-by-case basis.” Although the NPF guidance states that “most patients can restart psoriasis and/or psoriatic arthritis treatments after complete resolution of COVID-19 symptoms,” no specific advice was offered on the decision to stop treatments.

For protecting psoriasis patients from infection and managing COVID-19 in those who become infected, much of the NPF advice is consistent with that offered to patients without psoriasis. This involves practicing infection control that reduces risk of transmission. Both the NPF guidance and Dr. Duffin suggested telemedicine is appropriate for limiting in-patient visits under pandemic conditions.

Although patients with psoriasis are more likely than the general population to have the comorbidities associated with bad COVID-19 infection outcomes, according to the NPF guidance, Dr. Duffin called the overall data evaluating susceptibility among psoriasis patients “reassuring.” She cautioned that the data are still limited, but the evidence so far suggests that neither psoriasis nor biologics are independent risk factors for acquiring COVID-19 or having a worse outcome if infected.

Yet, more definitive data are needed, and Dr. Duffin advised clinicians and patients to consult the NPF website for updates. “More up-to-date information will certainly be added as we go forward,” she said at the meeting, jointly presented by the University of Louisville and Global Academy for Medical Education.

This NPF task force on COVID-19 is meeting every 2 weeks, according to Joel M. Gelfand, MD, professor of dermatology, University of Pennsylvania, Philadelphia, and cochair of the task force. Dr. Gelfand reported that updates are based on a discussion of the available data.

“We will be releasing additional recommendations as necessary based on the developments,” he said in an interview. Updates are not necessarily required at this frequency but can be if appropriate. The goal is to keep recommendations current and evidence-based.

Dr. Duffin reported financial relationships with Amgen, AbbVie, Bristol-Myers Squibb, Boehringer-Ingelheim, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Siena, and UCB. Dr. Gelfand reported financial relationships with AbbVie, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Pfizer, Roche, and UCB.

This publication and Global Academy for Medical Education are owned by the same parent company.
 

Clinical Psychiatry News is pleased to announce that Anique K. Forrester, MD, has joined its editorial advisory board.

Dr. Forrester, who is board certified in the subspecialty of psychosomatic medicine (consultation-liaison psychiatry), holds numerous leadership positions at the University of Maryland, Baltimore. She is director of the consultation-liaison psychiatry fellowship at the university and serves as director of education for the C-L psychiatry PGY-2 rotation. Dr. Forrester, an assistant professor, also serves as chair of the department of psychiatry’s diversity committee and is the coordinator of the cultural psychiatry resident course.

Dr. Forrester completed her psychiatry residency training as well as psychosomatic medicine fellowship training at Sidney Kimmel Medical College, Philadelphia. She is a diplomate of the American Board of Psychiatry and Neurology. In addition, Dr. Forrester is a member of the Academy of Consultation-Liaison Psychiatry. She is a graduate of Howard University, Washington.

Her research interests include perinatal psychiatry, psycho-oncology, and cultural competence in medicine.

Welcome aboard, Dr. Forrester!

Clinical Psychiatry News is pleased to announce that Anique K. Forrester, MD, has joined its editorial advisory board.

Dr. Forrester, who is board certified in the subspecialty of psychosomatic medicine (consultation-liaison psychiatry), holds numerous leadership positions at the University of Maryland, Baltimore. She is director of the consultation-liaison psychiatry fellowship at the university and serves as director of education for the C-L psychiatry PGY-2 rotation. Dr. Forrester, an assistant professor, also serves as chair of the department of psychiatry’s diversity committee and is the coordinator of the cultural psychiatry resident course.

Dr. Forrester completed her psychiatry residency training as well as psychosomatic medicine fellowship training at Sidney Kimmel Medical College, Philadelphia. She is a diplomate of the American Board of Psychiatry and Neurology. In addition, Dr. Forrester is a member of the Academy of Consultation-Liaison Psychiatry. She is a graduate of Howard University, Washington.

Her research interests include perinatal psychiatry, psycho-oncology, and cultural competence in medicine.

Welcome aboard, Dr. Forrester!

Clinical Psychiatry News is pleased to announce that Anique K. Forrester, MD, has joined its editorial advisory board.

Dr. Forrester, who is board certified in the subspecialty of psychosomatic medicine (consultation-liaison psychiatry), holds numerous leadership positions at the University of Maryland, Baltimore. She is director of the consultation-liaison psychiatry fellowship at the university and serves as director of education for the C-L psychiatry PGY-2 rotation. Dr. Forrester, an assistant professor, also serves as chair of the department of psychiatry’s diversity committee and is the coordinator of the cultural psychiatry resident course.

Dr. Forrester completed her psychiatry residency training as well as psychosomatic medicine fellowship training at Sidney Kimmel Medical College, Philadelphia. She is a diplomate of the American Board of Psychiatry and Neurology. In addition, Dr. Forrester is a member of the Academy of Consultation-Liaison Psychiatry. She is a graduate of Howard University, Washington.

Her research interests include perinatal psychiatry, psycho-oncology, and cultural competence in medicine.

Welcome aboard, Dr. Forrester!

Between 23,000 and 46,000 U.S. children live with chronic hepatitis C virus with a prevalence of 0.17% anti–hepatitis C virus (HCV) antibody positivity in those aged 6-11 years and 0.39% among children aged 12-19 years. In the United States, genotype 1 is most frequent, followed by genotypes 2 and 3. About 99% of cases result from vertical transmission; transfusion-related cases have not been observed in recent decades.Only viremic mothers are at risk of transmission as those who have spontaneously cleared HCV viremia or have been treated successfully do not risk transmission. Maternal HCV viral load appears to be a risk factor for HCV transmission, however transmission is reported at all levels of viremia.

In conjunction with the opioid epidemics, the prevalence of HCV infection has increased over the last decade. The Centers for Disease Control and Prevention reported that, between 2009 and 2014, the prevalence of HCV infection increased from 1.8 to 3.4 per 1,000 live births. They identified substantial state-to-state variation with the highest rate in West Virginia (22.6 per 1,000 live births), and the lowest in Hawaii (0.7 per 1,000 live births). The implications are clear that increasing numbers of newborns are exposed to HCV and, if transmission rates are between 1% and 5%, 80-400 U.S. infants each year acquire HCV infection.
 

HCV in children

HCV in children is almost always associated with persistent transaminitis. Chronic infection is defined as the persistence of HCV RNA for at least 6 months, and clearance of HCV infection is determined by the persistent disappearance of HCV RNA. Regardless of infection status, an infant may have detectable maternal anti-HCV antibody in serum until 18 months of age, resulting from passive transfer. In addition, prolonged infection can lead to cirrhosis, hepatocellular carcinoma, or decompensated liver disease. Potential extrahepatic manifestations including reduced physical and psychosocial health also are linked to chronic HCV. Autoimmune disease also has been reported in children with HCV. As well, the stigma of HCV elicits fear in school and child care settings that is a result of public misunderstanding regarding routes of hepatitis C transmission. No restriction of regular childhood activities is required in the daily life of HCV-infected children.

Taken together, increasing rates of HCV infection in pregnant women, increasing numbers of exposed and infected infants annually, potential for both short- and long-term morbidity, and curative nontoxic treatment, the paradigm for early identification and treatment at age 3 years is changing.
 

Screening for HCV

There is considerable discussion about which strategy for screening of at-risk infants is more appropriate. Some groups advocate for HCV-RNA testing within the first year of life. Proponents argue the use of a highly sensitive RNA assay early in life has potential to increase detection of infected infants while a negative result allows the conclusion the infant is not infected. Advocates hypothesize that early identification has potential to improve continued follow-up.

Opponents argue that early testing does not change the need for repeat testing after 18 months to confirm diagnosis. They also argue that HCV RNA is more expensive than an antibody-based testing; and treatment will not begin prior to age 3 as there is still opportunity for viremia to spontaneously clear.
 

Direct acting agents licensed

Ledipasvir/sofosbuvir (Harvoni) was initially demonstrated as curative for genotype 1, 4, 5, or 6 infection in a phase 2, multicenter, open-label study of 100 adolescents with genotype 1 treated for 12 weeks. Sustained virologic response (SVR) was documented in 98% of participants.The regimen was safe and well tolerated in this population, and the adult dosage formulation resulted in pharmacokinetic characteristics similar to those observed in adults. Two clinical trials supported the efficacy of ledipasvir/sofosbuvir in the pediatric population aged 3-11 years. This regimen also is recommended for interferon-experienced (± ribavirin, with or without an HCV protease inhibitor) children and adolescents aged 3 years or older with genotype 1 or 4. A 12-week course is recommended for patients without cirrhosis; 24 weeks is recommended for those with compensated cirrhosis. The combination of ledipasvir/sofosbuvir is the only treatment option for children aged 3-6 years with genotype 1, 4, 5, or 6 infection.

The efficacy of sofosbuvir/velpatasvir (Epclusa) once daily for 12 weeks was first evaluated in an open-label trial among children aged 6 years and older with genotype 1, 2, 3, 4, or 6 infection, without cirrhosis or with compensated cirrhosis. Subsequently, the “cocktail” was evaluated in children aged 6-12 years, with 76% genotype 1, 3% genotype 2, 15% genotype 3, and 6% genotype 4. SVR12 rates were 93% (50/54) in children with genotype 1, 91% (10/11) in those with genotype 3, and 100% in participants with genotype 2 (2/2) or genotype 4 (4/4). Sofosbuvir/velpatasvir was approved in March 2020 by the Food and Drug Administration for pediatric patients aged 6 years and older. Given its pangenotypic activity, safety, and efficacy, sofosbuvir/velpatasvir is currently recommended as a first choice for HCV treatment in children and adolescents aged at least 6 years.

