MDedge Rheumatology

This interview is a translation of a video blog that first appeared on Medscape France. It has been edited for clarity.

Which diet should we recommend to patients with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis? Weight loss, omega-3 supplements, the Mediterranean diet? What about exclusion diets? Jérémie Sellam, MD, PhD, from Saint-Antoine Hospital in Paris, summarizes the key points of the first set of dietary recommendations of the French Society for Rheumatology.

Transcript

Jérémie Sellam, MD, PhD: Hello, everyone. I’m Professor Jérémie Sellam. I’m a rheumatologist at Saint-Antoine Hospital, which is affiliated with the Sorbonne University in Paris. And I was fortunate enough to coordinate France’s first set of dietary recommendations – in fact, the world’s first set of dietary recommendations – for patients with chronic inflammatory rheumatic diseases. I worked on this project with Claire Daien, MD, PhD, who’s a rheumatologist at Montpellier University Hospital.

The idea of coming up with dietary recommendations for patients with inflammatory rheumatic diseases came, quite simply, from our clinical practice. We see that when patients learn they have polyarthritis or spondyloarthritis, they start to experiment with different diets. Many patients start exclusion diets and experiment in all sorts of ways with the food they eat. And although rheumatologists have been able to find some information here and there in the literature, they’ve been pretty much on their own when trying to come up with advice to give their patients. It was to address this issue that [Dr.] Daien and I set out to form a working group. Because when patients aren’t able to get sound advice and authoritative guidance from their doctors, medical associations, or patient advocacy organizations, they often look for information online, and that information is not always reliable or validated.

This group was made up of rheumatologists, some who work at hospitals and others in private practice. Also involved were physician nutrition specialists and registered dietitians. Operating under the auspices of the French Society for Rheumatology, these multidisciplinary experts conducted out a systematic literature review for the purpose of establishing and drafting recommendations. The result was a declaration of eight general principles and nine recommendations.
 

General principles

The first of the general principles states that nutritional advice is not a substitute for the pharmacologic treatment of chronic inflammatory rheumatic diseases. As you know, whether it’s methotrexate or biologics, pharmacologic treatments are essential for the proper management of chronic inflammatory rheumatic diseases. We know that these medications have an anti-inflammatory effect, reduce pain, and – particularly in the case of rheumatoid arthritis – have a structural effect. In other words, they prevent joint deterioration and destruction. Now, I can tell you that there’s currently no diet, and no dietary supplement, that has proven to be structurally effective. So, yes, dietary intervention might turn out to be promising for patients with chronic inflammatory rheumatic diseases, but pharmacologic treatment must still be part of the picture.

Another general principle emphasizes that dietary intervention is a way for patients to be actively involved in the overall care of their disease, beyond just taking their medication. We know that patients, when they suffer from chronic diseases, are looking for something more, beyond just taking medications. Encouraging them to take an interest in their diet, asking them about what they eat, giving them advice, and supporting their desire to become involved in this aspect of their treatment plan can give them a sense of empowerment.

Dietary interventions can have articular effects, and I’m going to speak about which interventions you can propose, but also which can be beneficial in terms of cardiovascular health and bone health. All of this is based on the literature. In these recommendations, we’ve taken into account not only laboratory experiments – where this or that diet is given to a mouse with arthritis – but also reviewed randomized controlled trials that compare an intervention group with a control group. This is the benchmark we used to determine whether or not a diet should be recommended.
 

The recommendations

As for the recommendations themselves, we wanted to start off by emphasizing weight loss and what can be called weight-loss support. There’s a link between obesity and the risk of developing rheumatoid arthritis, and also psoriatic arthropathy. And the more overweight a patient is, the more active their disease. In other words, patients with obesity are going to experience more pain, more instances of wakefulness, and more morning stiffness than their normal-weight peers. They’re also going to show symptoms that suggest that disease activity is not controlled well.

Several randomized controlled studies have shown that weight loss will improve systemic joint symptoms. In one particular study, patients with psoriatic arthropathy were started on [tumor necrosis factor] inhibitor therapy and one group followed a prescribed diet and the other had no restrictions on eating. More patients in the diet group than in the no-diet group achieved minimal disease activity. Of course, in some cases – for example, patients with complicated morbid obesity – it might be necessary to have a discussion about bariatric surgery.

But practically speaking, how does one proceed? First of all, patients should be weighed at each visit and, if they’re overweight or obese, the subject should be broached. But even after that conversation, the reality remains that it’s not easy to lose weight. So in the recommendations, we focused on the fact that it shouldn’t be left to the rheumatologist or treating physician alone to handle this challenging aspect of treatment. They should incorporate dietary and nutritional care by reaching out to a dietician or, in the case of complicated obesity – especially when the BMI is higher than 35 kg/m² – they can refer patients to a nutrition expert who can manage the patient’s obesity, come up with a weight-loss plan, and handle any complications that might arise.

We don’t speak about a low-calorie diet in the recommendations because a diet has a beginning and an end and, quite often, patients regain weight after stopping a diet. Instead, we speak about weight-loss support to point out that weight loss maintained through dietary changes brings about long-term control of disease activity.

In addition, we make two positive recommendations, which overlap, that can help patients control their disease: a Mediterranean diet and omega-3 supplements. One study showed that after participants with rheumatoid arthritis followed the Mediterranean diet for 1 year, those who also took omega-3 fish oil supplements were twice as likely to achieve remission (40% vs. 20%). This explains the interest in having omega-3 as part of the diet. Other studies have shown a broad benefit of the Mediterranean diet.

We know this diet: Fish, especially fatty fish; meat, but not every day, and white meat is best; and fruits and vegetables. In addition, exercise and stay hydrated. All of this can help patients who want to use diet as a means to control their disease. And, as I said earlier, studies have shown that omega-3 supplements have beneficial effects. These are essential polyunsaturated fatty acids, which can help control the disease and joint symptoms.

We also provide some exclusionary recommendations. Not all studies are done well, but it’s clear that there are no major benefits – in fact, no benefit at all – from vegan diets, gluten-free diets, or dairy-free diets. And with these diets, patients run the risk of developing deficiencies, so it’s important that patients are aware of this. We also have to keep in mind that exclusion diets can increase social isolation. Patients need to take part in meals; such gatherings are times for sharing and having social interactions. And I would say that they must be told that there are no data in the literature in support of these diets. But if they ever insist on this kind of intervention, I think that it’s better to advise them to do it under the supervision of a dietician and nutritionist, especially to prevent the development of deficiencies. We’re talking about deficiencies in things like calcium, vitamin B¹², and selenium.
 

Conclusion

As you can see, we have positive recommendations when the patient wants to do something beyond pharmacologic treatment: the Mediterranean diet and omega-3 supplements. And we have negative recommendations, marked by a warning about the risk of developing deficiencies. But I think we all understand the importance of paying close attention to how our patients are experimenting with food. Their diets and eating habits can give us ideas for research and reviews that could allow us to deepen our understanding of the effect of diet on disease, because currently, the quality of the data on some of the diets and types of dietary interventions out there is rather tenuous.

Thank you for listening. I’d also like to thank Claire Daien, MD, PhD, for conducting this project with me so that we could come up with all of these recommendations. I’m also grateful to the following nutrition societies and associations who were our partners: the French Society of Nutrition, the French-Speaking Society of Clinical Nutrition and Metabolism, the French Association for the Study of Obesity, and the French Association of Dieticians and Nutritionists. And patient associations, too, must be recognized, as some of their members participated: the French National Association Against Rheumatoid Arthritis, the French Spondyloarthritis Association, and the French Association for Polyarthritis and Chronic Inflammatory Rheumatic Diseases.

This interview is a translation of a video blog that first appeared on Medscape France. It has been edited for clarity.

Which diet should we recommend to patients with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis? Weight loss, omega-3 supplements, the Mediterranean diet? What about exclusion diets? Jérémie Sellam, MD, PhD, from Saint-Antoine Hospital in Paris, summarizes the key points of the first set of dietary recommendations of the French Society for Rheumatology.

Transcript

Jérémie Sellam, MD, PhD: Hello, everyone. I’m Professor Jérémie Sellam. I’m a rheumatologist at Saint-Antoine Hospital, which is affiliated with the Sorbonne University in Paris. And I was fortunate enough to coordinate France’s first set of dietary recommendations – in fact, the world’s first set of dietary recommendations – for patients with chronic inflammatory rheumatic diseases. I worked on this project with Claire Daien, MD, PhD, who’s a rheumatologist at Montpellier University Hospital.

The idea of coming up with dietary recommendations for patients with inflammatory rheumatic diseases came, quite simply, from our clinical practice. We see that when patients learn they have polyarthritis or spondyloarthritis, they start to experiment with different diets. Many patients start exclusion diets and experiment in all sorts of ways with the food they eat. And although rheumatologists have been able to find some information here and there in the literature, they’ve been pretty much on their own when trying to come up with advice to give their patients. It was to address this issue that [Dr.] Daien and I set out to form a working group. Because when patients aren’t able to get sound advice and authoritative guidance from their doctors, medical associations, or patient advocacy organizations, they often look for information online, and that information is not always reliable or validated.

This group was made up of rheumatologists, some who work at hospitals and others in private practice. Also involved were physician nutrition specialists and registered dietitians. Operating under the auspices of the French Society for Rheumatology, these multidisciplinary experts conducted out a systematic literature review for the purpose of establishing and drafting recommendations. The result was a declaration of eight general principles and nine recommendations.
 

General principles

The first of the general principles states that nutritional advice is not a substitute for the pharmacologic treatment of chronic inflammatory rheumatic diseases. As you know, whether it’s methotrexate or biologics, pharmacologic treatments are essential for the proper management of chronic inflammatory rheumatic diseases. We know that these medications have an anti-inflammatory effect, reduce pain, and – particularly in the case of rheumatoid arthritis – have a structural effect. In other words, they prevent joint deterioration and destruction. Now, I can tell you that there’s currently no diet, and no dietary supplement, that has proven to be structurally effective. So, yes, dietary intervention might turn out to be promising for patients with chronic inflammatory rheumatic diseases, but pharmacologic treatment must still be part of the picture.

