COPENHAGEN – Use of the dual interleukin (IL)–17 inhibitor bimekizumab (Bimzelx) was associated with rapid reductions in signs and symptoms of radiographic axial spondyloarthritis, reported investigators in the BE MOBILE 2 phase 3 trial.

At least half of all patients achieved an Ankylosing Spondylitis Disease Activity Score (ASDAS) of less than 2.1 by week 24 of treatment with bimekizumab, and there were marked reductions in objective signs of inflammation, reported Désiréé van der Heijde, MD, PhD, of Leiden (Netherlands) University Medical Center.

“The safety we have seen in this trial was consistent with what we have seen [with bimekizumab] in other trials and other diseases,” she said at the annual European Congress of Rheumatology.
 

IL-17 inhibitor times 2

Bimekizumab is a monoclonal immunoglobulin 1 antibody that selectively inhibits IL-17A and IL-17F. It is approved in the European Union for treating adults with moderate to severe plaque psoriasis.

In the BE MOBILE 2 trial, investigators enrolled patients aged 18 years and older who had ankylosing spondylitis, who met modified New York criteria, who had active disease at screening and at baseline, as defined by having a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of 4 or more and spinal pain of 4 or more on a scale of 0-10, and whose disease failed to respond to two different NSAIDs or who were either intolerant of or had contraindications to NSAIDs.

The patients were randomly assigned on a 2:1 basis to receive either bimekizumab 160 mg every 4 weeks (221 patients) or placebo (111 patients) for 16 weeks. All patients were switched over at 16 weeks to bimekizumab maintenance for up to 1 year of total treatment.

Dr. Van der Heijde reported 24-week data from the trial, including data from 8 weeks of additional follow-up.
 

All endpoints met

The trial met its primary endpoint of 40% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 40) at week 16. There was a 44.8% improvement with bimekizumab, compared with 22.6% with placebo (P < .001).

All secondary endpoints also favored the bimekizumab arm, including ASAS 40 among patients who had not previously received a tumor necrosis factor (TNF)–alpha inhibitor, ASAS 20, BASDAI functional index, ankylosing spondylitis quality-of-life index, and others.

Responses to bimekizumab were consistent across subpopulations of patients with or without prior TNF-alpha inhibitor exposure, Dr. van der Heidje said.

In addition, use of bimekizumab was associated with a significant improvement from baseline, compared with placebo, in objective measures of inflammation, including MRI spine Berlin score at week 16 (mean, –2.3 vs. 0; P < .001), Spondylitis Research Consortium of Canada (SPARCC) MRI sacroiliac joint score at week 16 (mean, –5.6 vs. 1.1), and high-sensitivity C-reactive protein at week 16 (mean, 2.4 vs. 6.3 mg/L; P < .001).

The most frequent treatment-related adverse events were nasopharyngitis, diarrhea, and oral candidiasis, all of which were more common in the bimekizumab arm, as well as headache, the incidence of which was similar between the arms.

Overall, 6.4% of patients taking bimekizumab had fungal infections, compared with none in the placebo group. The infections were mild or moderate, localized, and mucocutaneous in nature. Only two patients discontinued the drug because of fungal infections: one for oral candidiasis, and one for esophageal candidiasis.

‘Promising results’

Fabian Proft, MD, head of the clinical trials unit at Charité University Hospital in Berlin, who was not involved in the study, told this news organization that the data looked very good.

“These are the first phase 3 data on dual inhibition of IL-17A and F with bimekizumab in axial spondyloarthritis, and the data are really promising,” he said. “For nonradiographic disease, the data also look very promising, and when we’re looking into the future, it might be a therapeutic option for us as treating rheumatologists.”

The study was funded by UCB Pharma. Dr. van der Heijde has received consulting fees from the company and others. Dr. Proft has consulted for and has been on the speaker’s bureau for UCB and other pharmaceutical companies.

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

COPENHAGEN – Use of the dual interleukin (IL)–17 inhibitor bimekizumab (Bimzelx) was associated with rapid reductions in signs and symptoms of radiographic axial spondyloarthritis, reported investigators in the BE MOBILE 2 phase 3 trial.

At least half of all patients achieved an Ankylosing Spondylitis Disease Activity Score (ASDAS) of less than 2.1 by week 24 of treatment with bimekizumab, and there were marked reductions in objective signs of inflammation, reported Désiréé van der Heijde, MD, PhD, of Leiden (Netherlands) University Medical Center.

“The safety we have seen in this trial was consistent with what we have seen [with bimekizumab] in other trials and other diseases,” she said at the annual European Congress of Rheumatology.
 

IL-17 inhibitor times 2

Bimekizumab is a monoclonal immunoglobulin 1 antibody that selectively inhibits IL-17A and IL-17F. It is approved in the European Union for treating adults with moderate to severe plaque psoriasis.

In the BE MOBILE 2 trial, investigators enrolled patients aged 18 years and older who had ankylosing spondylitis, who met modified New York criteria, who had active disease at screening and at baseline, as defined by having a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of 4 or more and spinal pain of 4 or more on a scale of 0-10, and whose disease failed to respond to two different NSAIDs or who were either intolerant of or had contraindications to NSAIDs.

The patients were randomly assigned on a 2:1 basis to receive either bimekizumab 160 mg every 4 weeks (221 patients) or placebo (111 patients) for 16 weeks. All patients were switched over at 16 weeks to bimekizumab maintenance for up to 1 year of total treatment.

Dr. Van der Heijde reported 24-week data from the trial, including data from 8 weeks of additional follow-up.
 

All endpoints met

The trial met its primary endpoint of 40% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 40) at week 16. There was a 44.8% improvement with bimekizumab, compared with 22.6% with placebo (P < .001).

All secondary endpoints also favored the bimekizumab arm, including ASAS 40 among patients who had not previously received a tumor necrosis factor (TNF)–alpha inhibitor, ASAS 20, BASDAI functional index, ankylosing spondylitis quality-of-life index, and others.

Responses to bimekizumab were consistent across subpopulations of patients with or without prior TNF-alpha inhibitor exposure, Dr. van der Heidje said.

In addition, use of bimekizumab was associated with a significant improvement from baseline, compared with placebo, in objective measures of inflammation, including MRI spine Berlin score at week 16 (mean, –2.3 vs. 0; P < .001), Spondylitis Research Consortium of Canada (SPARCC) MRI sacroiliac joint score at week 16 (mean, –5.6 vs. 1.1), and high-sensitivity C-reactive protein at week 16 (mean, 2.4 vs. 6.3 mg/L; P < .001).

The most frequent treatment-related adverse events were nasopharyngitis, diarrhea, and oral candidiasis, all of which were more common in the bimekizumab arm, as well as headache, the incidence of which was similar between the arms.

Overall, 6.4% of patients taking bimekizumab had fungal infections, compared with none in the placebo group. The infections were mild or moderate, localized, and mucocutaneous in nature. Only two patients discontinued the drug because of fungal infections: one for oral candidiasis, and one for esophageal candidiasis.

‘Promising results’

Fabian Proft, MD, head of the clinical trials unit at Charité University Hospital in Berlin, who was not involved in the study, told this news organization that the data looked very good.

“These are the first phase 3 data on dual inhibition of IL-17A and F with bimekizumab in axial spondyloarthritis, and the data are really promising,” he said. “For nonradiographic disease, the data also look very promising, and when we’re looking into the future, it might be a therapeutic option for us as treating rheumatologists.”

The study was funded by UCB Pharma. Dr. van der Heijde has received consulting fees from the company and others. Dr. Proft has consulted for and has been on the speaker’s bureau for UCB and other pharmaceutical companies.

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

COPENHAGEN – Use of the dual interleukin (IL)–17 inhibitor bimekizumab (Bimzelx) was associated with rapid reductions in signs and symptoms of radiographic axial spondyloarthritis, reported investigators in the BE MOBILE 2 phase 3 trial.

At least half of all patients achieved an Ankylosing Spondylitis Disease Activity Score (ASDAS) of less than 2.1 by week 24 of treatment with bimekizumab, and there were marked reductions in objective signs of inflammation, reported Désiréé van der Heijde, MD, PhD, of Leiden (Netherlands) University Medical Center.

“The safety we have seen in this trial was consistent with what we have seen [with bimekizumab] in other trials and other diseases,” she said at the annual European Congress of Rheumatology.
 

IL-17 inhibitor times 2

Bimekizumab is a monoclonal immunoglobulin 1 antibody that selectively inhibits IL-17A and IL-17F. It is approved in the European Union for treating adults with moderate to severe plaque psoriasis.

In the BE MOBILE 2 trial, investigators enrolled patients aged 18 years and older who had ankylosing spondylitis, who met modified New York criteria, who had active disease at screening and at baseline, as defined by having a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of 4 or more and spinal pain of 4 or more on a scale of 0-10, and whose disease failed to respond to two different NSAIDs or who were either intolerant of or had contraindications to NSAIDs.

The patients were randomly assigned on a 2:1 basis to receive either bimekizumab 160 mg every 4 weeks (221 patients) or placebo (111 patients) for 16 weeks. All patients were switched over at 16 weeks to bimekizumab maintenance for up to 1 year of total treatment.

Dr. Van der Heijde reported 24-week data from the trial, including data from 8 weeks of additional follow-up.
 

All endpoints met

The trial met its primary endpoint of 40% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 40) at week 16. There was a 44.8% improvement with bimekizumab, compared with 22.6% with placebo (P < .001).

All secondary endpoints also favored the bimekizumab arm, including ASAS 40 among patients who had not previously received a tumor necrosis factor (TNF)–alpha inhibitor, ASAS 20, BASDAI functional index, ankylosing spondylitis quality-of-life index, and others.

Responses to bimekizumab were consistent across subpopulations of patients with or without prior TNF-alpha inhibitor exposure, Dr. van der Heidje said.

In addition, use of bimekizumab was associated with a significant improvement from baseline, compared with placebo, in objective measures of inflammation, including MRI spine Berlin score at week 16 (mean, –2.3 vs. 0; P < .001), Spondylitis Research Consortium of Canada (SPARCC) MRI sacroiliac joint score at week 16 (mean, –5.6 vs. 1.1), and high-sensitivity C-reactive protein at week 16 (mean, 2.4 vs. 6.3 mg/L; P < .001).

The most frequent treatment-related adverse events were nasopharyngitis, diarrhea, and oral candidiasis, all of which were more common in the bimekizumab arm, as well as headache, the incidence of which was similar between the arms.

Overall, 6.4% of patients taking bimekizumab had fungal infections, compared with none in the placebo group. The infections were mild or moderate, localized, and mucocutaneous in nature. Only two patients discontinued the drug because of fungal infections: one for oral candidiasis, and one for esophageal candidiasis.

‘Promising results’

Fabian Proft, MD, head of the clinical trials unit at Charité University Hospital in Berlin, who was not involved in the study, told this news organization that the data looked very good.

“These are the first phase 3 data on dual inhibition of IL-17A and F with bimekizumab in axial spondyloarthritis, and the data are really promising,” he said. “For nonradiographic disease, the data also look very promising, and when we’re looking into the future, it might be a therapeutic option for us as treating rheumatologists.”

The study was funded by UCB Pharma. Dr. van der Heijde has received consulting fees from the company and others. Dr. Proft has consulted for and has been on the speaker’s bureau for UCB and other pharmaceutical companies.

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

When Esther Freeman, MD, PhD, thinks back on what she learned about monkeypox during her training as a dermatologist and an infectious disease epidemiologist, it was widely considered a viral disease with rare outbreaks limited primarily to Central and Western Africa.

“Monkeypox is something we have traditionally only seen very rarely in the U.S.,” Dr. Freeman, director of Global Health Dermatology at Massachusetts General Hospital and Harvard Medical School, Boston, said in an interview. “In the past, outbreaks in the U.S. have been related to international travel or import of exotic pets, which is very different than what we’re seeing as a global community now.”

Courtesy Dr. Ester Freeman

A different clinical presentation

The clinical presentation of monkeypox cases in the current outbreak also differs from that of previous outbreaks. In the past, monkeypox rashes often morphed from a macule to a pustule and commonly affected the face, hands, feet, and trunk, with some patients harboring as many as 200 lesions at once. That pattern still occurs, but increasingly, the presentation is characterized by a more localized spread, especially in the genital region, which Dr. Freeman described as “unusual and not an area we traditionally thought of in the past as a focus for monkeypox.”

Also, affected individuals in the current outbreak may develop fewer lesions, sometimes between 1 and 5 instead of up to 200. “This doesn’t apply to everybody, but it is a bit of a different picture than what we’ve seen in case descriptions and photographs in the past from places like Central Africa,” she said. “What’s being reported out of case clusters from the United Kingdom and Spain is a mix, where some people are having more generalized involvement while others have more localized involvement.” Visual examples of the monkey pox rash can be found in photos from the United Kingdom, the country with the highest number of confirmed cases, on the CDC’s website, and in a report from Spain.

Clusters of monkeypox cases have been reported worldwide in men who have sex with men, “but this is not limited to a particular subgroup of people,” emphasizes Dr. Freeman, who is also a member of the American Academy of Dermatology’s Ad Hoc Task Force to Develop Monkeypox Content, which created an online resource for clinicians. “There are several mechanisms of spread, but direct contact with lesions or infected fluids is one,” she notes.

Moreover, “lesions associated with herpes, syphilis, and molluscum can look similar to a monkeypox lesion. If you have a patient with a new genital lesion and you’re not sure what it is, testing for monkeypox in addition to classic sexually transmitted infections like HSV or syphilis would be reasonable during the current outbreak situation.”

The 2022 monkeypox outbreak may pale in comparison to the spread of COVID-19 in terms of case numbers and societal impact, but dermatologists may be the first point of contact for a person infected with the monkeypox virus. “It’s important for dermatologists to be able to recognize monkeypox, because by recognizing cases, we can stop the outbreak,” Dr. Freeman said. “In theory, an infected person could show up in your clinic, regardless of where you practice in the U.S. But at the same time, it’s important not to panic. This is not COVID-19 all over again; this is different. Yes, it is an outbreak, but we already have a vaccine that works against monkeypox, and while one of the possible modes of transmission for monkeypox is respiratory, it’s much harder to transmit that way than SARS-CoV-2 – it requires closer and longer contact.”

Confirmation of a monkeypox virus infection is based on results of a PCR test based on swabs of a lesion. The AAD task force recommends contacting the local hospital epidemiologist, infection control personnel, and/or state health department about suspected cases, “as different locations will have different regulations on where to send the [PCR] test. If appropriate, the state health department will contact the CDC.”

According to the CDC, current recommendations for personal protective equipment for possible and confirmed monkeypox cases include gown, gloves, a National Institute for Occupational Safety and Health-approved N-95 mask, and eye protection.

 

Topical antiviral an option

If the lesions in a patient with suspected monkeypox have turned into pustules while waiting for the PCR test results, one option is to prescribe 3%-5% topical cidofovir, according to Stephen K. Tyring, MD, PhD, of the departments of dermatology, microbiology & molecular genetics, and internal medicine at the University of Texas Health Science Center, Houston. “That’s the effective antiviral that is most available,” he said. Generic cidofovir is also now available.

Dr. Tyring recommends rapid referral of immunocompromised patients with suspected monkeypox to an infectious disease expert and/or consulting with the CDC. “The pediatric population also seems to be at somewhat more risk, as has been seen in sub-Saharan Africa,” said Dr. Tyring, who is one of the editors of the textbook Tropical Dermatology. “Also, by definition, pregnant women are at more risk because their immune systems aren’t up to par. You also want to make sure that if monkeypox is on a person’s skin that they don’t get it in their eyes, because they could lose their vision.” He added that sub-Saharan Africa has a monkeypox mortality of up to 10%, “which is something we don’t see in the U.S. or Europe. Those of us who grew up in the 20th century got routine smallpox vaccines, and we therefore probably have a degree of immunity to monkeypox. But for the past 40 years or so, unless you are in the military, you are not going to get a routine vaccine to prevent smallpox.”
 

Incubation period, appearance of lesions

Monkeypox has a long incubation period. According to Dr. Freeman, from the point of exposure to the development of symptomatic lesions is typically 7-14 days but can vary from 5-21 days. “It’s important for people to be aware that their exposure may have been in the more distant past, not just a few days ago” she said. “Identifying cases as quickly as possible gives us a window where we can vaccinate close contacts.”

Dr. Freeman and Dr. Tyring reported having no relevant financial disclosures.

CDC guidance on vaccination before and after exposure to monkeypox can be found here . A general Q&A for health care professionals from the CDC can be found here.

When Esther Freeman, MD, PhD, thinks back on what she learned about monkeypox during her training as a dermatologist and an infectious disease epidemiologist, it was widely considered a viral disease with rare outbreaks limited primarily to Central and Western Africa.

“Monkeypox is something we have traditionally only seen very rarely in the U.S.,” Dr. Freeman, director of Global Health Dermatology at Massachusetts General Hospital and Harvard Medical School, Boston, said in an interview. “In the past, outbreaks in the U.S. have been related to international travel or import of exotic pets, which is very different than what we’re seeing as a global community now.”

Courtesy Dr. Ester Freeman

A different clinical presentation

The clinical presentation of monkeypox cases in the current outbreak also differs from that of previous outbreaks. In the past, monkeypox rashes often morphed from a macule to a pustule and commonly affected the face, hands, feet, and trunk, with some patients harboring as many as 200 lesions at once. That pattern still occurs, but increasingly, the presentation is characterized by a more localized spread, especially in the genital region, which Dr. Freeman described as “unusual and not an area we traditionally thought of in the past as a focus for monkeypox.”

Also, affected individuals in the current outbreak may develop fewer lesions, sometimes between 1 and 5 instead of up to 200. “This doesn’t apply to everybody, but it is a bit of a different picture than what we’ve seen in case descriptions and photographs in the past from places like Central Africa,” she said. “What’s being reported out of case clusters from the United Kingdom and Spain is a mix, where some people are having more generalized involvement while others have more localized involvement.” Visual examples of the monkey pox rash can be found in photos from the United Kingdom, the country with the highest number of confirmed cases, on the CDC’s website, and in a report from Spain.

Clusters of monkeypox cases have been reported worldwide in men who have sex with men, “but this is not limited to a particular subgroup of people,” emphasizes Dr. Freeman, who is also a member of the American Academy of Dermatology’s Ad Hoc Task Force to Develop Monkeypox Content, which created an online resource for clinicians. “There are several mechanisms of spread, but direct contact with lesions or infected fluids is one,” she notes.