The daily fixed-dose combination of glecaprevir/pibrentasvir (Mavyret) was approved in April 2019 for adolescents aged 12-17 years, and weighing at least 45 kg.Treatment is for 8 weeks, and includes treatment-naive patients without cirrhosis or those with compensated cirrhosis. SVR12 rates for Mavyret have ranged from 91% to 100 % across clinic trials. FDA approval and HCV guideline treatment recommendations for direct-acting antiviral (DAA)–experienced adolescents are based on clinical trial data from adults. Given its pangenotypic activity, safety, and efficacy record in adult patients, glecaprevir/pibrentasvir is recommended as a first choice for adolescent HCV treatment. Glecaprevir/pibrentasvir once approved for children less than 3 years of age will be safe and efficacious as a pangenotypic treatment option in children with chronic HCV infection.
 

Current recommendations

Tools for identifying HCV infected infants as early as a few months of age are available, yet studies demonstrate that a minority of at-risk children are tested for HCV using either an HCV polymerase chain reaction strategy early in life or an anti-HCV antibody strategy after 18 months of age.

Therapy with direct-acting agents is now licensed to those aged 3 years and offers the potential for cure, eliminating concern for possible progression after prolonged infection. Such therapy offers the potential to eliminate the stigma faced by many children as well as the hepatic and extrahepatic manifestations observed in children. Medication formulation and the child’s abilities to take the medication needs to be considered when prescribing DAAs. It is important to assess if the child can successfully swallow pills. Currently, Harvoni is the only medication that comes in both pellet and pill formulations. The dose is based on weight. The pellets need to be given in a small amount of nonacidic food; they cannot be chewed.

All children with chronic HCV infection are candidates for treatment. When significant fibrosis and/or cirrhosis is present treatment should not be delayed once the child is age 3 years; when only transaminitis is present, treatment can be delayed. In our experience, parents are eager to complete treatment before starting kindergarten.

Liver biopsy for obtaining liver tissue for histopathologic examination is not routinely indicated in children with chronic HCV infection but should be evaluated case by case. Noninvasive tests of hepatic fibrosis have been used in children, these include serologic markers (i.e., FibroSure) and radiologic tests such as ultrasound-based transient elastography (i.e., Fibroscan). Validation for pediatric patients is variable for the different serologic tests. Studies have shown that Fibroscan using the M probe is feasible for a wide range of ages, but poor patient cooperation may make measurement difficult.

Further details regarding dosing and choice of formulation is available at https://www.hcvguidelines.org/unique-populations/children.

Dr. Sabharwal is assistant professor of pediatrics at Boston University and attending physician in pediatric infectious diseases at Boston Medical Center. Ms. Moloney is an instructor in pediatrics at Boston University and a pediatric nurse practitioner in pediatric infectious diseases at Boston Medicine Center. Dr. Pelton is professor of pediatrics and epidemiology at Boston University and public health and senior attending physician at Boston Medical Center. Boston Medical Center received funding from AbbVie for study of Harvoni in Children 3 years of age and older. Email them at [email protected].

References

MMWR Morb Mortal Wkly Rep. 2017 May 12;66(18):470-3. Hepatol Commun. 2017 March 23. doi: 10.1002/hep4.1028. Hepatology. 2020 Feb;71(2):422-30. Lancet Gastroenterol Hepatol. 2019 Apr 11. doi: 10.1016/S2468-1253(19)30046-9. Arch Dis Child. 2006 Sep;91(9):781-5. J Pediatr Gastroenterol Nutr. 2010 Feb;50(2):123-31.

Between 23,000 and 46,000 U.S. children live with chronic hepatitis C virus with a prevalence of 0.17% anti–hepatitis C virus (HCV) antibody positivity in those aged 6-11 years and 0.39% among children aged 12-19 years. In the United States, genotype 1 is most frequent, followed by genotypes 2 and 3. About 99% of cases result from vertical transmission; transfusion-related cases have not been observed in recent decades.Only viremic mothers are at risk of transmission as those who have spontaneously cleared HCV viremia or have been treated successfully do not risk transmission. Maternal HCV viral load appears to be a risk factor for HCV transmission, however transmission is reported at all levels of viremia.

In conjunction with the opioid epidemics, the prevalence of HCV infection has increased over the last decade. The Centers for Disease Control and Prevention reported that, between 2009 and 2014, the prevalence of HCV infection increased from 1.8 to 3.4 per 1,000 live births. They identified substantial state-to-state variation with the highest rate in West Virginia (22.6 per 1,000 live births), and the lowest in Hawaii (0.7 per 1,000 live births). The implications are clear that increasing numbers of newborns are exposed to HCV and, if transmission rates are between 1% and 5%, 80-400 U.S. infants each year acquire HCV infection.
 

HCV in children

HCV in children is almost always associated with persistent transaminitis. Chronic infection is defined as the persistence of HCV RNA for at least 6 months, and clearance of HCV infection is determined by the persistent disappearance of HCV RNA. Regardless of infection status, an infant may have detectable maternal anti-HCV antibody in serum until 18 months of age, resulting from passive transfer. In addition, prolonged infection can lead to cirrhosis, hepatocellular carcinoma, or decompensated liver disease. Potential extrahepatic manifestations including reduced physical and psychosocial health also are linked to chronic HCV. Autoimmune disease also has been reported in children with HCV. As well, the stigma of HCV elicits fear in school and child care settings that is a result of public misunderstanding regarding routes of hepatitis C transmission. No restriction of regular childhood activities is required in the daily life of HCV-infected children.

Taken together, increasing rates of HCV infection in pregnant women, increasing numbers of exposed and infected infants annually, potential for both short- and long-term morbidity, and curative nontoxic treatment, the paradigm for early identification and treatment at age 3 years is changing.
 

Screening for HCV

There is considerable discussion about which strategy for screening of at-risk infants is more appropriate. Some groups advocate for HCV-RNA testing within the first year of life. Proponents argue the use of a highly sensitive RNA assay early in life has potential to increase detection of infected infants while a negative result allows the conclusion the infant is not infected. Advocates hypothesize that early identification has potential to improve continued follow-up.

Opponents argue that early testing does not change the need for repeat testing after 18 months to confirm diagnosis. They also argue that HCV RNA is more expensive than an antibody-based testing; and treatment will not begin prior to age 3 as there is still opportunity for viremia to spontaneously clear.
 

Direct acting agents licensed

Ledipasvir/sofosbuvir (Harvoni) was initially demonstrated as curative for genotype 1, 4, 5, or 6 infection in a phase 2, multicenter, open-label study of 100 adolescents with genotype 1 treated for 12 weeks. Sustained virologic response (SVR) was documented in 98% of participants.The regimen was safe and well tolerated in this population, and the adult dosage formulation resulted in pharmacokinetic characteristics similar to those observed in adults. Two clinical trials supported the efficacy of ledipasvir/sofosbuvir in the pediatric population aged 3-11 years. This regimen also is recommended for interferon-experienced (± ribavirin, with or without an HCV protease inhibitor) children and adolescents aged 3 years or older with genotype 1 or 4. A 12-week course is recommended for patients without cirrhosis; 24 weeks is recommended for those with compensated cirrhosis. The combination of ledipasvir/sofosbuvir is the only treatment option for children aged 3-6 years with genotype 1, 4, 5, or 6 infection.

The efficacy of sofosbuvir/velpatasvir (Epclusa) once daily for 12 weeks was first evaluated in an open-label trial among children aged 6 years and older with genotype 1, 2, 3, 4, or 6 infection, without cirrhosis or with compensated cirrhosis. Subsequently, the “cocktail” was evaluated in children aged 6-12 years, with 76% genotype 1, 3% genotype 2, 15% genotype 3, and 6% genotype 4. SVR12 rates were 93% (50/54) in children with genotype 1, 91% (10/11) in those with genotype 3, and 100% in participants with genotype 2 (2/2) or genotype 4 (4/4). Sofosbuvir/velpatasvir was approved in March 2020 by the Food and Drug Administration for pediatric patients aged 6 years and older. Given its pangenotypic activity, safety, and efficacy, sofosbuvir/velpatasvir is currently recommended as a first choice for HCV treatment in children and adolescents aged at least 6 years.

The daily fixed-dose combination of glecaprevir/pibrentasvir (Mavyret) was approved in April 2019 for adolescents aged 12-17 years, and weighing at least 45 kg.Treatment is for 8 weeks, and includes treatment-naive patients without cirrhosis or those with compensated cirrhosis. SVR12 rates for Mavyret have ranged from 91% to 100 % across clinic trials. FDA approval and HCV guideline treatment recommendations for direct-acting antiviral (DAA)–experienced adolescents are based on clinical trial data from adults. Given its pangenotypic activity, safety, and efficacy record in adult patients, glecaprevir/pibrentasvir is recommended as a first choice for adolescent HCV treatment. Glecaprevir/pibrentasvir once approved for children less than 3 years of age will be safe and efficacious as a pangenotypic treatment option in children with chronic HCV infection.
 

Current recommendations

Tools for identifying HCV infected infants as early as a few months of age are available, yet studies demonstrate that a minority of at-risk children are tested for HCV using either an HCV polymerase chain reaction strategy early in life or an anti-HCV antibody strategy after 18 months of age.

Therapy with direct-acting agents is now licensed to those aged 3 years and offers the potential for cure, eliminating concern for possible progression after prolonged infection. Such therapy offers the potential to eliminate the stigma faced by many children as well as the hepatic and extrahepatic manifestations observed in children. Medication formulation and the child’s abilities to take the medication needs to be considered when prescribing DAAs. It is important to assess if the child can successfully swallow pills. Currently, Harvoni is the only medication that comes in both pellet and pill formulations. The dose is based on weight. The pellets need to be given in a small amount of nonacidic food; they cannot be chewed.

