Telemedicine for patients with liver disease has made progress in recent years, but some key hurdles remain. Strategies that rely on patient ownership of mobile devices or reliable internet access will likely miss patients who have the greatest need for remote access.

This is one of the conclusions from a county-by-county study of access to liver specialty care and mortality, using data drawn from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiological Research (WONDER). The study was led by Jacqueline B. Henson, MD, of the Division of Gastroenterology, department of medicine, Duke University, Durham, N.C., and published in Hepatology.
 

Low-access areas

“Ultimately, no single telehealth strategy will be successful in all areas, and these will need to be tailored at the local and state level,” the authors wrote. “They will also depend on the persistence of policy changes enacted during the pandemic which made use and reimbursement for telehealth less restrictive.”

The researchers found that 69.5% of American counties had no gastrointestinal physicians. Moreover, 41.1% of counties were more than 100 miles away from a liver transplant (LT) center; 33.7% had no GI physicians and were more than 100 miles from a LT center. These categories represented populations of 48.8 million, 53.7 million, and 17.8 million. These counties had higher poverty rates, more unemployment, and lower educational attainment than did those that had GI physicians or were closer to LT centers. Distance from LT centers was associated with higher liver-related mortality (r = 0.24; P < .001) and density of GI providers (r = –0.12; P < .001).

Reduced access to specialty care for liver disease was also associated with decreased access to technology, including cell phones, smart phones, and internet service. Among counties in the highest death quartile and lowest access to care, 35.5% of households had no computer, 43.1% had no home internet, and only 19.2% of these had internet at broadband speeds.

“Use of platforms with lower internet speed requirements and that are compatible with mobile devices may help extend access, as could partnerships with local primary care and GI clinics,” they concluded. Further work should be done at the local and state levels to better understand the optimal strategies to reach their populations of need.
 

Missing ‘baseline ingredients’

Commenting on the study, Nancy Reau, MD, professor of medicine and chief of hepatology at Rush University Medical Center, Chicago, said that “anyone who takes care of vulnerable populations, whether elderly individuals or those who may be socioeconomically disadvantaged, realizes that we have to improve access to medical resources, and telehealth is certainly an attractive way of doing that.”

She added that a key message from the study is that attempts to improve access to disadvantaged populations, no matter how well-intentioned, are likely to provide the most benefit to those who have more resources than others. For example, not everyone has access to a smart phone or tablet: “Even if you have a tablet [or cell phone], you might have to go to the public library to get high speed internet, or you may not even have a public library. So, when something sounds like a great idea, such as expanding the academic footprint or access to integrative medicine through something like a virtual option, a lot of the individuals that you are targeting may not be able to engage,” said Dr. Reau.

For those working to expand access, it’s critical to get the perspective of underserved communities and remember that every patient is unique. Physicians may treat patients who are poor, or from disadvantaged areas, who nevertheless have successful telehealth visits. But that doesn’t mean everyone’s experience will be similar. “You can’t use those who have been successful in accessing telemedicine as an example for everyone else. Just because one person can do it doesn’t mean that everyone else can. Involving a practitioner or an advocate from the area that you’re trying to reach is imperative,” she explained.

The COVID-19 pandemic led to a big push for telehealth, and it may be tempting to believe that the transition to telehealth has been smooth. This study “demonstrates in a very granular way that a large number of Americans have no access to high-speed internet, or if they do, many don’t have access to the tools that would let them engage this way. You can’t make assumptions and use them to build a product,” continued Dr. Reau.

Innovative options are needed, such as working with primary care providers in rural or disadvantaged areas to setup pop-up hot spots where e-consultations could be performed. Working directly with broadband internet providers to set up access in specific locations for telehealth, or using products like Amazon Echo Show as a portal for telehealth, can also be tried. “Think about being innovative and recognize that these areas probably don’t have the baseline ingredients we thought they had,” suggested Dr. Reau.

The authors reported having no financial support. Dr. Reau has no relevant financial disclosures.

Telemedicine for patients with liver disease has made progress in recent years, but some key hurdles remain. Strategies that rely on patient ownership of mobile devices or reliable internet access will likely miss patients who have the greatest need for remote access.

This is one of the conclusions from a county-by-county study of access to liver specialty care and mortality, using data drawn from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiological Research (WONDER). The study was led by Jacqueline B. Henson, MD, of the Division of Gastroenterology, department of medicine, Duke University, Durham, N.C., and published in Hepatology.
 

Low-access areas

“Ultimately, no single telehealth strategy will be successful in all areas, and these will need to be tailored at the local and state level,” the authors wrote. “They will also depend on the persistence of policy changes enacted during the pandemic which made use and reimbursement for telehealth less restrictive.”

The researchers found that 69.5% of American counties had no gastrointestinal physicians. Moreover, 41.1% of counties were more than 100 miles away from a liver transplant (LT) center; 33.7% had no GI physicians and were more than 100 miles from a LT center. These categories represented populations of 48.8 million, 53.7 million, and 17.8 million. These counties had higher poverty rates, more unemployment, and lower educational attainment than did those that had GI physicians or were closer to LT centers. Distance from LT centers was associated with higher liver-related mortality (r = 0.24; P < .001) and density of GI providers (r = –0.12; P < .001).

Reduced access to specialty care for liver disease was also associated with decreased access to technology, including cell phones, smart phones, and internet service. Among counties in the highest death quartile and lowest access to care, 35.5% of households had no computer, 43.1% had no home internet, and only 19.2% of these had internet at broadband speeds.

“Use of platforms with lower internet speed requirements and that are compatible with mobile devices may help extend access, as could partnerships with local primary care and GI clinics,” they concluded. Further work should be done at the local and state levels to better understand the optimal strategies to reach their populations of need.
 

Missing ‘baseline ingredients’

Commenting on the study, Nancy Reau, MD, professor of medicine and chief of hepatology at Rush University Medical Center, Chicago, said that “anyone who takes care of vulnerable populations, whether elderly individuals or those who may be socioeconomically disadvantaged, realizes that we have to improve access to medical resources, and telehealth is certainly an attractive way of doing that.”

She added that a key message from the study is that attempts to improve access to disadvantaged populations, no matter how well-intentioned, are likely to provide the most benefit to those who have more resources than others. For example, not everyone has access to a smart phone or tablet: “Even if you have a tablet [or cell phone], you might have to go to the public library to get high speed internet, or you may not even have a public library. So, when something sounds like a great idea, such as expanding the academic footprint or access to integrative medicine through something like a virtual option, a lot of the individuals that you are targeting may not be able to engage,” said Dr. Reau.

For those working to expand access, it’s critical to get the perspective of underserved communities and remember that every patient is unique. Physicians may treat patients who are poor, or from disadvantaged areas, who nevertheless have successful telehealth visits. But that doesn’t mean everyone’s experience will be similar. “You can’t use those who have been successful in accessing telemedicine as an example for everyone else. Just because one person can do it doesn’t mean that everyone else can. Involving a practitioner or an advocate from the area that you’re trying to reach is imperative,” she explained.

The COVID-19 pandemic led to a big push for telehealth, and it may be tempting to believe that the transition to telehealth has been smooth. This study “demonstrates in a very granular way that a large number of Americans have no access to high-speed internet, or if they do, many don’t have access to the tools that would let them engage this way. You can’t make assumptions and use them to build a product,” continued Dr. Reau.

Innovative options are needed, such as working with primary care providers in rural or disadvantaged areas to setup pop-up hot spots where e-consultations could be performed. Working directly with broadband internet providers to set up access in specific locations for telehealth, or using products like Amazon Echo Show as a portal for telehealth, can also be tried. “Think about being innovative and recognize that these areas probably don’t have the baseline ingredients we thought they had,” suggested Dr. Reau.

The authors reported having no financial support. Dr. Reau has no relevant financial disclosures.

Telemedicine for patients with liver disease has made progress in recent years, but some key hurdles remain. Strategies that rely on patient ownership of mobile devices or reliable internet access will likely miss patients who have the greatest need for remote access.

This is one of the conclusions from a county-by-county study of access to liver specialty care and mortality, using data drawn from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiological Research (WONDER). The study was led by Jacqueline B. Henson, MD, of the Division of Gastroenterology, department of medicine, Duke University, Durham, N.C., and published in Hepatology.
 

Low-access areas

“Ultimately, no single telehealth strategy will be successful in all areas, and these will need to be tailored at the local and state level,” the authors wrote. “They will also depend on the persistence of policy changes enacted during the pandemic which made use and reimbursement for telehealth less restrictive.”

The researchers found that 69.5% of American counties had no gastrointestinal physicians. Moreover, 41.1% of counties were more than 100 miles away from a liver transplant (LT) center; 33.7% had no GI physicians and were more than 100 miles from a LT center. These categories represented populations of 48.8 million, 53.7 million, and 17.8 million. These counties had higher poverty rates, more unemployment, and lower educational attainment than did those that had GI physicians or were closer to LT centers. Distance from LT centers was associated with higher liver-related mortality (r = 0.24; P < .001) and density of GI providers (r = –0.12; P < .001).

Reduced access to specialty care for liver disease was also associated with decreased access to technology, including cell phones, smart phones, and internet service. Among counties in the highest death quartile and lowest access to care, 35.5% of households had no computer, 43.1% had no home internet, and only 19.2% of these had internet at broadband speeds.

“Use of platforms with lower internet speed requirements and that are compatible with mobile devices may help extend access, as could partnerships with local primary care and GI clinics,” they concluded. Further work should be done at the local and state levels to better understand the optimal strategies to reach their populations of need.
 

Missing ‘baseline ingredients’

Commenting on the study, Nancy Reau, MD, professor of medicine and chief of hepatology at Rush University Medical Center, Chicago, said that “anyone who takes care of vulnerable populations, whether elderly individuals or those who may be socioeconomically disadvantaged, realizes that we have to improve access to medical resources, and telehealth is certainly an attractive way of doing that.”

She added that a key message from the study is that attempts to improve access to disadvantaged populations, no matter how well-intentioned, are likely to provide the most benefit to those who have more resources than others. For example, not everyone has access to a smart phone or tablet: “Even if you have a tablet [or cell phone], you might have to go to the public library to get high speed internet, or you may not even have a public library. So, when something sounds like a great idea, such as expanding the academic footprint or access to integrative medicine through something like a virtual option, a lot of the individuals that you are targeting may not be able to engage,” said Dr. Reau.

For those working to expand access, it’s critical to get the perspective of underserved communities and remember that every patient is unique. Physicians may treat patients who are poor, or from disadvantaged areas, who nevertheless have successful telehealth visits. But that doesn’t mean everyone’s experience will be similar. “You can’t use those who have been successful in accessing telemedicine as an example for everyone else. Just because one person can do it doesn’t mean that everyone else can. Involving a practitioner or an advocate from the area that you’re trying to reach is imperative,” she explained.

The COVID-19 pandemic led to a big push for telehealth, and it may be tempting to believe that the transition to telehealth has been smooth. This study “demonstrates in a very granular way that a large number of Americans have no access to high-speed internet, or if they do, many don’t have access to the tools that would let them engage this way. You can’t make assumptions and use them to build a product,” continued Dr. Reau.

Innovative options are needed, such as working with primary care providers in rural or disadvantaged areas to setup pop-up hot spots where e-consultations could be performed. Working directly with broadband internet providers to set up access in specific locations for telehealth, or using products like Amazon Echo Show as a portal for telehealth, can also be tried. “Think about being innovative and recognize that these areas probably don’t have the baseline ingredients we thought they had,” suggested Dr. Reau.

The authors reported having no financial support. Dr. Reau has no relevant financial disclosures.

Key clinical point: A higher proportion of patients with psoriatic arthritis (PsA) receiving 15 mg upadacitinib achieved low disease activity (LDA) or remission after the first 6 months of treatment, with the difference being visible even after 1 year of treatment, compared to those who received a placebo.

Major finding: At week 24, a higher proportion of patients receiving 15 mg upadacitinib vs. placebo achieved Disease Activity in PsA LDA (range 35%-48% vs. 4%-16%; P < .05) and remission (range 7%-11% vs. 0%-3%; P < .05), with the responses sustained until 56 weeks.

Study details: This was a post hoc analysis of the SELECT-PsA 1 and SELECT-PsA 2 trials including 1386 adults with PsA and prior inadequate response/intolerance to ≥1 non-biologic or biologic disease-modifying antirheumatic drugs who were randomly assigned to receive upadacitinib (15 or 30 mg), adalimumab, or placebo.

Disclosures: This study was funded by AbbVie, Inc. Four authors declared being current or former employees or stockholders of AbbVie, and other authors reported ties with various sources.

Source: Mease P et al. Disease control with upadacitinib in patients with psoriatic arthritis: A post hoc analysis of the randomized, placebo-controlled SELECT-PsA 1 and 2 phase 3 trials. Rheumatol Ther. 2022 (May 23). Doi: 10.1007/s40744-022-00449-6

Key clinical point: A higher proportion of patients with psoriatic arthritis (PsA) receiving 15 mg upadacitinib achieved low disease activity (LDA) or remission after the first 6 months of treatment, with the difference being visible even after 1 year of treatment, compared to those who received a placebo.

Major finding: At week 24, a higher proportion of patients receiving 15 mg upadacitinib vs. placebo achieved Disease Activity in PsA LDA (range 35%-48% vs. 4%-16%; P < .05) and remission (range 7%-11% vs. 0%-3%; P < .05), with the responses sustained until 56 weeks.

Study details: This was a post hoc analysis of the SELECT-PsA 1 and SELECT-PsA 2 trials including 1386 adults with PsA and prior inadequate response/intolerance to ≥1 non-biologic or biologic disease-modifying antirheumatic drugs who were randomly assigned to receive upadacitinib (15 or 30 mg), adalimumab, or placebo.

Disclosures: This study was funded by AbbVie, Inc. Four authors declared being current or former employees or stockholders of AbbVie, and other authors reported ties with various sources.

Source: Mease P et al. Disease control with upadacitinib in patients with psoriatic arthritis: A post hoc analysis of the randomized, placebo-controlled SELECT-PsA 1 and 2 phase 3 trials. Rheumatol Ther. 2022 (May 23). Doi: 10.1007/s40744-022-00449-6

Key clinical point: A higher proportion of patients with psoriatic arthritis (PsA) receiving 15 mg upadacitinib achieved low disease activity (LDA) or remission after the first 6 months of treatment, with the difference being visible even after 1 year of treatment, compared to those who received a placebo.

Major finding: At week 24, a higher proportion of patients receiving 15 mg upadacitinib vs. placebo achieved Disease Activity in PsA LDA (range 35%-48% vs. 4%-16%; P < .05) and remission (range 7%-11% vs. 0%-3%; P < .05), with the responses sustained until 56 weeks.

Study details: This was a post hoc analysis of the SELECT-PsA 1 and SELECT-PsA 2 trials including 1386 adults with PsA and prior inadequate response/intolerance to ≥1 non-biologic or biologic disease-modifying antirheumatic drugs who were randomly assigned to receive upadacitinib (15 or 30 mg), adalimumab, or placebo.

Disclosures: This study was funded by AbbVie, Inc. Four authors declared being current or former employees or stockholders of AbbVie, and other authors reported ties with various sources.

Source: Mease P et al. Disease control with upadacitinib in patients with psoriatic arthritis: A post hoc analysis of the randomized, placebo-controlled SELECT-PsA 1 and 2 phase 3 trials. Rheumatol Ther. 2022 (May 23). Doi: 10.1007/s40744-022-00449-6

Key clinical point: A substantial proportion of patients with psoriatic arthritis (PsA) achieved resolution of enthesitis within a year of initiating nonsteroidal anti-inflammatory drugs (NSAID) or disease-modifying antirheumatic drugs (DMARD), although the odds were lower in patients with high joint disease activity at baseline.

