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Every year, an estimated 45 million Americans attempt some kind of diet to shed weight, especially after the holidays. Whether or not an individual is on a successful weight loss journey, at some point they probably will experience “diet fatigue.” This is the mental and emotional exhaustion associated with engaging in dieting behaviors like calorie counting, weighing and measuring food, meal planning and prepping, and restricting certain foods. 

Diet fatigue is a huge reason (but certainly not the only reason) why diets fail, as dieters can become so burned out that they ditch their diet, return to their former eating habits, blame themselves for their diet failure, and then repeat the cycle.

Alison* became my client just as her diet fatigue was starting to settle in. She had already lost 25 pounds in the prior 6 months while in a coaching program that focused primarily on hitting calorie and macro targets. She had been following an extremely high-protein regimen that relied heavily on animal sources and protein powders. I’m not against using powders to supplement protein needs, but in Alison’s case, she was consuming a powder-and-milk concoction twice per day in place of a meal with actual food. Not only had she become plain sick of the powder, but she was also concerned that all the protein was pushing vegetables off her plate. Alison had been following this plan quite strictly but admitted to indulging in weekend sweets. She recognized that this occasional indulgence could quickly morph into a full-on habit and undo her progress. While Alison had not yet reached her goal weight, we both agreed that she needed to change up her eating routine. 

Getting a patient through diet fatigue involves identifying which dieting behaviors are causing them the most angst and then guiding them toward a more sustainable approach that provides a similar benefit. For example, many dieters develop a huge disdain for calorie tracking, which they most often describe as tedious. One alternative to tracking calories is food journaling, which encourages accountability and mindfulness but is not as time-consuming as plugging every single ingredient you ingest into an app. Alison, however, didn’t have a problem with tracking, nor with weighing her food (as a Type A personality, she preferred having this kind of control). But she was clearly lacking a few things in her previous diet: variety, fiber, and flavor. In short, Alison was not enjoying her food — hence, her increased desire for treats on weekends, which she saw as a kind of reward for “being good” all week. 

To keep Alison from slipping into a weekend bingeing pattern, we discussed a few tweaks to her regimen. First, we had to ditch the protein powder in favor of balanced meals. I recommended reducing her daily protein target, which I felt was unnecessarily high. This provided some wiggle room to add a well-rounded dinner. I encouraged her to start adding spices and herbs to make dishes more exciting. 

Finally — and this one might be controversial — I encouraged Alison to actually plan for a weekly indulgence. In my experience working in the weight management space, complete restriction of a desired food always backfires, so it made sense for Alison to simply build the chocolate into her plan in a reasonable way. 

I’m confident that Alison will reach her weight loss goal (and keep the weight off) if food continues to bring her pleasure. When it comes to weight loss, I believe that if the solution is temporary, success will also be temporary. As a dietitian, preaching sustainable, long-term habit changes is my priority, not just because it’s responsible, but because it’s the only approach that truly works.

*Patient’s name changed to protect privacy. 

Ms. Hanks is a registered dietitian at Well by Messer in New York City. She disclosed no relevant conflicts of interest.

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

Every year, an estimated 45 million Americans attempt some kind of diet to shed weight, especially after the holidays. Whether or not an individual is on a successful weight loss journey, at some point they probably will experience “diet fatigue.” This is the mental and emotional exhaustion associated with engaging in dieting behaviors like calorie counting, weighing and measuring food, meal planning and prepping, and restricting certain foods. 

Diet fatigue is a huge reason (but certainly not the only reason) why diets fail, as dieters can become so burned out that they ditch their diet, return to their former eating habits, blame themselves for their diet failure, and then repeat the cycle.

Alison* became my client just as her diet fatigue was starting to settle in. She had already lost 25 pounds in the prior 6 months while in a coaching program that focused primarily on hitting calorie and macro targets. She had been following an extremely high-protein regimen that relied heavily on animal sources and protein powders. I’m not against using powders to supplement protein needs, but in Alison’s case, she was consuming a powder-and-milk concoction twice per day in place of a meal with actual food. Not only had she become plain sick of the powder, but she was also concerned that all the protein was pushing vegetables off her plate. Alison had been following this plan quite strictly but admitted to indulging in weekend sweets. She recognized that this occasional indulgence could quickly morph into a full-on habit and undo her progress. While Alison had not yet reached her goal weight, we both agreed that she needed to change up her eating routine. 

Getting a patient through diet fatigue involves identifying which dieting behaviors are causing them the most angst and then guiding them toward a more sustainable approach that provides a similar benefit. For example, many dieters develop a huge disdain for calorie tracking, which they most often describe as tedious. One alternative to tracking calories is food journaling, which encourages accountability and mindfulness but is not as time-consuming as plugging every single ingredient you ingest into an app. Alison, however, didn’t have a problem with tracking, nor with weighing her food (as a Type A personality, she preferred having this kind of control). But she was clearly lacking a few things in her previous diet: variety, fiber, and flavor. In short, Alison was not enjoying her food — hence, her increased desire for treats on weekends, which she saw as a kind of reward for “being good” all week. 

To keep Alison from slipping into a weekend bingeing pattern, we discussed a few tweaks to her regimen. First, we had to ditch the protein powder in favor of balanced meals. I recommended reducing her daily protein target, which I felt was unnecessarily high. This provided some wiggle room to add a well-rounded dinner. I encouraged her to start adding spices and herbs to make dishes more exciting. 

Finally — and this one might be controversial — I encouraged Alison to actually plan for a weekly indulgence. In my experience working in the weight management space, complete restriction of a desired food always backfires, so it made sense for Alison to simply build the chocolate into her plan in a reasonable way. 

I’m confident that Alison will reach her weight loss goal (and keep the weight off) if food continues to bring her pleasure. When it comes to weight loss, I believe that if the solution is temporary, success will also be temporary. As a dietitian, preaching sustainable, long-term habit changes is my priority, not just because it’s responsible, but because it’s the only approach that truly works.

*Patient’s name changed to protect privacy. 

Ms. Hanks is a registered dietitian at Well by Messer in New York City. She disclosed no relevant conflicts of interest.

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

Every year, an estimated 45 million Americans attempt some kind of diet to shed weight, especially after the holidays. Whether or not an individual is on a successful weight loss journey, at some point they probably will experience “diet fatigue.” This is the mental and emotional exhaustion associated with engaging in dieting behaviors like calorie counting, weighing and measuring food, meal planning and prepping, and restricting certain foods. 

Diet fatigue is a huge reason (but certainly not the only reason) why diets fail, as dieters can become so burned out that they ditch their diet, return to their former eating habits, blame themselves for their diet failure, and then repeat the cycle.

Alison* became my client just as her diet fatigue was starting to settle in. She had already lost 25 pounds in the prior 6 months while in a coaching program that focused primarily on hitting calorie and macro targets. She had been following an extremely high-protein regimen that relied heavily on animal sources and protein powders. I’m not against using powders to supplement protein needs, but in Alison’s case, she was consuming a powder-and-milk concoction twice per day in place of a meal with actual food. Not only had she become plain sick of the powder, but she was also concerned that all the protein was pushing vegetables off her plate. Alison had been following this plan quite strictly but admitted to indulging in weekend sweets. She recognized that this occasional indulgence could quickly morph into a full-on habit and undo her progress. While Alison had not yet reached her goal weight, we both agreed that she needed to change up her eating routine. 

Getting a patient through diet fatigue involves identifying which dieting behaviors are causing them the most angst and then guiding them toward a more sustainable approach that provides a similar benefit. For example, many dieters develop a huge disdain for calorie tracking, which they most often describe as tedious. One alternative to tracking calories is food journaling, which encourages accountability and mindfulness but is not as time-consuming as plugging every single ingredient you ingest into an app. Alison, however, didn’t have a problem with tracking, nor with weighing her food (as a Type A personality, she preferred having this kind of control). But she was clearly lacking a few things in her previous diet: variety, fiber, and flavor. In short, Alison was not enjoying her food — hence, her increased desire for treats on weekends, which she saw as a kind of reward for “being good” all week. 

To keep Alison from slipping into a weekend bingeing pattern, we discussed a few tweaks to her regimen. First, we had to ditch the protein powder in favor of balanced meals. I recommended reducing her daily protein target, which I felt was unnecessarily high. This provided some wiggle room to add a well-rounded dinner. I encouraged her to start adding spices and herbs to make dishes more exciting. 

Finally — and this one might be controversial — I encouraged Alison to actually plan for a weekly indulgence. In my experience working in the weight management space, complete restriction of a desired food always backfires, so it made sense for Alison to simply build the chocolate into her plan in a reasonable way. 

I’m confident that Alison will reach her weight loss goal (and keep the weight off) if food continues to bring her pleasure. When it comes to weight loss, I believe that if the solution is temporary, success will also be temporary. As a dietitian, preaching sustainable, long-term habit changes is my priority, not just because it’s responsible, but because it’s the only approach that truly works.

*Patient’s name changed to protect privacy. 

Ms. Hanks is a registered dietitian at Well by Messer in New York City. She disclosed no relevant conflicts of interest.

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

For people with obesity or type 2 diabetes, glucagon-like peptide 1 (GLP-1) agonists (including Mounjaro, Wegovy, and Ozempic) have been labeled miracle drugs. But they aren’t miraculous for everyone. Research indicates a significant portion of people discontinue using them within a year.

The main problems with GLP-1 agonists are that they are expensive and have a fairly high rate of side effects — such as nausea, vomiting, diarrhea, or constipation. Another big one is muscle loss.

A new study, published in Nature, shows a potential alternative to GLP-1 agonists with fewer side effects, at least in mice and nonhuman primates.

This lack of side effects, particularly in how the potential drug causes no muscle loss — and in fact engages muscle for some of its effect — sets it apart and makes it a potential alternative to GLP-1s. The key is not just reducing appetite but also increasing energy expenditure.

 

How It Works

The new approach targets a protein called NK2R — a member of the neurokinin receptor family, which has a role in a variety of physiological processes, including pain sensation, anxiety, and inflammation. 

“We were looking to see genetic linkages to metabolic health, and there NK2R was,” said Zach Gerhart-Hines, PhD, a professor studying molecular metabolism at the University of Copenhagen in Denmark and principal investigator of the study. The group then created a few long-acting agonists that are selective for NK2R. So far, they’ve tested them in mice and nonhuman primates.

“The data on new medicines targeting NK2R is very promising and highlights the potential of both reducing food intake and increasing energy expenditure,” said Daniel Drucker, MD, an endocrinologist and researcher at Lunenfeld-Tanenbaum Research Institute in Toronto who was not involved in the study.

“The drug activates a certain region in the hindbrain of the animal, which is controlling food intake, and it does so by reducing appetite without increasing nausea or vomiting,” explained Frederike Sass, a research assistant at the University of Copenhagen in Copenhagen, Denmark, who led the study.

Gerhart-Hines said that even at the highest dose, there were no incidents of vomiting among the nonhuman primates. Mice can’t vomit, but there are ways to tell if they feel unwell from a drug. One way researchers test that is to start feeding the mice sweetened water at the same time they’re given a drug. Then later, when the mice are no longer on the drug, they’re given a choice between sweetened and unsweetened water. If they weren’t feeling well on the drug, they’ll choose plain water because they associate the sweet water with feeling bad, otherwise mice prefer sweet water. Sass said that with the NK2R agonist, they continued to drink sweet water after the treatment, whereas when they gave the mice semaglutide, the mice preferred plain water posttreatment.

The researchers also monitored the animals’ psychological health, as NK2R has been associated with anxiety, but they observed no behavioral changes.

 

The Key Mechanism at Work

One big question is how the NK2R agonists work. The amphetamines people used for weight loss during the 1950s and 1960s worked by making people more active. GLP-1 agonists reduce appetite and lower blood sugar. This is not that. In their studies with animals, the researchers didn’t observe that the animals were more active nor were there changes in other biomarkers like insulin. So far, the main difference they found with the NK2R agonists is an increase in thermogenesis in certain muscles.

Another benefit of the NK2R treatments is that they don’t seem to have a big impact on lean mass — the nonfat component of body weight, namely muscle, bones, and organs. Studies indicate that 25%-39% of weight loss on GLP-1 agonists is lost muscle. According to DEXA scans of the mice, Gerhart-Hines said they observed no lean mass loss. (In mice, he noted, GLP-1 agonists can cause up to 50% lean mass loss).

And for people with both diabetes and obesity, “what we found with NK2R is that obese and diabetic models, whether mice or monkeys, respond much better to that treatment in terms of glucose control and body weight loss,” Gerhart-Hines said. He explained that GLP-1 agonists don’t work quite as well for weight loss in people with diabetes because the drug stimulates insulin production in a system that already has insulin issues and can cause more sugar to be stored as fat.

Further, GLP-1 agonists are peptide drugs, which are expensive to make. The NK2R agonists are small molecules that would be cheaper to produce, Gerhart-Hines believes. One candidate they’re testing would likely be given once daily, another once weekly.

The current surge in obesity and diabetes may be a direct consequence of our bodies’ decreased energy expenditure. “Compared to 80s and 90s, the average person is more physically active, but the overarching basal resting energy expenditure has gone down,” said Gerhart-Hines, according to research by John Speakman at the University of Aberdeen, Scotland. We don’t know why, though, he said, but guesses it could be our diets or climate controlled environments.

But the NK2R agonists are among the many currently being studied for weight loss, and it may be hard to compete with the GLP-1 agonists. “As GLP-1 medicines will soon achieve 25% weight loss and have an extensively studied safety profile, the task of producing better drugs that work well in most people, are well tolerated and also reduce the complications of cardiometabolic disease, is challenging but not impossible,” said Drucker.

Gerhart-Hines said they plan to start trials in humans in the next year, but he suspects it will be another 6 or 7 years before it comes to market, if the trials are successful.

“There’s people who want [a GLP-1 agonist] and can’t even get it,” Gerhart-Hines said. As far as weight loss drugs, he noted, “we are not even saturating the market right now.”

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

For people with obesity or type 2 diabetes, glucagon-like peptide 1 (GLP-1) agonists (including Mounjaro, Wegovy, and Ozempic) have been labeled miracle drugs. But they aren’t miraculous for everyone. Research indicates a significant portion of people discontinue using them within a year.

The main problems with GLP-1 agonists are that they are expensive and have a fairly high rate of side effects — such as nausea, vomiting, diarrhea, or constipation. Another big one is muscle loss.

A new study, published in Nature, shows a potential alternative to GLP-1 agonists with fewer side effects, at least in mice and nonhuman primates.

This lack of side effects, particularly in how the potential drug causes no muscle loss — and in fact engages muscle for some of its effect — sets it apart and makes it a potential alternative to GLP-1s. The key is not just reducing appetite but also increasing energy expenditure.

 

How It Works

The new approach targets a protein called NK2R — a member of the neurokinin receptor family, which has a role in a variety of physiological processes, including pain sensation, anxiety, and inflammation. 

“We were looking to see genetic linkages to metabolic health, and there NK2R was,” said Zach Gerhart-Hines, PhD, a professor studying molecular metabolism at the University of Copenhagen in Denmark and principal investigator of the study. The group then created a few long-acting agonists that are selective for NK2R. So far, they’ve tested them in mice and nonhuman primates.

“The data on new medicines targeting NK2R is very promising and highlights the potential of both reducing food intake and increasing energy expenditure,” said Daniel Drucker, MD, an endocrinologist and researcher at Lunenfeld-Tanenbaum Research Institute in Toronto who was not involved in the study.

“The drug activates a certain region in the hindbrain of the animal, which is controlling food intake, and it does so by reducing appetite without increasing nausea or vomiting,” explained Frederike Sass, a research assistant at the University of Copenhagen in Copenhagen, Denmark, who led the study.

Gerhart-Hines said that even at the highest dose, there were no incidents of vomiting among the nonhuman primates. Mice can’t vomit, but there are ways to tell if they feel unwell from a drug. One way researchers test that is to start feeding the mice sweetened water at the same time they’re given a drug. Then later, when the mice are no longer on the drug, they’re given a choice between sweetened and unsweetened water. If they weren’t feeling well on the drug, they’ll choose plain water because they associate the sweet water with feeling bad, otherwise mice prefer sweet water. Sass said that with the NK2R agonist, they continued to drink sweet water after the treatment, whereas when they gave the mice semaglutide, the mice preferred plain water posttreatment.

The researchers also monitored the animals’ psychological health, as NK2R has been associated with anxiety, but they observed no behavioral changes.

 

The Key Mechanism at Work

One big question is how the NK2R agonists work. The amphetamines people used for weight loss during the 1950s and 1960s worked by making people more active. GLP-1 agonists reduce appetite and lower blood sugar. This is not that. In their studies with animals, the researchers didn’t observe that the animals were more active nor were there changes in other biomarkers like insulin. So far, the main difference they found with the NK2R agonists is an increase in thermogenesis in certain muscles.

Another benefit of the NK2R treatments is that they don’t seem to have a big impact on lean mass — the nonfat component of body weight, namely muscle, bones, and organs. Studies indicate that 25%-39% of weight loss on GLP-1 agonists is lost muscle. According to DEXA scans of the mice, Gerhart-Hines said they observed no lean mass loss. (In mice, he noted, GLP-1 agonists can cause up to 50% lean mass loss).

And for people with both diabetes and obesity, “what we found with NK2R is that obese and diabetic models, whether mice or monkeys, respond much better to that treatment in terms of glucose control and body weight loss,” Gerhart-Hines said. He explained that GLP-1 agonists don’t work quite as well for weight loss in people with diabetes because the drug stimulates insulin production in a system that already has insulin issues and can cause more sugar to be stored as fat.

Further, GLP-1 agonists are peptide drugs, which are expensive to make. The NK2R agonists are small molecules that would be cheaper to produce, Gerhart-Hines believes. One candidate they’re testing would likely be given once daily, another once weekly.

The current surge in obesity and diabetes may be a direct consequence of our bodies’ decreased energy expenditure. “Compared to 80s and 90s, the average person is more physically active, but the overarching basal resting energy expenditure has gone down,” said Gerhart-Hines, according to research by John Speakman at the University of Aberdeen, Scotland. We don’t know why, though, he said, but guesses it could be our diets or climate controlled environments.

But the NK2R agonists are among the many currently being studied for weight loss, and it may be hard to compete with the GLP-1 agonists. “As GLP-1 medicines will soon achieve 25% weight loss and have an extensively studied safety profile, the task of producing better drugs that work well in most people, are well tolerated and also reduce the complications of cardiometabolic disease, is challenging but not impossible,” said Drucker.