All children with chronic HCV infection are candidates for treatment. When significant fibrosis and/or cirrhosis is present treatment should not be delayed once the child is age 3 years; when only transaminitis is present, treatment can be delayed. In our experience, parents are eager to complete treatment before starting kindergarten.

Liver biopsy for obtaining liver tissue for histopathologic examination is not routinely indicated in children with chronic HCV infection but should be evaluated case by case. Noninvasive tests of hepatic fibrosis have been used in children, these include serologic markers (i.e., FibroSure) and radiologic tests such as ultrasound-based transient elastography (i.e., Fibroscan). Validation for pediatric patients is variable for the different serologic tests. Studies have shown that Fibroscan using the M probe is feasible for a wide range of ages, but poor patient cooperation may make measurement difficult.

Further details regarding dosing and choice of formulation is available at https://www.hcvguidelines.org/unique-populations/children.

Dr. Sabharwal is assistant professor of pediatrics at Boston University and attending physician in pediatric infectious diseases at Boston Medical Center. Ms. Moloney is an instructor in pediatrics at Boston University and a pediatric nurse practitioner in pediatric infectious diseases at Boston Medicine Center. Dr. Pelton is professor of pediatrics and epidemiology at Boston University and public health and senior attending physician at Boston Medical Center. Boston Medical Center received funding from AbbVie for study of Harvoni in Children 3 years of age and older. Email them at [email protected].

References

MMWR Morb Mortal Wkly Rep. 2017 May 12;66(18):470-3. Hepatol Commun. 2017 March 23. doi: 10.1002/hep4.1028. Hepatology. 2020 Feb;71(2):422-30. Lancet Gastroenterol Hepatol. 2019 Apr 11. doi: 10.1016/S2468-1253(19)30046-9. Arch Dis Child. 2006 Sep;91(9):781-5. J Pediatr Gastroenterol Nutr. 2010 Feb;50(2):123-31.

Between 23,000 and 46,000 U.S. children live with chronic hepatitis C virus with a prevalence of 0.17% anti–hepatitis C virus (HCV) antibody positivity in those aged 6-11 years and 0.39% among children aged 12-19 years. In the United States, genotype 1 is most frequent, followed by genotypes 2 and 3. About 99% of cases result from vertical transmission; transfusion-related cases have not been observed in recent decades.Only viremic mothers are at risk of transmission as those who have spontaneously cleared HCV viremia or have been treated successfully do not risk transmission. Maternal HCV viral load appears to be a risk factor for HCV transmission, however transmission is reported at all levels of viremia.

In conjunction with the opioid epidemics, the prevalence of HCV infection has increased over the last decade. The Centers for Disease Control and Prevention reported that, between 2009 and 2014, the prevalence of HCV infection increased from 1.8 to 3.4 per 1,000 live births. They identified substantial state-to-state variation with the highest rate in West Virginia (22.6 per 1,000 live births), and the lowest in Hawaii (0.7 per 1,000 live births). The implications are clear that increasing numbers of newborns are exposed to HCV and, if transmission rates are between 1% and 5%, 80-400 U.S. infants each year acquire HCV infection.
 

HCV in children

HCV in children is almost always associated with persistent transaminitis. Chronic infection is defined as the persistence of HCV RNA for at least 6 months, and clearance of HCV infection is determined by the persistent disappearance of HCV RNA. Regardless of infection status, an infant may have detectable maternal anti-HCV antibody in serum until 18 months of age, resulting from passive transfer. In addition, prolonged infection can lead to cirrhosis, hepatocellular carcinoma, or decompensated liver disease. Potential extrahepatic manifestations including reduced physical and psychosocial health also are linked to chronic HCV. Autoimmune disease also has been reported in children with HCV. As well, the stigma of HCV elicits fear in school and child care settings that is a result of public misunderstanding regarding routes of hepatitis C transmission. No restriction of regular childhood activities is required in the daily life of HCV-infected children.

Taken together, increasing rates of HCV infection in pregnant women, increasing numbers of exposed and infected infants annually, potential for both short- and long-term morbidity, and curative nontoxic treatment, the paradigm for early identification and treatment at age 3 years is changing.
 

Screening for HCV

There is considerable discussion about which strategy for screening of at-risk infants is more appropriate. Some groups advocate for HCV-RNA testing within the first year of life. Proponents argue the use of a highly sensitive RNA assay early in life has potential to increase detection of infected infants while a negative result allows the conclusion the infant is not infected. Advocates hypothesize that early identification has potential to improve continued follow-up.

Opponents argue that early testing does not change the need for repeat testing after 18 months to confirm diagnosis. They also argue that HCV RNA is more expensive than an antibody-based testing; and treatment will not begin prior to age 3 as there is still opportunity for viremia to spontaneously clear.
 

Direct acting agents licensed

Ledipasvir/sofosbuvir (Harvoni) was initially demonstrated as curative for genotype 1, 4, 5, or 6 infection in a phase 2, multicenter, open-label study of 100 adolescents with genotype 1 treated for 12 weeks. Sustained virologic response (SVR) was documented in 98% of participants.The regimen was safe and well tolerated in this population, and the adult dosage formulation resulted in pharmacokinetic characteristics similar to those observed in adults. Two clinical trials supported the efficacy of ledipasvir/sofosbuvir in the pediatric population aged 3-11 years. This regimen also is recommended for interferon-experienced (± ribavirin, with or without an HCV protease inhibitor) children and adolescents aged 3 years or older with genotype 1 or 4. A 12-week course is recommended for patients without cirrhosis; 24 weeks is recommended for those with compensated cirrhosis. The combination of ledipasvir/sofosbuvir is the only treatment option for children aged 3-6 years with genotype 1, 4, 5, or 6 infection.

The efficacy of sofosbuvir/velpatasvir (Epclusa) once daily for 12 weeks was first evaluated in an open-label trial among children aged 6 years and older with genotype 1, 2, 3, 4, or 6 infection, without cirrhosis or with compensated cirrhosis. Subsequently, the “cocktail” was evaluated in children aged 6-12 years, with 76% genotype 1, 3% genotype 2, 15% genotype 3, and 6% genotype 4. SVR12 rates were 93% (50/54) in children with genotype 1, 91% (10/11) in those with genotype 3, and 100% in participants with genotype 2 (2/2) or genotype 4 (4/4). Sofosbuvir/velpatasvir was approved in March 2020 by the Food and Drug Administration for pediatric patients aged 6 years and older. Given its pangenotypic activity, safety, and efficacy, sofosbuvir/velpatasvir is currently recommended as a first choice for HCV treatment in children and adolescents aged at least 6 years.

The daily fixed-dose combination of glecaprevir/pibrentasvir (Mavyret) was approved in April 2019 for adolescents aged 12-17 years, and weighing at least 45 kg.Treatment is for 8 weeks, and includes treatment-naive patients without cirrhosis or those with compensated cirrhosis. SVR12 rates for Mavyret have ranged from 91% to 100 % across clinic trials. FDA approval and HCV guideline treatment recommendations for direct-acting antiviral (DAA)–experienced adolescents are based on clinical trial data from adults. Given its pangenotypic activity, safety, and efficacy record in adult patients, glecaprevir/pibrentasvir is recommended as a first choice for adolescent HCV treatment. Glecaprevir/pibrentasvir once approved for children less than 3 years of age will be safe and efficacious as a pangenotypic treatment option in children with chronic HCV infection.
 

Current recommendations

Tools for identifying HCV infected infants as early as a few months of age are available, yet studies demonstrate that a minority of at-risk children are tested for HCV using either an HCV polymerase chain reaction strategy early in life or an anti-HCV antibody strategy after 18 months of age.

Therapy with direct-acting agents is now licensed to those aged 3 years and offers the potential for cure, eliminating concern for possible progression after prolonged infection. Such therapy offers the potential to eliminate the stigma faced by many children as well as the hepatic and extrahepatic manifestations observed in children. Medication formulation and the child’s abilities to take the medication needs to be considered when prescribing DAAs. It is important to assess if the child can successfully swallow pills. Currently, Harvoni is the only medication that comes in both pellet and pill formulations. The dose is based on weight. The pellets need to be given in a small amount of nonacidic food; they cannot be chewed.

All children with chronic HCV infection are candidates for treatment. When significant fibrosis and/or cirrhosis is present treatment should not be delayed once the child is age 3 years; when only transaminitis is present, treatment can be delayed. In our experience, parents are eager to complete treatment before starting kindergarten.

Liver biopsy for obtaining liver tissue for histopathologic examination is not routinely indicated in children with chronic HCV infection but should be evaluated case by case. Noninvasive tests of hepatic fibrosis have been used in children, these include serologic markers (i.e., FibroSure) and radiologic tests such as ultrasound-based transient elastography (i.e., Fibroscan). Validation for pediatric patients is variable for the different serologic tests. Studies have shown that Fibroscan using the M probe is feasible for a wide range of ages, but poor patient cooperation may make measurement difficult.

Further details regarding dosing and choice of formulation is available at https://www.hcvguidelines.org/unique-populations/children.

Dr. Sabharwal is assistant professor of pediatrics at Boston University and attending physician in pediatric infectious diseases at Boston Medical Center. Ms. Moloney is an instructor in pediatrics at Boston University and a pediatric nurse practitioner in pediatric infectious diseases at Boston Medicine Center. Dr. Pelton is professor of pediatrics and epidemiology at Boston University and public health and senior attending physician at Boston Medical Center. Boston Medical Center received funding from AbbVie for study of Harvoni in Children 3 years of age and older. Email them at [email protected].