Another general principle emphasizes that dietary intervention is a way for patients to be actively involved in the overall care of their disease, beyond just taking their medication. We know that patients, when they suffer from chronic diseases, are looking for something more, beyond just taking medications. Encouraging them to take an interest in their diet, asking them about what they eat, giving them advice, and supporting their desire to become involved in this aspect of their treatment plan can give them a sense of empowerment.

Dietary interventions can have articular effects, and I’m going to speak about which interventions you can propose, but also which can be beneficial in terms of cardiovascular health and bone health. All of this is based on the literature. In these recommendations, we’ve taken into account not only laboratory experiments – where this or that diet is given to a mouse with arthritis – but also reviewed randomized controlled trials that compare an intervention group with a control group. This is the benchmark we used to determine whether or not a diet should be recommended.
 

The recommendations

As for the recommendations themselves, we wanted to start off by emphasizing weight loss and what can be called weight-loss support. There’s a link between obesity and the risk of developing rheumatoid arthritis, and also psoriatic arthropathy. And the more overweight a patient is, the more active their disease. In other words, patients with obesity are going to experience more pain, more instances of wakefulness, and more morning stiffness than their normal-weight peers. They’re also going to show symptoms that suggest that disease activity is not controlled well.

Several randomized controlled studies have shown that weight loss will improve systemic joint symptoms. In one particular study, patients with psoriatic arthropathy were started on [tumor necrosis factor] inhibitor therapy and one group followed a prescribed diet and the other had no restrictions on eating. More patients in the diet group than in the no-diet group achieved minimal disease activity. Of course, in some cases – for example, patients with complicated morbid obesity – it might be necessary to have a discussion about bariatric surgery.

But practically speaking, how does one proceed? First of all, patients should be weighed at each visit and, if they’re overweight or obese, the subject should be broached. But even after that conversation, the reality remains that it’s not easy to lose weight. So in the recommendations, we focused on the fact that it shouldn’t be left to the rheumatologist or treating physician alone to handle this challenging aspect of treatment. They should incorporate dietary and nutritional care by reaching out to a dietician or, in the case of complicated obesity – especially when the BMI is higher than 35 kg/m² – they can refer patients to a nutrition expert who can manage the patient’s obesity, come up with a weight-loss plan, and handle any complications that might arise.

We don’t speak about a low-calorie diet in the recommendations because a diet has a beginning and an end and, quite often, patients regain weight after stopping a diet. Instead, we speak about weight-loss support to point out that weight loss maintained through dietary changes brings about long-term control of disease activity.

In addition, we make two positive recommendations, which overlap, that can help patients control their disease: a Mediterranean diet and omega-3 supplements. One study showed that after participants with rheumatoid arthritis followed the Mediterranean diet for 1 year, those who also took omega-3 fish oil supplements were twice as likely to achieve remission (40% vs. 20%). This explains the interest in having omega-3 as part of the diet. Other studies have shown a broad benefit of the Mediterranean diet.

We know this diet: Fish, especially fatty fish; meat, but not every day, and white meat is best; and fruits and vegetables. In addition, exercise and stay hydrated. All of this can help patients who want to use diet as a means to control their disease. And, as I said earlier, studies have shown that omega-3 supplements have beneficial effects. These are essential polyunsaturated fatty acids, which can help control the disease and joint symptoms.

We also provide some exclusionary recommendations. Not all studies are done well, but it’s clear that there are no major benefits – in fact, no benefit at all – from vegan diets, gluten-free diets, or dairy-free diets. And with these diets, patients run the risk of developing deficiencies, so it’s important that patients are aware of this. We also have to keep in mind that exclusion diets can increase social isolation. Patients need to take part in meals; such gatherings are times for sharing and having social interactions. And I would say that they must be told that there are no data in the literature in support of these diets. But if they ever insist on this kind of intervention, I think that it’s better to advise them to do it under the supervision of a dietician and nutritionist, especially to prevent the development of deficiencies. We’re talking about deficiencies in things like calcium, vitamin B¹², and selenium.
 

Conclusion

As you can see, we have positive recommendations when the patient wants to do something beyond pharmacologic treatment: the Mediterranean diet and omega-3 supplements. And we have negative recommendations, marked by a warning about the risk of developing deficiencies. But I think we all understand the importance of paying close attention to how our patients are experimenting with food. Their diets and eating habits can give us ideas for research and reviews that could allow us to deepen our understanding of the effect of diet on disease, because currently, the quality of the data on some of the diets and types of dietary interventions out there is rather tenuous.

Thank you for listening. I’d also like to thank Claire Daien, MD, PhD, for conducting this project with me so that we could come up with all of these recommendations. I’m also grateful to the following nutrition societies and associations who were our partners: the French Society of Nutrition, the French-Speaking Society of Clinical Nutrition and Metabolism, the French Association for the Study of Obesity, and the French Association of Dieticians and Nutritionists. And patient associations, too, must be recognized, as some of their members participated: the French National Association Against Rheumatoid Arthritis, the French Spondyloarthritis Association, and the French Association for Polyarthritis and Chronic Inflammatory Rheumatic Diseases.

This interview is a translation of a video blog that first appeared on Medscape France. It has been edited for clarity.

Which diet should we recommend to patients with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis? Weight loss, omega-3 supplements, the Mediterranean diet? What about exclusion diets? Jérémie Sellam, MD, PhD, from Saint-Antoine Hospital in Paris, summarizes the key points of the first set of dietary recommendations of the French Society for Rheumatology.

Transcript

Jérémie Sellam, MD, PhD: Hello, everyone. I’m Professor Jérémie Sellam. I’m a rheumatologist at Saint-Antoine Hospital, which is affiliated with the Sorbonne University in Paris. And I was fortunate enough to coordinate France’s first set of dietary recommendations – in fact, the world’s first set of dietary recommendations – for patients with chronic inflammatory rheumatic diseases. I worked on this project with Claire Daien, MD, PhD, who’s a rheumatologist at Montpellier University Hospital.

The idea of coming up with dietary recommendations for patients with inflammatory rheumatic diseases came, quite simply, from our clinical practice. We see that when patients learn they have polyarthritis or spondyloarthritis, they start to experiment with different diets. Many patients start exclusion diets and experiment in all sorts of ways with the food they eat. And although rheumatologists have been able to find some information here and there in the literature, they’ve been pretty much on their own when trying to come up with advice to give their patients. It was to address this issue that [Dr.] Daien and I set out to form a working group. Because when patients aren’t able to get sound advice and authoritative guidance from their doctors, medical associations, or patient advocacy organizations, they often look for information online, and that information is not always reliable or validated.

This group was made up of rheumatologists, some who work at hospitals and others in private practice. Also involved were physician nutrition specialists and registered dietitians. Operating under the auspices of the French Society for Rheumatology, these multidisciplinary experts conducted out a systematic literature review for the purpose of establishing and drafting recommendations. The result was a declaration of eight general principles and nine recommendations.
 

General principles

The first of the general principles states that nutritional advice is not a substitute for the pharmacologic treatment of chronic inflammatory rheumatic diseases. As you know, whether it’s methotrexate or biologics, pharmacologic treatments are essential for the proper management of chronic inflammatory rheumatic diseases. We know that these medications have an anti-inflammatory effect, reduce pain, and – particularly in the case of rheumatoid arthritis – have a structural effect. In other words, they prevent joint deterioration and destruction. Now, I can tell you that there’s currently no diet, and no dietary supplement, that has proven to be structurally effective. So, yes, dietary intervention might turn out to be promising for patients with chronic inflammatory rheumatic diseases, but pharmacologic treatment must still be part of the picture.

Another general principle emphasizes that dietary intervention is a way for patients to be actively involved in the overall care of their disease, beyond just taking their medication. We know that patients, when they suffer from chronic diseases, are looking for something more, beyond just taking medications. Encouraging them to take an interest in their diet, asking them about what they eat, giving them advice, and supporting their desire to become involved in this aspect of their treatment plan can give them a sense of empowerment.

Dietary interventions can have articular effects, and I’m going to speak about which interventions you can propose, but also which can be beneficial in terms of cardiovascular health and bone health. All of this is based on the literature. In these recommendations, we’ve taken into account not only laboratory experiments – where this or that diet is given to a mouse with arthritis – but also reviewed randomized controlled trials that compare an intervention group with a control group. This is the benchmark we used to determine whether or not a diet should be recommended.
 

The recommendations

As for the recommendations themselves, we wanted to start off by emphasizing weight loss and what can be called weight-loss support. There’s a link between obesity and the risk of developing rheumatoid arthritis, and also psoriatic arthropathy. And the more overweight a patient is, the more active their disease. In other words, patients with obesity are going to experience more pain, more instances of wakefulness, and more morning stiffness than their normal-weight peers. They’re also going to show symptoms that suggest that disease activity is not controlled well.

Several randomized controlled studies have shown that weight loss will improve systemic joint symptoms. In one particular study, patients with psoriatic arthropathy were started on [tumor necrosis factor] inhibitor therapy and one group followed a prescribed diet and the other had no restrictions on eating. More patients in the diet group than in the no-diet group achieved minimal disease activity. Of course, in some cases – for example, patients with complicated morbid obesity – it might be necessary to have a discussion about bariatric surgery.

But practically speaking, how does one proceed? First of all, patients should be weighed at each visit and, if they’re overweight or obese, the subject should be broached. But even after that conversation, the reality remains that it’s not easy to lose weight. So in the recommendations, we focused on the fact that it shouldn’t be left to the rheumatologist or treating physician alone to handle this challenging aspect of treatment. They should incorporate dietary and nutritional care by reaching out to a dietician or, in the case of complicated obesity – especially when the BMI is higher than 35 kg/m² – they can refer patients to a nutrition expert who can manage the patient’s obesity, come up with a weight-loss plan, and handle any complications that might arise.