Gerhart-Hines said they plan to start trials in humans in the next year, but he suspects it will be another 6 or 7 years before it comes to market, if the trials are successful.

“There’s people who want [a GLP-1 agonist] and can’t even get it,” Gerhart-Hines said. As far as weight loss drugs, he noted, “we are not even saturating the market right now.”

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

For people with obesity or type 2 diabetes, glucagon-like peptide 1 (GLP-1) agonists (including Mounjaro, Wegovy, and Ozempic) have been labeled miracle drugs. But they aren’t miraculous for everyone. Research indicates a significant portion of people discontinue using them within a year.

The main problems with GLP-1 agonists are that they are expensive and have a fairly high rate of side effects — such as nausea, vomiting, diarrhea, or constipation. Another big one is muscle loss.

A new study, published in Nature, shows a potential alternative to GLP-1 agonists with fewer side effects, at least in mice and nonhuman primates.

This lack of side effects, particularly in how the potential drug causes no muscle loss — and in fact engages muscle for some of its effect — sets it apart and makes it a potential alternative to GLP-1s. The key is not just reducing appetite but also increasing energy expenditure.

 

How It Works

The new approach targets a protein called NK2R — a member of the neurokinin receptor family, which has a role in a variety of physiological processes, including pain sensation, anxiety, and inflammation. 

“We were looking to see genetic linkages to metabolic health, and there NK2R was,” said Zach Gerhart-Hines, PhD, a professor studying molecular metabolism at the University of Copenhagen in Denmark and principal investigator of the study. The group then created a few long-acting agonists that are selective for NK2R. So far, they’ve tested them in mice and nonhuman primates.

“The data on new medicines targeting NK2R is very promising and highlights the potential of both reducing food intake and increasing energy expenditure,” said Daniel Drucker, MD, an endocrinologist and researcher at Lunenfeld-Tanenbaum Research Institute in Toronto who was not involved in the study.

“The drug activates a certain region in the hindbrain of the animal, which is controlling food intake, and it does so by reducing appetite without increasing nausea or vomiting,” explained Frederike Sass, a research assistant at the University of Copenhagen in Copenhagen, Denmark, who led the study.

Gerhart-Hines said that even at the highest dose, there were no incidents of vomiting among the nonhuman primates. Mice can’t vomit, but there are ways to tell if they feel unwell from a drug. One way researchers test that is to start feeding the mice sweetened water at the same time they’re given a drug. Then later, when the mice are no longer on the drug, they’re given a choice between sweetened and unsweetened water. If they weren’t feeling well on the drug, they’ll choose plain water because they associate the sweet water with feeling bad, otherwise mice prefer sweet water. Sass said that with the NK2R agonist, they continued to drink sweet water after the treatment, whereas when they gave the mice semaglutide, the mice preferred plain water posttreatment.

The researchers also monitored the animals’ psychological health, as NK2R has been associated with anxiety, but they observed no behavioral changes.

 

The Key Mechanism at Work

One big question is how the NK2R agonists work. The amphetamines people used for weight loss during the 1950s and 1960s worked by making people more active. GLP-1 agonists reduce appetite and lower blood sugar. This is not that. In their studies with animals, the researchers didn’t observe that the animals were more active nor were there changes in other biomarkers like insulin. So far, the main difference they found with the NK2R agonists is an increase in thermogenesis in certain muscles.

Another benefit of the NK2R treatments is that they don’t seem to have a big impact on lean mass — the nonfat component of body weight, namely muscle, bones, and organs. Studies indicate that 25%-39% of weight loss on GLP-1 agonists is lost muscle. According to DEXA scans of the mice, Gerhart-Hines said they observed no lean mass loss. (In mice, he noted, GLP-1 agonists can cause up to 50% lean mass loss).

And for people with both diabetes and obesity, “what we found with NK2R is that obese and diabetic models, whether mice or monkeys, respond much better to that treatment in terms of glucose control and body weight loss,” Gerhart-Hines said. He explained that GLP-1 agonists don’t work quite as well for weight loss in people with diabetes because the drug stimulates insulin production in a system that already has insulin issues and can cause more sugar to be stored as fat.

Further, GLP-1 agonists are peptide drugs, which are expensive to make. The NK2R agonists are small molecules that would be cheaper to produce, Gerhart-Hines believes. One candidate they’re testing would likely be given once daily, another once weekly.

The current surge in obesity and diabetes may be a direct consequence of our bodies’ decreased energy expenditure. “Compared to 80s and 90s, the average person is more physically active, but the overarching basal resting energy expenditure has gone down,” said Gerhart-Hines, according to research by John Speakman at the University of Aberdeen, Scotland. We don’t know why, though, he said, but guesses it could be our diets or climate controlled environments.

But the NK2R agonists are among the many currently being studied for weight loss, and it may be hard to compete with the GLP-1 agonists. “As GLP-1 medicines will soon achieve 25% weight loss and have an extensively studied safety profile, the task of producing better drugs that work well in most people, are well tolerated and also reduce the complications of cardiometabolic disease, is challenging but not impossible,” said Drucker.

Gerhart-Hines said they plan to start trials in humans in the next year, but he suspects it will be another 6 or 7 years before it comes to market, if the trials are successful.

“There’s people who want [a GLP-1 agonist] and can’t even get it,” Gerhart-Hines said. As far as weight loss drugs, he noted, “we are not even saturating the market right now.”

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

Of all the currently available pharmacological and nonpharmacological therapies for attention deficit and hyperactivity disorder (ADHD) in adults, only stimulants and atomoxetine are effective at reducing core symptoms, results of a large comprehensive meta-analysis showed.

The study of 113 randomized controlled trials with nearly 15,000 adults with a formal diagnosis of ADHD also revealed that atomoxetine is less acceptable to patients and that results of efficacy of nonpharmacological strategies are inconsistent.

Data on long-term efficacy of ADHD therapies are lacking, investigators noted, so these results only apply to short-term efficacy.

“There is a lot of controversy about medication, so these are quite reassuring data and certainly reinforce the role of medication as a treatment for ADHD,” study investigator Samuele Cortese, MD, PhD, with University of Southampton, England, said during a press briefing hosted by the UK Science Media Center where the findings were released.

The results also point to the “possible role of nonpharmacological interventions, which are currently not well established in current guidelines. However, there is a need for better evidence to fully understand the exact effect of these nonpharmacological interventions,” Cortese noted.

The study was published online in The Lancet Psychiatry. 

 

Bridging the Knowledge Gap

Once thought to be a childhood disorder only, ADHD is now well-known to persist into adulthood, affecting roughly 2.5% of the general adult population worldwide. The comparative benefits and harms of available interventions for ADHD in adults remain unclear.

To address this knowledge gap, researchers did a comprehensive systematic review and component network meta-analysis comparing a broad range of drug and nondrug treatments for adults with ADHD across several outcomes.

For reducing core ADHD symptoms at 12 weeks, only stimulants and atomoxetine were better than placebo in self-reported and clinician-reported rating scales, the study team found.

For stimulants, the standardized mean differences (SMDs) on the self-reported and clinician-reported scales were 0.39 and 0.61, respectively. The corresponding SMDs for atomoxetine were 0.38 and 0.51.

There was no evidence that ADHD medications were better than placebo in improving additional relevant outcomes such as quality of life.

In terms of nondrug interventions, cognitive behavioral therapy, cognitive remediation, mindfulness, psychoeducation, and transcranial direct current stimulation were better than placebo only on clinician-reported measures, with SMDs of −1.35, −0.79, −0.77, and −0.78, respectively.

However, the evidence for nondrug strategies is less conclusive overall, with “discordant results across types of raters and based on a small body of evidence,” the authors wrote in their article.

And evidence for long-term efficacy (beyond 12 weeks) for ADHD interventions is “limited and under-investigated,” they said.

Regarding acceptability, all strategies were similar to placebo except for atomoxetine and guanfacine which had lower acceptability than placebo.

“It’s very important to emphasize that we focused on the average effect, not at an individual level,” first author Edoardo Ostinelli, MD, with University of Oxford, England, said at the briefing. “Therefore, we cannot make any recommendation at an individual level. We need studies with individual participant data so that we can personalize treatment.”

Cortese said the information from this analysis may be particularly important for “psychoeducation” of the patient before actually starting with a treatment plan. Patients often ask about nonpharmacological interventions and this study provides the “best synthesis of available data to inform these discussions,” he said.

 

Experts Weigh In 

Several experts weighed in on the results in a statement from the UK Science Media Center.

Celso Arango, MD, PhD, psychiatrist with Gregorio Marañón General University Hospital, Madrid, Spain, noted that there is a “clear shortage of research on ADHD in adulthood, particularly regarding medium-term (beyond 12 weeks) and long-term treatment outcomes. Consequently, the findings are applicable only to short-term treatment.”

Another strength of the study is that it was developed with input from people with ADHD, Arango added, making it “highly relevant.”

The majority of studies available for the analysis involved pharmacological treatments, which is important to consider when interpreting the findings, noted Katya Rubia, PhD, professor of cognitive neuroscience, King’s College London, England.

“For example, for neurostimulation, only 10 studies were included and on very heterogeneous stimulation methods,” Rubia said. “The evidence on the efficacy of neurostimulation is therefore hardly conclusive and more studies are needed to establish their efficacy.”

Roi Cohen Kadosh, PhD, professor of cognitive neuroscience, University of Surrey, Guildford, England, agreed. While the study is a “valuable contribution to the literature,” it sheds light on “both the scarcity of neurostimulation research and the limited exploration of combined treatment approaches for ADHD,” he said.

“While novel neurostimulation methods linked to neuroplasticity — such as those we have demonstrated to be superior in children with ADHD — were not covered here, they have shown promising and lasting benefits. In contrast, research in adults remains relatively underdeveloped. Moving forward, greater emphasis on innovative, tolerable, personalized, and sustainable neurostimulation approaches is essential to meet the unmet clinical needs of adults with ADHD,” Kadosh added.

In a commentary in The Lancet Psychiatry, David Coghill, MD, with The University of Melbourne, Australia, cautioned that the findings do not mean that potential benefits of nonpharmacological interventions should be dismissed.

“While some of the nonpharmacological treatments (eg, cognitive behavioral therapy, cognitive remediation, mindfulness, psychoeducation, and transcranial direct current stimulation) showed effects on clinician-rated outcomes similar to, and in some cases greater than, the pharmacological treatments, they did not show the same effects on self-reported outcomes. These interventions were therefore considered less robust than the pharmacological treatments that showed changes on both measurement types,” he wrote.

This study had no commercial funding. Ostinelli had received research and consultancy fees from Angelini Pharma. Cortese received reimbursement for travel and accommodation expenses in relation to lectures delivered for the Association for Child and Adolescent Central Health, the Canadian ADHD Alliance Resource, and the British Association of Psychopharmacology; and had received honoraria from MEDICE; and is chair of the European ADHD Guidelines Group. Arango, Rubia, and Kadosh had no relevant disclosures. Coghill had received honoraria from CCM Conecta, Takeda, Novartis, Servier, and MEDICE.

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

Of all the currently available pharmacological and nonpharmacological therapies for attention deficit and hyperactivity disorder (ADHD) in adults, only stimulants and atomoxetine are effective at reducing core symptoms, results of a large comprehensive meta-analysis showed.

The study of 113 randomized controlled trials with nearly 15,000 adults with a formal diagnosis of ADHD also revealed that atomoxetine is less acceptable to patients and that results of efficacy of nonpharmacological strategies are inconsistent.

Data on long-term efficacy of ADHD therapies are lacking, investigators noted, so these results only apply to short-term efficacy.

“There is a lot of controversy about medication, so these are quite reassuring data and certainly reinforce the role of medication as a treatment for ADHD,” study investigator Samuele Cortese, MD, PhD, with University of Southampton, England, said during a press briefing hosted by the UK Science Media Center where the findings were released.

The results also point to the “possible role of nonpharmacological interventions, which are currently not well established in current guidelines. However, there is a need for better evidence to fully understand the exact effect of these nonpharmacological interventions,” Cortese noted.

The study was published online in The Lancet Psychiatry. 

 

Bridging the Knowledge Gap

Once thought to be a childhood disorder only, ADHD is now well-known to persist into adulthood, affecting roughly 2.5% of the general adult population worldwide. The comparative benefits and harms of available interventions for ADHD in adults remain unclear.

To address this knowledge gap, researchers did a comprehensive systematic review and component network meta-analysis comparing a broad range of drug and nondrug treatments for adults with ADHD across several outcomes.

For reducing core ADHD symptoms at 12 weeks, only stimulants and atomoxetine were better than placebo in self-reported and clinician-reported rating scales, the study team found.

For stimulants, the standardized mean differences (SMDs) on the self-reported and clinician-reported scales were 0.39 and 0.61, respectively. The corresponding SMDs for atomoxetine were 0.38 and 0.51.

There was no evidence that ADHD medications were better than placebo in improving additional relevant outcomes such as quality of life.

In terms of nondrug interventions, cognitive behavioral therapy, cognitive remediation, mindfulness, psychoeducation, and transcranial direct current stimulation were better than placebo only on clinician-reported measures, with SMDs of −1.35, −0.79, −0.77, and −0.78, respectively.

However, the evidence for nondrug strategies is less conclusive overall, with “discordant results across types of raters and based on a small body of evidence,” the authors wrote in their article.

And evidence for long-term efficacy (beyond 12 weeks) for ADHD interventions is “limited and under-investigated,” they said.

Regarding acceptability, all strategies were similar to placebo except for atomoxetine and guanfacine which had lower acceptability than placebo.

“It’s very important to emphasize that we focused on the average effect, not at an individual level,” first author Edoardo Ostinelli, MD, with University of Oxford, England, said at the briefing. “Therefore, we cannot make any recommendation at an individual level. We need studies with individual participant data so that we can personalize treatment.”

Cortese said the information from this analysis may be particularly important for “psychoeducation” of the patient before actually starting with a treatment plan. Patients often ask about nonpharmacological interventions and this study provides the “best synthesis of available data to inform these discussions,” he said.

 

Experts Weigh In 

Several experts weighed in on the results in a statement from the UK Science Media Center.

Celso Arango, MD, PhD, psychiatrist with Gregorio Marañón General University Hospital, Madrid, Spain, noted that there is a “clear shortage of research on ADHD in adulthood, particularly regarding medium-term (beyond 12 weeks) and long-term treatment outcomes. Consequently, the findings are applicable only to short-term treatment.”

Another strength of the study is that it was developed with input from people with ADHD, Arango added, making it “highly relevant.”

The majority of studies available for the analysis involved pharmacological treatments, which is important to consider when interpreting the findings, noted Katya Rubia, PhD, professor of cognitive neuroscience, King’s College London, England.

“For example, for neurostimulation, only 10 studies were included and on very heterogeneous stimulation methods,” Rubia said. “The evidence on the efficacy of neurostimulation is therefore hardly conclusive and more studies are needed to establish their efficacy.”

Roi Cohen Kadosh, PhD, professor of cognitive neuroscience, University of Surrey, Guildford, England, agreed. While the study is a “valuable contribution to the literature,” it sheds light on “both the scarcity of neurostimulation research and the limited exploration of combined treatment approaches for ADHD,” he said.

“While novel neurostimulation methods linked to neuroplasticity — such as those we have demonstrated to be superior in children with ADHD — were not covered here, they have shown promising and lasting benefits. In contrast, research in adults remains relatively underdeveloped. Moving forward, greater emphasis on innovative, tolerable, personalized, and sustainable neurostimulation approaches is essential to meet the unmet clinical needs of adults with ADHD,” Kadosh added.

In a commentary in The Lancet Psychiatry, David Coghill, MD, with The University of Melbourne, Australia, cautioned that the findings do not mean that potential benefits of nonpharmacological interventions should be dismissed.

“While some of the nonpharmacological treatments (eg, cognitive behavioral therapy, cognitive remediation, mindfulness, psychoeducation, and transcranial direct current stimulation) showed effects on clinician-rated outcomes similar to, and in some cases greater than, the pharmacological treatments, they did not show the same effects on self-reported outcomes. These interventions were therefore considered less robust than the pharmacological treatments that showed changes on both measurement types,” he wrote.

This study had no commercial funding. Ostinelli had received research and consultancy fees from Angelini Pharma. Cortese received reimbursement for travel and accommodation expenses in relation to lectures delivered for the Association for Child and Adolescent Central Health, the Canadian ADHD Alliance Resource, and the British Association of Psychopharmacology; and had received honoraria from MEDICE; and is chair of the European ADHD Guidelines Group. Arango, Rubia, and Kadosh had no relevant disclosures. Coghill had received honoraria from CCM Conecta, Takeda, Novartis, Servier, and MEDICE.

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

Of all the currently available pharmacological and nonpharmacological therapies for attention deficit and hyperactivity disorder (ADHD) in adults, only stimulants and atomoxetine are effective at reducing core symptoms, results of a large comprehensive meta-analysis showed.

The study of 113 randomized controlled trials with nearly 15,000 adults with a formal diagnosis of ADHD also revealed that atomoxetine is less acceptable to patients and that results of efficacy of nonpharmacological strategies are inconsistent.

Data on long-term efficacy of ADHD therapies are lacking, investigators noted, so these results only apply to short-term efficacy.

“There is a lot of controversy about medication, so these are quite reassuring data and certainly reinforce the role of medication as a treatment for ADHD,” study investigator Samuele Cortese, MD, PhD, with University of Southampton, England, said during a press briefing hosted by the UK Science Media Center where the findings were released.

The results also point to the “possible role of nonpharmacological interventions, which are currently not well established in current guidelines. However, there is a need for better evidence to fully understand the exact effect of these nonpharmacological interventions,” Cortese noted.

The study was published online in The Lancet Psychiatry. 

 

Bridging the Knowledge Gap

Once thought to be a childhood disorder only, ADHD is now well-known to persist into adulthood, affecting roughly 2.5% of the general adult population worldwide. The comparative benefits and harms of available interventions for ADHD in adults remain unclear.

To address this knowledge gap, researchers did a comprehensive systematic review and component network meta-analysis comparing a broad range of drug and nondrug treatments for adults with ADHD across several outcomes.

For reducing core ADHD symptoms at 12 weeks, only stimulants and atomoxetine were better than placebo in self-reported and clinician-reported rating scales, the study team found.