References

MMWR Morb Mortal Wkly Rep. 2017 May 12;66(18):470-3. Hepatol Commun. 2017 March 23. doi: 10.1002/hep4.1028. Hepatology. 2020 Feb;71(2):422-30. Lancet Gastroenterol Hepatol. 2019 Apr 11. doi: 10.1016/S2468-1253(19)30046-9. Arch Dis Child. 2006 Sep;91(9):781-5. J Pediatr Gastroenterol Nutr. 2010 Feb;50(2):123-31.

Early reports showed high mortality from coronavirus disease 2019 (COVID-19), while current United States data mortality rates are lower, raising hope that new treatments and management strategies have improved outcomes. For instance, Centers for Disease Control and Prevention data show that 6.7% of cases resulted in death in April, compared with 1.9% in September.¹ However, the demographics of those infected have also changed, and more available testing may mean more comprehensive identification and earlier treatment. Nationally, for instance, the median age of confirmed cases was 38 years at the end of August, down from 46 years at the start of May.² Therefore, whether decreasing COVID-19 mortality rates simply reflect changing demographics or represent actual improvements in clinical care is unknown. The objective of this analysis was to assess outcomes over time in a single health system, accounting for changes in demographics, clinical factors, and severity of disease at presentation.

We analyzed monthly mortality rates for admissions between March 1 and August 31, 2020, in a single health system in New York City. Outcomes were obtained as of October 8, 2020. We included all hospitalizations of people 18 years and older with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection identified during the hospitalization or in the prior 2 weeks, excluding those admitted to hospice care. Patients with multiple hospitalizations (N=208 patients, 229 hospitalizations, 4.4%) were included repeatedly if they continued to have laboratory-confirmed disease. Patients without admission vital signs (N=28) were excluded. Mortality was defined as in-hospital death or discharge to hospice care. In-house laboratory testing began March 16 and all inpatients were tested for SARS-CoV-2 by April 1; elective surgeries resumed May 4-11 and were only conducted on confirmed SARS-CoV-2–negative patients.

All data were obtained from the electronic health record (Epic Systems, Verona, Wisconsin). Diagnosis codes were obtained from the problem list, past medical history, and billing codes. In addition, we used objective data such as hemoglobin A1c, ejection fraction, outpatient creatinine, and outpatient blood pressure to augment problem list diagnoses where relevant.

Based on prior literature, we constructed multivariable logistic regression models for mortality adjusting for age; sex; self-reported race and ethnicity; body mass index; smoking history; presence of hypertension, heart failure, hyperlipidemia, coronary artery disease, diabetes, cancer, chronic kidney disease, dementia, or pulmonary disease individually as dummy variables; and admission oxygen saturation, D-dimer, ferritin, and C-reactive protein.^3-6 In the first model (C statistic 0.82), we did not include month of admission as a covariate and calculated the ratio of the sum of observed and expected deaths (obtained from the model) in each month to obtain the standardized mortality ratio (SMR) for each month. We then multiplied each period’s SMR by the overall average crude mortality to generate monthly adjusted mortality rates. We calculated Poisson control limits and indicated points outside the control limits as significantly different.

In a second model (C statistic 0.84), we included month as a covariate and calculated average marginal effects (AME) for each time period by using the margins library in R,⁷ which uses a discrete first-difference in predicted outcomes to obtain the AME. The average marginal effect represents the percentage point difference between the reference period (March) and a subsequent time period in probability of death or discharge to hospice, for equivalent patients. We obtained lower and upper confidence intervals for the AME using a bootstrapping approach described in Green.⁸ Finally, we conducted two sensitivity analyses: one, restricting the analysis to only those patients with principal diagnosis of COVID-19, sepsis, or respiratory disease (see Appendix A for complete list of codes) and one restricting the analysis to only those with length of stay of at least 3 days.

All statistical analyses were conducted with R, version 4.0.2. All analyses used 2-sided statistical tests, and we considered a P value < .05 to be statistically significant without adjustment for multiple testing. The NYU institutional review board approved the study and granted a waiver of consent and a waiver of the Health Information Portability and Accountability Act.

We included 5,121 hospitalizations, of which 5,118 (99.94%) had known outcomes (death or hospital discharge). Peak hospitalizations occurred in late March to mid-April, which accounted for 53% of the hospitalizations. Median length of stay for patients who died or were discharged to hospice was 8 days (interquartile range, 4-15; max 140 days). The median age and the proportion male or with any comorbidity decreased over time (Table). For instance, the proportion with any chronic condition decreased from 81% in March to 72% in August.

Adjusted mortality dropped each month, from 25.6% in March to 7.6% in August (Table and Figure). The SMR declined progressively over time, from 1.26 (95% CI, 1.15-1.39) in March to 0.38 (95% CI, 0.12-0.88) in August (Table). The adjusted average marginal effect was also significantly lower than in March in every subsequent month, reaching a maximum of an average 18.2 (95% CI, 12.0-24.4) percentage point decrease in probability of death in August, accounting for changes in demographics and clinical severity (Table and Appendix B). The decrease in unadjusted mortality over time was observed across age groups (Appendix C).

Results of the two sensitivity analyses were similar (Appendices D and E), though attenuated in the case of the sepsis/respiratory cohort, with adjusted mortality falling from 31.4% to 14.4%, SMR decreasing from 1.28 (95% CI, 1.16-1.41) to 0.59 (95% CI, 0.16-1.50), and AME in August 17.0 percentage points (95% CI, 6.0-28.1).

In this study of COVID-19 mortality over 6 months at a single health system, we found that changes in demographics and severity of illness at presentation did not fully explain decreases in mortality seen over time. Even after risk adjustment for a variety of clinical and demographic factors, including severity of illness at presentation, mortality was significantly and progressively lower over the course of the study period.

Similar risk-adjusted results have been preliminarily reported among intensive care unit patients in a preprint from the United Kingdom.⁹ Incremental improvements in outcomes are likely a combination of increasing clinical experience, decreasing hospital volume, growing use of new pharmacologic treatments (such as systemic corticosteroids,¹⁰ remdesivir,¹¹ and anticytokine treatments), nonpharmacologic treatments (such as placing the patient in the prone position, or proning, rather than on their back), earlier intervention, community awareness, and, potentially, lower viral load exposure from increased mask wearing and social distancing.¹²

Strengths of this study include highly detailed electronic health record data on hospitalizations at three different hospitals, a diverse patient population,⁶ near-complete study outcomes, and a lengthy period of investigation of 6 months. However, this study does have limitations. All patients were from a single geographic region and treated within a single health system, though restricting data to one system reduces institution-level variability and allows us to assess how care may have evolved with growing experience. Aggregating data from numerous health systems that might be at different stages of local outbreaks, provide different quality of care, and contribute different numbers of patients in each period introduces its own biases. We were also unable to disentangle different potential explanatory factors given the observational nature of the study. Residual confounding, such as a higher proportion of particularly frail patients admitted in earlier periods, is also a possibility, though the fact that we observed declines across all age groups mitigates this concern. Thresholds for hospital admission may also have changed over time with less severely ill patients being admitted in the later time periods. While changing admission thresholds could have contributed to higher survival rates in the latter portions of the study, our inclusion of several highly predictive clinical and laboratory results likely captured many aspects of disease severity.

In summary, data from one health system suggest that COVID-19 remains a serious disease for high-risk patients, but that mortality rates are improving over time.

Early reports showed high mortality from coronavirus disease 2019 (COVID-19), while current United States data mortality rates are lower, raising hope that new treatments and management strategies have improved outcomes. For instance, Centers for Disease Control and Prevention data show that 6.7% of cases resulted in death in April, compared with 1.9% in September.¹ However, the demographics of those infected have also changed, and more available testing may mean more comprehensive identification and earlier treatment. Nationally, for instance, the median age of confirmed cases was 38 years at the end of August, down from 46 years at the start of May.² Therefore, whether decreasing COVID-19 mortality rates simply reflect changing demographics or represent actual improvements in clinical care is unknown. The objective of this analysis was to assess outcomes over time in a single health system, accounting for changes in demographics, clinical factors, and severity of disease at presentation.

We analyzed monthly mortality rates for admissions between March 1 and August 31, 2020, in a single health system in New York City. Outcomes were obtained as of October 8, 2020. We included all hospitalizations of people 18 years and older with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection identified during the hospitalization or in the prior 2 weeks, excluding those admitted to hospice care. Patients with multiple hospitalizations (N=208 patients, 229 hospitalizations, 4.4%) were included repeatedly if they continued to have laboratory-confirmed disease. Patients without admission vital signs (N=28) were excluded. Mortality was defined as in-hospital death or discharge to hospice care. In-house laboratory testing began March 16 and all inpatients were tested for SARS-CoV-2 by April 1; elective surgeries resumed May 4-11 and were only conducted on confirmed SARS-CoV-2–negative patients.

All data were obtained from the electronic health record (Epic Systems, Verona, Wisconsin). Diagnosis codes were obtained from the problem list, past medical history, and billing codes. In addition, we used objective data such as hemoglobin A1c, ejection fraction, outpatient creatinine, and outpatient blood pressure to augment problem list diagnoses where relevant.

Based on prior literature, we constructed multivariable logistic regression models for mortality adjusting for age; sex; self-reported race and ethnicity; body mass index; smoking history; presence of hypertension, heart failure, hyperlipidemia, coronary artery disease, diabetes, cancer, chronic kidney disease, dementia, or pulmonary disease individually as dummy variables; and admission oxygen saturation, D-dimer, ferritin, and C-reactive protein.^3-6 In the first model (C statistic 0.82), we did not include month of admission as a covariate and calculated the ratio of the sum of observed and expected deaths (obtained from the model) in each month to obtain the standardized mortality ratio (SMR) for each month. We then multiplied each period’s SMR by the overall average crude mortality to generate monthly adjusted mortality rates. We calculated Poisson control limits and indicated points outside the control limits as significantly different.

