During the ongoing COVID-19 pandemic, many people are spending endless hours at home looking at computer, phone, and television screens. Our population has turned to Internet use and television watching as a coping mechanism to deal with their isolation, boredom, stress, and fear of the virus. Indeed, some people have become addicted to watching television and binge-watching entire series in a single sitting on subscription streaming services.

A U.K. study showed that, during the lockdown, adults averaged spending 40% of their waking hours in front of a screen. After a long binge-watch, folks often forget what happened in the episodes or even the name of the program they viewed. When someone finds himself in this situation and can’t remember very much about what he actually watched, he feels as though he has wasted his own time and might become dysphoric and depressed. This type of viewer feels disconnected and forgets what he watched because he is experiencing passive enjoyment, rather than actively relating to the world.

So should television binge-watching give people feelings of guilt?

Fortunately, there are some positive factors about spending excessive time engrossed in these screens during a pandemic; some people use television viewing as a coping mechanism to deal with the reality and the fear of the coronavirus. Some beneficial aspects of television watching include:

• Escaping from the reality and stress of the pandemic in an emotionally safe, isolated cocoon.
• Experiencing safety from contracting COVID-19 by sheltering in place, isolating, and physical distancing from other people in the outside world.
• Experiencing a subdued, private, and mentally relaxing environment.
• Being productive and multitasking while watching television, for example, knit, sew, fold clothes, pay bills, write a letter, etc.

Despite many beneficial aspects of excessive television watching during the pandemic, we have to ask: Can too much television prove detrimental to our mental or physical well-being?
 

Associated mental, and physical problems

Cause and effect between excessive screen time and sleep disturbances is scientifically unproven, but there is an association between those factors.

Excessive screen time is associated with a sleep deficit, and a proper amount of sleep is necessary for optimal brain function, a healthy immune system, good memory, and overall well-being. Sleep cleans out the short-term memory stage from the information learned that day to make room for new memories. This allows us to store memories every day. An inadequate amount of sleep causes memory problems and cognitive deficits because we are not storing as many memories from days when we are sleep deprived. A good night’s sleep will prevent stress from one day to be carried over to the next day.

Lack of sleep affects people differently, but in some cases, a shortage of sleep can cause feelings of depression and isolation. Television, computer, and phone screens convey excessive damaging LED and blue light, detrimentally affecting our melatonin production and circadian rhythm. Blue light has wavelengths between 380 nm and 500 nm, and although blue wavelengths are beneficial in the day and increase positive mental mood, attention, and reaction times, blue wavelengths are destructive at night. Blue-light exposure suppresses the secretion of melatonin, which, as we know, is a hormone that influences circadian rhythms. The negative disruption of circadian rhythm throws the body’s biological clock in disarray and makes it more difficult for the mind to shut down at night.

Unfortunately, electronics with LED screens increase the amount of exposure to these blue wavelengths. In addition, the U.S. National Toxicology Program has suggested that a link exists between blue-light exposure at night to diabetes, heart disease, cancer, and obesity (Sci Tot Environ. 2017 Dec 31;[607-8]:1073-84).
 

Advice for patients and clinicians

Time spent watching television and using the Internet should be done in moderation. Make sure that patients understand that they should not feel guilty about watching television during these periods of isolation.

Encourage patients to be selective in their television viewing and to research available programs on streaming services and TV – and limit their screen time only to programs that truly interest them. Discourage them from watching television endlessly, hour after hour. Also, discourage patients from watching too much news. Instead, tell them to limit news to 1 hour per day, because news they perceive as bad might increase their overall anxiety.

Tell patients to engage in physical exercise every day; walk or run outside if possible. When inside, advise them to get up and walk around at least once per hour. Other advice we would like to offer patients and clinicians alike are:

• Put yourself on a schedule and go to sleep the same time each night and try to get 8 hours of sleep in a 24-hour period.
• Put away your devices 1 hour before going to bed or at least use dark mode, and wear blue-block glasses, since they are easier on the eyes and brain. Do not use television to put yourself to sleep. Spending too much time reading news stories is not a good idea, either, because doing so is mentally stimulating and can cause more uncertainty – making it difficult to sleep.
• Protect your eye health by purchasing and installing light bulbs with more internal red coating than blue. These bulbs will produce a warmer tone than the blue, and warmer tones will be less likely to shift circadian rhythm and suppress melatonin, thus reducing blue-light exposure. Blink your eyes often, and use eye solution for dry eyes.
• Sleep in total darkness to reduce your exposure to blue light. Take supplements with lutein and zeaxanthin, which may reduce the oxidative effects of blue light.

Encouraging patients to follow these guidelines – and adhering to them ourselves – should help us emerge from the COVID-19 pandemic mentally and physically healthy.

Dr. Cohen is board certified in psychiatry and has had a private practice in Philadelphia for more than 35 years. His areas of specialty include sports psychiatry, agoraphobia, depression, and substance abuse. In addition, Dr. Cohen is a former professor of psychiatry, family medicine, and otolaryngology at Thomas Jefferson University, Philadelphia. He has no conflicts of interest.

Ms. Cohen holds an MBA from Temple University, Philadelphia, with a focus on health care administration. Previously, Ms. Cohen was an associate administrator at Hahnemann University Hospital and an executive at the Health Services Council, both in Philadelphia. She currently writes biographical summaries of notable 18th- and 19th-century women. Ms. Cohen has no conflicts of interest.

During the ongoing COVID-19 pandemic, many people are spending endless hours at home looking at computer, phone, and television screens. Our population has turned to Internet use and television watching as a coping mechanism to deal with their isolation, boredom, stress, and fear of the virus. Indeed, some people have become addicted to watching television and binge-watching entire series in a single sitting on subscription streaming services.

A U.K. study showed that, during the lockdown, adults averaged spending 40% of their waking hours in front of a screen. After a long binge-watch, folks often forget what happened in the episodes or even the name of the program they viewed. When someone finds himself in this situation and can’t remember very much about what he actually watched, he feels as though he has wasted his own time and might become dysphoric and depressed. This type of viewer feels disconnected and forgets what he watched because he is experiencing passive enjoyment, rather than actively relating to the world.

So should television binge-watching give people feelings of guilt?

Fortunately, there are some positive factors about spending excessive time engrossed in these screens during a pandemic; some people use television viewing as a coping mechanism to deal with the reality and the fear of the coronavirus. Some beneficial aspects of television watching include:

• Escaping from the reality and stress of the pandemic in an emotionally safe, isolated cocoon.
• Experiencing safety from contracting COVID-19 by sheltering in place, isolating, and physical distancing from other people in the outside world.
• Experiencing a subdued, private, and mentally relaxing environment.
• Being productive and multitasking while watching television, for example, knit, sew, fold clothes, pay bills, write a letter, etc.

Despite many beneficial aspects of excessive television watching during the pandemic, we have to ask: Can too much television prove detrimental to our mental or physical well-being?
 

Associated mental, and physical problems

Cause and effect between excessive screen time and sleep disturbances is scientifically unproven, but there is an association between those factors.

Excessive screen time is associated with a sleep deficit, and a proper amount of sleep is necessary for optimal brain function, a healthy immune system, good memory, and overall well-being. Sleep cleans out the short-term memory stage from the information learned that day to make room for new memories. This allows us to store memories every day. An inadequate amount of sleep causes memory problems and cognitive deficits because we are not storing as many memories from days when we are sleep deprived. A good night’s sleep will prevent stress from one day to be carried over to the next day.

Lack of sleep affects people differently, but in some cases, a shortage of sleep can cause feelings of depression and isolation. Television, computer, and phone screens convey excessive damaging LED and blue light, detrimentally affecting our melatonin production and circadian rhythm. Blue light has wavelengths between 380 nm and 500 nm, and although blue wavelengths are beneficial in the day and increase positive mental mood, attention, and reaction times, blue wavelengths are destructive at night. Blue-light exposure suppresses the secretion of melatonin, which, as we know, is a hormone that influences circadian rhythms. The negative disruption of circadian rhythm throws the body’s biological clock in disarray and makes it more difficult for the mind to shut down at night.

Unfortunately, electronics with LED screens increase the amount of exposure to these blue wavelengths. In addition, the U.S. National Toxicology Program has suggested that a link exists between blue-light exposure at night to diabetes, heart disease, cancer, and obesity (Sci Tot Environ. 2017 Dec 31;[607-8]:1073-84).
 

Advice for patients and clinicians

Time spent watching television and using the Internet should be done in moderation. Make sure that patients understand that they should not feel guilty about watching television during these periods of isolation.

Encourage patients to be selective in their television viewing and to research available programs on streaming services and TV – and limit their screen time only to programs that truly interest them. Discourage them from watching television endlessly, hour after hour. Also, discourage patients from watching too much news. Instead, tell them to limit news to 1 hour per day, because news they perceive as bad might increase their overall anxiety.

Tell patients to engage in physical exercise every day; walk or run outside if possible. When inside, advise them to get up and walk around at least once per hour. Other advice we would like to offer patients and clinicians alike are:

• Put yourself on a schedule and go to sleep the same time each night and try to get 8 hours of sleep in a 24-hour period.
• Put away your devices 1 hour before going to bed or at least use dark mode, and wear blue-block glasses, since they are easier on the eyes and brain. Do not use television to put yourself to sleep. Spending too much time reading news stories is not a good idea, either, because doing so is mentally stimulating and can cause more uncertainty – making it difficult to sleep.
• Protect your eye health by purchasing and installing light bulbs with more internal red coating than blue. These bulbs will produce a warmer tone than the blue, and warmer tones will be less likely to shift circadian rhythm and suppress melatonin, thus reducing blue-light exposure. Blink your eyes often, and use eye solution for dry eyes.
• Sleep in total darkness to reduce your exposure to blue light. Take supplements with lutein and zeaxanthin, which may reduce the oxidative effects of blue light.

Encouraging patients to follow these guidelines – and adhering to them ourselves – should help us emerge from the COVID-19 pandemic mentally and physically healthy.

Dr. Cohen is board certified in psychiatry and has had a private practice in Philadelphia for more than 35 years. His areas of specialty include sports psychiatry, agoraphobia, depression, and substance abuse. In addition, Dr. Cohen is a former professor of psychiatry, family medicine, and otolaryngology at Thomas Jefferson University, Philadelphia. He has no conflicts of interest.

Ms. Cohen holds an MBA from Temple University, Philadelphia, with a focus on health care administration. Previously, Ms. Cohen was an associate administrator at Hahnemann University Hospital and an executive at the Health Services Council, both in Philadelphia. She currently writes biographical summaries of notable 18th- and 19th-century women. Ms. Cohen has no conflicts of interest.

During the ongoing COVID-19 pandemic, many people are spending endless hours at home looking at computer, phone, and television screens. Our population has turned to Internet use and television watching as a coping mechanism to deal with their isolation, boredom, stress, and fear of the virus. Indeed, some people have become addicted to watching television and binge-watching entire series in a single sitting on subscription streaming services.

A U.K. study showed that, during the lockdown, adults averaged spending 40% of their waking hours in front of a screen. After a long binge-watch, folks often forget what happened in the episodes or even the name of the program they viewed. When someone finds himself in this situation and can’t remember very much about what he actually watched, he feels as though he has wasted his own time and might become dysphoric and depressed. This type of viewer feels disconnected and forgets what he watched because he is experiencing passive enjoyment, rather than actively relating to the world.

So should television binge-watching give people feelings of guilt?

Fortunately, there are some positive factors about spending excessive time engrossed in these screens during a pandemic; some people use television viewing as a coping mechanism to deal with the reality and the fear of the coronavirus. Some beneficial aspects of television watching include:

• Escaping from the reality and stress of the pandemic in an emotionally safe, isolated cocoon.
• Experiencing safety from contracting COVID-19 by sheltering in place, isolating, and physical distancing from other people in the outside world.
• Experiencing a subdued, private, and mentally relaxing environment.
• Being productive and multitasking while watching television, for example, knit, sew, fold clothes, pay bills, write a letter, etc.

Despite many beneficial aspects of excessive television watching during the pandemic, we have to ask: Can too much television prove detrimental to our mental or physical well-being?
 

Associated mental, and physical problems

Cause and effect between excessive screen time and sleep disturbances is scientifically unproven, but there is an association between those factors.

Excessive screen time is associated with a sleep deficit, and a proper amount of sleep is necessary for optimal brain function, a healthy immune system, good memory, and overall well-being. Sleep cleans out the short-term memory stage from the information learned that day to make room for new memories. This allows us to store memories every day. An inadequate amount of sleep causes memory problems and cognitive deficits because we are not storing as many memories from days when we are sleep deprived. A good night’s sleep will prevent stress from one day to be carried over to the next day.

Lack of sleep affects people differently, but in some cases, a shortage of sleep can cause feelings of depression and isolation. Television, computer, and phone screens convey excessive damaging LED and blue light, detrimentally affecting our melatonin production and circadian rhythm. Blue light has wavelengths between 380 nm and 500 nm, and although blue wavelengths are beneficial in the day and increase positive mental mood, attention, and reaction times, blue wavelengths are destructive at night. Blue-light exposure suppresses the secretion of melatonin, which, as we know, is a hormone that influences circadian rhythms. The negative disruption of circadian rhythm throws the body’s biological clock in disarray and makes it more difficult for the mind to shut down at night.

Unfortunately, electronics with LED screens increase the amount of exposure to these blue wavelengths. In addition, the U.S. National Toxicology Program has suggested that a link exists between blue-light exposure at night to diabetes, heart disease, cancer, and obesity (Sci Tot Environ. 2017 Dec 31;[607-8]:1073-84).
 

Advice for patients and clinicians

Time spent watching television and using the Internet should be done in moderation. Make sure that patients understand that they should not feel guilty about watching television during these periods of isolation.

Encourage patients to be selective in their television viewing and to research available programs on streaming services and TV – and limit their screen time only to programs that truly interest them. Discourage them from watching television endlessly, hour after hour. Also, discourage patients from watching too much news. Instead, tell them to limit news to 1 hour per day, because news they perceive as bad might increase their overall anxiety.

Tell patients to engage in physical exercise every day; walk or run outside if possible. When inside, advise them to get up and walk around at least once per hour. Other advice we would like to offer patients and clinicians alike are:

• Put yourself on a schedule and go to sleep the same time each night and try to get 8 hours of sleep in a 24-hour period.
• Put away your devices 1 hour before going to bed or at least use dark mode, and wear blue-block glasses, since they are easier on the eyes and brain. Do not use television to put yourself to sleep. Spending too much time reading news stories is not a good idea, either, because doing so is mentally stimulating and can cause more uncertainty – making it difficult to sleep.
• Protect your eye health by purchasing and installing light bulbs with more internal red coating than blue. These bulbs will produce a warmer tone than the blue, and warmer tones will be less likely to shift circadian rhythm and suppress melatonin, thus reducing blue-light exposure. Blink your eyes often, and use eye solution for dry eyes.
• Sleep in total darkness to reduce your exposure to blue light. Take supplements with lutein and zeaxanthin, which may reduce the oxidative effects of blue light.

Encouraging patients to follow these guidelines – and adhering to them ourselves – should help us emerge from the COVID-19 pandemic mentally and physically healthy.

Dr. Cohen is board certified in psychiatry and has had a private practice in Philadelphia for more than 35 years. His areas of specialty include sports psychiatry, agoraphobia, depression, and substance abuse. In addition, Dr. Cohen is a former professor of psychiatry, family medicine, and otolaryngology at Thomas Jefferson University, Philadelphia. He has no conflicts of interest.

Ms. Cohen holds an MBA from Temple University, Philadelphia, with a focus on health care administration. Previously, Ms. Cohen was an associate administrator at Hahnemann University Hospital and an executive at the Health Services Council, both in Philadelphia. She currently writes biographical summaries of notable 18th- and 19th-century women. Ms. Cohen has no conflicts of interest.

Brepocitinib, a first-in-class topical inhibitor of both tyrosine kinase 2 and Janus kinase 1, proved effective for treatment of mild to moderate atopic dermatitis (AD), and with a safety profile essentially indistinguishable from vehicle cream in a phase 2b randomized trial, Megan N. Landis, MD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.

The study included 240 adolescents and adults with mild to moderate AD at 70 sites in the United States and nine other countries. Patients’ mean baseline Eczema Area and Severity Index (EASI) score was 7.3, with 9.2% of their body surface area being involved. Participants were equally split between mild and moderate disease. They were randomized to 6 weeks of double-blind treatment in one of eight study arms: once-daily topical brepocitinib at a concentration of 0.1%, 0.3%, 1%, or 3%; twice-daily brepocitinib at 1% or 3%; or once- or twice-daily vehicle cream.

The primary endpoint was change in EASI score from baseline to week 6. Brepocitinib 1% and 3% once daily and 1% twice daily outperformed vehicle, with EASI score reductions of 70.1%, 67.9%, and 75%, respectively, compared with a 44.4% decrease among those in the once-daily vehicle control group and a 47.6% reduction among those in the twice-daily vehicle control group, according to Dr. Landis, a dermatologist at the University of Louisville (Ky).