We don’t speak about a low-calorie diet in the recommendations because a diet has a beginning and an end and, quite often, patients regain weight after stopping a diet. Instead, we speak about weight-loss support to point out that weight loss maintained through dietary changes brings about long-term control of disease activity.

In addition, we make two positive recommendations, which overlap, that can help patients control their disease: a Mediterranean diet and omega-3 supplements. One study showed that after participants with rheumatoid arthritis followed the Mediterranean diet for 1 year, those who also took omega-3 fish oil supplements were twice as likely to achieve remission (40% vs. 20%). This explains the interest in having omega-3 as part of the diet. Other studies have shown a broad benefit of the Mediterranean diet.

We know this diet: Fish, especially fatty fish; meat, but not every day, and white meat is best; and fruits and vegetables. In addition, exercise and stay hydrated. All of this can help patients who want to use diet as a means to control their disease. And, as I said earlier, studies have shown that omega-3 supplements have beneficial effects. These are essential polyunsaturated fatty acids, which can help control the disease and joint symptoms.

We also provide some exclusionary recommendations. Not all studies are done well, but it’s clear that there are no major benefits – in fact, no benefit at all – from vegan diets, gluten-free diets, or dairy-free diets. And with these diets, patients run the risk of developing deficiencies, so it’s important that patients are aware of this. We also have to keep in mind that exclusion diets can increase social isolation. Patients need to take part in meals; such gatherings are times for sharing and having social interactions. And I would say that they must be told that there are no data in the literature in support of these diets. But if they ever insist on this kind of intervention, I think that it’s better to advise them to do it under the supervision of a dietician and nutritionist, especially to prevent the development of deficiencies. We’re talking about deficiencies in things like calcium, vitamin B¹², and selenium.
 

Conclusion

As you can see, we have positive recommendations when the patient wants to do something beyond pharmacologic treatment: the Mediterranean diet and omega-3 supplements. And we have negative recommendations, marked by a warning about the risk of developing deficiencies. But I think we all understand the importance of paying close attention to how our patients are experimenting with food. Their diets and eating habits can give us ideas for research and reviews that could allow us to deepen our understanding of the effect of diet on disease, because currently, the quality of the data on some of the diets and types of dietary interventions out there is rather tenuous.

Thank you for listening. I’d also like to thank Claire Daien, MD, PhD, for conducting this project with me so that we could come up with all of these recommendations. I’m also grateful to the following nutrition societies and associations who were our partners: the French Society of Nutrition, the French-Speaking Society of Clinical Nutrition and Metabolism, the French Association for the Study of Obesity, and the French Association of Dieticians and Nutritionists. And patient associations, too, must be recognized, as some of their members participated: the French National Association Against Rheumatoid Arthritis, the French Spondyloarthritis Association, and the French Association for Polyarthritis and Chronic Inflammatory Rheumatic Diseases.

People with long-COVID “brain fog” may be able to recover mental abilities that were dulled or stolen from them by the virus through an approach that has improved the effects of stroke, traumatic brain injury, and other post-viral disorders, doctors and scientists say.

For a lucky portion of the population, COVID-19 lasts a handful of days with minor symptoms. But for an estimated 37% who contract the virus, symptoms can linger for weeks, months, or even years. One of the most common symptoms of long COVID is brain fog: a life-altering condition characterized by slow thinking, confusion, difficulty remembering things, and poor concentration.

A type of rehabilitation program that allows the brain to rewire itself has been successful in improving the lives of people with brain fog. The approaches are based on the concept of neuroplasticity: The ability of neural networks in the brain to change, adapt, and strengthen, much like a muscle in the body that has been trained and exercised.

“The brain’s ability to bounce back from injury is what neuroplasticity is, and I’ve worked with people in our rehab clinic who have had brain tumors or suffer the effects of surgery or radiation on the brain, and people who have had West Nile virus, HIV, and meningitis,” said Tom Bergquist, PhD, clinical neuropsychologist at Mayo Clinic in Rochester, Minn. “There’s not a week that goes by that I don’t see someone recovering from COVID-19.”

One of the approaches used in the clinic is errorless learning, or having a patient with memory problems repeat information a certain number of times without error. The repetition helps rebuild those memory skills that were weakened during infection, Dr. Bergquist says.

People who have experienced brain fog after other viral infections have seen improvements with these approaches. Ben Ahrens, co-founder and CEO of re-origin – a company that offers neuroplasticity therapy – says he had long-term cognitive issues after a Lyme disease infection. Posttreatment Lyme disease syndrome, or chronic Lyme disease, occurs in about 1 in 10 people who are infected.

Mr. Ahrens says he was struck with Lyme 10 years ago and had brain fog, joint pain, and brain lesions detectable on scans for several years after infection.

According to Mr. Ahrens, neuroplasticity-based therapies help combat what researchers have found may be a lingering memory of past infections that lead to a heightened immune response, causing lingering symptoms.

“Essentially, what we believe is happening here, is the brain has learned that these symptoms are life-threatening – because, in fact, they can be,” Mr. Ahrens said. “The brain’s one job is to protect the body, and once it’s learned to associate these symptoms with that potentially very dangerous pathogen, even after it’s gone, things like a normal headache can trigger an immune cascade.”

Studies are underway at the University of Alabama at Birmingham to examine whether constraint-induced therapy – an approach rooted in neuroplasticity and historically used for loss of limb and speech function – is also effective for cognitive impairments like brain fog.

One technique they use is called shaping, which requires a person to repeatedly carry out their personal best function of impaired use – for example, remembering household tasks they have previously forgotten. That is done multiple times over several weeks in the clinic, and patients are given ways to transfer those skills to real-life use.

So far, the results are promising, said Edward Taub, PhD, researcher and professor of psychology at the University of Alabama at Birmingham.

When used in the past for physical impairments, researchers have noted not just clinical improvements, but structural changes. It led to an increase in the brain’s gray matter – which allows individuals to control movement, memory, and emotions – and improved white matter, which helps communication between gray matter areas.

Though results of the cognitive studies have not been published, Dr. Taub said patients with brain fog have shown improvement after just 35 hours of therapy and are nearly 100% improved after 6 months.

“The idea behind this is that the brain is responsive to use,” Dr. Taub said. “The amount of brain territory that’s dedicated to supporting or mediating a given behavioral function depends on the demands placed on the brain.”

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

People with long-COVID “brain fog” may be able to recover mental abilities that were dulled or stolen from them by the virus through an approach that has improved the effects of stroke, traumatic brain injury, and other post-viral disorders, doctors and scientists say.

For a lucky portion of the population, COVID-19 lasts a handful of days with minor symptoms. But for an estimated 37% who contract the virus, symptoms can linger for weeks, months, or even years. One of the most common symptoms of long COVID is brain fog: a life-altering condition characterized by slow thinking, confusion, difficulty remembering things, and poor concentration.

A type of rehabilitation program that allows the brain to rewire itself has been successful in improving the lives of people with brain fog. The approaches are based on the concept of neuroplasticity: The ability of neural networks in the brain to change, adapt, and strengthen, much like a muscle in the body that has been trained and exercised.

“The brain’s ability to bounce back from injury is what neuroplasticity is, and I’ve worked with people in our rehab clinic who have had brain tumors or suffer the effects of surgery or radiation on the brain, and people who have had West Nile virus, HIV, and meningitis,” said Tom Bergquist, PhD, clinical neuropsychologist at Mayo Clinic in Rochester, Minn. “There’s not a week that goes by that I don’t see someone recovering from COVID-19.”

One of the approaches used in the clinic is errorless learning, or having a patient with memory problems repeat information a certain number of times without error. The repetition helps rebuild those memory skills that were weakened during infection, Dr. Bergquist says.

People who have experienced brain fog after other viral infections have seen improvements with these approaches. Ben Ahrens, co-founder and CEO of re-origin – a company that offers neuroplasticity therapy – says he had long-term cognitive issues after a Lyme disease infection. Posttreatment Lyme disease syndrome, or chronic Lyme disease, occurs in about 1 in 10 people who are infected.

Mr. Ahrens says he was struck with Lyme 10 years ago and had brain fog, joint pain, and brain lesions detectable on scans for several years after infection.

According to Mr. Ahrens, neuroplasticity-based therapies help combat what researchers have found may be a lingering memory of past infections that lead to a heightened immune response, causing lingering symptoms.

“Essentially, what we believe is happening here, is the brain has learned that these symptoms are life-threatening – because, in fact, they can be,” Mr. Ahrens said. “The brain’s one job is to protect the body, and once it’s learned to associate these symptoms with that potentially very dangerous pathogen, even after it’s gone, things like a normal headache can trigger an immune cascade.”

Studies are underway at the University of Alabama at Birmingham to examine whether constraint-induced therapy – an approach rooted in neuroplasticity and historically used for loss of limb and speech function – is also effective for cognitive impairments like brain fog.

One technique they use is called shaping, which requires a person to repeatedly carry out their personal best function of impaired use – for example, remembering household tasks they have previously forgotten. That is done multiple times over several weeks in the clinic, and patients are given ways to transfer those skills to real-life use.

So far, the results are promising, said Edward Taub, PhD, researcher and professor of psychology at the University of Alabama at Birmingham.

When used in the past for physical impairments, researchers have noted not just clinical improvements, but structural changes. It led to an increase in the brain’s gray matter – which allows individuals to control movement, memory, and emotions – and improved white matter, which helps communication between gray matter areas.

Though results of the cognitive studies have not been published, Dr. Taub said patients with brain fog have shown improvement after just 35 hours of therapy and are nearly 100% improved after 6 months.

“The idea behind this is that the brain is responsive to use,” Dr. Taub said. “The amount of brain territory that’s dedicated to supporting or mediating a given behavioral function depends on the demands placed on the brain.”