Moreover, “lesions associated with herpes, syphilis, and molluscum can look similar to a monkeypox lesion. If you have a patient with a new genital lesion and you’re not sure what it is, testing for monkeypox in addition to classic sexually transmitted infections like HSV or syphilis would be reasonable during the current outbreak situation.”

The 2022 monkeypox outbreak may pale in comparison to the spread of COVID-19 in terms of case numbers and societal impact, but dermatologists may be the first point of contact for a person infected with the monkeypox virus. “It’s important for dermatologists to be able to recognize monkeypox, because by recognizing cases, we can stop the outbreak,” Dr. Freeman said. “In theory, an infected person could show up in your clinic, regardless of where you practice in the U.S. But at the same time, it’s important not to panic. This is not COVID-19 all over again; this is different. Yes, it is an outbreak, but we already have a vaccine that works against monkeypox, and while one of the possible modes of transmission for monkeypox is respiratory, it’s much harder to transmit that way than SARS-CoV-2 – it requires closer and longer contact.”

Confirmation of a monkeypox virus infection is based on results of a PCR test based on swabs of a lesion. The AAD task force recommends contacting the local hospital epidemiologist, infection control personnel, and/or state health department about suspected cases, “as different locations will have different regulations on where to send the [PCR] test. If appropriate, the state health department will contact the CDC.”

According to the CDC, current recommendations for personal protective equipment for possible and confirmed monkeypox cases include gown, gloves, a National Institute for Occupational Safety and Health-approved N-95 mask, and eye protection.

 

Topical antiviral an option

If the lesions in a patient with suspected monkeypox have turned into pustules while waiting for the PCR test results, one option is to prescribe 3%-5% topical cidofovir, according to Stephen K. Tyring, MD, PhD, of the departments of dermatology, microbiology & molecular genetics, and internal medicine at the University of Texas Health Science Center, Houston. “That’s the effective antiviral that is most available,” he said. Generic cidofovir is also now available.

Dr. Tyring recommends rapid referral of immunocompromised patients with suspected monkeypox to an infectious disease expert and/or consulting with the CDC. “The pediatric population also seems to be at somewhat more risk, as has been seen in sub-Saharan Africa,” said Dr. Tyring, who is one of the editors of the textbook Tropical Dermatology. “Also, by definition, pregnant women are at more risk because their immune systems aren’t up to par. You also want to make sure that if monkeypox is on a person’s skin that they don’t get it in their eyes, because they could lose their vision.” He added that sub-Saharan Africa has a monkeypox mortality of up to 10%, “which is something we don’t see in the U.S. or Europe. Those of us who grew up in the 20th century got routine smallpox vaccines, and we therefore probably have a degree of immunity to monkeypox. But for the past 40 years or so, unless you are in the military, you are not going to get a routine vaccine to prevent smallpox.”
 

Incubation period, appearance of lesions

Monkeypox has a long incubation period. According to Dr. Freeman, from the point of exposure to the development of symptomatic lesions is typically 7-14 days but can vary from 5-21 days. “It’s important for people to be aware that their exposure may have been in the more distant past, not just a few days ago” she said. “Identifying cases as quickly as possible gives us a window where we can vaccinate close contacts.”

Dr. Freeman and Dr. Tyring reported having no relevant financial disclosures.

CDC guidance on vaccination before and after exposure to monkeypox can be found here . A general Q&A for health care professionals from the CDC can be found here.

When Esther Freeman, MD, PhD, thinks back on what she learned about monkeypox during her training as a dermatologist and an infectious disease epidemiologist, it was widely considered a viral disease with rare outbreaks limited primarily to Central and Western Africa.

“Monkeypox is something we have traditionally only seen very rarely in the U.S.,” Dr. Freeman, director of Global Health Dermatology at Massachusetts General Hospital and Harvard Medical School, Boston, said in an interview. “In the past, outbreaks in the U.S. have been related to international travel or import of exotic pets, which is very different than what we’re seeing as a global community now.”

Courtesy Dr. Ester Freeman

A different clinical presentation

The clinical presentation of monkeypox cases in the current outbreak also differs from that of previous outbreaks. In the past, monkeypox rashes often morphed from a macule to a pustule and commonly affected the face, hands, feet, and trunk, with some patients harboring as many as 200 lesions at once. That pattern still occurs, but increasingly, the presentation is characterized by a more localized spread, especially in the genital region, which Dr. Freeman described as “unusual and not an area we traditionally thought of in the past as a focus for monkeypox.”

Also, affected individuals in the current outbreak may develop fewer lesions, sometimes between 1 and 5 instead of up to 200. “This doesn’t apply to everybody, but it is a bit of a different picture than what we’ve seen in case descriptions and photographs in the past from places like Central Africa,” she said. “What’s being reported out of case clusters from the United Kingdom and Spain is a mix, where some people are having more generalized involvement while others have more localized involvement.” Visual examples of the monkey pox rash can be found in photos from the United Kingdom, the country with the highest number of confirmed cases, on the CDC’s website, and in a report from Spain.

Clusters of monkeypox cases have been reported worldwide in men who have sex with men, “but this is not limited to a particular subgroup of people,” emphasizes Dr. Freeman, who is also a member of the American Academy of Dermatology’s Ad Hoc Task Force to Develop Monkeypox Content, which created an online resource for clinicians. “There are several mechanisms of spread, but direct contact with lesions or infected fluids is one,” she notes.

Moreover, “lesions associated with herpes, syphilis, and molluscum can look similar to a monkeypox lesion. If you have a patient with a new genital lesion and you’re not sure what it is, testing for monkeypox in addition to classic sexually transmitted infections like HSV or syphilis would be reasonable during the current outbreak situation.”

The 2022 monkeypox outbreak may pale in comparison to the spread of COVID-19 in terms of case numbers and societal impact, but dermatologists may be the first point of contact for a person infected with the monkeypox virus. “It’s important for dermatologists to be able to recognize monkeypox, because by recognizing cases, we can stop the outbreak,” Dr. Freeman said. “In theory, an infected person could show up in your clinic, regardless of where you practice in the U.S. But at the same time, it’s important not to panic. This is not COVID-19 all over again; this is different. Yes, it is an outbreak, but we already have a vaccine that works against monkeypox, and while one of the possible modes of transmission for monkeypox is respiratory, it’s much harder to transmit that way than SARS-CoV-2 – it requires closer and longer contact.”

Confirmation of a monkeypox virus infection is based on results of a PCR test based on swabs of a lesion. The AAD task force recommends contacting the local hospital epidemiologist, infection control personnel, and/or state health department about suspected cases, “as different locations will have different regulations on where to send the [PCR] test. If appropriate, the state health department will contact the CDC.”

According to the CDC, current recommendations for personal protective equipment for possible and confirmed monkeypox cases include gown, gloves, a National Institute for Occupational Safety and Health-approved N-95 mask, and eye protection.

 

Topical antiviral an option

If the lesions in a patient with suspected monkeypox have turned into pustules while waiting for the PCR test results, one option is to prescribe 3%-5% topical cidofovir, according to Stephen K. Tyring, MD, PhD, of the departments of dermatology, microbiology & molecular genetics, and internal medicine at the University of Texas Health Science Center, Houston. “That’s the effective antiviral that is most available,” he said. Generic cidofovir is also now available.

Dr. Tyring recommends rapid referral of immunocompromised patients with suspected monkeypox to an infectious disease expert and/or consulting with the CDC. “The pediatric population also seems to be at somewhat more risk, as has been seen in sub-Saharan Africa,” said Dr. Tyring, who is one of the editors of the textbook Tropical Dermatology. “Also, by definition, pregnant women are at more risk because their immune systems aren’t up to par. You also want to make sure that if monkeypox is on a person’s skin that they don’t get it in their eyes, because they could lose their vision.” He added that sub-Saharan Africa has a monkeypox mortality of up to 10%, “which is something we don’t see in the U.S. or Europe. Those of us who grew up in the 20th century got routine smallpox vaccines, and we therefore probably have a degree of immunity to monkeypox. But for the past 40 years or so, unless you are in the military, you are not going to get a routine vaccine to prevent smallpox.”
 

Incubation period, appearance of lesions

Monkeypox has a long incubation period. According to Dr. Freeman, from the point of exposure to the development of symptomatic lesions is typically 7-14 days but can vary from 5-21 days. “It’s important for people to be aware that their exposure may have been in the more distant past, not just a few days ago” she said. “Identifying cases as quickly as possible gives us a window where we can vaccinate close contacts.”

Dr. Freeman and Dr. Tyring reported having no relevant financial disclosures.

CDC guidance on vaccination before and after exposure to monkeypox can be found here . A general Q&A for health care professionals from the CDC can be found here.

Despite a new meta-analysis claiming to show that testosterone replacement therapy for men with hypogonadism does not increase the risk of cardiovascular outcomes such as myocardial infarction or stroke, experts say the jury is still out.

A more definitive answer for cardiovascular safety of testosterone therapy will come from the TRAVERSE dedicated cardiovascular outcome trial, sponsored by AbbVie, which will have up to 5 years of follow-up, with results expected later this year.

The current meta-analysis by Jemma Hudson of Aberdeen (Scotland) University and colleagues was published online in The Lancet Healthy Longevity. The work will also be presented June 13 at ENDO 2022, the Endocrine Society’s annual meeting in Atlanta, Georgia, by senior author Channa Y. Jayasena, MD, PhD.

In 2014, the U.S. Food and Drug Administration mandated a label on testosterone products warning of possible increased cardiovascular risks and to reserve the therapy for symptomatic hypogonadism only. In contrast, the European Medicines Agency concluded that when hypogonadism is properly diagnosed and managed, there is currently no clear, consistent evidence that testosterone therapy causes increased cardiovascular risk.

To address this uncertainty, Dr. Hudson and colleagues formed a global collaborative to obtain individual patient data on cardiovascular outcomes from randomized controlled trials of testosterone therapy for men with hypogonadism.

They pooled data from 35 trials published from 1992 to Aug. 27, 2018, including 17 trials (3,431 patients) for which the researchers obtained patient-level data. The individual trials were 3-12 months long, except for one 3-year trial.

During a mean follow-up of 9.5 months, there was no significant increase in cardiovascular outcomes in men randomized to testosterone therapy versus placebo (odds ratio, 1.07; P = .62), nor were there any significantly increased risks of death, stroke, or different types of cardiovascular outcome, although those numbers were small.  

This is “the most comprehensive study to date investigating the safety of testosterone treatment of hypogonadism,” according to the researchers. “The current results provide some reassurance about the short-term to medium-term safety of testosterone to treat male hypogonadism,” they conclude.

However, they also acknowledge that “long-term data are needed to fully evaluate the safety of testosterone.”

Erin D. Michos, MD, coauthor of an accompanying editorial, told this news organization, “This study doesn’t say to me that low testosterone necessarily needs to be treated. It’s still not indicated in people just for a low number [for blood testosterone] with less-severe symptoms. It really comes down to each individual person, how symptomatic they are, and their cardiovascular risk.”

‘Trial is not definitive’

Dr. Michos is not the only person to be skeptical. Together with Steven Nissen, MD, an investigator for the TRAVERSE trial, she agrees that this new evidence is not yet decisive, largely because the individual trials in the meta-analysis were short and not designed as cardiovascular outcome trials.

Dr. Nissen, a cardiologist at Cleveland Clinic, added that the individual trials were heterogeneous, with “very few real cardiovascular events,” so the meta-analysis “is not definitive,” he said in an interview.

While this meta-analysis “that pooled together a lot of smaller studies is reassuring that there’s no signal of harm, it’s really inconclusive because the follow-up was really short – a mean of only 9.5 months – and you really need a larger study with longer follow up to be more conclusive,” Dr. Michos noted.

“We should have more data soon” from TRAVERSE, said Dr. Michos, from the division of cardiology, Johns Hopkins University, Baltimore, who is not involved with that study.

Meanwhile, “I don’t think [this analysis] changes the current recommendations,” she said.

“We should continue to use caution as indicated by the FDA label and only use testosterone therapy selectively in people who have true symptoms of hypogonadism,” and be cautious about using it particularly in men at higher cardiovascular risk because of family history or known personal heart disease.

On the other hand, the meta-analysis did not show harm, she noted, “so we don’t necessarily need to pull patients off therapy if they are already taking it. But I wouldn’t right now just start new patients on it unless they had a strong indication.”

“Certainly, great caution is advised regarding the use of testosterone replacement therapy in people with established atherosclerosis due to the findings of plaque progression in the testosterone trials and the excess cardiovascular events observed in the TOM trial, write Dr. Michos and fellow editorialist Matthew J. Budoff, MD, of University of California, Los Angeles, in their editorial.
 

Earlier data inconclusive

Testosterone concentrations progressively decline in men with advancing age, at about 2% per year, Dr. Michos and Dr. Budoff write. In addition, men with obesity or with diabetes have low levels of testosterone, Dr. Michos noted.

Low testosterone blood levels have been associated with insulin resistance, inflammation, dyslipidemia, and atherosclerosis. Testosterone replacement therapy has been used to increase libido, improve erectile dysfunction, and boost energy levels, mood, and muscle strength.

But it is well known that testosterone increases hematocrit, which has the potential to increase the risk of venous thromboembolism.

Two large observational studies have reported increased risks of myocardial infarction, stroke, and death in men taking testosterone, compared with nonusers, but the study designs have been widely criticized, Dr. Hudson and coauthors say in their article.  

A placebo-controlled trial was stopped early by its data- and safety-monitoring board following increased cardiovascular events in men aged 65 and older who received 6 months of testosterone. Other controlled trials have not observed these effects, but none was sufficiently powered.
 

Meta-analysis results

Dr. Hudson and colleagues performed a meta-analysis of 35 trials in 5,601 men aged 18 years and older with low baseline testosterone (≤ 350 nmol/dL) who had been randomized to testosterone replacement therapy or placebo for at least 3 months, for which there were data on mortality, stroke, and cardiovascular outcomes.

The men were a mean age of 65, had a mean body mass index of 30 kg/m², and most (88%) were White. A quarter had angina, 8% had a previous myocardial infarction, and 27% had diabetes. 

Cardiovascular and cerebrovascular outcomes were not primary outcomes.

During a mean follow-up of 9.5 months, in the 13 trials that provided this information, the rate of cardiovascular events was similar in the men who received testosterone (120/1,601, 7.5%) compared with those who received placebo (110/1,519, 7.2%).

In the 14 trials that provided this information, fewer deaths were reported during testosterone treatment (6/1,621, 0.4%) than during placebo treatment (12/1,537, 0.8%), but these numbers were too small to establish whether testosterone reduced mortality risk.

The most common cardiovascular events were arrhythmia, followed by coronary heart disease, heart failure, and myocardial infarction.

Patient age, baseline testosterone, smoking status, or diabetes status were not associated with cardiovascular risk.

The only detected adverse effects were edema and a modest lowering of HDL cholesterol.

“Men who develop sexual dysfunction, unexplained anemia, or osteoporosis should be tested for low testosterone,” senior author of the meta-analysis Dr. Jayasena said in an email to this news organization.

However, Dr. Jayasena added, “Mass screening for testosterone has no benefit in asymptomatic men.”

“Older men may still benefit from testosterone, but only if they have the clinical features [of hypogonadism] and low testosterone levels,” he concluded.  

The current study is supported by the Health Technology Assessment program of the National Institute for Health Research. The TRAVERSE trial is sponsored by AbbVie. Dr. Jayasena has reported receiving research grants from LogixX Pharma. Dr. Hudson has reported no relevant financial relationships. Disclosures for the other authors are listed in the article. Dr. Michos has reported receiving support from the Amato Fund in Women’s Cardiovascular Health at Johns Hopkins School of Medicine and serving on medical advisory boards for Novartis, Esperion, Amarin, and AstraZeneca outside the submitted work. Dr. Budoff has reported receiving grant support from General Electric.
 

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

Despite a new meta-analysis claiming to show that testosterone replacement therapy for men with hypogonadism does not increase the risk of cardiovascular outcomes such as myocardial infarction or stroke, experts say the jury is still out.

A more definitive answer for cardiovascular safety of testosterone therapy will come from the TRAVERSE dedicated cardiovascular outcome trial, sponsored by AbbVie, which will have up to 5 years of follow-up, with results expected later this year.

The current meta-analysis by Jemma Hudson of Aberdeen (Scotland) University and colleagues was published online in The Lancet Healthy Longevity. The work will also be presented June 13 at ENDO 2022, the Endocrine Society’s annual meeting in Atlanta, Georgia, by senior author Channa Y. Jayasena, MD, PhD.

In 2014, the U.S. Food and Drug Administration mandated a label on testosterone products warning of possible increased cardiovascular risks and to reserve the therapy for symptomatic hypogonadism only. In contrast, the European Medicines Agency concluded that when hypogonadism is properly diagnosed and managed, there is currently no clear, consistent evidence that testosterone therapy causes increased cardiovascular risk.

To address this uncertainty, Dr. Hudson and colleagues formed a global collaborative to obtain individual patient data on cardiovascular outcomes from randomized controlled trials of testosterone therapy for men with hypogonadism.

They pooled data from 35 trials published from 1992 to Aug. 27, 2018, including 17 trials (3,431 patients) for which the researchers obtained patient-level data. The individual trials were 3-12 months long, except for one 3-year trial.

During a mean follow-up of 9.5 months, there was no significant increase in cardiovascular outcomes in men randomized to testosterone therapy versus placebo (odds ratio, 1.07; P = .62), nor were there any significantly increased risks of death, stroke, or different types of cardiovascular outcome, although those numbers were small.  

This is “the most comprehensive study to date investigating the safety of testosterone treatment of hypogonadism,” according to the researchers. “The current results provide some reassurance about the short-term to medium-term safety of testosterone to treat male hypogonadism,” they conclude.

However, they also acknowledge that “long-term data are needed to fully evaluate the safety of testosterone.”

Erin D. Michos, MD, coauthor of an accompanying editorial, told this news organization, “This study doesn’t say to me that low testosterone necessarily needs to be treated. It’s still not indicated in people just for a low number [for blood testosterone] with less-severe symptoms. It really comes down to each individual person, how symptomatic they are, and their cardiovascular risk.”

‘Trial is not definitive’

Dr. Michos is not the only person to be skeptical. Together with Steven Nissen, MD, an investigator for the TRAVERSE trial, she agrees that this new evidence is not yet decisive, largely because the individual trials in the meta-analysis were short and not designed as cardiovascular outcome trials.