The key secondary efficacy endpoint was the proportion of patients achieving an Investigator’s Global Assessment (IGA) score of 0 or 1 – clear or almost clear skin – plus at least a 2-point reduction at week 6. This occurred in a dose-dependent fashion in 27.8%-44.4% of patients on once-daily brepocitinib, all significantly better results than the 10.8% rate in once-daily controls. Patients on the TYK2/JAK1 inhibitor at 0.3% twice daily had a 33.3% IGA response rate, versus 13.9% with twice-daily vehicle, also a significant difference.

A 90% reduction in EASI score at week 6, or EASI 90 response, occurred in a dose-dependent fashion in 27.8%-41.7% of patients on 0.3%, 1%, and 3% of patients on once-daily brepocitinib, all significantly better than the 10.8% rate with once-daily vehicle, and in 27% of patients on brepocitinib 1% twice daily, versus 8.3% with twice-daily vehicle.

Improvement in itch was another secondary endpoint. A clinically meaningful week-6 improvement of at least 4 points on the Peak Pruritus Numerical Rating Scale was documented in 45.2% of patients on 1% brepocitinib once daily, 50% on 3% once daily, and 40.7% on 1% brepocitinib twice daily, all significantly better than the roughly 17% itch response rate in controls.

Treatment-emergent adverse events were about one-third more frequent in controls than in brepocitinib-treated patients. These events were overwhelmingly mild and were similar in nature in the two groups. There was no dose-dependent increase in treatment-emergent adverse events in the brepocitinib patients. Moreover, no serious treatment-emergent adverse events occurred during the study, nor were there any cases of herpes zoster or malignancies, and no changes in laboratory parameters or ECG findings.

Pfizer sponsored the phase 2b AD trial of the topical TYK2/JAK1 inhibitor, which is also in phase 2 studies for psoriatic arthritis, psoriasis, lupus, and alopecia areata.

Dr. Landis reported serving as a paid investigator for Pfizer and numerous other pharmaceutical companies.

[email protected]

Brepocitinib, a first-in-class topical inhibitor of both tyrosine kinase 2 and Janus kinase 1, proved effective for treatment of mild to moderate atopic dermatitis (AD), and with a safety profile essentially indistinguishable from vehicle cream in a phase 2b randomized trial, Megan N. Landis, MD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.

The study included 240 adolescents and adults with mild to moderate AD at 70 sites in the United States and nine other countries. Patients’ mean baseline Eczema Area and Severity Index (EASI) score was 7.3, with 9.2% of their body surface area being involved. Participants were equally split between mild and moderate disease. They were randomized to 6 weeks of double-blind treatment in one of eight study arms: once-daily topical brepocitinib at a concentration of 0.1%, 0.3%, 1%, or 3%; twice-daily brepocitinib at 1% or 3%; or once- or twice-daily vehicle cream.

The primary endpoint was change in EASI score from baseline to week 6. Brepocitinib 1% and 3% once daily and 1% twice daily outperformed vehicle, with EASI score reductions of 70.1%, 67.9%, and 75%, respectively, compared with a 44.4% decrease among those in the once-daily vehicle control group and a 47.6% reduction among those in the twice-daily vehicle control group, according to Dr. Landis, a dermatologist at the University of Louisville (Ky).

The key secondary efficacy endpoint was the proportion of patients achieving an Investigator’s Global Assessment (IGA) score of 0 or 1 – clear or almost clear skin – plus at least a 2-point reduction at week 6. This occurred in a dose-dependent fashion in 27.8%-44.4% of patients on once-daily brepocitinib, all significantly better results than the 10.8% rate in once-daily controls. Patients on the TYK2/JAK1 inhibitor at 0.3% twice daily had a 33.3% IGA response rate, versus 13.9% with twice-daily vehicle, also a significant difference.

A 90% reduction in EASI score at week 6, or EASI 90 response, occurred in a dose-dependent fashion in 27.8%-41.7% of patients on 0.3%, 1%, and 3% of patients on once-daily brepocitinib, all significantly better than the 10.8% rate with once-daily vehicle, and in 27% of patients on brepocitinib 1% twice daily, versus 8.3% with twice-daily vehicle.

Improvement in itch was another secondary endpoint. A clinically meaningful week-6 improvement of at least 4 points on the Peak Pruritus Numerical Rating Scale was documented in 45.2% of patients on 1% brepocitinib once daily, 50% on 3% once daily, and 40.7% on 1% brepocitinib twice daily, all significantly better than the roughly 17% itch response rate in controls.

Treatment-emergent adverse events were about one-third more frequent in controls than in brepocitinib-treated patients. These events were overwhelmingly mild and were similar in nature in the two groups. There was no dose-dependent increase in treatment-emergent adverse events in the brepocitinib patients. Moreover, no serious treatment-emergent adverse events occurred during the study, nor were there any cases of herpes zoster or malignancies, and no changes in laboratory parameters or ECG findings.

Pfizer sponsored the phase 2b AD trial of the topical TYK2/JAK1 inhibitor, which is also in phase 2 studies for psoriatic arthritis, psoriasis, lupus, and alopecia areata.

Dr. Landis reported serving as a paid investigator for Pfizer and numerous other pharmaceutical companies.

[email protected]

Brepocitinib, a first-in-class topical inhibitor of both tyrosine kinase 2 and Janus kinase 1, proved effective for treatment of mild to moderate atopic dermatitis (AD), and with a safety profile essentially indistinguishable from vehicle cream in a phase 2b randomized trial, Megan N. Landis, MD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.

The study included 240 adolescents and adults with mild to moderate AD at 70 sites in the United States and nine other countries. Patients’ mean baseline Eczema Area and Severity Index (EASI) score was 7.3, with 9.2% of their body surface area being involved. Participants were equally split between mild and moderate disease. They were randomized to 6 weeks of double-blind treatment in one of eight study arms: once-daily topical brepocitinib at a concentration of 0.1%, 0.3%, 1%, or 3%; twice-daily brepocitinib at 1% or 3%; or once- or twice-daily vehicle cream.

The primary endpoint was change in EASI score from baseline to week 6. Brepocitinib 1% and 3% once daily and 1% twice daily outperformed vehicle, with EASI score reductions of 70.1%, 67.9%, and 75%, respectively, compared with a 44.4% decrease among those in the once-daily vehicle control group and a 47.6% reduction among those in the twice-daily vehicle control group, according to Dr. Landis, a dermatologist at the University of Louisville (Ky).

The key secondary efficacy endpoint was the proportion of patients achieving an Investigator’s Global Assessment (IGA) score of 0 or 1 – clear or almost clear skin – plus at least a 2-point reduction at week 6. This occurred in a dose-dependent fashion in 27.8%-44.4% of patients on once-daily brepocitinib, all significantly better results than the 10.8% rate in once-daily controls. Patients on the TYK2/JAK1 inhibitor at 0.3% twice daily had a 33.3% IGA response rate, versus 13.9% with twice-daily vehicle, also a significant difference.

A 90% reduction in EASI score at week 6, or EASI 90 response, occurred in a dose-dependent fashion in 27.8%-41.7% of patients on 0.3%, 1%, and 3% of patients on once-daily brepocitinib, all significantly better than the 10.8% rate with once-daily vehicle, and in 27% of patients on brepocitinib 1% twice daily, versus 8.3% with twice-daily vehicle.

Improvement in itch was another secondary endpoint. A clinically meaningful week-6 improvement of at least 4 points on the Peak Pruritus Numerical Rating Scale was documented in 45.2% of patients on 1% brepocitinib once daily, 50% on 3% once daily, and 40.7% on 1% brepocitinib twice daily, all significantly better than the roughly 17% itch response rate in controls.

Treatment-emergent adverse events were about one-third more frequent in controls than in brepocitinib-treated patients. These events were overwhelmingly mild and were similar in nature in the two groups. There was no dose-dependent increase in treatment-emergent adverse events in the brepocitinib patients. Moreover, no serious treatment-emergent adverse events occurred during the study, nor were there any cases of herpes zoster or malignancies, and no changes in laboratory parameters or ECG findings.

Pfizer sponsored the phase 2b AD trial of the topical TYK2/JAK1 inhibitor, which is also in phase 2 studies for psoriatic arthritis, psoriasis, lupus, and alopecia areata.

Dr. Landis reported serving as a paid investigator for Pfizer and numerous other pharmaceutical companies.

[email protected]

In an ideal world, people could afford sacubitril/valsartan (Entresto), and clinicians would be allowed to prescribe it using clinical judgment as their guide. The imprimatur of an “[Food and Drug Administration]–labeled indication” would be unnecessary.

This is not our world. Guideline writers, third-party payers, and FDA regulators now play major roles in clinical decisions.

The angiotensin receptor neprilysin inhibitor is approved for use in patients with heart failure with reduced ejection fraction (HFrEF). In December 2020, an FDA advisory committee voted 12-1 in support of a vaguely worded question: Does PARAGON-HF provide sufficient evidence to support any indication for the drug in patients with heart failure with preserved ejection fraction (HFpEF)? The committee did not reach a consensus on what that indication should be.

Before I list five reasons why I hope the FDA does not approve the drug for any indication in patients with HFpEF, let’s review the seminal trial.
 

PARAGON-HF

PARAGON-HF randomly assigned slightly more than 4,800 patients with symptomatic HFpEF (left ventricular ejection fraction [LVEF] ≥45%) to sacubitril/valsartan or valsartan alone. The primary endpoint was total hospitalizations for heart failure (HHF) and death because of cardiovascular (CV) events.

Sacubitril/valsartan reduced the rate of the primary endpoint by 13% (rate ratio, 0.87; 95% confidence interval, 0.75-1.01; P = .06). There were 894 primary endpoint events in the sacubitril/valsartan arm, compared with 1,009 events in the valsartan arm.

The lower rate of events in the sacubitril/valsartan arm was driven by fewer hospitalizations for heart failure. CV death was essentially the same in both arms (204 deaths in the sacubitril/valsartan group versus 212 deaths in the valsartan group).

A note on the patients: the investigators screened more than 10,000 patients and enrolled less than half of them. The mean age was 73 years; 52% of patients were women, but only 2% were Black. The mean LVEF was 57%; 95% of patients had hypertension and were receiving diuretics at baseline.

Now to the five reasons not to approve the drug for this indication.
 

1. Uncertainty of benefit in HFpEF

A P value for the primary endpoint greater than the threshold of .05 suggests some degree of uncertainty. A nice way of describing this uncertainty is with a Bayesian analysis. Whereas a P value tells you the chance of seeing these results if the drug has no benefit, the Bayesian approach tells you the chance of drug benefit given the trial results.

By email, James Brophy, MD, a senior scientist in the Centre for Outcomes Research and Evaluation at McGill University, Montreal, showed me a Bayesian calculation of PARAGON-HF. He estimated a 38% chance that sacubitril/valsartan had a clinically meaningful 15% reduction in the primary endpoint, a 3% chance that it worsens outcomes, and a 58% chance that it is essentially no better than valsartan.

The take-home is that, in PARAGON-HF, a best-case scenario involving select high-risk patients with run-in periods and trial-level follow-up, there is substantial uncertainty as to whether the drug is any better than a generic standard.
 

2. Modest effect size in PARAGON-HF

Let’s assume the benefit seen in PARAGON-HF is not caused by chance. Was the effect clinically significant?

For context, consider the large effect size that sacubitril/valsartan had versus enalapril for patients with HFrEF.

In PARADIGM-HF, sacubitril/valsartan led to a 20% reduction in the composite primary endpoint. Importantly, this included equal reductions in both HHF and CV death. All-cause death was also significantly reduced in the active arm.

Because patients with HFpEF have a similarly poor prognosis as those with HFrEF, a truly beneficial drug should reduce not only HHF but also CV death and overall death. The lack of effect on these “harder” endpoints in PARAGON-HF points to a far more modest effect size for sacubitril/valsartan in HFpEF.

What’s more, even the signal of reduced HHF in PARAGON-HF is tenuous. The PARAGON-HF authors chose total HHF, whereas previous trials in patients with HFpEF used first HHF as their primary endpoint. Had PARAGON-HF followed the methods of prior trials, first HHF would not have made statistical significance (hazard ratio, 0.90; 95% CI, 0.79-1.04)
 

3. Subgroups not compelling

Proponents highlight the possibility that sacubitril/valsartan exerted a heterogenous effect in two subgroups.

In women, sacubitril/valsartan resulted in a 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.59-0.90), whereas men showed no significant difference (HR, 1.03; 95% CI, 0.85-1.25). And the drug seemed to have little benefit over valsartan in patients with a median LVEF greater than 57%.

The problem with subgroups is that, if you look at enough of them, some can be positive on the basis of chance alone. For instance, patients enrolled in western Europe had an outsized benefit from sacubitril/valsartan, compared with patients from other areas.

FDA reviewers noted: “It is possible that the heterogeneity of treatment effect observed in the subgroups by gender and LVEF in PARAGON-HF is a chance finding.”

By email, clinical trial expert Sanjay Kaul, MD, from Cedars-Sinai Medical Center in Los Angeles, expressed serious concern with the subgroup analyses in PARAGON-HF because the sex interaction was confined to HHF alone. There was no interaction for other outcomes, such as CV death, all-cause mortality, renal endpoints, blood pressure, or lowering of N-terminal of the prohormone brain natriuretic peptide.

Similarly, the interaction with ejection fraction was confined to total HHF; it was not seen with New York Heart Association class improvement, all-cause mortality, quality of life, renal endpoints, or time to first event.

Dr. Kaul also emphasized something cardiologists know well, “that ejection fraction is not a static variable and is expected to change during the course of the trial.” This point makes it hard to believe that a partially subjective measurement, such as LVEF, could be a precise modifier of benefit.
 

4. Approval would stop research

If the FDA approves sacubitril/valsartan for patients with HFpEF, there is a near-zero chance we will learn whether there are subsets of patients who benefit more or less from the drug.

It will be the defibrillator problem all over again. Namely, while the average effect of a defibrillator is to reduce mortality in patients with HFrEF, in approximately 9 of 10 patients the implanted device is never used. Efforts to find subgroups that are most likely to need (or not need) an implantable defibrillator have been impossible because industry has no incentive to fund trials that may narrow the number of patients who qualify for their product.

It will be the same with sacubitril/valsartan. This is not nefarious; it is merely a limitation of industry funding of trials.
 

5. Opportunity costs

The category of HFpEF is vast.

FDA approval – even for a subset of these patients – would have huge cost implications. I understand cost issues are considered outside the purview of the FDA, but health care spending isn’t infinite. Money spent covering this costly drug is money not available for other things.

Despite this nation’s wealth, we struggle to provide even basic care to large numbers of people. Approval of an expensive drug with no or modest benefit will only exacerbate these stark disparities.
 

Conclusion

Given our current system of health care delivery, my pragmatic answer is for the FDA to say no to sacubitril/valsartan for HFpEF.

If you believe the drug has outsized benefits in women or those with mild impairment of systolic function, the way to answer these questions is not with subgroup analyses from a trial that did not reach statistical significance in its primary endpoint, but with more randomized trials. Isn’t that what “exploratory” subgroups are for?

Holding off on an indication for HFpEF will force proponents to define a subset of patients who garner a clear and substantial benefit from sacubitril/valsartan.

Dr. Mandrola practices cardiac electrophysiology in Louisville, Ky., and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. MDedge is part of the Medscape Professional Network.

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

In an ideal world, people could afford sacubitril/valsartan (Entresto), and clinicians would be allowed to prescribe it using clinical judgment as their guide. The imprimatur of an “[Food and Drug Administration]–labeled indication” would be unnecessary.

This is not our world. Guideline writers, third-party payers, and FDA regulators now play major roles in clinical decisions.

The angiotensin receptor neprilysin inhibitor is approved for use in patients with heart failure with reduced ejection fraction (HFrEF). In December 2020, an FDA advisory committee voted 12-1 in support of a vaguely worded question: Does PARAGON-HF provide sufficient evidence to support any indication for the drug in patients with heart failure with preserved ejection fraction (HFpEF)? The committee did not reach a consensus on what that indication should be.

Before I list five reasons why I hope the FDA does not approve the drug for any indication in patients with HFpEF, let’s review the seminal trial.
 

PARAGON-HF

PARAGON-HF randomly assigned slightly more than 4,800 patients with symptomatic HFpEF (left ventricular ejection fraction [LVEF] ≥45%) to sacubitril/valsartan or valsartan alone. The primary endpoint was total hospitalizations for heart failure (HHF) and death because of cardiovascular (CV) events.

Sacubitril/valsartan reduced the rate of the primary endpoint by 13% (rate ratio, 0.87; 95% confidence interval, 0.75-1.01; P = .06). There were 894 primary endpoint events in the sacubitril/valsartan arm, compared with 1,009 events in the valsartan arm.

The lower rate of events in the sacubitril/valsartan arm was driven by fewer hospitalizations for heart failure. CV death was essentially the same in both arms (204 deaths in the sacubitril/valsartan group versus 212 deaths in the valsartan group).

A note on the patients: the investigators screened more than 10,000 patients and enrolled less than half of them. The mean age was 73 years; 52% of patients were women, but only 2% were Black. The mean LVEF was 57%; 95% of patients had hypertension and were receiving diuretics at baseline.