Major finding: Complete resolution of enthesitis was achieved by 86.12% of patients within a mean period of 8.73 months from therapy initiation, with higher joint activity at baseline being associated with a lower chance of enthesitis resolution (odds ratio 0.97; P = .01).

Study details: Findings are from a retrospective analysis of prospectively collected data of 526 patients with PsA and enthesitis who received no treatment/only NSAID (n = 142), conventional DMARD ± NSAID but without targeted DMARD (n = 196), or targeted DMARD with or without other medications (n = 188).

Disclosures: Dr. Mathew and Dr. Chandran received funding from the National Psoriasis Foundation and University of Toronto, respectively. The authors declared no conflicts of interest.

Source: Mathew AJ et al. Effectiveness of disease modifying anti-rheumatic drugs for enthesitis in a prospective longitudinal psoriatic arthritis cohort. J Rheumatol. 2022 (Jun 1). Doi: 10.3899/jrheum.211231

Key clinical point: A substantial proportion of patients with psoriatic arthritis (PsA) achieved resolution of enthesitis within a year of initiating nonsteroidal anti-inflammatory drugs (NSAID) or disease-modifying antirheumatic drugs (DMARD), although the odds were lower in patients with high joint disease activity at baseline.

Major finding: Complete resolution of enthesitis was achieved by 86.12% of patients within a mean period of 8.73 months from therapy initiation, with higher joint activity at baseline being associated with a lower chance of enthesitis resolution (odds ratio 0.97; P = .01).

Study details: Findings are from a retrospective analysis of prospectively collected data of 526 patients with PsA and enthesitis who received no treatment/only NSAID (n = 142), conventional DMARD ± NSAID but without targeted DMARD (n = 196), or targeted DMARD with or without other medications (n = 188).

Disclosures: Dr. Mathew and Dr. Chandran received funding from the National Psoriasis Foundation and University of Toronto, respectively. The authors declared no conflicts of interest.

Source: Mathew AJ et al. Effectiveness of disease modifying anti-rheumatic drugs for enthesitis in a prospective longitudinal psoriatic arthritis cohort. J Rheumatol. 2022 (Jun 1). Doi: 10.3899/jrheum.211231

Key clinical point: A substantial proportion of patients with psoriatic arthritis (PsA) achieved resolution of enthesitis within a year of initiating nonsteroidal anti-inflammatory drugs (NSAID) or disease-modifying antirheumatic drugs (DMARD), although the odds were lower in patients with high joint disease activity at baseline.

Major finding: Complete resolution of enthesitis was achieved by 86.12% of patients within a mean period of 8.73 months from therapy initiation, with higher joint activity at baseline being associated with a lower chance of enthesitis resolution (odds ratio 0.97; P = .01).

Study details: Findings are from a retrospective analysis of prospectively collected data of 526 patients with PsA and enthesitis who received no treatment/only NSAID (n = 142), conventional DMARD ± NSAID but without targeted DMARD (n = 196), or targeted DMARD with or without other medications (n = 188).

Disclosures: Dr. Mathew and Dr. Chandran received funding from the National Psoriasis Foundation and University of Toronto, respectively. The authors declared no conflicts of interest.

Source: Mathew AJ et al. Effectiveness of disease modifying anti-rheumatic drugs for enthesitis in a prospective longitudinal psoriatic arthritis cohort. J Rheumatol. 2022 (Jun 1). Doi: 10.3899/jrheum.211231

Similar to a phenomenon already well documented in women, inadequate nutrition appears to be linked to hormonal abnormalities and potentially preventable tibial cortical bone density loss in athletic men, according to results of a small, prospective study.

Based on these findings, “we suspect that a subset of male runners might not be fueling their bodies with enough nutrition and calories for their physical activity,” reported Melanie S. Haines, MD, at the annual meeting of the Endocrine Society.

This is not the first study to suggest male athletes are at risk of a condition equivalent to what has been commonly referred to as the female athlete triad, but it enlarges the objective data that the phenomenon is real, and it makes insufficient availability of energy the likely cause.

In women, the triad is described as a lack of adequate stored energy, irregular menses, and bone density loss. In men, menstrual cycles are not relevant, of course, but this study like others suggests a link between the failure to maintain adequate stores of energy, disturbances in hormone function, and decreased bone density in both men and women, Dr. Haines explained.
 

RED-S vs. male or female athlete triad

“There is now a move away from the term female athlete triad or male athlete triad,” Dr. Haines reported. Rather the factors of failing to maintain adequate energy for metabolic demands, hormonal disturbances, and bone density loss appear to be relevant to both sexes, according to Dr. Haines, an endocrinologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, both in Boston. She said several groups, including the International Olympic Committee (IOC), have transitioned to the term RED-S to apply to both sexes.

“RED-S is an acronym for relative energy deficiency in sport, and it appears to be gaining traction,” Dr. Haines said in an interview.

According to her study and others, excessive lean body mass from failure to supply sufficient energy for physiological needs “negatively affects hormones and bone,” Dr. Haines explained. In men and women, endocrine disturbances are triggered when insufficient calories lead to inadequate macro- and micronutrients.

In this study, 31 men aged 16-30 years were evaluated. Fifteen were in the athlete group, defined by running at least 30 miles per week for at least the previous 6 months. There were 16 control subjects; all exercised less than 2 hours per week and did not participate in team sports, but they were not permitted in the study if their body mass index exceeded 27.5 kg/m².
 

Athletes vs. otherwise healthy controls

Conditions that affect bone health were exclusion criteria in both groups, and neither group was permitted to take medications affecting bone health other than dietary calcium or vitamin D supplements for 2 months prior to the study.

Tibial cortical porosity was significantly greater – signaling deterioration in microarchitecture – in athletes, compared with control subjects (P = .003), according to quantitative computed tomography measurements. There was also significantly lower tibial cortical bone mineral density (P = .008) among athletes relative to controls.

Conversely, tibial trabecular measures of bone density and architecture were better among athletes than controls, but this was expected and did not contradict the hypothesis of the study.

“Trabecular bone refers to the inner part of the bone, which increases with weight-bearing exercise, but cortical bone is the outer shell, and the source of stress fractures,” Dr. Haines explained.

The median age of both the athletes and the controls was 24 years. Baseline measurements were similar. Body mass index, fat mass, estradiol, and leptin were all numerically lower in the athletes than controls, but none were significant, although there was a trend for the difference in leptin (P = .085).
 

Hormones correlated with tibial failure load

When these characteristics were evaluated in the context of mean tibial failure load, a metric related to strength, there was a strongly significant positive association with lean body mass (R = 0.85; P < 0.001) and estradiol level (R = 0.66; P = .007). The relationship with leptin also reached significance (R = 0.59; P = .046).

Unexpectedly, there was no relationship between testosterone and tibial failure load. The reason is unclear, but Dr. Haines’s interpretation is that the relationship between specific hormonal disturbances and bone density loss “might not be as simple” as once hypothesized.

The next step is a longitudinal evaluation of the same group of athletes to follow changes in the relationship between these variables over time, according to Dr. Haines.

Eventually, with evidence that there is a causal relationship between nutrition, hormonal changes, and bone loss, the research in this area will focus on better detection of risk and prophylactic strategies.

“Intervention trials to show that we can prevent stress factors will be difficult to perform,” Dr. Haines acknowledged, but she said that preventing adverse changes in bone at relatively young ages could have implications for long-term bone health, including protection from osteoporosis later in life.

The research presented by Dr. Haines is consistent with an area of research that is several decades old, at least in females, according to Siobhan M. Statuta, MD, a sports medicine primary care specialist at the University of Virginia, Charlottesville. The evidence that the same phenomenon occurs in men is more recent, but she said that it is now well accepted the there is a parallel hormonal issue in men and women.

“It is not a question of not eating enough. Often, athletes continue to consume the same diet, but their activity increases,” Dr. Statuta explained. “The problem is that they are not supplying enough of the calories they need to sustain the energy they are expending. You might say they are not fueling their engines appropriately.”

In 2014, the International Olympic Committee published a consensus statement on RED-S. They described this as a condition in which a state of energy deficiency leads to numerous complications in athletes, not just osteoporosis. Rather, a host of physiological systems, ranging from gastrointestinal complaints to cardiovascular events, were described.
 

RED-S addresses health beyond bones

“The RED-S theory is better described as a spoke-and-wheel concept rather than a triad. While inadequate energy availability is important to both, RED-S places this at the center of the wheel with spokes leading to all the possible complications rather than as a first event in a limited triad,” Dr. Statuta said in an interview.

However, she noted that the term RED-S is not yet appropriate to replace that of the male and female athlete triad.

“More research is required to hash out the relationship of a body in a state of energy deficiency and how it affects the entire body, which is the principle of RED-S,” Dr. Statuta said. “There likely are scientific effects, and we are currently investigating these relationships more.”

“These are really quite similar entities but have different foci,” she added. Based on data collected over several decades, “the triad narrows in on two body systems affected by low energy – the reproductive system and bones. RED-S incorporates these same systems yet adds on many more organ systems.

The original group of researchers have remained loyal to the concept of the triad that involves inadequate availability of energy followed by hormonal irregularities and osteoporosis. This group, the Female and Male Athlete Triad Coalition, has issued publications on this topic several times. Consensus statements were updated last year.

“The premise is that the triad leading to bone loss is shared by both men and women, even if the clinical manifestations differ,” said Dr. Statuta. The most notable difference is that men do not experience menstrual irregularities, but Dr. Statuta suggested that the clinical consequences are not necessarily any less.

“Males do not have menstrual cycles as an outward marker of an endocrine disturbance, so it is harder to recognize clinically, but I think there is agreement that not having enough energy available is the trigger of endocrine changes and then bone loss is relevant to both sexes,” she said. She said this is supported by a growing body of evidence, including the data presented by Dr. Haines at the Endocrine Society meeting.

Dr. Haines and Dr. Statuta report no potential conflicts of interest.

Similar to a phenomenon already well documented in women, inadequate nutrition appears to be linked to hormonal abnormalities and potentially preventable tibial cortical bone density loss in athletic men, according to results of a small, prospective study.

Based on these findings, “we suspect that a subset of male runners might not be fueling their bodies with enough nutrition and calories for their physical activity,” reported Melanie S. Haines, MD, at the annual meeting of the Endocrine Society.

This is not the first study to suggest male athletes are at risk of a condition equivalent to what has been commonly referred to as the female athlete triad, but it enlarges the objective data that the phenomenon is real, and it makes insufficient availability of energy the likely cause.

In women, the triad is described as a lack of adequate stored energy, irregular menses, and bone density loss. In men, menstrual cycles are not relevant, of course, but this study like others suggests a link between the failure to maintain adequate stores of energy, disturbances in hormone function, and decreased bone density in both men and women, Dr. Haines explained.
 

RED-S vs. male or female athlete triad

“There is now a move away from the term female athlete triad or male athlete triad,” Dr. Haines reported. Rather the factors of failing to maintain adequate energy for metabolic demands, hormonal disturbances, and bone density loss appear to be relevant to both sexes, according to Dr. Haines, an endocrinologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, both in Boston. She said several groups, including the International Olympic Committee (IOC), have transitioned to the term RED-S to apply to both sexes.

“RED-S is an acronym for relative energy deficiency in sport, and it appears to be gaining traction,” Dr. Haines said in an interview.

According to her study and others, excessive lean body mass from failure to supply sufficient energy for physiological needs “negatively affects hormones and bone,” Dr. Haines explained. In men and women, endocrine disturbances are triggered when insufficient calories lead to inadequate macro- and micronutrients.

In this study, 31 men aged 16-30 years were evaluated. Fifteen were in the athlete group, defined by running at least 30 miles per week for at least the previous 6 months. There were 16 control subjects; all exercised less than 2 hours per week and did not participate in team sports, but they were not permitted in the study if their body mass index exceeded 27.5 kg/m².
 

Athletes vs. otherwise healthy controls

Conditions that affect bone health were exclusion criteria in both groups, and neither group was permitted to take medications affecting bone health other than dietary calcium or vitamin D supplements for 2 months prior to the study.

Tibial cortical porosity was significantly greater – signaling deterioration in microarchitecture – in athletes, compared with control subjects (P = .003), according to quantitative computed tomography measurements. There was also significantly lower tibial cortical bone mineral density (P = .008) among athletes relative to controls.

Conversely, tibial trabecular measures of bone density and architecture were better among athletes than controls, but this was expected and did not contradict the hypothesis of the study.

“Trabecular bone refers to the inner part of the bone, which increases with weight-bearing exercise, but cortical bone is the outer shell, and the source of stress fractures,” Dr. Haines explained.

The median age of both the athletes and the controls was 24 years. Baseline measurements were similar. Body mass index, fat mass, estradiol, and leptin were all numerically lower in the athletes than controls, but none were significant, although there was a trend for the difference in leptin (P = .085).
 

Hormones correlated with tibial failure load

When these characteristics were evaluated in the context of mean tibial failure load, a metric related to strength, there was a strongly significant positive association with lean body mass (R = 0.85; P < 0.001) and estradiol level (R = 0.66; P = .007). The relationship with leptin also reached significance (R = 0.59; P = .046).

Unexpectedly, there was no relationship between testosterone and tibial failure load. The reason is unclear, but Dr. Haines’s interpretation is that the relationship between specific hormonal disturbances and bone density loss “might not be as simple” as once hypothesized.

The next step is a longitudinal evaluation of the same group of athletes to follow changes in the relationship between these variables over time, according to Dr. Haines.

Eventually, with evidence that there is a causal relationship between nutrition, hormonal changes, and bone loss, the research in this area will focus on better detection of risk and prophylactic strategies.

“Intervention trials to show that we can prevent stress factors will be difficult to perform,” Dr. Haines acknowledged, but she said that preventing adverse changes in bone at relatively young ages could have implications for long-term bone health, including protection from osteoporosis later in life.

The research presented by Dr. Haines is consistent with an area of research that is several decades old, at least in females, according to Siobhan M. Statuta, MD, a sports medicine primary care specialist at the University of Virginia, Charlottesville. The evidence that the same phenomenon occurs in men is more recent, but she said that it is now well accepted the there is a parallel hormonal issue in men and women.

“It is not a question of not eating enough. Often, athletes continue to consume the same diet, but their activity increases,” Dr. Statuta explained. “The problem is that they are not supplying enough of the calories they need to sustain the energy they are expending. You might say they are not fueling their engines appropriately.”

In 2014, the International Olympic Committee published a consensus statement on RED-S. They described this as a condition in which a state of energy deficiency leads to numerous complications in athletes, not just osteoporosis. Rather, a host of physiological systems, ranging from gastrointestinal complaints to cardiovascular events, were described.
 

RED-S addresses health beyond bones

“The RED-S theory is better described as a spoke-and-wheel concept rather than a triad. While inadequate energy availability is important to both, RED-S places this at the center of the wheel with spokes leading to all the possible complications rather than as a first event in a limited triad,” Dr. Statuta said in an interview.

However, she noted that the term RED-S is not yet appropriate to replace that of the male and female athlete triad.

“More research is required to hash out the relationship of a body in a state of energy deficiency and how it affects the entire body, which is the principle of RED-S,” Dr. Statuta said. “There likely are scientific effects, and we are currently investigating these relationships more.”

“These are really quite similar entities but have different foci,” she added. Based on data collected over several decades, “the triad narrows in on two body systems affected by low energy – the reproductive system and bones. RED-S incorporates these same systems yet adds on many more organ systems.

The original group of researchers have remained loyal to the concept of the triad that involves inadequate availability of energy followed by hormonal irregularities and osteoporosis. This group, the Female and Male Athlete Triad Coalition, has issued publications on this topic several times. Consensus statements were updated last year.