Dr. Nissen, a cardiologist at Cleveland Clinic, added that the individual trials were heterogeneous, with “very few real cardiovascular events,” so the meta-analysis “is not definitive,” he said in an interview.

While this meta-analysis “that pooled together a lot of smaller studies is reassuring that there’s no signal of harm, it’s really inconclusive because the follow-up was really short – a mean of only 9.5 months – and you really need a larger study with longer follow up to be more conclusive,” Dr. Michos noted.

“We should have more data soon” from TRAVERSE, said Dr. Michos, from the division of cardiology, Johns Hopkins University, Baltimore, who is not involved with that study.

Meanwhile, “I don’t think [this analysis] changes the current recommendations,” she said.

“We should continue to use caution as indicated by the FDA label and only use testosterone therapy selectively in people who have true symptoms of hypogonadism,” and be cautious about using it particularly in men at higher cardiovascular risk because of family history or known personal heart disease.

On the other hand, the meta-analysis did not show harm, she noted, “so we don’t necessarily need to pull patients off therapy if they are already taking it. But I wouldn’t right now just start new patients on it unless they had a strong indication.”

“Certainly, great caution is advised regarding the use of testosterone replacement therapy in people with established atherosclerosis due to the findings of plaque progression in the testosterone trials and the excess cardiovascular events observed in the TOM trial, write Dr. Michos and fellow editorialist Matthew J. Budoff, MD, of University of California, Los Angeles, in their editorial.
 

Earlier data inconclusive

Testosterone concentrations progressively decline in men with advancing age, at about 2% per year, Dr. Michos and Dr. Budoff write. In addition, men with obesity or with diabetes have low levels of testosterone, Dr. Michos noted.

Low testosterone blood levels have been associated with insulin resistance, inflammation, dyslipidemia, and atherosclerosis. Testosterone replacement therapy has been used to increase libido, improve erectile dysfunction, and boost energy levels, mood, and muscle strength.

But it is well known that testosterone increases hematocrit, which has the potential to increase the risk of venous thromboembolism.

Two large observational studies have reported increased risks of myocardial infarction, stroke, and death in men taking testosterone, compared with nonusers, but the study designs have been widely criticized, Dr. Hudson and coauthors say in their article.  

A placebo-controlled trial was stopped early by its data- and safety-monitoring board following increased cardiovascular events in men aged 65 and older who received 6 months of testosterone. Other controlled trials have not observed these effects, but none was sufficiently powered.
 

Meta-analysis results

Dr. Hudson and colleagues performed a meta-analysis of 35 trials in 5,601 men aged 18 years and older with low baseline testosterone (≤ 350 nmol/dL) who had been randomized to testosterone replacement therapy or placebo for at least 3 months, for which there were data on mortality, stroke, and cardiovascular outcomes.

The men were a mean age of 65, had a mean body mass index of 30 kg/m², and most (88%) were White. A quarter had angina, 8% had a previous myocardial infarction, and 27% had diabetes. 

Cardiovascular and cerebrovascular outcomes were not primary outcomes.

During a mean follow-up of 9.5 months, in the 13 trials that provided this information, the rate of cardiovascular events was similar in the men who received testosterone (120/1,601, 7.5%) compared with those who received placebo (110/1,519, 7.2%).

In the 14 trials that provided this information, fewer deaths were reported during testosterone treatment (6/1,621, 0.4%) than during placebo treatment (12/1,537, 0.8%), but these numbers were too small to establish whether testosterone reduced mortality risk.

The most common cardiovascular events were arrhythmia, followed by coronary heart disease, heart failure, and myocardial infarction.

Patient age, baseline testosterone, smoking status, or diabetes status were not associated with cardiovascular risk.

The only detected adverse effects were edema and a modest lowering of HDL cholesterol.

“Men who develop sexual dysfunction, unexplained anemia, or osteoporosis should be tested for low testosterone,” senior author of the meta-analysis Dr. Jayasena said in an email to this news organization.

However, Dr. Jayasena added, “Mass screening for testosterone has no benefit in asymptomatic men.”

“Older men may still benefit from testosterone, but only if they have the clinical features [of hypogonadism] and low testosterone levels,” he concluded.  

The current study is supported by the Health Technology Assessment program of the National Institute for Health Research. The TRAVERSE trial is sponsored by AbbVie. Dr. Jayasena has reported receiving research grants from LogixX Pharma. Dr. Hudson has reported no relevant financial relationships. Disclosures for the other authors are listed in the article. Dr. Michos has reported receiving support from the Amato Fund in Women’s Cardiovascular Health at Johns Hopkins School of Medicine and serving on medical advisory boards for Novartis, Esperion, Amarin, and AstraZeneca outside the submitted work. Dr. Budoff has reported receiving grant support from General Electric.
 

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

Despite a new meta-analysis claiming to show that testosterone replacement therapy for men with hypogonadism does not increase the risk of cardiovascular outcomes such as myocardial infarction or stroke, experts say the jury is still out.

A more definitive answer for cardiovascular safety of testosterone therapy will come from the TRAVERSE dedicated cardiovascular outcome trial, sponsored by AbbVie, which will have up to 5 years of follow-up, with results expected later this year.

The current meta-analysis by Jemma Hudson of Aberdeen (Scotland) University and colleagues was published online in The Lancet Healthy Longevity. The work will also be presented June 13 at ENDO 2022, the Endocrine Society’s annual meeting in Atlanta, Georgia, by senior author Channa Y. Jayasena, MD, PhD.

In 2014, the U.S. Food and Drug Administration mandated a label on testosterone products warning of possible increased cardiovascular risks and to reserve the therapy for symptomatic hypogonadism only. In contrast, the European Medicines Agency concluded that when hypogonadism is properly diagnosed and managed, there is currently no clear, consistent evidence that testosterone therapy causes increased cardiovascular risk.

To address this uncertainty, Dr. Hudson and colleagues formed a global collaborative to obtain individual patient data on cardiovascular outcomes from randomized controlled trials of testosterone therapy for men with hypogonadism.

They pooled data from 35 trials published from 1992 to Aug. 27, 2018, including 17 trials (3,431 patients) for which the researchers obtained patient-level data. The individual trials were 3-12 months long, except for one 3-year trial.

During a mean follow-up of 9.5 months, there was no significant increase in cardiovascular outcomes in men randomized to testosterone therapy versus placebo (odds ratio, 1.07; P = .62), nor were there any significantly increased risks of death, stroke, or different types of cardiovascular outcome, although those numbers were small.  

This is “the most comprehensive study to date investigating the safety of testosterone treatment of hypogonadism,” according to the researchers. “The current results provide some reassurance about the short-term to medium-term safety of testosterone to treat male hypogonadism,” they conclude.

However, they also acknowledge that “long-term data are needed to fully evaluate the safety of testosterone.”

Erin D. Michos, MD, coauthor of an accompanying editorial, told this news organization, “This study doesn’t say to me that low testosterone necessarily needs to be treated. It’s still not indicated in people just for a low number [for blood testosterone] with less-severe symptoms. It really comes down to each individual person, how symptomatic they are, and their cardiovascular risk.”

‘Trial is not definitive’

Dr. Michos is not the only person to be skeptical. Together with Steven Nissen, MD, an investigator for the TRAVERSE trial, she agrees that this new evidence is not yet decisive, largely because the individual trials in the meta-analysis were short and not designed as cardiovascular outcome trials.

Dr. Nissen, a cardiologist at Cleveland Clinic, added that the individual trials were heterogeneous, with “very few real cardiovascular events,” so the meta-analysis “is not definitive,” he said in an interview.

While this meta-analysis “that pooled together a lot of smaller studies is reassuring that there’s no signal of harm, it’s really inconclusive because the follow-up was really short – a mean of only 9.5 months – and you really need a larger study with longer follow up to be more conclusive,” Dr. Michos noted.

“We should have more data soon” from TRAVERSE, said Dr. Michos, from the division of cardiology, Johns Hopkins University, Baltimore, who is not involved with that study.

Meanwhile, “I don’t think [this analysis] changes the current recommendations,” she said.

“We should continue to use caution as indicated by the FDA label and only use testosterone therapy selectively in people who have true symptoms of hypogonadism,” and be cautious about using it particularly in men at higher cardiovascular risk because of family history or known personal heart disease.

On the other hand, the meta-analysis did not show harm, she noted, “so we don’t necessarily need to pull patients off therapy if they are already taking it. But I wouldn’t right now just start new patients on it unless they had a strong indication.”

“Certainly, great caution is advised regarding the use of testosterone replacement therapy in people with established atherosclerosis due to the findings of plaque progression in the testosterone trials and the excess cardiovascular events observed in the TOM trial, write Dr. Michos and fellow editorialist Matthew J. Budoff, MD, of University of California, Los Angeles, in their editorial.
 

Earlier data inconclusive

Testosterone concentrations progressively decline in men with advancing age, at about 2% per year, Dr. Michos and Dr. Budoff write. In addition, men with obesity or with diabetes have low levels of testosterone, Dr. Michos noted.

Low testosterone blood levels have been associated with insulin resistance, inflammation, dyslipidemia, and atherosclerosis. Testosterone replacement therapy has been used to increase libido, improve erectile dysfunction, and boost energy levels, mood, and muscle strength.

But it is well known that testosterone increases hematocrit, which has the potential to increase the risk of venous thromboembolism.

Two large observational studies have reported increased risks of myocardial infarction, stroke, and death in men taking testosterone, compared with nonusers, but the study designs have been widely criticized, Dr. Hudson and coauthors say in their article.  

A placebo-controlled trial was stopped early by its data- and safety-monitoring board following increased cardiovascular events in men aged 65 and older who received 6 months of testosterone. Other controlled trials have not observed these effects, but none was sufficiently powered.
 

Meta-analysis results

Dr. Hudson and colleagues performed a meta-analysis of 35 trials in 5,601 men aged 18 years and older with low baseline testosterone (≤ 350 nmol/dL) who had been randomized to testosterone replacement therapy or placebo for at least 3 months, for which there were data on mortality, stroke, and cardiovascular outcomes.

The men were a mean age of 65, had a mean body mass index of 30 kg/m², and most (88%) were White. A quarter had angina, 8% had a previous myocardial infarction, and 27% had diabetes. 

Cardiovascular and cerebrovascular outcomes were not primary outcomes.

During a mean follow-up of 9.5 months, in the 13 trials that provided this information, the rate of cardiovascular events was similar in the men who received testosterone (120/1,601, 7.5%) compared with those who received placebo (110/1,519, 7.2%).

In the 14 trials that provided this information, fewer deaths were reported during testosterone treatment (6/1,621, 0.4%) than during placebo treatment (12/1,537, 0.8%), but these numbers were too small to establish whether testosterone reduced mortality risk.

The most common cardiovascular events were arrhythmia, followed by coronary heart disease, heart failure, and myocardial infarction.

Patient age, baseline testosterone, smoking status, or diabetes status were not associated with cardiovascular risk.

The only detected adverse effects were edema and a modest lowering of HDL cholesterol.

“Men who develop sexual dysfunction, unexplained anemia, or osteoporosis should be tested for low testosterone,” senior author of the meta-analysis Dr. Jayasena said in an email to this news organization.

However, Dr. Jayasena added, “Mass screening for testosterone has no benefit in asymptomatic men.”

“Older men may still benefit from testosterone, but only if they have the clinical features [of hypogonadism] and low testosterone levels,” he concluded.  

The current study is supported by the Health Technology Assessment program of the National Institute for Health Research. The TRAVERSE trial is sponsored by AbbVie. Dr. Jayasena has reported receiving research grants from LogixX Pharma. Dr. Hudson has reported no relevant financial relationships. Disclosures for the other authors are listed in the article. Dr. Michos has reported receiving support from the Amato Fund in Women’s Cardiovascular Health at Johns Hopkins School of Medicine and serving on medical advisory boards for Novartis, Esperion, Amarin, and AstraZeneca outside the submitted work. Dr. Budoff has reported receiving grant support from General Electric.
 

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

CHARLOTTE, N.C. – Overnight sleep electroencephalography (EEG) contains an abundance of brain wave data that could be mined to identify an individual’s risk for a host of health outcomes, including dementia, cognitive impairment, and cardiovascular events, a researcher reported at the annual meeting of the Associated Professional Sleep Societies. “Sleep EEGs contain decodable information about the risk of unfavorable outcomes,” said Haoqi Sun, PhD, an instructor of neurology at Massachusetts General Hospital, Boston, and lead study author. “The results suggest that it’s feasible to use sleep to identify people with high risk of unfavorable outcomes and it strengthens the concept of sleep as a window into brain and general health.”

The researchers performed a quantitative analysis of sleep data collected on 8,673 adults who had diagnostic sleep studies that included polysomnography (PSG). The analysis used ICD codes to consider these 11 health outcomes: dementia, mild cognitive impairment (MCI) or dementia, ischemic stroke, intracranial hemorrhage, atrial fibrillation, myocardial infarction, type 2 diabetes, hypertension, bipolar disorder, depression, and mortality.

Then, Dr. Sun explained, they extracted 86 spectral and time-domain features of REM and non-REM sleep from sleep EEG recordings, and analyzed that data by adjusting for eight covariates including age, sex, body mass index, and use of benzodiazepines, antidepressants, sedatives, antiseizure drugs, and stimulants.

Participants were partitioned into three sleep-quality groups: poor, average, and good. The outcome-wise mean prediction difference in 10-year cumulative incidence was 2.3% for the poor sleep group, 0.5% for the average sleep group, and 1.3% for the good sleep group.

The outcomes with the three greatest poor to average risk ratios were dementia (6.2; 95% confidence interval, 4.5-9.3), mortality (5.7; 95% CI, 5-7.5) and MCI or dementia (4; 95% CI, 3.2-4.9).
 

Ready for the clinic?

In an interview, Dr. Sun said the results demonstrated the potential of using EEG brain wave data to predict health outcomes on an individual basis, although he acknowledged that most of the 86 sleep features the researchers used are not readily available in the clinic.

He noted the spectral features used in the study can be captured through software compatible with PSG. “From there you can identify the various bands, the different frequency ranges, and then you can easily see within this range whether a person has a higher power or lower power,” he said. However, the spindle and slow-oscillation features that researchers used in the study are beyond the reach of most clinics.
 

Next steps

This research is in its early stage, Dr. Sun said, but at some point the data collected from sleep studies could be paired with machine learning to make the model workable for evaluating individual patients. “Our goal is to first make this individualized,” he said. “We want to minimize the noise in the recording and minimize the night-to-night variability in the findings. There is some clinical-informed approach and there is also some algorithm-informed approach where you can minimize the variation over time.”

The model also has the potential to predict outcomes, particularly with chronic diseases such as diabetes and dementia, well before a diagnosis is made, he said.
 

‘Fascinating’ and ‘provocative’

Donald Bliwise, PhD, professor of neurology at Emory Sleep Center in Atlanta, said the study was “fascinating; it’s provocative; it’s exciting and interesting,” but added, “Sleep is vital for health. That’s abundantly clear in a study like that, but trying to push it a little bit further with all of these 86 measurements of the EEG, I think it becomes complicated.”

The study methodology, particularly the use of cumulative incidence of various diseases, was laudable, he said, and the use of simpler EEG-measured sleep features, such as alpha band power, “make intuitive sense.”

But it’s less clear on how the more sophisticated features the study model used – for example, kurtosis of theta frequency or coupling between spindle and slow oscillation – rank on sleep quality, he said, adding that the researchers have most likely done that but couldn’t add that into the format of the presentation.

“Kurtosis of the theta frequency band we don’t get on everyone in the sleep lab,” Dr. Bliwise said. “We might be able to, but I don’t know how to quite plug that into a turnkey model.”

The clinical components of the study were conducted by M. Brandon Westover, MD, PhD, at Massachusetts General Hospital, and Robert J. Thomas, MD, at Beth Israel Deaconess Medical Center, both in Boston. The study received support from the American Academy of Sleep Medicine Foundation. Dr. Sun has no relevant disclosures. Dr. Bliwise has no disclosures.

CHARLOTTE, N.C. – Overnight sleep electroencephalography (EEG) contains an abundance of brain wave data that could be mined to identify an individual’s risk for a host of health outcomes, including dementia, cognitive impairment, and cardiovascular events, a researcher reported at the annual meeting of the Associated Professional Sleep Societies. “Sleep EEGs contain decodable information about the risk of unfavorable outcomes,” said Haoqi Sun, PhD, an instructor of neurology at Massachusetts General Hospital, Boston, and lead study author. “The results suggest that it’s feasible to use sleep to identify people with high risk of unfavorable outcomes and it strengthens the concept of sleep as a window into brain and general health.”

The researchers performed a quantitative analysis of sleep data collected on 8,673 adults who had diagnostic sleep studies that included polysomnography (PSG). The analysis used ICD codes to consider these 11 health outcomes: dementia, mild cognitive impairment (MCI) or dementia, ischemic stroke, intracranial hemorrhage, atrial fibrillation, myocardial infarction, type 2 diabetes, hypertension, bipolar disorder, depression, and mortality.

Then, Dr. Sun explained, they extracted 86 spectral and time-domain features of REM and non-REM sleep from sleep EEG recordings, and analyzed that data by adjusting for eight covariates including age, sex, body mass index, and use of benzodiazepines, antidepressants, sedatives, antiseizure drugs, and stimulants.

Participants were partitioned into three sleep-quality groups: poor, average, and good. The outcome-wise mean prediction difference in 10-year cumulative incidence was 2.3% for the poor sleep group, 0.5% for the average sleep group, and 1.3% for the good sleep group.

The outcomes with the three greatest poor to average risk ratios were dementia (6.2; 95% confidence interval, 4.5-9.3), mortality (5.7; 95% CI, 5-7.5) and MCI or dementia (4; 95% CI, 3.2-4.9).
 

Ready for the clinic?

In an interview, Dr. Sun said the results demonstrated the potential of using EEG brain wave data to predict health outcomes on an individual basis, although he acknowledged that most of the 86 sleep features the researchers used are not readily available in the clinic.

He noted the spectral features used in the study can be captured through software compatible with PSG. “From there you can identify the various bands, the different frequency ranges, and then you can easily see within this range whether a person has a higher power or lower power,” he said. However, the spindle and slow-oscillation features that researchers used in the study are beyond the reach of most clinics.
 