For stimulants, the standardized mean differences (SMDs) on the self-reported and clinician-reported scales were 0.39 and 0.61, respectively. The corresponding SMDs for atomoxetine were 0.38 and 0.51.

There was no evidence that ADHD medications were better than placebo in improving additional relevant outcomes such as quality of life.

In terms of nondrug interventions, cognitive behavioral therapy, cognitive remediation, mindfulness, psychoeducation, and transcranial direct current stimulation were better than placebo only on clinician-reported measures, with SMDs of −1.35, −0.79, −0.77, and −0.78, respectively.

However, the evidence for nondrug strategies is less conclusive overall, with “discordant results across types of raters and based on a small body of evidence,” the authors wrote in their article.

And evidence for long-term efficacy (beyond 12 weeks) for ADHD interventions is “limited and under-investigated,” they said.

Regarding acceptability, all strategies were similar to placebo except for atomoxetine and guanfacine which had lower acceptability than placebo.

“It’s very important to emphasize that we focused on the average effect, not at an individual level,” first author Edoardo Ostinelli, MD, with University of Oxford, England, said at the briefing. “Therefore, we cannot make any recommendation at an individual level. We need studies with individual participant data so that we can personalize treatment.”

Cortese said the information from this analysis may be particularly important for “psychoeducation” of the patient before actually starting with a treatment plan. Patients often ask about nonpharmacological interventions and this study provides the “best synthesis of available data to inform these discussions,” he said.

 

Experts Weigh In 

Several experts weighed in on the results in a statement from the UK Science Media Center.

Celso Arango, MD, PhD, psychiatrist with Gregorio Marañón General University Hospital, Madrid, Spain, noted that there is a “clear shortage of research on ADHD in adulthood, particularly regarding medium-term (beyond 12 weeks) and long-term treatment outcomes. Consequently, the findings are applicable only to short-term treatment.”

Another strength of the study is that it was developed with input from people with ADHD, Arango added, making it “highly relevant.”

The majority of studies available for the analysis involved pharmacological treatments, which is important to consider when interpreting the findings, noted Katya Rubia, PhD, professor of cognitive neuroscience, King’s College London, England.

“For example, for neurostimulation, only 10 studies were included and on very heterogeneous stimulation methods,” Rubia said. “The evidence on the efficacy of neurostimulation is therefore hardly conclusive and more studies are needed to establish their efficacy.”

Roi Cohen Kadosh, PhD, professor of cognitive neuroscience, University of Surrey, Guildford, England, agreed. While the study is a “valuable contribution to the literature,” it sheds light on “both the scarcity of neurostimulation research and the limited exploration of combined treatment approaches for ADHD,” he said.

“While novel neurostimulation methods linked to neuroplasticity — such as those we have demonstrated to be superior in children with ADHD — were not covered here, they have shown promising and lasting benefits. In contrast, research in adults remains relatively underdeveloped. Moving forward, greater emphasis on innovative, tolerable, personalized, and sustainable neurostimulation approaches is essential to meet the unmet clinical needs of adults with ADHD,” Kadosh added.

In a commentary in The Lancet Psychiatry, David Coghill, MD, with The University of Melbourne, Australia, cautioned that the findings do not mean that potential benefits of nonpharmacological interventions should be dismissed.

“While some of the nonpharmacological treatments (eg, cognitive behavioral therapy, cognitive remediation, mindfulness, psychoeducation, and transcranial direct current stimulation) showed effects on clinician-rated outcomes similar to, and in some cases greater than, the pharmacological treatments, they did not show the same effects on self-reported outcomes. These interventions were therefore considered less robust than the pharmacological treatments that showed changes on both measurement types,” he wrote.

This study had no commercial funding. Ostinelli had received research and consultancy fees from Angelini Pharma. Cortese received reimbursement for travel and accommodation expenses in relation to lectures delivered for the Association for Child and Adolescent Central Health, the Canadian ADHD Alliance Resource, and the British Association of Psychopharmacology; and had received honoraria from MEDICE; and is chair of the European ADHD Guidelines Group. Arango, Rubia, and Kadosh had no relevant disclosures. Coghill had received honoraria from CCM Conecta, Takeda, Novartis, Servier, and MEDICE.

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

NEW YORK, NY — Work over the past several years has reframed hidradenitis suppurativa (HS) as a large-field inflammatory process, a recharacterization that has immediate relevance to treatment strategies and goals, according to two investigators intimately involved in much of the recent progress.

“Success is being achieved by targeting multiple inflammatory axes in HS, and therapeutics are evolving rapidly,” reported James G. Krueger, MD, PhD, head of the Laboratory of Investigative Dermatology, Rockefeller University, New York, NY.

The activity of targeted anti-inflammatory therapies — bimekizumab just joined adalimumab and secukinumab as a third approved biologic for HS — is not news, but the degree to which inflammation is upregulated systemically, not just at areas of skin involvement, has changed the conceptualization of HS.

HS Is a Systemic Inflammatory Disease

Relative to psoriasis, for which there are many parallels, “HS is hugely more inflammatory in the systemic circulation,” Krueger said at the 27th Annual Winter Symposium — Advances in Medical and Surgical Dermatology (MSWS) 2024. Yet, HS is also more complex involving additional pathways that appear to include dysbiosis. The concept of follicular occlusion, once a common explanation for HS, has been left far behind.

“Unlike psoriasis, which we can treat really well by inhibiting a single pathway target, HS is just not that simple,” Krueger said. Although largely an inflammatory process, the cascade of inflammatory factors for specific manifestations, such as tunnels, means that optimal therapy in one case might have little benefit in another.

The relatively new evidence that HS activity is not confined to lesional skin might be the most important recent step toward new strategies to target disease. These studies were performed by Kristina Navrazhina, MD, PhD, now a resident in dermatology at the Icahn School of Medicine at Mount Sinai, New York. She received her PhD while studying HS activity in non-lesional skin. Her work has led her to conclude that the best chance for better outcomes in HS is early diagnosis and treatment. Although this is generally true of any pathology, the changes in the HS phenotype once fistulae form includes a poor response to conventional therapies. 

In fact, based on her work in evaluating HS activity in non-lesional skin, Navrazhina has shown that “many patients with modest lesions already have advanced disease.” Consistent with the premise that HS is a deeply systemic inflammatory process, nodules, considered an early manifestation, turn out to be “the tip of the iceberg.”

 

Non-Lesional HS Skin Is Inflamed

When she has employed RNA sequencing based on tape strip sampling from completely normal skin away from nodules, interleukin (IL)-17 and a broad array of other inflammatory markers were found to be upregulated. When she performed ultrasound to look for disease activity under the normal skin, she has often found tunnels already formed. Doppler ultrasound showed some of these tunnels were actively draining.

This might provide a partial explanation for why therapies are not always effective even when clinical signs of disease are modest. 

“Are we missing the opportunity for intervening?” Navrazhina asked, noting that early intervention has been limited traditionally by extremely long diagnostic delays. Citing the literature, Navrazhina said the average delay is 7 years for HS versus 1 year for psoriasis. Patients often cycle through 3 or 4 providers before the diagnosis is made, she said.

Awakening first-line clinicians to the signs and symptoms of HS, whether in the emergency room or primary care, is a critical message because of the incrementally difficult task to control disease once fistulae have formed. 

Krueger made the same appeal. For the neutrophilic inflammation that characterizes nodules, targeted therapies are often effective, but he agreed that available therapies are generally far less so once tunnels form.

 

Role Seen for Bacteria in HS Pathogenesis

One reason might be an interaction between anaerobic bacteria and the keratinocytes that form the tunnel walls, according to Krueger. Although HS is not typically considered an infectious disease, he reported that the interaction of these bacteria with keratinocytes is associated with expression of approximately 1000 inflammatory gene products. The process of tunnel formation is traced to how factors recruited by upregulated inflammation, such as chemokines, coordinate.

He described recent work pursing novel strategies such as highly targeted antibiotics or inhibitors of complement factor C5a, which has been proposed as a biomarker for HS, to intervene in preventing or reversing HS tunnels. 

While this work progresses, one of the most Important unmet needs in HS is an accepted measure of clinically meaningful improvement in advanced disease, particularly the impact of therapy on HS tunnels, according to Krueger. 

“There is no measure of tunnel activity that the FDA accepts in evaluating drugs,” he noted, which will be essential for approving therapies that offer this benefit. 

A phase 3 trials program for one of the promising drugs, sonelokimab, was announced early in 2024. A nanobody that targets IL-17A/A, IL-17A/F, and IL-17F/F, the small size of this molecule permits exceptional tissue penetration while the broad anti-IL-17 activity has a high degree of theoretical potential in late-stage HS, according to Krueger. 

There are numerous pieces of the HS puzzle that are still missing, but both Krueger and Navrazhina are enthusiastic about new targets and opportunities for disease control that are stemming from a better understanding of the underlying pathophysiology. Not least, both indicated that testing for inflammatory phenotypes will allow for individualized therapeutic choices with a maximum likelihood of response, particularly if earlier diagnosis permits earlier treatment. 

“Due to the heterogeneity of HS, it is hard to know who will respond to which treatment or which treatment should be started first,” Navrazhina said. She thinks that early measures of the inflammatory profile in nodules or even non-lesional skin might provide that guidance. 

Both Krueger and Navrazhina reported no financial relationships relevant to this work. 

 

A version of this article appeared on Medscape.com.

NEW YORK, NY — Work over the past several years has reframed hidradenitis suppurativa (HS) as a large-field inflammatory process, a recharacterization that has immediate relevance to treatment strategies and goals, according to two investigators intimately involved in much of the recent progress.

“Success is being achieved by targeting multiple inflammatory axes in HS, and therapeutics are evolving rapidly,” reported James G. Krueger, MD, PhD, head of the Laboratory of Investigative Dermatology, Rockefeller University, New York, NY.

The activity of targeted anti-inflammatory therapies — bimekizumab just joined adalimumab and secukinumab as a third approved biologic for HS — is not news, but the degree to which inflammation is upregulated systemically, not just at areas of skin involvement, has changed the conceptualization of HS.

HS Is a Systemic Inflammatory Disease

Relative to psoriasis, for which there are many parallels, “HS is hugely more inflammatory in the systemic circulation,” Krueger said at the 27th Annual Winter Symposium — Advances in Medical and Surgical Dermatology (MSWS) 2024. Yet, HS is also more complex involving additional pathways that appear to include dysbiosis. The concept of follicular occlusion, once a common explanation for HS, has been left far behind.

“Unlike psoriasis, which we can treat really well by inhibiting a single pathway target, HS is just not that simple,” Krueger said. Although largely an inflammatory process, the cascade of inflammatory factors for specific manifestations, such as tunnels, means that optimal therapy in one case might have little benefit in another.

The relatively new evidence that HS activity is not confined to lesional skin might be the most important recent step toward new strategies to target disease. These studies were performed by Kristina Navrazhina, MD, PhD, now a resident in dermatology at the Icahn School of Medicine at Mount Sinai, New York. She received her PhD while studying HS activity in non-lesional skin. Her work has led her to conclude that the best chance for better outcomes in HS is early diagnosis and treatment. Although this is generally true of any pathology, the changes in the HS phenotype once fistulae form includes a poor response to conventional therapies. 

In fact, based on her work in evaluating HS activity in non-lesional skin, Navrazhina has shown that “many patients with modest lesions already have advanced disease.” Consistent with the premise that HS is a deeply systemic inflammatory process, nodules, considered an early manifestation, turn out to be “the tip of the iceberg.”

 

Non-Lesional HS Skin Is Inflamed

When she has employed RNA sequencing based on tape strip sampling from completely normal skin away from nodules, interleukin (IL)-17 and a broad array of other inflammatory markers were found to be upregulated. When she performed ultrasound to look for disease activity under the normal skin, she has often found tunnels already formed. Doppler ultrasound showed some of these tunnels were actively draining.

This might provide a partial explanation for why therapies are not always effective even when clinical signs of disease are modest. 

“Are we missing the opportunity for intervening?” Navrazhina asked, noting that early intervention has been limited traditionally by extremely long diagnostic delays. Citing the literature, Navrazhina said the average delay is 7 years for HS versus 1 year for psoriasis. Patients often cycle through 3 or 4 providers before the diagnosis is made, she said.

Awakening first-line clinicians to the signs and symptoms of HS, whether in the emergency room or primary care, is a critical message because of the incrementally difficult task to control disease once fistulae have formed. 

Krueger made the same appeal. For the neutrophilic inflammation that characterizes nodules, targeted therapies are often effective, but he agreed that available therapies are generally far less so once tunnels form.

 

Role Seen for Bacteria in HS Pathogenesis

One reason might be an interaction between anaerobic bacteria and the keratinocytes that form the tunnel walls, according to Krueger. Although HS is not typically considered an infectious disease, he reported that the interaction of these bacteria with keratinocytes is associated with expression of approximately 1000 inflammatory gene products. The process of tunnel formation is traced to how factors recruited by upregulated inflammation, such as chemokines, coordinate.

He described recent work pursing novel strategies such as highly targeted antibiotics or inhibitors of complement factor C5a, which has been proposed as a biomarker for HS, to intervene in preventing or reversing HS tunnels. 

While this work progresses, one of the most Important unmet needs in HS is an accepted measure of clinically meaningful improvement in advanced disease, particularly the impact of therapy on HS tunnels, according to Krueger. 

“There is no measure of tunnel activity that the FDA accepts in evaluating drugs,” he noted, which will be essential for approving therapies that offer this benefit. 

A phase 3 trials program for one of the promising drugs, sonelokimab, was announced early in 2024. A nanobody that targets IL-17A/A, IL-17A/F, and IL-17F/F, the small size of this molecule permits exceptional tissue penetration while the broad anti-IL-17 activity has a high degree of theoretical potential in late-stage HS, according to Krueger. 

There are numerous pieces of the HS puzzle that are still missing, but both Krueger and Navrazhina are enthusiastic about new targets and opportunities for disease control that are stemming from a better understanding of the underlying pathophysiology. Not least, both indicated that testing for inflammatory phenotypes will allow for individualized therapeutic choices with a maximum likelihood of response, particularly if earlier diagnosis permits earlier treatment. 

“Due to the heterogeneity of HS, it is hard to know who will respond to which treatment or which treatment should be started first,” Navrazhina said. She thinks that early measures of the inflammatory profile in nodules or even non-lesional skin might provide that guidance. 

Both Krueger and Navrazhina reported no financial relationships relevant to this work. 

 

A version of this article appeared on Medscape.com.

NEW YORK, NY — Work over the past several years has reframed hidradenitis suppurativa (HS) as a large-field inflammatory process, a recharacterization that has immediate relevance to treatment strategies and goals, according to two investigators intimately involved in much of the recent progress.

“Success is being achieved by targeting multiple inflammatory axes in HS, and therapeutics are evolving rapidly,” reported James G. Krueger, MD, PhD, head of the Laboratory of Investigative Dermatology, Rockefeller University, New York, NY.

The activity of targeted anti-inflammatory therapies — bimekizumab just joined adalimumab and secukinumab as a third approved biologic for HS — is not news, but the degree to which inflammation is upregulated systemically, not just at areas of skin involvement, has changed the conceptualization of HS.

HS Is a Systemic Inflammatory Disease

Relative to psoriasis, for which there are many parallels, “HS is hugely more inflammatory in the systemic circulation,” Krueger said at the 27th Annual Winter Symposium — Advances in Medical and Surgical Dermatology (MSWS) 2024. Yet, HS is also more complex involving additional pathways that appear to include dysbiosis. The concept of follicular occlusion, once a common explanation for HS, has been left far behind.

“Unlike psoriasis, which we can treat really well by inhibiting a single pathway target, HS is just not that simple,” Krueger said. Although largely an inflammatory process, the cascade of inflammatory factors for specific manifestations, such as tunnels, means that optimal therapy in one case might have little benefit in another.

The relatively new evidence that HS activity is not confined to lesional skin might be the most important recent step toward new strategies to target disease. These studies were performed by Kristina Navrazhina, MD, PhD, now a resident in dermatology at the Icahn School of Medicine at Mount Sinai, New York. She received her PhD while studying HS activity in non-lesional skin. Her work has led her to conclude that the best chance for better outcomes in HS is early diagnosis and treatment. Although this is generally true of any pathology, the changes in the HS phenotype once fistulae form includes a poor response to conventional therapies. 

In fact, based on her work in evaluating HS activity in non-lesional skin, Navrazhina has shown that “many patients with modest lesions already have advanced disease.” Consistent with the premise that HS is a deeply systemic inflammatory process, nodules, considered an early manifestation, turn out to be “the tip of the iceberg.”

 

Non-Lesional HS Skin Is Inflamed

When she has employed RNA sequencing based on tape strip sampling from completely normal skin away from nodules, interleukin (IL)-17 and a broad array of other inflammatory markers were found to be upregulated. When she performed ultrasound to look for disease activity under the normal skin, she has often found tunnels already formed. Doppler ultrasound showed some of these tunnels were actively draining.

This might provide a partial explanation for why therapies are not always effective even when clinical signs of disease are modest. 

“Are we missing the opportunity for intervening?” Navrazhina asked, noting that early intervention has been limited traditionally by extremely long diagnostic delays. Citing the literature, Navrazhina said the average delay is 7 years for HS versus 1 year for psoriasis. Patients often cycle through 3 or 4 providers before the diagnosis is made, she said.

Awakening first-line clinicians to the signs and symptoms of HS, whether in the emergency room or primary care, is a critical message because of the incrementally difficult task to control disease once fistulae have formed. 

Krueger made the same appeal. For the neutrophilic inflammation that characterizes nodules, targeted therapies are often effective, but he agreed that available therapies are generally far less so once tunnels form.

 

Role Seen for Bacteria in HS Pathogenesis

One reason might be an interaction between anaerobic bacteria and the keratinocytes that form the tunnel walls, according to Krueger. Although HS is not typically considered an infectious disease, he reported that the interaction of these bacteria with keratinocytes is associated with expression of approximately 1000 inflammatory gene products. The process of tunnel formation is traced to how factors recruited by upregulated inflammation, such as chemokines, coordinate.

He described recent work pursing novel strategies such as highly targeted antibiotics or inhibitors of complement factor C5a, which has been proposed as a biomarker for HS, to intervene in preventing or reversing HS tunnels. 

While this work progresses, one of the most Important unmet needs in HS is an accepted measure of clinically meaningful improvement in advanced disease, particularly the impact of therapy on HS tunnels, according to Krueger. 