“The premise is that the triad leading to bone loss is shared by both men and women, even if the clinical manifestations differ,” said Dr. Statuta. The most notable difference is that men do not experience menstrual irregularities, but Dr. Statuta suggested that the clinical consequences are not necessarily any less.

“Males do not have menstrual cycles as an outward marker of an endocrine disturbance, so it is harder to recognize clinically, but I think there is agreement that not having enough energy available is the trigger of endocrine changes and then bone loss is relevant to both sexes,” she said. She said this is supported by a growing body of evidence, including the data presented by Dr. Haines at the Endocrine Society meeting.

Dr. Haines and Dr. Statuta report no potential conflicts of interest.

Similar to a phenomenon already well documented in women, inadequate nutrition appears to be linked to hormonal abnormalities and potentially preventable tibial cortical bone density loss in athletic men, according to results of a small, prospective study.

Based on these findings, “we suspect that a subset of male runners might not be fueling their bodies with enough nutrition and calories for their physical activity,” reported Melanie S. Haines, MD, at the annual meeting of the Endocrine Society.

This is not the first study to suggest male athletes are at risk of a condition equivalent to what has been commonly referred to as the female athlete triad, but it enlarges the objective data that the phenomenon is real, and it makes insufficient availability of energy the likely cause.

In women, the triad is described as a lack of adequate stored energy, irregular menses, and bone density loss. In men, menstrual cycles are not relevant, of course, but this study like others suggests a link between the failure to maintain adequate stores of energy, disturbances in hormone function, and decreased bone density in both men and women, Dr. Haines explained.
 

RED-S vs. male or female athlete triad

“There is now a move away from the term female athlete triad or male athlete triad,” Dr. Haines reported. Rather the factors of failing to maintain adequate energy for metabolic demands, hormonal disturbances, and bone density loss appear to be relevant to both sexes, according to Dr. Haines, an endocrinologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, both in Boston. She said several groups, including the International Olympic Committee (IOC), have transitioned to the term RED-S to apply to both sexes.

“RED-S is an acronym for relative energy deficiency in sport, and it appears to be gaining traction,” Dr. Haines said in an interview.

According to her study and others, excessive lean body mass from failure to supply sufficient energy for physiological needs “negatively affects hormones and bone,” Dr. Haines explained. In men and women, endocrine disturbances are triggered when insufficient calories lead to inadequate macro- and micronutrients.

In this study, 31 men aged 16-30 years were evaluated. Fifteen were in the athlete group, defined by running at least 30 miles per week for at least the previous 6 months. There were 16 control subjects; all exercised less than 2 hours per week and did not participate in team sports, but they were not permitted in the study if their body mass index exceeded 27.5 kg/m².
 

Athletes vs. otherwise healthy controls

Conditions that affect bone health were exclusion criteria in both groups, and neither group was permitted to take medications affecting bone health other than dietary calcium or vitamin D supplements for 2 months prior to the study.

Tibial cortical porosity was significantly greater – signaling deterioration in microarchitecture – in athletes, compared with control subjects (P = .003), according to quantitative computed tomography measurements. There was also significantly lower tibial cortical bone mineral density (P = .008) among athletes relative to controls.

Conversely, tibial trabecular measures of bone density and architecture were better among athletes than controls, but this was expected and did not contradict the hypothesis of the study.

“Trabecular bone refers to the inner part of the bone, which increases with weight-bearing exercise, but cortical bone is the outer shell, and the source of stress fractures,” Dr. Haines explained.

The median age of both the athletes and the controls was 24 years. Baseline measurements were similar. Body mass index, fat mass, estradiol, and leptin were all numerically lower in the athletes than controls, but none were significant, although there was a trend for the difference in leptin (P = .085).
 

Hormones correlated with tibial failure load

When these characteristics were evaluated in the context of mean tibial failure load, a metric related to strength, there was a strongly significant positive association with lean body mass (R = 0.85; P < 0.001) and estradiol level (R = 0.66; P = .007). The relationship with leptin also reached significance (R = 0.59; P = .046).

Unexpectedly, there was no relationship between testosterone and tibial failure load. The reason is unclear, but Dr. Haines’s interpretation is that the relationship between specific hormonal disturbances and bone density loss “might not be as simple” as once hypothesized.

The next step is a longitudinal evaluation of the same group of athletes to follow changes in the relationship between these variables over time, according to Dr. Haines.

Eventually, with evidence that there is a causal relationship between nutrition, hormonal changes, and bone loss, the research in this area will focus on better detection of risk and prophylactic strategies.

“Intervention trials to show that we can prevent stress factors will be difficult to perform,” Dr. Haines acknowledged, but she said that preventing adverse changes in bone at relatively young ages could have implications for long-term bone health, including protection from osteoporosis later in life.

The research presented by Dr. Haines is consistent with an area of research that is several decades old, at least in females, according to Siobhan M. Statuta, MD, a sports medicine primary care specialist at the University of Virginia, Charlottesville. The evidence that the same phenomenon occurs in men is more recent, but she said that it is now well accepted the there is a parallel hormonal issue in men and women.

“It is not a question of not eating enough. Often, athletes continue to consume the same diet, but their activity increases,” Dr. Statuta explained. “The problem is that they are not supplying enough of the calories they need to sustain the energy they are expending. You might say they are not fueling their engines appropriately.”

In 2014, the International Olympic Committee published a consensus statement on RED-S. They described this as a condition in which a state of energy deficiency leads to numerous complications in athletes, not just osteoporosis. Rather, a host of physiological systems, ranging from gastrointestinal complaints to cardiovascular events, were described.
 

RED-S addresses health beyond bones

“The RED-S theory is better described as a spoke-and-wheel concept rather than a triad. While inadequate energy availability is important to both, RED-S places this at the center of the wheel with spokes leading to all the possible complications rather than as a first event in a limited triad,” Dr. Statuta said in an interview.

However, she noted that the term RED-S is not yet appropriate to replace that of the male and female athlete triad.

“More research is required to hash out the relationship of a body in a state of energy deficiency and how it affects the entire body, which is the principle of RED-S,” Dr. Statuta said. “There likely are scientific effects, and we are currently investigating these relationships more.”

“These are really quite similar entities but have different foci,” she added. Based on data collected over several decades, “the triad narrows in on two body systems affected by low energy – the reproductive system and bones. RED-S incorporates these same systems yet adds on many more organ systems.

The original group of researchers have remained loyal to the concept of the triad that involves inadequate availability of energy followed by hormonal irregularities and osteoporosis. This group, the Female and Male Athlete Triad Coalition, has issued publications on this topic several times. Consensus statements were updated last year.

“The premise is that the triad leading to bone loss is shared by both men and women, even if the clinical manifestations differ,” said Dr. Statuta. The most notable difference is that men do not experience menstrual irregularities, but Dr. Statuta suggested that the clinical consequences are not necessarily any less.

“Males do not have menstrual cycles as an outward marker of an endocrine disturbance, so it is harder to recognize clinically, but I think there is agreement that not having enough energy available is the trigger of endocrine changes and then bone loss is relevant to both sexes,” she said. She said this is supported by a growing body of evidence, including the data presented by Dr. Haines at the Endocrine Society meeting.

Dr. Haines and Dr. Statuta report no potential conflicts of interest.

Whether hemophilia A patients should stick with effective nonfactor therapy or join a clinical trial for a potential cure with gene therapy cure – this question was debated at he annual meeting of the European Hematology Association.

Ultimately, results of a very informal polling of the online audience suggested a strong leaning toward the known benefits of nonfactor therapy, as opposed to as-yet unapproved gene therapy. Although Benjamin Samelson-Jones, MD, PhD, argued for gene therapy, he also saluted the progress made that had enabled such choices.

“Our patients and the field have greatly benefited from this broad spectrum of different therapies and how they’ve been implemented, and it’s a truly exciting time because there will continue to be advancements in both these therapeutic modalities in the next 5-10 years,” said Dr. Samelson-Jones, an assistant professor of pediatrics in the division of hematology at the Children’s Hospital of Philadelphia.
 

Game changers emerge

Hemophilia A, characterized by a hereditary deficiency in factor VIII disorder, has long involved prophylaxis treatment with procoagulant factor replacement therapy that requires intravenous injection as often as several times a week. This can cause problems with venous access that are particularly burdensome for child patients.

Nonfactor therapy, currently consisting of the approved emicizumab but with more agents in development, provides coagulation without replacement of factor VIII. Importantly, this treatment requires only subcutaneous injection which, after a loading dose period, may be needed weekly or even just once a month.

However, in 2018, at approximately the same time that emicizumab was approved, patients with hemophilia A became eligible to enroll in clinical trials for the far more revolutionary concept of gene therapy, with the chance to become infusion free after just a single infusion.

There are caveats aplenty. Four of the therapies now in phase 3 development are adeno-associated viral vectors that are liver directed, meaning that patients need to be closely followed in the first months post infusion, with regular blood tests and other monitoring.

Notably, once patients receive an infusion, they cannot receive another, because of the buildup of antibodies.

“I think [this is] most important when considering current gene therapy – a patient can only receive it once, based on current technology,” Dr. Samelson-Jones said in an interview.“That means if a patient received gene therapy in 2023, and something better is developed in 2025, they are unlikely to be able to receive it.”

Nevertheless, with favorable phase 3 data reported in March 2022 in the New England Journal of Medicine, the first gene therapy for hemophilia A, valoctocogene roxaparvovec (BioMarin), appears poised for possible regulatory approval very soon.

“I expect this product to be approved in the next year, though I been previously surprised before about delays in this product’s clinical development,” Dr. Samelson-Jones said.
 

Pros of nonfactor therapy

Arguing on the side of nonfactor therapy in the debate, Roseline d’Oiron, MD, underscored the extent to which nonfactor therapy has dramatically transformed lives.

With intravenous injections, “the burden of the stress and anxiety of the injections is underestimated, even when you don’t have venous access problems,” said Dr. d’Oiron, a clinician investigator at the University Paris XI.

The heavy toll that these therapeutic challenges have had on patients’ lives and identities has been documented in patient advocacy reports, underscoring that “the availability of subcutaneous therapies through the nonfactor therapies for hemophilia A has really been a game changer,” said Dr. d’Oiron, who is also the associate director of the Reference Centre for Hemophilia and Other Congenital Rare Bleeding Disorders, Congenital Platelets Disorders, and von Willebrand Disease at Bicêtre (France) Hospital AP-HP.

She noted that newer therapies in development show the potential to offer longer half-lives, providing “even more improvement with wider intervals between the subcutaneous injections.”

The efficacy of nonfactor therapies also translates to lower rates of joint bleeding, which represent the most common complication in hemophilia, potentially causing acute or chronic pain.

“These therapies allow a life that is much closer to what would be considered a normal life, and especially allowing some physical activities with the prevention of bleeding episodes,” Dr. d’Oiron said. “The drugs have a good safety profile and are completely changing the picture of this disease.”

Dr. d’Oiron noted that, in the real-world clinical setting, there is no debate over nonfactor versus gene therapy. Most prefer to stick with what is already working well for them.

“In my clinical practice, only a very limited number of patients are really willing and considering the switch to gene therapy,” she said. “They feel that the nonfactor therapy is filling their previous unmet needs quite well, and the impression is that we don’t necessarily need look for something different.”
 

Limitations of nonfactor therapy

Echoing that he has had the same favorable experiences with patients on emicizumab as described by Dr. d’Oiron, Dr. Samelson-Jones, pointed out key caveats that significantly differentiate it from gene therapy, not the least of which is the basic issue of the requirement of injections.

“Even with longer half-lives, approximately monthly injections are still required with nonfactor therapy,” which can – and have – been compromised by any range of societal disruptions, including a pandemic or supply issues.

Furthermore, the mechanism of nonfactor therapies in providing hemostatic regulation outside of normal factor VIII is unregulated, with ‘no easy ‘off’ switch,’ he explained.

“The balance that nonfactor agents provide between pro- and anticoagulant forces is inherently more fragile – more like a knife’s edge, and has resulted in the risk for thrombotic complications in most examples of nonfactor therapies,” he said.

In addition, the therapies have unknown immunogenicity, with an increased risk of the development of antidrug antibodies, called inhibitors, a theoretical complication of nonfactor therapies, if factor VIII is only administered in the setting of bleeds or perioperatively, Dr. Samelson-Jones said.

That being said, “nonfactor agents are not for all patients with hemophilia A in the future – but rather gene therapy is,” he noted.
 

Normal hemostasis ‘only achievable with gene therapy’

In contrast to nonfactor therapy, just one infusion of gene therapy “ideally offers many years of potentially curative hemostatic protection,” Dr. Samuelson-Jones said. “The ultimate goal, I believe, is to achieve normal hemostasis and health equity, and I contend this goal is only really achievable with gene therapy.”

He noted that, while gene therapies will require initial monitoring, “once the gene therapy recipient is 3 or 12 months out, the monitoring really de-escalates, and the patient is free from all drug delivery or needing to be in close contact with their treatment center.”

Regarding concerns about not being able to receive gene therapy more than once, Dr. Samuelson-Jones said that work is underway to develop alternative viral vectors and nonviral vectors that may overcome those challenges.

Overall, he underscored that challenges are par for the course in the development of any novel therapeutic approach.

For instance, similar challenges were experienced 10 years ago in the development of gene therapy for hemophilia B. However, with advances, “they’ve now been able to achieve long-term sustained levels in the normal ordinary curative range. And I’m optimistic that similar advances may be able to be achieved for factor VIII gene transfer,” he said.
 

Nonfactor therapies as bridge?

That being said, nonfactor therapies are going to be essential in treating patients until such advances come to fruition, Dr. Samelson-Jones noted.

“I would agree that nonfactor therapies in 2022 have really simplified and improved the convenience of prophylaxis,” he said, “but I would view them as a bridging therapy until gene therapy goes through clinical development and are licensed for all patients with hemophilia.”

While Dr. d’Oiron agreed with that possibility, she countered that, when it comes to crossing over to gene therapy, some very long bridges might be needed.

“I would love to have a therapy that would be both extremely safe and effective and offering a cure and normalization of hemostasis,” she said. “But I’m afraid that the current available gene therapy that might be arriving soon still does no fulfill all of these criteria. I think there are a lot of questions so far.”

Ultimately, Dr. Samelson-Jones conceded that the success of emicizumab has set a high bar in the minds of clinicians and patients alike, which will strongly influence perceptions of any alternative approaches –and of participation in clinical trials.

“I think that, unequivocally, emicizumab has changed the risk-benefit discussion about enrolling in clinical trials, and in gene therapy in particular,” he said. “And I think it also has set the threshold for efficacy – and if a gene therapy product in development can’t achieve bleeding control that is similar to that provided with emicizumab, then that is not a product that is going to be able to continue in clinical development.”

Importantly, both debaters underscored the need for ongoing efforts to make the novel – and therefore costly therapies accessible to all, through organizations including the World Federation of Hemophilia Humanitarian Aid Program.

“It would be my hope that we can then extend all of these great therapies to the majority of undertreated patients with hemophilia around the world,” Dr. Samelson-Jones said. “I think that’s an issue that must be addressed with all of these novel therapies.”

Commenting on these issues, Riitta Lassila, MD, professor of coagulation medicine at the Comprehensive Cancer Center at Helsinki University Hospital, , who moderated the debate, said it has also been her experience that some patients express reluctance to enter the gene therapy trials

“There are two groups of patients, just as in the healthy population as well,” she said in an interview. “Some more ready to take risks and some are very hesitant [regarding] anything new. We do have the saying: If something is not broken, don’t fix it.”

She noted the additional concern that while the therapy has been successful in hemophilia B, factor VIII involves a larger construct and may have limitations with hemophilia A.