Next steps

This research is in its early stage, Dr. Sun said, but at some point the data collected from sleep studies could be paired with machine learning to make the model workable for evaluating individual patients. “Our goal is to first make this individualized,” he said. “We want to minimize the noise in the recording and minimize the night-to-night variability in the findings. There is some clinical-informed approach and there is also some algorithm-informed approach where you can minimize the variation over time.”

The model also has the potential to predict outcomes, particularly with chronic diseases such as diabetes and dementia, well before a diagnosis is made, he said.
 

‘Fascinating’ and ‘provocative’

Donald Bliwise, PhD, professor of neurology at Emory Sleep Center in Atlanta, said the study was “fascinating; it’s provocative; it’s exciting and interesting,” but added, “Sleep is vital for health. That’s abundantly clear in a study like that, but trying to push it a little bit further with all of these 86 measurements of the EEG, I think it becomes complicated.”

The study methodology, particularly the use of cumulative incidence of various diseases, was laudable, he said, and the use of simpler EEG-measured sleep features, such as alpha band power, “make intuitive sense.”

But it’s less clear on how the more sophisticated features the study model used – for example, kurtosis of theta frequency or coupling between spindle and slow oscillation – rank on sleep quality, he said, adding that the researchers have most likely done that but couldn’t add that into the format of the presentation.

“Kurtosis of the theta frequency band we don’t get on everyone in the sleep lab,” Dr. Bliwise said. “We might be able to, but I don’t know how to quite plug that into a turnkey model.”

The clinical components of the study were conducted by M. Brandon Westover, MD, PhD, at Massachusetts General Hospital, and Robert J. Thomas, MD, at Beth Israel Deaconess Medical Center, both in Boston. The study received support from the American Academy of Sleep Medicine Foundation. Dr. Sun has no relevant disclosures. Dr. Bliwise has no disclosures.

CHARLOTTE, N.C. – Overnight sleep electroencephalography (EEG) contains an abundance of brain wave data that could be mined to identify an individual’s risk for a host of health outcomes, including dementia, cognitive impairment, and cardiovascular events, a researcher reported at the annual meeting of the Associated Professional Sleep Societies. “Sleep EEGs contain decodable information about the risk of unfavorable outcomes,” said Haoqi Sun, PhD, an instructor of neurology at Massachusetts General Hospital, Boston, and lead study author. “The results suggest that it’s feasible to use sleep to identify people with high risk of unfavorable outcomes and it strengthens the concept of sleep as a window into brain and general health.”

The researchers performed a quantitative analysis of sleep data collected on 8,673 adults who had diagnostic sleep studies that included polysomnography (PSG). The analysis used ICD codes to consider these 11 health outcomes: dementia, mild cognitive impairment (MCI) or dementia, ischemic stroke, intracranial hemorrhage, atrial fibrillation, myocardial infarction, type 2 diabetes, hypertension, bipolar disorder, depression, and mortality.

Then, Dr. Sun explained, they extracted 86 spectral and time-domain features of REM and non-REM sleep from sleep EEG recordings, and analyzed that data by adjusting for eight covariates including age, sex, body mass index, and use of benzodiazepines, antidepressants, sedatives, antiseizure drugs, and stimulants.

Participants were partitioned into three sleep-quality groups: poor, average, and good. The outcome-wise mean prediction difference in 10-year cumulative incidence was 2.3% for the poor sleep group, 0.5% for the average sleep group, and 1.3% for the good sleep group.

The outcomes with the three greatest poor to average risk ratios were dementia (6.2; 95% confidence interval, 4.5-9.3), mortality (5.7; 95% CI, 5-7.5) and MCI or dementia (4; 95% CI, 3.2-4.9).
 

Ready for the clinic?

In an interview, Dr. Sun said the results demonstrated the potential of using EEG brain wave data to predict health outcomes on an individual basis, although he acknowledged that most of the 86 sleep features the researchers used are not readily available in the clinic.

He noted the spectral features used in the study can be captured through software compatible with PSG. “From there you can identify the various bands, the different frequency ranges, and then you can easily see within this range whether a person has a higher power or lower power,” he said. However, the spindle and slow-oscillation features that researchers used in the study are beyond the reach of most clinics.
 

Next steps

This research is in its early stage, Dr. Sun said, but at some point the data collected from sleep studies could be paired with machine learning to make the model workable for evaluating individual patients. “Our goal is to first make this individualized,” he said. “We want to minimize the noise in the recording and minimize the night-to-night variability in the findings. There is some clinical-informed approach and there is also some algorithm-informed approach where you can minimize the variation over time.”

The model also has the potential to predict outcomes, particularly with chronic diseases such as diabetes and dementia, well before a diagnosis is made, he said.
 

‘Fascinating’ and ‘provocative’

Donald Bliwise, PhD, professor of neurology at Emory Sleep Center in Atlanta, said the study was “fascinating; it’s provocative; it’s exciting and interesting,” but added, “Sleep is vital for health. That’s abundantly clear in a study like that, but trying to push it a little bit further with all of these 86 measurements of the EEG, I think it becomes complicated.”

The study methodology, particularly the use of cumulative incidence of various diseases, was laudable, he said, and the use of simpler EEG-measured sleep features, such as alpha band power, “make intuitive sense.”

But it’s less clear on how the more sophisticated features the study model used – for example, kurtosis of theta frequency or coupling between spindle and slow oscillation – rank on sleep quality, he said, adding that the researchers have most likely done that but couldn’t add that into the format of the presentation.

“Kurtosis of the theta frequency band we don’t get on everyone in the sleep lab,” Dr. Bliwise said. “We might be able to, but I don’t know how to quite plug that into a turnkey model.”

The clinical components of the study were conducted by M. Brandon Westover, MD, PhD, at Massachusetts General Hospital, and Robert J. Thomas, MD, at Beth Israel Deaconess Medical Center, both in Boston. The study received support from the American Academy of Sleep Medicine Foundation. Dr. Sun has no relevant disclosures. Dr. Bliwise has no disclosures.

NATIONAL HARBOR, MD – Just 2 days before she spoke in a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers, University of Colorado neurologist Anna Shah, MD, asked a 26-year-old patient with MS about whether she planned to have children. Absolutely not, the young woman replied. “I read online that I can give birth to a baby with MS, which is crazy.”

The patient didn’t understand the risk of having a child with MS – it’s thought to be 2%-5% if one parent has the condition – but she wouldn’t have learned the facts if Dr. Shah hadn’t asked the right questions. “It’s really important for us as a community to know how to be proactive with discussions [about pregnancy],” she said.

As she noted, an estimated 75% of patients with MS are women, most are diagnosed during prime child-bearing years, and many pregnancies in general – an estimated half – are not planned. And while a higher percentage of women with MS are having children than in the past, she said, misinformation remains common. In fact, physicians can be part of the problem.

Dr. Shaw highlighted a 2019 Italian survey that found that 16% of 395 people with MS reported that they were discouraged from having children, mainly by medical professionals, after their diagnosis. Seven percent said they never wanted to become parents because of their MS. A 2021 survey of 332 patients with MS in the United States, United Kingdom, France, Germany, Italy, and Spain, found that 56% reported that MS played a role in their decisions about family planning, and 14% of those decided not to have children.

In regard to women of child-bearing age, Dr. Shah recommends that family planning and contraception should be discussed at the initial visit and every subsequent visit. Open-ended, individualized questions are key. “We don’t know what patients don’t share with us,” she said.

Make sure to consider the timing of any plans to have children, she said. If the patient wants to have children within a year, talk about matters such as whether disease activity is well-controlled (6-12 months of good control is ideal) and whether current disease-modifying therapies are safe. Make sure to get a baseline prepartum MRI scan, she said.

If the patients don’t want to have children, make sure they are using a reliable strategy to avoid conception. Be aware that modafinil – “not one that immediately comes to mind” – may decrease the efficacy of oral contraceptives, she said, as can anticonvulsants (phenytoin, carbamazepine, oxcarbazepine, topiramate, and primidone). Oral contraceptives, meanwhile, may decrease levels of lamotrigine.

What if a patient has trouble conceiving? There are some hints in research that MS may boost the risk of infertility in women, Dr. Shah said. That’s why she recommends that colleagues consider referring a patient to an infertility specialist after attempting conception for 6 months as opposed to the general recommendation for 12 months.

Dr. Shah disclosed advisory board service (Genentech) and development of nonbranded educational programming through Novartis and the National Committee for Quality Assurance.

NATIONAL HARBOR, MD – Just 2 days before she spoke in a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers, University of Colorado neurologist Anna Shah, MD, asked a 26-year-old patient with MS about whether she planned to have children. Absolutely not, the young woman replied. “I read online that I can give birth to a baby with MS, which is crazy.”

The patient didn’t understand the risk of having a child with MS – it’s thought to be 2%-5% if one parent has the condition – but she wouldn’t have learned the facts if Dr. Shah hadn’t asked the right questions. “It’s really important for us as a community to know how to be proactive with discussions [about pregnancy],” she said.

As she noted, an estimated 75% of patients with MS are women, most are diagnosed during prime child-bearing years, and many pregnancies in general – an estimated half – are not planned. And while a higher percentage of women with MS are having children than in the past, she said, misinformation remains common. In fact, physicians can be part of the problem.

Dr. Shaw highlighted a 2019 Italian survey that found that 16% of 395 people with MS reported that they were discouraged from having children, mainly by medical professionals, after their diagnosis. Seven percent said they never wanted to become parents because of their MS. A 2021 survey of 332 patients with MS in the United States, United Kingdom, France, Germany, Italy, and Spain, found that 56% reported that MS played a role in their decisions about family planning, and 14% of those decided not to have children.

In regard to women of child-bearing age, Dr. Shah recommends that family planning and contraception should be discussed at the initial visit and every subsequent visit. Open-ended, individualized questions are key. “We don’t know what patients don’t share with us,” she said.

Make sure to consider the timing of any plans to have children, she said. If the patient wants to have children within a year, talk about matters such as whether disease activity is well-controlled (6-12 months of good control is ideal) and whether current disease-modifying therapies are safe. Make sure to get a baseline prepartum MRI scan, she said.

If the patients don’t want to have children, make sure they are using a reliable strategy to avoid conception. Be aware that modafinil – “not one that immediately comes to mind” – may decrease the efficacy of oral contraceptives, she said, as can anticonvulsants (phenytoin, carbamazepine, oxcarbazepine, topiramate, and primidone). Oral contraceptives, meanwhile, may decrease levels of lamotrigine.

What if a patient has trouble conceiving? There are some hints in research that MS may boost the risk of infertility in women, Dr. Shah said. That’s why she recommends that colleagues consider referring a patient to an infertility specialist after attempting conception for 6 months as opposed to the general recommendation for 12 months.

Dr. Shah disclosed advisory board service (Genentech) and development of nonbranded educational programming through Novartis and the National Committee for Quality Assurance.

NATIONAL HARBOR, MD – Just 2 days before she spoke in a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers, University of Colorado neurologist Anna Shah, MD, asked a 26-year-old patient with MS about whether she planned to have children. Absolutely not, the young woman replied. “I read online that I can give birth to a baby with MS, which is crazy.”

The patient didn’t understand the risk of having a child with MS – it’s thought to be 2%-5% if one parent has the condition – but she wouldn’t have learned the facts if Dr. Shah hadn’t asked the right questions. “It’s really important for us as a community to know how to be proactive with discussions [about pregnancy],” she said.

As she noted, an estimated 75% of patients with MS are women, most are diagnosed during prime child-bearing years, and many pregnancies in general – an estimated half – are not planned. And while a higher percentage of women with MS are having children than in the past, she said, misinformation remains common. In fact, physicians can be part of the problem.

Dr. Shaw highlighted a 2019 Italian survey that found that 16% of 395 people with MS reported that they were discouraged from having children, mainly by medical professionals, after their diagnosis. Seven percent said they never wanted to become parents because of their MS. A 2021 survey of 332 patients with MS in the United States, United Kingdom, France, Germany, Italy, and Spain, found that 56% reported that MS played a role in their decisions about family planning, and 14% of those decided not to have children.

In regard to women of child-bearing age, Dr. Shah recommends that family planning and contraception should be discussed at the initial visit and every subsequent visit. Open-ended, individualized questions are key. “We don’t know what patients don’t share with us,” she said.

Make sure to consider the timing of any plans to have children, she said. If the patient wants to have children within a year, talk about matters such as whether disease activity is well-controlled (6-12 months of good control is ideal) and whether current disease-modifying therapies are safe. Make sure to get a baseline prepartum MRI scan, she said.

If the patients don’t want to have children, make sure they are using a reliable strategy to avoid conception. Be aware that modafinil – “not one that immediately comes to mind” – may decrease the efficacy of oral contraceptives, she said, as can anticonvulsants (phenytoin, carbamazepine, oxcarbazepine, topiramate, and primidone). Oral contraceptives, meanwhile, may decrease levels of lamotrigine.

What if a patient has trouble conceiving? There are some hints in research that MS may boost the risk of infertility in women, Dr. Shah said. That’s why she recommends that colleagues consider referring a patient to an infertility specialist after attempting conception for 6 months as opposed to the general recommendation for 12 months.

Dr. Shah disclosed advisory board service (Genentech) and development of nonbranded educational programming through Novartis and the National Committee for Quality Assurance.

Angela Intili, MD, an ob.gyn., was used to seeing her medical malpractice insurance premium rise slightly every couple of years. But she was shocked by the drastic rise she recently experienced.

In the last 2 years, Dr. Intili’s premiums shot from $60,000 to $130,000, she said.

“After 30 years of practice, this is the first time I’ve asked myself if I can even afford to continue practicing obstetrics and gynecology,” said Dr. Intili, 62, of Joliet, Ill. “It’s gotten very difficult to make ends meet as far as overhead because of the liability costs. I still love what I’m doing but I don’t know if I can afford to do it anymore.”

Even more frustrating for Dr. Intili was learning that claims in Illinois have sharply declined. From 2016 to 2020, tort filings in Illinois decreased by 43%, according to a state report.

“If claims are going down, I don’t understand why premium payments are going up,” she said.

Physicians across the country are experiencing a similar paradox. Claims are down, yet premiums are rising.

Medscape’s Malpractice Report 2021 found that 42% of primary care physicians were sued in 2020 through mid-2021, down from 52% in 2019. Fifty-six percent of specialists were sued in 2020 through mid-2021 compared with 62% in 2019, the report found. The pandemic was undoubtedly behind the decrease in suits, according to legal experts.

Yet, physicians paid higher premiums in 2021 and are on track for increases again in 2022, according to data and analysts.

According to Conning, direct premiums written for physicians increased 7.0% in 2021 (from $5.01 billion to $5.36 billion). Conning, an investment management firm that serves the insurance industry, analyzes annual financial reports filed by insurers to state insurance departments. The Medical Liability Monitor’s 2021 report found that premiums for internists, surgeons, and ob.gyns. in states without Patient Compensation Funds rose by an average of 2% in 2021.

The disparities raise questions about why physicians are paying higher premiums when having fewer claims is likely saving insurers’ money. Shouldn’t physicians’ rates reflect the reduction in claims?
 

Cases plummet during pandemic

During the pandemic, the volume of new medical malpractice claims dwindled to nearly nothing, said Michael Matray, editor of the Medical Liability Monitor, a national publication that analyzes medical liability insurance premiums.

“The court system closed for a while,” he said. “No elective procedures were being done in 2020 and the early parts of 2021. If you have no treatment, you have no malpractice, so of course, claims frequency tumbled down to a trickle.”

The number of large awards also decreased during the pandemic, noted Bill Burns, a director of insurance research at Conning.

“For claims that were already in the system, many of them could not be resolved because of the court closures, inability to take statements and depositions, etc.,” he said. “This resulted in a drop in verdicts.”

In 2021, there were 16 medical malpractice verdicts of $10 million or more in the United States, according to TransRe, an international reinsurance company that tracks large verdicts. In 2020, there were six verdicts of $10 million or more, TransRe research found. This is down from 52 verdicts of $10 million or more in 2019 and 46 verdicts of $10 million or more in 2018.

But although the pandemic lowered claims and decreased the number of payouts, one important aspect was untouched by the COVID era, said Richard E. Anderson, MD, chairman and CEO for The Doctors Company, a national medical liability insurer, and TDC Group.

“It’s a fair question: If claims are down, why are premiums continuing to go up?” Dr. Anderson said. “The answer is severity.”
 

High-dollar verdicts pave expensive path

The upward trend in severity has continued for about 6 years and has not slowed, Dr. Anderson said. Severity refers to high-dollar verdicts and settlements.

“We’re seeing record-high verdicts all over the country,” he said. “We used to have maps that showed the top 10 medical malpractice verdicts or awards, and they would be clustered where you’d expect them to be, New York, Florida, Illinois, and so forth. Now, if you look at those top 10 verdicts, they could be anywhere in the country.”

In Minnesota for instance, a jury awarded a record $111 million in damages to a college student in May after finding a hospital and an orthopedic surgeon negligent in treating his broken leg. In April, a Kansas City jury awarded a family $25 million after finding that an ob.gyn. and hospital failed to properly treat a mother in labor, causing brain damage to her infant.  

Such record payouts factor into premium costs, said Ned Rand Jr., CEO for ProAssurance, a national medical liability insurer. Though only a minority of claims reach that level, when a high award occurs, it puts pressure on the ultimate cost to resolve claims, he said. The frequency of claims filed is also expected to soon rebound, he noted.

“As we price the product sitting here today, we have to factor both of those in,” Mr. Rand said. “That’s why we, as an industry, continue to see, by and large, rates going up. And we fell behind. Some of this severity, in particular, as an industry, we weren’t pricing fully for, so we’ve been playing catch-up.”

High-dollar awards – also called nuclear verdicts – set the arena for future settlements in similar cases, Dr. Anderson added.

“If it was an orthopedic case for instance, and there was a similar injury in another case, that’s the trial lawyers’ starting point for the award,” he said. “Now, they’re not going to get it, but it distorts the negotiations. As we have more and more nuclear verdicts, it becomes harder to settle claims for reasonable amounts.”
 

What does 2022 have in store?

Analysts say the backlog of malpractice claims in the court system could prove calamitous for premiums and the liability landscape.

Courts are slogging through the pileup caused by the pandemic, but it’s estimated that there is still about a one-third larger case backlog than normal, according to Mr. Matray.

Such delayed claims may end up costing more because of social inflation, said Mr. Burns.

“People look at the world differently than they did 2 years ago,” he said. “A jury may have awarded $5 million for a claim a few years ago. But then the pandemic hits, and we have the George Floyd incident, and we have people out of work and a shortage in baby formula. Yet, companies are still making a lot of money and many insurance companies are turning record profits. Today, that jury may look at a sympathetic malpractice victim and award $10 million for the same claim.”