In a second model (C statistic 0.84), we included month as a covariate and calculated average marginal effects (AME) for each time period by using the margins library in R,⁷ which uses a discrete first-difference in predicted outcomes to obtain the AME. The average marginal effect represents the percentage point difference between the reference period (March) and a subsequent time period in probability of death or discharge to hospice, for equivalent patients. We obtained lower and upper confidence intervals for the AME using a bootstrapping approach described in Green.⁸ Finally, we conducted two sensitivity analyses: one, restricting the analysis to only those patients with principal diagnosis of COVID-19, sepsis, or respiratory disease (see Appendix A for complete list of codes) and one restricting the analysis to only those with length of stay of at least 3 days.

All statistical analyses were conducted with R, version 4.0.2. All analyses used 2-sided statistical tests, and we considered a P value < .05 to be statistically significant without adjustment for multiple testing. The NYU institutional review board approved the study and granted a waiver of consent and a waiver of the Health Information Portability and Accountability Act.

We included 5,121 hospitalizations, of which 5,118 (99.94%) had known outcomes (death or hospital discharge). Peak hospitalizations occurred in late March to mid-April, which accounted for 53% of the hospitalizations. Median length of stay for patients who died or were discharged to hospice was 8 days (interquartile range, 4-15; max 140 days). The median age and the proportion male or with any comorbidity decreased over time (Table). For instance, the proportion with any chronic condition decreased from 81% in March to 72% in August.

Adjusted mortality dropped each month, from 25.6% in March to 7.6% in August (Table and Figure). The SMR declined progressively over time, from 1.26 (95% CI, 1.15-1.39) in March to 0.38 (95% CI, 0.12-0.88) in August (Table). The adjusted average marginal effect was also significantly lower than in March in every subsequent month, reaching a maximum of an average 18.2 (95% CI, 12.0-24.4) percentage point decrease in probability of death in August, accounting for changes in demographics and clinical severity (Table and Appendix B). The decrease in unadjusted mortality over time was observed across age groups (Appendix C).

Results of the two sensitivity analyses were similar (Appendices D and E), though attenuated in the case of the sepsis/respiratory cohort, with adjusted mortality falling from 31.4% to 14.4%, SMR decreasing from 1.28 (95% CI, 1.16-1.41) to 0.59 (95% CI, 0.16-1.50), and AME in August 17.0 percentage points (95% CI, 6.0-28.1).

In this study of COVID-19 mortality over 6 months at a single health system, we found that changes in demographics and severity of illness at presentation did not fully explain decreases in mortality seen over time. Even after risk adjustment for a variety of clinical and demographic factors, including severity of illness at presentation, mortality was significantly and progressively lower over the course of the study period.

Similar risk-adjusted results have been preliminarily reported among intensive care unit patients in a preprint from the United Kingdom.⁹ Incremental improvements in outcomes are likely a combination of increasing clinical experience, decreasing hospital volume, growing use of new pharmacologic treatments (such as systemic corticosteroids,¹⁰ remdesivir,¹¹ and anticytokine treatments), nonpharmacologic treatments (such as placing the patient in the prone position, or proning, rather than on their back), earlier intervention, community awareness, and, potentially, lower viral load exposure from increased mask wearing and social distancing.¹²

Strengths of this study include highly detailed electronic health record data on hospitalizations at three different hospitals, a diverse patient population,⁶ near-complete study outcomes, and a lengthy period of investigation of 6 months. However, this study does have limitations. All patients were from a single geographic region and treated within a single health system, though restricting data to one system reduces institution-level variability and allows us to assess how care may have evolved with growing experience. Aggregating data from numerous health systems that might be at different stages of local outbreaks, provide different quality of care, and contribute different numbers of patients in each period introduces its own biases. We were also unable to disentangle different potential explanatory factors given the observational nature of the study. Residual confounding, such as a higher proportion of particularly frail patients admitted in earlier periods, is also a possibility, though the fact that we observed declines across all age groups mitigates this concern. Thresholds for hospital admission may also have changed over time with less severely ill patients being admitted in the later time periods. While changing admission thresholds could have contributed to higher survival rates in the latter portions of the study, our inclusion of several highly predictive clinical and laboratory results likely captured many aspects of disease severity.

In summary, data from one health system suggest that COVID-19 remains a serious disease for high-risk patients, but that mortality rates are improving over time.

Early reports showed high mortality from coronavirus disease 2019 (COVID-19), while current United States data mortality rates are lower, raising hope that new treatments and management strategies have improved outcomes. For instance, Centers for Disease Control and Prevention data show that 6.7% of cases resulted in death in April, compared with 1.9% in September.¹ However, the demographics of those infected have also changed, and more available testing may mean more comprehensive identification and earlier treatment. Nationally, for instance, the median age of confirmed cases was 38 years at the end of August, down from 46 years at the start of May.² Therefore, whether decreasing COVID-19 mortality rates simply reflect changing demographics or represent actual improvements in clinical care is unknown. The objective of this analysis was to assess outcomes over time in a single health system, accounting for changes in demographics, clinical factors, and severity of disease at presentation.

We analyzed monthly mortality rates for admissions between March 1 and August 31, 2020, in a single health system in New York City. Outcomes were obtained as of October 8, 2020. We included all hospitalizations of people 18 years and older with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection identified during the hospitalization or in the prior 2 weeks, excluding those admitted to hospice care. Patients with multiple hospitalizations (N=208 patients, 229 hospitalizations, 4.4%) were included repeatedly if they continued to have laboratory-confirmed disease. Patients without admission vital signs (N=28) were excluded. Mortality was defined as in-hospital death or discharge to hospice care. In-house laboratory testing began March 16 and all inpatients were tested for SARS-CoV-2 by April 1; elective surgeries resumed May 4-11 and were only conducted on confirmed SARS-CoV-2–negative patients.

All data were obtained from the electronic health record (Epic Systems, Verona, Wisconsin). Diagnosis codes were obtained from the problem list, past medical history, and billing codes. In addition, we used objective data such as hemoglobin A1c, ejection fraction, outpatient creatinine, and outpatient blood pressure to augment problem list diagnoses where relevant.

Based on prior literature, we constructed multivariable logistic regression models for mortality adjusting for age; sex; self-reported race and ethnicity; body mass index; smoking history; presence of hypertension, heart failure, hyperlipidemia, coronary artery disease, diabetes, cancer, chronic kidney disease, dementia, or pulmonary disease individually as dummy variables; and admission oxygen saturation, D-dimer, ferritin, and C-reactive protein.^3-6 In the first model (C statistic 0.82), we did not include month of admission as a covariate and calculated the ratio of the sum of observed and expected deaths (obtained from the model) in each month to obtain the standardized mortality ratio (SMR) for each month. We then multiplied each period’s SMR by the overall average crude mortality to generate monthly adjusted mortality rates. We calculated Poisson control limits and indicated points outside the control limits as significantly different.

In a second model (C statistic 0.84), we included month as a covariate and calculated average marginal effects (AME) for each time period by using the margins library in R,⁷ which uses a discrete first-difference in predicted outcomes to obtain the AME. The average marginal effect represents the percentage point difference between the reference period (March) and a subsequent time period in probability of death or discharge to hospice, for equivalent patients. We obtained lower and upper confidence intervals for the AME using a bootstrapping approach described in Green.⁸ Finally, we conducted two sensitivity analyses: one, restricting the analysis to only those patients with principal diagnosis of COVID-19, sepsis, or respiratory disease (see Appendix A for complete list of codes) and one restricting the analysis to only those with length of stay of at least 3 days.

All statistical analyses were conducted with R, version 4.0.2. All analyses used 2-sided statistical tests, and we considered a P value < .05 to be statistically significant without adjustment for multiple testing. The NYU institutional review board approved the study and granted a waiver of consent and a waiver of the Health Information Portability and Accountability Act.

We included 5,121 hospitalizations, of which 5,118 (99.94%) had known outcomes (death or hospital discharge). Peak hospitalizations occurred in late March to mid-April, which accounted for 53% of the hospitalizations. Median length of stay for patients who died or were discharged to hospice was 8 days (interquartile range, 4-15; max 140 days). The median age and the proportion male or with any comorbidity decreased over time (Table). For instance, the proportion with any chronic condition decreased from 81% in March to 72% in August.

Adjusted mortality dropped each month, from 25.6% in March to 7.6% in August (Table and Figure). The SMR declined progressively over time, from 1.26 (95% CI, 1.15-1.39) in March to 0.38 (95% CI, 0.12-0.88) in August (Table). The adjusted average marginal effect was also significantly lower than in March in every subsequent month, reaching a maximum of an average 18.2 (95% CI, 12.0-24.4) percentage point decrease in probability of death in August, accounting for changes in demographics and clinical severity (Table and Appendix B). The decrease in unadjusted mortality over time was observed across age groups (Appendix C).

Results of the two sensitivity analyses were similar (Appendices D and E), though attenuated in the case of the sepsis/respiratory cohort, with adjusted mortality falling from 31.4% to 14.4%, SMR decreasing from 1.28 (95% CI, 1.16-1.41) to 0.59 (95% CI, 0.16-1.50), and AME in August 17.0 percentage points (95% CI, 6.0-28.1).

In this study of COVID-19 mortality over 6 months at a single health system, we found that changes in demographics and severity of illness at presentation did not fully explain decreases in mortality seen over time. Even after risk adjustment for a variety of clinical and demographic factors, including severity of illness at presentation, mortality was significantly and progressively lower over the course of the study period.