Furthermore, “the sustainability of factor VIII production may decrease in a couple of years, and the treatment duration could remain suboptimal,” Dr. Lassila said. “However, hemostasis seems to still [be achieved] with gene therapy, so maybe there will be more efficient solutions in the future.”

Dr. Samuelson-Jones has been a consultant for Pfizer, Bayer, Genentech, Frontera, and Cabaletta and serves on the scientific advisory board of GeneVentiv. Dr. d’Oiron has reported relationships with Baxalta/Shire, Bayer, Biomarin, CSL Behring, LFB, NovoNordisk, Octapharma, Pfizer, Roche, and Sobi. Dr. Lassila has been an adviser for Roche (emicizumab) and Biomarin and CSL for gene therapy.

Whether hemophilia A patients should stick with effective nonfactor therapy or join a clinical trial for a potential cure with gene therapy cure – this question was debated at he annual meeting of the European Hematology Association.

Ultimately, results of a very informal polling of the online audience suggested a strong leaning toward the known benefits of nonfactor therapy, as opposed to as-yet unapproved gene therapy. Although Benjamin Samelson-Jones, MD, PhD, argued for gene therapy, he also saluted the progress made that had enabled such choices.

“Our patients and the field have greatly benefited from this broad spectrum of different therapies and how they’ve been implemented, and it’s a truly exciting time because there will continue to be advancements in both these therapeutic modalities in the next 5-10 years,” said Dr. Samelson-Jones, an assistant professor of pediatrics in the division of hematology at the Children’s Hospital of Philadelphia.
 

Game changers emerge

Hemophilia A, characterized by a hereditary deficiency in factor VIII disorder, has long involved prophylaxis treatment with procoagulant factor replacement therapy that requires intravenous injection as often as several times a week. This can cause problems with venous access that are particularly burdensome for child patients.

Nonfactor therapy, currently consisting of the approved emicizumab but with more agents in development, provides coagulation without replacement of factor VIII. Importantly, this treatment requires only subcutaneous injection which, after a loading dose period, may be needed weekly or even just once a month.

However, in 2018, at approximately the same time that emicizumab was approved, patients with hemophilia A became eligible to enroll in clinical trials for the far more revolutionary concept of gene therapy, with the chance to become infusion free after just a single infusion.

There are caveats aplenty. Four of the therapies now in phase 3 development are adeno-associated viral vectors that are liver directed, meaning that patients need to be closely followed in the first months post infusion, with regular blood tests and other monitoring.

Notably, once patients receive an infusion, they cannot receive another, because of the buildup of antibodies.

“I think [this is] most important when considering current gene therapy – a patient can only receive it once, based on current technology,” Dr. Samelson-Jones said in an interview.“That means if a patient received gene therapy in 2023, and something better is developed in 2025, they are unlikely to be able to receive it.”

Nevertheless, with favorable phase 3 data reported in March 2022 in the New England Journal of Medicine, the first gene therapy for hemophilia A, valoctocogene roxaparvovec (BioMarin), appears poised for possible regulatory approval very soon.

“I expect this product to be approved in the next year, though I been previously surprised before about delays in this product’s clinical development,” Dr. Samelson-Jones said.
 

Pros of nonfactor therapy

Arguing on the side of nonfactor therapy in the debate, Roseline d’Oiron, MD, underscored the extent to which nonfactor therapy has dramatically transformed lives.

With intravenous injections, “the burden of the stress and anxiety of the injections is underestimated, even when you don’t have venous access problems,” said Dr. d’Oiron, a clinician investigator at the University Paris XI.

The heavy toll that these therapeutic challenges have had on patients’ lives and identities has been documented in patient advocacy reports, underscoring that “the availability of subcutaneous therapies through the nonfactor therapies for hemophilia A has really been a game changer,” said Dr. d’Oiron, who is also the associate director of the Reference Centre for Hemophilia and Other Congenital Rare Bleeding Disorders, Congenital Platelets Disorders, and von Willebrand Disease at Bicêtre (France) Hospital AP-HP.

She noted that newer therapies in development show the potential to offer longer half-lives, providing “even more improvement with wider intervals between the subcutaneous injections.”

The efficacy of nonfactor therapies also translates to lower rates of joint bleeding, which represent the most common complication in hemophilia, potentially causing acute or chronic pain.

“These therapies allow a life that is much closer to what would be considered a normal life, and especially allowing some physical activities with the prevention of bleeding episodes,” Dr. d’Oiron said. “The drugs have a good safety profile and are completely changing the picture of this disease.”

Dr. d’Oiron noted that, in the real-world clinical setting, there is no debate over nonfactor versus gene therapy. Most prefer to stick with what is already working well for them.

“In my clinical practice, only a very limited number of patients are really willing and considering the switch to gene therapy,” she said. “They feel that the nonfactor therapy is filling their previous unmet needs quite well, and the impression is that we don’t necessarily need look for something different.”
 

Limitations of nonfactor therapy

Echoing that he has had the same favorable experiences with patients on emicizumab as described by Dr. d’Oiron, Dr. Samelson-Jones, pointed out key caveats that significantly differentiate it from gene therapy, not the least of which is the basic issue of the requirement of injections.

“Even with longer half-lives, approximately monthly injections are still required with nonfactor therapy,” which can – and have – been compromised by any range of societal disruptions, including a pandemic or supply issues.

Furthermore, the mechanism of nonfactor therapies in providing hemostatic regulation outside of normal factor VIII is unregulated, with ‘no easy ‘off’ switch,’ he explained.

“The balance that nonfactor agents provide between pro- and anticoagulant forces is inherently more fragile – more like a knife’s edge, and has resulted in the risk for thrombotic complications in most examples of nonfactor therapies,” he said.

In addition, the therapies have unknown immunogenicity, with an increased risk of the development of antidrug antibodies, called inhibitors, a theoretical complication of nonfactor therapies, if factor VIII is only administered in the setting of bleeds or perioperatively, Dr. Samelson-Jones said.

That being said, “nonfactor agents are not for all patients with hemophilia A in the future – but rather gene therapy is,” he noted.
 

Normal hemostasis ‘only achievable with gene therapy’

In contrast to nonfactor therapy, just one infusion of gene therapy “ideally offers many years of potentially curative hemostatic protection,” Dr. Samuelson-Jones said. “The ultimate goal, I believe, is to achieve normal hemostasis and health equity, and I contend this goal is only really achievable with gene therapy.”

He noted that, while gene therapies will require initial monitoring, “once the gene therapy recipient is 3 or 12 months out, the monitoring really de-escalates, and the patient is free from all drug delivery or needing to be in close contact with their treatment center.”

Regarding concerns about not being able to receive gene therapy more than once, Dr. Samuelson-Jones said that work is underway to develop alternative viral vectors and nonviral vectors that may overcome those challenges.

Overall, he underscored that challenges are par for the course in the development of any novel therapeutic approach.

For instance, similar challenges were experienced 10 years ago in the development of gene therapy for hemophilia B. However, with advances, “they’ve now been able to achieve long-term sustained levels in the normal ordinary curative range. And I’m optimistic that similar advances may be able to be achieved for factor VIII gene transfer,” he said.
 

Nonfactor therapies as bridge?

That being said, nonfactor therapies are going to be essential in treating patients until such advances come to fruition, Dr. Samelson-Jones noted.

“I would agree that nonfactor therapies in 2022 have really simplified and improved the convenience of prophylaxis,” he said, “but I would view them as a bridging therapy until gene therapy goes through clinical development and are licensed for all patients with hemophilia.”

While Dr. d’Oiron agreed with that possibility, she countered that, when it comes to crossing over to gene therapy, some very long bridges might be needed.

“I would love to have a therapy that would be both extremely safe and effective and offering a cure and normalization of hemostasis,” she said. “But I’m afraid that the current available gene therapy that might be arriving soon still does no fulfill all of these criteria. I think there are a lot of questions so far.”

Ultimately, Dr. Samelson-Jones conceded that the success of emicizumab has set a high bar in the minds of clinicians and patients alike, which will strongly influence perceptions of any alternative approaches –and of participation in clinical trials.

“I think that, unequivocally, emicizumab has changed the risk-benefit discussion about enrolling in clinical trials, and in gene therapy in particular,” he said. “And I think it also has set the threshold for efficacy – and if a gene therapy product in development can’t achieve bleeding control that is similar to that provided with emicizumab, then that is not a product that is going to be able to continue in clinical development.”

Importantly, both debaters underscored the need for ongoing efforts to make the novel – and therefore costly therapies accessible to all, through organizations including the World Federation of Hemophilia Humanitarian Aid Program.

“It would be my hope that we can then extend all of these great therapies to the majority of undertreated patients with hemophilia around the world,” Dr. Samelson-Jones said. “I think that’s an issue that must be addressed with all of these novel therapies.”

Commenting on these issues, Riitta Lassila, MD, professor of coagulation medicine at the Comprehensive Cancer Center at Helsinki University Hospital, , who moderated the debate, said it has also been her experience that some patients express reluctance to enter the gene therapy trials

“There are two groups of patients, just as in the healthy population as well,” she said in an interview. “Some more ready to take risks and some are very hesitant [regarding] anything new. We do have the saying: If something is not broken, don’t fix it.”

She noted the additional concern that while the therapy has been successful in hemophilia B, factor VIII involves a larger construct and may have limitations with hemophilia A.

Furthermore, “the sustainability of factor VIII production may decrease in a couple of years, and the treatment duration could remain suboptimal,” Dr. Lassila said. “However, hemostasis seems to still [be achieved] with gene therapy, so maybe there will be more efficient solutions in the future.”

Dr. Samuelson-Jones has been a consultant for Pfizer, Bayer, Genentech, Frontera, and Cabaletta and serves on the scientific advisory board of GeneVentiv. Dr. d’Oiron has reported relationships with Baxalta/Shire, Bayer, Biomarin, CSL Behring, LFB, NovoNordisk, Octapharma, Pfizer, Roche, and Sobi. Dr. Lassila has been an adviser for Roche (emicizumab) and Biomarin and CSL for gene therapy.

Whether hemophilia A patients should stick with effective nonfactor therapy or join a clinical trial for a potential cure with gene therapy cure – this question was debated at he annual meeting of the European Hematology Association.

Ultimately, results of a very informal polling of the online audience suggested a strong leaning toward the known benefits of nonfactor therapy, as opposed to as-yet unapproved gene therapy. Although Benjamin Samelson-Jones, MD, PhD, argued for gene therapy, he also saluted the progress made that had enabled such choices.

“Our patients and the field have greatly benefited from this broad spectrum of different therapies and how they’ve been implemented, and it’s a truly exciting time because there will continue to be advancements in both these therapeutic modalities in the next 5-10 years,” said Dr. Samelson-Jones, an assistant professor of pediatrics in the division of hematology at the Children’s Hospital of Philadelphia.
 

Game changers emerge

Hemophilia A, characterized by a hereditary deficiency in factor VIII disorder, has long involved prophylaxis treatment with procoagulant factor replacement therapy that requires intravenous injection as often as several times a week. This can cause problems with venous access that are particularly burdensome for child patients.

Nonfactor therapy, currently consisting of the approved emicizumab but with more agents in development, provides coagulation without replacement of factor VIII. Importantly, this treatment requires only subcutaneous injection which, after a loading dose period, may be needed weekly or even just once a month.

However, in 2018, at approximately the same time that emicizumab was approved, patients with hemophilia A became eligible to enroll in clinical trials for the far more revolutionary concept of gene therapy, with the chance to become infusion free after just a single infusion.

There are caveats aplenty. Four of the therapies now in phase 3 development are adeno-associated viral vectors that are liver directed, meaning that patients need to be closely followed in the first months post infusion, with regular blood tests and other monitoring.

Notably, once patients receive an infusion, they cannot receive another, because of the buildup of antibodies.

“I think [this is] most important when considering current gene therapy – a patient can only receive it once, based on current technology,” Dr. Samelson-Jones said in an interview.“That means if a patient received gene therapy in 2023, and something better is developed in 2025, they are unlikely to be able to receive it.”

Nevertheless, with favorable phase 3 data reported in March 2022 in the New England Journal of Medicine, the first gene therapy for hemophilia A, valoctocogene roxaparvovec (BioMarin), appears poised for possible regulatory approval very soon.

“I expect this product to be approved in the next year, though I been previously surprised before about delays in this product’s clinical development,” Dr. Samelson-Jones said.
 

Pros of nonfactor therapy

Arguing on the side of nonfactor therapy in the debate, Roseline d’Oiron, MD, underscored the extent to which nonfactor therapy has dramatically transformed lives.

With intravenous injections, “the burden of the stress and anxiety of the injections is underestimated, even when you don’t have venous access problems,” said Dr. d’Oiron, a clinician investigator at the University Paris XI.

The heavy toll that these therapeutic challenges have had on patients’ lives and identities has been documented in patient advocacy reports, underscoring that “the availability of subcutaneous therapies through the nonfactor therapies for hemophilia A has really been a game changer,” said Dr. d’Oiron, who is also the associate director of the Reference Centre for Hemophilia and Other Congenital Rare Bleeding Disorders, Congenital Platelets Disorders, and von Willebrand Disease at Bicêtre (France) Hospital AP-HP.

She noted that newer therapies in development show the potential to offer longer half-lives, providing “even more improvement with wider intervals between the subcutaneous injections.”

The efficacy of nonfactor therapies also translates to lower rates of joint bleeding, which represent the most common complication in hemophilia, potentially causing acute or chronic pain.

“These therapies allow a life that is much closer to what would be considered a normal life, and especially allowing some physical activities with the prevention of bleeding episodes,” Dr. d’Oiron said. “The drugs have a good safety profile and are completely changing the picture of this disease.”

Dr. d’Oiron noted that, in the real-world clinical setting, there is no debate over nonfactor versus gene therapy. Most prefer to stick with what is already working well for them.

“In my clinical practice, only a very limited number of patients are really willing and considering the switch to gene therapy,” she said. “They feel that the nonfactor therapy is filling their previous unmet needs quite well, and the impression is that we don’t necessarily need look for something different.”
 

Limitations of nonfactor therapy

Echoing that he has had the same favorable experiences with patients on emicizumab as described by Dr. d’Oiron, Dr. Samelson-Jones, pointed out key caveats that significantly differentiate it from gene therapy, not the least of which is the basic issue of the requirement of injections.

“Even with longer half-lives, approximately monthly injections are still required with nonfactor therapy,” which can – and have – been compromised by any range of societal disruptions, including a pandemic or supply issues.

Furthermore, the mechanism of nonfactor therapies in providing hemostatic regulation outside of normal factor VIII is unregulated, with ‘no easy ‘off’ switch,’ he explained.

“The balance that nonfactor agents provide between pro- and anticoagulant forces is inherently more fragile – more like a knife’s edge, and has resulted in the risk for thrombotic complications in most examples of nonfactor therapies,” he said.

In addition, the therapies have unknown immunogenicity, with an increased risk of the development of antidrug antibodies, called inhibitors, a theoretical complication of nonfactor therapies, if factor VIII is only administered in the setting of bleeds or perioperatively, Dr. Samelson-Jones said.

That being said, “nonfactor agents are not for all patients with hemophilia A in the future – but rather gene therapy is,” he noted.
 

Normal hemostasis ‘only achievable with gene therapy’

In contrast to nonfactor therapy, just one infusion of gene therapy “ideally offers many years of potentially curative hemostatic protection,” Dr. Samuelson-Jones said. “The ultimate goal, I believe, is to achieve normal hemostasis and health equity, and I contend this goal is only really achievable with gene therapy.”

He noted that, while gene therapies will require initial monitoring, “once the gene therapy recipient is 3 or 12 months out, the monitoring really de-escalates, and the patient is free from all drug delivery or needing to be in close contact with their treatment center.”

Regarding concerns about not being able to receive gene therapy more than once, Dr. Samuelson-Jones said that work is underway to develop alternative viral vectors and nonviral vectors that may overcome those challenges.