Now to the five reasons not to approve the drug for this indication.
 

1. Uncertainty of benefit in HFpEF

A P value for the primary endpoint greater than the threshold of .05 suggests some degree of uncertainty. A nice way of describing this uncertainty is with a Bayesian analysis. Whereas a P value tells you the chance of seeing these results if the drug has no benefit, the Bayesian approach tells you the chance of drug benefit given the trial results.

By email, James Brophy, MD, a senior scientist in the Centre for Outcomes Research and Evaluation at McGill University, Montreal, showed me a Bayesian calculation of PARAGON-HF. He estimated a 38% chance that sacubitril/valsartan had a clinically meaningful 15% reduction in the primary endpoint, a 3% chance that it worsens outcomes, and a 58% chance that it is essentially no better than valsartan.

The take-home is that, in PARAGON-HF, a best-case scenario involving select high-risk patients with run-in periods and trial-level follow-up, there is substantial uncertainty as to whether the drug is any better than a generic standard.
 

2. Modest effect size in PARAGON-HF

Let’s assume the benefit seen in PARAGON-HF is not caused by chance. Was the effect clinically significant?

For context, consider the large effect size that sacubitril/valsartan had versus enalapril for patients with HFrEF.

In PARADIGM-HF, sacubitril/valsartan led to a 20% reduction in the composite primary endpoint. Importantly, this included equal reductions in both HHF and CV death. All-cause death was also significantly reduced in the active arm.

Because patients with HFpEF have a similarly poor prognosis as those with HFrEF, a truly beneficial drug should reduce not only HHF but also CV death and overall death. The lack of effect on these “harder” endpoints in PARAGON-HF points to a far more modest effect size for sacubitril/valsartan in HFpEF.

What’s more, even the signal of reduced HHF in PARAGON-HF is tenuous. The PARAGON-HF authors chose total HHF, whereas previous trials in patients with HFpEF used first HHF as their primary endpoint. Had PARAGON-HF followed the methods of prior trials, first HHF would not have made statistical significance (hazard ratio, 0.90; 95% CI, 0.79-1.04)
 

3. Subgroups not compelling

Proponents highlight the possibility that sacubitril/valsartan exerted a heterogenous effect in two subgroups.

In women, sacubitril/valsartan resulted in a 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.59-0.90), whereas men showed no significant difference (HR, 1.03; 95% CI, 0.85-1.25). And the drug seemed to have little benefit over valsartan in patients with a median LVEF greater than 57%.

The problem with subgroups is that, if you look at enough of them, some can be positive on the basis of chance alone. For instance, patients enrolled in western Europe had an outsized benefit from sacubitril/valsartan, compared with patients from other areas.

FDA reviewers noted: “It is possible that the heterogeneity of treatment effect observed in the subgroups by gender and LVEF in PARAGON-HF is a chance finding.”

By email, clinical trial expert Sanjay Kaul, MD, from Cedars-Sinai Medical Center in Los Angeles, expressed serious concern with the subgroup analyses in PARAGON-HF because the sex interaction was confined to HHF alone. There was no interaction for other outcomes, such as CV death, all-cause mortality, renal endpoints, blood pressure, or lowering of N-terminal of the prohormone brain natriuretic peptide.

Similarly, the interaction with ejection fraction was confined to total HHF; it was not seen with New York Heart Association class improvement, all-cause mortality, quality of life, renal endpoints, or time to first event.

Dr. Kaul also emphasized something cardiologists know well, “that ejection fraction is not a static variable and is expected to change during the course of the trial.” This point makes it hard to believe that a partially subjective measurement, such as LVEF, could be a precise modifier of benefit.
 

4. Approval would stop research

If the FDA approves sacubitril/valsartan for patients with HFpEF, there is a near-zero chance we will learn whether there are subsets of patients who benefit more or less from the drug.

It will be the defibrillator problem all over again. Namely, while the average effect of a defibrillator is to reduce mortality in patients with HFrEF, in approximately 9 of 10 patients the implanted device is never used. Efforts to find subgroups that are most likely to need (or not need) an implantable defibrillator have been impossible because industry has no incentive to fund trials that may narrow the number of patients who qualify for their product.

It will be the same with sacubitril/valsartan. This is not nefarious; it is merely a limitation of industry funding of trials.
 

5. Opportunity costs

The category of HFpEF is vast.

FDA approval – even for a subset of these patients – would have huge cost implications. I understand cost issues are considered outside the purview of the FDA, but health care spending isn’t infinite. Money spent covering this costly drug is money not available for other things.

Despite this nation’s wealth, we struggle to provide even basic care to large numbers of people. Approval of an expensive drug with no or modest benefit will only exacerbate these stark disparities.
 

Conclusion

Given our current system of health care delivery, my pragmatic answer is for the FDA to say no to sacubitril/valsartan for HFpEF.

If you believe the drug has outsized benefits in women or those with mild impairment of systolic function, the way to answer these questions is not with subgroup analyses from a trial that did not reach statistical significance in its primary endpoint, but with more randomized trials. Isn’t that what “exploratory” subgroups are for?

Holding off on an indication for HFpEF will force proponents to define a subset of patients who garner a clear and substantial benefit from sacubitril/valsartan.

Dr. Mandrola practices cardiac electrophysiology in Louisville, Ky., and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. MDedge is part of the Medscape Professional Network.

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

In an ideal world, people could afford sacubitril/valsartan (Entresto), and clinicians would be allowed to prescribe it using clinical judgment as their guide. The imprimatur of an “[Food and Drug Administration]–labeled indication” would be unnecessary.

This is not our world. Guideline writers, third-party payers, and FDA regulators now play major roles in clinical decisions.

The angiotensin receptor neprilysin inhibitor is approved for use in patients with heart failure with reduced ejection fraction (HFrEF). In December 2020, an FDA advisory committee voted 12-1 in support of a vaguely worded question: Does PARAGON-HF provide sufficient evidence to support any indication for the drug in patients with heart failure with preserved ejection fraction (HFpEF)? The committee did not reach a consensus on what that indication should be.

Before I list five reasons why I hope the FDA does not approve the drug for any indication in patients with HFpEF, let’s review the seminal trial.
 

PARAGON-HF

PARAGON-HF randomly assigned slightly more than 4,800 patients with symptomatic HFpEF (left ventricular ejection fraction [LVEF] ≥45%) to sacubitril/valsartan or valsartan alone. The primary endpoint was total hospitalizations for heart failure (HHF) and death because of cardiovascular (CV) events.

Sacubitril/valsartan reduced the rate of the primary endpoint by 13% (rate ratio, 0.87; 95% confidence interval, 0.75-1.01; P = .06). There were 894 primary endpoint events in the sacubitril/valsartan arm, compared with 1,009 events in the valsartan arm.

The lower rate of events in the sacubitril/valsartan arm was driven by fewer hospitalizations for heart failure. CV death was essentially the same in both arms (204 deaths in the sacubitril/valsartan group versus 212 deaths in the valsartan group).

A note on the patients: the investigators screened more than 10,000 patients and enrolled less than half of them. The mean age was 73 years; 52% of patients were women, but only 2% were Black. The mean LVEF was 57%; 95% of patients had hypertension and were receiving diuretics at baseline.

Now to the five reasons not to approve the drug for this indication.
 

1. Uncertainty of benefit in HFpEF

A P value for the primary endpoint greater than the threshold of .05 suggests some degree of uncertainty. A nice way of describing this uncertainty is with a Bayesian analysis. Whereas a P value tells you the chance of seeing these results if the drug has no benefit, the Bayesian approach tells you the chance of drug benefit given the trial results.

By email, James Brophy, MD, a senior scientist in the Centre for Outcomes Research and Evaluation at McGill University, Montreal, showed me a Bayesian calculation of PARAGON-HF. He estimated a 38% chance that sacubitril/valsartan had a clinically meaningful 15% reduction in the primary endpoint, a 3% chance that it worsens outcomes, and a 58% chance that it is essentially no better than valsartan.

The take-home is that, in PARAGON-HF, a best-case scenario involving select high-risk patients with run-in periods and trial-level follow-up, there is substantial uncertainty as to whether the drug is any better than a generic standard.
 

2. Modest effect size in PARAGON-HF

Let’s assume the benefit seen in PARAGON-HF is not caused by chance. Was the effect clinically significant?

For context, consider the large effect size that sacubitril/valsartan had versus enalapril for patients with HFrEF.

In PARADIGM-HF, sacubitril/valsartan led to a 20% reduction in the composite primary endpoint. Importantly, this included equal reductions in both HHF and CV death. All-cause death was also significantly reduced in the active arm.

Because patients with HFpEF have a similarly poor prognosis as those with HFrEF, a truly beneficial drug should reduce not only HHF but also CV death and overall death. The lack of effect on these “harder” endpoints in PARAGON-HF points to a far more modest effect size for sacubitril/valsartan in HFpEF.

What’s more, even the signal of reduced HHF in PARAGON-HF is tenuous. The PARAGON-HF authors chose total HHF, whereas previous trials in patients with HFpEF used first HHF as their primary endpoint. Had PARAGON-HF followed the methods of prior trials, first HHF would not have made statistical significance (hazard ratio, 0.90; 95% CI, 0.79-1.04)
 

3. Subgroups not compelling

Proponents highlight the possibility that sacubitril/valsartan exerted a heterogenous effect in two subgroups.

In women, sacubitril/valsartan resulted in a 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.59-0.90), whereas men showed no significant difference (HR, 1.03; 95% CI, 0.85-1.25). And the drug seemed to have little benefit over valsartan in patients with a median LVEF greater than 57%.

The problem with subgroups is that, if you look at enough of them, some can be positive on the basis of chance alone. For instance, patients enrolled in western Europe had an outsized benefit from sacubitril/valsartan, compared with patients from other areas.

FDA reviewers noted: “It is possible that the heterogeneity of treatment effect observed in the subgroups by gender and LVEF in PARAGON-HF is a chance finding.”

By email, clinical trial expert Sanjay Kaul, MD, from Cedars-Sinai Medical Center in Los Angeles, expressed serious concern with the subgroup analyses in PARAGON-HF because the sex interaction was confined to HHF alone. There was no interaction for other outcomes, such as CV death, all-cause mortality, renal endpoints, blood pressure, or lowering of N-terminal of the prohormone brain natriuretic peptide.

Similarly, the interaction with ejection fraction was confined to total HHF; it was not seen with New York Heart Association class improvement, all-cause mortality, quality of life, renal endpoints, or time to first event.

Dr. Kaul also emphasized something cardiologists know well, “that ejection fraction is not a static variable and is expected to change during the course of the trial.” This point makes it hard to believe that a partially subjective measurement, such as LVEF, could be a precise modifier of benefit.
 

4. Approval would stop research

If the FDA approves sacubitril/valsartan for patients with HFpEF, there is a near-zero chance we will learn whether there are subsets of patients who benefit more or less from the drug.

It will be the defibrillator problem all over again. Namely, while the average effect of a defibrillator is to reduce mortality in patients with HFrEF, in approximately 9 of 10 patients the implanted device is never used. Efforts to find subgroups that are most likely to need (or not need) an implantable defibrillator have been impossible because industry has no incentive to fund trials that may narrow the number of patients who qualify for their product.

It will be the same with sacubitril/valsartan. This is not nefarious; it is merely a limitation of industry funding of trials.
 

5. Opportunity costs

The category of HFpEF is vast.

FDA approval – even for a subset of these patients – would have huge cost implications. I understand cost issues are considered outside the purview of the FDA, but health care spending isn’t infinite. Money spent covering this costly drug is money not available for other things.

Despite this nation’s wealth, we struggle to provide even basic care to large numbers of people. Approval of an expensive drug with no or modest benefit will only exacerbate these stark disparities.
 

Conclusion

Given our current system of health care delivery, my pragmatic answer is for the FDA to say no to sacubitril/valsartan for HFpEF.

If you believe the drug has outsized benefits in women or those with mild impairment of systolic function, the way to answer these questions is not with subgroup analyses from a trial that did not reach statistical significance in its primary endpoint, but with more randomized trials. Isn’t that what “exploratory” subgroups are for?

Holding off on an indication for HFpEF will force proponents to define a subset of patients who garner a clear and substantial benefit from sacubitril/valsartan.

Dr. Mandrola practices cardiac electrophysiology in Louisville, Ky., and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. MDedge is part of the Medscape Professional Network.

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

Clinical trials enrolling patients with progressive multiple sclerosis (MS) commonly use the Expanded Disability Status Scale (EDSS), an instrument that looks at impairment across several different functional domains, as a primary outcome measure. But results from a new analysis of trial data suggest that the EDSS, in use since 1983, may be a noisier or more variation-prone measure of MS disease progression than two other widely used measures: the timed 25-foot walk and the 9-hole peg test.

For their research, published in the Jan. 5 issue of Neurology, Marcus W. Koch, MD, PhD, of the department of neurosciences at Hotchkiss Brain Institute at the University of Calgary (Alta.) and colleagues looked at data from the placebo arms of two randomized trials that collectively enrolled nearly 700 patients with secondary progressive MS (SPMS). The trials were similar in terms of baseline patient characteristics and level of disability.
 

Comparing three outcome measures

The investigators compared disability progression and improvement across each of the three instruments and their combinations. Because improvement is understood to occur only rarely in untreated secondary progressive MS, most improvement picked up in the placebo arm of a trial is assumed to be noise from random variation or measurement error.

Dr. Koch and colleagues found that the EDSS showed higher rates of improvement than the other tests. The EDSS also showed the smallest differences between progression and improvement among the three instruments, with improvement rate over time increasing in parallel with disability progression rates. With the other two tests, improvement rates remained low – at 10% or less – while disability was seen steadily increasing over time.

The results, the investigators wrote in their analysis, suggest that the timed 25-foot walk and 9-hole peg test are the more reliable outcome measures. The reason “may simply lie in the fact that both the timed 25-foot walk and 9-hole peg test are objective and quantitative interval-scaled measures while the EDSS is a graded categorical measure.” As primary outcome measures in clinical trials, “the lower noise of the timed 25-foot walk and 9-hole peg test may make them preferable over the EDSS,” Dr. Koch and colleagues concluded. The investigators noted that a 2019 analysis of different MS disability scales across more than 13,000 patients in 14 trials did not find such stark differences – but that the patients in the pooled trials had less disability at baseline (median EDSS score of 2.5, compared with 6.0 for the two trials in Dr. Koch and colleagues’ study). This suggests, the investigators wrote, “that the timed 25-foot walk and 9-hole peg test may be more useful outcomes in patients with a progressive disease course and with greater baseline disability.”
 

‘Considerable implications’ for the design of future clinical trials

In an accompanying editorial, Tomas Kalincik, MD, PhD, of the University of Melbourne, along with colleagues in Italy and Britain, praised Dr. Koch and colleagues’ study as having “considerable implications for the design of future clinical trials because detecting a treatment effect on an outcome that is subject to large measurement error is difficult.” Most trials in progressive MS use change in EDSS score as their primary or key secondary outcomes. “However, as the authors elegantly show, other, more reliable clinical outcomes are needed. As we are revisiting our biological hypotheses for treatment of progressive MS, perhaps the time has come that we should also revisit the instruments that we use to examine their efficacy.”

The editorialists allowed for the possibility that something besides noise or measurement error could be responsible for the disparities seen across the instruments. “An alternative interpretation of the presented results could be that recovery of neurologic function is more common in SPMS than what we had previously thought and that EDSS is more sensitive to its detection than the other two measures,” they wrote.

Dr. Koch and colleagues’ study received no outside funding. Dr. Koch disclosed consulting fees and other financial support from several drug manufacturers, and three coauthors also disclosed financial relationships with pharmaceutical companies. All three editorial writers disclosed similar relationships.

Clinical trials enrolling patients with progressive multiple sclerosis (MS) commonly use the Expanded Disability Status Scale (EDSS), an instrument that looks at impairment across several different functional domains, as a primary outcome measure. But results from a new analysis of trial data suggest that the EDSS, in use since 1983, may be a noisier or more variation-prone measure of MS disease progression than two other widely used measures: the timed 25-foot walk and the 9-hole peg test.

For their research, published in the Jan. 5 issue of Neurology, Marcus W. Koch, MD, PhD, of the department of neurosciences at Hotchkiss Brain Institute at the University of Calgary (Alta.) and colleagues looked at data from the placebo arms of two randomized trials that collectively enrolled nearly 700 patients with secondary progressive MS (SPMS). The trials were similar in terms of baseline patient characteristics and level of disability.
 

Comparing three outcome measures

The investigators compared disability progression and improvement across each of the three instruments and their combinations. Because improvement is understood to occur only rarely in untreated secondary progressive MS, most improvement picked up in the placebo arm of a trial is assumed to be noise from random variation or measurement error.

Dr. Koch and colleagues found that the EDSS showed higher rates of improvement than the other tests. The EDSS also showed the smallest differences between progression and improvement among the three instruments, with improvement rate over time increasing in parallel with disability progression rates. With the other two tests, improvement rates remained low – at 10% or less – while disability was seen steadily increasing over time.