Concerns also exist about a potential surge of new malpractice claims. Mr. Rand compares the possible wave to a large bubble.

“I liken it to a cartoon, when one character grabs the hose and a big bubble forms as the water builds up,” he said. “Then the character releases, and water comes flooding out. As an industry, we wait, wondering: Is there going to be this flood of claims as the court systems reopen and the statute of limitations approach around some of these claims? That’s an ongoing concern.”

As for impending premiums, physicians can expect rises in 2022 and again in 2023, according to Chris Wojciechowski, a partner at TigerRisk Partners, a reinsurance broker.

“In general, there is a lot of uncertainty around the state of the economy, the tort environment, litigation post COVID, and overall volatility across the capital markets,” he said. “Furthermore, thanks to social and financial inflation, the potential for very severe verdicts has increased dramatically, and as courthouses reopen, the trends are not looking favorable. While many of the physician carriers have strong balance sheets, they can’t lose money on an underwriting basis forever.”

For Dr. Intili, the Illinois ob.gyn., news of another impending increase in 2022 is distressing. She expects another 10%-20% rise in 2022, she said. If she were younger and earlier in her career, she might’ve considered moving, she said, but her family lives in Illinois and she cares for her older parents.

“I’m not ready to retire,” Dr. Intili said. “I’m looking into options, possibly becoming a hospitalist or doing locum tenens work. I’ve been a solo practitioner for 27 years and I love the autonomy. But these high premiums are making it almost impossible to continue.”

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

Angela Intili, MD, an ob.gyn., was used to seeing her medical malpractice insurance premium rise slightly every couple of years. But she was shocked by the drastic rise she recently experienced.

In the last 2 years, Dr. Intili’s premiums shot from $60,000 to $130,000, she said.

“After 30 years of practice, this is the first time I’ve asked myself if I can even afford to continue practicing obstetrics and gynecology,” said Dr. Intili, 62, of Joliet, Ill. “It’s gotten very difficult to make ends meet as far as overhead because of the liability costs. I still love what I’m doing but I don’t know if I can afford to do it anymore.”

Even more frustrating for Dr. Intili was learning that claims in Illinois have sharply declined. From 2016 to 2020, tort filings in Illinois decreased by 43%, according to a state report.

“If claims are going down, I don’t understand why premium payments are going up,” she said.

Physicians across the country are experiencing a similar paradox. Claims are down, yet premiums are rising.

Medscape’s Malpractice Report 2021 found that 42% of primary care physicians were sued in 2020 through mid-2021, down from 52% in 2019. Fifty-six percent of specialists were sued in 2020 through mid-2021 compared with 62% in 2019, the report found. The pandemic was undoubtedly behind the decrease in suits, according to legal experts.

Yet, physicians paid higher premiums in 2021 and are on track for increases again in 2022, according to data and analysts.

According to Conning, direct premiums written for physicians increased 7.0% in 2021 (from $5.01 billion to $5.36 billion). Conning, an investment management firm that serves the insurance industry, analyzes annual financial reports filed by insurers to state insurance departments. The Medical Liability Monitor’s 2021 report found that premiums for internists, surgeons, and ob.gyns. in states without Patient Compensation Funds rose by an average of 2% in 2021.

The disparities raise questions about why physicians are paying higher premiums when having fewer claims is likely saving insurers’ money. Shouldn’t physicians’ rates reflect the reduction in claims?
 

Cases plummet during pandemic

During the pandemic, the volume of new medical malpractice claims dwindled to nearly nothing, said Michael Matray, editor of the Medical Liability Monitor, a national publication that analyzes medical liability insurance premiums.

“The court system closed for a while,” he said. “No elective procedures were being done in 2020 and the early parts of 2021. If you have no treatment, you have no malpractice, so of course, claims frequency tumbled down to a trickle.”

The number of large awards also decreased during the pandemic, noted Bill Burns, a director of insurance research at Conning.

“For claims that were already in the system, many of them could not be resolved because of the court closures, inability to take statements and depositions, etc.,” he said. “This resulted in a drop in verdicts.”

In 2021, there were 16 medical malpractice verdicts of $10 million or more in the United States, according to TransRe, an international reinsurance company that tracks large verdicts. In 2020, there were six verdicts of $10 million or more, TransRe research found. This is down from 52 verdicts of $10 million or more in 2019 and 46 verdicts of $10 million or more in 2018.

But although the pandemic lowered claims and decreased the number of payouts, one important aspect was untouched by the COVID era, said Richard E. Anderson, MD, chairman and CEO for The Doctors Company, a national medical liability insurer, and TDC Group.

“It’s a fair question: If claims are down, why are premiums continuing to go up?” Dr. Anderson said. “The answer is severity.”
 

High-dollar verdicts pave expensive path

The upward trend in severity has continued for about 6 years and has not slowed, Dr. Anderson said. Severity refers to high-dollar verdicts and settlements.

“We’re seeing record-high verdicts all over the country,” he said. “We used to have maps that showed the top 10 medical malpractice verdicts or awards, and they would be clustered where you’d expect them to be, New York, Florida, Illinois, and so forth. Now, if you look at those top 10 verdicts, they could be anywhere in the country.”

In Minnesota for instance, a jury awarded a record $111 million in damages to a college student in May after finding a hospital and an orthopedic surgeon negligent in treating his broken leg. In April, a Kansas City jury awarded a family $25 million after finding that an ob.gyn. and hospital failed to properly treat a mother in labor, causing brain damage to her infant.  

Such record payouts factor into premium costs, said Ned Rand Jr., CEO for ProAssurance, a national medical liability insurer. Though only a minority of claims reach that level, when a high award occurs, it puts pressure on the ultimate cost to resolve claims, he said. The frequency of claims filed is also expected to soon rebound, he noted.

“As we price the product sitting here today, we have to factor both of those in,” Mr. Rand said. “That’s why we, as an industry, continue to see, by and large, rates going up. And we fell behind. Some of this severity, in particular, as an industry, we weren’t pricing fully for, so we’ve been playing catch-up.”

High-dollar awards – also called nuclear verdicts – set the arena for future settlements in similar cases, Dr. Anderson added.

“If it was an orthopedic case for instance, and there was a similar injury in another case, that’s the trial lawyers’ starting point for the award,” he said. “Now, they’re not going to get it, but it distorts the negotiations. As we have more and more nuclear verdicts, it becomes harder to settle claims for reasonable amounts.”
 

What does 2022 have in store?

Analysts say the backlog of malpractice claims in the court system could prove calamitous for premiums and the liability landscape.

Courts are slogging through the pileup caused by the pandemic, but it’s estimated that there is still about a one-third larger case backlog than normal, according to Mr. Matray.

Such delayed claims may end up costing more because of social inflation, said Mr. Burns.

“People look at the world differently than they did 2 years ago,” he said. “A jury may have awarded $5 million for a claim a few years ago. But then the pandemic hits, and we have the George Floyd incident, and we have people out of work and a shortage in baby formula. Yet, companies are still making a lot of money and many insurance companies are turning record profits. Today, that jury may look at a sympathetic malpractice victim and award $10 million for the same claim.”

Concerns also exist about a potential surge of new malpractice claims. Mr. Rand compares the possible wave to a large bubble.

“I liken it to a cartoon, when one character grabs the hose and a big bubble forms as the water builds up,” he said. “Then the character releases, and water comes flooding out. As an industry, we wait, wondering: Is there going to be this flood of claims as the court systems reopen and the statute of limitations approach around some of these claims? That’s an ongoing concern.”

As for impending premiums, physicians can expect rises in 2022 and again in 2023, according to Chris Wojciechowski, a partner at TigerRisk Partners, a reinsurance broker.

“In general, there is a lot of uncertainty around the state of the economy, the tort environment, litigation post COVID, and overall volatility across the capital markets,” he said. “Furthermore, thanks to social and financial inflation, the potential for very severe verdicts has increased dramatically, and as courthouses reopen, the trends are not looking favorable. While many of the physician carriers have strong balance sheets, they can’t lose money on an underwriting basis forever.”

For Dr. Intili, the Illinois ob.gyn., news of another impending increase in 2022 is distressing. She expects another 10%-20% rise in 2022, she said. If she were younger and earlier in her career, she might’ve considered moving, she said, but her family lives in Illinois and she cares for her older parents.

“I’m not ready to retire,” Dr. Intili said. “I’m looking into options, possibly becoming a hospitalist or doing locum tenens work. I’ve been a solo practitioner for 27 years and I love the autonomy. But these high premiums are making it almost impossible to continue.”

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

Angela Intili, MD, an ob.gyn., was used to seeing her medical malpractice insurance premium rise slightly every couple of years. But she was shocked by the drastic rise she recently experienced.

In the last 2 years, Dr. Intili’s premiums shot from $60,000 to $130,000, she said.

“After 30 years of practice, this is the first time I’ve asked myself if I can even afford to continue practicing obstetrics and gynecology,” said Dr. Intili, 62, of Joliet, Ill. “It’s gotten very difficult to make ends meet as far as overhead because of the liability costs. I still love what I’m doing but I don’t know if I can afford to do it anymore.”

Even more frustrating for Dr. Intili was learning that claims in Illinois have sharply declined. From 2016 to 2020, tort filings in Illinois decreased by 43%, according to a state report.

“If claims are going down, I don’t understand why premium payments are going up,” she said.

Physicians across the country are experiencing a similar paradox. Claims are down, yet premiums are rising.

Medscape’s Malpractice Report 2021 found that 42% of primary care physicians were sued in 2020 through mid-2021, down from 52% in 2019. Fifty-six percent of specialists were sued in 2020 through mid-2021 compared with 62% in 2019, the report found. The pandemic was undoubtedly behind the decrease in suits, according to legal experts.

Yet, physicians paid higher premiums in 2021 and are on track for increases again in 2022, according to data and analysts.

According to Conning, direct premiums written for physicians increased 7.0% in 2021 (from $5.01 billion to $5.36 billion). Conning, an investment management firm that serves the insurance industry, analyzes annual financial reports filed by insurers to state insurance departments. The Medical Liability Monitor’s 2021 report found that premiums for internists, surgeons, and ob.gyns. in states without Patient Compensation Funds rose by an average of 2% in 2021.

The disparities raise questions about why physicians are paying higher premiums when having fewer claims is likely saving insurers’ money. Shouldn’t physicians’ rates reflect the reduction in claims?
 

Cases plummet during pandemic

During the pandemic, the volume of new medical malpractice claims dwindled to nearly nothing, said Michael Matray, editor of the Medical Liability Monitor, a national publication that analyzes medical liability insurance premiums.

“The court system closed for a while,” he said. “No elective procedures were being done in 2020 and the early parts of 2021. If you have no treatment, you have no malpractice, so of course, claims frequency tumbled down to a trickle.”

The number of large awards also decreased during the pandemic, noted Bill Burns, a director of insurance research at Conning.

“For claims that were already in the system, many of them could not be resolved because of the court closures, inability to take statements and depositions, etc.,” he said. “This resulted in a drop in verdicts.”

In 2021, there were 16 medical malpractice verdicts of $10 million or more in the United States, according to TransRe, an international reinsurance company that tracks large verdicts. In 2020, there were six verdicts of $10 million or more, TransRe research found. This is down from 52 verdicts of $10 million or more in 2019 and 46 verdicts of $10 million or more in 2018.

But although the pandemic lowered claims and decreased the number of payouts, one important aspect was untouched by the COVID era, said Richard E. Anderson, MD, chairman and CEO for The Doctors Company, a national medical liability insurer, and TDC Group.

“It’s a fair question: If claims are down, why are premiums continuing to go up?” Dr. Anderson said. “The answer is severity.”
 

High-dollar verdicts pave expensive path

The upward trend in severity has continued for about 6 years and has not slowed, Dr. Anderson said. Severity refers to high-dollar verdicts and settlements.

“We’re seeing record-high verdicts all over the country,” he said. “We used to have maps that showed the top 10 medical malpractice verdicts or awards, and they would be clustered where you’d expect them to be, New York, Florida, Illinois, and so forth. Now, if you look at those top 10 verdicts, they could be anywhere in the country.”

In Minnesota for instance, a jury awarded a record $111 million in damages to a college student in May after finding a hospital and an orthopedic surgeon negligent in treating his broken leg. In April, a Kansas City jury awarded a family $25 million after finding that an ob.gyn. and hospital failed to properly treat a mother in labor, causing brain damage to her infant.  

Such record payouts factor into premium costs, said Ned Rand Jr., CEO for ProAssurance, a national medical liability insurer. Though only a minority of claims reach that level, when a high award occurs, it puts pressure on the ultimate cost to resolve claims, he said. The frequency of claims filed is also expected to soon rebound, he noted.

“As we price the product sitting here today, we have to factor both of those in,” Mr. Rand said. “That’s why we, as an industry, continue to see, by and large, rates going up. And we fell behind. Some of this severity, in particular, as an industry, we weren’t pricing fully for, so we’ve been playing catch-up.”

High-dollar awards – also called nuclear verdicts – set the arena for future settlements in similar cases, Dr. Anderson added.

“If it was an orthopedic case for instance, and there was a similar injury in another case, that’s the trial lawyers’ starting point for the award,” he said. “Now, they’re not going to get it, but it distorts the negotiations. As we have more and more nuclear verdicts, it becomes harder to settle claims for reasonable amounts.”
 

What does 2022 have in store?

Analysts say the backlog of malpractice claims in the court system could prove calamitous for premiums and the liability landscape.

Courts are slogging through the pileup caused by the pandemic, but it’s estimated that there is still about a one-third larger case backlog than normal, according to Mr. Matray.

Such delayed claims may end up costing more because of social inflation, said Mr. Burns.

“People look at the world differently than they did 2 years ago,” he said. “A jury may have awarded $5 million for a claim a few years ago. But then the pandemic hits, and we have the George Floyd incident, and we have people out of work and a shortage in baby formula. Yet, companies are still making a lot of money and many insurance companies are turning record profits. Today, that jury may look at a sympathetic malpractice victim and award $10 million for the same claim.”

Concerns also exist about a potential surge of new malpractice claims. Mr. Rand compares the possible wave to a large bubble.

“I liken it to a cartoon, when one character grabs the hose and a big bubble forms as the water builds up,” he said. “Then the character releases, and water comes flooding out. As an industry, we wait, wondering: Is there going to be this flood of claims as the court systems reopen and the statute of limitations approach around some of these claims? That’s an ongoing concern.”

As for impending premiums, physicians can expect rises in 2022 and again in 2023, according to Chris Wojciechowski, a partner at TigerRisk Partners, a reinsurance broker.

“In general, there is a lot of uncertainty around the state of the economy, the tort environment, litigation post COVID, and overall volatility across the capital markets,” he said. “Furthermore, thanks to social and financial inflation, the potential for very severe verdicts has increased dramatically, and as courthouses reopen, the trends are not looking favorable. While many of the physician carriers have strong balance sheets, they can’t lose money on an underwriting basis forever.”

For Dr. Intili, the Illinois ob.gyn., news of another impending increase in 2022 is distressing. She expects another 10%-20% rise in 2022, she said. If she were younger and earlier in her career, she might’ve considered moving, she said, but her family lives in Illinois and she cares for her older parents.

“I’m not ready to retire,” Dr. Intili said. “I’m looking into options, possibly becoming a hospitalist or doing locum tenens work. I’ve been a solo practitioner for 27 years and I love the autonomy. But these high premiums are making it almost impossible to continue.”

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

Opioid use in the elderly is associated with an almost 40% increased risk of dementia in new findings that suggest exposure to these drugs may be another modifiable risk factor for dementia.

“Clinicians and others may want to consider that opioid exposure in those aged 75-80 increases dementia risk, and to balance the potential benefits of opioid use in old age with adverse side effects,” said Stephen Z. Levine, PhD, professor, department of community mental health, University of Haifa (Israel).

The study was published online in the American Journal of Geriatric Psychiatry.
 

Widespread use

Evidence points to a relatively high rate of opioid prescriptions among older adults. A Morbidity and Mortality Weekly Report noted 19.2% of the U.S. adult population filled an opioid prescription in 2018, with the rate in those over 65 double that of adults aged 20-24 years (25% vs. 11.2%).

Disorders and illnesses for which opioids might be prescribed, including cancer and some pain conditions, “are far more prevalent in old age than at a younger age,” said Dr. Levine.

This high rate of opioid use underscores the need to consider the risks of opioid use in old age, said Dr. Levine. “Unfortunately, studies of the association between opioid use and dementia risk in old age are few, and their results are inconsistent.”

The study included 91,307 Israeli citizens aged 60 and over without dementia who were enrolled in the Meuhedet Healthcare Services, a nonprofit health maintenance organization (HMO) serving 14% of the country’s population. Meuhedet has maintained an up-to-date dementia registry since 2002.

The average age of the study sample was 68.29 years at the start of the study (in 2012).

In Israel, opioids are prescribed for a 30-day period. In this study, opioid exposure was defined as opioid medication fills covering 60 days (or two prescriptions) within a 120-day interval.

The primary outcome was incident dementia during follow-up from Jan. 1, 2013 to Oct. 30, 2017. The analysis controlled for a number of factors, including age, sex, smoking status, health conditions such as arthritis, depression, diabetes, osteoporosis, cognitive decline, vitamin deficiencies, cancer, cardiovascular conditions, and hospitalizations for falls.

Researchers also accounted for the competing risk of mortality.

During the study, 3.1% of subjects were exposed to opioids at a mean age of 73.94 years, and 5.8% of subjects developed dementia at an average age of 78.07 years.
 

Increased dementia risk

The risk of incident dementia was significantly increased in those exposed to opioids versus unexposed individuals in the 75- to 80-year age group (adjusted hazard ratio, 1.39; 95% confidence interval, 1.01-1.92; z statistic = 2.02; P < .05).

The authors noted the effect size for opioid exposure in this elderly age group is like other potentially modifiable risk factors for dementia, including body mass index and smoking.

The current study could not determine the biological explanation for the increased dementia risk among older opioid users. “Causal notions are challenging in observational studies and should be viewed with caution,” Dr. Levine noted.

However, a plausible mechanism highlighted in the literature is that opioids promote apoptosis of microglia and neurons that contribute to neurodegenerative diseases, he said.