Similar risk-adjusted results have been preliminarily reported among intensive care unit patients in a preprint from the United Kingdom.⁹ Incremental improvements in outcomes are likely a combination of increasing clinical experience, decreasing hospital volume, growing use of new pharmacologic treatments (such as systemic corticosteroids,¹⁰ remdesivir,¹¹ and anticytokine treatments), nonpharmacologic treatments (such as placing the patient in the prone position, or proning, rather than on their back), earlier intervention, community awareness, and, potentially, lower viral load exposure from increased mask wearing and social distancing.¹²

Strengths of this study include highly detailed electronic health record data on hospitalizations at three different hospitals, a diverse patient population,⁶ near-complete study outcomes, and a lengthy period of investigation of 6 months. However, this study does have limitations. All patients were from a single geographic region and treated within a single health system, though restricting data to one system reduces institution-level variability and allows us to assess how care may have evolved with growing experience. Aggregating data from numerous health systems that might be at different stages of local outbreaks, provide different quality of care, and contribute different numbers of patients in each period introduces its own biases. We were also unable to disentangle different potential explanatory factors given the observational nature of the study. Residual confounding, such as a higher proportion of particularly frail patients admitted in earlier periods, is also a possibility, though the fact that we observed declines across all age groups mitigates this concern. Thresholds for hospital admission may also have changed over time with less severely ill patients being admitted in the later time periods. While changing admission thresholds could have contributed to higher survival rates in the latter portions of the study, our inclusion of several highly predictive clinical and laboratory results likely captured many aspects of disease severity.

In summary, data from one health system suggest that COVID-19 remains a serious disease for high-risk patients, but that mortality rates are improving over time.

Acalabrutinib, a next-generation Bruton tyrosine kinase inhibitor, provides prolonged progression-free survival and better tolerability, compared with standard-of-care regimens for relapsed or refractory chronic lymphocytic leukemia (CLL), according to final results from the phase 3 ASCEND study.

Courtesy Wikimedia Commons/Nephron/Creative Commons BY-SA-3.0

The estimated 18-month progression-free survival (PFS) at a median of 22 months was 82% in 155 patients treated with acalabrutinib, compared with 48% in 155 treated with investigator’s choice of either idelalisib-rituximab (IdR) or bendamustine-rituximab (BR), which were given in 119 and 36 patients, respectively, Paolo Ghia, MD, PhD, reported at the Society of Hematologic Oncology virtual meeting.

The benefits of acalabrutinib were apparent regardless of high-risk genetic characteristics: Those with and without both del(17p) and TP53 mutations had similarly good PFS outcomes with acalabrutinib versus IdR/BR (HRs, 0.11 and 0.29, respectively), as did those with versus without unmutated IgVH (HRs, 0.28 and 0.30, respectively), said Dr. Ghia, professor of medical oncology at the Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan.

The median overall survival was not reached in either arm, but estimated 18-month OS was 88% in both groups, likely because of the crossover being allowed for nonresponders in the IdR/BR groups, he noted.
 

Overall responses

The investigator-assessed overall response rates, including partial response or better, were also similar in the groups at 80% and 84%, respectively, and ORR, including partial response with lymphocytosis, was 92% versus 88%.

The duration of response was not reached in the acalabrutinib arm versus 18 months with IdR/BR, and estimated duration of response was 85% versus 49%.

The median drug exposure with acalabrutinib was approximately double that with IdR and about four times that of BR, Dr. Ghia said, noting that the difference between acalabrutinib and BR is explained by the short 6-month duration of treatment with BR, but the difference between acalabrutinib and IdR is because of adverse events (AEs).
 

Adverse events

AEs were the most common reason for treatment discontinuation in all three groups, but they led to discontinuation in only 16% with acalabrutinib versus 56% with IdR, he added.

The rates of AEs and AEs of clinical interest were generally similar to those reported at the interim analysis as presented in 2019 at the European Hematology Association annual meeting and published in the Journal of Clinical Oncology, despite the additional 6 months of follow up, he said.

Additionally, the incidence of grade 3 or higher AEs, serious AEs, and treatment-related AEs were all greater with IdR than with acalabrutinib or BR. The most common AEs with acalabrutinib were headache, neutropenia, diarrhea, and upper-respiratory infection, which were mostly grade 1 or 2. The most common grade 3 or higher AEs were neutropenia, anemia, and pneumonia, which were reported in 12%, 17%, and 7% of patients.
 

Confirmatory results

“The final results from the ASCEND study confirm the findings at the interim analysis and support the favorable efficacy and safety of acalabrutinib versus standard-of-care regimens ... in patients with relapsed/refractory CLL,” Dr. Ghia said.

“Overall, these final results from ASCENT support the use of acalabrutinib in patients with relapsed/refractory CLL, including those with high-risk genetic features.”

This study was sponsored by Acerta Pharma. Dr. Ghia reported consulting or advisory roles, grant or research funding, and/or honoraria from Abbvie, BeiGene, Janssen, Gilead Sciences, Sunesis Pharmaceuticals, Juno Therapeutics, ArQule, Adaptive Biotechnologies, Dynamo Therapeutics, MEI Pharma, and Novartis.

[email protected]

SOURCE: Ghia P et al. SOHO 2020, Abstract CLL-091.

Acalabrutinib, a next-generation Bruton tyrosine kinase inhibitor, provides prolonged progression-free survival and better tolerability, compared with standard-of-care regimens for relapsed or refractory chronic lymphocytic leukemia (CLL), according to final results from the phase 3 ASCEND study.

Courtesy Wikimedia Commons/Nephron/Creative Commons BY-SA-3.0

The estimated 18-month progression-free survival (PFS) at a median of 22 months was 82% in 155 patients treated with acalabrutinib, compared with 48% in 155 treated with investigator’s choice of either idelalisib-rituximab (IdR) or bendamustine-rituximab (BR), which were given in 119 and 36 patients, respectively, Paolo Ghia, MD, PhD, reported at the Society of Hematologic Oncology virtual meeting.

The benefits of acalabrutinib were apparent regardless of high-risk genetic characteristics: Those with and without both del(17p) and TP53 mutations had similarly good PFS outcomes with acalabrutinib versus IdR/BR (HRs, 0.11 and 0.29, respectively), as did those with versus without unmutated IgVH (HRs, 0.28 and 0.30, respectively), said Dr. Ghia, professor of medical oncology at the Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan.

The median overall survival was not reached in either arm, but estimated 18-month OS was 88% in both groups, likely because of the crossover being allowed for nonresponders in the IdR/BR groups, he noted.
 

Overall responses

The investigator-assessed overall response rates, including partial response or better, were also similar in the groups at 80% and 84%, respectively, and ORR, including partial response with lymphocytosis, was 92% versus 88%.

The duration of response was not reached in the acalabrutinib arm versus 18 months with IdR/BR, and estimated duration of response was 85% versus 49%.

The median drug exposure with acalabrutinib was approximately double that with IdR and about four times that of BR, Dr. Ghia said, noting that the difference between acalabrutinib and BR is explained by the short 6-month duration of treatment with BR, but the difference between acalabrutinib and IdR is because of adverse events (AEs).
 

Adverse events

AEs were the most common reason for treatment discontinuation in all three groups, but they led to discontinuation in only 16% with acalabrutinib versus 56% with IdR, he added.

The rates of AEs and AEs of clinical interest were generally similar to those reported at the interim analysis as presented in 2019 at the European Hematology Association annual meeting and published in the Journal of Clinical Oncology, despite the additional 6 months of follow up, he said.

Additionally, the incidence of grade 3 or higher AEs, serious AEs, and treatment-related AEs were all greater with IdR than with acalabrutinib or BR. The most common AEs with acalabrutinib were headache, neutropenia, diarrhea, and upper-respiratory infection, which were mostly grade 1 or 2. The most common grade 3 or higher AEs were neutropenia, anemia, and pneumonia, which were reported in 12%, 17%, and 7% of patients.
 

Confirmatory results

“The final results from the ASCEND study confirm the findings at the interim analysis and support the favorable efficacy and safety of acalabrutinib versus standard-of-care regimens ... in patients with relapsed/refractory CLL,” Dr. Ghia said.

“Overall, these final results from ASCENT support the use of acalabrutinib in patients with relapsed/refractory CLL, including those with high-risk genetic features.”

This study was sponsored by Acerta Pharma. Dr. Ghia reported consulting or advisory roles, grant or research funding, and/or honoraria from Abbvie, BeiGene, Janssen, Gilead Sciences, Sunesis Pharmaceuticals, Juno Therapeutics, ArQule, Adaptive Biotechnologies, Dynamo Therapeutics, MEI Pharma, and Novartis.

[email protected]

SOURCE: Ghia P et al. SOHO 2020, Abstract CLL-091.

Acalabrutinib, a next-generation Bruton tyrosine kinase inhibitor, provides prolonged progression-free survival and better tolerability, compared with standard-of-care regimens for relapsed or refractory chronic lymphocytic leukemia (CLL), according to final results from the phase 3 ASCEND study.

Courtesy Wikimedia Commons/Nephron/Creative Commons BY-SA-3.0

The estimated 18-month progression-free survival (PFS) at a median of 22 months was 82% in 155 patients treated with acalabrutinib, compared with 48% in 155 treated with investigator’s choice of either idelalisib-rituximab (IdR) or bendamustine-rituximab (BR), which were given in 119 and 36 patients, respectively, Paolo Ghia, MD, PhD, reported at the Society of Hematologic Oncology virtual meeting.

The benefits of acalabrutinib were apparent regardless of high-risk genetic characteristics: Those with and without both del(17p) and TP53 mutations had similarly good PFS outcomes with acalabrutinib versus IdR/BR (HRs, 0.11 and 0.29, respectively), as did those with versus without unmutated IgVH (HRs, 0.28 and 0.30, respectively), said Dr. Ghia, professor of medical oncology at the Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan.

The median overall survival was not reached in either arm, but estimated 18-month OS was 88% in both groups, likely because of the crossover being allowed for nonresponders in the IdR/BR groups, he noted.
 