The results, the investigators wrote in their analysis, suggest that the timed 25-foot walk and 9-hole peg test are the more reliable outcome measures. The reason “may simply lie in the fact that both the timed 25-foot walk and 9-hole peg test are objective and quantitative interval-scaled measures while the EDSS is a graded categorical measure.” As primary outcome measures in clinical trials, “the lower noise of the timed 25-foot walk and 9-hole peg test may make them preferable over the EDSS,” Dr. Koch and colleagues concluded. The investigators noted that a 2019 analysis of different MS disability scales across more than 13,000 patients in 14 trials did not find such stark differences – but that the patients in the pooled trials had less disability at baseline (median EDSS score of 2.5, compared with 6.0 for the two trials in Dr. Koch and colleagues’ study). This suggests, the investigators wrote, “that the timed 25-foot walk and 9-hole peg test may be more useful outcomes in patients with a progressive disease course and with greater baseline disability.”
 

‘Considerable implications’ for the design of future clinical trials

In an accompanying editorial, Tomas Kalincik, MD, PhD, of the University of Melbourne, along with colleagues in Italy and Britain, praised Dr. Koch and colleagues’ study as having “considerable implications for the design of future clinical trials because detecting a treatment effect on an outcome that is subject to large measurement error is difficult.” Most trials in progressive MS use change in EDSS score as their primary or key secondary outcomes. “However, as the authors elegantly show, other, more reliable clinical outcomes are needed. As we are revisiting our biological hypotheses for treatment of progressive MS, perhaps the time has come that we should also revisit the instruments that we use to examine their efficacy.”

The editorialists allowed for the possibility that something besides noise or measurement error could be responsible for the disparities seen across the instruments. “An alternative interpretation of the presented results could be that recovery of neurologic function is more common in SPMS than what we had previously thought and that EDSS is more sensitive to its detection than the other two measures,” they wrote.

Dr. Koch and colleagues’ study received no outside funding. Dr. Koch disclosed consulting fees and other financial support from several drug manufacturers, and three coauthors also disclosed financial relationships with pharmaceutical companies. All three editorial writers disclosed similar relationships.

Clinical trials enrolling patients with progressive multiple sclerosis (MS) commonly use the Expanded Disability Status Scale (EDSS), an instrument that looks at impairment across several different functional domains, as a primary outcome measure. But results from a new analysis of trial data suggest that the EDSS, in use since 1983, may be a noisier or more variation-prone measure of MS disease progression than two other widely used measures: the timed 25-foot walk and the 9-hole peg test.

For their research, published in the Jan. 5 issue of Neurology, Marcus W. Koch, MD, PhD, of the department of neurosciences at Hotchkiss Brain Institute at the University of Calgary (Alta.) and colleagues looked at data from the placebo arms of two randomized trials that collectively enrolled nearly 700 patients with secondary progressive MS (SPMS). The trials were similar in terms of baseline patient characteristics and level of disability.
 

Comparing three outcome measures

The investigators compared disability progression and improvement across each of the three instruments and their combinations. Because improvement is understood to occur only rarely in untreated secondary progressive MS, most improvement picked up in the placebo arm of a trial is assumed to be noise from random variation or measurement error.

Dr. Koch and colleagues found that the EDSS showed higher rates of improvement than the other tests. The EDSS also showed the smallest differences between progression and improvement among the three instruments, with improvement rate over time increasing in parallel with disability progression rates. With the other two tests, improvement rates remained low – at 10% or less – while disability was seen steadily increasing over time.

The results, the investigators wrote in their analysis, suggest that the timed 25-foot walk and 9-hole peg test are the more reliable outcome measures. The reason “may simply lie in the fact that both the timed 25-foot walk and 9-hole peg test are objective and quantitative interval-scaled measures while the EDSS is a graded categorical measure.” As primary outcome measures in clinical trials, “the lower noise of the timed 25-foot walk and 9-hole peg test may make them preferable over the EDSS,” Dr. Koch and colleagues concluded. The investigators noted that a 2019 analysis of different MS disability scales across more than 13,000 patients in 14 trials did not find such stark differences – but that the patients in the pooled trials had less disability at baseline (median EDSS score of 2.5, compared with 6.0 for the two trials in Dr. Koch and colleagues’ study). This suggests, the investigators wrote, “that the timed 25-foot walk and 9-hole peg test may be more useful outcomes in patients with a progressive disease course and with greater baseline disability.”
 

‘Considerable implications’ for the design of future clinical trials

In an accompanying editorial, Tomas Kalincik, MD, PhD, of the University of Melbourne, along with colleagues in Italy and Britain, praised Dr. Koch and colleagues’ study as having “considerable implications for the design of future clinical trials because detecting a treatment effect on an outcome that is subject to large measurement error is difficult.” Most trials in progressive MS use change in EDSS score as their primary or key secondary outcomes. “However, as the authors elegantly show, other, more reliable clinical outcomes are needed. As we are revisiting our biological hypotheses for treatment of progressive MS, perhaps the time has come that we should also revisit the instruments that we use to examine their efficacy.”

The editorialists allowed for the possibility that something besides noise or measurement error could be responsible for the disparities seen across the instruments. “An alternative interpretation of the presented results could be that recovery of neurologic function is more common in SPMS than what we had previously thought and that EDSS is more sensitive to its detection than the other two measures,” they wrote.

Dr. Koch and colleagues’ study received no outside funding. Dr. Koch disclosed consulting fees and other financial support from several drug manufacturers, and three coauthors also disclosed financial relationships with pharmaceutical companies. All three editorial writers disclosed similar relationships.

Atopic dermatitis, commonly known as eczema, affects at least 10% of adults in the industrialized world. In recent years, research has broadened our understanding of the underlying mechanisms that drive the condition, leading to identification of potential targets and development of new therapies.

Dr Mark Lebwohl, chairman of the Department of Dermatology at the Icahn School of Medicine at Mount Sinai in New York City, explains that the March 2017 approval of dupilumab for moderate to severe atopic dermatitis touched off a new era of systemic treatments. Dozens of new drugs are being investigated, many with promising trial results, giving hope to the millions of patients who suffer from the persistent itch that defines the skin condition.

In this ReCAP, Dr Lebwohl summarizes current knowledge of the pathogenesis of atopic dermatitis and highlights the most promising new therapies in the works.

--

Professor and Chairman, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY.

Mark G. Lebwohl, MD, has disclosed the following relevant financial information:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Allergan; Almirall; Arcutis Biotherapeutics; Avotres Therapeutics; BirchBioMed Inc.; Boehringer Ingelheim; Bristol-Myers Squibb Company; Cara Therapeutics; Castle Biosciences; Corrona; Dermavant Sciences; Evelo Biosciences; Foundation for Research and Education in Dermatology; Inozyme Pharma; Leo Pharma; Meiji Seika Pharma Co.; Menlo Dermatology Medical Group; Mitsubishi Tanabe Pharma America; NeuroDerm; Pfizer Inc.; Promius Pharma LLC; Dr. Reddy's Laboratories; Theravance Biopharma, Inc.; Verrica Pharmaceuticals Inc. ¬

Received research grant from: AbbVie; Amgen Inc.; Arcutis Biotherapeutics; AstraZeneca Pharmaceuticals LP; Boehringer Ingelheim; Celgene Corporation; CLINUVEL; Eli Lilly and Company; Incyte Corporation; Ortho-McNeil-Janssen Pharmaceuticals, Inc.; Kadmon Corporation; Leo Pharma; MedImmune Inc.; Novartis Pharmaceuticals Corporation; Ortho Dermatologics; Pfizer Inc.; SCIderm; UCB, Inc.; Vidac Pharma.

Atopic dermatitis, commonly known as eczema, affects at least 10% of adults in the industrialized world. In recent years, research has broadened our understanding of the underlying mechanisms that drive the condition, leading to identification of potential targets and development of new therapies.

Dr Mark Lebwohl, chairman of the Department of Dermatology at the Icahn School of Medicine at Mount Sinai in New York City, explains that the March 2017 approval of dupilumab for moderate to severe atopic dermatitis touched off a new era of systemic treatments. Dozens of new drugs are being investigated, many with promising trial results, giving hope to the millions of patients who suffer from the persistent itch that defines the skin condition.

In this ReCAP, Dr Lebwohl summarizes current knowledge of the pathogenesis of atopic dermatitis and highlights the most promising new therapies in the works.

--

Professor and Chairman, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY.

Mark G. Lebwohl, MD, has disclosed the following relevant financial information:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Allergan; Almirall; Arcutis Biotherapeutics; Avotres Therapeutics; BirchBioMed Inc.; Boehringer Ingelheim; Bristol-Myers Squibb Company; Cara Therapeutics; Castle Biosciences; Corrona; Dermavant Sciences; Evelo Biosciences; Foundation for Research and Education in Dermatology; Inozyme Pharma; Leo Pharma; Meiji Seika Pharma Co.; Menlo Dermatology Medical Group; Mitsubishi Tanabe Pharma America; NeuroDerm; Pfizer Inc.; Promius Pharma LLC; Dr. Reddy's Laboratories; Theravance Biopharma, Inc.; Verrica Pharmaceuticals Inc. ¬

Received research grant from: AbbVie; Amgen Inc.; Arcutis Biotherapeutics; AstraZeneca Pharmaceuticals LP; Boehringer Ingelheim; Celgene Corporation; CLINUVEL; Eli Lilly and Company; Incyte Corporation; Ortho-McNeil-Janssen Pharmaceuticals, Inc.; Kadmon Corporation; Leo Pharma; MedImmune Inc.; Novartis Pharmaceuticals Corporation; Ortho Dermatologics; Pfizer Inc.; SCIderm; UCB, Inc.; Vidac Pharma.

Atopic dermatitis, commonly known as eczema, affects at least 10% of adults in the industrialized world. In recent years, research has broadened our understanding of the underlying mechanisms that drive the condition, leading to identification of potential targets and development of new therapies.

Dr Mark Lebwohl, chairman of the Department of Dermatology at the Icahn School of Medicine at Mount Sinai in New York City, explains that the March 2017 approval of dupilumab for moderate to severe atopic dermatitis touched off a new era of systemic treatments. Dozens of new drugs are being investigated, many with promising trial results, giving hope to the millions of patients who suffer from the persistent itch that defines the skin condition.

In this ReCAP, Dr Lebwohl summarizes current knowledge of the pathogenesis of atopic dermatitis and highlights the most promising new therapies in the works.

--

Professor and Chairman, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY.

Mark G. Lebwohl, MD, has disclosed the following relevant financial information:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Allergan; Almirall; Arcutis Biotherapeutics; Avotres Therapeutics; BirchBioMed Inc.; Boehringer Ingelheim; Bristol-Myers Squibb Company; Cara Therapeutics; Castle Biosciences; Corrona; Dermavant Sciences; Evelo Biosciences; Foundation for Research and Education in Dermatology; Inozyme Pharma; Leo Pharma; Meiji Seika Pharma Co.; Menlo Dermatology Medical Group; Mitsubishi Tanabe Pharma America; NeuroDerm; Pfizer Inc.; Promius Pharma LLC; Dr. Reddy's Laboratories; Theravance Biopharma, Inc.; Verrica Pharmaceuticals Inc. ¬

Received research grant from: AbbVie; Amgen Inc.; Arcutis Biotherapeutics; AstraZeneca Pharmaceuticals LP; Boehringer Ingelheim; Celgene Corporation; CLINUVEL; Eli Lilly and Company; Incyte Corporation; Ortho-McNeil-Janssen Pharmaceuticals, Inc.; Kadmon Corporation; Leo Pharma; MedImmune Inc.; Novartis Pharmaceuticals Corporation; Ortho Dermatologics; Pfizer Inc.; SCIderm; UCB, Inc.; Vidac Pharma.

The COVID-19 variants that have emerged in the United Kingdom, Brazil, South Africa and now Southern California are eliciting two notably distinct responses from U.S. public health officials.

janiecbros/iStock/Getty Images Plus

First, broad concern. A variant that wreaked havoc in the United Kingdom, leading to a spike in cases and hospitalizations, is surfacing in a growing number of places in the United States. During the week of Jan. 24, another worrisome variant seen in Brazil surfaced in Minnesota. If these or other strains significantly change the way the virus transmits and attacks the body, as scientists fear they might, they could cause yet another prolonged surge in illness and death in the U.S., even as cases have begun to plateau and vaccines are rolling out.

On the other hand, variants aren’t novel or even uncommon in viral illnesses. The viruses that trigger common colds and flus regularly evolve. Even if a mutated strain of SARS-CoV-2, the virus that causes COVID-19, makes it more contagious or makes people sicker, the basic public health response stays the same: Monitor the virus, and any mutations, as it moves across communities. Use masking, testing, physical distancing, and quarantine to contain the spread.

The problem is that the U.S. has struggled with every step of its public health response in its first year of battle against COVID-19. And that raises the question of whether the nation will devote the attention and resources needed to outflank the virus as it evolves.

Researchers are quick to stress that a coronavirus mutation in itself is no cause for alarm. In the course of making millions and billions of copies as part of the infection process, small changes to a virus’s genome happen all the time as a function of evolutionary biology.

“The word ‘variant’ and the word ‘mutation’ have these scary connotations, and they aren’t necessarily scary,” said Kelly Wroblewski, director of infectious disease programs for the Association of Public Health Laboratories.

When a mutation rings public health alarms, it’s typically because it has combined with other mutations and, collectively, changed how the virus behaves. At that point, it may be named a variant. A variant can make a virus spread faster, or more easily jump between species. It can make a virus more successful at making people sicker, or change how our immune systems respond.

SARS-CoV-2 has been mutating for as long as we’ve known about it; mutations were identified by scientists throughout 2020. Though relevant scientifically – mutations can actually be helpful, acting like a fingerprint that allows scientists to track a virus’s spread – the identified strains mostly carried little concern for public health.

Then came the end of the year, when several variants began drawing scrutiny. One of the most concerning, first detected in the United Kingdom, appears to make the virus more transmissible. Emerging evidence suggests it also could be deadlier, though scientists are still debating that.

We know more about the U.K. variant than others not because it’s necessarily worse, but because the British have one of the best virus surveillance programs in the world, said William Hanage, PhD, an epidemiologist and a professor at Harvard University.

By contrast, the U.S. has one of the weakest genomic surveillance programs of any rich country, Dr. Hanage said. “As it is, people like me cobble together partnerships with places and try and beg them” for samples, he said on a recent call with reporters.

Other variant strains were identified in South Africa and Brazil, and they share some mutations with the U.K. variant. That those changes evolved independently in several parts of the world suggests they might present an evolutionary advantage for the virus. Yet another strain was recently identified in Southern California and flagged due to its increasing presence in hard-hit cities like Los Angeles.

The Southern California strain was detected because a team of researchers at Cedars-Sinai, a hospital and research center in Los Angeles, has unfettered access to patient samples. They were able to see that the strain made up a growing share of cases at the hospital in recent weeks, as well as among the limited number of other samples haphazardly collected at a network of labs in the region.

Not only does the U.S. do less genomic sequencing than most wealthy countries, but it also does its surveillance by happenstance. That means it takes longer to detect new strains and draw conclusions about them. It’s not yet clear, for example, whether that Southern California strain was truly worthy of a press release.

Vast swaths of America’s privatized and decentralized system of health care aren’t set up to send samples to public health or academic labs. “I’m more concerned about the systems to detect variants than I am these particular variants,” said Mark Pandori, PhD, director of Nevada’s public health laboratory and associate professor at the University of Nevada-Reno School of Medicine.

Limited genomic surveillance of viruses is yet another side effect of a fragmented and underfunded public health system that’s struggled to test, track contacts and get COVID-19 under control throughout the pandemic, Ms. Wroblewski said.

The nation’s public health infrastructure, generally funded on a disease-by-disease basis, has decent systems set up to sequence flu, foodborne illnesses and tuberculosis, but there has been no national strategy on COVID-19. “To look for variants, it needs to be a national picture if it’s going to be done well,” Ms. Wroblewski said.

The Biden administration has outlined a strategy for a national response to COVID-19, which includes expanded surveillance for variants.

So far, vaccines for COVID-19 appear to protect against the known variants. Moderna has said its vaccine is effective against the U.K. and South African strains, though it yields fewer antibodies in the face of the latter. The company is working to develop a revised dose of the vaccine that could be added to the current two-shot regimen as a precaution.

But a lot of damage can be done in the time it will take to roll out the current vaccine, let alone an update.

Even with limited sampling, the U.K. variant has been detected in more than two dozen U.S. states, and the Centers for Disease Control and Prevention has warned it could be the predominant strain in the U.S. by March. When it took off in the United Kingdom at the end of last year, it caused a swell in cases, overwhelmed hospitals, and led to a holiday lockdown. Whether the U.S. faces the same fate could depend on which strains it is competing against, and how the public behaves in the weeks ahead.

Already risky interactions among people could, on average, get a little riskier. Many researchers are calling for better masks and better indoor ventilation. But any updates on recommendations likely would play at the margins. Even if variants spread more easily, the same recommendations public health experts have been espousing for months – masking, physical distancing, and limiting time indoors with others – will be the best way to ward them off, said Kirsten Bibbins-Domingo, MD, a physician and professor at the University of California, San Francisco.