The study included 14 sensitivity analyses, including those that looked at females, subjects older than 70, smokers, and groups with and without comorbid health conditions. The only sensitivity analysis that didn’t have similar findings to the primary analysis looked at dementia risk restricted to subjects without a vitamin deficiency.

“It’s reassuring that 13 or 14 sensitivity analyses found a significant association between opioid exposure and dementia risk,” said Dr. Levine.

Some prior studies did not show an association between opioid exposure and dementia risk. One possible reason for the discrepancy with the current findings is that the previous research didn’t account for age-specific opioid use effects, or the competing risk of mortality, said Dr. Levine.

Clinicians have a number of potential alternatives to opioids to treat various conditions including acetaminophen, non-steroidal anti-inflammatory drugs, amine reuptake inhibitors (ARIs), membrane stabilizers, muscle relaxants, topical capsaicin, botulinum toxin, cannabinoids, and steroids.

A limitation of the study was that it didn’t adjust for all possible comorbid health conditions, including vascular conditions, or for use of benzodiazepines, and surgical procedures.

In addition, since up to 50% of dementia cases are undetected, it’s possible some in the unexposed opioid group may actually have undiagnosed dementia, thereby reducing the effect sizes in the results.

Reverse causality is also a possibility as the neuropathological process associated with dementia could have started prior to opioid exposure. In addition, the results are limited to prolonged opioid exposure.
 

Interpret with caution

Commenting on the study, David Knopman, MD, a neurologist at Mayo Clinic in Rochester, Minn., whose research involves late-life cognitive disorders, was skeptical.

“On the face of it, the fact that an association was seen only in one narrow age range – 75+ to 80 years – ought to raise serious suspicion about the reliability and validity of the claim that opioid use is a risk factor for dementia, he said.

Although the researchers performed several sensitivity analyses, including accounting for mortality, “pharmacoepidemiological studies are terribly sensitive to residual biases” related to physician and patient choices related to medication use, added Dr. Knopman.

The claim that opioids are a dementia risk “should be viewed with great caution” and should not influence use of opioids where they’re truly indicated, he said.

“It would be a great pity if patients with pain requiring opioids avoid them because of fears about dementia based on the dubious relationship between age and opioid use.”

Dr. Levine and Dr. Knopman report no relevant financial disclosures.

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

Opioid use in the elderly is associated with an almost 40% increased risk of dementia in new findings that suggest exposure to these drugs may be another modifiable risk factor for dementia.

“Clinicians and others may want to consider that opioid exposure in those aged 75-80 increases dementia risk, and to balance the potential benefits of opioid use in old age with adverse side effects,” said Stephen Z. Levine, PhD, professor, department of community mental health, University of Haifa (Israel).

The study was published online in the American Journal of Geriatric Psychiatry.
 

Widespread use

Evidence points to a relatively high rate of opioid prescriptions among older adults. A Morbidity and Mortality Weekly Report noted 19.2% of the U.S. adult population filled an opioid prescription in 2018, with the rate in those over 65 double that of adults aged 20-24 years (25% vs. 11.2%).

Disorders and illnesses for which opioids might be prescribed, including cancer and some pain conditions, “are far more prevalent in old age than at a younger age,” said Dr. Levine.

This high rate of opioid use underscores the need to consider the risks of opioid use in old age, said Dr. Levine. “Unfortunately, studies of the association between opioid use and dementia risk in old age are few, and their results are inconsistent.”

The study included 91,307 Israeli citizens aged 60 and over without dementia who were enrolled in the Meuhedet Healthcare Services, a nonprofit health maintenance organization (HMO) serving 14% of the country’s population. Meuhedet has maintained an up-to-date dementia registry since 2002.

The average age of the study sample was 68.29 years at the start of the study (in 2012).

In Israel, opioids are prescribed for a 30-day period. In this study, opioid exposure was defined as opioid medication fills covering 60 days (or two prescriptions) within a 120-day interval.

The primary outcome was incident dementia during follow-up from Jan. 1, 2013 to Oct. 30, 2017. The analysis controlled for a number of factors, including age, sex, smoking status, health conditions such as arthritis, depression, diabetes, osteoporosis, cognitive decline, vitamin deficiencies, cancer, cardiovascular conditions, and hospitalizations for falls.

Researchers also accounted for the competing risk of mortality.

During the study, 3.1% of subjects were exposed to opioids at a mean age of 73.94 years, and 5.8% of subjects developed dementia at an average age of 78.07 years.
 

Increased dementia risk

The risk of incident dementia was significantly increased in those exposed to opioids versus unexposed individuals in the 75- to 80-year age group (adjusted hazard ratio, 1.39; 95% confidence interval, 1.01-1.92; z statistic = 2.02; P < .05).

The authors noted the effect size for opioid exposure in this elderly age group is like other potentially modifiable risk factors for dementia, including body mass index and smoking.

The current study could not determine the biological explanation for the increased dementia risk among older opioid users. “Causal notions are challenging in observational studies and should be viewed with caution,” Dr. Levine noted.

However, a plausible mechanism highlighted in the literature is that opioids promote apoptosis of microglia and neurons that contribute to neurodegenerative diseases, he said.

The study included 14 sensitivity analyses, including those that looked at females, subjects older than 70, smokers, and groups with and without comorbid health conditions. The only sensitivity analysis that didn’t have similar findings to the primary analysis looked at dementia risk restricted to subjects without a vitamin deficiency.

“It’s reassuring that 13 or 14 sensitivity analyses found a significant association between opioid exposure and dementia risk,” said Dr. Levine.

Some prior studies did not show an association between opioid exposure and dementia risk. One possible reason for the discrepancy with the current findings is that the previous research didn’t account for age-specific opioid use effects, or the competing risk of mortality, said Dr. Levine.

Clinicians have a number of potential alternatives to opioids to treat various conditions including acetaminophen, non-steroidal anti-inflammatory drugs, amine reuptake inhibitors (ARIs), membrane stabilizers, muscle relaxants, topical capsaicin, botulinum toxin, cannabinoids, and steroids.

A limitation of the study was that it didn’t adjust for all possible comorbid health conditions, including vascular conditions, or for use of benzodiazepines, and surgical procedures.

In addition, since up to 50% of dementia cases are undetected, it’s possible some in the unexposed opioid group may actually have undiagnosed dementia, thereby reducing the effect sizes in the results.

Reverse causality is also a possibility as the neuropathological process associated with dementia could have started prior to opioid exposure. In addition, the results are limited to prolonged opioid exposure.
 

Interpret with caution

Commenting on the study, David Knopman, MD, a neurologist at Mayo Clinic in Rochester, Minn., whose research involves late-life cognitive disorders, was skeptical.

“On the face of it, the fact that an association was seen only in one narrow age range – 75+ to 80 years – ought to raise serious suspicion about the reliability and validity of the claim that opioid use is a risk factor for dementia, he said.

Although the researchers performed several sensitivity analyses, including accounting for mortality, “pharmacoepidemiological studies are terribly sensitive to residual biases” related to physician and patient choices related to medication use, added Dr. Knopman.

The claim that opioids are a dementia risk “should be viewed with great caution” and should not influence use of opioids where they’re truly indicated, he said.

“It would be a great pity if patients with pain requiring opioids avoid them because of fears about dementia based on the dubious relationship between age and opioid use.”

Dr. Levine and Dr. Knopman report no relevant financial disclosures.

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

Opioid use in the elderly is associated with an almost 40% increased risk of dementia in new findings that suggest exposure to these drugs may be another modifiable risk factor for dementia.

“Clinicians and others may want to consider that opioid exposure in those aged 75-80 increases dementia risk, and to balance the potential benefits of opioid use in old age with adverse side effects,” said Stephen Z. Levine, PhD, professor, department of community mental health, University of Haifa (Israel).

The study was published online in the American Journal of Geriatric Psychiatry.
 

Widespread use

Evidence points to a relatively high rate of opioid prescriptions among older adults. A Morbidity and Mortality Weekly Report noted 19.2% of the U.S. adult population filled an opioid prescription in 2018, with the rate in those over 65 double that of adults aged 20-24 years (25% vs. 11.2%).

Disorders and illnesses for which opioids might be prescribed, including cancer and some pain conditions, “are far more prevalent in old age than at a younger age,” said Dr. Levine.

This high rate of opioid use underscores the need to consider the risks of opioid use in old age, said Dr. Levine. “Unfortunately, studies of the association between opioid use and dementia risk in old age are few, and their results are inconsistent.”

The study included 91,307 Israeli citizens aged 60 and over without dementia who were enrolled in the Meuhedet Healthcare Services, a nonprofit health maintenance organization (HMO) serving 14% of the country’s population. Meuhedet has maintained an up-to-date dementia registry since 2002.

The average age of the study sample was 68.29 years at the start of the study (in 2012).

In Israel, opioids are prescribed for a 30-day period. In this study, opioid exposure was defined as opioid medication fills covering 60 days (or two prescriptions) within a 120-day interval.

The primary outcome was incident dementia during follow-up from Jan. 1, 2013 to Oct. 30, 2017. The analysis controlled for a number of factors, including age, sex, smoking status, health conditions such as arthritis, depression, diabetes, osteoporosis, cognitive decline, vitamin deficiencies, cancer, cardiovascular conditions, and hospitalizations for falls.

Researchers also accounted for the competing risk of mortality.

During the study, 3.1% of subjects were exposed to opioids at a mean age of 73.94 years, and 5.8% of subjects developed dementia at an average age of 78.07 years.
 

Increased dementia risk

The risk of incident dementia was significantly increased in those exposed to opioids versus unexposed individuals in the 75- to 80-year age group (adjusted hazard ratio, 1.39; 95% confidence interval, 1.01-1.92; z statistic = 2.02; P < .05).

The authors noted the effect size for opioid exposure in this elderly age group is like other potentially modifiable risk factors for dementia, including body mass index and smoking.

The current study could not determine the biological explanation for the increased dementia risk among older opioid users. “Causal notions are challenging in observational studies and should be viewed with caution,” Dr. Levine noted.

However, a plausible mechanism highlighted in the literature is that opioids promote apoptosis of microglia and neurons that contribute to neurodegenerative diseases, he said.

The study included 14 sensitivity analyses, including those that looked at females, subjects older than 70, smokers, and groups with and without comorbid health conditions. The only sensitivity analysis that didn’t have similar findings to the primary analysis looked at dementia risk restricted to subjects without a vitamin deficiency.

“It’s reassuring that 13 or 14 sensitivity analyses found a significant association between opioid exposure and dementia risk,” said Dr. Levine.

Some prior studies did not show an association between opioid exposure and dementia risk. One possible reason for the discrepancy with the current findings is that the previous research didn’t account for age-specific opioid use effects, or the competing risk of mortality, said Dr. Levine.

Clinicians have a number of potential alternatives to opioids to treat various conditions including acetaminophen, non-steroidal anti-inflammatory drugs, amine reuptake inhibitors (ARIs), membrane stabilizers, muscle relaxants, topical capsaicin, botulinum toxin, cannabinoids, and steroids.

A limitation of the study was that it didn’t adjust for all possible comorbid health conditions, including vascular conditions, or for use of benzodiazepines, and surgical procedures.

In addition, since up to 50% of dementia cases are undetected, it’s possible some in the unexposed opioid group may actually have undiagnosed dementia, thereby reducing the effect sizes in the results.

Reverse causality is also a possibility as the neuropathological process associated with dementia could have started prior to opioid exposure. In addition, the results are limited to prolonged opioid exposure.
 

Interpret with caution

Commenting on the study, David Knopman, MD, a neurologist at Mayo Clinic in Rochester, Minn., whose research involves late-life cognitive disorders, was skeptical.

“On the face of it, the fact that an association was seen only in one narrow age range – 75+ to 80 years – ought to raise serious suspicion about the reliability and validity of the claim that opioid use is a risk factor for dementia, he said.

Although the researchers performed several sensitivity analyses, including accounting for mortality, “pharmacoepidemiological studies are terribly sensitive to residual biases” related to physician and patient choices related to medication use, added Dr. Knopman.

The claim that opioids are a dementia risk “should be viewed with great caution” and should not influence use of opioids where they’re truly indicated, he said.

“It would be a great pity if patients with pain requiring opioids avoid them because of fears about dementia based on the dubious relationship between age and opioid use.”

Dr. Levine and Dr. Knopman report no relevant financial disclosures.

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

NATIONAL HARBOR, MD. – Treating neuromyelitis optica spectrum disorder (NMOSD) with the recently approved monoclonal antibody inebilizumab (Uplizna, Horizon Therapeutics) is effective across patient genotypes – including a common genetic variation linked to reduced response to anti-CD20 therapies, new research shows.

The phase 3 N-MOmentum Study previously showed safety and efficacy for inebilizumab over placebo in more than 200 adults with NMOSD.

A new analysis focused on participants who were carriers of either the F/F allele, which is known to reduce the effectiveness of certain monoclonal antibodies, or the rs396991 V-allele, which has not been associated with a reduced response.

Results showed no significant differences between the two carrier groups in NMOSD activity, including annual rates of new/enlarging T2 lesions, during the trial and up to 6 months after treatment with inebilizumab.

“These data illustrate how mechanistic precision in treatment design can help patients gain benefit from their regimen regardless of the genetic make-up of their immune systems,” coinvestigator Bruce Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco, Weill Institute for Neurosciences, said in a press release.

“The combination of efficacy, safety, and ease of administration with twice-yearly infusions make this product an excellent choice for first-line therapy in NMOSD,” Dr. Cree said.

The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

B-cell depletion

Inebilizumab has also been approved in China, Japan, and South Korea for the treatment of NMOSD, a rare and severe autoantibody-mediated disease of the central nervous system that includes NMO and related syndromes.

The drug’s B-cell depletion capability is credited with reducing inflammation, lesion formation, and astrocyte damage. The latter can cause severe effects in an NMOSD attack, affecting the optic nerve, spinal cord, and brain.

Manifestations can range from loss of vision to paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain or respiratory failure. Attacks can also result in cumulative damage and disability, the researchers noted.

Results from the original double-blind trial of 230 adults with NMOSD showed that treatment with inebilizumab demonstrated efficacy and safety over placebo. However, questions have remained regarding the treatment’s effectiveness, specifically among patients with the FCGR3A (F/F) allele, a genetic variant that encodes the low-affinity Fc gamma receptor IIIa.

This genotype is known to reduce the effectiveness of certain monoclonal antibodies and anti-CD20 therapies, notably rituximab, in disorders such as NMOSD.

With up to 40% of White and Black individuals known to carry the F/F allele, inebilizumab was designed specifically with that risk in mind, with strong binding to the allele.

Although inebilizumab joins two other Food and Drug Administration–approved treatments for NMOSD – eculizumab and satralizumab – neither of those have a mechanism involving the FCGRA3 receptor. Therefore, those drugs are not a concern for individuals with those genotypes.

To evaluate inebilizumab’s effects among patients with the F/F allele, Dr. Cree and colleagues assessed data on a subset of 142 patients from the N-MOmentum trial.

The study included a 28-week randomized controlled period in which adults with NMOSD received either 300 mg of intravenous inebilizumab or placebo on days 1 and 15, followed by an optional open-label period of at least 2 years. During the open-label phase, all patients received 300 mg of IV inebilizumab every 26 weeks.

Of the 142 patients in the genetic analysis, 104 received inebilizumab and 38 received placebo. In addition, 68 group participants were carriers of the F/F allele, while 74 carried the rs396991 V-allele.
 

No significant differences

Prior to the trial, annualized attack rates (AARs) and disability, as assessed by change in the Expanded Disability Status Scale (EDSS) scores, were nominally higher in the V allele group from disease onset to trial enrollment.

During the trial’s first 6 months, AARs and annual rates of new/enlarging T2 lesions were nominally lower in inebilizumab-treated V allele participants compared with the F/F allele participants, although the differences were not statistically significant.

The AAR was 0.1 for the V allele group vs. 0.3 for the F/F allele group (hazard ratio, 0.40; P = .17). The annual rate of new/enlarging T2 lesions was 1.4 vs. 1.7 (risk ratio, 0.91; P = .88), respectively.

However, at the end of the randomized controlled period, there were no significant differences between the two genotype groups. There was also little difference in clinical metrics of NMOSD activity or B-cell depletion between the two genotype groups during the open-label period involving the long-term repeated inebilizumab dosing.

“Though greater B-cell depletion was observed in inebilizumab-treated V allele participants, compared with F/F participants during the first 6 months, no significant difference in NMOSD activity was observed during this time period,” the investigators reported.

“No differences in B-cell depletion or NMOSD disease activity were observed after 6 months of inebilizumab treatment,” they added.

Dr. Cree noted the study showed that, overall, inebiluzumab’s efficacy was not adversely affected by a polymorphism in the Fc gamma receptor. “These types of genetic analyses may help inform future screening mechanisms to tailor treatment strategies that can optimize the response rate for each patient,” he said.

Dr. Cree added the higher degree of disease activity among those carrying the alleles at baseline is notable and deserves further investigation. That finding “suggests that the presence of the F/F allele is to some extent protective of the detrimental effects the auto-antibody directed against aquaporin-4 that underlies NMOSD pathogenesis,” he said.
 

A new era?

Commenting on the study, Marcelo Matiello, MD, assistant professor of neurology at Harvard Medical School and associate director of the Neuromyelitis Optica clinic at Massachusetts General Hospital, both in Boston, said the findings provide valuable insights into risks for key patient subgroups.

“The data is quite important because we know that with other conditions, such as rheumatoid arthritis, people with this particular genotype do have lower response and are more likely to be refractory,” said Dr. Matiello, who was not involved with the research.

He noted that rituximab is the most commonly used medication in the United States for NMOSD. “It’s not FDA approved, but because of extensive experience, and many case series and small prospective studies, most NMO patients are using rituximab,” Dr. Matiello said. However, the drug’s mechanism “can be compromised” by the F/F allele, he added.

The new findings “provide a good understanding that this medication would likely be superior to patients with this genotype,” he said.

“I think it’s a new era,” Dr. Matiello added. “Not only do we have approved medication for this very severe disease, but we can find out who can benefit most. So, I think this is exciting and is a major step in more individualized appropriate use.”

The study was funded by Horizon Therapeutics. Dr. Cree has consulted for Horizon Therapeutics. Dr. Matiello reported no relevant financial relationships.

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

NATIONAL HARBOR, MD. – Treating neuromyelitis optica spectrum disorder (NMOSD) with the recently approved monoclonal antibody inebilizumab (Uplizna, Horizon Therapeutics) is effective across patient genotypes – including a common genetic variation linked to reduced response to anti-CD20 therapies, new research shows.