“There is no measure of tunnel activity that the FDA accepts in evaluating drugs,” he noted, which will be essential for approving therapies that offer this benefit. 

A phase 3 trials program for one of the promising drugs, sonelokimab, was announced early in 2024. A nanobody that targets IL-17A/A, IL-17A/F, and IL-17F/F, the small size of this molecule permits exceptional tissue penetration while the broad anti-IL-17 activity has a high degree of theoretical potential in late-stage HS, according to Krueger. 

There are numerous pieces of the HS puzzle that are still missing, but both Krueger and Navrazhina are enthusiastic about new targets and opportunities for disease control that are stemming from a better understanding of the underlying pathophysiology. Not least, both indicated that testing for inflammatory phenotypes will allow for individualized therapeutic choices with a maximum likelihood of response, particularly if earlier diagnosis permits earlier treatment. 

“Due to the heterogeneity of HS, it is hard to know who will respond to which treatment or which treatment should be started first,” Navrazhina said. She thinks that early measures of the inflammatory profile in nodules or even non-lesional skin might provide that guidance. 

Both Krueger and Navrazhina reported no financial relationships relevant to this work. 

 

A version of this article appeared on Medscape.com.

Despite being a targeted therapy, antibody-drug conjugates (ADCs) can cause significant off-target toxicity to the eyes of patients being treated for advanced multiple myeloma or cervical cancer, yet the risks remain relatively unknown, according to oncologists and ophthalmologists.

Such experts called for greater collaboration between oncologists and ophthalmologists, in interviews with Medscape Medical News.

ADCs combine a monoclonal antibody targeted at an antigen overexpressed on cancer cells with a toxic chemotherapy payload — the aim being to maximize the effectiveness of the drug against the tumor while minimizing the damage to healthy tissues and reducing systemic toxicity.

Yet trastuzumab duocarmazine (T-Duo), a third-generation human epidermal growth factor receptor 2 (HER2)–targeted ADC designed to treat HER2-positive breast cancer, was recently found to have a notable adverse effect in the TULIP trial of 437 patients.

As reported by Medscape Medical News, the drug was associated with a significant increase in progression-free survival over physician’s choice of therapy. However, 78% of patients in the ADC group experienced at least one treatment-emergent ocular toxicity adverse event vs 29.2% of those in the control group.

Moreover, grade 3 or high ocular toxicity events were reported by 21% of patients in the experimental group compared with none of those who received physician’s choice.

 

Ocular Toxicities Seen on Ocular Surface

Ocular toxicities with these drugs are “not necessarily a new thing,” said Joann J. Kang, MD, director, Cornea and Refractive Surgery, and associate professor of ophthalmology at Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.

“But what we’re seeing with certain ADCs is a lot of ocular toxicity, especially on the ocular surface,” with the degree toxicity varying depending on the ADC in question. “It’s definitely a real concern.”

Kang noted that separate from T-Duo, certain ADCs already come with black box warnings for ocular toxicity, including:

• Belantamab mafodotin (Blenrep) — approved for relapsed or refractory multiple myeloma and carries a warning specifically for keratopathy.
• Tisotumab vedotin (Tivdak) — indicated for recurrent or metastatic cervical cancer and can cause changes in the corneal epithelium and conjunctiva.
• Mirvetuximab soravtansine (Elahere) — used to treat folate receptor (FR) alpha–positive ovarian, fallopian tube, and peritoneal cancers and can lead to keratopathy, blurred vision, and dry eyes.

Indeed, the American Academy of Ophthalmology 2024 annual meeting saw research presented indicating that mirvetuximab was associated with moderate or severe corneal toxicity in 47% of patients treated for primary gynecologic malignancies.

As reported by Medscape Medical News, the study, by researchers at Byers Eye Institute of Stanford University in Stanford, California, was a retrospective analysis of 36 eyes of 18 women who received mirvetuximab for FR alpha–positive, platinum-resistant primary ovarian cancer.

 

What Are the Causes?

But why would a drug that is targeted specifically to a cancer tumor, thanks to the presence of a monoclonal antibody, cause off-target effects such as ocular toxicity?

Kathy D. Miller, MD, professor of oncology and medicine at Indiana University School of Medicine in Indianapolis, pointed out that they are targeted in a relative and not absolute sense, meaning that the antigen target may not be truly limited to the tumor cells.

There can also be “a lot of ways that you could get systemic toxicities,” she said.

For example, if the linker connecting the antibody and the chemotherapy payload breaks prematurely or is not stable, or if the drug leaches out into the tumor microenvironment and then is “picked up into the circulation, that can give you systemic toxicity,” she said.

In addition, the drug may, once it is in the tumor cells, be metabolized to an active metabolite that could, again, result in systemic exposure.

 

Side Effects Are Underappreciated and Distressing

Ocular toxicity remains underappreciated among oncologists prescribing these drugs. One reason is that it “did not get enough attention” in the initial clinical trial reports, Miller said she suspects.

Another potential reason for this is that “we’re not used to thinking about it because it’s not particularly common among the drugs that oncologists use frequently,” she added. Additionally, it tends to come up later during treatment, “so people have to be on therapy for some time before you start to see it.”

Nevertheless, Miller underlined that ocular toxicity “can be particularly distressing for patients, as it’s uncomfortable [and] can lead to scarring, so some of the vision issues can be permanent.”

“We often see in these situations that there are different types of ocular toxicities that present in different patients,” said Jane L. Meisel, MD, co-director, Breast Medical Oncology, Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta.

“Corneal damage is pretty common, and patients can present with blurry vision, or dry eyes, or light sensitivity. And unlike some side effects, these are things that really impact people at every waking moment of their day.”

“So they’re pretty clinically significant side effects, even if they’re not life-threatening,” Meisel emphasized.

Miller suspects that more heavily pretreated patients may be more likely to experience ocular toxicity, as “there’s a much higher incidence of dry eyes in our patients than we recognize.”

She added: “We don’t usually ask about it, and we certainly don’t routinely do Schirmer’s tests,” which determine whether the eye produces enough tears to keep it moist.

 

Preventive Measures

For patients receiving tisotumab or mirvetuximab who experience ocular toxicity, Kang said the recommendation is to use steroid eye drops before, during, and after treatment with the ADC.

However, she noted that steroids have not been found to be useful in patients given belantamab, so clinicians have tried vasoconstrictor eye drops immediately prior to the infusion, as well as ocular cooling masks, which “are thought to help by reducing blood supply to the ocular areas.”

Other approaches to minimize ocular toxicity have included longer infusion times, so it’s “not so much of a hefty dose at one time,” Kang added.

She underlined that grade 2 and 3 ocular toxicities can lead to dose delays or dose modifications, and “usually by the time you get a grade 4 event, then you may need to discontinue the medication.”

This can have consequences for the patients because they are often “very sick, and this may be their third agent that they’re trying,” or it may be that their tumor is responding to a new treatment, but it has to be withheld because of an ocular toxicity.

“It can be incredibly frustrating for patients, and also for oncologists, and then for ophthalmologists,” Kang said.

 

Closer Collaboration Between Specialists Needed

What’s known about ocular side effects in patients taking ADCs underlines that there is a need for closer collaboration between oncologists and ophthalmologists.

“In oncology, especially as immunotherapies came to the forefront, our relationships with our endocrinology colleagues have become stronger because we’ve needed them to help us manage things like thyroid toxicity and pituitary issues related to immunotherapy,” Meisel said.

With toxicities that may be “very impactful for patient quality of life, like ocular toxicity, we will need to learn more about them and develop protocols for management, along with our ophthalmology colleagues, so that we can keep patients as comfortable as possible, while maximizing the efficacy of these drugs.”

Miller agreed, saying oncologists need to have “a conversation with a local ophthalmologist,” although she conceded that, in many areas, such specialists “are in short supply.”

The oncologist “not only needs to be aware” of and looking for ocular toxicity when using these ADCs but also needs to be thinking: “If I run into trouble here, who’s my ophthalmology backup? Are they familiar with this drug? And do we have a plan for the multispecialty management of patients who run into this toxicity?”

 

Setting Counts When Assessing Toxicities

But do all these considerations mean that ADCs’ potential ocular toxicity should give clinicians pause when considering whether to use these drugs?

“What my patients most want are drugs that work; that are effective in controlling their tumors,” Miller said.

“Every drug we use has potential toxicities, and which toxicities are most physically troublesome [or] are the greatest concern may vary from patient to patient, and it may vary a lot from patients with metastatic disease to those in the curative setting.”

She explained that “toxicities that might not be prohibitive at all in the metastatic setting [may] have to be a much bigger part of our considerations” when moving drugs into the adjuvant or neoadjuvant setting.

This, Miller underlined, is where the ocular toxicity with these ADCs “may be much more prohibitive.”

TULIP was funded by Byondis BV.

Turner declared relationships with Novartis, AstraZeneca, Pfizer, Merck Sharp & Dohme, Lilly, Repare Therapeutics, Roche, GlaxoSmithKline, Gilead Sciences, Inivata, Guardant Health, Exact Sciences, and Relay Therapeutics.

Meisel declared relationships with Novartis, AstraZeneca, Genentech, Seagen, Olema Oncology, GE Healthcare, Pfizer, Stemline, and Sermonix Pharmaceuticals.

 

A version of this article appeared on Medscape.com.

Despite being a targeted therapy, antibody-drug conjugates (ADCs) can cause significant off-target toxicity to the eyes of patients being treated for advanced multiple myeloma or cervical cancer, yet the risks remain relatively unknown, according to oncologists and ophthalmologists.

Such experts called for greater collaboration between oncologists and ophthalmologists, in interviews with Medscape Medical News.

ADCs combine a monoclonal antibody targeted at an antigen overexpressed on cancer cells with a toxic chemotherapy payload — the aim being to maximize the effectiveness of the drug against the tumor while minimizing the damage to healthy tissues and reducing systemic toxicity.

Yet trastuzumab duocarmazine (T-Duo), a third-generation human epidermal growth factor receptor 2 (HER2)–targeted ADC designed to treat HER2-positive breast cancer, was recently found to have a notable adverse effect in the TULIP trial of 437 patients.

As reported by Medscape Medical News, the drug was associated with a significant increase in progression-free survival over physician’s choice of therapy. However, 78% of patients in the ADC group experienced at least one treatment-emergent ocular toxicity adverse event vs 29.2% of those in the control group.

Moreover, grade 3 or high ocular toxicity events were reported by 21% of patients in the experimental group compared with none of those who received physician’s choice.

 

Ocular Toxicities Seen on Ocular Surface

Ocular toxicities with these drugs are “not necessarily a new thing,” said Joann J. Kang, MD, director, Cornea and Refractive Surgery, and associate professor of ophthalmology at Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.

“But what we’re seeing with certain ADCs is a lot of ocular toxicity, especially on the ocular surface,” with the degree toxicity varying depending on the ADC in question. “It’s definitely a real concern.”

Kang noted that separate from T-Duo, certain ADCs already come with black box warnings for ocular toxicity, including:

• Belantamab mafodotin (Blenrep) — approved for relapsed or refractory multiple myeloma and carries a warning specifically for keratopathy.
• Tisotumab vedotin (Tivdak) — indicated for recurrent or metastatic cervical cancer and can cause changes in the corneal epithelium and conjunctiva.
• Mirvetuximab soravtansine (Elahere) — used to treat folate receptor (FR) alpha–positive ovarian, fallopian tube, and peritoneal cancers and can lead to keratopathy, blurred vision, and dry eyes.

Indeed, the American Academy of Ophthalmology 2024 annual meeting saw research presented indicating that mirvetuximab was associated with moderate or severe corneal toxicity in 47% of patients treated for primary gynecologic malignancies.

As reported by Medscape Medical News, the study, by researchers at Byers Eye Institute of Stanford University in Stanford, California, was a retrospective analysis of 36 eyes of 18 women who received mirvetuximab for FR alpha–positive, platinum-resistant primary ovarian cancer.

 

What Are the Causes?

But why would a drug that is targeted specifically to a cancer tumor, thanks to the presence of a monoclonal antibody, cause off-target effects such as ocular toxicity?

Kathy D. Miller, MD, professor of oncology and medicine at Indiana University School of Medicine in Indianapolis, pointed out that they are targeted in a relative and not absolute sense, meaning that the antigen target may not be truly limited to the tumor cells.

There can also be “a lot of ways that you could get systemic toxicities,” she said.

For example, if the linker connecting the antibody and the chemotherapy payload breaks prematurely or is not stable, or if the drug leaches out into the tumor microenvironment and then is “picked up into the circulation, that can give you systemic toxicity,” she said.

In addition, the drug may, once it is in the tumor cells, be metabolized to an active metabolite that could, again, result in systemic exposure.

 

Side Effects Are Underappreciated and Distressing

Ocular toxicity remains underappreciated among oncologists prescribing these drugs. One reason is that it “did not get enough attention” in the initial clinical trial reports, Miller said she suspects.

Another potential reason for this is that “we’re not used to thinking about it because it’s not particularly common among the drugs that oncologists use frequently,” she added. Additionally, it tends to come up later during treatment, “so people have to be on therapy for some time before you start to see it.”

Nevertheless, Miller underlined that ocular toxicity “can be particularly distressing for patients, as it’s uncomfortable [and] can lead to scarring, so some of the vision issues can be permanent.”

“We often see in these situations that there are different types of ocular toxicities that present in different patients,” said Jane L. Meisel, MD, co-director, Breast Medical Oncology, Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta.

“Corneal damage is pretty common, and patients can present with blurry vision, or dry eyes, or light sensitivity. And unlike some side effects, these are things that really impact people at every waking moment of their day.”

“So they’re pretty clinically significant side effects, even if they’re not life-threatening,” Meisel emphasized.

Miller suspects that more heavily pretreated patients may be more likely to experience ocular toxicity, as “there’s a much higher incidence of dry eyes in our patients than we recognize.”

She added: “We don’t usually ask about it, and we certainly don’t routinely do Schirmer’s tests,” which determine whether the eye produces enough tears to keep it moist.

 

Preventive Measures

For patients receiving tisotumab or mirvetuximab who experience ocular toxicity, Kang said the recommendation is to use steroid eye drops before, during, and after treatment with the ADC.

However, she noted that steroids have not been found to be useful in patients given belantamab, so clinicians have tried vasoconstrictor eye drops immediately prior to the infusion, as well as ocular cooling masks, which “are thought to help by reducing blood supply to the ocular areas.”

Other approaches to minimize ocular toxicity have included longer infusion times, so it’s “not so much of a hefty dose at one time,” Kang added.

She underlined that grade 2 and 3 ocular toxicities can lead to dose delays or dose modifications, and “usually by the time you get a grade 4 event, then you may need to discontinue the medication.”

This can have consequences for the patients because they are often “very sick, and this may be their third agent that they’re trying,” or it may be that their tumor is responding to a new treatment, but it has to be withheld because of an ocular toxicity.

“It can be incredibly frustrating for patients, and also for oncologists, and then for ophthalmologists,” Kang said.

 

Closer Collaboration Between Specialists Needed

What’s known about ocular side effects in patients taking ADCs underlines that there is a need for closer collaboration between oncologists and ophthalmologists.

“In oncology, especially as immunotherapies came to the forefront, our relationships with our endocrinology colleagues have become stronger because we’ve needed them to help us manage things like thyroid toxicity and pituitary issues related to immunotherapy,” Meisel said.

With toxicities that may be “very impactful for patient quality of life, like ocular toxicity, we will need to learn more about them and develop protocols for management, along with our ophthalmology colleagues, so that we can keep patients as comfortable as possible, while maximizing the efficacy of these drugs.”

Miller agreed, saying oncologists need to have “a conversation with a local ophthalmologist,” although she conceded that, in many areas, such specialists “are in short supply.”

The oncologist “not only needs to be aware” of and looking for ocular toxicity when using these ADCs but also needs to be thinking: “If I run into trouble here, who’s my ophthalmology backup? Are they familiar with this drug? And do we have a plan for the multispecialty management of patients who run into this toxicity?”

 

Setting Counts When Assessing Toxicities

But do all these considerations mean that ADCs’ potential ocular toxicity should give clinicians pause when considering whether to use these drugs?

“What my patients most want are drugs that work; that are effective in controlling their tumors,” Miller said.

“Every drug we use has potential toxicities, and which toxicities are most physically troublesome [or] are the greatest concern may vary from patient to patient, and it may vary a lot from patients with metastatic disease to those in the curative setting.”

She explained that “toxicities that might not be prohibitive at all in the metastatic setting [may] have to be a much bigger part of our considerations” when moving drugs into the adjuvant or neoadjuvant setting.

This, Miller underlined, is where the ocular toxicity with these ADCs “may be much more prohibitive.”

TULIP was funded by Byondis BV.

Turner declared relationships with Novartis, AstraZeneca, Pfizer, Merck Sharp & Dohme, Lilly, Repare Therapeutics, Roche, GlaxoSmithKline, Gilead Sciences, Inivata, Guardant Health, Exact Sciences, and Relay Therapeutics.

Meisel declared relationships with Novartis, AstraZeneca, Genentech, Seagen, Olema Oncology, GE Healthcare, Pfizer, Stemline, and Sermonix Pharmaceuticals.

 

A version of this article appeared on Medscape.com.

Despite being a targeted therapy, antibody-drug conjugates (ADCs) can cause significant off-target toxicity to the eyes of patients being treated for advanced multiple myeloma or cervical cancer, yet the risks remain relatively unknown, according to oncologists and ophthalmologists.

Such experts called for greater collaboration between oncologists and ophthalmologists, in interviews with Medscape Medical News.

ADCs combine a monoclonal antibody targeted at an antigen overexpressed on cancer cells with a toxic chemotherapy payload — the aim being to maximize the effectiveness of the drug against the tumor while minimizing the damage to healthy tissues and reducing systemic toxicity.

Yet trastuzumab duocarmazine (T-Duo), a third-generation human epidermal growth factor receptor 2 (HER2)–targeted ADC designed to treat HER2-positive breast cancer, was recently found to have a notable adverse effect in the TULIP trial of 437 patients.

As reported by Medscape Medical News, the drug was associated with a significant increase in progression-free survival over physician’s choice of therapy. However, 78% of patients in the ADC group experienced at least one treatment-emergent ocular toxicity adverse event vs 29.2% of those in the control group.

Moreover, grade 3 or high ocular toxicity events were reported by 21% of patients in the experimental group compared with none of those who received physician’s choice.