“It’s very unsexy what the solutions are,” Dr. Bibbins-Domingo said. “But we need everyone to do them.”

That doesn’t make the task simple. Masking remains controversial in many states, and the public’s patience for maintaining physical distance has worn thin.

Adding to the concerns: Though case numbers stabilized in many parts of the U.S. in January, they have stabilized at rates many times what they were during previous periods in the pandemic or in other parts of the world. Having all that virus in so many bodies creates more opportunities for new mutations and new variants to emerge.

“If we keep letting this thing sneak around, it’s going to get around all the measures we take against it, and that’s the worst possible thing,” said Nevada’s Dr. Pandori.

Compared with less virulent strains, a more contagious variant likely will require that more people be vaccinated before a community can see the benefits of widespread immunity. It’s a bleak outlook for a nation already falling behind in the race to vaccinate enough people to bring the pandemic under control.

“When your best solution is to ask people to do the things that they don’t like to do anyway, that’s very scary,” said Dr. Bibbins-Domingo.
 

This story was produced by KHN, which publishes California Healthline, an editorially independent service of the California Health Care Foundation.

The COVID-19 variants that have emerged in the United Kingdom, Brazil, South Africa and now Southern California are eliciting two notably distinct responses from U.S. public health officials.

janiecbros/iStock/Getty Images Plus

First, broad concern. A variant that wreaked havoc in the United Kingdom, leading to a spike in cases and hospitalizations, is surfacing in a growing number of places in the United States. During the week of Jan. 24, another worrisome variant seen in Brazil surfaced in Minnesota. If these or other strains significantly change the way the virus transmits and attacks the body, as scientists fear they might, they could cause yet another prolonged surge in illness and death in the U.S., even as cases have begun to plateau and vaccines are rolling out.

On the other hand, variants aren’t novel or even uncommon in viral illnesses. The viruses that trigger common colds and flus regularly evolve. Even if a mutated strain of SARS-CoV-2, the virus that causes COVID-19, makes it more contagious or makes people sicker, the basic public health response stays the same: Monitor the virus, and any mutations, as it moves across communities. Use masking, testing, physical distancing, and quarantine to contain the spread.

The problem is that the U.S. has struggled with every step of its public health response in its first year of battle against COVID-19. And that raises the question of whether the nation will devote the attention and resources needed to outflank the virus as it evolves.

Researchers are quick to stress that a coronavirus mutation in itself is no cause for alarm. In the course of making millions and billions of copies as part of the infection process, small changes to a virus’s genome happen all the time as a function of evolutionary biology.

“The word ‘variant’ and the word ‘mutation’ have these scary connotations, and they aren’t necessarily scary,” said Kelly Wroblewski, director of infectious disease programs for the Association of Public Health Laboratories.

When a mutation rings public health alarms, it’s typically because it has combined with other mutations and, collectively, changed how the virus behaves. At that point, it may be named a variant. A variant can make a virus spread faster, or more easily jump between species. It can make a virus more successful at making people sicker, or change how our immune systems respond.

SARS-CoV-2 has been mutating for as long as we’ve known about it; mutations were identified by scientists throughout 2020. Though relevant scientifically – mutations can actually be helpful, acting like a fingerprint that allows scientists to track a virus’s spread – the identified strains mostly carried little concern for public health.

Then came the end of the year, when several variants began drawing scrutiny. One of the most concerning, first detected in the United Kingdom, appears to make the virus more transmissible. Emerging evidence suggests it also could be deadlier, though scientists are still debating that.

We know more about the U.K. variant than others not because it’s necessarily worse, but because the British have one of the best virus surveillance programs in the world, said William Hanage, PhD, an epidemiologist and a professor at Harvard University.

By contrast, the U.S. has one of the weakest genomic surveillance programs of any rich country, Dr. Hanage said. “As it is, people like me cobble together partnerships with places and try and beg them” for samples, he said on a recent call with reporters.

Other variant strains were identified in South Africa and Brazil, and they share some mutations with the U.K. variant. That those changes evolved independently in several parts of the world suggests they might present an evolutionary advantage for the virus. Yet another strain was recently identified in Southern California and flagged due to its increasing presence in hard-hit cities like Los Angeles.

The Southern California strain was detected because a team of researchers at Cedars-Sinai, a hospital and research center in Los Angeles, has unfettered access to patient samples. They were able to see that the strain made up a growing share of cases at the hospital in recent weeks, as well as among the limited number of other samples haphazardly collected at a network of labs in the region.

Not only does the U.S. do less genomic sequencing than most wealthy countries, but it also does its surveillance by happenstance. That means it takes longer to detect new strains and draw conclusions about them. It’s not yet clear, for example, whether that Southern California strain was truly worthy of a press release.

Vast swaths of America’s privatized and decentralized system of health care aren’t set up to send samples to public health or academic labs. “I’m more concerned about the systems to detect variants than I am these particular variants,” said Mark Pandori, PhD, director of Nevada’s public health laboratory and associate professor at the University of Nevada-Reno School of Medicine.

Limited genomic surveillance of viruses is yet another side effect of a fragmented and underfunded public health system that’s struggled to test, track contacts and get COVID-19 under control throughout the pandemic, Ms. Wroblewski said.

The nation’s public health infrastructure, generally funded on a disease-by-disease basis, has decent systems set up to sequence flu, foodborne illnesses and tuberculosis, but there has been no national strategy on COVID-19. “To look for variants, it needs to be a national picture if it’s going to be done well,” Ms. Wroblewski said.

The Biden administration has outlined a strategy for a national response to COVID-19, which includes expanded surveillance for variants.

So far, vaccines for COVID-19 appear to protect against the known variants. Moderna has said its vaccine is effective against the U.K. and South African strains, though it yields fewer antibodies in the face of the latter. The company is working to develop a revised dose of the vaccine that could be added to the current two-shot regimen as a precaution.

But a lot of damage can be done in the time it will take to roll out the current vaccine, let alone an update.

Even with limited sampling, the U.K. variant has been detected in more than two dozen U.S. states, and the Centers for Disease Control and Prevention has warned it could be the predominant strain in the U.S. by March. When it took off in the United Kingdom at the end of last year, it caused a swell in cases, overwhelmed hospitals, and led to a holiday lockdown. Whether the U.S. faces the same fate could depend on which strains it is competing against, and how the public behaves in the weeks ahead.

Already risky interactions among people could, on average, get a little riskier. Many researchers are calling for better masks and better indoor ventilation. But any updates on recommendations likely would play at the margins. Even if variants spread more easily, the same recommendations public health experts have been espousing for months – masking, physical distancing, and limiting time indoors with others – will be the best way to ward them off, said Kirsten Bibbins-Domingo, MD, a physician and professor at the University of California, San Francisco.

“It’s very unsexy what the solutions are,” Dr. Bibbins-Domingo said. “But we need everyone to do them.”

That doesn’t make the task simple. Masking remains controversial in many states, and the public’s patience for maintaining physical distance has worn thin.

Adding to the concerns: Though case numbers stabilized in many parts of the U.S. in January, they have stabilized at rates many times what they were during previous periods in the pandemic or in other parts of the world. Having all that virus in so many bodies creates more opportunities for new mutations and new variants to emerge.

“If we keep letting this thing sneak around, it’s going to get around all the measures we take against it, and that’s the worst possible thing,” said Nevada’s Dr. Pandori.

Compared with less virulent strains, a more contagious variant likely will require that more people be vaccinated before a community can see the benefits of widespread immunity. It’s a bleak outlook for a nation already falling behind in the race to vaccinate enough people to bring the pandemic under control.

“When your best solution is to ask people to do the things that they don’t like to do anyway, that’s very scary,” said Dr. Bibbins-Domingo.
 

This story was produced by KHN, which publishes California Healthline, an editorially independent service of the California Health Care Foundation.

The COVID-19 variants that have emerged in the United Kingdom, Brazil, South Africa and now Southern California are eliciting two notably distinct responses from U.S. public health officials.

janiecbros/iStock/Getty Images Plus

First, broad concern. A variant that wreaked havoc in the United Kingdom, leading to a spike in cases and hospitalizations, is surfacing in a growing number of places in the United States. During the week of Jan. 24, another worrisome variant seen in Brazil surfaced in Minnesota. If these or other strains significantly change the way the virus transmits and attacks the body, as scientists fear they might, they could cause yet another prolonged surge in illness and death in the U.S., even as cases have begun to plateau and vaccines are rolling out.

On the other hand, variants aren’t novel or even uncommon in viral illnesses. The viruses that trigger common colds and flus regularly evolve. Even if a mutated strain of SARS-CoV-2, the virus that causes COVID-19, makes it more contagious or makes people sicker, the basic public health response stays the same: Monitor the virus, and any mutations, as it moves across communities. Use masking, testing, physical distancing, and quarantine to contain the spread.

The problem is that the U.S. has struggled with every step of its public health response in its first year of battle against COVID-19. And that raises the question of whether the nation will devote the attention and resources needed to outflank the virus as it evolves.

Researchers are quick to stress that a coronavirus mutation in itself is no cause for alarm. In the course of making millions and billions of copies as part of the infection process, small changes to a virus’s genome happen all the time as a function of evolutionary biology.

“The word ‘variant’ and the word ‘mutation’ have these scary connotations, and they aren’t necessarily scary,” said Kelly Wroblewski, director of infectious disease programs for the Association of Public Health Laboratories.

When a mutation rings public health alarms, it’s typically because it has combined with other mutations and, collectively, changed how the virus behaves. At that point, it may be named a variant. A variant can make a virus spread faster, or more easily jump between species. It can make a virus more successful at making people sicker, or change how our immune systems respond.

SARS-CoV-2 has been mutating for as long as we’ve known about it; mutations were identified by scientists throughout 2020. Though relevant scientifically – mutations can actually be helpful, acting like a fingerprint that allows scientists to track a virus’s spread – the identified strains mostly carried little concern for public health.

Then came the end of the year, when several variants began drawing scrutiny. One of the most concerning, first detected in the United Kingdom, appears to make the virus more transmissible. Emerging evidence suggests it also could be deadlier, though scientists are still debating that.

We know more about the U.K. variant than others not because it’s necessarily worse, but because the British have one of the best virus surveillance programs in the world, said William Hanage, PhD, an epidemiologist and a professor at Harvard University.

By contrast, the U.S. has one of the weakest genomic surveillance programs of any rich country, Dr. Hanage said. “As it is, people like me cobble together partnerships with places and try and beg them” for samples, he said on a recent call with reporters.

Other variant strains were identified in South Africa and Brazil, and they share some mutations with the U.K. variant. That those changes evolved independently in several parts of the world suggests they might present an evolutionary advantage for the virus. Yet another strain was recently identified in Southern California and flagged due to its increasing presence in hard-hit cities like Los Angeles.

The Southern California strain was detected because a team of researchers at Cedars-Sinai, a hospital and research center in Los Angeles, has unfettered access to patient samples. They were able to see that the strain made up a growing share of cases at the hospital in recent weeks, as well as among the limited number of other samples haphazardly collected at a network of labs in the region.

Not only does the U.S. do less genomic sequencing than most wealthy countries, but it also does its surveillance by happenstance. That means it takes longer to detect new strains and draw conclusions about them. It’s not yet clear, for example, whether that Southern California strain was truly worthy of a press release.

Vast swaths of America’s privatized and decentralized system of health care aren’t set up to send samples to public health or academic labs. “I’m more concerned about the systems to detect variants than I am these particular variants,” said Mark Pandori, PhD, director of Nevada’s public health laboratory and associate professor at the University of Nevada-Reno School of Medicine.

Limited genomic surveillance of viruses is yet another side effect of a fragmented and underfunded public health system that’s struggled to test, track contacts and get COVID-19 under control throughout the pandemic, Ms. Wroblewski said.

The nation’s public health infrastructure, generally funded on a disease-by-disease basis, has decent systems set up to sequence flu, foodborne illnesses and tuberculosis, but there has been no national strategy on COVID-19. “To look for variants, it needs to be a national picture if it’s going to be done well,” Ms. Wroblewski said.

The Biden administration has outlined a strategy for a national response to COVID-19, which includes expanded surveillance for variants.

So far, vaccines for COVID-19 appear to protect against the known variants. Moderna has said its vaccine is effective against the U.K. and South African strains, though it yields fewer antibodies in the face of the latter. The company is working to develop a revised dose of the vaccine that could be added to the current two-shot regimen as a precaution.

But a lot of damage can be done in the time it will take to roll out the current vaccine, let alone an update.

Even with limited sampling, the U.K. variant has been detected in more than two dozen U.S. states, and the Centers for Disease Control and Prevention has warned it could be the predominant strain in the U.S. by March. When it took off in the United Kingdom at the end of last year, it caused a swell in cases, overwhelmed hospitals, and led to a holiday lockdown. Whether the U.S. faces the same fate could depend on which strains it is competing against, and how the public behaves in the weeks ahead.

Already risky interactions among people could, on average, get a little riskier. Many researchers are calling for better masks and better indoor ventilation. But any updates on recommendations likely would play at the margins. Even if variants spread more easily, the same recommendations public health experts have been espousing for months – masking, physical distancing, and limiting time indoors with others – will be the best way to ward them off, said Kirsten Bibbins-Domingo, MD, a physician and professor at the University of California, San Francisco.

“It’s very unsexy what the solutions are,” Dr. Bibbins-Domingo said. “But we need everyone to do them.”

That doesn’t make the task simple. Masking remains controversial in many states, and the public’s patience for maintaining physical distance has worn thin.

Adding to the concerns: Though case numbers stabilized in many parts of the U.S. in January, they have stabilized at rates many times what they were during previous periods in the pandemic or in other parts of the world. Having all that virus in so many bodies creates more opportunities for new mutations and new variants to emerge.

“If we keep letting this thing sneak around, it’s going to get around all the measures we take against it, and that’s the worst possible thing,” said Nevada’s Dr. Pandori.

Compared with less virulent strains, a more contagious variant likely will require that more people be vaccinated before a community can see the benefits of widespread immunity. It’s a bleak outlook for a nation already falling behind in the race to vaccinate enough people to bring the pandemic under control.

“When your best solution is to ask people to do the things that they don’t like to do anyway, that’s very scary,” said Dr. Bibbins-Domingo.
 

This story was produced by KHN, which publishes California Healthline, an editorially independent service of the California Health Care Foundation.

Experts discuss how to best protect people with diabetes from serious COVID-19 outcomes in a newly published article that summarizes in-depth discussions on the topic from a conference held online last year.

Lead author and Diabetes Technology Society founder and director David C. Klonoff, MD, said in an interview: “To my knowledge this is the largest article or learning that has been written anywhere ever about the co-occurrence of COVID-19 and diabetes and how COVID-19 affects diabetes ... There are a lot of different dimensions.” 

The 37-page report covers all sessions from the Virtual International COVID-19 and Diabetes Summit, held Aug. 26-27, 2020, which had 800 attendees from six continents, on topics including pathophysiology and COVID-19 risk factors, the impact of social determinants of health on diabetes and COVID-19, and psychological aspects of the COVID-19 pandemic for people with diabetes.

The freely available report was published online Jan. 21 in the Journal of Diabetes Science and Technology by Jennifer Y. Zhang of the Diabetes Technology Society, Burlingame, Calif., and colleagues.

Other topics include medications and vaccines, outpatient diabetes management during the COVID-19 pandemic and the growth of telehealth, inpatient management of diabetes in patients with or without COVID-19, ethical considerations, children, pregnancy, economics of care for COVID-19, government policy, regulation of tests and treatments, patient surveillance/privacy, and research gaps and opportunities.

“A comprehensive report like this is so important because it covers such a wide range of topics that are all relevant when it comes to protecting patients with diabetes during a pandemic. Our report aims to bring together all these different aspects of policy during the pandemic, patient physiology, and patient psychology, so I hope it will be widely read and widely appreciated,” Ms. Zhang said in an interview.

Two important clinical trends arising as a result of the pandemic – the advent of telehealth in diabetes management and the use of continuous glucose monitoring (CGM) in hospital – are expected to continue even after COVID-19 abates, said Dr. Klonoff, medical director of the Diabetes Research Institute at Mills-Peninsula Medical Center, San Mateo, Calif.


 

Telehealth in diabetes here to stay, in U.S. at least  

Dr. Klonoff noted that with diabetes telehealth, or “telediabetes” as it’s been dubbed, by using downloaded device data patients don’t have to travel, pay for parking, or take as much time off work. “There are advantages ... patients really like it,” he said.

And for health care providers, an advantage of remote visits is that the clinician can look at the patient while reviewing the patient’s data. “With telehealth for diabetes, the patient’s face and the software data are right next to each other on the same screen. Even as I’m typing I’m looking at the patient ... I consider that a huge advantage,” Dr. Klonoff said.

Rule changes early in the pandemic made the shift to telehealth in the United States possible, he said.

“Fortunately, Medicare and other payers are covering telehealth. It used to be there was no coverage, so that was a damper. Now that it’s covered I don’t think that’s going to go back. Everybody likes it,” he said. 
 