The phase 3 N-MOmentum Study previously showed safety and efficacy for inebilizumab over placebo in more than 200 adults with NMOSD.

A new analysis focused on participants who were carriers of either the F/F allele, which is known to reduce the effectiveness of certain monoclonal antibodies, or the rs396991 V-allele, which has not been associated with a reduced response.

Results showed no significant differences between the two carrier groups in NMOSD activity, including annual rates of new/enlarging T2 lesions, during the trial and up to 6 months after treatment with inebilizumab.

“These data illustrate how mechanistic precision in treatment design can help patients gain benefit from their regimen regardless of the genetic make-up of their immune systems,” coinvestigator Bruce Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco, Weill Institute for Neurosciences, said in a press release.

“The combination of efficacy, safety, and ease of administration with twice-yearly infusions make this product an excellent choice for first-line therapy in NMOSD,” Dr. Cree said.

The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

B-cell depletion

Inebilizumab has also been approved in China, Japan, and South Korea for the treatment of NMOSD, a rare and severe autoantibody-mediated disease of the central nervous system that includes NMO and related syndromes.

The drug’s B-cell depletion capability is credited with reducing inflammation, lesion formation, and astrocyte damage. The latter can cause severe effects in an NMOSD attack, affecting the optic nerve, spinal cord, and brain.

Manifestations can range from loss of vision to paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain or respiratory failure. Attacks can also result in cumulative damage and disability, the researchers noted.

Results from the original double-blind trial of 230 adults with NMOSD showed that treatment with inebilizumab demonstrated efficacy and safety over placebo. However, questions have remained regarding the treatment’s effectiveness, specifically among patients with the FCGR3A (F/F) allele, a genetic variant that encodes the low-affinity Fc gamma receptor IIIa.

This genotype is known to reduce the effectiveness of certain monoclonal antibodies and anti-CD20 therapies, notably rituximab, in disorders such as NMOSD.

With up to 40% of White and Black individuals known to carry the F/F allele, inebilizumab was designed specifically with that risk in mind, with strong binding to the allele.

Although inebilizumab joins two other Food and Drug Administration–approved treatments for NMOSD – eculizumab and satralizumab – neither of those have a mechanism involving the FCGRA3 receptor. Therefore, those drugs are not a concern for individuals with those genotypes.

To evaluate inebilizumab’s effects among patients with the F/F allele, Dr. Cree and colleagues assessed data on a subset of 142 patients from the N-MOmentum trial.

The study included a 28-week randomized controlled period in which adults with NMOSD received either 300 mg of intravenous inebilizumab or placebo on days 1 and 15, followed by an optional open-label period of at least 2 years. During the open-label phase, all patients received 300 mg of IV inebilizumab every 26 weeks.

Of the 142 patients in the genetic analysis, 104 received inebilizumab and 38 received placebo. In addition, 68 group participants were carriers of the F/F allele, while 74 carried the rs396991 V-allele.
 

No significant differences

Prior to the trial, annualized attack rates (AARs) and disability, as assessed by change in the Expanded Disability Status Scale (EDSS) scores, were nominally higher in the V allele group from disease onset to trial enrollment.

During the trial’s first 6 months, AARs and annual rates of new/enlarging T2 lesions were nominally lower in inebilizumab-treated V allele participants compared with the F/F allele participants, although the differences were not statistically significant.

The AAR was 0.1 for the V allele group vs. 0.3 for the F/F allele group (hazard ratio, 0.40; P = .17). The annual rate of new/enlarging T2 lesions was 1.4 vs. 1.7 (risk ratio, 0.91; P = .88), respectively.

However, at the end of the randomized controlled period, there were no significant differences between the two genotype groups. There was also little difference in clinical metrics of NMOSD activity or B-cell depletion between the two genotype groups during the open-label period involving the long-term repeated inebilizumab dosing.

“Though greater B-cell depletion was observed in inebilizumab-treated V allele participants, compared with F/F participants during the first 6 months, no significant difference in NMOSD activity was observed during this time period,” the investigators reported.

“No differences in B-cell depletion or NMOSD disease activity were observed after 6 months of inebilizumab treatment,” they added.

Dr. Cree noted the study showed that, overall, inebiluzumab’s efficacy was not adversely affected by a polymorphism in the Fc gamma receptor. “These types of genetic analyses may help inform future screening mechanisms to tailor treatment strategies that can optimize the response rate for each patient,” he said.

Dr. Cree added the higher degree of disease activity among those carrying the alleles at baseline is notable and deserves further investigation. That finding “suggests that the presence of the F/F allele is to some extent protective of the detrimental effects the auto-antibody directed against aquaporin-4 that underlies NMOSD pathogenesis,” he said.
 

A new era?

Commenting on the study, Marcelo Matiello, MD, assistant professor of neurology at Harvard Medical School and associate director of the Neuromyelitis Optica clinic at Massachusetts General Hospital, both in Boston, said the findings provide valuable insights into risks for key patient subgroups.

“The data is quite important because we know that with other conditions, such as rheumatoid arthritis, people with this particular genotype do have lower response and are more likely to be refractory,” said Dr. Matiello, who was not involved with the research.

He noted that rituximab is the most commonly used medication in the United States for NMOSD. “It’s not FDA approved, but because of extensive experience, and many case series and small prospective studies, most NMO patients are using rituximab,” Dr. Matiello said. However, the drug’s mechanism “can be compromised” by the F/F allele, he added.

The new findings “provide a good understanding that this medication would likely be superior to patients with this genotype,” he said.

“I think it’s a new era,” Dr. Matiello added. “Not only do we have approved medication for this very severe disease, but we can find out who can benefit most. So, I think this is exciting and is a major step in more individualized appropriate use.”

The study was funded by Horizon Therapeutics. Dr. Cree has consulted for Horizon Therapeutics. Dr. Matiello reported no relevant financial relationships.

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

NATIONAL HARBOR, MD. – Treating neuromyelitis optica spectrum disorder (NMOSD) with the recently approved monoclonal antibody inebilizumab (Uplizna, Horizon Therapeutics) is effective across patient genotypes – including a common genetic variation linked to reduced response to anti-CD20 therapies, new research shows.

The phase 3 N-MOmentum Study previously showed safety and efficacy for inebilizumab over placebo in more than 200 adults with NMOSD.

A new analysis focused on participants who were carriers of either the F/F allele, which is known to reduce the effectiveness of certain monoclonal antibodies, or the rs396991 V-allele, which has not been associated with a reduced response.

Results showed no significant differences between the two carrier groups in NMOSD activity, including annual rates of new/enlarging T2 lesions, during the trial and up to 6 months after treatment with inebilizumab.

“These data illustrate how mechanistic precision in treatment design can help patients gain benefit from their regimen regardless of the genetic make-up of their immune systems,” coinvestigator Bruce Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco, Weill Institute for Neurosciences, said in a press release.

“The combination of efficacy, safety, and ease of administration with twice-yearly infusions make this product an excellent choice for first-line therapy in NMOSD,” Dr. Cree said.

The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

B-cell depletion

Inebilizumab has also been approved in China, Japan, and South Korea for the treatment of NMOSD, a rare and severe autoantibody-mediated disease of the central nervous system that includes NMO and related syndromes.

The drug’s B-cell depletion capability is credited with reducing inflammation, lesion formation, and astrocyte damage. The latter can cause severe effects in an NMOSD attack, affecting the optic nerve, spinal cord, and brain.

Manifestations can range from loss of vision to paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain or respiratory failure. Attacks can also result in cumulative damage and disability, the researchers noted.

Results from the original double-blind trial of 230 adults with NMOSD showed that treatment with inebilizumab demonstrated efficacy and safety over placebo. However, questions have remained regarding the treatment’s effectiveness, specifically among patients with the FCGR3A (F/F) allele, a genetic variant that encodes the low-affinity Fc gamma receptor IIIa.

This genotype is known to reduce the effectiveness of certain monoclonal antibodies and anti-CD20 therapies, notably rituximab, in disorders such as NMOSD.

With up to 40% of White and Black individuals known to carry the F/F allele, inebilizumab was designed specifically with that risk in mind, with strong binding to the allele.

Although inebilizumab joins two other Food and Drug Administration–approved treatments for NMOSD – eculizumab and satralizumab – neither of those have a mechanism involving the FCGRA3 receptor. Therefore, those drugs are not a concern for individuals with those genotypes.

To evaluate inebilizumab’s effects among patients with the F/F allele, Dr. Cree and colleagues assessed data on a subset of 142 patients from the N-MOmentum trial.

The study included a 28-week randomized controlled period in which adults with NMOSD received either 300 mg of intravenous inebilizumab or placebo on days 1 and 15, followed by an optional open-label period of at least 2 years. During the open-label phase, all patients received 300 mg of IV inebilizumab every 26 weeks.

Of the 142 patients in the genetic analysis, 104 received inebilizumab and 38 received placebo. In addition, 68 group participants were carriers of the F/F allele, while 74 carried the rs396991 V-allele.
 

No significant differences

Prior to the trial, annualized attack rates (AARs) and disability, as assessed by change in the Expanded Disability Status Scale (EDSS) scores, were nominally higher in the V allele group from disease onset to trial enrollment.

During the trial’s first 6 months, AARs and annual rates of new/enlarging T2 lesions were nominally lower in inebilizumab-treated V allele participants compared with the F/F allele participants, although the differences were not statistically significant.

The AAR was 0.1 for the V allele group vs. 0.3 for the F/F allele group (hazard ratio, 0.40; P = .17). The annual rate of new/enlarging T2 lesions was 1.4 vs. 1.7 (risk ratio, 0.91; P = .88), respectively.

However, at the end of the randomized controlled period, there were no significant differences between the two genotype groups. There was also little difference in clinical metrics of NMOSD activity or B-cell depletion between the two genotype groups during the open-label period involving the long-term repeated inebilizumab dosing.

“Though greater B-cell depletion was observed in inebilizumab-treated V allele participants, compared with F/F participants during the first 6 months, no significant difference in NMOSD activity was observed during this time period,” the investigators reported.

“No differences in B-cell depletion or NMOSD disease activity were observed after 6 months of inebilizumab treatment,” they added.

Dr. Cree noted the study showed that, overall, inebiluzumab’s efficacy was not adversely affected by a polymorphism in the Fc gamma receptor. “These types of genetic analyses may help inform future screening mechanisms to tailor treatment strategies that can optimize the response rate for each patient,” he said.

Dr. Cree added the higher degree of disease activity among those carrying the alleles at baseline is notable and deserves further investigation. That finding “suggests that the presence of the F/F allele is to some extent protective of the detrimental effects the auto-antibody directed against aquaporin-4 that underlies NMOSD pathogenesis,” he said.
 

A new era?

Commenting on the study, Marcelo Matiello, MD, assistant professor of neurology at Harvard Medical School and associate director of the Neuromyelitis Optica clinic at Massachusetts General Hospital, both in Boston, said the findings provide valuable insights into risks for key patient subgroups.

“The data is quite important because we know that with other conditions, such as rheumatoid arthritis, people with this particular genotype do have lower response and are more likely to be refractory,” said Dr. Matiello, who was not involved with the research.

He noted that rituximab is the most commonly used medication in the United States for NMOSD. “It’s not FDA approved, but because of extensive experience, and many case series and small prospective studies, most NMO patients are using rituximab,” Dr. Matiello said. However, the drug’s mechanism “can be compromised” by the F/F allele, he added.

The new findings “provide a good understanding that this medication would likely be superior to patients with this genotype,” he said.

“I think it’s a new era,” Dr. Matiello added. “Not only do we have approved medication for this very severe disease, but we can find out who can benefit most. So, I think this is exciting and is a major step in more individualized appropriate use.”

The study was funded by Horizon Therapeutics. Dr. Cree has consulted for Horizon Therapeutics. Dr. Matiello reported no relevant financial relationships.

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

MILAN, Italy – The antisense oligonucleotide vupanorsen substantially reduces very-low-density-lipoprotein (VLDL) and remnant cholesterol levels in patients with raised lipids despite statin therapy, suggests a subanalysis of TRANSLATE-TIMI 70 that appears to offer more hope than the primary study findings.

Vupanorsen targets hepatic angiopoietin-like protein 3 (ANGPTL3), which inhibits enzymes involved in triglyceride and cholesterol metabolism.

Earlier this year, headline data from TRANSLATE-TIMI 70 suggested that the drug reduced triglycerides and non–high-density-lipoprotein cholesterol to a degree that was significant but not clinically meaningful for cardiovascular risk reduction.

Moreover, as reported by this news organization, there were safety concerns over increases in liver enzymes among patients taking the drug, as well as dose-related increases in hepatic fat.

As a result, Pfizer announced that it would discontinue its clinical development program for vupanorsen and return the development rights to Ionis, following the signing of a worldwide exclusive agreement in November 2019.

Now, Nicholas A. Marston, MD, MPH, cardiovascular medicine, Brigham and Women’s Hospital, Boston, has presented a post-hoc analysis of the phase 2b study, showing that the drug reduces VLDL and remnant cholesterol levels by up to 60%.

These were closely tied to reductions in ANGPTL3 levels, although substantial reductions in cholesterol levels were achieved even at less than maximal reductions in ANGPTL3, where the impact on safety outcomes was reduced.

Dr. Marston said that lower doses of vupanorsen, where the safety effects would be less, or other drugs that inhibit ANGPTL3, “may have an important role in patients with residual dyslipidemia despite current therapy.”

The results were presented at the 90th European Atherosclerosis Society Congress on May 23.

Dr. Marston told this news organization that some of the reductions they saw with the lower doses of vupanorsen were “just as good as any other therapy, and the safety profile was … much better than at the highest dose.”

They wanted to pursue the subgroup analysis, despite Pfizer’s announcement, partly to “learn something in terms of the potential efficacy of the ANGPTL3 pathway in general.”

Dr. Marston said that Ionis is now focused on ANGPTL3, and the current results suggest that it “works very well,” so if other drugs are able to achieve the same efficacy as vupanorsen “but without the effects,” then it may “get elbowed out.”

Børge G. Nordestgaard, MD, PhD, of Herlev and Gentofte Hospital, Copenhagen, who was not involved in the study, called the findings “very encouraging.”

He told this news organization that being able to reduce LDL cholesterol as well as VLDL and remnant cholesterol is “exactly what I would be dreaming about” with a drug like vupanorsen.

Dr. Nordestgaard nevertheless underlined that “one would have to look carefully” at the safety of the drug.

“If it was my money, I would certainly try to look into if this was some sort of transient thing. Even when they started talking about statins, there was also this transient increase in alanine transaminase that seems to go away after a while,” he said.

“But of course, if this was persistent and triglycerides in the liver kept accumulating, then it’s a problem,” Dr. Nordestgaard added, “and then you would need to have some sort of thinking about whether you could couple it with something that got rid of the liver fat.”

He also agreed with Dr. Marston that, even if vupanorsen does not clear all hurdles before making it to market, the approach is promising.

“The target,” Dr. Nordestgaard said, seems “fantastic, from my point of view anyway.”

Dr. Marston explained that VLDL cholesterol, remnant cholesterol, and triglycerides are “surrogates for triglyceride-rich” lipoproteins, and that they are “increasingly recognized” as cardiovascular risk factors.

He highlighted that currently available therapies achieve reductions of these compounds of between 30% and 50%.

TRANSLATE-TIMI 70 included adults on stable statin therapy who had a triglyceride level of 150 mg/dL to 500 mg/dL and a non-HDL cholesterol level of 100 mg/dL or higher.

The participants were randomly assigned to one of six 2- or 4-week dosing schedules of vupanorsen or placebo and followed up over 24 weeks for a series of primary and additional endpoints, as well as safety outcomes.

The team recruited 286 individuals, who had a median age of 64 years; 44% were female. The majority (87%) were white.

The mean body mass index was 32 kg/m², 50% had diabetes, 13% had experienced a prior myocardial infarction, and 51% were receiving high-intensity statins.

As previously reported, vupanorsen was associated with a reduction in non-HDL cholesterol vs. placebo of 22%-28%, alongside a 6%-15% reduction in apolipoprotein B levels and an 8%-16% reduction in LDL cholesterol.

In contrast, Dr. Marston showed that the various dosing schedules of the drug were associated with reductions in levels of VLDL cholesterol of 52%-66% vs. placebo at 24 weeks.

Over the same period, remnant cholesterol levels were lowered by 42%-59% vs. placebo, and triglycerides were reduced by 44%-57% in patients given vupanorsen.

There were also reductions in ANGPTL3 levels of 70%-95%.

Subgroup analysis indicated that the effect of vupanorsen was seen regardless of age, sex, body mass index, presence of diabetes, baseline triglycerides, and intensity of statin therapy.

Dr. Marston highlighted that the reductions in triglycerides, VLDL cholesterol, and remnant cholesterol levels were directly related to those for ANGPTL3 levels, but that the reductions remained meaningful even at less than maximal reductions in ANGPTL.

For example, even when ANGPTL3 levels were reduced by 70%, there were 50% reductions in triglyceride levels, 70% reductions in VLDL cholesterol levels, and a 50% drop in remnant cholesterol levels.

This, he noted, is important given that safety signals such as increases in alanine transaminase and hepatic fat occurred in a dose-dependent manner with ANGPTL3 reductions and were “most pronounced” only at the highest level of ANGPTL3 reduction.

The TRANSLATE-TIMI 70 study was sponsored by Pfizer. Dr. Marston disclosed relationships with Pfizer, Amgen, Ionis, Novartis, and AstraZeneca. Dr. Nordestgaard disclosed relationships with AstraZeneca, Sanofi, Regeneron, Akcea, Ionis, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Esperion, and Silence Therapeutics.

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

MILAN, Italy – The antisense oligonucleotide vupanorsen substantially reduces very-low-density-lipoprotein (VLDL) and remnant cholesterol levels in patients with raised lipids despite statin therapy, suggests a subanalysis of TRANSLATE-TIMI 70 that appears to offer more hope than the primary study findings.

Vupanorsen targets hepatic angiopoietin-like protein 3 (ANGPTL3), which inhibits enzymes involved in triglyceride and cholesterol metabolism.

Earlier this year, headline data from TRANSLATE-TIMI 70 suggested that the drug reduced triglycerides and non–high-density-lipoprotein cholesterol to a degree that was significant but not clinically meaningful for cardiovascular risk reduction.

Moreover, as reported by this news organization, there were safety concerns over increases in liver enzymes among patients taking the drug, as well as dose-related increases in hepatic fat.