 

Ocular Toxicities Seen on Ocular Surface

Ocular toxicities with these drugs are “not necessarily a new thing,” said Joann J. Kang, MD, director, Cornea and Refractive Surgery, and associate professor of ophthalmology at Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.

“But what we’re seeing with certain ADCs is a lot of ocular toxicity, especially on the ocular surface,” with the degree toxicity varying depending on the ADC in question. “It’s definitely a real concern.”

Kang noted that separate from T-Duo, certain ADCs already come with black box warnings for ocular toxicity, including:

• Belantamab mafodotin (Blenrep) — approved for relapsed or refractory multiple myeloma and carries a warning specifically for keratopathy.
• Tisotumab vedotin (Tivdak) — indicated for recurrent or metastatic cervical cancer and can cause changes in the corneal epithelium and conjunctiva.
• Mirvetuximab soravtansine (Elahere) — used to treat folate receptor (FR) alpha–positive ovarian, fallopian tube, and peritoneal cancers and can lead to keratopathy, blurred vision, and dry eyes.

Indeed, the American Academy of Ophthalmology 2024 annual meeting saw research presented indicating that mirvetuximab was associated with moderate or severe corneal toxicity in 47% of patients treated for primary gynecologic malignancies.

As reported by Medscape Medical News, the study, by researchers at Byers Eye Institute of Stanford University in Stanford, California, was a retrospective analysis of 36 eyes of 18 women who received mirvetuximab for FR alpha–positive, platinum-resistant primary ovarian cancer.

 

What Are the Causes?

But why would a drug that is targeted specifically to a cancer tumor, thanks to the presence of a monoclonal antibody, cause off-target effects such as ocular toxicity?

Kathy D. Miller, MD, professor of oncology and medicine at Indiana University School of Medicine in Indianapolis, pointed out that they are targeted in a relative and not absolute sense, meaning that the antigen target may not be truly limited to the tumor cells.

There can also be “a lot of ways that you could get systemic toxicities,” she said.

For example, if the linker connecting the antibody and the chemotherapy payload breaks prematurely or is not stable, or if the drug leaches out into the tumor microenvironment and then is “picked up into the circulation, that can give you systemic toxicity,” she said.

In addition, the drug may, once it is in the tumor cells, be metabolized to an active metabolite that could, again, result in systemic exposure.

 

Side Effects Are Underappreciated and Distressing

Ocular toxicity remains underappreciated among oncologists prescribing these drugs. One reason is that it “did not get enough attention” in the initial clinical trial reports, Miller said she suspects.

Another potential reason for this is that “we’re not used to thinking about it because it’s not particularly common among the drugs that oncologists use frequently,” she added. Additionally, it tends to come up later during treatment, “so people have to be on therapy for some time before you start to see it.”

Nevertheless, Miller underlined that ocular toxicity “can be particularly distressing for patients, as it’s uncomfortable [and] can lead to scarring, so some of the vision issues can be permanent.”

“We often see in these situations that there are different types of ocular toxicities that present in different patients,” said Jane L. Meisel, MD, co-director, Breast Medical Oncology, Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta.

“Corneal damage is pretty common, and patients can present with blurry vision, or dry eyes, or light sensitivity. And unlike some side effects, these are things that really impact people at every waking moment of their day.”

“So they’re pretty clinically significant side effects, even if they’re not life-threatening,” Meisel emphasized.

Miller suspects that more heavily pretreated patients may be more likely to experience ocular toxicity, as “there’s a much higher incidence of dry eyes in our patients than we recognize.”

She added: “We don’t usually ask about it, and we certainly don’t routinely do Schirmer’s tests,” which determine whether the eye produces enough tears to keep it moist.

 

Preventive Measures

For patients receiving tisotumab or mirvetuximab who experience ocular toxicity, Kang said the recommendation is to use steroid eye drops before, during, and after treatment with the ADC.

However, she noted that steroids have not been found to be useful in patients given belantamab, so clinicians have tried vasoconstrictor eye drops immediately prior to the infusion, as well as ocular cooling masks, which “are thought to help by reducing blood supply to the ocular areas.”

Other approaches to minimize ocular toxicity have included longer infusion times, so it’s “not so much of a hefty dose at one time,” Kang added.

She underlined that grade 2 and 3 ocular toxicities can lead to dose delays or dose modifications, and “usually by the time you get a grade 4 event, then you may need to discontinue the medication.”

This can have consequences for the patients because they are often “very sick, and this may be their third agent that they’re trying,” or it may be that their tumor is responding to a new treatment, but it has to be withheld because of an ocular toxicity.

“It can be incredibly frustrating for patients, and also for oncologists, and then for ophthalmologists,” Kang said.

 

Closer Collaboration Between Specialists Needed

What’s known about ocular side effects in patients taking ADCs underlines that there is a need for closer collaboration between oncologists and ophthalmologists.

“In oncology, especially as immunotherapies came to the forefront, our relationships with our endocrinology colleagues have become stronger because we’ve needed them to help us manage things like thyroid toxicity and pituitary issues related to immunotherapy,” Meisel said.

With toxicities that may be “very impactful for patient quality of life, like ocular toxicity, we will need to learn more about them and develop protocols for management, along with our ophthalmology colleagues, so that we can keep patients as comfortable as possible, while maximizing the efficacy of these drugs.”

Miller agreed, saying oncologists need to have “a conversation with a local ophthalmologist,” although she conceded that, in many areas, such specialists “are in short supply.”

The oncologist “not only needs to be aware” of and looking for ocular toxicity when using these ADCs but also needs to be thinking: “If I run into trouble here, who’s my ophthalmology backup? Are they familiar with this drug? And do we have a plan for the multispecialty management of patients who run into this toxicity?”

 

Setting Counts When Assessing Toxicities

But do all these considerations mean that ADCs’ potential ocular toxicity should give clinicians pause when considering whether to use these drugs?

“What my patients most want are drugs that work; that are effective in controlling their tumors,” Miller said.

“Every drug we use has potential toxicities, and which toxicities are most physically troublesome [or] are the greatest concern may vary from patient to patient, and it may vary a lot from patients with metastatic disease to those in the curative setting.”

She explained that “toxicities that might not be prohibitive at all in the metastatic setting [may] have to be a much bigger part of our considerations” when moving drugs into the adjuvant or neoadjuvant setting.

This, Miller underlined, is where the ocular toxicity with these ADCs “may be much more prohibitive.”

TULIP was funded by Byondis BV.

Turner declared relationships with Novartis, AstraZeneca, Pfizer, Merck Sharp & Dohme, Lilly, Repare Therapeutics, Roche, GlaxoSmithKline, Gilead Sciences, Inivata, Guardant Health, Exact Sciences, and Relay Therapeutics.

Meisel declared relationships with Novartis, AstraZeneca, Genentech, Seagen, Olema Oncology, GE Healthcare, Pfizer, Stemline, and Sermonix Pharmaceuticals.

 

A version of this article appeared on Medscape.com.

In the treatment of relapsed or refractory follicular lymphoma (R/R FL), the addition of tafasitamab to a standard 2-drug combination of lenalidomide and rituximab (len+R) significantly improves progression-free survival, with no increases in safety events.

“This study is the first to validate combining two monoclonal antibodies (anti-CD19 with anti-CD20) in the treatment of lymphoma,” said first author Laurie H. Sehn, MD, MPH, a clinical professor with the BC Cancer Centre for Lymphoid Cancer and the University of British Columbia in Vancouver, Canada. She presented the findings at the American Society of Hematology 2024 Annual Meeting.

“Tafasitamab plus lenalidomide and rituximab can be administered in community as well as academic settings and represents a potential new standard-of-care option for patients with R/R follicular lymphoma,” she noted.

The results are from the international, phase 3 inMIND multicenter trial involving 548 patients with R/R FL, with a median age of 64. Of the patients, 45% had been treated with two or more prior lines of therapy.

At a median follow up of 14.1 months, those randomized to treatment with tafasitamab and len+R (n = 273) had a significantly lower risk for progression, relapse, or death than those receiving the double therapy with placebo (n = 275), with a median progression-free survival of 22.4 months vs 13.9 months, respectively (hazard ratio [HR], 0.43; P < .0001).

Improved progression-free survival was observed across all prespecified subgroups, including patients with disease progression within 24 months, those who were refractory to prior anti-CD20 monoclonal antibodies, and who received multiple prior lines of therapy.

“Although this study was not powered for individual subgroups, it is clear that there’s a significant benefit of tafasitamab in all subgroups regardless of status of [disease progression within 24 months] and regardless of refractoriness to prior anti-CD20 monoclonal antibodies,” Sehn noted.

FL, the most common, indolent form of B-cell non-Hodgkin lymphoma (NHL), is commonly treated with frontline therapy of chemoimmunotherapy; however, response durations begin to dwindle after successive lines of treatment.

Lenalidomide and rituximab are approved and commonly used in the treatment of FL after more than one prior line of treatment.

With tafasitamab, which is administered intravenously, already having been approved for use in combination with lenalidomide in the treatment of R/R diffuse large B-cell lymphoma, based on results of the previous L-MIND study, Sehn and colleagues investigated its benefits in FL or marginal zone NHL.

Of the patients included in the trial, 55% were men and 79% had intermediate or high-risk FLIPI scores, referring to the FL International Prognostic Index, a scoring system used for predicting prognoses of patients with FL.

Treatment in the study consisted of 12 mg/kg intravenous tafasitamab or placebo on days 1, 8, 15, and 22 of cycles 1-3 and days 1 and 15 of cycles 4-12, with standard dosing of len+R for up to 12 cycles of 28 days each. 

In terms of the data cutoff, patients in the tafasitamab arm received a median of 12 cycles of treatment vs 11 cycles for placebo, and 19% and 15% were still on treatment, respectively, at the cut-off. 

Of the patients, 81% and 84%, respectively, had discontinued treatment primarily because of treatment completion (54% and 43%) or disease progression (11% and 31%). 

In addition to the progression-free survival primary endpoint, the tafasitamab arm also had a higher rate of complete response (CR) on PET (49.4% vs 39.8%; P = .029) and higher overall response rate (83.5% vs 72.4%; P = .0014) than the placebo arm. 

The duration of response was also higher with tafasitamab (median, 21.2 months vs 13.6 months; HR, 0.47; P < .0001).

Overall survival data, though immature, also favored tafasitamab (HR, 0.59). 

The two arms had similar rates of treatment-emergent adverse events, with similar toxicity profiles and no new significant safety signals related to tafasitamab. The rates of discontinuations and dose reductions were similar, with a median dose intensity of 86% with tafasitamab vs 87%.

The most common grade 3 or 4 adverse events were similar between the tafasitamab and placebo groups, including neutropenia (40% vs 38%, respectively), pneumonia (8% vs 5%), thrombocytopenia (6% vs 7%), decreased neutrophils (6% vs 7%), COVID-19 (6% vs 2%), and COVID-19 pneumonia (5% vs 1%). 

“Importantly, the addition of tafasitamab did not impede the delivery of lenalidomide and rituximab, with similar observed dose discontinuations or interruptions in both cohorts,” Sehn said.

“The inMIND phase 3 study met its primary endpoint of improved progression-free survival with the addition of tafasitamab to lenalidomide and rituximab in patients with R/R follicular lymphoma, representing a 57% reduction in the risk of progression, relapse, or death,” Sehn said.

Commenting on the study, Juan Pablo Alderuccio, MD, an associate professor of medicine, Division of Hematology in the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine in Florida, said the findings are notable in that “this is the first time two monoclonal antibodies have been tested in follicular lymphoma.”

“The study demonstrates that simultaneously targeting CD19 and CD20 improves outcomes,” he said in an interview.

Alderuccio noted the key caveats include that “PET/CT complete response correlates well with survival in follicular lymphoma. In this study, the PET/CT CR rate was 49.4%, underscoring the need for longer follow-ups to better assess those responses’ durability.”

“Another caveat of this regimen is the treatment schedule, which requires weekly tafasitamab infusions during cycles 1-3 and every 2 weeks during cycles 4-12. This is associated with rituximab and lenalidomide administration,” he said.

Ultimately, “the results underscore the potential of tafasitamab in combination with lenalidomide and rituximab to become a new treatment option in the second-line or later follicular lymphoma.”

“However, I would like to see more follow-up data before considering it a new standard of care,” he cautioned.

The study was funded by Incyte. Sehn reported ties with AbbVie, Amgen, AstraZeneca, BeiGene, BMS/Celgene, Genmab, Kite/Gilead, Incyte, Janssen, and Merck. Alderuccio disclosed relationships with Genmab, ADC Therapeutics, BeiGene, AbbVie, Genentech, Novartis, Regeneron, and Lilly.

A version of this article appeared on Medscape.com.

In the treatment of relapsed or refractory follicular lymphoma (R/R FL), the addition of tafasitamab to a standard 2-drug combination of lenalidomide and rituximab (len+R) significantly improves progression-free survival, with no increases in safety events.

“This study is the first to validate combining two monoclonal antibodies (anti-CD19 with anti-CD20) in the treatment of lymphoma,” said first author Laurie H. Sehn, MD, MPH, a clinical professor with the BC Cancer Centre for Lymphoid Cancer and the University of British Columbia in Vancouver, Canada. She presented the findings at the American Society of Hematology 2024 Annual Meeting.

“Tafasitamab plus lenalidomide and rituximab can be administered in community as well as academic settings and represents a potential new standard-of-care option for patients with R/R follicular lymphoma,” she noted.

The results are from the international, phase 3 inMIND multicenter trial involving 548 patients with R/R FL, with a median age of 64. Of the patients, 45% had been treated with two or more prior lines of therapy.

At a median follow up of 14.1 months, those randomized to treatment with tafasitamab and len+R (n = 273) had a significantly lower risk for progression, relapse, or death than those receiving the double therapy with placebo (n = 275), with a median progression-free survival of 22.4 months vs 13.9 months, respectively (hazard ratio [HR], 0.43; P < .0001).

Improved progression-free survival was observed across all prespecified subgroups, including patients with disease progression within 24 months, those who were refractory to prior anti-CD20 monoclonal antibodies, and who received multiple prior lines of therapy.

“Although this study was not powered for individual subgroups, it is clear that there’s a significant benefit of tafasitamab in all subgroups regardless of status of [disease progression within 24 months] and regardless of refractoriness to prior anti-CD20 monoclonal antibodies,” Sehn noted.

FL, the most common, indolent form of B-cell non-Hodgkin lymphoma (NHL), is commonly treated with frontline therapy of chemoimmunotherapy; however, response durations begin to dwindle after successive lines of treatment.

Lenalidomide and rituximab are approved and commonly used in the treatment of FL after more than one prior line of treatment.

With tafasitamab, which is administered intravenously, already having been approved for use in combination with lenalidomide in the treatment of R/R diffuse large B-cell lymphoma, based on results of the previous L-MIND study, Sehn and colleagues investigated its benefits in FL or marginal zone NHL.

Of the patients included in the trial, 55% were men and 79% had intermediate or high-risk FLIPI scores, referring to the FL International Prognostic Index, a scoring system used for predicting prognoses of patients with FL.

Treatment in the study consisted of 12 mg/kg intravenous tafasitamab or placebo on days 1, 8, 15, and 22 of cycles 1-3 and days 1 and 15 of cycles 4-12, with standard dosing of len+R for up to 12 cycles of 28 days each. 

In terms of the data cutoff, patients in the tafasitamab arm received a median of 12 cycles of treatment vs 11 cycles for placebo, and 19% and 15% were still on treatment, respectively, at the cut-off. 

Of the patients, 81% and 84%, respectively, had discontinued treatment primarily because of treatment completion (54% and 43%) or disease progression (11% and 31%). 

In addition to the progression-free survival primary endpoint, the tafasitamab arm also had a higher rate of complete response (CR) on PET (49.4% vs 39.8%; P = .029) and higher overall response rate (83.5% vs 72.4%; P = .0014) than the placebo arm. 

The duration of response was also higher with tafasitamab (median, 21.2 months vs 13.6 months; HR, 0.47; P < .0001).

Overall survival data, though immature, also favored tafasitamab (HR, 0.59). 

The two arms had similar rates of treatment-emergent adverse events, with similar toxicity profiles and no new significant safety signals related to tafasitamab. The rates of discontinuations and dose reductions were similar, with a median dose intensity of 86% with tafasitamab vs 87%.

The most common grade 3 or 4 adverse events were similar between the tafasitamab and placebo groups, including neutropenia (40% vs 38%, respectively), pneumonia (8% vs 5%), thrombocytopenia (6% vs 7%), decreased neutrophils (6% vs 7%), COVID-19 (6% vs 2%), and COVID-19 pneumonia (5% vs 1%). 

“Importantly, the addition of tafasitamab did not impede the delivery of lenalidomide and rituximab, with similar observed dose discontinuations or interruptions in both cohorts,” Sehn said.

“The inMIND phase 3 study met its primary endpoint of improved progression-free survival with the addition of tafasitamab to lenalidomide and rituximab in patients with R/R follicular lymphoma, representing a 57% reduction in the risk of progression, relapse, or death,” Sehn said.

Commenting on the study, Juan Pablo Alderuccio, MD, an associate professor of medicine, Division of Hematology in the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine in Florida, said the findings are notable in that “this is the first time two monoclonal antibodies have been tested in follicular lymphoma.”

“The study demonstrates that simultaneously targeting CD19 and CD20 improves outcomes,” he said in an interview.

Alderuccio noted the key caveats include that “PET/CT complete response correlates well with survival in follicular lymphoma. In this study, the PET/CT CR rate was 49.4%, underscoring the need for longer follow-ups to better assess those responses’ durability.”

“Another caveat of this regimen is the treatment schedule, which requires weekly tafasitamab infusions during cycles 1-3 and every 2 weeks during cycles 4-12. This is associated with rituximab and lenalidomide administration,” he said.

Ultimately, “the results underscore the potential of tafasitamab in combination with lenalidomide and rituximab to become a new treatment option in the second-line or later follicular lymphoma.”

“However, I would like to see more follow-up data before considering it a new standard of care,” he cautioned.

The study was funded by Incyte. Sehn reported ties with AbbVie, Amgen, AstraZeneca, BeiGene, BMS/Celgene, Genmab, Kite/Gilead, Incyte, Janssen, and Merck. Alderuccio disclosed relationships with Genmab, ADC Therapeutics, BeiGene, AbbVie, Genentech, Novartis, Regeneron, and Lilly.