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

People with long-COVID “brain fog” may be able to recover mental abilities that were dulled or stolen from them by the virus through an approach that has improved the effects of stroke, traumatic brain injury, and other post-viral disorders, doctors and scientists say.

For a lucky portion of the population, COVID-19 lasts a handful of days with minor symptoms. But for an estimated 37% who contract the virus, symptoms can linger for weeks, months, or even years. One of the most common symptoms of long COVID is brain fog: a life-altering condition characterized by slow thinking, confusion, difficulty remembering things, and poor concentration.

A type of rehabilitation program that allows the brain to rewire itself has been successful in improving the lives of people with brain fog. The approaches are based on the concept of neuroplasticity: The ability of neural networks in the brain to change, adapt, and strengthen, much like a muscle in the body that has been trained and exercised.

“The brain’s ability to bounce back from injury is what neuroplasticity is, and I’ve worked with people in our rehab clinic who have had brain tumors or suffer the effects of surgery or radiation on the brain, and people who have had West Nile virus, HIV, and meningitis,” said Tom Bergquist, PhD, clinical neuropsychologist at Mayo Clinic in Rochester, Minn. “There’s not a week that goes by that I don’t see someone recovering from COVID-19.”

One of the approaches used in the clinic is errorless learning, or having a patient with memory problems repeat information a certain number of times without error. The repetition helps rebuild those memory skills that were weakened during infection, Dr. Bergquist says.

People who have experienced brain fog after other viral infections have seen improvements with these approaches. Ben Ahrens, co-founder and CEO of re-origin – a company that offers neuroplasticity therapy – says he had long-term cognitive issues after a Lyme disease infection. Posttreatment Lyme disease syndrome, or chronic Lyme disease, occurs in about 1 in 10 people who are infected.

Mr. Ahrens says he was struck with Lyme 10 years ago and had brain fog, joint pain, and brain lesions detectable on scans for several years after infection.

According to Mr. Ahrens, neuroplasticity-based therapies help combat what researchers have found may be a lingering memory of past infections that lead to a heightened immune response, causing lingering symptoms.

“Essentially, what we believe is happening here, is the brain has learned that these symptoms are life-threatening – because, in fact, they can be,” Mr. Ahrens said. “The brain’s one job is to protect the body, and once it’s learned to associate these symptoms with that potentially very dangerous pathogen, even after it’s gone, things like a normal headache can trigger an immune cascade.”

Studies are underway at the University of Alabama at Birmingham to examine whether constraint-induced therapy – an approach rooted in neuroplasticity and historically used for loss of limb and speech function – is also effective for cognitive impairments like brain fog.

One technique they use is called shaping, which requires a person to repeatedly carry out their personal best function of impaired use – for example, remembering household tasks they have previously forgotten. That is done multiple times over several weeks in the clinic, and patients are given ways to transfer those skills to real-life use.

So far, the results are promising, said Edward Taub, PhD, researcher and professor of psychology at the University of Alabama at Birmingham.

When used in the past for physical impairments, researchers have noted not just clinical improvements, but structural changes. It led to an increase in the brain’s gray matter – which allows individuals to control movement, memory, and emotions – and improved white matter, which helps communication between gray matter areas.

Though results of the cognitive studies have not been published, Dr. Taub said patients with brain fog have shown improvement after just 35 hours of therapy and are nearly 100% improved after 6 months.

“The idea behind this is that the brain is responsive to use,” Dr. Taub said. “The amount of brain territory that’s dedicated to supporting or mediating a given behavioral function depends on the demands placed on the brain.”

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

Guselkumab (Tremfya) received Food and Drug Administration approval for the treatment of psoriatic arthritis (PsA) almost 2 years ago on the basis of a phase 3 trial, but a new substudy from that trial has now demonstrated long-term benefit in the subgroup of patients who entered the trial with axial involvement, according to data presented at the annual meeting of the Canadian Rheumatology Association.

“The symptom relief was clinically meaningful and durable through week 100,” reported Dafna D. Gladman, MD, professor of medicine and director of the psoriatic arthritis program at the University of Toronto.

In the previously published double-blind, placebo-controlled DISCOVER-2 trial, two dosing regimens of the interleukin-23 (IL-23) inhibitor guselkumab were compared with placebo in biologic-naive patients. The active regimens were similarly effective relative to placebo for the primary endpoint of 20% improvement in American College of Rheumatology response criteria (ACR20) at week 24.

In this new long-term subgroup analysis, outcomes at 2 years were evaluated in the 246 patients with axial involvement (33.3% of the total number of 739 evaluable patients). Baseline characteristics across treatment groups in this subset of the DISCOVER-2 trial were similar.
 

Guselkumab exhibits nearly twofold advantage

At 24 weeks relative to baseline, the improvement on multiple axial involvement outcome measures was approximately twofold greater with active therapy than with placebo. For example, the mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score fell 2.6 points in both active treatment arms versus 1.4 on placebo.

The same relative advantage was observed when the BASDAI spinal pain subscore was isolated. There were also comparable responses on a modified BASDAI that excluded the peripheral pain response, and the Ankylosing Spondylitis Disease Activity Score (ASDAS).

When evaluated at week 52 and again at week 100, all outcomes employed to evaluate change in axial involvement were sustained. Many were further improved. In patients who initiated therapy on placebo, all of whom were switched to guselkumab at the end of the 24-week double-blind period, at least the same degree of axial symptom control relative to baseline was achieved at both time periods.

Incremental improvement observed over time

“For most measures there was further improvement at 2 years, and there was generally consistent response across patient groups stratified by HLA [human leucocyte antigen] status,” Dr. Gladman reported.

Relative to the 2.6-point reduction in the BASDAI score in the two guselkumab arms at week 24, the reductions reached 3.0, 3.1, and 3.3 at 100 weeks in the every-4-week guselkumab group, every-8-week guselkumab group, and the crossed-over placebo group, respectively. For ASDAS, the reductions at week 24 were 1.4, 1.5, and 0.7 points and reached 1.6, 1.7, and 1.6 points at 100 weeks in the every-4-week, every-8-week, and placebo crossover groups, respectively.

The sustained improvement is consistent with a previous post hoc analysis in which data from the phase 3 DISCOVER-1 trial were pooled with those from DISCOVER-2. This analysis focused on the 312 patients in these studies with axial disease documented by imaging. Again, the study showed improvement at week 24 was sustained at week 52 independent of HLA-B27 status.
 

Need for MRI confirmation seen

The potential problem with this new analysis as well as the previous analysis is the absence of MRI to provide objective evidence of axial involvement, according to Walter P. Maksymowych, MD, professor in the division of rheumatology at the University of Alberta, Edmonton.

Noting that previous studies have indicated that axial involvement assessed by investigators is not reliable even when performed with x-rays, Dr. Maksymowych said these data would be much more reassuring with MRI controls.

“We have seen little correlation between clinical symptoms and MRI manifestations of disease,” he said.

Dr. Gladman conceded this point. Baseline MRI was performed in some of the patients in this subgroup analysis, but it was not mandated. As a result, the data support benefit from guselkumab for symptomatic axial involvement, but she indicated that better evidence of a disease-modifying effect is expected from a more rigorous placebo-controlled trial of guselkumab called STAR.

This trial is requiring MRI at baseline and at week 24 and is using the Spondyloarthritis Research Consortium of Canada (SPARCC) score to assess change. Dr. Gladman said the trial is enrolling “as we speak.”

Overall, Dr. Gladman agreed with Dr. Maksymowych that objective biomarkers are important for demonstrating that treatments are improving long-term outcomes, not just relieving symptoms.

Guselkumab manufacturer Janssen supported the post hoc analysis. Dr. Gladman reported financial relationships with AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead Janssen, Novartis, Pfizer, and UCB. Dr. Maksymowych reported financial relationships with AbbVie, Boehringer Ingelheim, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, and UCB.

Guselkumab (Tremfya) received Food and Drug Administration approval for the treatment of psoriatic arthritis (PsA) almost 2 years ago on the basis of a phase 3 trial, but a new substudy from that trial has now demonstrated long-term benefit in the subgroup of patients who entered the trial with axial involvement, according to data presented at the annual meeting of the Canadian Rheumatology Association.

“The symptom relief was clinically meaningful and durable through week 100,” reported Dafna D. Gladman, MD, professor of medicine and director of the psoriatic arthritis program at the University of Toronto.

In the previously published double-blind, placebo-controlled DISCOVER-2 trial, two dosing regimens of the interleukin-23 (IL-23) inhibitor guselkumab were compared with placebo in biologic-naive patients. The active regimens were similarly effective relative to placebo for the primary endpoint of 20% improvement in American College of Rheumatology response criteria (ACR20) at week 24.

In this new long-term subgroup analysis, outcomes at 2 years were evaluated in the 246 patients with axial involvement (33.3% of the total number of 739 evaluable patients). Baseline characteristics across treatment groups in this subset of the DISCOVER-2 trial were similar.
 

Guselkumab exhibits nearly twofold advantage

At 24 weeks relative to baseline, the improvement on multiple axial involvement outcome measures was approximately twofold greater with active therapy than with placebo. For example, the mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score fell 2.6 points in both active treatment arms versus 1.4 on placebo.

The same relative advantage was observed when the BASDAI spinal pain subscore was isolated. There were also comparable responses on a modified BASDAI that excluded the peripheral pain response, and the Ankylosing Spondylitis Disease Activity Score (ASDAS).

When evaluated at week 52 and again at week 100, all outcomes employed to evaluate change in axial involvement were sustained. Many were further improved. In patients who initiated therapy on placebo, all of whom were switched to guselkumab at the end of the 24-week double-blind period, at least the same degree of axial symptom control relative to baseline was achieved at both time periods.

Incremental improvement observed over time

“For most measures there was further improvement at 2 years, and there was generally consistent response across patient groups stratified by HLA [human leucocyte antigen] status,” Dr. Gladman reported.