Overall responses

The investigator-assessed overall response rates, including partial response or better, were also similar in the groups at 80% and 84%, respectively, and ORR, including partial response with lymphocytosis, was 92% versus 88%.

The duration of response was not reached in the acalabrutinib arm versus 18 months with IdR/BR, and estimated duration of response was 85% versus 49%.

The median drug exposure with acalabrutinib was approximately double that with IdR and about four times that of BR, Dr. Ghia said, noting that the difference between acalabrutinib and BR is explained by the short 6-month duration of treatment with BR, but the difference between acalabrutinib and IdR is because of adverse events (AEs).
 

Adverse events

AEs were the most common reason for treatment discontinuation in all three groups, but they led to discontinuation in only 16% with acalabrutinib versus 56% with IdR, he added.

The rates of AEs and AEs of clinical interest were generally similar to those reported at the interim analysis as presented in 2019 at the European Hematology Association annual meeting and published in the Journal of Clinical Oncology, despite the additional 6 months of follow up, he said.

Additionally, the incidence of grade 3 or higher AEs, serious AEs, and treatment-related AEs were all greater with IdR than with acalabrutinib or BR. The most common AEs with acalabrutinib were headache, neutropenia, diarrhea, and upper-respiratory infection, which were mostly grade 1 or 2. The most common grade 3 or higher AEs were neutropenia, anemia, and pneumonia, which were reported in 12%, 17%, and 7% of patients.
 

Confirmatory results

“The final results from the ASCEND study confirm the findings at the interim analysis and support the favorable efficacy and safety of acalabrutinib versus standard-of-care regimens ... in patients with relapsed/refractory CLL,” Dr. Ghia said.

“Overall, these final results from ASCENT support the use of acalabrutinib in patients with relapsed/refractory CLL, including those with high-risk genetic features.”

This study was sponsored by Acerta Pharma. Dr. Ghia reported consulting or advisory roles, grant or research funding, and/or honoraria from Abbvie, BeiGene, Janssen, Gilead Sciences, Sunesis Pharmaceuticals, Juno Therapeutics, ArQule, Adaptive Biotechnologies, Dynamo Therapeutics, MEI Pharma, and Novartis.

[email protected]

SOURCE: Ghia P et al. SOHO 2020, Abstract CLL-091.

When assessing inflammatory dermatoses in children with skin of color, it may be necessary to train the eye to recognize subtle changes and colors other than red, a doctor suggested at the virtual American Academy of Pediatrics annual meeting.

First, doctors should see whether they can detect any erythema, said Latanya T. Benjamin, MD, associate professor of pediatric dermatology at Florida Atlantic University, Boca Raton. “If the answer is no because of the background competing chromophore, then shift your focus off of the erythema and perhaps onto other colors that the skin can demonstrate,” such as red-brown, violaceous, or grayish hues.

Comparing involved areas with normal skin also may help. “Sometimes you can pick up subtleties in colors that way,” Dr. Benjamin said.

Finally, look for other changes that could relate to the patient’s condition. For example, when diagnosing acne, Dr. Benjamin looks for pigmentary sequelae like hyperpigmentation. “If a patient has atopic dermatitis, is there hypopigmentation on other areas of the face?”

Consider cutaneous T-cell lymphoma in the differential diagnosis of generalized hypopigmented patches and plaques in patients with darker skin types, Dr. Benjamin noted. Other diagnoses that may result in hypopigmentation include pityriasis alba, vitiligo, tinea versicolor, ash-leaf macules, Hansen’s disease, postinflammatory hypopigmentation secondary to atopic dermatitis, and tinea corporis.

Be sensitive to the fact that changes in skin color can be “very annoying or devastating to the family,” even with medically benign conditions such as pityriasis alba, Dr. Benjamin added.

Detecting redness in brown skin tones can take practice, Candrice R. Heath, MD, a member of the board of directors for the Skin of Color Society, commented in an interview.

Furthermore, presentations vary. For instance, depictions of atopic dermatitis in educational materials may focus on red patches and plaques but “miss that there are several presentations in those with darker skin tones, including follicular prominence, hyperpigmented plaques, and coin-shaped lesions,” said Dr. Heath, assistant professor of dermatology at Temple University, Philadelphia.

“The skin of color population is growing,” noted Dr. Heath. “By 2023, there will be more children with skin of color than without in the United States.”

While Dr. Heath has lectured about skin of color as it relates to pediatric patients for years, “now with the nation’s renewed interest in disparities in health care, it is the perfect time to highlight conditions that present more commonly in skin of color and present differently in those with skin of color.”

Dr. Benjamin had no conflicts of interest. Dr. Heath serves as associate editor of Cutis, which is owned by the same company as this publication.

[email protected]

When assessing inflammatory dermatoses in children with skin of color, it may be necessary to train the eye to recognize subtle changes and colors other than red, a doctor suggested at the virtual American Academy of Pediatrics annual meeting.

First, doctors should see whether they can detect any erythema, said Latanya T. Benjamin, MD, associate professor of pediatric dermatology at Florida Atlantic University, Boca Raton. “If the answer is no because of the background competing chromophore, then shift your focus off of the erythema and perhaps onto other colors that the skin can demonstrate,” such as red-brown, violaceous, or grayish hues.

Comparing involved areas with normal skin also may help. “Sometimes you can pick up subtleties in colors that way,” Dr. Benjamin said.

Finally, look for other changes that could relate to the patient’s condition. For example, when diagnosing acne, Dr. Benjamin looks for pigmentary sequelae like hyperpigmentation. “If a patient has atopic dermatitis, is there hypopigmentation on other areas of the face?”

Consider cutaneous T-cell lymphoma in the differential diagnosis of generalized hypopigmented patches and plaques in patients with darker skin types, Dr. Benjamin noted. Other diagnoses that may result in hypopigmentation include pityriasis alba, vitiligo, tinea versicolor, ash-leaf macules, Hansen’s disease, postinflammatory hypopigmentation secondary to atopic dermatitis, and tinea corporis.

Be sensitive to the fact that changes in skin color can be “very annoying or devastating to the family,” even with medically benign conditions such as pityriasis alba, Dr. Benjamin added.

Detecting redness in brown skin tones can take practice, Candrice R. Heath, MD, a member of the board of directors for the Skin of Color Society, commented in an interview.

Furthermore, presentations vary. For instance, depictions of atopic dermatitis in educational materials may focus on red patches and plaques but “miss that there are several presentations in those with darker skin tones, including follicular prominence, hyperpigmented plaques, and coin-shaped lesions,” said Dr. Heath, assistant professor of dermatology at Temple University, Philadelphia.

“The skin of color population is growing,” noted Dr. Heath. “By 2023, there will be more children with skin of color than without in the United States.”

While Dr. Heath has lectured about skin of color as it relates to pediatric patients for years, “now with the nation’s renewed interest in disparities in health care, it is the perfect time to highlight conditions that present more commonly in skin of color and present differently in those with skin of color.”

Dr. Benjamin had no conflicts of interest. Dr. Heath serves as associate editor of Cutis, which is owned by the same company as this publication.

[email protected]

When assessing inflammatory dermatoses in children with skin of color, it may be necessary to train the eye to recognize subtle changes and colors other than red, a doctor suggested at the virtual American Academy of Pediatrics annual meeting.

First, doctors should see whether they can detect any erythema, said Latanya T. Benjamin, MD, associate professor of pediatric dermatology at Florida Atlantic University, Boca Raton. “If the answer is no because of the background competing chromophore, then shift your focus off of the erythema and perhaps onto other colors that the skin can demonstrate,” such as red-brown, violaceous, or grayish hues.

Comparing involved areas with normal skin also may help. “Sometimes you can pick up subtleties in colors that way,” Dr. Benjamin said.

Finally, look for other changes that could relate to the patient’s condition. For example, when diagnosing acne, Dr. Benjamin looks for pigmentary sequelae like hyperpigmentation. “If a patient has atopic dermatitis, is there hypopigmentation on other areas of the face?”

Consider cutaneous T-cell lymphoma in the differential diagnosis of generalized hypopigmented patches and plaques in patients with darker skin types, Dr. Benjamin noted. Other diagnoses that may result in hypopigmentation include pityriasis alba, vitiligo, tinea versicolor, ash-leaf macules, Hansen’s disease, postinflammatory hypopigmentation secondary to atopic dermatitis, and tinea corporis.

Be sensitive to the fact that changes in skin color can be “very annoying or devastating to the family,” even with medically benign conditions such as pityriasis alba, Dr. Benjamin added.

Detecting redness in brown skin tones can take practice, Candrice R. Heath, MD, a member of the board of directors for the Skin of Color Society, commented in an interview.

Furthermore, presentations vary. For instance, depictions of atopic dermatitis in educational materials may focus on red patches and plaques but “miss that there are several presentations in those with darker skin tones, including follicular prominence, hyperpigmented plaques, and coin-shaped lesions,” said Dr. Heath, assistant professor of dermatology at Temple University, Philadelphia.

“The skin of color population is growing,” noted Dr. Heath. “By 2023, there will be more children with skin of color than without in the United States.”

While Dr. Heath has lectured about skin of color as it relates to pediatric patients for years, “now with the nation’s renewed interest in disparities in health care, it is the perfect time to highlight conditions that present more commonly in skin of color and present differently in those with skin of color.”

Dr. Benjamin had no conflicts of interest. Dr. Heath serves as associate editor of Cutis, which is owned by the same company as this publication.

[email protected]

Red-haired women were significantly more likely than were women with nonred hair to have elevated levels of C-reactive protein that may increase risk for cardiovascular conditions, according to data from nearly 9,000 women participating in the Nurses’ Health Study.

“Positive associations between red hair and cardiovascular disease and cancer in women, but not men, have been reported,” wrote Rebecca I. Hartman, MD, of Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues.