A version of this article appeared on Medscape.com.

In the treatment of relapsed or refractory follicular lymphoma (R/R FL), the addition of tafasitamab to a standard 2-drug combination of lenalidomide and rituximab (len+R) significantly improves progression-free survival, with no increases in safety events.

“This study is the first to validate combining two monoclonal antibodies (anti-CD19 with anti-CD20) in the treatment of lymphoma,” said first author Laurie H. Sehn, MD, MPH, a clinical professor with the BC Cancer Centre for Lymphoid Cancer and the University of British Columbia in Vancouver, Canada. She presented the findings at the American Society of Hematology 2024 Annual Meeting.

“Tafasitamab plus lenalidomide and rituximab can be administered in community as well as academic settings and represents a potential new standard-of-care option for patients with R/R follicular lymphoma,” she noted.

The results are from the international, phase 3 inMIND multicenter trial involving 548 patients with R/R FL, with a median age of 64. Of the patients, 45% had been treated with two or more prior lines of therapy.

At a median follow up of 14.1 months, those randomized to treatment with tafasitamab and len+R (n = 273) had a significantly lower risk for progression, relapse, or death than those receiving the double therapy with placebo (n = 275), with a median progression-free survival of 22.4 months vs 13.9 months, respectively (hazard ratio [HR], 0.43; P < .0001).

Improved progression-free survival was observed across all prespecified subgroups, including patients with disease progression within 24 months, those who were refractory to prior anti-CD20 monoclonal antibodies, and who received multiple prior lines of therapy.

“Although this study was not powered for individual subgroups, it is clear that there’s a significant benefit of tafasitamab in all subgroups regardless of status of [disease progression within 24 months] and regardless of refractoriness to prior anti-CD20 monoclonal antibodies,” Sehn noted.

FL, the most common, indolent form of B-cell non-Hodgkin lymphoma (NHL), is commonly treated with frontline therapy of chemoimmunotherapy; however, response durations begin to dwindle after successive lines of treatment.

Lenalidomide and rituximab are approved and commonly used in the treatment of FL after more than one prior line of treatment.

With tafasitamab, which is administered intravenously, already having been approved for use in combination with lenalidomide in the treatment of R/R diffuse large B-cell lymphoma, based on results of the previous L-MIND study, Sehn and colleagues investigated its benefits in FL or marginal zone NHL.

Of the patients included in the trial, 55% were men and 79% had intermediate or high-risk FLIPI scores, referring to the FL International Prognostic Index, a scoring system used for predicting prognoses of patients with FL.

Treatment in the study consisted of 12 mg/kg intravenous tafasitamab or placebo on days 1, 8, 15, and 22 of cycles 1-3 and days 1 and 15 of cycles 4-12, with standard dosing of len+R for up to 12 cycles of 28 days each. 

In terms of the data cutoff, patients in the tafasitamab arm received a median of 12 cycles of treatment vs 11 cycles for placebo, and 19% and 15% were still on treatment, respectively, at the cut-off. 

Of the patients, 81% and 84%, respectively, had discontinued treatment primarily because of treatment completion (54% and 43%) or disease progression (11% and 31%). 

In addition to the progression-free survival primary endpoint, the tafasitamab arm also had a higher rate of complete response (CR) on PET (49.4% vs 39.8%; P = .029) and higher overall response rate (83.5% vs 72.4%; P = .0014) than the placebo arm. 

The duration of response was also higher with tafasitamab (median, 21.2 months vs 13.6 months; HR, 0.47; P < .0001).

Overall survival data, though immature, also favored tafasitamab (HR, 0.59). 

The two arms had similar rates of treatment-emergent adverse events, with similar toxicity profiles and no new significant safety signals related to tafasitamab. The rates of discontinuations and dose reductions were similar, with a median dose intensity of 86% with tafasitamab vs 87%.

The most common grade 3 or 4 adverse events were similar between the tafasitamab and placebo groups, including neutropenia (40% vs 38%, respectively), pneumonia (8% vs 5%), thrombocytopenia (6% vs 7%), decreased neutrophils (6% vs 7%), COVID-19 (6% vs 2%), and COVID-19 pneumonia (5% vs 1%). 

“Importantly, the addition of tafasitamab did not impede the delivery of lenalidomide and rituximab, with similar observed dose discontinuations or interruptions in both cohorts,” Sehn said.

“The inMIND phase 3 study met its primary endpoint of improved progression-free survival with the addition of tafasitamab to lenalidomide and rituximab in patients with R/R follicular lymphoma, representing a 57% reduction in the risk of progression, relapse, or death,” Sehn said.

Commenting on the study, Juan Pablo Alderuccio, MD, an associate professor of medicine, Division of Hematology in the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine in Florida, said the findings are notable in that “this is the first time two monoclonal antibodies have been tested in follicular lymphoma.”

“The study demonstrates that simultaneously targeting CD19 and CD20 improves outcomes,” he said in an interview.

Alderuccio noted the key caveats include that “PET/CT complete response correlates well with survival in follicular lymphoma. In this study, the PET/CT CR rate was 49.4%, underscoring the need for longer follow-ups to better assess those responses’ durability.”

“Another caveat of this regimen is the treatment schedule, which requires weekly tafasitamab infusions during cycles 1-3 and every 2 weeks during cycles 4-12. This is associated with rituximab and lenalidomide administration,” he said.

Ultimately, “the results underscore the potential of tafasitamab in combination with lenalidomide and rituximab to become a new treatment option in the second-line or later follicular lymphoma.”

“However, I would like to see more follow-up data before considering it a new standard of care,” he cautioned.

The study was funded by Incyte. Sehn reported ties with AbbVie, Amgen, AstraZeneca, BeiGene, BMS/Celgene, Genmab, Kite/Gilead, Incyte, Janssen, and Merck. Alderuccio disclosed relationships with Genmab, ADC Therapeutics, BeiGene, AbbVie, Genentech, Novartis, Regeneron, and Lilly.

A version of this article appeared on Medscape.com.

A new diagnostic test can accurately distinguish osteoarthritis (OA) from inflammatory arthritis using two synovial fluid biomarkers, according to research published in the Journal of Orthopaedic Research on December 18, 2024.

However, experts question whether such a test would be useful.

“The need would seem to be fairly limited, mostly those with single joint involvement and a lack of other systemic features to specify a diagnosis, which is not that common, at least in rheumatology, where there are usually features in the history and physical that can clarify the diagnosis,” said Amanda E. Nelson, MD, MSCR, professor of medicine in the Division of Rheumatology, Allergy, and Immunology at the University of North Carolina at Chapel Hill. She was not involved with the research.

The test uses an algorithm that incorporates concentrations of cartilage oligomeric matrix protein (COMP) and interleukin 8 (IL-8) in synovial fluid. The researchers hypothesized that a ratio of the two biomarkers could distinguish between primary OA and other inflammatory arthritic diagnoses.

“Primary OA is unlikely when either COMP concentration or COMP/IL‐8 ratio in the synovial fluid is low since these conditions indicate either lack of cartilage degradation or presence of high inflammation,” wrote Daniel Keter and coauthors at CD Diagnostics, Claymont, Delaware, and CD Laboratories, Towson, Maryland. “In contrast, a high COMP concentration result in combination with high COMP/IL‐8 ratio would be suggestive of low inflammation in the setting of cartilage deterioration, which is indicative of primary OA.”

In patients with OA, synovial fluid can be difficult to aspirate in sufficient amounts for testing, Nelson said.

“If synovial fluid is present and able to be aspirated, it is unclear if this test has any benefit over a simple, standard cell count and crystal assessment, which can also distinguish between osteoarthritis and more inflammatory arthritides,” she said.

 

Differentiating OA

To test this potential diagnostic algorithm, researchers obtained 171 knee synovial fluid samples from approved clinical remnant sample sources and a biovendor. All samples were annotated with an existing arthritic diagnosis, including 54 with primary OA, 57 with rheumatoid arthritis (RA), 30 with crystal arthritis (CA), and 30 with native septic arthritis (NSA).

Researchers assigned a CA diagnosis based on the presence of monosodium urate or calcium pyrophosphate dehydrate crystals in the synovial fluid, and NSA was determined via the Synovasure Alpha Defensin test. OA was confirmed via radiograph as Kellgren‐Lawrence grades 2‐4 with no other arthritic diagnoses. RA samples were purchased via a biovendor, and researchers were not provided with diagnosis‐confirming data.

All samples were randomized and blinded before testing, and researchers used enzyme-linked immunosorbent assay tests for both COMP and IL-8 biomarkers.

Of the 54 OA samples, 47 tested positive for OA using the COMP + COMP/IL-8 ratio algorithm. Of the 117 samples with inflammatory arthritis, 13 tested positive for OA. Overall, the diagnostic algorithm demonstrated a clinical sensitivity of 87.0% and specificity of 88.9%. The positive predictive value was 78.3%, while the negative predictive value was 93.7%.

 

Unclear Clinical Need

Nelson noted that while this test aims to differentiate between arthritic diagnoses, patients can also have multiple conditions.

“Many individuals with rheumatoid arthritis will develop osteoarthritis, but they can have both, so a yes/no test is of unclear utility,” she said. OA and calcium pyrophosphate deposition (CPPD) disease can often occur together, “but the driver is really the OA, and the CPPD is present but not actively inflammatory,” she continued. “Septic arthritis should be readily distinguishable by cell count alone [and again, can coexist with any of the other conditions], and a thorough history and physical should be able to differentiate in most cases.”

While these results from this study are “reasonably impressive,” more clinical information is needed to interpret these results, added C. Kent Kwoh, MD, director of the University of Arizona Arthritis Center and professor of medicine and medical imaging at the University of Arizona College of Medicine, Tucson, Arizona.

Because the study is retrospective in nature and researchers obtained specimens from different sources, it was not clear if these patients were being treated when these samples were taken and if their various conditions were controlled or flaring.

“I would say this is a reasonable first step,” Kwoh said. “We would need prospective studies, more clinical characterization, and potentially longitudinal studies to understand when this test may be useful.”

This research was internally funded by Zimmer Biomet. All authors were employees of CD Diagnostics or CD Laboratories, both of which are subsidiaries of Zimmer Biomet. Kwoh reported receiving grants or contracts with AbbVie, Artiva, Eli Lilly and Company, Bristol Myers Squibb, Cumberland, Pfizer, GSK, and Galapagos, and consulting fees from TrialSpark/Formation Bio, Express Scripts, GSK, TLC BioSciences, and AposHealth. He participates on Data Safety Monitoring or Advisory Boards of Moebius Medical, Sun Pharma, Novartis, Xalud, and Kolon TissueGene. Nelson reported no relevant disclosures.

 

A version of this article appeared on Medscape.com.

A new diagnostic test can accurately distinguish osteoarthritis (OA) from inflammatory arthritis using two synovial fluid biomarkers, according to research published in the Journal of Orthopaedic Research on December 18, 2024.

However, experts question whether such a test would be useful.

“The need would seem to be fairly limited, mostly those with single joint involvement and a lack of other systemic features to specify a diagnosis, which is not that common, at least in rheumatology, where there are usually features in the history and physical that can clarify the diagnosis,” said Amanda E. Nelson, MD, MSCR, professor of medicine in the Division of Rheumatology, Allergy, and Immunology at the University of North Carolina at Chapel Hill. She was not involved with the research.

The test uses an algorithm that incorporates concentrations of cartilage oligomeric matrix protein (COMP) and interleukin 8 (IL-8) in synovial fluid. The researchers hypothesized that a ratio of the two biomarkers could distinguish between primary OA and other inflammatory arthritic diagnoses.

“Primary OA is unlikely when either COMP concentration or COMP/IL‐8 ratio in the synovial fluid is low since these conditions indicate either lack of cartilage degradation or presence of high inflammation,” wrote Daniel Keter and coauthors at CD Diagnostics, Claymont, Delaware, and CD Laboratories, Towson, Maryland. “In contrast, a high COMP concentration result in combination with high COMP/IL‐8 ratio would be suggestive of low inflammation in the setting of cartilage deterioration, which is indicative of primary OA.”

In patients with OA, synovial fluid can be difficult to aspirate in sufficient amounts for testing, Nelson said.

“If synovial fluid is present and able to be aspirated, it is unclear if this test has any benefit over a simple, standard cell count and crystal assessment, which can also distinguish between osteoarthritis and more inflammatory arthritides,” she said.

 

Differentiating OA

To test this potential diagnostic algorithm, researchers obtained 171 knee synovial fluid samples from approved clinical remnant sample sources and a biovendor. All samples were annotated with an existing arthritic diagnosis, including 54 with primary OA, 57 with rheumatoid arthritis (RA), 30 with crystal arthritis (CA), and 30 with native septic arthritis (NSA).

Researchers assigned a CA diagnosis based on the presence of monosodium urate or calcium pyrophosphate dehydrate crystals in the synovial fluid, and NSA was determined via the Synovasure Alpha Defensin test. OA was confirmed via radiograph as Kellgren‐Lawrence grades 2‐4 with no other arthritic diagnoses. RA samples were purchased via a biovendor, and researchers were not provided with diagnosis‐confirming data.

All samples were randomized and blinded before testing, and researchers used enzyme-linked immunosorbent assay tests for both COMP and IL-8 biomarkers.

Of the 54 OA samples, 47 tested positive for OA using the COMP + COMP/IL-8 ratio algorithm. Of the 117 samples with inflammatory arthritis, 13 tested positive for OA. Overall, the diagnostic algorithm demonstrated a clinical sensitivity of 87.0% and specificity of 88.9%. The positive predictive value was 78.3%, while the negative predictive value was 93.7%.

 

Unclear Clinical Need

Nelson noted that while this test aims to differentiate between arthritic diagnoses, patients can also have multiple conditions.

“Many individuals with rheumatoid arthritis will develop osteoarthritis, but they can have both, so a yes/no test is of unclear utility,” she said. OA and calcium pyrophosphate deposition (CPPD) disease can often occur together, “but the driver is really the OA, and the CPPD is present but not actively inflammatory,” she continued. “Septic arthritis should be readily distinguishable by cell count alone [and again, can coexist with any of the other conditions], and a thorough history and physical should be able to differentiate in most cases.”

While these results from this study are “reasonably impressive,” more clinical information is needed to interpret these results, added C. Kent Kwoh, MD, director of the University of Arizona Arthritis Center and professor of medicine and medical imaging at the University of Arizona College of Medicine, Tucson, Arizona.

Because the study is retrospective in nature and researchers obtained specimens from different sources, it was not clear if these patients were being treated when these samples were taken and if their various conditions were controlled or flaring.

“I would say this is a reasonable first step,” Kwoh said. “We would need prospective studies, more clinical characterization, and potentially longitudinal studies to understand when this test may be useful.”

This research was internally funded by Zimmer Biomet. All authors were employees of CD Diagnostics or CD Laboratories, both of which are subsidiaries of Zimmer Biomet. Kwoh reported receiving grants or contracts with AbbVie, Artiva, Eli Lilly and Company, Bristol Myers Squibb, Cumberland, Pfizer, GSK, and Galapagos, and consulting fees from TrialSpark/Formation Bio, Express Scripts, GSK, TLC BioSciences, and AposHealth. He participates on Data Safety Monitoring or Advisory Boards of Moebius Medical, Sun Pharma, Novartis, Xalud, and Kolon TissueGene. Nelson reported no relevant disclosures.

 

A version of this article appeared on Medscape.com.

A new diagnostic test can accurately distinguish osteoarthritis (OA) from inflammatory arthritis using two synovial fluid biomarkers, according to research published in the Journal of Orthopaedic Research on December 18, 2024.

However, experts question whether such a test would be useful.

“The need would seem to be fairly limited, mostly those with single joint involvement and a lack of other systemic features to specify a diagnosis, which is not that common, at least in rheumatology, where there are usually features in the history and physical that can clarify the diagnosis,” said Amanda E. Nelson, MD, MSCR, professor of medicine in the Division of Rheumatology, Allergy, and Immunology at the University of North Carolina at Chapel Hill. She was not involved with the research.

The test uses an algorithm that incorporates concentrations of cartilage oligomeric matrix protein (COMP) and interleukin 8 (IL-8) in synovial fluid. The researchers hypothesized that a ratio of the two biomarkers could distinguish between primary OA and other inflammatory arthritic diagnoses.

“Primary OA is unlikely when either COMP concentration or COMP/IL‐8 ratio in the synovial fluid is low since these conditions indicate either lack of cartilage degradation or presence of high inflammation,” wrote Daniel Keter and coauthors at CD Diagnostics, Claymont, Delaware, and CD Laboratories, Towson, Maryland. “In contrast, a high COMP concentration result in combination with high COMP/IL‐8 ratio would be suggestive of low inflammation in the setting of cartilage deterioration, which is indicative of primary OA.”

In patients with OA, synovial fluid can be difficult to aspirate in sufficient amounts for testing, Nelson said.

“If synovial fluid is present and able to be aspirated, it is unclear if this test has any benefit over a simple, standard cell count and crystal assessment, which can also distinguish between osteoarthritis and more inflammatory arthritides,” she said.

 

Differentiating OA

To test this potential diagnostic algorithm, researchers obtained 171 knee synovial fluid samples from approved clinical remnant sample sources and a biovendor. All samples were annotated with an existing arthritic diagnosis, including 54 with primary OA, 57 with rheumatoid arthritis (RA), 30 with crystal arthritis (CA), and 30 with native septic arthritis (NSA).

Researchers assigned a CA diagnosis based on the presence of monosodium urate or calcium pyrophosphate dehydrate crystals in the synovial fluid, and NSA was determined via the Synovasure Alpha Defensin test. OA was confirmed via radiograph as Kellgren‐Lawrence grades 2‐4 with no other arthritic diagnoses. RA samples were purchased via a biovendor, and researchers were not provided with diagnosis‐confirming data.

All samples were randomized and blinded before testing, and researchers used enzyme-linked immunosorbent assay tests for both COMP and IL-8 biomarkers.

Of the 54 OA samples, 47 tested positive for OA using the COMP + COMP/IL-8 ratio algorithm. Of the 117 samples with inflammatory arthritis, 13 tested positive for OA. Overall, the diagnostic algorithm demonstrated a clinical sensitivity of 87.0% and specificity of 88.9%. The positive predictive value was 78.3%, while the negative predictive value was 93.7%.

 

Unclear Clinical Need

Nelson noted that while this test aims to differentiate between arthritic diagnoses, patients can also have multiple conditions.