Relative to the 2.6-point reduction in the BASDAI score in the two guselkumab arms at week 24, the reductions reached 3.0, 3.1, and 3.3 at 100 weeks in the every-4-week guselkumab group, every-8-week guselkumab group, and the crossed-over placebo group, respectively. For ASDAS, the reductions at week 24 were 1.4, 1.5, and 0.7 points and reached 1.6, 1.7, and 1.6 points at 100 weeks in the every-4-week, every-8-week, and placebo crossover groups, respectively.

The sustained improvement is consistent with a previous post hoc analysis in which data from the phase 3 DISCOVER-1 trial were pooled with those from DISCOVER-2. This analysis focused on the 312 patients in these studies with axial disease documented by imaging. Again, the study showed improvement at week 24 was sustained at week 52 independent of HLA-B27 status.
 

Need for MRI confirmation seen

The potential problem with this new analysis as well as the previous analysis is the absence of MRI to provide objective evidence of axial involvement, according to Walter P. Maksymowych, MD, professor in the division of rheumatology at the University of Alberta, Edmonton.

Noting that previous studies have indicated that axial involvement assessed by investigators is not reliable even when performed with x-rays, Dr. Maksymowych said these data would be much more reassuring with MRI controls.

“We have seen little correlation between clinical symptoms and MRI manifestations of disease,” he said.

Dr. Gladman conceded this point. Baseline MRI was performed in some of the patients in this subgroup analysis, but it was not mandated. As a result, the data support benefit from guselkumab for symptomatic axial involvement, but she indicated that better evidence of a disease-modifying effect is expected from a more rigorous placebo-controlled trial of guselkumab called STAR.

This trial is requiring MRI at baseline and at week 24 and is using the Spondyloarthritis Research Consortium of Canada (SPARCC) score to assess change. Dr. Gladman said the trial is enrolling “as we speak.”

Overall, Dr. Gladman agreed with Dr. Maksymowych that objective biomarkers are important for demonstrating that treatments are improving long-term outcomes, not just relieving symptoms.

Guselkumab manufacturer Janssen supported the post hoc analysis. Dr. Gladman reported financial relationships with AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead Janssen, Novartis, Pfizer, and UCB. Dr. Maksymowych reported financial relationships with AbbVie, Boehringer Ingelheim, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, and UCB.

Guselkumab (Tremfya) received Food and Drug Administration approval for the treatment of psoriatic arthritis (PsA) almost 2 years ago on the basis of a phase 3 trial, but a new substudy from that trial has now demonstrated long-term benefit in the subgroup of patients who entered the trial with axial involvement, according to data presented at the annual meeting of the Canadian Rheumatology Association.

“The symptom relief was clinically meaningful and durable through week 100,” reported Dafna D. Gladman, MD, professor of medicine and director of the psoriatic arthritis program at the University of Toronto.

In the previously published double-blind, placebo-controlled DISCOVER-2 trial, two dosing regimens of the interleukin-23 (IL-23) inhibitor guselkumab were compared with placebo in biologic-naive patients. The active regimens were similarly effective relative to placebo for the primary endpoint of 20% improvement in American College of Rheumatology response criteria (ACR20) at week 24.

In this new long-term subgroup analysis, outcomes at 2 years were evaluated in the 246 patients with axial involvement (33.3% of the total number of 739 evaluable patients). Baseline characteristics across treatment groups in this subset of the DISCOVER-2 trial were similar.
 

Guselkumab exhibits nearly twofold advantage

At 24 weeks relative to baseline, the improvement on multiple axial involvement outcome measures was approximately twofold greater with active therapy than with placebo. For example, the mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score fell 2.6 points in both active treatment arms versus 1.4 on placebo.

The same relative advantage was observed when the BASDAI spinal pain subscore was isolated. There were also comparable responses on a modified BASDAI that excluded the peripheral pain response, and the Ankylosing Spondylitis Disease Activity Score (ASDAS).

When evaluated at week 52 and again at week 100, all outcomes employed to evaluate change in axial involvement were sustained. Many were further improved. In patients who initiated therapy on placebo, all of whom were switched to guselkumab at the end of the 24-week double-blind period, at least the same degree of axial symptom control relative to baseline was achieved at both time periods.

Incremental improvement observed over time

“For most measures there was further improvement at 2 years, and there was generally consistent response across patient groups stratified by HLA [human leucocyte antigen] status,” Dr. Gladman reported.

Relative to the 2.6-point reduction in the BASDAI score in the two guselkumab arms at week 24, the reductions reached 3.0, 3.1, and 3.3 at 100 weeks in the every-4-week guselkumab group, every-8-week guselkumab group, and the crossed-over placebo group, respectively. For ASDAS, the reductions at week 24 were 1.4, 1.5, and 0.7 points and reached 1.6, 1.7, and 1.6 points at 100 weeks in the every-4-week, every-8-week, and placebo crossover groups, respectively.

The sustained improvement is consistent with a previous post hoc analysis in which data from the phase 3 DISCOVER-1 trial were pooled with those from DISCOVER-2. This analysis focused on the 312 patients in these studies with axial disease documented by imaging. Again, the study showed improvement at week 24 was sustained at week 52 independent of HLA-B27 status.
 

Need for MRI confirmation seen

The potential problem with this new analysis as well as the previous analysis is the absence of MRI to provide objective evidence of axial involvement, according to Walter P. Maksymowych, MD, professor in the division of rheumatology at the University of Alberta, Edmonton.

Noting that previous studies have indicated that axial involvement assessed by investigators is not reliable even when performed with x-rays, Dr. Maksymowych said these data would be much more reassuring with MRI controls.

“We have seen little correlation between clinical symptoms and MRI manifestations of disease,” he said.

Dr. Gladman conceded this point. Baseline MRI was performed in some of the patients in this subgroup analysis, but it was not mandated. As a result, the data support benefit from guselkumab for symptomatic axial involvement, but she indicated that better evidence of a disease-modifying effect is expected from a more rigorous placebo-controlled trial of guselkumab called STAR.

This trial is requiring MRI at baseline and at week 24 and is using the Spondyloarthritis Research Consortium of Canada (SPARCC) score to assess change. Dr. Gladman said the trial is enrolling “as we speak.”

Overall, Dr. Gladman agreed with Dr. Maksymowych that objective biomarkers are important for demonstrating that treatments are improving long-term outcomes, not just relieving symptoms.

Guselkumab manufacturer Janssen supported the post hoc analysis. Dr. Gladman reported financial relationships with AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead Janssen, Novartis, Pfizer, and UCB. Dr. Maksymowych reported financial relationships with AbbVie, Boehringer Ingelheim, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, and UCB.

Goffin’s cockatoo? More like golfin’ cockatoo

Can birds play golf? Of course not; it’s ridiculous. Humans can barely play golf, and we invented the sport. Anyway, moving on to “Brian retraction injury after elective aneurysm clipping.”

Hang on, we’re now hearing that a group of researchers, as part of a large international project comparing children’s innovation and problem-solving skills with those of cockatoos, have in fact taught a group of Goffin’s cockatoos how to play golf. Huh. What an oddly specific project. All right, fine, I guess we’ll go with the golf-playing birds.

Goffin Lab

Golf may seem very simple at its core. It is, essentially, whacking a ball with a stick. But the Scots who invented the game were undertaking a complex project involving combined usage of multiple tools, and until now, only primates were thought to be capable of utilizing compound tools to play games such as golf.

For this latest research, published in Scientific Reports, our intrepid birds were given a rudimentary form of golf to play (featuring a stick, a ball, and a closed box to get the ball through). Putting the ball through the hole gave the bird a reward. Not every cockatoo was able to hole out, but three did, with each inventing a unique way to manipulate the stick to hit the ball.

As entertaining as it would be to simply teach some birds how to play golf, we do loop back around to medical relevance. While children are perfectly capable of using tools, young children in particular are actually quite bad at using tools to solve novel solutions. Present a 5-year-old with a stick, a ball, and a hole, and that child might not figure out what the cockatoos did. The research really does give insight into the psychology behind the development of complex tools and technology by our ancient ancestors, according to the researchers.

We’re not entirely convinced this isn’t an elaborate ploy to get a bird out onto the PGA Tour. The LOTME staff can see the future headline already: “Painted bunting wins Valspar Championship in epic playoff.”
 

Work out now, sweat never

Okay, show of hands: Who’s familiar with “Name that tune?” The TV game show got a reboot last year, but some of us are old enough to remember the 1970s version hosted by national treasure Tom Kennedy.

Edith Cowan University

The contestants try to identify a song as quickly as possible, claiming that they “can name that tune in five notes.” Or four notes, or three. Well, welcome to “Name that exercise study.”

Senior author Masatoshi Nakamura, PhD, and associates gathered together 39 students from Niigata (Japan) University of Health and Welfare and had them perform one isometric, concentric, or eccentric bicep curl with a dumbbell for 3 seconds a day at maximum effort for 5 days a week, over 4 weeks. And yes, we did say 3 seconds.

“Lifting the weight sees the bicep in concentric contraction, lowering the weight sees it in eccentric contraction, while holding the weight parallel to the ground is isometric,” they explained in a statement on Eurekalert.

The three exercise groups were compared with a group that did no exercise, and after 4 weeks of rigorous but brief science, the group doing eccentric contractions had the best results, as their overall muscle strength increased by 11.5%. After a total of just 60 seconds of exercise in 4 weeks. That’s 60 seconds. In 4 weeks.

Big news, but maybe we can do better. “Tom, we can do that exercise in 2 seconds.”

And one! And two! Whoa, feel the burn.
 

Tingling over anxiety

Apparently there are two kinds of people in this world. Those who love ASMR and those who just don’t get it.

ASMR, for those who don’t know, is the autonomous sensory meridian response. An online community has surfaced, with video creators making tapping sounds, whispering, or brushing mannequin hair to elicit “a pleasant tingling sensation originating from the scalp and neck which can spread to the rest of the body” from viewers, Charlotte M. Eid and associates said in PLOS One.