Overall, he underscored that challenges are par for the course in the development of any novel therapeutic approach.

For instance, similar challenges were experienced 10 years ago in the development of gene therapy for hemophilia B. However, with advances, “they’ve now been able to achieve long-term sustained levels in the normal ordinary curative range. And I’m optimistic that similar advances may be able to be achieved for factor VIII gene transfer,” he said.
 

Nonfactor therapies as bridge?

That being said, nonfactor therapies are going to be essential in treating patients until such advances come to fruition, Dr. Samelson-Jones noted.

“I would agree that nonfactor therapies in 2022 have really simplified and improved the convenience of prophylaxis,” he said, “but I would view them as a bridging therapy until gene therapy goes through clinical development and are licensed for all patients with hemophilia.”

While Dr. d’Oiron agreed with that possibility, she countered that, when it comes to crossing over to gene therapy, some very long bridges might be needed.

“I would love to have a therapy that would be both extremely safe and effective and offering a cure and normalization of hemostasis,” she said. “But I’m afraid that the current available gene therapy that might be arriving soon still does no fulfill all of these criteria. I think there are a lot of questions so far.”

Ultimately, Dr. Samelson-Jones conceded that the success of emicizumab has set a high bar in the minds of clinicians and patients alike, which will strongly influence perceptions of any alternative approaches –and of participation in clinical trials.

“I think that, unequivocally, emicizumab has changed the risk-benefit discussion about enrolling in clinical trials, and in gene therapy in particular,” he said. “And I think it also has set the threshold for efficacy – and if a gene therapy product in development can’t achieve bleeding control that is similar to that provided with emicizumab, then that is not a product that is going to be able to continue in clinical development.”

Importantly, both debaters underscored the need for ongoing efforts to make the novel – and therefore costly therapies accessible to all, through organizations including the World Federation of Hemophilia Humanitarian Aid Program.

“It would be my hope that we can then extend all of these great therapies to the majority of undertreated patients with hemophilia around the world,” Dr. Samelson-Jones said. “I think that’s an issue that must be addressed with all of these novel therapies.”

Commenting on these issues, Riitta Lassila, MD, professor of coagulation medicine at the Comprehensive Cancer Center at Helsinki University Hospital, , who moderated the debate, said it has also been her experience that some patients express reluctance to enter the gene therapy trials

“There are two groups of patients, just as in the healthy population as well,” she said in an interview. “Some more ready to take risks and some are very hesitant [regarding] anything new. We do have the saying: If something is not broken, don’t fix it.”

She noted the additional concern that while the therapy has been successful in hemophilia B, factor VIII involves a larger construct and may have limitations with hemophilia A.

Furthermore, “the sustainability of factor VIII production may decrease in a couple of years, and the treatment duration could remain suboptimal,” Dr. Lassila said. “However, hemostasis seems to still [be achieved] with gene therapy, so maybe there will be more efficient solutions in the future.”

Dr. Samuelson-Jones has been a consultant for Pfizer, Bayer, Genentech, Frontera, and Cabaletta and serves on the scientific advisory board of GeneVentiv. Dr. d’Oiron has reported relationships with Baxalta/Shire, Bayer, Biomarin, CSL Behring, LFB, NovoNordisk, Octapharma, Pfizer, Roche, and Sobi. Dr. Lassila has been an adviser for Roche (emicizumab) and Biomarin and CSL for gene therapy.

The White House announced an effort on June 21 to require tobacco companies to reduce nicotine levels in cigarettes sold in the United States.

The Department of Health and Human Services posted a notice that details plans for a new rule to create a maximum allowed amount of nicotine in certain tobacco products. The Food and Drug Administration would take the action, the notice said, “to reduce addictiveness to certain tobacco products, thus giving addicted users a greater ability to quit.” The product standard would also help keep nonsmokers interested in trying tobacco, mainly youth, from starting to smoke and become regulars.

AtnoYdur/Thinkstock

“Lowering nicotine levels to minimally addictive or non-addictive levels would decrease the likelihood that future generations of young people become addicted to cigarettes and help more currently addicted smokers to quit,” FDA Commissioner Robert Califf, MD, said in a statement.

The FDA, in charge of regulating cigarettes, issues a proposed rule when changes are discussed. That would be followed by a period for public comments before a final rule could be issued.

The proposed rule was first reported by The Washington Post.

The FDA in 2018 published a study in the New England Journal of Medicine that estimated that a potential limit on nicotine in cigarettes could, by the year 2100, prevent more than 33 million people from becoming regular smokers, and prevent the deaths of more than 8 million people from tobacco-related illnesses.

The action to reduce nicotine levels would fit in with President Joe Biden’s goal of reducing cancer death rates by half over 25 years. Each year, according to the American Cancer Society, about 480,000 deaths (about 1 in 5) are related to smoking. Currently, about 34 million American adults still smoke cigarettes.

Matthew Myers, president of the Campaign for Tobacco-Free Kids, called the proposed rule a “truly game-changing proposal.”

“There is no other single action our country can take that would prevent more young people from becoming addicted to tobacco or have a greater impact on reducing deaths from cancer, cardiovascular disease and respiratory disease,” Mr. Myers said in a statement.

However, he said, “these gains will only be realized if the administration and the FDA demonstrate a full-throated commitment to finalizing and implementing this proposal.”

The FDA proposed the nicotine reduction strategy in talks with the White House and the Department of Health and Human Services early in 2021, according to the Post.

Earlier this year, the FDA issued a proposed rule to ban menthol flavoring in cigarettes. The agency is accepting public comments though July 5.

The action of reducing nicotine levels would likely take years to complete, Mitch Zeller, JD, recently retired director of the FDA Center for Tobacco Products, told the Post.

In 2018, the FDA issued a proposed ruling to set a standard for maximum nicotine levels in cigarettes.

Advocates say the action of slashing nicotine, the active – and addictive – ingredient in cigarettes, would save millions of lives for generations to come. Opponents liken it to the prohibition of alcohol in the 1920s and predict the action will fail.

Others say that if limits are put on nicotine levels, adults should have greater access to noncombustible alternatives.

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

The White House announced an effort on June 21 to require tobacco companies to reduce nicotine levels in cigarettes sold in the United States.

The Department of Health and Human Services posted a notice that details plans for a new rule to create a maximum allowed amount of nicotine in certain tobacco products. The Food and Drug Administration would take the action, the notice said, “to reduce addictiveness to certain tobacco products, thus giving addicted users a greater ability to quit.” The product standard would also help keep nonsmokers interested in trying tobacco, mainly youth, from starting to smoke and become regulars.

AtnoYdur/Thinkstock

“Lowering nicotine levels to minimally addictive or non-addictive levels would decrease the likelihood that future generations of young people become addicted to cigarettes and help more currently addicted smokers to quit,” FDA Commissioner Robert Califf, MD, said in a statement.

The FDA, in charge of regulating cigarettes, issues a proposed rule when changes are discussed. That would be followed by a period for public comments before a final rule could be issued.

The proposed rule was first reported by The Washington Post.

The FDA in 2018 published a study in the New England Journal of Medicine that estimated that a potential limit on nicotine in cigarettes could, by the year 2100, prevent more than 33 million people from becoming regular smokers, and prevent the deaths of more than 8 million people from tobacco-related illnesses.

The action to reduce nicotine levels would fit in with President Joe Biden’s goal of reducing cancer death rates by half over 25 years. Each year, according to the American Cancer Society, about 480,000 deaths (about 1 in 5) are related to smoking. Currently, about 34 million American adults still smoke cigarettes.

Matthew Myers, president of the Campaign for Tobacco-Free Kids, called the proposed rule a “truly game-changing proposal.”

“There is no other single action our country can take that would prevent more young people from becoming addicted to tobacco or have a greater impact on reducing deaths from cancer, cardiovascular disease and respiratory disease,” Mr. Myers said in a statement.

However, he said, “these gains will only be realized if the administration and the FDA demonstrate a full-throated commitment to finalizing and implementing this proposal.”

The FDA proposed the nicotine reduction strategy in talks with the White House and the Department of Health and Human Services early in 2021, according to the Post.

Earlier this year, the FDA issued a proposed rule to ban menthol flavoring in cigarettes. The agency is accepting public comments though July 5.

The action of reducing nicotine levels would likely take years to complete, Mitch Zeller, JD, recently retired director of the FDA Center for Tobacco Products, told the Post.

In 2018, the FDA issued a proposed ruling to set a standard for maximum nicotine levels in cigarettes.

Advocates say the action of slashing nicotine, the active – and addictive – ingredient in cigarettes, would save millions of lives for generations to come. Opponents liken it to the prohibition of alcohol in the 1920s and predict the action will fail.

Others say that if limits are put on nicotine levels, adults should have greater access to noncombustible alternatives.

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

The White House announced an effort on June 21 to require tobacco companies to reduce nicotine levels in cigarettes sold in the United States.

The Department of Health and Human Services posted a notice that details plans for a new rule to create a maximum allowed amount of nicotine in certain tobacco products. The Food and Drug Administration would take the action, the notice said, “to reduce addictiveness to certain tobacco products, thus giving addicted users a greater ability to quit.” The product standard would also help keep nonsmokers interested in trying tobacco, mainly youth, from starting to smoke and become regulars.

AtnoYdur/Thinkstock

“Lowering nicotine levels to minimally addictive or non-addictive levels would decrease the likelihood that future generations of young people become addicted to cigarettes and help more currently addicted smokers to quit,” FDA Commissioner Robert Califf, MD, said in a statement.

The FDA, in charge of regulating cigarettes, issues a proposed rule when changes are discussed. That would be followed by a period for public comments before a final rule could be issued.

The proposed rule was first reported by The Washington Post.

The FDA in 2018 published a study in the New England Journal of Medicine that estimated that a potential limit on nicotine in cigarettes could, by the year 2100, prevent more than 33 million people from becoming regular smokers, and prevent the deaths of more than 8 million people from tobacco-related illnesses.

The action to reduce nicotine levels would fit in with President Joe Biden’s goal of reducing cancer death rates by half over 25 years. Each year, according to the American Cancer Society, about 480,000 deaths (about 1 in 5) are related to smoking. Currently, about 34 million American adults still smoke cigarettes.

Matthew Myers, president of the Campaign for Tobacco-Free Kids, called the proposed rule a “truly game-changing proposal.”

“There is no other single action our country can take that would prevent more young people from becoming addicted to tobacco or have a greater impact on reducing deaths from cancer, cardiovascular disease and respiratory disease,” Mr. Myers said in a statement.

However, he said, “these gains will only be realized if the administration and the FDA demonstrate a full-throated commitment to finalizing and implementing this proposal.”

The FDA proposed the nicotine reduction strategy in talks with the White House and the Department of Health and Human Services early in 2021, according to the Post.

Earlier this year, the FDA issued a proposed rule to ban menthol flavoring in cigarettes. The agency is accepting public comments though July 5.

The action of reducing nicotine levels would likely take years to complete, Mitch Zeller, JD, recently retired director of the FDA Center for Tobacco Products, told the Post.

In 2018, the FDA issued a proposed ruling to set a standard for maximum nicotine levels in cigarettes.

Advocates say the action of slashing nicotine, the active – and addictive – ingredient in cigarettes, would save millions of lives for generations to come. Opponents liken it to the prohibition of alcohol in the 1920s and predict the action will fail.

Others say that if limits are put on nicotine levels, adults should have greater access to noncombustible alternatives.

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

The hemophilia A treatment paradigm has shifted away from simply maintaining a prophylaxis trough level of 1% towards a focus on patient outcomes and leading healthy, active lives, according to a recent report in The Journal of Medicine in Life.

To get there, the World Federation of Hemophilia (WFH) has recognized that physicians need to aim for higher trough levels so patients can lead as normal a life as possible, but there’s debate about which levels are ideal.

“There is increasing recognition and evidence from the literature that factor trough levels of 1%-3% are insufficient to prevent bleeds in all patients with hemophilia. It has also been suggested that maintaining higher factor levels (above 10%) may be optimal to prevent subclinical bleeding and the gradual progression of joint disease over a lifespan in very active patients,” according to the report.

The paper was a summary of expert opinion on the issue and a range of other current and future challenges in hemophilia care. Switzerland-based Sobi surveyed nine hemophilia experts in central Europe for their insights, then convened an advisory panel to flesh out their responses.

They were asked for their thoughts on the efficacy of factor versus non-factor replacement therapy when aiming for a 3%-5% target trough for hemophilia A prophylaxis.

About half said non-factor therapy was more effective, while the other half favored factor therapy because it has similar efficacy and allows the tailoring of treatment to individual pharmacokinetic data, physical activity, and the condition of the musculoskeletal system.

However, “if the new treatment aim for [prophylaxis] is to increase the trough level, existing and future prophylactic regimens are likely to require adjustment. Maintaining such high trough levels in some patients may lead to the re-shortening of longer treatment intervals and, consequently, an increase of previously reduced factor consumption, which has been an important benefit of [extended half-life] products,” the report noted.

“This creates space for next-generation FVIII replacement therapy,” such as Sobi’s efanesoctocog alfa, which has been granted fast-track designation in the United States for hemophilia treatment, the report notes.

There was also a split in opinion on whether factor therapy offered similar or improved efficacy, compared with non-factor therapy when prophylaxis is intensified to aim for a 10% trough in very active patients. Factor prophylaxis “may be preferable for active hemophilia A” because of the greater personalization, it said.

The experts noted that trough levels are just one aspect of patient care; the overall aim is a better quality of life. The panel was asked about how quality of life could be enhanced in the future. More than half said that the move towards personalized treatment is key, including greater use of telemedicine applications such as Sobi’s florio HAEMO and Takeda’s MyPKFit.

“In addition, most of the experts agreed that novel therapies such as the new class of FVIII replacement therapy, efanesoctocog alfa (BIVV001), would become another mainstream therapy due to its potential to achieve personalized, extended protection against all bleeding types in patients with severe hemophilia A,” the report said.

In the meantime, the advent of extended half-life products and novel non-factor therapies such as emicizumab; subcutaneous siRNA prophylactic therapies such as fitusiran; and anti-tissue factor pathway inhibitors such as marstacimab – each with different mechanisms of action – has led to new challenges in laboratory monitoring.

For more personalized treatment to happen, “it will be necessary for specialized clinical laboratories to be fully equipped with the required equipment, product-specific reagents, and expertise to perform appropriate assays and monitor levels of coagulation activity,” the report noted.

Thrombin generation assays to measure the dynamics of blood coagulation are promising. “There’s significant potential for monitoring the efficacy” of prophylaxis across various established and novel hemophilia treatments, but the approach “is still in its infancy,” the report noted.

Overall, “new and emerging therapies such as novel [extended half-life] factor concentrates and non-factor treatments will likely reshape hemophilia care within the next decade, providing more efficacious and convenient management options and possibly curative therapies,” it said.

The work was funded by Sobi. Most of the panelists disclosed speaker/advisor fees and/or research funding from the company, as well as many others.

The hemophilia A treatment paradigm has shifted away from simply maintaining a prophylaxis trough level of 1% towards a focus on patient outcomes and leading healthy, active lives, according to a recent report in The Journal of Medicine in Life.

To get there, the World Federation of Hemophilia (WFH) has recognized that physicians need to aim for higher trough levels so patients can lead as normal a life as possible, but there’s debate about which levels are ideal.

“There is increasing recognition and evidence from the literature that factor trough levels of 1%-3% are insufficient to prevent bleeds in all patients with hemophilia. It has also been suggested that maintaining higher factor levels (above 10%) may be optimal to prevent subclinical bleeding and the gradual progression of joint disease over a lifespan in very active patients,” according to the report.