As a result, Pfizer announced that it would discontinue its clinical development program for vupanorsen and return the development rights to Ionis, following the signing of a worldwide exclusive agreement in November 2019.

Now, Nicholas A. Marston, MD, MPH, cardiovascular medicine, Brigham and Women’s Hospital, Boston, has presented a post-hoc analysis of the phase 2b study, showing that the drug reduces VLDL and remnant cholesterol levels by up to 60%.

These were closely tied to reductions in ANGPTL3 levels, although substantial reductions in cholesterol levels were achieved even at less than maximal reductions in ANGPTL3, where the impact on safety outcomes was reduced.

Dr. Marston said that lower doses of vupanorsen, where the safety effects would be less, or other drugs that inhibit ANGPTL3, “may have an important role in patients with residual dyslipidemia despite current therapy.”

The results were presented at the 90th European Atherosclerosis Society Congress on May 23.

Dr. Marston told this news organization that some of the reductions they saw with the lower doses of vupanorsen were “just as good as any other therapy, and the safety profile was … much better than at the highest dose.”

They wanted to pursue the subgroup analysis, despite Pfizer’s announcement, partly to “learn something in terms of the potential efficacy of the ANGPTL3 pathway in general.”

Dr. Marston said that Ionis is now focused on ANGPTL3, and the current results suggest that it “works very well,” so if other drugs are able to achieve the same efficacy as vupanorsen “but without the effects,” then it may “get elbowed out.”

Børge G. Nordestgaard, MD, PhD, of Herlev and Gentofte Hospital, Copenhagen, who was not involved in the study, called the findings “very encouraging.”

He told this news organization that being able to reduce LDL cholesterol as well as VLDL and remnant cholesterol is “exactly what I would be dreaming about” with a drug like vupanorsen.

Dr. Nordestgaard nevertheless underlined that “one would have to look carefully” at the safety of the drug.

“If it was my money, I would certainly try to look into if this was some sort of transient thing. Even when they started talking about statins, there was also this transient increase in alanine transaminase that seems to go away after a while,” he said.

“But of course, if this was persistent and triglycerides in the liver kept accumulating, then it’s a problem,” Dr. Nordestgaard added, “and then you would need to have some sort of thinking about whether you could couple it with something that got rid of the liver fat.”

He also agreed with Dr. Marston that, even if vupanorsen does not clear all hurdles before making it to market, the approach is promising.

“The target,” Dr. Nordestgaard said, seems “fantastic, from my point of view anyway.”

Dr. Marston explained that VLDL cholesterol, remnant cholesterol, and triglycerides are “surrogates for triglyceride-rich” lipoproteins, and that they are “increasingly recognized” as cardiovascular risk factors.

He highlighted that currently available therapies achieve reductions of these compounds of between 30% and 50%.

TRANSLATE-TIMI 70 included adults on stable statin therapy who had a triglyceride level of 150 mg/dL to 500 mg/dL and a non-HDL cholesterol level of 100 mg/dL or higher.

The participants were randomly assigned to one of six 2- or 4-week dosing schedules of vupanorsen or placebo and followed up over 24 weeks for a series of primary and additional endpoints, as well as safety outcomes.

The team recruited 286 individuals, who had a median age of 64 years; 44% were female. The majority (87%) were white.

The mean body mass index was 32 kg/m², 50% had diabetes, 13% had experienced a prior myocardial infarction, and 51% were receiving high-intensity statins.

As previously reported, vupanorsen was associated with a reduction in non-HDL cholesterol vs. placebo of 22%-28%, alongside a 6%-15% reduction in apolipoprotein B levels and an 8%-16% reduction in LDL cholesterol.

In contrast, Dr. Marston showed that the various dosing schedules of the drug were associated with reductions in levels of VLDL cholesterol of 52%-66% vs. placebo at 24 weeks.

Over the same period, remnant cholesterol levels were lowered by 42%-59% vs. placebo, and triglycerides were reduced by 44%-57% in patients given vupanorsen.

There were also reductions in ANGPTL3 levels of 70%-95%.

Subgroup analysis indicated that the effect of vupanorsen was seen regardless of age, sex, body mass index, presence of diabetes, baseline triglycerides, and intensity of statin therapy.

Dr. Marston highlighted that the reductions in triglycerides, VLDL cholesterol, and remnant cholesterol levels were directly related to those for ANGPTL3 levels, but that the reductions remained meaningful even at less than maximal reductions in ANGPTL.

For example, even when ANGPTL3 levels were reduced by 70%, there were 50% reductions in triglyceride levels, 70% reductions in VLDL cholesterol levels, and a 50% drop in remnant cholesterol levels.

This, he noted, is important given that safety signals such as increases in alanine transaminase and hepatic fat occurred in a dose-dependent manner with ANGPTL3 reductions and were “most pronounced” only at the highest level of ANGPTL3 reduction.

The TRANSLATE-TIMI 70 study was sponsored by Pfizer. Dr. Marston disclosed relationships with Pfizer, Amgen, Ionis, Novartis, and AstraZeneca. Dr. Nordestgaard disclosed relationships with AstraZeneca, Sanofi, Regeneron, Akcea, Ionis, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Esperion, and Silence Therapeutics.

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

MILAN, Italy – The antisense oligonucleotide vupanorsen substantially reduces very-low-density-lipoprotein (VLDL) and remnant cholesterol levels in patients with raised lipids despite statin therapy, suggests a subanalysis of TRANSLATE-TIMI 70 that appears to offer more hope than the primary study findings.

Vupanorsen targets hepatic angiopoietin-like protein 3 (ANGPTL3), which inhibits enzymes involved in triglyceride and cholesterol metabolism.

Earlier this year, headline data from TRANSLATE-TIMI 70 suggested that the drug reduced triglycerides and non–high-density-lipoprotein cholesterol to a degree that was significant but not clinically meaningful for cardiovascular risk reduction.

Moreover, as reported by this news organization, there were safety concerns over increases in liver enzymes among patients taking the drug, as well as dose-related increases in hepatic fat.

As a result, Pfizer announced that it would discontinue its clinical development program for vupanorsen and return the development rights to Ionis, following the signing of a worldwide exclusive agreement in November 2019.

Now, Nicholas A. Marston, MD, MPH, cardiovascular medicine, Brigham and Women’s Hospital, Boston, has presented a post-hoc analysis of the phase 2b study, showing that the drug reduces VLDL and remnant cholesterol levels by up to 60%.

These were closely tied to reductions in ANGPTL3 levels, although substantial reductions in cholesterol levels were achieved even at less than maximal reductions in ANGPTL3, where the impact on safety outcomes was reduced.

Dr. Marston said that lower doses of vupanorsen, where the safety effects would be less, or other drugs that inhibit ANGPTL3, “may have an important role in patients with residual dyslipidemia despite current therapy.”

The results were presented at the 90th European Atherosclerosis Society Congress on May 23.

Dr. Marston told this news organization that some of the reductions they saw with the lower doses of vupanorsen were “just as good as any other therapy, and the safety profile was … much better than at the highest dose.”

They wanted to pursue the subgroup analysis, despite Pfizer’s announcement, partly to “learn something in terms of the potential efficacy of the ANGPTL3 pathway in general.”

Dr. Marston said that Ionis is now focused on ANGPTL3, and the current results suggest that it “works very well,” so if other drugs are able to achieve the same efficacy as vupanorsen “but without the effects,” then it may “get elbowed out.”

Børge G. Nordestgaard, MD, PhD, of Herlev and Gentofte Hospital, Copenhagen, who was not involved in the study, called the findings “very encouraging.”

He told this news organization that being able to reduce LDL cholesterol as well as VLDL and remnant cholesterol is “exactly what I would be dreaming about” with a drug like vupanorsen.

Dr. Nordestgaard nevertheless underlined that “one would have to look carefully” at the safety of the drug.

“If it was my money, I would certainly try to look into if this was some sort of transient thing. Even when they started talking about statins, there was also this transient increase in alanine transaminase that seems to go away after a while,” he said.

“But of course, if this was persistent and triglycerides in the liver kept accumulating, then it’s a problem,” Dr. Nordestgaard added, “and then you would need to have some sort of thinking about whether you could couple it with something that got rid of the liver fat.”

He also agreed with Dr. Marston that, even if vupanorsen does not clear all hurdles before making it to market, the approach is promising.

“The target,” Dr. Nordestgaard said, seems “fantastic, from my point of view anyway.”

Dr. Marston explained that VLDL cholesterol, remnant cholesterol, and triglycerides are “surrogates for triglyceride-rich” lipoproteins, and that they are “increasingly recognized” as cardiovascular risk factors.

He highlighted that currently available therapies achieve reductions of these compounds of between 30% and 50%.

TRANSLATE-TIMI 70 included adults on stable statin therapy who had a triglyceride level of 150 mg/dL to 500 mg/dL and a non-HDL cholesterol level of 100 mg/dL or higher.

The participants were randomly assigned to one of six 2- or 4-week dosing schedules of vupanorsen or placebo and followed up over 24 weeks for a series of primary and additional endpoints, as well as safety outcomes.

The team recruited 286 individuals, who had a median age of 64 years; 44% were female. The majority (87%) were white.

The mean body mass index was 32 kg/m², 50% had diabetes, 13% had experienced a prior myocardial infarction, and 51% were receiving high-intensity statins.

As previously reported, vupanorsen was associated with a reduction in non-HDL cholesterol vs. placebo of 22%-28%, alongside a 6%-15% reduction in apolipoprotein B levels and an 8%-16% reduction in LDL cholesterol.

In contrast, Dr. Marston showed that the various dosing schedules of the drug were associated with reductions in levels of VLDL cholesterol of 52%-66% vs. placebo at 24 weeks.

Over the same period, remnant cholesterol levels were lowered by 42%-59% vs. placebo, and triglycerides were reduced by 44%-57% in patients given vupanorsen.

There were also reductions in ANGPTL3 levels of 70%-95%.

Subgroup analysis indicated that the effect of vupanorsen was seen regardless of age, sex, body mass index, presence of diabetes, baseline triglycerides, and intensity of statin therapy.

Dr. Marston highlighted that the reductions in triglycerides, VLDL cholesterol, and remnant cholesterol levels were directly related to those for ANGPTL3 levels, but that the reductions remained meaningful even at less than maximal reductions in ANGPTL.

For example, even when ANGPTL3 levels were reduced by 70%, there were 50% reductions in triglyceride levels, 70% reductions in VLDL cholesterol levels, and a 50% drop in remnant cholesterol levels.

This, he noted, is important given that safety signals such as increases in alanine transaminase and hepatic fat occurred in a dose-dependent manner with ANGPTL3 reductions and were “most pronounced” only at the highest level of ANGPTL3 reduction.

The TRANSLATE-TIMI 70 study was sponsored by Pfizer. Dr. Marston disclosed relationships with Pfizer, Amgen, Ionis, Novartis, and AstraZeneca. Dr. Nordestgaard disclosed relationships with AstraZeneca, Sanofi, Regeneron, Akcea, Ionis, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Esperion, and Silence Therapeutics.

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

Those moles, skin tags, and liver spots should stay on your skin until you see a doctor, according to a new alert from the U.S. Food and Drug Administration. The alert warns against the use of over-the-counter products for removing moles, seborrheic keratoses (wart-like growths that are often brown), or skin tags, emphasizing that none are approved by the FDA for at-home use.

Dermatologists and the FDA say these products may lead to scarring and disfigurement.

Risks include “skin injuries, infection requiring antibiotics, scarring, and delayed skin cancer diagnosis and treatment,” according to the alert, which adds that the agency has received reports of people “who developed permanent skin injuries and infections after using products marketed as mole or skin tag removers. “

These products come in the form of gels, liquids, sticks, or ointments and commonly contain ingredients like salicylic acid, which are cytotoxic, or cell-killing. These chemicals are what make the products potentially dangerous, as each contains unregulated, and likely very high, amounts of these corrosive agents. Even products marketed as natural or organic have these same issues, said Adam Friedman, MD, professor and chief of dermatology at George Washington University, Washington, who notes that bloodroot is another ingredient found in these products.

Dr. Friedman explained that using these products without the supervision of a health care provider can create a chemical burn in the skin, leading to scarring. He’s treated patients for open wounds and infected ulcers caused by these products. “Over my career, I’ve seen many cases of patients coming in with self-inflicted harm due to using these quote, unquote, safe and natural products to remove benign, or even worse, potentially malignant neoplasms,” he told this news organization.

Another concern is that these spots on the skin are often the only sign of a serious issue – cancer. Early signs of melanoma, a type of skin cancer, include large, misshapen, or rapidly changing moles. Dr. Friedman said that if a patient uses one of these products on what is actually a cancerous mole, they will likely only remove the surface, and in turn, destroy the only sign of cancer – effectively killing the canary in the coal mine.

There’s a good chance that the root of the mole has been left intact under the skin surface, and as a result, the cancer has the potential to spread unnoticed. “If people aren’t going to a dermatologist to be properly diagnosed and properly managed, they’re going to cause more harm by thinking that they’ve taken care of a problem,” he said.

If you are concerned about any type of spot on your skin, a visit to the dermatologist will prove much simpler and safer for treating it than doing so at home. In the office, Dr. Friedman said, providers can use a range of highly studied techniques to remove skin lesions with minimal pain and scarring. From freezing, burning, snipping, or a quick moment under a scalpel, you’ll be healed in no time.

Anyone who has experienced an adverse event with one of these products and health care professionals should report cases to the FDA’s MedWatch Adverse Event Reporting Program.

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

Those moles, skin tags, and liver spots should stay on your skin until you see a doctor, according to a new alert from the U.S. Food and Drug Administration. The alert warns against the use of over-the-counter products for removing moles, seborrheic keratoses (wart-like growths that are often brown), or skin tags, emphasizing that none are approved by the FDA for at-home use.

Dermatologists and the FDA say these products may lead to scarring and disfigurement.

Risks include “skin injuries, infection requiring antibiotics, scarring, and delayed skin cancer diagnosis and treatment,” according to the alert, which adds that the agency has received reports of people “who developed permanent skin injuries and infections after using products marketed as mole or skin tag removers. “

These products come in the form of gels, liquids, sticks, or ointments and commonly contain ingredients like salicylic acid, which are cytotoxic, or cell-killing. These chemicals are what make the products potentially dangerous, as each contains unregulated, and likely very high, amounts of these corrosive agents. Even products marketed as natural or organic have these same issues, said Adam Friedman, MD, professor and chief of dermatology at George Washington University, Washington, who notes that bloodroot is another ingredient found in these products.

Dr. Friedman explained that using these products without the supervision of a health care provider can create a chemical burn in the skin, leading to scarring. He’s treated patients for open wounds and infected ulcers caused by these products. “Over my career, I’ve seen many cases of patients coming in with self-inflicted harm due to using these quote, unquote, safe and natural products to remove benign, or even worse, potentially malignant neoplasms,” he told this news organization.

Another concern is that these spots on the skin are often the only sign of a serious issue – cancer. Early signs of melanoma, a type of skin cancer, include large, misshapen, or rapidly changing moles. Dr. Friedman said that if a patient uses one of these products on what is actually a cancerous mole, they will likely only remove the surface, and in turn, destroy the only sign of cancer – effectively killing the canary in the coal mine.

There’s a good chance that the root of the mole has been left intact under the skin surface, and as a result, the cancer has the potential to spread unnoticed. “If people aren’t going to a dermatologist to be properly diagnosed and properly managed, they’re going to cause more harm by thinking that they’ve taken care of a problem,” he said.

If you are concerned about any type of spot on your skin, a visit to the dermatologist will prove much simpler and safer for treating it than doing so at home. In the office, Dr. Friedman said, providers can use a range of highly studied techniques to remove skin lesions with minimal pain and scarring. From freezing, burning, snipping, or a quick moment under a scalpel, you’ll be healed in no time.

Anyone who has experienced an adverse event with one of these products and health care professionals should report cases to the FDA’s MedWatch Adverse Event Reporting Program.

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

Those moles, skin tags, and liver spots should stay on your skin until you see a doctor, according to a new alert from the U.S. Food and Drug Administration. The alert warns against the use of over-the-counter products for removing moles, seborrheic keratoses (wart-like growths that are often brown), or skin tags, emphasizing that none are approved by the FDA for at-home use.

Dermatologists and the FDA say these products may lead to scarring and disfigurement.

Risks include “skin injuries, infection requiring antibiotics, scarring, and delayed skin cancer diagnosis and treatment,” according to the alert, which adds that the agency has received reports of people “who developed permanent skin injuries and infections after using products marketed as mole or skin tag removers. “

These products come in the form of gels, liquids, sticks, or ointments and commonly contain ingredients like salicylic acid, which are cytotoxic, or cell-killing. These chemicals are what make the products potentially dangerous, as each contains unregulated, and likely very high, amounts of these corrosive agents. Even products marketed as natural or organic have these same issues, said Adam Friedman, MD, professor and chief of dermatology at George Washington University, Washington, who notes that bloodroot is another ingredient found in these products.

Dr. Friedman explained that using these products without the supervision of a health care provider can create a chemical burn in the skin, leading to scarring. He’s treated patients for open wounds and infected ulcers caused by these products. “Over my career, I’ve seen many cases of patients coming in with self-inflicted harm due to using these quote, unquote, safe and natural products to remove benign, or even worse, potentially malignant neoplasms,” he told this news organization.

Another concern is that these spots on the skin are often the only sign of a serious issue – cancer. Early signs of melanoma, a type of skin cancer, include large, misshapen, or rapidly changing moles. Dr. Friedman said that if a patient uses one of these products on what is actually a cancerous mole, they will likely only remove the surface, and in turn, destroy the only sign of cancer – effectively killing the canary in the coal mine.

There’s a good chance that the root of the mole has been left intact under the skin surface, and as a result, the cancer has the potential to spread unnoticed. “If people aren’t going to a dermatologist to be properly diagnosed and properly managed, they’re going to cause more harm by thinking that they’ve taken care of a problem,” he said.

If you are concerned about any type of spot on your skin, a visit to the dermatologist will prove much simpler and safer for treating it than doing so at home. In the office, Dr. Friedman said, providers can use a range of highly studied techniques to remove skin lesions with minimal pain and scarring. From freezing, burning, snipping, or a quick moment under a scalpel, you’ll be healed in no time.

Anyone who has experienced an adverse event with one of these products and health care professionals should report cases to the FDA’s MedWatch Adverse Event Reporting Program.

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