In a study published in the Journal of Investigative Dermatology, they reviewed data from the Nurses’ Health Study, a 1976 cohort study of 121,700 women registered nurses in the United States. They analyzed blood specimens from 8,994 women that were collected between 1989 and 1990. Participants’ natural hair color was determined by asking them their natural hair color at age 21 years, with choices of red, blonde, light brown, dark brown, or black. Overall, dark brown/black hair was the most common color (45%) and 390 of the women (4.3%) had red hair.

The average CRP levels were significantly higher for women with red hair (3.7 mg/L), compared with those with blonde (3.3 mg/L), light brown (3.0 mg/mL), or dark brown/black (3.2 mg/L).

Using the CRP levels for red-haired women as a reference, women with blond, light brown, and dark brown/black hair averaged significantly lower CRP levels than those of red-haired women in an age-adjusted model (–15.2%, –18/1%, and –14.2%, respectively) and in a multivariate analysis (–12.7%, –14.1%, and –10.9%, respectively).

Non-red-haired women had significantly lower odds of high CRP levels compared with red-haired women, with odds ratios of 0.62, 0.60, and 0.67 for women with blonde, light brown, and dark brown/black hair, respectively, in multivariate analysis, the researchers found.

The study was limited by several factors including the use of self-reports for hair color and the relative homogeneity of the Nurses’ Health Study, which has a population of mostly white, female health professionals, the researchers noted.

However, the findings of significantly increased CRP levels “could potentially explain a prior report of increased risks of cardiovascular disease and cancer in red-haired women,” they said. “Although, we observed similar associations in the NHS between red hair and cardiovascular disease and cancer, they were not statistically significant,” they added.

Additional studies are needed to validate and examine the clinical significance of the results, they concluded.

“Elevated CRP levels, a marker of inflammation, have been associated with increased risk for several diseases, including colon cancer and heart disease,” lead author Dr. Hartman said in an interview. “Another study suggested red-haired women have elevated risks of cardiovascular disease and cancer. We wanted to see if different levels of inflammation in red-haired women could possibly explain these findings.”

She said she was not surprised by the findings, “as they were in line with our hypothesis.” In addition, “animal studies suggest that the gene most responsible for red hair, MC1R, may be linked to inflammation,” she said.

While red-haired women were found to have higher CRP levels in the study, “the underlying mechanism and clinical significance remain unknown,” and more research is needed, Dr. Hartman emphasized. “First, our findings need to be validated in women and also examined in men. If our findings are validated, future studies should examine the mechanism of CRP elevation in red-haired women, and whether these women have elevated risks of colon cancer and heart disease,” she said.

“If red-haired women do have increased levels of inflammation, and as a result have elevated risks of colon cancer and heart disease, then future interventions can focus on enhanced screening and possibly chemoprevention in this population,” she added.

The study was supported by the National Institutes of Health. Lead author Dr. Hartman was supported by an American Skin Association Research Grant.
 

SOURCE: Hartman RI et al. J Invest Dermatol. 2020 Oct 12. doi: 10.1016/j.jid.2020.09.015.

Red-haired women were significantly more likely than were women with nonred hair to have elevated levels of C-reactive protein that may increase risk for cardiovascular conditions, according to data from nearly 9,000 women participating in the Nurses’ Health Study.

“Positive associations between red hair and cardiovascular disease and cancer in women, but not men, have been reported,” wrote Rebecca I. Hartman, MD, of Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues.

In a study published in the Journal of Investigative Dermatology, they reviewed data from the Nurses’ Health Study, a 1976 cohort study of 121,700 women registered nurses in the United States. They analyzed blood specimens from 8,994 women that were collected between 1989 and 1990. Participants’ natural hair color was determined by asking them their natural hair color at age 21 years, with choices of red, blonde, light brown, dark brown, or black. Overall, dark brown/black hair was the most common color (45%) and 390 of the women (4.3%) had red hair.

The average CRP levels were significantly higher for women with red hair (3.7 mg/L), compared with those with blonde (3.3 mg/L), light brown (3.0 mg/mL), or dark brown/black (3.2 mg/L).

Using the CRP levels for red-haired women as a reference, women with blond, light brown, and dark brown/black hair averaged significantly lower CRP levels than those of red-haired women in an age-adjusted model (–15.2%, –18/1%, and –14.2%, respectively) and in a multivariate analysis (–12.7%, –14.1%, and –10.9%, respectively).

Non-red-haired women had significantly lower odds of high CRP levels compared with red-haired women, with odds ratios of 0.62, 0.60, and 0.67 for women with blonde, light brown, and dark brown/black hair, respectively, in multivariate analysis, the researchers found.

The study was limited by several factors including the use of self-reports for hair color and the relative homogeneity of the Nurses’ Health Study, which has a population of mostly white, female health professionals, the researchers noted.

However, the findings of significantly increased CRP levels “could potentially explain a prior report of increased risks of cardiovascular disease and cancer in red-haired women,” they said. “Although, we observed similar associations in the NHS between red hair and cardiovascular disease and cancer, they were not statistically significant,” they added.

Additional studies are needed to validate and examine the clinical significance of the results, they concluded.

“Elevated CRP levels, a marker of inflammation, have been associated with increased risk for several diseases, including colon cancer and heart disease,” lead author Dr. Hartman said in an interview. “Another study suggested red-haired women have elevated risks of cardiovascular disease and cancer. We wanted to see if different levels of inflammation in red-haired women could possibly explain these findings.”

She said she was not surprised by the findings, “as they were in line with our hypothesis.” In addition, “animal studies suggest that the gene most responsible for red hair, MC1R, may be linked to inflammation,” she said.

While red-haired women were found to have higher CRP levels in the study, “the underlying mechanism and clinical significance remain unknown,” and more research is needed, Dr. Hartman emphasized. “First, our findings need to be validated in women and also examined in men. If our findings are validated, future studies should examine the mechanism of CRP elevation in red-haired women, and whether these women have elevated risks of colon cancer and heart disease,” she said.

“If red-haired women do have increased levels of inflammation, and as a result have elevated risks of colon cancer and heart disease, then future interventions can focus on enhanced screening and possibly chemoprevention in this population,” she added.

The study was supported by the National Institutes of Health. Lead author Dr. Hartman was supported by an American Skin Association Research Grant.
 

SOURCE: Hartman RI et al. J Invest Dermatol. 2020 Oct 12. doi: 10.1016/j.jid.2020.09.015.

Red-haired women were significantly more likely than were women with nonred hair to have elevated levels of C-reactive protein that may increase risk for cardiovascular conditions, according to data from nearly 9,000 women participating in the Nurses’ Health Study.

“Positive associations between red hair and cardiovascular disease and cancer in women, but not men, have been reported,” wrote Rebecca I. Hartman, MD, of Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues.

In a study published in the Journal of Investigative Dermatology, they reviewed data from the Nurses’ Health Study, a 1976 cohort study of 121,700 women registered nurses in the United States. They analyzed blood specimens from 8,994 women that were collected between 1989 and 1990. Participants’ natural hair color was determined by asking them their natural hair color at age 21 years, with choices of red, blonde, light brown, dark brown, or black. Overall, dark brown/black hair was the most common color (45%) and 390 of the women (4.3%) had red hair.

The average CRP levels were significantly higher for women with red hair (3.7 mg/L), compared with those with blonde (3.3 mg/L), light brown (3.0 mg/mL), or dark brown/black (3.2 mg/L).

Using the CRP levels for red-haired women as a reference, women with blond, light brown, and dark brown/black hair averaged significantly lower CRP levels than those of red-haired women in an age-adjusted model (–15.2%, –18/1%, and –14.2%, respectively) and in a multivariate analysis (–12.7%, –14.1%, and –10.9%, respectively).

Non-red-haired women had significantly lower odds of high CRP levels compared with red-haired women, with odds ratios of 0.62, 0.60, and 0.67 for women with blonde, light brown, and dark brown/black hair, respectively, in multivariate analysis, the researchers found.

The study was limited by several factors including the use of self-reports for hair color and the relative homogeneity of the Nurses’ Health Study, which has a population of mostly white, female health professionals, the researchers noted.

However, the findings of significantly increased CRP levels “could potentially explain a prior report of increased risks of cardiovascular disease and cancer in red-haired women,” they said. “Although, we observed similar associations in the NHS between red hair and cardiovascular disease and cancer, they were not statistically significant,” they added.

Additional studies are needed to validate and examine the clinical significance of the results, they concluded.

“Elevated CRP levels, a marker of inflammation, have been associated with increased risk for several diseases, including colon cancer and heart disease,” lead author Dr. Hartman said in an interview. “Another study suggested red-haired women have elevated risks of cardiovascular disease and cancer. We wanted to see if different levels of inflammation in red-haired women could possibly explain these findings.”

She said she was not surprised by the findings, “as they were in line with our hypothesis.” In addition, “animal studies suggest that the gene most responsible for red hair, MC1R, may be linked to inflammation,” she said.

While red-haired women were found to have higher CRP levels in the study, “the underlying mechanism and clinical significance remain unknown,” and more research is needed, Dr. Hartman emphasized. “First, our findings need to be validated in women and also examined in men. If our findings are validated, future studies should examine the mechanism of CRP elevation in red-haired women, and whether these women have elevated risks of colon cancer and heart disease,” she said.

“If red-haired women do have increased levels of inflammation, and as a result have elevated risks of colon cancer and heart disease, then future interventions can focus on enhanced screening and possibly chemoprevention in this population,” she added.

The study was supported by the National Institutes of Health. Lead author Dr. Hartman was supported by an American Skin Association Research Grant.
 

SOURCE: Hartman RI et al. J Invest Dermatol. 2020 Oct 12. doi: 10.1016/j.jid.2020.09.015.