The people who are into these types of videos are more likely to have higher levels of neuroticism than those who aren’t, which gives ASMR the potential to be a nontraditional form of treatment for anxiety and/or neuroticism, they suggested.

The research involved a group of 64 volunteers who watched an ASMR video meant to trigger the tingles and then completed questionnaires to evaluate their levels of neuroticism, trait anxiety, and state anxiety, said Ms. Eid and associates of Northumbria University in Newcastle-upon-Tyne, England.

The people who had a history of producing tingles from ASMR videos in the past had higher levels of anxiety, compared with those who didn’t. Those who responded to triggers also received some benefit from the video in the study, reporting lower levels of neuroticism and anxiety after watching, the investigators found.

Although people who didn’t have a history of tingles didn’t feel any reduction in anxiety after the video, that didn’t stop the people who weren’t familiar with the genre from catching tingles.

So if you find yourself a little high strung or anxious, or if you can’t sleep, consider watching a person pretending to give you a makeover or using fingernails to tap on books for some relaxation. Don’t knock it until you try it!
 

Living in the past? Not so far-fetched

It’s usually an insult when people tell us to stop living in the past, but the joke’s on them because we really do live in the past. By 15 seconds, to be exact, according to researchers from the University of California, Berkeley.

Mauro Manassi

But wait, did you just read that last sentence 15 seconds ago, even though it feels like real time? Did we just type these words now, or 15 seconds ago?

Think of your brain as a web page you’re constantly refreshing. We are constantly seeing new pictures, images, and colors, and your brain is responsible for keeping everything in chronological order. This new research suggests that our brains show us images from 15 seconds prior. Is your mind blown yet?

“One could say our brain is procrastinating. It’s too much work to constantly update images, so it sticks to the past because the past is a good predictor of the present. We recycle information from the past because it’s faster, more efficient and less work,” senior author David Whitney explained in a statement from the university.

It seems like the 15-second rule helps us not lose our minds by keeping a steady flow of information, but it could be a bit dangerous if someone, such as a surgeon, needs to see things with extreme precision.

And now we are definitely feeling a bit anxious about our upcoming heart/spleen/gallbladder replacement. … Where’s that link to the ASMR video?

Goffin’s cockatoo? More like golfin’ cockatoo

Can birds play golf? Of course not; it’s ridiculous. Humans can barely play golf, and we invented the sport. Anyway, moving on to “Brian retraction injury after elective aneurysm clipping.”

Hang on, we’re now hearing that a group of researchers, as part of a large international project comparing children’s innovation and problem-solving skills with those of cockatoos, have in fact taught a group of Goffin’s cockatoos how to play golf. Huh. What an oddly specific project. All right, fine, I guess we’ll go with the golf-playing birds.

Goffin Lab

Golf may seem very simple at its core. It is, essentially, whacking a ball with a stick. But the Scots who invented the game were undertaking a complex project involving combined usage of multiple tools, and until now, only primates were thought to be capable of utilizing compound tools to play games such as golf.

For this latest research, published in Scientific Reports, our intrepid birds were given a rudimentary form of golf to play (featuring a stick, a ball, and a closed box to get the ball through). Putting the ball through the hole gave the bird a reward. Not every cockatoo was able to hole out, but three did, with each inventing a unique way to manipulate the stick to hit the ball.

As entertaining as it would be to simply teach some birds how to play golf, we do loop back around to medical relevance. While children are perfectly capable of using tools, young children in particular are actually quite bad at using tools to solve novel solutions. Present a 5-year-old with a stick, a ball, and a hole, and that child might not figure out what the cockatoos did. The research really does give insight into the psychology behind the development of complex tools and technology by our ancient ancestors, according to the researchers.

We’re not entirely convinced this isn’t an elaborate ploy to get a bird out onto the PGA Tour. The LOTME staff can see the future headline already: “Painted bunting wins Valspar Championship in epic playoff.”
 

Work out now, sweat never

Okay, show of hands: Who’s familiar with “Name that tune?” The TV game show got a reboot last year, but some of us are old enough to remember the 1970s version hosted by national treasure Tom Kennedy.

Edith Cowan University

The contestants try to identify a song as quickly as possible, claiming that they “can name that tune in five notes.” Or four notes, or three. Well, welcome to “Name that exercise study.”

Senior author Masatoshi Nakamura, PhD, and associates gathered together 39 students from Niigata (Japan) University of Health and Welfare and had them perform one isometric, concentric, or eccentric bicep curl with a dumbbell for 3 seconds a day at maximum effort for 5 days a week, over 4 weeks. And yes, we did say 3 seconds.

“Lifting the weight sees the bicep in concentric contraction, lowering the weight sees it in eccentric contraction, while holding the weight parallel to the ground is isometric,” they explained in a statement on Eurekalert.

The three exercise groups were compared with a group that did no exercise, and after 4 weeks of rigorous but brief science, the group doing eccentric contractions had the best results, as their overall muscle strength increased by 11.5%. After a total of just 60 seconds of exercise in 4 weeks. That’s 60 seconds. In 4 weeks.

Big news, but maybe we can do better. “Tom, we can do that exercise in 2 seconds.”

And one! And two! Whoa, feel the burn.
 

Tingling over anxiety

Apparently there are two kinds of people in this world. Those who love ASMR and those who just don’t get it.

ASMR, for those who don’t know, is the autonomous sensory meridian response. An online community has surfaced, with video creators making tapping sounds, whispering, or brushing mannequin hair to elicit “a pleasant tingling sensation originating from the scalp and neck which can spread to the rest of the body” from viewers, Charlotte M. Eid and associates said in PLOS One.

The people who are into these types of videos are more likely to have higher levels of neuroticism than those who aren’t, which gives ASMR the potential to be a nontraditional form of treatment for anxiety and/or neuroticism, they suggested.

The research involved a group of 64 volunteers who watched an ASMR video meant to trigger the tingles and then completed questionnaires to evaluate their levels of neuroticism, trait anxiety, and state anxiety, said Ms. Eid and associates of Northumbria University in Newcastle-upon-Tyne, England.

The people who had a history of producing tingles from ASMR videos in the past had higher levels of anxiety, compared with those who didn’t. Those who responded to triggers also received some benefit from the video in the study, reporting lower levels of neuroticism and anxiety after watching, the investigators found.

Although people who didn’t have a history of tingles didn’t feel any reduction in anxiety after the video, that didn’t stop the people who weren’t familiar with the genre from catching tingles.

So if you find yourself a little high strung or anxious, or if you can’t sleep, consider watching a person pretending to give you a makeover or using fingernails to tap on books for some relaxation. Don’t knock it until you try it!
 

Living in the past? Not so far-fetched

It’s usually an insult when people tell us to stop living in the past, but the joke’s on them because we really do live in the past. By 15 seconds, to be exact, according to researchers from the University of California, Berkeley.

Mauro Manassi

But wait, did you just read that last sentence 15 seconds ago, even though it feels like real time? Did we just type these words now, or 15 seconds ago?

Think of your brain as a web page you’re constantly refreshing. We are constantly seeing new pictures, images, and colors, and your brain is responsible for keeping everything in chronological order. This new research suggests that our brains show us images from 15 seconds prior. Is your mind blown yet?

“One could say our brain is procrastinating. It’s too much work to constantly update images, so it sticks to the past because the past is a good predictor of the present. We recycle information from the past because it’s faster, more efficient and less work,” senior author David Whitney explained in a statement from the university.

It seems like the 15-second rule helps us not lose our minds by keeping a steady flow of information, but it could be a bit dangerous if someone, such as a surgeon, needs to see things with extreme precision.

And now we are definitely feeling a bit anxious about our upcoming heart/spleen/gallbladder replacement. … Where’s that link to the ASMR video?

Goffin’s cockatoo? More like golfin’ cockatoo

Can birds play golf? Of course not; it’s ridiculous. Humans can barely play golf, and we invented the sport. Anyway, moving on to “Brian retraction injury after elective aneurysm clipping.”

Hang on, we’re now hearing that a group of researchers, as part of a large international project comparing children’s innovation and problem-solving skills with those of cockatoos, have in fact taught a group of Goffin’s cockatoos how to play golf. Huh. What an oddly specific project. All right, fine, I guess we’ll go with the golf-playing birds.

Goffin Lab

Golf may seem very simple at its core. It is, essentially, whacking a ball with a stick. But the Scots who invented the game were undertaking a complex project involving combined usage of multiple tools, and until now, only primates were thought to be capable of utilizing compound tools to play games such as golf.

For this latest research, published in Scientific Reports, our intrepid birds were given a rudimentary form of golf to play (featuring a stick, a ball, and a closed box to get the ball through). Putting the ball through the hole gave the bird a reward. Not every cockatoo was able to hole out, but three did, with each inventing a unique way to manipulate the stick to hit the ball.

As entertaining as it would be to simply teach some birds how to play golf, we do loop back around to medical relevance. While children are perfectly capable of using tools, young children in particular are actually quite bad at using tools to solve novel solutions. Present a 5-year-old with a stick, a ball, and a hole, and that child might not figure out what the cockatoos did. The research really does give insight into the psychology behind the development of complex tools and technology by our ancient ancestors, according to the researchers.

We’re not entirely convinced this isn’t an elaborate ploy to get a bird out onto the PGA Tour. The LOTME staff can see the future headline already: “Painted bunting wins Valspar Championship in epic playoff.”
 

Work out now, sweat never

Okay, show of hands: Who’s familiar with “Name that tune?” The TV game show got a reboot last year, but some of us are old enough to remember the 1970s version hosted by national treasure Tom Kennedy.

Edith Cowan University

The contestants try to identify a song as quickly as possible, claiming that they “can name that tune in five notes.” Or four notes, or three. Well, welcome to “Name that exercise study.”