“Many individuals with rheumatoid arthritis will develop osteoarthritis, but they can have both, so a yes/no test is of unclear utility,” she said. OA and calcium pyrophosphate deposition (CPPD) disease can often occur together, “but the driver is really the OA, and the CPPD is present but not actively inflammatory,” she continued. “Septic arthritis should be readily distinguishable by cell count alone [and again, can coexist with any of the other conditions], and a thorough history and physical should be able to differentiate in most cases.”

While these results from this study are “reasonably impressive,” more clinical information is needed to interpret these results, added C. Kent Kwoh, MD, director of the University of Arizona Arthritis Center and professor of medicine and medical imaging at the University of Arizona College of Medicine, Tucson, Arizona.

Because the study is retrospective in nature and researchers obtained specimens from different sources, it was not clear if these patients were being treated when these samples were taken and if their various conditions were controlled or flaring.

“I would say this is a reasonable first step,” Kwoh said. “We would need prospective studies, more clinical characterization, and potentially longitudinal studies to understand when this test may be useful.”

This research was internally funded by Zimmer Biomet. All authors were employees of CD Diagnostics or CD Laboratories, both of which are subsidiaries of Zimmer Biomet. Kwoh reported receiving grants or contracts with AbbVie, Artiva, Eli Lilly and Company, Bristol Myers Squibb, Cumberland, Pfizer, GSK, and Galapagos, and consulting fees from TrialSpark/Formation Bio, Express Scripts, GSK, TLC BioSciences, and AposHealth. He participates on Data Safety Monitoring or Advisory Boards of Moebius Medical, Sun Pharma, Novartis, Xalud, and Kolon TissueGene. Nelson reported no relevant disclosures.

 

A version of this article appeared on Medscape.com.

TOPLINE:

Mannkind expects to submit a request for a supplemental new drug application meeting to the Food and Drug Administration (FDA) for its inhaled human insulin (Afrezza Inhalation Powder). Currently indicated to improve glycemic control in adults with diabetes, the company announced 6-month results from its phase 3 INHALE-1 study of inhaled human insulin in children and adolescents aged 4-17.

METHODOLOGY:

• INHALE-1 is a 26-week, open-label clinical trial that randomized 230 subjects aged 4-17 years with type 1 or type 2 diabetes to either inhaled pre-meal insulin or multiple daily injections (MDI) of rapid-acting insulin analog, both in combination with basal insulin.
• The primary endpoint was a noninferior change in hemoglobin A1c levels, compared with MDI after 26 weeks.
• A 26-week extension phase in which all remaining MDI patients were switched to inhaled insulin is ongoing.

TAKEAWAY:

• In the full intent-to-treat (ITT) population analysis, the between-group difference in mean A1c change over 26 weeks exceeded the prespecified non-inferiority margin of 0.4% (0.435%), but this was largely driven by the variability of a single patient who didn’t adhere to the study protocol.
• A modified ITT analysis excluding that person did not exceed the predetermined threshold of 0.4% (0.370%), thereby establishing noninferiority of inhaled insulin with MDI.
• Over 26 weeks of treatment, there were no differences in lung function parameters between the treatment groups, with mean forced expiratory volume at 1 second (FEV1) at baseline vs 26 weeks of 2.901 liters (99.6% of predicted) vs 2.934 L (96.6%) in the inhaled insulin group and 2.948 L (102.3%) vs 2.957 (98%), respectively, in the MDI group.
• There were no differences between groups or concerns in other safety measures, including hypoglycemia.

IN PRACTICE:

“It was exciting to partner with MannKind and help lead this study to potentially expand the use of inhaled insulin, which is currently used successfully by many adults with diabetes, to a population that hasn’t had a treatment option other than injectable insulin in the history of their care,” said INHALE-1 investigator Roy W. Beck, MD, PhD, founder of the Jaeb Center for Health Research, Tampa, Florida.

“The 6-month results are clinically meaningful and show Afrezza as a potential future treatment option for a growing pediatric population living with type 1 and type 2 diabetes,” Beck added.

 

SOURCE:

The results of the study were announced at a Mannkind press release on December 16, 2024.

SAFETY INFORMATION:

Inhaled insulin is not recommended for the treatment of diabetic ketoacidosis or in patients who smoke or have recently stopped smoking.

Warning: Risk for acute bronchospasm in patients with chronic lung disease

• Acute bronchospasm has been observed in Afrezza-treated patients with asthma and chronic obstructive pulmonary disease (COPD)
• Afrezza is contraindicated in patients with chronic lung disease such as asthma or COPD
• Before initiating Afrezza, perform a detailed medical history, physical examination, and spirometry (FEV1) to identify potential lung disease in all patients
• Most common adverse reactions are hypoglycemia, cough, and throat pain or irritation.
•  

DISCLOSURES:

This study was funded by MannKind.

A version of this article appeared on Medscape.com.

TOPLINE:

Mannkind expects to submit a request for a supplemental new drug application meeting to the Food and Drug Administration (FDA) for its inhaled human insulin (Afrezza Inhalation Powder). Currently indicated to improve glycemic control in adults with diabetes, the company announced 6-month results from its phase 3 INHALE-1 study of inhaled human insulin in children and adolescents aged 4-17.

METHODOLOGY:

• INHALE-1 is a 26-week, open-label clinical trial that randomized 230 subjects aged 4-17 years with type 1 or type 2 diabetes to either inhaled pre-meal insulin or multiple daily injections (MDI) of rapid-acting insulin analog, both in combination with basal insulin.
• The primary endpoint was a noninferior change in hemoglobin A1c levels, compared with MDI after 26 weeks.
• A 26-week extension phase in which all remaining MDI patients were switched to inhaled insulin is ongoing.

TAKEAWAY:

• In the full intent-to-treat (ITT) population analysis, the between-group difference in mean A1c change over 26 weeks exceeded the prespecified non-inferiority margin of 0.4% (0.435%), but this was largely driven by the variability of a single patient who didn’t adhere to the study protocol.
• A modified ITT analysis excluding that person did not exceed the predetermined threshold of 0.4% (0.370%), thereby establishing noninferiority of inhaled insulin with MDI.
• Over 26 weeks of treatment, there were no differences in lung function parameters between the treatment groups, with mean forced expiratory volume at 1 second (FEV1) at baseline vs 26 weeks of 2.901 liters (99.6% of predicted) vs 2.934 L (96.6%) in the inhaled insulin group and 2.948 L (102.3%) vs 2.957 (98%), respectively, in the MDI group.
• There were no differences between groups or concerns in other safety measures, including hypoglycemia.

IN PRACTICE:

“It was exciting to partner with MannKind and help lead this study to potentially expand the use of inhaled insulin, which is currently used successfully by many adults with diabetes, to a population that hasn’t had a treatment option other than injectable insulin in the history of their care,” said INHALE-1 investigator Roy W. Beck, MD, PhD, founder of the Jaeb Center for Health Research, Tampa, Florida.

“The 6-month results are clinically meaningful and show Afrezza as a potential future treatment option for a growing pediatric population living with type 1 and type 2 diabetes,” Beck added.

 

SOURCE:

The results of the study were announced at a Mannkind press release on December 16, 2024.

SAFETY INFORMATION:

Inhaled insulin is not recommended for the treatment of diabetic ketoacidosis or in patients who smoke or have recently stopped smoking.

Warning: Risk for acute bronchospasm in patients with chronic lung disease

• Acute bronchospasm has been observed in Afrezza-treated patients with asthma and chronic obstructive pulmonary disease (COPD)
• Afrezza is contraindicated in patients with chronic lung disease such as asthma or COPD
• Before initiating Afrezza, perform a detailed medical history, physical examination, and spirometry (FEV1) to identify potential lung disease in all patients
• Most common adverse reactions are hypoglycemia, cough, and throat pain or irritation.
•  

DISCLOSURES:

This study was funded by MannKind.

A version of this article appeared on Medscape.com.

TOPLINE:

Mannkind expects to submit a request for a supplemental new drug application meeting to the Food and Drug Administration (FDA) for its inhaled human insulin (Afrezza Inhalation Powder). Currently indicated to improve glycemic control in adults with diabetes, the company announced 6-month results from its phase 3 INHALE-1 study of inhaled human insulin in children and adolescents aged 4-17.

METHODOLOGY:

• INHALE-1 is a 26-week, open-label clinical trial that randomized 230 subjects aged 4-17 years with type 1 or type 2 diabetes to either inhaled pre-meal insulin or multiple daily injections (MDI) of rapid-acting insulin analog, both in combination with basal insulin.
• The primary endpoint was a noninferior change in hemoglobin A1c levels, compared with MDI after 26 weeks.
• A 26-week extension phase in which all remaining MDI patients were switched to inhaled insulin is ongoing.

TAKEAWAY:

• In the full intent-to-treat (ITT) population analysis, the between-group difference in mean A1c change over 26 weeks exceeded the prespecified non-inferiority margin of 0.4% (0.435%), but this was largely driven by the variability of a single patient who didn’t adhere to the study protocol.
• A modified ITT analysis excluding that person did not exceed the predetermined threshold of 0.4% (0.370%), thereby establishing noninferiority of inhaled insulin with MDI.
• Over 26 weeks of treatment, there were no differences in lung function parameters between the treatment groups, with mean forced expiratory volume at 1 second (FEV1) at baseline vs 26 weeks of 2.901 liters (99.6% of predicted) vs 2.934 L (96.6%) in the inhaled insulin group and 2.948 L (102.3%) vs 2.957 (98%), respectively, in the MDI group.
• There were no differences between groups or concerns in other safety measures, including hypoglycemia.

IN PRACTICE:

“It was exciting to partner with MannKind and help lead this study to potentially expand the use of inhaled insulin, which is currently used successfully by many adults with diabetes, to a population that hasn’t had a treatment option other than injectable insulin in the history of their care,” said INHALE-1 investigator Roy W. Beck, MD, PhD, founder of the Jaeb Center for Health Research, Tampa, Florida.

“The 6-month results are clinically meaningful and show Afrezza as a potential future treatment option for a growing pediatric population living with type 1 and type 2 diabetes,” Beck added.

 

SOURCE:

The results of the study were announced at a Mannkind press release on December 16, 2024.

SAFETY INFORMATION:

Inhaled insulin is not recommended for the treatment of diabetic ketoacidosis or in patients who smoke or have recently stopped smoking.

Warning: Risk for acute bronchospasm in patients with chronic lung disease

• Acute bronchospasm has been observed in Afrezza-treated patients with asthma and chronic obstructive pulmonary disease (COPD)
• Afrezza is contraindicated in patients with chronic lung disease such as asthma or COPD
• Before initiating Afrezza, perform a detailed medical history, physical examination, and spirometry (FEV1) to identify potential lung disease in all patients
• Most common adverse reactions are hypoglycemia, cough, and throat pain or irritation.
•  

DISCLOSURES:

This study was funded by MannKind.

A version of this article appeared on Medscape.com.

In the latest effort to address the mental health crisis among adolescents, legislation in California would require social media platforms to come with a “black box” mental health warning label.

Despite growing evidence linking young people’s use of social media to significant health risks including depression, anxiety, and suicidal thoughts, social media companies have failed to be transparent about the risks, said Assembly member Rebecca Bauer-Kahan (D-Orinda), who introduced Assembly Bill (AB) 56.

“AB 56 ensures that families are armed with clear, actionable information to understand these dangers and make decisions that prioritizes their children’s well-being,” she said in a press release.

Bauer-Kahan noted that 95% of teens report using at least one social media platform and that more than one third say they use social media almost constantly.

“There is a powerful profit motive to keep our young people hooked online and engaged and it is exploiting the human psychology with notifications, likes, endless scrolling, and algorithmic amplification that is harming our children every day,” she said at a press conference on December 9 announcing the bill.

The warning labels are an equitable and transparent way to communicate the risks that social media poses to young users, California’s Attorney General Rob Bonta, a sponsor of AB 56, said in a press release.

Speaking at the press conference, Bonta said social media has many “incredible benefits” from giving people an outlet of expression to providing access to critical information but “there is no disputing the fact, it can have an enormously detrimental and dangerous impact on our young people. You cannot debate that. Our children are suffering.”

If AB 56 is successful, he said social media platforms would be required to display a “black box warning” for all users that would appear upon the first use of a platform and weekly thereafter.

The proposed language for the warning label is: “The Surgeon General has advised that there are ample indicators that social media can have a profound risk of harm to the mental health and well-being of children and adolescents.”

“This warning label isn’t a panacea, we know that, but it is another tool in our toolbox. It’s one prong in what has to be a multi-pronged continued, coordinated effort to address this public health crisis,” Bonta said.

Reached for comment, Bonta’s office said sponsorship of the bill was informed by their ongoing work to create a safer online space for children and teens and by the US Surgeon General’s call to Congress to add warning labels to social media.

In June, US Surgeon General Vivek Murthy, MD, said a Surgeon General’s warning label is needed to address the mental health emergency among adolescents and noted that evidence from tobacco studies shows warning labels can increase awareness and change behavior. In September, the attorneys general of 42 states announced their support of the proposal.

Also in September, US Senators John Fetterman (D-PA) and Katie Britt (R-AL) introduced the Stop the Scroll Act to create a mental health warning label requirement for social media platforms.

In a controversial move in November, Australia passed the world’s first law banning social media for children younger than 16 years. The law gives platforms such as TikTok, Facebook, X, Snapchat, and Instagram 1 year to figure out how to implement the ban before facing fines of up 50 million Australian dollars ($33 million) for systemic failures to prevent children younger than 16 years from holding accounts.

 

‘A Broken Fire Alarm’

“Slapping a warning label on social media is like a broken fire alarm going off with no evidence of smoke. It ignores the reality that most teens view social media as an important outlet for social connection,” Todd O’Boyle, with the tech industry policy group Chamber of Progress, said in a statement on AB 56.

He highlighted a 2022 Pew Research Center survey reporting that most teens credit social media with deepening connections and providing a support network and a 2020 study reporting that social media is not a strong or consistent risk factor for depressive symptoms in US adolescents.

O’Boyle predicted that, without strong evidence, AB 56 will run into the same “First Amendment buzzsaw” that has doomed other California kids’ bills.

Pediatrician Jason Nagata, MD, University of California San Francisco, points out in Bonta’s press release that social media can displace time for other healthful activities including sleep, exercise, and in-person socialization.

“While social media can provide educational content, it can also provide misinformation about health and expose children to content that damages their mental well-being. These are risks that adolescents and their parents should be aware of,” Nagata said.

Indeed, a tearful Victoria Hinks of Larkspur, California, spoke at the press conference of her 16-year-old daughter, Alexandra, who committed suicide 4 months ago after being sucked into social media and served content on self-harm, eating disorders, suicidal ideation, and glamorization of suicide.

“She was led down dark rabbit holes she had no hope of escaping,” Hinks said. “There is not a bone in my body that doubts social media played a role leading her to that final irreversible decision.”

Jim Steyer, CEO and founder of Common Sense Media, applauded California for being the first state to introduce social media warning label legislation. The group plans to lobby for similar proposals in other states he said at the press conference, noting that there are “tens of thousands of Alexandras out there.”

“We have seat belt laws, we have warning labels on cigarettes and alcohol, and that’s what we’re doing here,” Steyer said. “It’s a straightforward simple proposition, which is put your kids and teenagers first, put their self-interest first and hold the largest, most powerful, and wealthy companies in all of our lifetimes accountable for the harms that have happened on their platforms.”

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

In the latest effort to address the mental health crisis among adolescents, legislation in California would require social media platforms to come with a “black box” mental health warning label.

Despite growing evidence linking young people’s use of social media to significant health risks including depression, anxiety, and suicidal thoughts, social media companies have failed to be transparent about the risks, said Assembly member Rebecca Bauer-Kahan (D-Orinda), who introduced Assembly Bill (AB) 56.

“AB 56 ensures that families are armed with clear, actionable information to understand these dangers and make decisions that prioritizes their children’s well-being,” she said in a press release.

Bauer-Kahan noted that 95% of teens report using at least one social media platform and that more than one third say they use social media almost constantly.

“There is a powerful profit motive to keep our young people hooked online and engaged and it is exploiting the human psychology with notifications, likes, endless scrolling, and algorithmic amplification that is harming our children every day,” she said at a press conference on December 9 announcing the bill.

The warning labels are an equitable and transparent way to communicate the risks that social media poses to young users, California’s Attorney General Rob Bonta, a sponsor of AB 56, said in a press release.

Speaking at the press conference, Bonta said social media has many “incredible benefits” from giving people an outlet of expression to providing access to critical information but “there is no disputing the fact, it can have an enormously detrimental and dangerous impact on our young people. You cannot debate that. Our children are suffering.”

If AB 56 is successful, he said social media platforms would be required to display a “black box warning” for all users that would appear upon the first use of a platform and weekly thereafter.

The proposed language for the warning label is: “The Surgeon General has advised that there are ample indicators that social media can have a profound risk of harm to the mental health and well-being of children and adolescents.”

“This warning label isn’t a panacea, we know that, but it is another tool in our toolbox. It’s one prong in what has to be a multi-pronged continued, coordinated effort to address this public health crisis,” Bonta said.

Reached for comment, Bonta’s office said sponsorship of the bill was informed by their ongoing work to create a safer online space for children and teens and by the US Surgeon General’s call to Congress to add warning labels to social media.

In June, US Surgeon General Vivek Murthy, MD, said a Surgeon General’s warning label is needed to address the mental health emergency among adolescents and noted that evidence from tobacco studies shows warning labels can increase awareness and change behavior. In September, the attorneys general of 42 states announced their support of the proposal.

Also in September, US Senators John Fetterman (D-PA) and Katie Britt (R-AL) introduced the Stop the Scroll Act to create a mental health warning label requirement for social media platforms.

In a controversial move in November, Australia passed the world’s first law banning social media for children younger than 16 years. The law gives platforms such as TikTok, Facebook, X, Snapchat, and Instagram 1 year to figure out how to implement the ban before facing fines of up 50 million Australian dollars ($33 million) for systemic failures to prevent children younger than 16 years from holding accounts.

 

‘A Broken Fire Alarm’

“Slapping a warning label on social media is like a broken fire alarm going off with no evidence of smoke. It ignores the reality that most teens view social media as an important outlet for social connection,” Todd O’Boyle, with the tech industry policy group Chamber of Progress, said in a statement on AB 56.