CGM in hospitals helps detect hypoglycemia on wards

Regarding the increase of inpatient CGM (continuous glucose monitoring) prompted by the need to minimize patient exposure of nursing staff during the pandemic and the relaxing of Food and Drug Administration rules about its use, Dr. Klonoff said this phenomenon has led to two other positive developments.

“For FDA, it’s actually an opportunity to see some data collected. To do a clinical trial [prior to] March 2020 you had to go through a lot of processes to do a study. Once it becomes part of clinical care, then you can collect a lot of data,” he noted.   

Moreover, Dr. Klonoff said there’s an important new area where hospital use of CGM is emerging: detection of hypoglycemia on wards.

“When a patient is in the ICU, if they become hypoglycemic or hyperglycemic it will likely be detected. But on the wards, they simply don’t get the same attention. Just about every doctor has had a case where somebody drifted into hypoglycemia that wasn’t recognized and maybe even died,” he explained.

If, however, “patients treated with insulin could all have CGMs that would be so useful. It would send out an alarm. A lot of times people don’t eat when you think they will. Suddenly the insulin dose is inappropriate and the nurse didn’t realize. Or, if IV nutrition stops and the insulin is given [it can be harmful].”

Another example, he said, is a common scenario when insulin is used in patients who are treated with steroids. “They need insulin, but then the steroid is decreased and the insulin dose isn’t decreased fast enough. All those situations can be helped with CGM.”

Overall, he concluded, COVID-19 has provided many lessons, which are “expanding our horizons.”

Ms. Zhang has reported no relevant financial relationships. Dr. Klonoff has reported being a consultant for Dexcom, EOFlow, Fractyl, Lifecare, Novo Nordisk, Roche Diagnostics, Samsung, and Thirdwayv.

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

Experts discuss how to best protect people with diabetes from serious COVID-19 outcomes in a newly published article that summarizes in-depth discussions on the topic from a conference held online last year.

Lead author and Diabetes Technology Society founder and director David C. Klonoff, MD, said in an interview: “To my knowledge this is the largest article or learning that has been written anywhere ever about the co-occurrence of COVID-19 and diabetes and how COVID-19 affects diabetes ... There are a lot of different dimensions.” 

The 37-page report covers all sessions from the Virtual International COVID-19 and Diabetes Summit, held Aug. 26-27, 2020, which had 800 attendees from six continents, on topics including pathophysiology and COVID-19 risk factors, the impact of social determinants of health on diabetes and COVID-19, and psychological aspects of the COVID-19 pandemic for people with diabetes.

The freely available report was published online Jan. 21 in the Journal of Diabetes Science and Technology by Jennifer Y. Zhang of the Diabetes Technology Society, Burlingame, Calif., and colleagues.

Other topics include medications and vaccines, outpatient diabetes management during the COVID-19 pandemic and the growth of telehealth, inpatient management of diabetes in patients with or without COVID-19, ethical considerations, children, pregnancy, economics of care for COVID-19, government policy, regulation of tests and treatments, patient surveillance/privacy, and research gaps and opportunities.

“A comprehensive report like this is so important because it covers such a wide range of topics that are all relevant when it comes to protecting patients with diabetes during a pandemic. Our report aims to bring together all these different aspects of policy during the pandemic, patient physiology, and patient psychology, so I hope it will be widely read and widely appreciated,” Ms. Zhang said in an interview.

Two important clinical trends arising as a result of the pandemic – the advent of telehealth in diabetes management and the use of continuous glucose monitoring (CGM) in hospital – are expected to continue even after COVID-19 abates, said Dr. Klonoff, medical director of the Diabetes Research Institute at Mills-Peninsula Medical Center, San Mateo, Calif.


 

Telehealth in diabetes here to stay, in U.S. at least  

Dr. Klonoff noted that with diabetes telehealth, or “telediabetes” as it’s been dubbed, by using downloaded device data patients don’t have to travel, pay for parking, or take as much time off work. “There are advantages ... patients really like it,” he said.

And for health care providers, an advantage of remote visits is that the clinician can look at the patient while reviewing the patient’s data. “With telehealth for diabetes, the patient’s face and the software data are right next to each other on the same screen. Even as I’m typing I’m looking at the patient ... I consider that a huge advantage,” Dr. Klonoff said.

Rule changes early in the pandemic made the shift to telehealth in the United States possible, he said.

“Fortunately, Medicare and other payers are covering telehealth. It used to be there was no coverage, so that was a damper. Now that it’s covered I don’t think that’s going to go back. Everybody likes it,” he said. 
 

CGM in hospitals helps detect hypoglycemia on wards

Regarding the increase of inpatient CGM (continuous glucose monitoring) prompted by the need to minimize patient exposure of nursing staff during the pandemic and the relaxing of Food and Drug Administration rules about its use, Dr. Klonoff said this phenomenon has led to two other positive developments.

“For FDA, it’s actually an opportunity to see some data collected. To do a clinical trial [prior to] March 2020 you had to go through a lot of processes to do a study. Once it becomes part of clinical care, then you can collect a lot of data,” he noted.   

Moreover, Dr. Klonoff said there’s an important new area where hospital use of CGM is emerging: detection of hypoglycemia on wards.

“When a patient is in the ICU, if they become hypoglycemic or hyperglycemic it will likely be detected. But on the wards, they simply don’t get the same attention. Just about every doctor has had a case where somebody drifted into hypoglycemia that wasn’t recognized and maybe even died,” he explained.

If, however, “patients treated with insulin could all have CGMs that would be so useful. It would send out an alarm. A lot of times people don’t eat when you think they will. Suddenly the insulin dose is inappropriate and the nurse didn’t realize. Or, if IV nutrition stops and the insulin is given [it can be harmful].”

Another example, he said, is a common scenario when insulin is used in patients who are treated with steroids. “They need insulin, but then the steroid is decreased and the insulin dose isn’t decreased fast enough. All those situations can be helped with CGM.”

Overall, he concluded, COVID-19 has provided many lessons, which are “expanding our horizons.”

Ms. Zhang has reported no relevant financial relationships. Dr. Klonoff has reported being a consultant for Dexcom, EOFlow, Fractyl, Lifecare, Novo Nordisk, Roche Diagnostics, Samsung, and Thirdwayv.

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

Experts discuss how to best protect people with diabetes from serious COVID-19 outcomes in a newly published article that summarizes in-depth discussions on the topic from a conference held online last year.

Lead author and Diabetes Technology Society founder and director David C. Klonoff, MD, said in an interview: “To my knowledge this is the largest article or learning that has been written anywhere ever about the co-occurrence of COVID-19 and diabetes and how COVID-19 affects diabetes ... There are a lot of different dimensions.” 

The 37-page report covers all sessions from the Virtual International COVID-19 and Diabetes Summit, held Aug. 26-27, 2020, which had 800 attendees from six continents, on topics including pathophysiology and COVID-19 risk factors, the impact of social determinants of health on diabetes and COVID-19, and psychological aspects of the COVID-19 pandemic for people with diabetes.

The freely available report was published online Jan. 21 in the Journal of Diabetes Science and Technology by Jennifer Y. Zhang of the Diabetes Technology Society, Burlingame, Calif., and colleagues.

Other topics include medications and vaccines, outpatient diabetes management during the COVID-19 pandemic and the growth of telehealth, inpatient management of diabetes in patients with or without COVID-19, ethical considerations, children, pregnancy, economics of care for COVID-19, government policy, regulation of tests and treatments, patient surveillance/privacy, and research gaps and opportunities.

“A comprehensive report like this is so important because it covers such a wide range of topics that are all relevant when it comes to protecting patients with diabetes during a pandemic. Our report aims to bring together all these different aspects of policy during the pandemic, patient physiology, and patient psychology, so I hope it will be widely read and widely appreciated,” Ms. Zhang said in an interview.

Two important clinical trends arising as a result of the pandemic – the advent of telehealth in diabetes management and the use of continuous glucose monitoring (CGM) in hospital – are expected to continue even after COVID-19 abates, said Dr. Klonoff, medical director of the Diabetes Research Institute at Mills-Peninsula Medical Center, San Mateo, Calif.


 

Telehealth in diabetes here to stay, in U.S. at least  

Dr. Klonoff noted that with diabetes telehealth, or “telediabetes” as it’s been dubbed, by using downloaded device data patients don’t have to travel, pay for parking, or take as much time off work. “There are advantages ... patients really like it,” he said.

And for health care providers, an advantage of remote visits is that the clinician can look at the patient while reviewing the patient’s data. “With telehealth for diabetes, the patient’s face and the software data are right next to each other on the same screen. Even as I’m typing I’m looking at the patient ... I consider that a huge advantage,” Dr. Klonoff said.

Rule changes early in the pandemic made the shift to telehealth in the United States possible, he said.

“Fortunately, Medicare and other payers are covering telehealth. It used to be there was no coverage, so that was a damper. Now that it’s covered I don’t think that’s going to go back. Everybody likes it,” he said. 
 

CGM in hospitals helps detect hypoglycemia on wards

Regarding the increase of inpatient CGM (continuous glucose monitoring) prompted by the need to minimize patient exposure of nursing staff during the pandemic and the relaxing of Food and Drug Administration rules about its use, Dr. Klonoff said this phenomenon has led to two other positive developments.

“For FDA, it’s actually an opportunity to see some data collected. To do a clinical trial [prior to] March 2020 you had to go through a lot of processes to do a study. Once it becomes part of clinical care, then you can collect a lot of data,” he noted.   

Moreover, Dr. Klonoff said there’s an important new area where hospital use of CGM is emerging: detection of hypoglycemia on wards.

“When a patient is in the ICU, if they become hypoglycemic or hyperglycemic it will likely be detected. But on the wards, they simply don’t get the same attention. Just about every doctor has had a case where somebody drifted into hypoglycemia that wasn’t recognized and maybe even died,” he explained.

If, however, “patients treated with insulin could all have CGMs that would be so useful. It would send out an alarm. A lot of times people don’t eat when you think they will. Suddenly the insulin dose is inappropriate and the nurse didn’t realize. Or, if IV nutrition stops and the insulin is given [it can be harmful].”

Another example, he said, is a common scenario when insulin is used in patients who are treated with steroids. “They need insulin, but then the steroid is decreased and the insulin dose isn’t decreased fast enough. All those situations can be helped with CGM.”

Overall, he concluded, COVID-19 has provided many lessons, which are “expanding our horizons.”

Ms. Zhang has reported no relevant financial relationships. Dr. Klonoff has reported being a consultant for Dexcom, EOFlow, Fractyl, Lifecare, Novo Nordisk, Roche Diagnostics, Samsung, and Thirdwayv.

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

The incidence of idiopathic intracranial hypertension (IIH) – characterized by increased cerebrospinal fluid (CSF) pressure – is rising considerably, corresponding to population increases in body mass index (BMI), a new study has shown. “The condition is associated with a high rate of health care utilization, so the increasing incidence has important implications for health care professionals and policy makers in addressing the associated comorbidities,” said senior author William Owen Pickrell, PhD, Swansea University (Wales).

The study was published online Jan. 20 in Neurology.

IIH is a condition of unknown etiology that is strongly associated with obesity, the researchers noted. Predominantly affecting women of childbearing age, it causes chronic disabling headaches, visual disturbance, and in a minority of patients, permanent visual loss. The definitive management is weight loss, but a minority of patients require surgery to preserve vision.

People with IIH potentially have high rates of health care utilization, multiple specialist consultations, diagnostic tests, CSF diversion procedures, and complications related to CSF diversion surgery.  
 

Population study in Wales

Given that there is a paucity of data regarding the epidemiology, health care utilization, and outcomes of people with IIH, Dr. Pickrell and colleagues conducted the current retrospective cohort study, which aimed to determine the temporal trends of IIH incidence and prevalence in Wales and health care utilization associated with IIH. They also investigated the effects of socioeconomic deprivation and obesity on IIH epidemiology.

For the study, they used and validated primary and secondary care IIH diagnostic codes within the Secure Anonymised Information Linkage data bank, which is part of the national e-health records research infrastructure for Wales, to ascertain IIH cases and controls between 2003 and 2017. In total, 35 million patient-years of data were analyzed. Information was recorded on body mass index, deprivation quintile, CSF diversion surgery, and unscheduled hospital admissions in case and control cohorts.

“This is the first time the diagnostic codes for this condition have been validated. This is important as it is critical if we are studying a condition to know that the individuals we are studying actually have that condition,” Dr. Pickrell commented. “We were able to establish that the diagnostic codes were 92% sensitive and 87% specific – that’s pretty good.”

Results showed a significant increase in IIH incidence and prevalence in Wales. The prevalence of IIH in Wales increased sixfold from 12/100,000 in 2003 to 76/100,000 in 2017, and the incidence of IIH increased threefold from 2.3/100,000 per year in 2003 to 7.8/100,000 per year in 2017. This corresponded with increases in obesity rates: 29% of the population was obese in 2003, compared with 40% in 2017.
 

Reasons for the increase

“The considerable increase in IIH incidence is multifactorial but likely predominately due to rising obesity rates,” the authors noted. “The worldwide prevalence of obesity nearly tripled between 1975 and 2016 and therefore these results also have global relevance.”

The increase in IIH incidence may also be attributable to increased IIH diagnosis rates because of raised awareness of the condition and greater use of digital fundoscopy at routine optometry appointments, they suggested.

“We found a strong association between increasing BMI, sex (being female), and IIH. Around 85% of our IIH cohort were female, similar to other studies, and we also found a significant association with increased deprivation and IIH, particularly in women,” the authors reported.

IIH is associated with increasing deprivation in women even after adjusting for obesity suggesting additional etiologic factors associated with deprivation apart from BMI; this effect was not seen in men, pointing to sex-specific drivers for IIH, they added.

The results also show that individuals with IIH have increased rates of unscheduled health care utilization compared with a matched-control cohort. The rate ratio for unscheduled hospital admissions in the IIH cohort, compared with controls was 5.28.

“A considerable proportion of this excess in unscheduled hospital admissions occurs at the time of diagnosis and can be explained by the need for urgent investigation of papilloedema with brain imaging and spinal fluid analysis. However, there is also a considerable excess in unscheduled hospital admissions up to 2 years after diagnosis,” the authors reported.

They suggested that these admissions are likely to be for severe headache, and they say there is some scope to reduce emergency admissions through better management of headache, patient education, and rapid access to outpatient specialist advice.

They also pointed out that the rate of unscheduled admissions is higher in the IIH cohort in the 3 years leading up to diagnosis, suggesting an opportunity for earlier diagnosis and earlier intervention.

In their study population, 8% of patients with IIH received CSF diversion procedures a mean of 1.3 years after diagnosis, and these patients showed significantly increased unscheduled health care admission rates, compared with IIH patients who had not undergone such procedures.

“There are frequent complications with the shunts after surgery, which causes a high revision rate,” Dr. Pickrell commented. In this study, 40% of patients undergoing CSF diversion needed at least one CSF shunt revision procedure.

The study was supported by the Brain Repair and Intracranial Neurotherapeutics unit, Wales Gene Park, Health Data Research UK, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Wales), Public Health Agency (Northern Ireland), British Heart Foundation, and Wellcome Trust. The authors reported no relevant financial relationships.

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

The incidence of idiopathic intracranial hypertension (IIH) – characterized by increased cerebrospinal fluid (CSF) pressure – is rising considerably, corresponding to population increases in body mass index (BMI), a new study has shown. “The condition is associated with a high rate of health care utilization, so the increasing incidence has important implications for health care professionals and policy makers in addressing the associated comorbidities,” said senior author William Owen Pickrell, PhD, Swansea University (Wales).

The study was published online Jan. 20 in Neurology.

IIH is a condition of unknown etiology that is strongly associated with obesity, the researchers noted. Predominantly affecting women of childbearing age, it causes chronic disabling headaches, visual disturbance, and in a minority of patients, permanent visual loss. The definitive management is weight loss, but a minority of patients require surgery to preserve vision.

People with IIH potentially have high rates of health care utilization, multiple specialist consultations, diagnostic tests, CSF diversion procedures, and complications related to CSF diversion surgery.  
 

Population study in Wales

Given that there is a paucity of data regarding the epidemiology, health care utilization, and outcomes of people with IIH, Dr. Pickrell and colleagues conducted the current retrospective cohort study, which aimed to determine the temporal trends of IIH incidence and prevalence in Wales and health care utilization associated with IIH. They also investigated the effects of socioeconomic deprivation and obesity on IIH epidemiology.

For the study, they used and validated primary and secondary care IIH diagnostic codes within the Secure Anonymised Information Linkage data bank, which is part of the national e-health records research infrastructure for Wales, to ascertain IIH cases and controls between 2003 and 2017. In total, 35 million patient-years of data were analyzed. Information was recorded on body mass index, deprivation quintile, CSF diversion surgery, and unscheduled hospital admissions in case and control cohorts.

“This is the first time the diagnostic codes for this condition have been validated. This is important as it is critical if we are studying a condition to know that the individuals we are studying actually have that condition,” Dr. Pickrell commented. “We were able to establish that the diagnostic codes were 92% sensitive and 87% specific – that’s pretty good.”