Senior author Masatoshi Nakamura, PhD, and associates gathered together 39 students from Niigata (Japan) University of Health and Welfare and had them perform one isometric, concentric, or eccentric bicep curl with a dumbbell for 3 seconds a day at maximum effort for 5 days a week, over 4 weeks. And yes, we did say 3 seconds.

“Lifting the weight sees the bicep in concentric contraction, lowering the weight sees it in eccentric contraction, while holding the weight parallel to the ground is isometric,” they explained in a statement on Eurekalert.

The three exercise groups were compared with a group that did no exercise, and after 4 weeks of rigorous but brief science, the group doing eccentric contractions had the best results, as their overall muscle strength increased by 11.5%. After a total of just 60 seconds of exercise in 4 weeks. That’s 60 seconds. In 4 weeks.

Big news, but maybe we can do better. “Tom, we can do that exercise in 2 seconds.”

And one! And two! Whoa, feel the burn.
 

Tingling over anxiety

Apparently there are two kinds of people in this world. Those who love ASMR and those who just don’t get it.

ASMR, for those who don’t know, is the autonomous sensory meridian response. An online community has surfaced, with video creators making tapping sounds, whispering, or brushing mannequin hair to elicit “a pleasant tingling sensation originating from the scalp and neck which can spread to the rest of the body” from viewers, Charlotte M. Eid and associates said in PLOS One.

The people who are into these types of videos are more likely to have higher levels of neuroticism than those who aren’t, which gives ASMR the potential to be a nontraditional form of treatment for anxiety and/or neuroticism, they suggested.

The research involved a group of 64 volunteers who watched an ASMR video meant to trigger the tingles and then completed questionnaires to evaluate their levels of neuroticism, trait anxiety, and state anxiety, said Ms. Eid and associates of Northumbria University in Newcastle-upon-Tyne, England.

The people who had a history of producing tingles from ASMR videos in the past had higher levels of anxiety, compared with those who didn’t. Those who responded to triggers also received some benefit from the video in the study, reporting lower levels of neuroticism and anxiety after watching, the investigators found.

Although people who didn’t have a history of tingles didn’t feel any reduction in anxiety after the video, that didn’t stop the people who weren’t familiar with the genre from catching tingles.

So if you find yourself a little high strung or anxious, or if you can’t sleep, consider watching a person pretending to give you a makeover or using fingernails to tap on books for some relaxation. Don’t knock it until you try it!
 

Living in the past? Not so far-fetched

It’s usually an insult when people tell us to stop living in the past, but the joke’s on them because we really do live in the past. By 15 seconds, to be exact, according to researchers from the University of California, Berkeley.

Mauro Manassi

But wait, did you just read that last sentence 15 seconds ago, even though it feels like real time? Did we just type these words now, or 15 seconds ago?

Think of your brain as a web page you’re constantly refreshing. We are constantly seeing new pictures, images, and colors, and your brain is responsible for keeping everything in chronological order. This new research suggests that our brains show us images from 15 seconds prior. Is your mind blown yet?

“One could say our brain is procrastinating. It’s too much work to constantly update images, so it sticks to the past because the past is a good predictor of the present. We recycle information from the past because it’s faster, more efficient and less work,” senior author David Whitney explained in a statement from the university.

It seems like the 15-second rule helps us not lose our minds by keeping a steady flow of information, but it could be a bit dangerous if someone, such as a surgeon, needs to see things with extreme precision.

And now we are definitely feeling a bit anxious about our upcoming heart/spleen/gallbladder replacement. … Where’s that link to the ASMR video?

Long COVID can affect adults, young people, and children, and now for the first time, in a landmark study accepted for publication in the Archives of Disease in Childhood, formal agreement has been made on a research definition for post–acute COVID-19, or “long COVID” as it is commonly known, in children and young people.

The researchers charged themselves with a single objective – to derive a research definition for long COVID (post–acute COVID-19) in children and young people to allow comparisons between research studies. Specifically, so studies on prevalence, course, and outcome of long COVID in this age group can be reliably compared, because to date there has been no consensus. In fact, the authors pointed out how the “slew of definitions” currently used all differ in number, type, and duration of symptoms, which hampers research efforts. In addition, the lack of definition consensus has contributed to very wide reported variations in the estimated prevalence of long COVID in children of 1%-51%, with the authors saying that a “consistently applied definition of long COVID will help reduce the variability of prevalence estimates.”
 

Statements sequentially whittled down

“Using robust consensus methodology,” the authors said, “we derived a research definition for long COVID in children and young people.”

To achieve the definition consensus, a three-phase online Delphi process was used, followed by a virtual consensus meeting. The 123 participants registered to take part in the study included 23 people (19%) in a lived experience panel, 50 (42%) in the researcher or researcher/service delivery combined panel and 47 (39%) in the service delivery panel. Of 120 registered participants, 105 (88%) completed phase 1, 86 eligible participants (82% of those completing phase 1) completed phase 2 and 77 eligible participants (90% of those completing phase 2) completed phase 3. Seventeen participants attended and voted at the consensus meeting – 4 (23%) from the service delivery panel, 11 (65%) from the researcher panel, and 2 (12%) from the lived experience panel.

Presented with 49 statements in each phase, participants scored these from 1-9 based on how important they were perceived to be with regards inclusion in the research definition of long COVID in children and young people. Having been sequentially whittled down in three phases, 10 statements were discussed at the consensus meeting, and a panel of eight 11- to 17-year-olds affected by long COVID also reviewed the statements to reach a final agreement.

Five of the statements were agreed to be included in the definition, which stated that long COVID in children and young people is a condition in which a child or young person has symptoms (at least one of which is a physical symptom) that have continued or developed after a diagnosis of COVID-19 (confirmed with one or more positive COVID tests); impact their physical, mental, or social well-being; are interfering with some aspect of daily living (for example, school, work, home, or relationships); and persist for a minimum duration of 12 weeks after initial testing for COVID-19 (even if symptoms have waxed and waned over that period).

David Strain, MBChB, MD, chair of the BMA board of science and clinical senior lecturer and honorary consultant, University of Exeter (England), told the Science Media Centre: “A Delphi study builds a consensus from the world’s experts by presenting a series of statements and continuing to refine them until there is agreement as to what the definition of pediatric long COVID should be.” He added: “This is vitally important in order to align the global research effort into long COVID.”
 

Reassuringly similar

From the agreed five statements, a further research definition was proposed to align with the World Health Organization definition for adults: “Post–COVID-19 condition occurs in young people with a history of confirmed SARS CoV-2 infection, with at least one persisting physical symptom for a minimum duration of 12 weeks after initial testing that cannot be explained by an alternative diagnosis. The symptoms have an impact on everyday functioning, may continue or develop after COVID-19 infection, and may fluctuate or relapse over time.”

The authors concluded: “This is the first research definition of long COVID (post–COVID-19 condition) in children and young people and complements the clinical case definition in adults proposed by WHO,” adding that the two definitions are “reassuringly similar.”

They reiterated how widespread adoption of this definition would allow comparisons between studies such that a core outcome set can be developed and the prevalence, course and outcome of long COVID in children and young people can be reliably evaluated, which “will substantially help strengthen the evidence base on this debilitating condition.”

In addition, the authors said that a consistently applied definition of long COVID will help to provide a “more accurate picture on the true impact of the condition.”

The researchers emphasized the need to differentiate between a clinical case definition and a research definition of long COVID and explained: “It is understandable that the patient groups representing people with long COVID are concerned about a definition that could restrict access to services that are needed.”

They went on to say that in their view the decision whether a child or young person can see a health care professional, access any support needed, or be referred, investigated, or treated for long COVID should be a “shared decision involving the young person, their carers, and clinicians.”

Dr. Strain reinforced that it was important that the definition was a research one and not a clinical one, pointing out that the 12-week period in the research definition “does not necessarily mean that a child or young person should need to wait 3 months before being offered help or assistance from their health care team, indeed a 3-month delay in offering support to a child or young person, at this vitally important period of their educational development, could have lasting long-term impacts.”

A version of this article first appeared on Medscape.co.uk.

Long COVID can affect adults, young people, and children, and now for the first time, in a landmark study accepted for publication in the Archives of Disease in Childhood, formal agreement has been made on a research definition for post–acute COVID-19, or “long COVID” as it is commonly known, in children and young people.

The researchers charged themselves with a single objective – to derive a research definition for long COVID (post–acute COVID-19) in children and young people to allow comparisons between research studies. Specifically, so studies on prevalence, course, and outcome of long COVID in this age group can be reliably compared, because to date there has been no consensus. In fact, the authors pointed out how the “slew of definitions” currently used all differ in number, type, and duration of symptoms, which hampers research efforts. In addition, the lack of definition consensus has contributed to very wide reported variations in the estimated prevalence of long COVID in children of 1%-51%, with the authors saying that a “consistently applied definition of long COVID will help reduce the variability of prevalence estimates.”
 

Statements sequentially whittled down

“Using robust consensus methodology,” the authors said, “we derived a research definition for long COVID in children and young people.”

To achieve the definition consensus, a three-phase online Delphi process was used, followed by a virtual consensus meeting. The 123 participants registered to take part in the study included 23 people (19%) in a lived experience panel, 50 (42%) in the researcher or researcher/service delivery combined panel and 47 (39%) in the service delivery panel. Of 120 registered participants, 105 (88%) completed phase 1, 86 eligible participants (82% of those completing phase 1) completed phase 2 and 77 eligible participants (90% of those completing phase 2) completed phase 3. Seventeen participants attended and voted at the consensus meeting – 4 (23%) from the service delivery panel, 11 (65%) from the researcher panel, and 2 (12%) from the lived experience panel.

Presented with 49 statements in each phase, participants scored these from 1-9 based on how important they were perceived to be with regards inclusion in the research definition of long COVID in children and young people. Having been sequentially whittled down in three phases, 10 statements were discussed at the consensus meeting, and a panel of eight 11- to 17-year-olds affected by long COVID also reviewed the statements to reach a final agreement.