He highlighted a 2022 Pew Research Center survey reporting that most teens credit social media with deepening connections and providing a support network and a 2020 study reporting that social media is not a strong or consistent risk factor for depressive symptoms in US adolescents.

O’Boyle predicted that, without strong evidence, AB 56 will run into the same “First Amendment buzzsaw” that has doomed other California kids’ bills.

Pediatrician Jason Nagata, MD, University of California San Francisco, points out in Bonta’s press release that social media can displace time for other healthful activities including sleep, exercise, and in-person socialization.

“While social media can provide educational content, it can also provide misinformation about health and expose children to content that damages their mental well-being. These are risks that adolescents and their parents should be aware of,” Nagata said.

Indeed, a tearful Victoria Hinks of Larkspur, California, spoke at the press conference of her 16-year-old daughter, Alexandra, who committed suicide 4 months ago after being sucked into social media and served content on self-harm, eating disorders, suicidal ideation, and glamorization of suicide.

“She was led down dark rabbit holes she had no hope of escaping,” Hinks said. “There is not a bone in my body that doubts social media played a role leading her to that final irreversible decision.”

Jim Steyer, CEO and founder of Common Sense Media, applauded California for being the first state to introduce social media warning label legislation. The group plans to lobby for similar proposals in other states he said at the press conference, noting that there are “tens of thousands of Alexandras out there.”

“We have seat belt laws, we have warning labels on cigarettes and alcohol, and that’s what we’re doing here,” Steyer said. “It’s a straightforward simple proposition, which is put your kids and teenagers first, put their self-interest first and hold the largest, most powerful, and wealthy companies in all of our lifetimes accountable for the harms that have happened on their platforms.”

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

In the latest effort to address the mental health crisis among adolescents, legislation in California would require social media platforms to come with a “black box” mental health warning label.

Despite growing evidence linking young people’s use of social media to significant health risks including depression, anxiety, and suicidal thoughts, social media companies have failed to be transparent about the risks, said Assembly member Rebecca Bauer-Kahan (D-Orinda), who introduced Assembly Bill (AB) 56.

“AB 56 ensures that families are armed with clear, actionable information to understand these dangers and make decisions that prioritizes their children’s well-being,” she said in a press release.

Bauer-Kahan noted that 95% of teens report using at least one social media platform and that more than one third say they use social media almost constantly.

“There is a powerful profit motive to keep our young people hooked online and engaged and it is exploiting the human psychology with notifications, likes, endless scrolling, and algorithmic amplification that is harming our children every day,” she said at a press conference on December 9 announcing the bill.

The warning labels are an equitable and transparent way to communicate the risks that social media poses to young users, California’s Attorney General Rob Bonta, a sponsor of AB 56, said in a press release.

Speaking at the press conference, Bonta said social media has many “incredible benefits” from giving people an outlet of expression to providing access to critical information but “there is no disputing the fact, it can have an enormously detrimental and dangerous impact on our young people. You cannot debate that. Our children are suffering.”

If AB 56 is successful, he said social media platforms would be required to display a “black box warning” for all users that would appear upon the first use of a platform and weekly thereafter.

The proposed language for the warning label is: “The Surgeon General has advised that there are ample indicators that social media can have a profound risk of harm to the mental health and well-being of children and adolescents.”

“This warning label isn’t a panacea, we know that, but it is another tool in our toolbox. It’s one prong in what has to be a multi-pronged continued, coordinated effort to address this public health crisis,” Bonta said.

Reached for comment, Bonta’s office said sponsorship of the bill was informed by their ongoing work to create a safer online space for children and teens and by the US Surgeon General’s call to Congress to add warning labels to social media.

In June, US Surgeon General Vivek Murthy, MD, said a Surgeon General’s warning label is needed to address the mental health emergency among adolescents and noted that evidence from tobacco studies shows warning labels can increase awareness and change behavior. In September, the attorneys general of 42 states announced their support of the proposal.

Also in September, US Senators John Fetterman (D-PA) and Katie Britt (R-AL) introduced the Stop the Scroll Act to create a mental health warning label requirement for social media platforms.

In a controversial move in November, Australia passed the world’s first law banning social media for children younger than 16 years. The law gives platforms such as TikTok, Facebook, X, Snapchat, and Instagram 1 year to figure out how to implement the ban before facing fines of up 50 million Australian dollars ($33 million) for systemic failures to prevent children younger than 16 years from holding accounts.

 

‘A Broken Fire Alarm’

“Slapping a warning label on social media is like a broken fire alarm going off with no evidence of smoke. It ignores the reality that most teens view social media as an important outlet for social connection,” Todd O’Boyle, with the tech industry policy group Chamber of Progress, said in a statement on AB 56.

He highlighted a 2022 Pew Research Center survey reporting that most teens credit social media with deepening connections and providing a support network and a 2020 study reporting that social media is not a strong or consistent risk factor for depressive symptoms in US adolescents.

O’Boyle predicted that, without strong evidence, AB 56 will run into the same “First Amendment buzzsaw” that has doomed other California kids’ bills.

Pediatrician Jason Nagata, MD, University of California San Francisco, points out in Bonta’s press release that social media can displace time for other healthful activities including sleep, exercise, and in-person socialization.

“While social media can provide educational content, it can also provide misinformation about health and expose children to content that damages their mental well-being. These are risks that adolescents and their parents should be aware of,” Nagata said.

Indeed, a tearful Victoria Hinks of Larkspur, California, spoke at the press conference of her 16-year-old daughter, Alexandra, who committed suicide 4 months ago after being sucked into social media and served content on self-harm, eating disorders, suicidal ideation, and glamorization of suicide.

“She was led down dark rabbit holes she had no hope of escaping,” Hinks said. “There is not a bone in my body that doubts social media played a role leading her to that final irreversible decision.”

Jim Steyer, CEO and founder of Common Sense Media, applauded California for being the first state to introduce social media warning label legislation. The group plans to lobby for similar proposals in other states he said at the press conference, noting that there are “tens of thousands of Alexandras out there.”

“We have seat belt laws, we have warning labels on cigarettes and alcohol, and that’s what we’re doing here,” Steyer said. “It’s a straightforward simple proposition, which is put your kids and teenagers first, put their self-interest first and hold the largest, most powerful, and wealthy companies in all of our lifetimes accountable for the harms that have happened on their platforms.”

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

Adults with high cholesterol taking statins may have a significantly higher risk of developing glaucoma than those not taking the cholesterol-lowering drugs, an observational study of a large research database found.

The study, published in Ophthalmology Glaucoma, analyzed electronic health records of 79,742 adults with hyperlipidemia in the All of Us Research Program database from 2017 to 2022. The repository is maintained by the National Institutes of Health and provides data for research into precision medicine.

The 6365 statin users in the study population had a 47% greater unadjusted prevalence of glaucoma than nonusers of the drugs (P < .001) and a 13% greater prevalence in models that adjusted for potential confounding variables (P = .02). The researchers also found statin users had significantly higher levels of low-density lipoprotein cholesterol (LDL-C), but even patients with optimal levels of LDL-C had higher rates of glaucoma.

 

‘A Little Unusual’

Drawing any clinically relevant conclusions from this latest study would be premature, said Victoria Tseng, MD, PhD, an assistant professor at UCLA Stein Eye Institute and Doheny Eye Centers UCLA, and the senior author of the study. “I certainly would not be telling my patients on statins to stop their statins.”

Tseng acknowledged her group’s finding runs counter to previous studies that found statins may help prevent glaucoma or at least have no effect on the eye disease, although the association between cholesterol and glaucoma has been well established.

A 2019 analysis of nearly 137,000 participants in three population studies found no connection between statin use and the risk for primary open-angle glaucoma. A 2012 study of more than 500,000 people with high cholesterol found statin use was associated with a significant reduction in the risk for open-angle glaucoma.

“It’s a little unusual that we found the opposite,” Tseng said in an interview.

One explanation is the observational nature of the AoU analysis Tseng’s group conducted. “We don’t know what these people look like or how well the data were collected, so we’re going off of what’s there in the database,” she said.

Another explanation could be the nature of hyperlipidemia itself, she said. “There have definitely been studies that suggest increased cholesterol levels are associated with an increased risk of glaucoma. Presumably, you’re not going to be taking a statin unless your cholesterol is a little worse.”

While the study analysis attempted to control for cholesterol levels, Tseng noted, “there could be some residual confounding from that.”

Statin users in the study had an average LDL-C level of 144.9 mg/dL vs 136.3 mg/dL in the population not taking any cholesterol medication (P < .001). Statin users with optimal LDL-C, defined as less than 100 mg/dL, had a 39% greater adjusted prevalence of glaucoma (P = .02), while those with high LDL-C (160-189 mg/dL) had a 37% greater adjusted prevalence (P = .005).

Age was another factor in the risk for glaucoma, the study found. Statin users aged 60-69 years had an adjusted rate of glaucoma 28% greater than that for nonusers (P = .05).

Laboratory studies may help clarify the relationships between statins and glaucoma, Tseng said. That could include putting statins directly on the optic nerve of laboratory mice and further investigating how statins affect the mechanisms that influence eye pressure, a key driver of glaucoma. From a population study perspective, a randomized trial of glaucoma patients comparing the effect of statins and other cholesterol-lowering medications with nonuse may provide answers.

 

Database Strengths and Limitations

The study “adds to the somewhat mixed literature on the potential association between statins and glaucoma,” Sophia Wang, MD, MS, a glaucoma specialist at Stanford Byers Eye Institute in Palo Alto, California, said in an interview.

The AoU research cohort is a “notable strength” of the new paper, added Wang, who has used the AoU database to study the relationship between blood pressure, blood pressure medications, and glaucoma.

“The population is especially large and diverse, with a large proportion of participants from backgrounds that are traditionally underrepresented in research,” she said. And The inclusion of both medical records and survey data means the health information on the cohort is detailed and longitudinal.

“The authors make excellent use here of the data by including in their analyses results of laboratory investigations — LDL-C, notably — which wouldn’t be readily available in other types of datasets such as claims datasets,” she said.

However, the database has limitations as well, including its reliance on coding, which is prone to errors, to determine glaucoma diagnosis and missing information on eye examinations. In addition, the study used one LDL-C measurement rather than multiple measurements, Wang pointed out, “and we know that LDL-C can vary over time.”

The study was funded by Research to Prevent Blindness. Tseng and Wang reported no relevant financial relationships to disclose.

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

Adults with high cholesterol taking statins may have a significantly higher risk of developing glaucoma than those not taking the cholesterol-lowering drugs, an observational study of a large research database found.

The study, published in Ophthalmology Glaucoma, analyzed electronic health records of 79,742 adults with hyperlipidemia in the All of Us Research Program database from 2017 to 2022. The repository is maintained by the National Institutes of Health and provides data for research into precision medicine.

The 6365 statin users in the study population had a 47% greater unadjusted prevalence of glaucoma than nonusers of the drugs (P < .001) and a 13% greater prevalence in models that adjusted for potential confounding variables (P = .02). The researchers also found statin users had significantly higher levels of low-density lipoprotein cholesterol (LDL-C), but even patients with optimal levels of LDL-C had higher rates of glaucoma.

 

‘A Little Unusual’

Drawing any clinically relevant conclusions from this latest study would be premature, said Victoria Tseng, MD, PhD, an assistant professor at UCLA Stein Eye Institute and Doheny Eye Centers UCLA, and the senior author of the study. “I certainly would not be telling my patients on statins to stop their statins.”

Tseng acknowledged her group’s finding runs counter to previous studies that found statins may help prevent glaucoma or at least have no effect on the eye disease, although the association between cholesterol and glaucoma has been well established.

A 2019 analysis of nearly 137,000 participants in three population studies found no connection between statin use and the risk for primary open-angle glaucoma. A 2012 study of more than 500,000 people with high cholesterol found statin use was associated with a significant reduction in the risk for open-angle glaucoma.

“It’s a little unusual that we found the opposite,” Tseng said in an interview.

One explanation is the observational nature of the AoU analysis Tseng’s group conducted. “We don’t know what these people look like or how well the data were collected, so we’re going off of what’s there in the database,” she said.

Another explanation could be the nature of hyperlipidemia itself, she said. “There have definitely been studies that suggest increased cholesterol levels are associated with an increased risk of glaucoma. Presumably, you’re not going to be taking a statin unless your cholesterol is a little worse.”

While the study analysis attempted to control for cholesterol levels, Tseng noted, “there could be some residual confounding from that.”

Statin users in the study had an average LDL-C level of 144.9 mg/dL vs 136.3 mg/dL in the population not taking any cholesterol medication (P < .001). Statin users with optimal LDL-C, defined as less than 100 mg/dL, had a 39% greater adjusted prevalence of glaucoma (P = .02), while those with high LDL-C (160-189 mg/dL) had a 37% greater adjusted prevalence (P = .005).

Age was another factor in the risk for glaucoma, the study found. Statin users aged 60-69 years had an adjusted rate of glaucoma 28% greater than that for nonusers (P = .05).

Laboratory studies may help clarify the relationships between statins and glaucoma, Tseng said. That could include putting statins directly on the optic nerve of laboratory mice and further investigating how statins affect the mechanisms that influence eye pressure, a key driver of glaucoma. From a population study perspective, a randomized trial of glaucoma patients comparing the effect of statins and other cholesterol-lowering medications with nonuse may provide answers.

 

Database Strengths and Limitations

The study “adds to the somewhat mixed literature on the potential association between statins and glaucoma,” Sophia Wang, MD, MS, a glaucoma specialist at Stanford Byers Eye Institute in Palo Alto, California, said in an interview.

The AoU research cohort is a “notable strength” of the new paper, added Wang, who has used the AoU database to study the relationship between blood pressure, blood pressure medications, and glaucoma.

“The population is especially large and diverse, with a large proportion of participants from backgrounds that are traditionally underrepresented in research,” she said. And The inclusion of both medical records and survey data means the health information on the cohort is detailed and longitudinal.

“The authors make excellent use here of the data by including in their analyses results of laboratory investigations — LDL-C, notably — which wouldn’t be readily available in other types of datasets such as claims datasets,” she said.

However, the database has limitations as well, including its reliance on coding, which is prone to errors, to determine glaucoma diagnosis and missing information on eye examinations. In addition, the study used one LDL-C measurement rather than multiple measurements, Wang pointed out, “and we know that LDL-C can vary over time.”

The study was funded by Research to Prevent Blindness. Tseng and Wang reported no relevant financial relationships to disclose.

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

Adults with high cholesterol taking statins may have a significantly higher risk of developing glaucoma than those not taking the cholesterol-lowering drugs, an observational study of a large research database found.

The study, published in Ophthalmology Glaucoma, analyzed electronic health records of 79,742 adults with hyperlipidemia in the All of Us Research Program database from 2017 to 2022. The repository is maintained by the National Institutes of Health and provides data for research into precision medicine.

The 6365 statin users in the study population had a 47% greater unadjusted prevalence of glaucoma than nonusers of the drugs (P < .001) and a 13% greater prevalence in models that adjusted for potential confounding variables (P = .02). The researchers also found statin users had significantly higher levels of low-density lipoprotein cholesterol (LDL-C), but even patients with optimal levels of LDL-C had higher rates of glaucoma.

 

‘A Little Unusual’

Drawing any clinically relevant conclusions from this latest study would be premature, said Victoria Tseng, MD, PhD, an assistant professor at UCLA Stein Eye Institute and Doheny Eye Centers UCLA, and the senior author of the study. “I certainly would not be telling my patients on statins to stop their statins.”

Tseng acknowledged her group’s finding runs counter to previous studies that found statins may help prevent glaucoma or at least have no effect on the eye disease, although the association between cholesterol and glaucoma has been well established.

A 2019 analysis of nearly 137,000 participants in three population studies found no connection between statin use and the risk for primary open-angle glaucoma. A 2012 study of more than 500,000 people with high cholesterol found statin use was associated with a significant reduction in the risk for open-angle glaucoma.

“It’s a little unusual that we found the opposite,” Tseng said in an interview.

One explanation is the observational nature of the AoU analysis Tseng’s group conducted. “We don’t know what these people look like or how well the data were collected, so we’re going off of what’s there in the database,” she said.

Another explanation could be the nature of hyperlipidemia itself, she said. “There have definitely been studies that suggest increased cholesterol levels are associated with an increased risk of glaucoma. Presumably, you’re not going to be taking a statin unless your cholesterol is a little worse.”

While the study analysis attempted to control for cholesterol levels, Tseng noted, “there could be some residual confounding from that.”

Statin users in the study had an average LDL-C level of 144.9 mg/dL vs 136.3 mg/dL in the population not taking any cholesterol medication (P < .001). Statin users with optimal LDL-C, defined as less than 100 mg/dL, had a 39% greater adjusted prevalence of glaucoma (P = .02), while those with high LDL-C (160-189 mg/dL) had a 37% greater adjusted prevalence (P = .005).

Age was another factor in the risk for glaucoma, the study found. Statin users aged 60-69 years had an adjusted rate of glaucoma 28% greater than that for nonusers (P = .05).

Laboratory studies may help clarify the relationships between statins and glaucoma, Tseng said. That could include putting statins directly on the optic nerve of laboratory mice and further investigating how statins affect the mechanisms that influence eye pressure, a key driver of glaucoma. From a population study perspective, a randomized trial of glaucoma patients comparing the effect of statins and other cholesterol-lowering medications with nonuse may provide answers.

 

Database Strengths and Limitations

The study “adds to the somewhat mixed literature on the potential association between statins and glaucoma,” Sophia Wang, MD, MS, a glaucoma specialist at Stanford Byers Eye Institute in Palo Alto, California, said in an interview.

The AoU research cohort is a “notable strength” of the new paper, added Wang, who has used the AoU database to study the relationship between blood pressure, blood pressure medications, and glaucoma.

“The population is especially large and diverse, with a large proportion of participants from backgrounds that are traditionally underrepresented in research,” she said. And The inclusion of both medical records and survey data means the health information on the cohort is detailed and longitudinal.

“The authors make excellent use here of the data by including in their analyses results of laboratory investigations — LDL-C, notably — which wouldn’t be readily available in other types of datasets such as claims datasets,” she said.

However, the database has limitations as well, including its reliance on coding, which is prone to errors, to determine glaucoma diagnosis and missing information on eye examinations. In addition, the study used one LDL-C measurement rather than multiple measurements, Wang pointed out, “and we know that LDL-C can vary over time.”

The study was funded by Research to Prevent Blindness. Tseng and Wang reported no relevant financial relationships to disclose.

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