The paper was a summary of expert opinion on the issue and a range of other current and future challenges in hemophilia care. Switzerland-based Sobi surveyed nine hemophilia experts in central Europe for their insights, then convened an advisory panel to flesh out their responses.

They were asked for their thoughts on the efficacy of factor versus non-factor replacement therapy when aiming for a 3%-5% target trough for hemophilia A prophylaxis.

About half said non-factor therapy was more effective, while the other half favored factor therapy because it has similar efficacy and allows the tailoring of treatment to individual pharmacokinetic data, physical activity, and the condition of the musculoskeletal system.

However, “if the new treatment aim for [prophylaxis] is to increase the trough level, existing and future prophylactic regimens are likely to require adjustment. Maintaining such high trough levels in some patients may lead to the re-shortening of longer treatment intervals and, consequently, an increase of previously reduced factor consumption, which has been an important benefit of [extended half-life] products,” the report noted.

“This creates space for next-generation FVIII replacement therapy,” such as Sobi’s efanesoctocog alfa, which has been granted fast-track designation in the United States for hemophilia treatment, the report notes.

There was also a split in opinion on whether factor therapy offered similar or improved efficacy, compared with non-factor therapy when prophylaxis is intensified to aim for a 10% trough in very active patients. Factor prophylaxis “may be preferable for active hemophilia A” because of the greater personalization, it said.

The experts noted that trough levels are just one aspect of patient care; the overall aim is a better quality of life. The panel was asked about how quality of life could be enhanced in the future. More than half said that the move towards personalized treatment is key, including greater use of telemedicine applications such as Sobi’s florio HAEMO and Takeda’s MyPKFit.

“In addition, most of the experts agreed that novel therapies such as the new class of FVIII replacement therapy, efanesoctocog alfa (BIVV001), would become another mainstream therapy due to its potential to achieve personalized, extended protection against all bleeding types in patients with severe hemophilia A,” the report said.

In the meantime, the advent of extended half-life products and novel non-factor therapies such as emicizumab; subcutaneous siRNA prophylactic therapies such as fitusiran; and anti-tissue factor pathway inhibitors such as marstacimab – each with different mechanisms of action – has led to new challenges in laboratory monitoring.

For more personalized treatment to happen, “it will be necessary for specialized clinical laboratories to be fully equipped with the required equipment, product-specific reagents, and expertise to perform appropriate assays and monitor levels of coagulation activity,” the report noted.

Thrombin generation assays to measure the dynamics of blood coagulation are promising. “There’s significant potential for monitoring the efficacy” of prophylaxis across various established and novel hemophilia treatments, but the approach “is still in its infancy,” the report noted.

Overall, “new and emerging therapies such as novel [extended half-life] factor concentrates and non-factor treatments will likely reshape hemophilia care within the next decade, providing more efficacious and convenient management options and possibly curative therapies,” it said.

The work was funded by Sobi. Most of the panelists disclosed speaker/advisor fees and/or research funding from the company, as well as many others.

The hemophilia A treatment paradigm has shifted away from simply maintaining a prophylaxis trough level of 1% towards a focus on patient outcomes and leading healthy, active lives, according to a recent report in The Journal of Medicine in Life.

To get there, the World Federation of Hemophilia (WFH) has recognized that physicians need to aim for higher trough levels so patients can lead as normal a life as possible, but there’s debate about which levels are ideal.

“There is increasing recognition and evidence from the literature that factor trough levels of 1%-3% are insufficient to prevent bleeds in all patients with hemophilia. It has also been suggested that maintaining higher factor levels (above 10%) may be optimal to prevent subclinical bleeding and the gradual progression of joint disease over a lifespan in very active patients,” according to the report.

The paper was a summary of expert opinion on the issue and a range of other current and future challenges in hemophilia care. Switzerland-based Sobi surveyed nine hemophilia experts in central Europe for their insights, then convened an advisory panel to flesh out their responses.

They were asked for their thoughts on the efficacy of factor versus non-factor replacement therapy when aiming for a 3%-5% target trough for hemophilia A prophylaxis.

About half said non-factor therapy was more effective, while the other half favored factor therapy because it has similar efficacy and allows the tailoring of treatment to individual pharmacokinetic data, physical activity, and the condition of the musculoskeletal system.

However, “if the new treatment aim for [prophylaxis] is to increase the trough level, existing and future prophylactic regimens are likely to require adjustment. Maintaining such high trough levels in some patients may lead to the re-shortening of longer treatment intervals and, consequently, an increase of previously reduced factor consumption, which has been an important benefit of [extended half-life] products,” the report noted.

“This creates space for next-generation FVIII replacement therapy,” such as Sobi’s efanesoctocog alfa, which has been granted fast-track designation in the United States for hemophilia treatment, the report notes.

There was also a split in opinion on whether factor therapy offered similar or improved efficacy, compared with non-factor therapy when prophylaxis is intensified to aim for a 10% trough in very active patients. Factor prophylaxis “may be preferable for active hemophilia A” because of the greater personalization, it said.

The experts noted that trough levels are just one aspect of patient care; the overall aim is a better quality of life. The panel was asked about how quality of life could be enhanced in the future. More than half said that the move towards personalized treatment is key, including greater use of telemedicine applications such as Sobi’s florio HAEMO and Takeda’s MyPKFit.

“In addition, most of the experts agreed that novel therapies such as the new class of FVIII replacement therapy, efanesoctocog alfa (BIVV001), would become another mainstream therapy due to its potential to achieve personalized, extended protection against all bleeding types in patients with severe hemophilia A,” the report said.

In the meantime, the advent of extended half-life products and novel non-factor therapies such as emicizumab; subcutaneous siRNA prophylactic therapies such as fitusiran; and anti-tissue factor pathway inhibitors such as marstacimab – each with different mechanisms of action – has led to new challenges in laboratory monitoring.

For more personalized treatment to happen, “it will be necessary for specialized clinical laboratories to be fully equipped with the required equipment, product-specific reagents, and expertise to perform appropriate assays and monitor levels of coagulation activity,” the report noted.

Thrombin generation assays to measure the dynamics of blood coagulation are promising. “There’s significant potential for monitoring the efficacy” of prophylaxis across various established and novel hemophilia treatments, but the approach “is still in its infancy,” the report noted.

Overall, “new and emerging therapies such as novel [extended half-life] factor concentrates and non-factor treatments will likely reshape hemophilia care within the next decade, providing more efficacious and convenient management options and possibly curative therapies,” it said.

The work was funded by Sobi. Most of the panelists disclosed speaker/advisor fees and/or research funding from the company, as well as many others.

Over the past decade, the U.S. Food and Drug Administration has approved new cancer drugs twice as fast as the European Medicines Agency (EMA), often using accelerated pathways, a new analysis shows.

Between 2010 and 2019, the FDA approved almost all oncology therapies ahead of the EMA. Drugs entered the United States market about 8 months (241 days) before European market authorization.

But do quicker review times translate to wins for patients?

“The faster FDA approval process potentially provides earlier access to potentially life-prolonging medications for patients with cancer in the United States,” Ali Raza Khaki, MD, department of oncology, Stanford (Calif.) University School of Medicine, told this news organization. “On the surface, this is a good thing. However, it comes with limitations.”

Earlier drug approval often means greater uncertainty about an agent’s benefit – most notably, whether it will improve a patient’s survival or quality of life. Dr. Khaki pointed to a study published in JAMA Internal Medicine, which found that only 19 of 93 (20%) cancer drugs that had been recently approved through the FDA’s accelerated approval pathway demonstrated an improvement in overall survival.

In the new study, published online in JAMA Network Open, Dr. Khaki and colleagues found that among the 89 cancer drugs approved in the United States and Europe between January 2010 and December 2019, the FDA approved 85 (95%) before European authorization and four (5%) after.

The researchers found that the median FDA review time was half that of the EMA’s (200 vs. 426 days). Furthermore, 64 new drug applications (72%) were submitted to the FDA first, compared with 21 (23%) to the EMA.

Of the drugs approved through an accelerated pathway, three were ultimately pulled from the U.S. market, compared with one in Europe.

“These early drug approvals that later lead to withdrawal expose many more patients to toxicity, including financial toxicity, given the high cost of cancer medications,” Dr. Khaki commented.

In addition, 35 oncology therapies (39%) were approved by the FDA before trial results were published, compared with only eight (9%) by the EMA. Although FDA drug labels contain some information about efficacy and toxicity, scientific publications often have much more, including details about study populations and toxicities.

“Without this information, providers may be limited in their knowledge about patient selection, clinical benefit, and optimal toxicity management,” Dr. Khaki said.

Jeff Allen PhD, president and CEO of the nonprofit Friends of Cancer Research, who wasn’t involved in the study, believes that an FDA approval before publication shouldn’t be “particularly concerning.”

“Peer-reviewed publication is an important component of validating and communicating scientific findings, but the processes and time lines for individual journals can be highly variable,” he said. “I don’t think we would want to see a situation where potential beneficial treatments are held up due to unrelated publication processes.”

The author of an invited commentary in JAMA Network Open had a different take on the study findings.

“A tempting interpretation” of this study is that the FDA is a “superior agency for expedited review times that bring cancer drugs to patients earlier,” Kristina Jenei, BSN, MSc, with the University of British Columbia School of Population and Public Health, writes. In addition, the fact that more drugs were pulled from the market after approval in the United States than in Europe could be interpreted to mean that the system is working as it should.

Although the speed of FDA reviews and the number of subsequent approvals have increased over time, the proportion of cancer drugs that improve survival has declined. In addition, because the FDA’s follow-up of postmarketing studies has been “inconsistent,” a substantial number of cancer drugs that were approved through accelerated pathways have remained on the market for years without confirmation of their benefit.

Although regulatory agencies must balance earlier patient access to novel treatments with evidence that the therapies are effective and safe, “faster review times and approvals are not cause for celebration; better patient outcomes are,” Ms. Jenei writes. “In other words, quality over quantity.”

The study was supported by the National Cancer Institute. Dr. Khaki reported stock ownership from Merck and stock ownership from Sanofi outside the submitted work. Dr. Allen and Ms. Jenei have disclosed no relevant financial relationships.

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

Over the past decade, the U.S. Food and Drug Administration has approved new cancer drugs twice as fast as the European Medicines Agency (EMA), often using accelerated pathways, a new analysis shows.

Between 2010 and 2019, the FDA approved almost all oncology therapies ahead of the EMA. Drugs entered the United States market about 8 months (241 days) before European market authorization.

But do quicker review times translate to wins for patients?

“The faster FDA approval process potentially provides earlier access to potentially life-prolonging medications for patients with cancer in the United States,” Ali Raza Khaki, MD, department of oncology, Stanford (Calif.) University School of Medicine, told this news organization. “On the surface, this is a good thing. However, it comes with limitations.”

Earlier drug approval often means greater uncertainty about an agent’s benefit – most notably, whether it will improve a patient’s survival or quality of life. Dr. Khaki pointed to a study published in JAMA Internal Medicine, which found that only 19 of 93 (20%) cancer drugs that had been recently approved through the FDA’s accelerated approval pathway demonstrated an improvement in overall survival.

In the new study, published online in JAMA Network Open, Dr. Khaki and colleagues found that among the 89 cancer drugs approved in the United States and Europe between January 2010 and December 2019, the FDA approved 85 (95%) before European authorization and four (5%) after.

The researchers found that the median FDA review time was half that of the EMA’s (200 vs. 426 days). Furthermore, 64 new drug applications (72%) were submitted to the FDA first, compared with 21 (23%) to the EMA.

Of the drugs approved through an accelerated pathway, three were ultimately pulled from the U.S. market, compared with one in Europe.

“These early drug approvals that later lead to withdrawal expose many more patients to toxicity, including financial toxicity, given the high cost of cancer medications,” Dr. Khaki commented.

In addition, 35 oncology therapies (39%) were approved by the FDA before trial results were published, compared with only eight (9%) by the EMA. Although FDA drug labels contain some information about efficacy and toxicity, scientific publications often have much more, including details about study populations and toxicities.

“Without this information, providers may be limited in their knowledge about patient selection, clinical benefit, and optimal toxicity management,” Dr. Khaki said.

Jeff Allen PhD, president and CEO of the nonprofit Friends of Cancer Research, who wasn’t involved in the study, believes that an FDA approval before publication shouldn’t be “particularly concerning.”

“Peer-reviewed publication is an important component of validating and communicating scientific findings, but the processes and time lines for individual journals can be highly variable,” he said. “I don’t think we would want to see a situation where potential beneficial treatments are held up due to unrelated publication processes.”

The author of an invited commentary in JAMA Network Open had a different take on the study findings.

“A tempting interpretation” of this study is that the FDA is a “superior agency for expedited review times that bring cancer drugs to patients earlier,” Kristina Jenei, BSN, MSc, with the University of British Columbia School of Population and Public Health, writes. In addition, the fact that more drugs were pulled from the market after approval in the United States than in Europe could be interpreted to mean that the system is working as it should.

Although the speed of FDA reviews and the number of subsequent approvals have increased over time, the proportion of cancer drugs that improve survival has declined. In addition, because the FDA’s follow-up of postmarketing studies has been “inconsistent,” a substantial number of cancer drugs that were approved through accelerated pathways have remained on the market for years without confirmation of their benefit.

Although regulatory agencies must balance earlier patient access to novel treatments with evidence that the therapies are effective and safe, “faster review times and approvals are not cause for celebration; better patient outcomes are,” Ms. Jenei writes. “In other words, quality over quantity.”

The study was supported by the National Cancer Institute. Dr. Khaki reported stock ownership from Merck and stock ownership from Sanofi outside the submitted work. Dr. Allen and Ms. Jenei have disclosed no relevant financial relationships.

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

Over the past decade, the U.S. Food and Drug Administration has approved new cancer drugs twice as fast as the European Medicines Agency (EMA), often using accelerated pathways, a new analysis shows.

Between 2010 and 2019, the FDA approved almost all oncology therapies ahead of the EMA. Drugs entered the United States market about 8 months (241 days) before European market authorization.

But do quicker review times translate to wins for patients?

“The faster FDA approval process potentially provides earlier access to potentially life-prolonging medications for patients with cancer in the United States,” Ali Raza Khaki, MD, department of oncology, Stanford (Calif.) University School of Medicine, told this news organization. “On the surface, this is a good thing. However, it comes with limitations.”

Earlier drug approval often means greater uncertainty about an agent’s benefit – most notably, whether it will improve a patient’s survival or quality of life. Dr. Khaki pointed to a study published in JAMA Internal Medicine, which found that only 19 of 93 (20%) cancer drugs that had been recently approved through the FDA’s accelerated approval pathway demonstrated an improvement in overall survival.

In the new study, published online in JAMA Network Open, Dr. Khaki and colleagues found that among the 89 cancer drugs approved in the United States and Europe between January 2010 and December 2019, the FDA approved 85 (95%) before European authorization and four (5%) after.

The researchers found that the median FDA review time was half that of the EMA’s (200 vs. 426 days). Furthermore, 64 new drug applications (72%) were submitted to the FDA first, compared with 21 (23%) to the EMA.

Of the drugs approved through an accelerated pathway, three were ultimately pulled from the U.S. market, compared with one in Europe.

“These early drug approvals that later lead to withdrawal expose many more patients to toxicity, including financial toxicity, given the high cost of cancer medications,” Dr. Khaki commented.

In addition, 35 oncology therapies (39%) were approved by the FDA before trial results were published, compared with only eight (9%) by the EMA. Although FDA drug labels contain some information about efficacy and toxicity, scientific publications often have much more, including details about study populations and toxicities.

“Without this information, providers may be limited in their knowledge about patient selection, clinical benefit, and optimal toxicity management,” Dr. Khaki said.

Jeff Allen PhD, president and CEO of the nonprofit Friends of Cancer Research, who wasn’t involved in the study, believes that an FDA approval before publication shouldn’t be “particularly concerning.”