Results showed a significant increase in IIH incidence and prevalence in Wales. The prevalence of IIH in Wales increased sixfold from 12/100,000 in 2003 to 76/100,000 in 2017, and the incidence of IIH increased threefold from 2.3/100,000 per year in 2003 to 7.8/100,000 per year in 2017. This corresponded with increases in obesity rates: 29% of the population was obese in 2003, compared with 40% in 2017.
 

Reasons for the increase

“The considerable increase in IIH incidence is multifactorial but likely predominately due to rising obesity rates,” the authors noted. “The worldwide prevalence of obesity nearly tripled between 1975 and 2016 and therefore these results also have global relevance.”

The increase in IIH incidence may also be attributable to increased IIH diagnosis rates because of raised awareness of the condition and greater use of digital fundoscopy at routine optometry appointments, they suggested.

“We found a strong association between increasing BMI, sex (being female), and IIH. Around 85% of our IIH cohort were female, similar to other studies, and we also found a significant association with increased deprivation and IIH, particularly in women,” the authors reported.

IIH is associated with increasing deprivation in women even after adjusting for obesity suggesting additional etiologic factors associated with deprivation apart from BMI; this effect was not seen in men, pointing to sex-specific drivers for IIH, they added.

The results also show that individuals with IIH have increased rates of unscheduled health care utilization compared with a matched-control cohort. The rate ratio for unscheduled hospital admissions in the IIH cohort, compared with controls was 5.28.

“A considerable proportion of this excess in unscheduled hospital admissions occurs at the time of diagnosis and can be explained by the need for urgent investigation of papilloedema with brain imaging and spinal fluid analysis. However, there is also a considerable excess in unscheduled hospital admissions up to 2 years after diagnosis,” the authors reported.

They suggested that these admissions are likely to be for severe headache, and they say there is some scope to reduce emergency admissions through better management of headache, patient education, and rapid access to outpatient specialist advice.

They also pointed out that the rate of unscheduled admissions is higher in the IIH cohort in the 3 years leading up to diagnosis, suggesting an opportunity for earlier diagnosis and earlier intervention.

In their study population, 8% of patients with IIH received CSF diversion procedures a mean of 1.3 years after diagnosis, and these patients showed significantly increased unscheduled health care admission rates, compared with IIH patients who had not undergone such procedures.

“There are frequent complications with the shunts after surgery, which causes a high revision rate,” Dr. Pickrell commented. In this study, 40% of patients undergoing CSF diversion needed at least one CSF shunt revision procedure.

The study was supported by the Brain Repair and Intracranial Neurotherapeutics unit, Wales Gene Park, Health Data Research UK, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Wales), Public Health Agency (Northern Ireland), British Heart Foundation, and Wellcome Trust. The authors reported no relevant financial relationships.

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

The incidence of idiopathic intracranial hypertension (IIH) – characterized by increased cerebrospinal fluid (CSF) pressure – is rising considerably, corresponding to population increases in body mass index (BMI), a new study has shown. “The condition is associated with a high rate of health care utilization, so the increasing incidence has important implications for health care professionals and policy makers in addressing the associated comorbidities,” said senior author William Owen Pickrell, PhD, Swansea University (Wales).

The study was published online Jan. 20 in Neurology.

IIH is a condition of unknown etiology that is strongly associated with obesity, the researchers noted. Predominantly affecting women of childbearing age, it causes chronic disabling headaches, visual disturbance, and in a minority of patients, permanent visual loss. The definitive management is weight loss, but a minority of patients require surgery to preserve vision.

People with IIH potentially have high rates of health care utilization, multiple specialist consultations, diagnostic tests, CSF diversion procedures, and complications related to CSF diversion surgery.  
 

Population study in Wales

Given that there is a paucity of data regarding the epidemiology, health care utilization, and outcomes of people with IIH, Dr. Pickrell and colleagues conducted the current retrospective cohort study, which aimed to determine the temporal trends of IIH incidence and prevalence in Wales and health care utilization associated with IIH. They also investigated the effects of socioeconomic deprivation and obesity on IIH epidemiology.

For the study, they used and validated primary and secondary care IIH diagnostic codes within the Secure Anonymised Information Linkage data bank, which is part of the national e-health records research infrastructure for Wales, to ascertain IIH cases and controls between 2003 and 2017. In total, 35 million patient-years of data were analyzed. Information was recorded on body mass index, deprivation quintile, CSF diversion surgery, and unscheduled hospital admissions in case and control cohorts.

“This is the first time the diagnostic codes for this condition have been validated. This is important as it is critical if we are studying a condition to know that the individuals we are studying actually have that condition,” Dr. Pickrell commented. “We were able to establish that the diagnostic codes were 92% sensitive and 87% specific – that’s pretty good.”

Results showed a significant increase in IIH incidence and prevalence in Wales. The prevalence of IIH in Wales increased sixfold from 12/100,000 in 2003 to 76/100,000 in 2017, and the incidence of IIH increased threefold from 2.3/100,000 per year in 2003 to 7.8/100,000 per year in 2017. This corresponded with increases in obesity rates: 29% of the population was obese in 2003, compared with 40% in 2017.
 

Reasons for the increase

“The considerable increase in IIH incidence is multifactorial but likely predominately due to rising obesity rates,” the authors noted. “The worldwide prevalence of obesity nearly tripled between 1975 and 2016 and therefore these results also have global relevance.”

The increase in IIH incidence may also be attributable to increased IIH diagnosis rates because of raised awareness of the condition and greater use of digital fundoscopy at routine optometry appointments, they suggested.

“We found a strong association between increasing BMI, sex (being female), and IIH. Around 85% of our IIH cohort were female, similar to other studies, and we also found a significant association with increased deprivation and IIH, particularly in women,” the authors reported.

IIH is associated with increasing deprivation in women even after adjusting for obesity suggesting additional etiologic factors associated with deprivation apart from BMI; this effect was not seen in men, pointing to sex-specific drivers for IIH, they added.

The results also show that individuals with IIH have increased rates of unscheduled health care utilization compared with a matched-control cohort. The rate ratio for unscheduled hospital admissions in the IIH cohort, compared with controls was 5.28.

“A considerable proportion of this excess in unscheduled hospital admissions occurs at the time of diagnosis and can be explained by the need for urgent investigation of papilloedema with brain imaging and spinal fluid analysis. However, there is also a considerable excess in unscheduled hospital admissions up to 2 years after diagnosis,” the authors reported.

They suggested that these admissions are likely to be for severe headache, and they say there is some scope to reduce emergency admissions through better management of headache, patient education, and rapid access to outpatient specialist advice.

They also pointed out that the rate of unscheduled admissions is higher in the IIH cohort in the 3 years leading up to diagnosis, suggesting an opportunity for earlier diagnosis and earlier intervention.

In their study population, 8% of patients with IIH received CSF diversion procedures a mean of 1.3 years after diagnosis, and these patients showed significantly increased unscheduled health care admission rates, compared with IIH patients who had not undergone such procedures.

“There are frequent complications with the shunts after surgery, which causes a high revision rate,” Dr. Pickrell commented. In this study, 40% of patients undergoing CSF diversion needed at least one CSF shunt revision procedure.

The study was supported by the Brain Repair and Intracranial Neurotherapeutics unit, Wales Gene Park, Health Data Research UK, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Wales), Public Health Agency (Northern Ireland), British Heart Foundation, and Wellcome Trust. The authors reported no relevant financial relationships.

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

First-line trifluridine/tipiracil plus bevacizumab (TT-B) offered a slight survival benefit over capecitabine plus bevacizumab (C-B) in patients with unresectable metastatic colorectal cancer in the final analysis of the TASCO1 trial.

The median progression-free survival (PFS) in the phase 2 trial showed a difference of 1.41 months favoring TT-B over C-B, but this difference was not statistically significant.

The median overall survival was 4.64 months longer with TT-B than with C-B. However, the final analysis of TASCO1 was not designed to be comparative for overall survival, “so no formal statistical analysis is presented, and survival is a secondary endpoint,” noted investigator Eric Van Cutsem, MD, PhD, of University Hospital Gasthuisberg in Leuven, Belgium.

Dr. Van Cutsem presented the final results of TASCO1 at the 2021 Gastrointestinal Cancers Symposium (abstract 14).

Prior results from the trial were reported last year (Ann Oncol. 2020 Sep;31[9]:1160-68).
 

About trifluridine/tipiracil

Trifluridine/tipiracil is an oral drug combining the thymidine analogue trifluridine with tipiracil, an inhibitor of trifluridine degradation. The drug was approved by the Food and Drug Administration in 2015 under the trade name Lonsurf for the treatment of refractory metastatic colorectal cancer, and in 2019 for patients with metastatic gastric cancer or gastroesophageal junction cancer that had been treated with at least two lines of chemotherapy.

Trifluridine/tipiracil was associated with a brief but statistically significant survival benefit when compared with placebo in patients with heavily pretreated metastatic gastric cancer in the TAS-102 Gastric Study (Lancet Oncol. 2018 Nov;19[11]:1437-48).

In a separate analysis of the study, trifluridine/tipiracil was associated with significantly better overall survival and PFS than placebo in patients who had undergone gastrectomy (JAMA Oncol. 2019 Oct 10;6[1]:e193531).
 

TASCO1 details

In TASCO1, investigators enrolled patients with colorectal cancer who had never received systemic therapy for unresectable metastatic disease, and who were judged to be ineligible for intensive therapy due to advanced age, low tumor burden, poor performance status, comorbidities, or other clinical reasons.

After stratification by RAS status, performance status, and region, patients were randomly assigned to receive TT-B (n = 77) or C-B (n = 76).

TT-B consisted of oral trifluridine/tipiracil at 35 mg/m² twice daily on days 1-5 and 8-12 every 4 weeks plus bevacizumab at 5 mg/kg intravenously on days 1 and 15 every 4 weeks.

C-B consisted of oral capecitabine at 1,250 or 1,000 mg/m² twice a day on days 1-14 every 3 weeks plus bevacizumab at 7.5 mg/kg IV on day 1 every 3 weeks.
 

Final results

The median PFS, the primary endpoint, was 9.23 months with TT-B and 7.82 months with C-B. The difference was not statistically significant, with the upper limit of the 95% confidence interval crossing 1.

The median overall survival was 22.31 months with TT-B and 17.67 months with C-B (hazard ratio, 0.78; 95% CI, 0.55-1.10).

Dr. Van Cutsem pointed out that more patients in the TT-B arm had subsequent therapies compared with patients in the C-B arm – 59.7% vs. 40.8%.

He also noted that the safety profile of TT-B “remains unchanged from the initial analysis.”

Grade 3 or greater neutropenia, decreased neutrophil count, anemia, and decreased white blood cell count were all higher among patients on TT-B, but grade 3 or greater febrile neutropenia was similar between the groups.

Patients in the TT-B arm had more frequent grade 3 or greater nausea, vomiting, and hypertension. Grade 3 or higher hand-foot syndrome and diarrhea were both more common with C-B.

At the study cutoff date in September 2020, 66 patients in each arm had died.

Dr. Van Cutsem said more data on the efficacy of TT-B vs. C-B will come from the ongoing phase 3 SOLSTICE trial. Results from this trial are expected in late 2022.
 

‘The jury is still out’

The final results from TASCO1 suggest there may be some benefit from TT-B in patients with treatment-naive metastatic colorectal cancer, “but we don’t use it in the first line,” said Jeffery Clark, MD, an oncologist who was not involved in the study.

The trial supports the benefit of combining trifluridine/tipiracil with bevacizumab, and the results were “somewhat better” than he had expected, said Dr. Clark, director of clinical trials support at Mass General Cancer Center in Boston.

“Even though the results are encouraging, there were a couple of things about the trial that one has to at least think about,” Dr. Clark said in an interview.

He noted, for example, that a higher proportion of patients assigned to TT-B had prior adjuvant therapy (27.3% vs. 19.7%), and patients in the TT-B arm were also more likely to have second lines of systemic therapy, which could have skewed the results in favor of the experimental arm.

“I think, basically, the jury is still out until we see the results of the SOLSTICE trial,” he said.

The TASCO1 study was funded by Servier and Taiho. Dr. Van Cutsem has received research funding and served on an advisory board for Servier and other companies. Dr. Clark reported no relevant disclosures.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

First-line trifluridine/tipiracil plus bevacizumab (TT-B) offered a slight survival benefit over capecitabine plus bevacizumab (C-B) in patients with unresectable metastatic colorectal cancer in the final analysis of the TASCO1 trial.

The median progression-free survival (PFS) in the phase 2 trial showed a difference of 1.41 months favoring TT-B over C-B, but this difference was not statistically significant.

The median overall survival was 4.64 months longer with TT-B than with C-B. However, the final analysis of TASCO1 was not designed to be comparative for overall survival, “so no formal statistical analysis is presented, and survival is a secondary endpoint,” noted investigator Eric Van Cutsem, MD, PhD, of University Hospital Gasthuisberg in Leuven, Belgium.

Dr. Van Cutsem presented the final results of TASCO1 at the 2021 Gastrointestinal Cancers Symposium (abstract 14).

Prior results from the trial were reported last year (Ann Oncol. 2020 Sep;31[9]:1160-68).
 

About trifluridine/tipiracil

Trifluridine/tipiracil is an oral drug combining the thymidine analogue trifluridine with tipiracil, an inhibitor of trifluridine degradation. The drug was approved by the Food and Drug Administration in 2015 under the trade name Lonsurf for the treatment of refractory metastatic colorectal cancer, and in 2019 for patients with metastatic gastric cancer or gastroesophageal junction cancer that had been treated with at least two lines of chemotherapy.

Trifluridine/tipiracil was associated with a brief but statistically significant survival benefit when compared with placebo in patients with heavily pretreated metastatic gastric cancer in the TAS-102 Gastric Study (Lancet Oncol. 2018 Nov;19[11]:1437-48).

In a separate analysis of the study, trifluridine/tipiracil was associated with significantly better overall survival and PFS than placebo in patients who had undergone gastrectomy (JAMA Oncol. 2019 Oct 10;6[1]:e193531).
 

TASCO1 details

In TASCO1, investigators enrolled patients with colorectal cancer who had never received systemic therapy for unresectable metastatic disease, and who were judged to be ineligible for intensive therapy due to advanced age, low tumor burden, poor performance status, comorbidities, or other clinical reasons.

After stratification by RAS status, performance status, and region, patients were randomly assigned to receive TT-B (n = 77) or C-B (n = 76).

TT-B consisted of oral trifluridine/tipiracil at 35 mg/m² twice daily on days 1-5 and 8-12 every 4 weeks plus bevacizumab at 5 mg/kg intravenously on days 1 and 15 every 4 weeks.

C-B consisted of oral capecitabine at 1,250 or 1,000 mg/m² twice a day on days 1-14 every 3 weeks plus bevacizumab at 7.5 mg/kg IV on day 1 every 3 weeks.
 

Final results

The median PFS, the primary endpoint, was 9.23 months with TT-B and 7.82 months with C-B. The difference was not statistically significant, with the upper limit of the 95% confidence interval crossing 1.

The median overall survival was 22.31 months with TT-B and 17.67 months with C-B (hazard ratio, 0.78; 95% CI, 0.55-1.10).

Dr. Van Cutsem pointed out that more patients in the TT-B arm had subsequent therapies compared with patients in the C-B arm – 59.7% vs. 40.8%.

He also noted that the safety profile of TT-B “remains unchanged from the initial analysis.”

Grade 3 or greater neutropenia, decreased neutrophil count, anemia, and decreased white blood cell count were all higher among patients on TT-B, but grade 3 or greater febrile neutropenia was similar between the groups.

Patients in the TT-B arm had more frequent grade 3 or greater nausea, vomiting, and hypertension. Grade 3 or higher hand-foot syndrome and diarrhea were both more common with C-B.

At the study cutoff date in September 2020, 66 patients in each arm had died.

Dr. Van Cutsem said more data on the efficacy of TT-B vs. C-B will come from the ongoing phase 3 SOLSTICE trial. Results from this trial are expected in late 2022.
 

‘The jury is still out’

The final results from TASCO1 suggest there may be some benefit from TT-B in patients with treatment-naive metastatic colorectal cancer, “but we don’t use it in the first line,” said Jeffery Clark, MD, an oncologist who was not involved in the study.

The trial supports the benefit of combining trifluridine/tipiracil with bevacizumab, and the results were “somewhat better” than he had expected, said Dr. Clark, director of clinical trials support at Mass General Cancer Center in Boston.

“Even though the results are encouraging, there were a couple of things about the trial that one has to at least think about,” Dr. Clark said in an interview.

He noted, for example, that a higher proportion of patients assigned to TT-B had prior adjuvant therapy (27.3% vs. 19.7%), and patients in the TT-B arm were also more likely to have second lines of systemic therapy, which could have skewed the results in favor of the experimental arm.

“I think, basically, the jury is still out until we see the results of the SOLSTICE trial,” he said.

The TASCO1 study was funded by Servier and Taiho. Dr. Van Cutsem has received research funding and served on an advisory board for Servier and other companies. Dr. Clark reported no relevant disclosures.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

First-line trifluridine/tipiracil plus bevacizumab (TT-B) offered a slight survival benefit over capecitabine plus bevacizumab (C-B) in patients with unresectable metastatic colorectal cancer in the final analysis of the TASCO1 trial.