“Peer-reviewed publication is an important component of validating and communicating scientific findings, but the processes and time lines for individual journals can be highly variable,” he said. “I don’t think we would want to see a situation where potential beneficial treatments are held up due to unrelated publication processes.”

The author of an invited commentary in JAMA Network Open had a different take on the study findings.

“A tempting interpretation” of this study is that the FDA is a “superior agency for expedited review times that bring cancer drugs to patients earlier,” Kristina Jenei, BSN, MSc, with the University of British Columbia School of Population and Public Health, writes. In addition, the fact that more drugs were pulled from the market after approval in the United States than in Europe could be interpreted to mean that the system is working as it should.

Although the speed of FDA reviews and the number of subsequent approvals have increased over time, the proportion of cancer drugs that improve survival has declined. In addition, because the FDA’s follow-up of postmarketing studies has been “inconsistent,” a substantial number of cancer drugs that were approved through accelerated pathways have remained on the market for years without confirmation of their benefit.

Although regulatory agencies must balance earlier patient access to novel treatments with evidence that the therapies are effective and safe, “faster review times and approvals are not cause for celebration; better patient outcomes are,” Ms. Jenei writes. “In other words, quality over quantity.”

The study was supported by the National Cancer Institute. Dr. Khaki reported stock ownership from Merck and stock ownership from Sanofi outside the submitted work. Dr. Allen and Ms. Jenei have disclosed no relevant financial relationships.

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

Adults in the United States increasingly perceive electronic cigarettes, or e-cigarettes, as “more harmful” than traditional cigarettes, according to a new study published in the American Journal of Preventive Medicine.

In addition, the percentage of people who exclusively used traditional cigarettes almost doubled between 2019 and 2020 among those who perceived e-cigarettes as more harmful, jumping from 8.4% in 2019 to 16.3% in 2020.

“We were able to show that these changes in perception potentially changed behaviors on a population level,” said Priti Bandi, PhD, principal scientist at the American Cancer Society in Atlanta and lead author of the study.

Since e-cigarettes entered the U.S. market in 2006, public health experts have questioned claims from manufacturers that the products work as a harm reduction tool to help traditional cigarette smokers to quit. Public perceptions have generally been that e-cigarettes are safer for a person’s health. While the research is still emerging on the long-term health outcomes of users, public opinion has shifted since the introduction of the devices.

The new study showed a sharp change in public perception of e-cigarettes following media coverage of cases of users who presented to emergency rooms with mysterious lung symptoms in 2019. The Centers for Disease Control and Prevention eventually found that what are now called e-cigarette or vaping product use–associated lung injuries were linked to vitamin E acetate, an additive to tetrahydrocannabinol-containing products but not nicotine.

The last update from the CDC came in February 2020, shortly before the COVID-19 pandemic swept through the United States, prompting a sharp shift to investigate the new virus among both health care providers and researchers.

Dr. Bandi and colleagues gathered 2018-2020 data from a National Institutes of Health database called the Health Information National Trends Survey, a mail-based, nationally representative, cross-sectional survey of U.S. adults and their attitudes of cancer and health-related information. More than 3,000 people each year responded to questions about e-cigarettes.

The study found that the percentage of people who believed e-cigarettes to be more harmful than traditional cigarettes more than tripled from 6.8% in 2018 to 28.3% in 2020. Fewer people also viewed e-cigarettes as less harmful than traditional cigarettes, falling from 17.6% in 2018 to 11.4% in 2020. Fewer people also said they were unsure about which product was more harmful.

Among those who believed e-cigarettes were “relatively” less harmful than traditional cigarettes, use of e-cigarettes jumped from 15.3% in 2019 to 26.7% in 2020.
 

The implications

The main finding that people started smoking cigarettes when they thought e-cigarettes were more harmful should be a wake-up to public health officials and doctors who communicate health risks to patients, according to Dr. Bandi and other experts.

Messaging should be more nuanced, Dr. Bandi said. Many adults use e-cigarettes as a cessation tool, and she and other experts point to research that shows the products are, at least in the short-term, less harmful especially as a smoking cessation tool. Vapes are among the most popular tools people use when they want to quit smoking – with the majority of U.S. adults using vapes either partially or fully to quit, according to the CDC.

Some countries, such as England, are moving to allow doctors to prescribe e-cigarettes to help reduce smoking rates. United Kingdom regulatory authorities in 2021 said they’re considering allowing licensing the devices for use in smoking cessation.

“There is an absolute need for ongoing, accurate communication from public health authorities targeted toward the appropriate audiences,” Bandi said.

Ashley Brooks-Russell, PhD, MPH, associate professor at the University of Colorado at Denver, Aurora, said the finding that perceptions can change behavior is good news. However, the bad news is that adults overcorrected and switched to cigarettes, which are proven to cause cancer and other health conditions.

“We’re good in public health about messaging that cigarettes are bad, that tobacco is broadly harmful,” Dr. Brooks-Russell said in an interview. “We’re really bad at talking about lesser options, like if you’re going to smoke, e-cigarettes are less harmful.” 

But other health leaders warn that e-cigarettes might produce the same adverse health outcomes, or worse, as cigarettes. The only way researchers will gain a conclusive answer is decades into a patient’s life. Until then, it’s not clear if any potential benefit from smoking cessation will outweigh the risks.

“This research should remind healthcare providers to find out what products patients are using, how much, and if those patients experience health issues later on,” said Kevin McQueen, MHA, lead respiratory director at University of Colorado Health System and president of the Colorado Respiratory Care Society.

“My concern is that while people are starting to think e-cigarettes are more dangerous, some people still think they are safe – and we don’t know how much safer they are,” he said. “And we aren’t going to know until 10, 15, 20 years from now.”

All authors were employed by the American Cancer Society at the time of the study, which receives grants from private and corporate foundations, including foundations associated with companies in the health sector for research outside of the submitted work. The authors are not funded by or key personnel for any of these grants, and their salaries are solely funded through American Cancer Society funds. No other financial disclosures were reported.

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

Adults in the United States increasingly perceive electronic cigarettes, or e-cigarettes, as “more harmful” than traditional cigarettes, according to a new study published in the American Journal of Preventive Medicine.

In addition, the percentage of people who exclusively used traditional cigarettes almost doubled between 2019 and 2020 among those who perceived e-cigarettes as more harmful, jumping from 8.4% in 2019 to 16.3% in 2020.

“We were able to show that these changes in perception potentially changed behaviors on a population level,” said Priti Bandi, PhD, principal scientist at the American Cancer Society in Atlanta and lead author of the study.

Since e-cigarettes entered the U.S. market in 2006, public health experts have questioned claims from manufacturers that the products work as a harm reduction tool to help traditional cigarette smokers to quit. Public perceptions have generally been that e-cigarettes are safer for a person’s health. While the research is still emerging on the long-term health outcomes of users, public opinion has shifted since the introduction of the devices.

The new study showed a sharp change in public perception of e-cigarettes following media coverage of cases of users who presented to emergency rooms with mysterious lung symptoms in 2019. The Centers for Disease Control and Prevention eventually found that what are now called e-cigarette or vaping product use–associated lung injuries were linked to vitamin E acetate, an additive to tetrahydrocannabinol-containing products but not nicotine.

The last update from the CDC came in February 2020, shortly before the COVID-19 pandemic swept through the United States, prompting a sharp shift to investigate the new virus among both health care providers and researchers.

Dr. Bandi and colleagues gathered 2018-2020 data from a National Institutes of Health database called the Health Information National Trends Survey, a mail-based, nationally representative, cross-sectional survey of U.S. adults and their attitudes of cancer and health-related information. More than 3,000 people each year responded to questions about e-cigarettes.

The study found that the percentage of people who believed e-cigarettes to be more harmful than traditional cigarettes more than tripled from 6.8% in 2018 to 28.3% in 2020. Fewer people also viewed e-cigarettes as less harmful than traditional cigarettes, falling from 17.6% in 2018 to 11.4% in 2020. Fewer people also said they were unsure about which product was more harmful.

Among those who believed e-cigarettes were “relatively” less harmful than traditional cigarettes, use of e-cigarettes jumped from 15.3% in 2019 to 26.7% in 2020.
 

The implications

The main finding that people started smoking cigarettes when they thought e-cigarettes were more harmful should be a wake-up to public health officials and doctors who communicate health risks to patients, according to Dr. Bandi and other experts.

Messaging should be more nuanced, Dr. Bandi said. Many adults use e-cigarettes as a cessation tool, and she and other experts point to research that shows the products are, at least in the short-term, less harmful especially as a smoking cessation tool. Vapes are among the most popular tools people use when they want to quit smoking – with the majority of U.S. adults using vapes either partially or fully to quit, according to the CDC.

Some countries, such as England, are moving to allow doctors to prescribe e-cigarettes to help reduce smoking rates. United Kingdom regulatory authorities in 2021 said they’re considering allowing licensing the devices for use in smoking cessation.

“There is an absolute need for ongoing, accurate communication from public health authorities targeted toward the appropriate audiences,” Bandi said.

Ashley Brooks-Russell, PhD, MPH, associate professor at the University of Colorado at Denver, Aurora, said the finding that perceptions can change behavior is good news. However, the bad news is that adults overcorrected and switched to cigarettes, which are proven to cause cancer and other health conditions.

“We’re good in public health about messaging that cigarettes are bad, that tobacco is broadly harmful,” Dr. Brooks-Russell said in an interview. “We’re really bad at talking about lesser options, like if you’re going to smoke, e-cigarettes are less harmful.” 

But other health leaders warn that e-cigarettes might produce the same adverse health outcomes, or worse, as cigarettes. The only way researchers will gain a conclusive answer is decades into a patient’s life. Until then, it’s not clear if any potential benefit from smoking cessation will outweigh the risks.

“This research should remind healthcare providers to find out what products patients are using, how much, and if those patients experience health issues later on,” said Kevin McQueen, MHA, lead respiratory director at University of Colorado Health System and president of the Colorado Respiratory Care Society.

“My concern is that while people are starting to think e-cigarettes are more dangerous, some people still think they are safe – and we don’t know how much safer they are,” he said. “And we aren’t going to know until 10, 15, 20 years from now.”

All authors were employed by the American Cancer Society at the time of the study, which receives grants from private and corporate foundations, including foundations associated with companies in the health sector for research outside of the submitted work. The authors are not funded by or key personnel for any of these grants, and their salaries are solely funded through American Cancer Society funds. No other financial disclosures were reported.

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

Adults in the United States increasingly perceive electronic cigarettes, or e-cigarettes, as “more harmful” than traditional cigarettes, according to a new study published in the American Journal of Preventive Medicine.

In addition, the percentage of people who exclusively used traditional cigarettes almost doubled between 2019 and 2020 among those who perceived e-cigarettes as more harmful, jumping from 8.4% in 2019 to 16.3% in 2020.

“We were able to show that these changes in perception potentially changed behaviors on a population level,” said Priti Bandi, PhD, principal scientist at the American Cancer Society in Atlanta and lead author of the study.

Since e-cigarettes entered the U.S. market in 2006, public health experts have questioned claims from manufacturers that the products work as a harm reduction tool to help traditional cigarette smokers to quit. Public perceptions have generally been that e-cigarettes are safer for a person’s health. While the research is still emerging on the long-term health outcomes of users, public opinion has shifted since the introduction of the devices.

The new study showed a sharp change in public perception of e-cigarettes following media coverage of cases of users who presented to emergency rooms with mysterious lung symptoms in 2019. The Centers for Disease Control and Prevention eventually found that what are now called e-cigarette or vaping product use–associated lung injuries were linked to vitamin E acetate, an additive to tetrahydrocannabinol-containing products but not nicotine.

The last update from the CDC came in February 2020, shortly before the COVID-19 pandemic swept through the United States, prompting a sharp shift to investigate the new virus among both health care providers and researchers.

Dr. Bandi and colleagues gathered 2018-2020 data from a National Institutes of Health database called the Health Information National Trends Survey, a mail-based, nationally representative, cross-sectional survey of U.S. adults and their attitudes of cancer and health-related information. More than 3,000 people each year responded to questions about e-cigarettes.

The study found that the percentage of people who believed e-cigarettes to be more harmful than traditional cigarettes more than tripled from 6.8% in 2018 to 28.3% in 2020. Fewer people also viewed e-cigarettes as less harmful than traditional cigarettes, falling from 17.6% in 2018 to 11.4% in 2020. Fewer people also said they were unsure about which product was more harmful.

Among those who believed e-cigarettes were “relatively” less harmful than traditional cigarettes, use of e-cigarettes jumped from 15.3% in 2019 to 26.7% in 2020.
 

The implications

The main finding that people started smoking cigarettes when they thought e-cigarettes were more harmful should be a wake-up to public health officials and doctors who communicate health risks to patients, according to Dr. Bandi and other experts.

Messaging should be more nuanced, Dr. Bandi said. Many adults use e-cigarettes as a cessation tool, and she and other experts point to research that shows the products are, at least in the short-term, less harmful especially as a smoking cessation tool. Vapes are among the most popular tools people use when they want to quit smoking – with the majority of U.S. adults using vapes either partially or fully to quit, according to the CDC.

Some countries, such as England, are moving to allow doctors to prescribe e-cigarettes to help reduce smoking rates. United Kingdom regulatory authorities in 2021 said they’re considering allowing licensing the devices for use in smoking cessation.

“There is an absolute need for ongoing, accurate communication from public health authorities targeted toward the appropriate audiences,” Bandi said.

Ashley Brooks-Russell, PhD, MPH, associate professor at the University of Colorado at Denver, Aurora, said the finding that perceptions can change behavior is good news. However, the bad news is that adults overcorrected and switched to cigarettes, which are proven to cause cancer and other health conditions.

“We’re good in public health about messaging that cigarettes are bad, that tobacco is broadly harmful,” Dr. Brooks-Russell said in an interview. “We’re really bad at talking about lesser options, like if you’re going to smoke, e-cigarettes are less harmful.” 

But other health leaders warn that e-cigarettes might produce the same adverse health outcomes, or worse, as cigarettes. The only way researchers will gain a conclusive answer is decades into a patient’s life. Until then, it’s not clear if any potential benefit from smoking cessation will outweigh the risks.

“This research should remind healthcare providers to find out what products patients are using, how much, and if those patients experience health issues later on,” said Kevin McQueen, MHA, lead respiratory director at University of Colorado Health System and president of the Colorado Respiratory Care Society.

“My concern is that while people are starting to think e-cigarettes are more dangerous, some people still think they are safe – and we don’t know how much safer they are,” he said. “And we aren’t going to know until 10, 15, 20 years from now.”

All authors were employed by the American Cancer Society at the time of the study, which receives grants from private and corporate foundations, including foundations associated with companies in the health sector for research outside of the submitted work. The authors are not funded by or key personnel for any of these grants, and their salaries are solely funded through American Cancer Society funds. No other financial disclosures were reported.

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

ATLANTA – Disturbances in ovulation that didn’t produce any actual changes in the menstrual cycle of women were extremely common during the first year of the COVID-19 pandemic and were linked to emotional stress, according to the findings of an “experiment of nature” that allowed for comparison with women a decade earlier.

Findings from two studies of reproductive-age women, one conducted in 2006-2008 and the other in 2020-2021, were presented by Jerilynn C. Prior, MD, at the annual meeting of the Endocrine Society.

The comparison of the two time periods yielded several novel findings. “I was taught in medical school that when women don’t eat enough they lose their period. But what we now understand is there’s a graded response to various stressors, acting through the hypothalamus in a common pathway. There is a gradation of disturbances, some of which are subclinical or not obvious,” said Dr. Prior, professor of endocrinology and metabolism at the University of British Columbia, Vancouver.