The median progression-free survival (PFS) in the phase 2 trial showed a difference of 1.41 months favoring TT-B over C-B, but this difference was not statistically significant.

The median overall survival was 4.64 months longer with TT-B than with C-B. However, the final analysis of TASCO1 was not designed to be comparative for overall survival, “so no formal statistical analysis is presented, and survival is a secondary endpoint,” noted investigator Eric Van Cutsem, MD, PhD, of University Hospital Gasthuisberg in Leuven, Belgium.

Dr. Van Cutsem presented the final results of TASCO1 at the 2021 Gastrointestinal Cancers Symposium (abstract 14).

Prior results from the trial were reported last year (Ann Oncol. 2020 Sep;31[9]:1160-68).
 

About trifluridine/tipiracil

Trifluridine/tipiracil is an oral drug combining the thymidine analogue trifluridine with tipiracil, an inhibitor of trifluridine degradation. The drug was approved by the Food and Drug Administration in 2015 under the trade name Lonsurf for the treatment of refractory metastatic colorectal cancer, and in 2019 for patients with metastatic gastric cancer or gastroesophageal junction cancer that had been treated with at least two lines of chemotherapy.

Trifluridine/tipiracil was associated with a brief but statistically significant survival benefit when compared with placebo in patients with heavily pretreated metastatic gastric cancer in the TAS-102 Gastric Study (Lancet Oncol. 2018 Nov;19[11]:1437-48).

In a separate analysis of the study, trifluridine/tipiracil was associated with significantly better overall survival and PFS than placebo in patients who had undergone gastrectomy (JAMA Oncol. 2019 Oct 10;6[1]:e193531).
 

TASCO1 details

In TASCO1, investigators enrolled patients with colorectal cancer who had never received systemic therapy for unresectable metastatic disease, and who were judged to be ineligible for intensive therapy due to advanced age, low tumor burden, poor performance status, comorbidities, or other clinical reasons.

After stratification by RAS status, performance status, and region, patients were randomly assigned to receive TT-B (n = 77) or C-B (n = 76).

TT-B consisted of oral trifluridine/tipiracil at 35 mg/m² twice daily on days 1-5 and 8-12 every 4 weeks plus bevacizumab at 5 mg/kg intravenously on days 1 and 15 every 4 weeks.

C-B consisted of oral capecitabine at 1,250 or 1,000 mg/m² twice a day on days 1-14 every 3 weeks plus bevacizumab at 7.5 mg/kg IV on day 1 every 3 weeks.
 

Final results

The median PFS, the primary endpoint, was 9.23 months with TT-B and 7.82 months with C-B. The difference was not statistically significant, with the upper limit of the 95% confidence interval crossing 1.

The median overall survival was 22.31 months with TT-B and 17.67 months with C-B (hazard ratio, 0.78; 95% CI, 0.55-1.10).

Dr. Van Cutsem pointed out that more patients in the TT-B arm had subsequent therapies compared with patients in the C-B arm – 59.7% vs. 40.8%.

He also noted that the safety profile of TT-B “remains unchanged from the initial analysis.”

Grade 3 or greater neutropenia, decreased neutrophil count, anemia, and decreased white blood cell count were all higher among patients on TT-B, but grade 3 or greater febrile neutropenia was similar between the groups.

Patients in the TT-B arm had more frequent grade 3 or greater nausea, vomiting, and hypertension. Grade 3 or higher hand-foot syndrome and diarrhea were both more common with C-B.

At the study cutoff date in September 2020, 66 patients in each arm had died.

Dr. Van Cutsem said more data on the efficacy of TT-B vs. C-B will come from the ongoing phase 3 SOLSTICE trial. Results from this trial are expected in late 2022.
 

‘The jury is still out’

The final results from TASCO1 suggest there may be some benefit from TT-B in patients with treatment-naive metastatic colorectal cancer, “but we don’t use it in the first line,” said Jeffery Clark, MD, an oncologist who was not involved in the study.

The trial supports the benefit of combining trifluridine/tipiracil with bevacizumab, and the results were “somewhat better” than he had expected, said Dr. Clark, director of clinical trials support at Mass General Cancer Center in Boston.

“Even though the results are encouraging, there were a couple of things about the trial that one has to at least think about,” Dr. Clark said in an interview.

He noted, for example, that a higher proportion of patients assigned to TT-B had prior adjuvant therapy (27.3% vs. 19.7%), and patients in the TT-B arm were also more likely to have second lines of systemic therapy, which could have skewed the results in favor of the experimental arm.

“I think, basically, the jury is still out until we see the results of the SOLSTICE trial,” he said.

The TASCO1 study was funded by Servier and Taiho. Dr. Van Cutsem has received research funding and served on an advisory board for Servier and other companies. Dr. Clark reported no relevant disclosures.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Are pediatric atopic dermatitis and atopic dermatitis the same disease?

“Maybe not,” Jonathan I. Silverberg, MD, PhD, MPH, said during the Revolutionizing Atopic Dermatitis symposium.

Dr. Silverberg, director of clinical research in the division of dermatology at George Washington University, Washington, based his comments largely on a review that he and his colleagues carried out to understand how features of atopic dermatitis (AD) vary by region globally as well as by age. They identified 101 studies with sufficient data for meta-analysis and stratified the results by pediatric and adult age groups.

Several signs and symptoms occurred with similar frequency among pediatric and adult patients, including pruritus, xerosis, flexural involvement, extensor involvement, early onset of disease, comorbid atopy, head and neck involvement, and ophthalmic comorbidities. However, adults were found to have more signs of chronic disease, more hand eczema, different patterns of hand eczema, and a stronger relationship of disease activity with emotional factors. Meanwhile, children were found to have more exudative or weeping lesions, more perifollicular eczema, and more pityriasis alba.

Dr. Silverberg showed photos of three adults with varied presentations of extensor involvement, including one “who had a lot of lichenification and thickening of the skin, but over knees where you might think about psoriasis,” he said. “All three of these patients were of Southeast Asian descent. That happens to be a region where this feature was reported much more commonly. It may even tie to some underlying immunopathophysiologic differences of the disease across different patient populations.”

AD signs that occur more commonly in adults than children include lichenification (100% vs. 48%), urticaria (32% vs. 20%), popular lichenoid lesions (46% vs. 8%), Hertoghe’s sign (25% vs. 2%), erythroderma (29% vs. 1%), and nodular prurigo (18% vs. 4%).

Hand eczema features also differ between adults and children, including hand or foot dermatitis (44% vs. 25%), dyshidrosis/pompholyx (21% vs. 3%), knuckle dermatitis (25% vs. 8%), nail involvement (15% vs. 8%), and fissured heels. However, ventral wrist dermatitis was found to be more than twice as common in children, compared with adults (34% vs. 15%).

Other signs of AD were more common in children, compared with adults, including exudative eczema (61% vs. 42%), pityriasis alba (28% vs. 18%), Dennie-Morgan infraorbital folds (47% vs. 36%), seborrheic dermatitis–like lesions (40% vs. 18%), and perifollicular accentuation (37% vs. 21%). “This is such an important sign to wrap your head around and get comfortable assessing,” he said. “I have seen patients who are erythrodermic with follicular eczema who were told that they were crazy and had psychogenic itch, and they should go to a shrink.”

AD triggers can differ between adults and children as well, including course influenced by emotions/environmental factors (72% vs. 32%), worsening itch worse (65% vs. 49%), course influenced by environment (62% vs. 37%), and course influenced by emotions (70% vs. 15%).

According to Dr. Silverberg, emerging research suggests that there may be differences in the immune pathways activated in pediatric versus adult AD. Specifically, more Th17 and interferon-gamma in AD lesions have been observed in children, compared with adults, and more Th22 and Th17 in nonlesional AD have been seen in children, compared with adults. “This leads to a question: Will children respond differently than adults to treatment?” Dr. Silverberg said. “We see that omalizumab doesn’t seem to help much in adults, yet a recent study suggested that it might work reasonably well for children. Dupilumab has different dosing requirements and potentially different responses between the pediatric and adult populations.”

Age differences in AD may also be related to differences in the skin microbiome. In 2016, researchers led by Richard L. Gallo, MD, PhD, professor of dermatology, University of California, San Diego, compared the skin microbiome between adults and children with AD by swabbing the volar forearm and performing 16S rRNA gene sequencing. The study included 59 young children, 13 teenagers, and 56 adults with AD as well as 68 age-matched non-atopic healthy controls. The researchers found a greater abundance of Streptococcus, Granulicatella, Gemella, Rothia, and Haemophilus in young children, compared with adults, while Propionibacterium, Corynebacterium, Staphylococcus, Lactobacillus, Finegoldia, and Anaerococcus were more abundant in adults, compared with children.

Dr. Silverberg reported that he is a consultant to and/or an advisory board member for several pharmaceutical companies. He is also a speaker for Regeneron and Sanofi and has received a grant from Galderma.

[email protected]

Are pediatric atopic dermatitis and atopic dermatitis the same disease?

“Maybe not,” Jonathan I. Silverberg, MD, PhD, MPH, said during the Revolutionizing Atopic Dermatitis symposium.

Dr. Silverberg, director of clinical research in the division of dermatology at George Washington University, Washington, based his comments largely on a review that he and his colleagues carried out to understand how features of atopic dermatitis (AD) vary by region globally as well as by age. They identified 101 studies with sufficient data for meta-analysis and stratified the results by pediatric and adult age groups.

Several signs and symptoms occurred with similar frequency among pediatric and adult patients, including pruritus, xerosis, flexural involvement, extensor involvement, early onset of disease, comorbid atopy, head and neck involvement, and ophthalmic comorbidities. However, adults were found to have more signs of chronic disease, more hand eczema, different patterns of hand eczema, and a stronger relationship of disease activity with emotional factors. Meanwhile, children were found to have more exudative or weeping lesions, more perifollicular eczema, and more pityriasis alba.

Dr. Silverberg showed photos of three adults with varied presentations of extensor involvement, including one “who had a lot of lichenification and thickening of the skin, but over knees where you might think about psoriasis,” he said. “All three of these patients were of Southeast Asian descent. That happens to be a region where this feature was reported much more commonly. It may even tie to some underlying immunopathophysiologic differences of the disease across different patient populations.”

AD signs that occur more commonly in adults than children include lichenification (100% vs. 48%), urticaria (32% vs. 20%), popular lichenoid lesions (46% vs. 8%), Hertoghe’s sign (25% vs. 2%), erythroderma (29% vs. 1%), and nodular prurigo (18% vs. 4%).

Hand eczema features also differ between adults and children, including hand or foot dermatitis (44% vs. 25%), dyshidrosis/pompholyx (21% vs. 3%), knuckle dermatitis (25% vs. 8%), nail involvement (15% vs. 8%), and fissured heels. However, ventral wrist dermatitis was found to be more than twice as common in children, compared with adults (34% vs. 15%).

Other signs of AD were more common in children, compared with adults, including exudative eczema (61% vs. 42%), pityriasis alba (28% vs. 18%), Dennie-Morgan infraorbital folds (47% vs. 36%), seborrheic dermatitis–like lesions (40% vs. 18%), and perifollicular accentuation (37% vs. 21%). “This is such an important sign to wrap your head around and get comfortable assessing,” he said. “I have seen patients who are erythrodermic with follicular eczema who were told that they were crazy and had psychogenic itch, and they should go to a shrink.”

AD triggers can differ between adults and children as well, including course influenced by emotions/environmental factors (72% vs. 32%), worsening itch worse (65% vs. 49%), course influenced by environment (62% vs. 37%), and course influenced by emotions (70% vs. 15%).

According to Dr. Silverberg, emerging research suggests that there may be differences in the immune pathways activated in pediatric versus adult AD. Specifically, more Th17 and interferon-gamma in AD lesions have been observed in children, compared with adults, and more Th22 and Th17 in nonlesional AD have been seen in children, compared with adults. “This leads to a question: Will children respond differently than adults to treatment?” Dr. Silverberg said. “We see that omalizumab doesn’t seem to help much in adults, yet a recent study suggested that it might work reasonably well for children. Dupilumab has different dosing requirements and potentially different responses between the pediatric and adult populations.”

Age differences in AD may also be related to differences in the skin microbiome. In 2016, researchers led by Richard L. Gallo, MD, PhD, professor of dermatology, University of California, San Diego, compared the skin microbiome between adults and children with AD by swabbing the volar forearm and performing 16S rRNA gene sequencing. The study included 59 young children, 13 teenagers, and 56 adults with AD as well as 68 age-matched non-atopic healthy controls. The researchers found a greater abundance of Streptococcus, Granulicatella, Gemella, Rothia, and Haemophilus in young children, compared with adults, while Propionibacterium, Corynebacterium, Staphylococcus, Lactobacillus, Finegoldia, and Anaerococcus were more abundant in adults, compared with children.

Dr. Silverberg reported that he is a consultant to and/or an advisory board member for several pharmaceutical companies. He is also a speaker for Regeneron and Sanofi and has received a grant from Galderma.

[email protected]

Are pediatric atopic dermatitis and atopic dermatitis the same disease?

“Maybe not,” Jonathan I. Silverberg, MD, PhD, MPH, said during the Revolutionizing Atopic Dermatitis symposium.

Dr. Silverberg, director of clinical research in the division of dermatology at George Washington University, Washington, based his comments largely on a review that he and his colleagues carried out to understand how features of atopic dermatitis (AD) vary by region globally as well as by age. They identified 101 studies with sufficient data for meta-analysis and stratified the results by pediatric and adult age groups.

Several signs and symptoms occurred with similar frequency among pediatric and adult patients, including pruritus, xerosis, flexural involvement, extensor involvement, early onset of disease, comorbid atopy, head and neck involvement, and ophthalmic comorbidities. However, adults were found to have more signs of chronic disease, more hand eczema, different patterns of hand eczema, and a stronger relationship of disease activity with emotional factors. Meanwhile, children were found to have more exudative or weeping lesions, more perifollicular eczema, and more pityriasis alba.

Dr. Silverberg showed photos of three adults with varied presentations of extensor involvement, including one “who had a lot of lichenification and thickening of the skin, but over knees where you might think about psoriasis,” he said. “All three of these patients were of Southeast Asian descent. That happens to be a region where this feature was reported much more commonly. It may even tie to some underlying immunopathophysiologic differences of the disease across different patient populations.”

AD signs that occur more commonly in adults than children include lichenification (100% vs. 48%), urticaria (32% vs. 20%), popular lichenoid lesions (46% vs. 8%), Hertoghe’s sign (25% vs. 2%), erythroderma (29% vs. 1%), and nodular prurigo (18% vs. 4%).

Hand eczema features also differ between adults and children, including hand or foot dermatitis (44% vs. 25%), dyshidrosis/pompholyx (21% vs. 3%), knuckle dermatitis (25% vs. 8%), nail involvement (15% vs. 8%), and fissured heels. However, ventral wrist dermatitis was found to be more than twice as common in children, compared with adults (34% vs. 15%).

Other signs of AD were more common in children, compared with adults, including exudative eczema (61% vs. 42%), pityriasis alba (28% vs. 18%), Dennie-Morgan infraorbital folds (47% vs. 36%), seborrheic dermatitis–like lesions (40% vs. 18%), and perifollicular accentuation (37% vs. 21%). “This is such an important sign to wrap your head around and get comfortable assessing,” he said. “I have seen patients who are erythrodermic with follicular eczema who were told that they were crazy and had psychogenic itch, and they should go to a shrink.”

AD triggers can differ between adults and children as well, including course influenced by emotions/environmental factors (72% vs. 32%), worsening itch worse (65% vs. 49%), course influenced by environment (62% vs. 37%), and course influenced by emotions (70% vs. 15%).

According to Dr. Silverberg, emerging research suggests that there may be differences in the immune pathways activated in pediatric versus adult AD. Specifically, more Th17 and interferon-gamma in AD lesions have been observed in children, compared with adults, and more Th22 and Th17 in nonlesional AD have been seen in children, compared with adults. “This leads to a question: Will children respond differently than adults to treatment?” Dr. Silverberg said. “We see that omalizumab doesn’t seem to help much in adults, yet a recent study suggested that it might work reasonably well for children. Dupilumab has different dosing requirements and potentially different responses between the pediatric and adult populations.”

Age differences in AD may also be related to differences in the skin microbiome. In 2016, researchers led by Richard L. Gallo, MD, PhD, professor of dermatology, University of California, San Diego, compared the skin microbiome between adults and children with AD by swabbing the volar forearm and performing 16S rRNA gene sequencing. The study included 59 young children, 13 teenagers, and 56 adults with AD as well as 68 age-matched non-atopic healthy controls. The researchers found a greater abundance of Streptococcus, Granulicatella, Gemella, Rothia, and Haemophilus in young children, compared with adults, while Propionibacterium, Corynebacterium, Staphylococcus, Lactobacillus, Finegoldia, and Anaerococcus were more abundant in adults, compared with children.

Dr. Silverberg reported that he is a consultant to and/or an advisory board member for several pharmaceutical companies. He is also a speaker for Regeneron and Sanofi and has received a grant from Galderma.

[email protected]