Moreover, women’s menstrual cycle lengths didn’t differ across the two time periods, despite a dramatic 63% decrement in normal ovulatory function related to increased depression, anxiety, and outside stresses that the women reported in diaries.

“Assuming that regular cycles need normal ovulation is something we should just get out of our minds. It changes our concept about what’s normal if we only know about the cycle length,” she observed.

It will be critical going forward to see whether the ovulatory disturbances have resolved as the pandemic has shifted “because there’s strong evidence that ovulatory disturbances, even with normal cycle length, are related to bone loss and some evidence it’s related to early heart attacks, breast and endometrial cancers,” Dr. Prior said during a press conference.

Lisa Nainggolan/MDedge News

Asked to comment, session moderator Genevieve Neal-Perry, MD, PhD, told this news organization: “I think what we can take away is that stress itself is a modifier of the way the brain and the gonads communicate with each other, and that then has an impact on ovulatory function.”

Dr. Neal-Perry noted that the association of stress and ovulatory disruption has been reported in various ways previously, but “clearly it doesn’t affect everyone. What we don’t know is who is most susceptible. There have been some studies showing a genetic predisposition and a genetic anomaly that actually makes them more susceptible to the impact of stress on the reproductive system.”

But the lack of data on weight change in the study cohorts is a limitation. “To me one of the more important questions was what was going on with weight. Just looking at a static number doesn’t tell you whether there were changes. We know that weight gain or weight loss can stress the reproductive axis,” noted Dr. Neal-Parry of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.
 

‘Experiment of nature’ revealed invisible effect of pandemic stress

The women in both cohorts of the Menstruation Ovulation Study (MOS) were healthy volunteers aged 19-35 years recruited from the metropolitan Vancouver region. All were menstruating monthly and none were taking hormonal birth control. Recruitment for the second cohort had begun just prior to the March 2020 COVID-19 pandemic lockdown.

Interviewer-administered questionnaires (CaMos) covering demographics, socioeconomic status, and reproductive history, and daily diaries kept by the women (menstrual cycle diary) were identical for both cohorts.

Assessments of ovulation differed for the two studies but were cross-validated. For the earlier time period, ovulation was assessed by a threefold increase in follicular-to-luteal urinary progesterone (PdG). For the pandemic-era study, the validated quantitative basal temperature (QBT) method was used.

There were 301 women in the earlier cohort and 125 during the pandemic. Both were an average age of about 29 years and had a body mass index of about 24.3 kg/m² (within the normal range). The pandemic cohort was more racially/ethnically diverse than the earlier one and more in-line with recent census data.

More of the women were nulliparous during the pandemic than earlier (92.7% vs. 80.4%; P = .002).

The distribution of menstrual cycle lengths didn’t differ, with both cohorts averaging about 30 days (P = .893). However, while 90% of the women in the earlier cohort ovulated normally, only 37% did during the pandemic, a highly significant difference (P < .0001).

Thus, during the pandemic, 63% of women had “silent ovulatory disturbances,” either with short luteal phases after ovulation or no ovulation, compared with just 10% in the earlier cohort, “which is remarkable, unbelievable actually,” Dr. Prior remarked.  

The difference wasn’t explained by any of the demographic information collected either, including socioeconomic status, lifestyle, or reproductive history variables.

And it wasn’t because of COVID-19 vaccination, as the vaccine wasn’t available when most of the women were recruited, and of the 79 who were recruited during vaccine availability, only two received a COVID-19 vaccine during the study (and both had normal ovulation).

Employment changes, caring responsibilities, and worry likely causes

The information from the diaries was more revealing. Several diary components were far more common during the pandemic, including negative mood (feeling depressed or anxious, sleep problems, and outside stresses), self-worth, interest in sex, energy level, and appetite. All were significantly different between the two cohorts (P < .001) and between those with and without ovulatory disturbances.

“So menstrual cycle lengths and long cycles didn’t differ, but there was a much higher prevalence of silent or subclinical ovulatory disturbances, and these were related to the increased stresses that women recorded in their diaries. This means that the estrogen levels were pretty close to normal but the progesterone levels were remarkably decreased,” Dr. Prior said.

Interestingly, reported menstrual cramps were also significantly more common during the pandemic and associated with ovulatory disruption.

“That is a new observation because previously we’ve always thought that you needed to ovulate in order to even have cramps,” she commented.

Asked whether COVID-19 itself might have played a role, Dr. Prior said no woman in the study tested positive for the virus or had long COVID.

“As far as I’m aware, it was the changes in employment … and caring for elders and worry about illness in somebody you loved that was related,” she said.

Asked what she thinks the result would be if the study were conducted now, she said: “I don’t know. We’re still in a stressful time with inflation and not complete recovery, so probably the issue is still very present.”

Dr. Prior and Dr. Neal-Perry have reported no relevant financial relationships.

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

ATLANTA – Disturbances in ovulation that didn’t produce any actual changes in the menstrual cycle of women were extremely common during the first year of the COVID-19 pandemic and were linked to emotional stress, according to the findings of an “experiment of nature” that allowed for comparison with women a decade earlier.

Findings from two studies of reproductive-age women, one conducted in 2006-2008 and the other in 2020-2021, were presented by Jerilynn C. Prior, MD, at the annual meeting of the Endocrine Society.

The comparison of the two time periods yielded several novel findings. “I was taught in medical school that when women don’t eat enough they lose their period. But what we now understand is there’s a graded response to various stressors, acting through the hypothalamus in a common pathway. There is a gradation of disturbances, some of which are subclinical or not obvious,” said Dr. Prior, professor of endocrinology and metabolism at the University of British Columbia, Vancouver.

Moreover, women’s menstrual cycle lengths didn’t differ across the two time periods, despite a dramatic 63% decrement in normal ovulatory function related to increased depression, anxiety, and outside stresses that the women reported in diaries.

“Assuming that regular cycles need normal ovulation is something we should just get out of our minds. It changes our concept about what’s normal if we only know about the cycle length,” she observed.

It will be critical going forward to see whether the ovulatory disturbances have resolved as the pandemic has shifted “because there’s strong evidence that ovulatory disturbances, even with normal cycle length, are related to bone loss and some evidence it’s related to early heart attacks, breast and endometrial cancers,” Dr. Prior said during a press conference.

Lisa Nainggolan/MDedge News

Asked to comment, session moderator Genevieve Neal-Perry, MD, PhD, told this news organization: “I think what we can take away is that stress itself is a modifier of the way the brain and the gonads communicate with each other, and that then has an impact on ovulatory function.”

Dr. Neal-Perry noted that the association of stress and ovulatory disruption has been reported in various ways previously, but “clearly it doesn’t affect everyone. What we don’t know is who is most susceptible. There have been some studies showing a genetic predisposition and a genetic anomaly that actually makes them more susceptible to the impact of stress on the reproductive system.”

But the lack of data on weight change in the study cohorts is a limitation. “To me one of the more important questions was what was going on with weight. Just looking at a static number doesn’t tell you whether there were changes. We know that weight gain or weight loss can stress the reproductive axis,” noted Dr. Neal-Parry of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.
 

‘Experiment of nature’ revealed invisible effect of pandemic stress

The women in both cohorts of the Menstruation Ovulation Study (MOS) were healthy volunteers aged 19-35 years recruited from the metropolitan Vancouver region. All were menstruating monthly and none were taking hormonal birth control. Recruitment for the second cohort had begun just prior to the March 2020 COVID-19 pandemic lockdown.

Interviewer-administered questionnaires (CaMos) covering demographics, socioeconomic status, and reproductive history, and daily diaries kept by the women (menstrual cycle diary) were identical for both cohorts.

Assessments of ovulation differed for the two studies but were cross-validated. For the earlier time period, ovulation was assessed by a threefold increase in follicular-to-luteal urinary progesterone (PdG). For the pandemic-era study, the validated quantitative basal temperature (QBT) method was used.

There were 301 women in the earlier cohort and 125 during the pandemic. Both were an average age of about 29 years and had a body mass index of about 24.3 kg/m² (within the normal range). The pandemic cohort was more racially/ethnically diverse than the earlier one and more in-line with recent census data.

More of the women were nulliparous during the pandemic than earlier (92.7% vs. 80.4%; P = .002).

The distribution of menstrual cycle lengths didn’t differ, with both cohorts averaging about 30 days (P = .893). However, while 90% of the women in the earlier cohort ovulated normally, only 37% did during the pandemic, a highly significant difference (P < .0001).

Thus, during the pandemic, 63% of women had “silent ovulatory disturbances,” either with short luteal phases after ovulation or no ovulation, compared with just 10% in the earlier cohort, “which is remarkable, unbelievable actually,” Dr. Prior remarked.  

The difference wasn’t explained by any of the demographic information collected either, including socioeconomic status, lifestyle, or reproductive history variables.

And it wasn’t because of COVID-19 vaccination, as the vaccine wasn’t available when most of the women were recruited, and of the 79 who were recruited during vaccine availability, only two received a COVID-19 vaccine during the study (and both had normal ovulation).

Employment changes, caring responsibilities, and worry likely causes

The information from the diaries was more revealing. Several diary components were far more common during the pandemic, including negative mood (feeling depressed or anxious, sleep problems, and outside stresses), self-worth, interest in sex, energy level, and appetite. All were significantly different between the two cohorts (P < .001) and between those with and without ovulatory disturbances.

“So menstrual cycle lengths and long cycles didn’t differ, but there was a much higher prevalence of silent or subclinical ovulatory disturbances, and these were related to the increased stresses that women recorded in their diaries. This means that the estrogen levels were pretty close to normal but the progesterone levels were remarkably decreased,” Dr. Prior said.

Interestingly, reported menstrual cramps were also significantly more common during the pandemic and associated with ovulatory disruption.

“That is a new observation because previously we’ve always thought that you needed to ovulate in order to even have cramps,” she commented.

Asked whether COVID-19 itself might have played a role, Dr. Prior said no woman in the study tested positive for the virus or had long COVID.

“As far as I’m aware, it was the changes in employment … and caring for elders and worry about illness in somebody you loved that was related,” she said.

Asked what she thinks the result would be if the study were conducted now, she said: “I don’t know. We’re still in a stressful time with inflation and not complete recovery, so probably the issue is still very present.”

Dr. Prior and Dr. Neal-Perry have reported no relevant financial relationships.

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

ATLANTA – Disturbances in ovulation that didn’t produce any actual changes in the menstrual cycle of women were extremely common during the first year of the COVID-19 pandemic and were linked to emotional stress, according to the findings of an “experiment of nature” that allowed for comparison with women a decade earlier.

Findings from two studies of reproductive-age women, one conducted in 2006-2008 and the other in 2020-2021, were presented by Jerilynn C. Prior, MD, at the annual meeting of the Endocrine Society.

The comparison of the two time periods yielded several novel findings. “I was taught in medical school that when women don’t eat enough they lose their period. But what we now understand is there’s a graded response to various stressors, acting through the hypothalamus in a common pathway. There is a gradation of disturbances, some of which are subclinical or not obvious,” said Dr. Prior, professor of endocrinology and metabolism at the University of British Columbia, Vancouver.

Moreover, women’s menstrual cycle lengths didn’t differ across the two time periods, despite a dramatic 63% decrement in normal ovulatory function related to increased depression, anxiety, and outside stresses that the women reported in diaries.

“Assuming that regular cycles need normal ovulation is something we should just get out of our minds. It changes our concept about what’s normal if we only know about the cycle length,” she observed.

It will be critical going forward to see whether the ovulatory disturbances have resolved as the pandemic has shifted “because there’s strong evidence that ovulatory disturbances, even with normal cycle length, are related to bone loss and some evidence it’s related to early heart attacks, breast and endometrial cancers,” Dr. Prior said during a press conference.

Lisa Nainggolan/MDedge News

Asked to comment, session moderator Genevieve Neal-Perry, MD, PhD, told this news organization: “I think what we can take away is that stress itself is a modifier of the way the brain and the gonads communicate with each other, and that then has an impact on ovulatory function.”

Dr. Neal-Perry noted that the association of stress and ovulatory disruption has been reported in various ways previously, but “clearly it doesn’t affect everyone. What we don’t know is who is most susceptible. There have been some studies showing a genetic predisposition and a genetic anomaly that actually makes them more susceptible to the impact of stress on the reproductive system.”

But the lack of data on weight change in the study cohorts is a limitation. “To me one of the more important questions was what was going on with weight. Just looking at a static number doesn’t tell you whether there were changes. We know that weight gain or weight loss can stress the reproductive axis,” noted Dr. Neal-Parry of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.
 

‘Experiment of nature’ revealed invisible effect of pandemic stress

The women in both cohorts of the Menstruation Ovulation Study (MOS) were healthy volunteers aged 19-35 years recruited from the metropolitan Vancouver region. All were menstruating monthly and none were taking hormonal birth control. Recruitment for the second cohort had begun just prior to the March 2020 COVID-19 pandemic lockdown.

Interviewer-administered questionnaires (CaMos) covering demographics, socioeconomic status, and reproductive history, and daily diaries kept by the women (menstrual cycle diary) were identical for both cohorts.

Assessments of ovulation differed for the two studies but were cross-validated. For the earlier time period, ovulation was assessed by a threefold increase in follicular-to-luteal urinary progesterone (PdG). For the pandemic-era study, the validated quantitative basal temperature (QBT) method was used.

There were 301 women in the earlier cohort and 125 during the pandemic. Both were an average age of about 29 years and had a body mass index of about 24.3 kg/m² (within the normal range). The pandemic cohort was more racially/ethnically diverse than the earlier one and more in-line with recent census data.

More of the women were nulliparous during the pandemic than earlier (92.7% vs. 80.4%; P = .002).

The distribution of menstrual cycle lengths didn’t differ, with both cohorts averaging about 30 days (P = .893). However, while 90% of the women in the earlier cohort ovulated normally, only 37% did during the pandemic, a highly significant difference (P < .0001).

Thus, during the pandemic, 63% of women had “silent ovulatory disturbances,” either with short luteal phases after ovulation or no ovulation, compared with just 10% in the earlier cohort, “which is remarkable, unbelievable actually,” Dr. Prior remarked.  

The difference wasn’t explained by any of the demographic information collected either, including socioeconomic status, lifestyle, or reproductive history variables.

And it wasn’t because of COVID-19 vaccination, as the vaccine wasn’t available when most of the women were recruited, and of the 79 who were recruited during vaccine availability, only two received a COVID-19 vaccine during the study (and both had normal ovulation).

Employment changes, caring responsibilities, and worry likely causes

The information from the diaries was more revealing. Several diary components were far more common during the pandemic, including negative mood (feeling depressed or anxious, sleep problems, and outside stresses), self-worth, interest in sex, energy level, and appetite. All were significantly different between the two cohorts (P < .001) and between those with and without ovulatory disturbances.

“So menstrual cycle lengths and long cycles didn’t differ, but there was a much higher prevalence of silent or subclinical ovulatory disturbances, and these were related to the increased stresses that women recorded in their diaries. This means that the estrogen levels were pretty close to normal but the progesterone levels were remarkably decreased,” Dr. Prior said.

Interestingly, reported menstrual cramps were also significantly more common during the pandemic and associated with ovulatory disruption.

“That is a new observation because previously we’ve always thought that you needed to ovulate in order to even have cramps,” she commented.

Asked whether COVID-19 itself might have played a role, Dr. Prior said no woman in the study tested positive for the virus or had long COVID.

“As far as I’m aware, it was the changes in employment … and caring for elders and worry about illness in somebody you loved that was related,” she said.

Asked what she thinks the result would be if the study were conducted now, she said: “I don’t know. We’re still in a stressful time with inflation and not complete recovery, so probably the issue is still very present.”

Dr. Prior and Dr. Neal-Perry have reported no relevant financial relationships.

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