Five of the statements were agreed to be included in the definition, which stated that long COVID in children and young people is a condition in which a child or young person has symptoms (at least one of which is a physical symptom) that have continued or developed after a diagnosis of COVID-19 (confirmed with one or more positive COVID tests); impact their physical, mental, or social well-being; are interfering with some aspect of daily living (for example, school, work, home, or relationships); and persist for a minimum duration of 12 weeks after initial testing for COVID-19 (even if symptoms have waxed and waned over that period).

David Strain, MBChB, MD, chair of the BMA board of science and clinical senior lecturer and honorary consultant, University of Exeter (England), told the Science Media Centre: “A Delphi study builds a consensus from the world’s experts by presenting a series of statements and continuing to refine them until there is agreement as to what the definition of pediatric long COVID should be.” He added: “This is vitally important in order to align the global research effort into long COVID.”
 

Reassuringly similar

From the agreed five statements, a further research definition was proposed to align with the World Health Organization definition for adults: “Post–COVID-19 condition occurs in young people with a history of confirmed SARS CoV-2 infection, with at least one persisting physical symptom for a minimum duration of 12 weeks after initial testing that cannot be explained by an alternative diagnosis. The symptoms have an impact on everyday functioning, may continue or develop after COVID-19 infection, and may fluctuate or relapse over time.”

The authors concluded: “This is the first research definition of long COVID (post–COVID-19 condition) in children and young people and complements the clinical case definition in adults proposed by WHO,” adding that the two definitions are “reassuringly similar.”

They reiterated how widespread adoption of this definition would allow comparisons between studies such that a core outcome set can be developed and the prevalence, course and outcome of long COVID in children and young people can be reliably evaluated, which “will substantially help strengthen the evidence base on this debilitating condition.”

In addition, the authors said that a consistently applied definition of long COVID will help to provide a “more accurate picture on the true impact of the condition.”

The researchers emphasized the need to differentiate between a clinical case definition and a research definition of long COVID and explained: “It is understandable that the patient groups representing people with long COVID are concerned about a definition that could restrict access to services that are needed.”

They went on to say that in their view the decision whether a child or young person can see a health care professional, access any support needed, or be referred, investigated, or treated for long COVID should be a “shared decision involving the young person, their carers, and clinicians.”

Dr. Strain reinforced that it was important that the definition was a research one and not a clinical one, pointing out that the 12-week period in the research definition “does not necessarily mean that a child or young person should need to wait 3 months before being offered help or assistance from their health care team, indeed a 3-month delay in offering support to a child or young person, at this vitally important period of their educational development, could have lasting long-term impacts.”

A version of this article first appeared on Medscape.co.uk.

Long COVID can affect adults, young people, and children, and now for the first time, in a landmark study accepted for publication in the Archives of Disease in Childhood, formal agreement has been made on a research definition for post–acute COVID-19, or “long COVID” as it is commonly known, in children and young people.

The researchers charged themselves with a single objective – to derive a research definition for long COVID (post–acute COVID-19) in children and young people to allow comparisons between research studies. Specifically, so studies on prevalence, course, and outcome of long COVID in this age group can be reliably compared, because to date there has been no consensus. In fact, the authors pointed out how the “slew of definitions” currently used all differ in number, type, and duration of symptoms, which hampers research efforts. In addition, the lack of definition consensus has contributed to very wide reported variations in the estimated prevalence of long COVID in children of 1%-51%, with the authors saying that a “consistently applied definition of long COVID will help reduce the variability of prevalence estimates.”
 

Statements sequentially whittled down

“Using robust consensus methodology,” the authors said, “we derived a research definition for long COVID in children and young people.”

To achieve the definition consensus, a three-phase online Delphi process was used, followed by a virtual consensus meeting. The 123 participants registered to take part in the study included 23 people (19%) in a lived experience panel, 50 (42%) in the researcher or researcher/service delivery combined panel and 47 (39%) in the service delivery panel. Of 120 registered participants, 105 (88%) completed phase 1, 86 eligible participants (82% of those completing phase 1) completed phase 2 and 77 eligible participants (90% of those completing phase 2) completed phase 3. Seventeen participants attended and voted at the consensus meeting – 4 (23%) from the service delivery panel, 11 (65%) from the researcher panel, and 2 (12%) from the lived experience panel.

Presented with 49 statements in each phase, participants scored these from 1-9 based on how important they were perceived to be with regards inclusion in the research definition of long COVID in children and young people. Having been sequentially whittled down in three phases, 10 statements were discussed at the consensus meeting, and a panel of eight 11- to 17-year-olds affected by long COVID also reviewed the statements to reach a final agreement.

Five of the statements were agreed to be included in the definition, which stated that long COVID in children and young people is a condition in which a child or young person has symptoms (at least one of which is a physical symptom) that have continued or developed after a diagnosis of COVID-19 (confirmed with one or more positive COVID tests); impact their physical, mental, or social well-being; are interfering with some aspect of daily living (for example, school, work, home, or relationships); and persist for a minimum duration of 12 weeks after initial testing for COVID-19 (even if symptoms have waxed and waned over that period).

David Strain, MBChB, MD, chair of the BMA board of science and clinical senior lecturer and honorary consultant, University of Exeter (England), told the Science Media Centre: “A Delphi study builds a consensus from the world’s experts by presenting a series of statements and continuing to refine them until there is agreement as to what the definition of pediatric long COVID should be.” He added: “This is vitally important in order to align the global research effort into long COVID.”
 

Reassuringly similar

From the agreed five statements, a further research definition was proposed to align with the World Health Organization definition for adults: “Post–COVID-19 condition occurs in young people with a history of confirmed SARS CoV-2 infection, with at least one persisting physical symptom for a minimum duration of 12 weeks after initial testing that cannot be explained by an alternative diagnosis. The symptoms have an impact on everyday functioning, may continue or develop after COVID-19 infection, and may fluctuate or relapse over time.”

The authors concluded: “This is the first research definition of long COVID (post–COVID-19 condition) in children and young people and complements the clinical case definition in adults proposed by WHO,” adding that the two definitions are “reassuringly similar.”

They reiterated how widespread adoption of this definition would allow comparisons between studies such that a core outcome set can be developed and the prevalence, course and outcome of long COVID in children and young people can be reliably evaluated, which “will substantially help strengthen the evidence base on this debilitating condition.”

In addition, the authors said that a consistently applied definition of long COVID will help to provide a “more accurate picture on the true impact of the condition.”

The researchers emphasized the need to differentiate between a clinical case definition and a research definition of long COVID and explained: “It is understandable that the patient groups representing people with long COVID are concerned about a definition that could restrict access to services that are needed.”

They went on to say that in their view the decision whether a child or young person can see a health care professional, access any support needed, or be referred, investigated, or treated for long COVID should be a “shared decision involving the young person, their carers, and clinicians.”

Dr. Strain reinforced that it was important that the definition was a research one and not a clinical one, pointing out that the 12-week period in the research definition “does not necessarily mean that a child or young person should need to wait 3 months before being offered help or assistance from their health care team, indeed a 3-month delay in offering support to a child or young person, at this vitally important period of their educational development, could have lasting long-term impacts.”

A version of this article first appeared on Medscape.co.uk.

It’s a story of promise at a time of urgent need.

Scientists are optimistic about new evidence into what is causing long COVID, a panel of research experts brought together by the New York State Department of Health said.

They proposed many theories on what might be driving long COVID. A role for a virus “cryptic reservoir” that could reactivate at any time, “viral remnants” that trigger chronic inflammation, and action by “autoimmune antibodies” that cause ongoing symptoms are possibilities.

In fact, it’s likely that research will show long COVID is a condition with more than one cause, the experts said during a recent webinar.

People might experience post-infection problems, including organ damage that takes time to heal after initial COVID-19 illness. Or they may be living with post-immune factors, including ongoing immune system responses triggered by autoantibodies.

Determining the cause or causes of long COVID is essential for treatment. For example, if one person’s symptoms persist because of an overactive immune system, “we need to provide immunosuppressant therapies,” Akiko Iwasaki, PhD, said. “But we don’t want to give that to someone who has a persistent virus reservoir,” meaning remnants of the virus remain in their bodies.

Interestingly, a study preprint, which has not been peer reviewed, found dogs were accurate more than half the time in sniffing out long COVID, said Dr. Iwasaki, professor of immunobiology and developmental biology at Yale University, New Haven, Conn.

The dogs were tasked with identifying 45 people with long COVID versus 188 people without it. The findings suggest the presence of a unique chemical in the sweat of people with long COVID that could someday lead to a diagnostic test.
 

Viral persistence possible

If one of the main theories holds, it could be that the coronavirus somehow remains in the body in some form for some people after COVID-19.

Mady Hornig, MD, agreed this is a possibility that needs to be investigated further.

“A weakened immune response to an infection may mean that you have cryptic reservoirs of virus that are continuing to cause symptoms,” she said during the briefing. Dr. Hornig is a doctor-scientist specializing in epidemiology at Columbia University, New York.

“That may explain why some patients with long COVID feel better after vaccination,” because the vaccine creates a strong antibody response to fight COVID-19, Dr. Iwasaki said.

Researchers are unearthing additional potential factors contributing to long COVID.

Viral persistence could also reactivate other dormant viruses in the body, such as Epstein-Barr virus (EBV), said Lawrence Purpura, MD, MPH, an infectious disease specialist at New York Presbyterian/Columbia University. Reactivation of Epstein-Barr is one of four identifying signs of long COVID revealed in a Jan. 25 study published in the journal Cell.
 

Immune overactivation also possible?

For other people with long COVID, it’s not the virus sticking around but the body’s reaction that’s the issue.

Investigators suggest autoimmunity plays a role, and they point to the presence of autoantibodies, for example.

When these autoantibodies persist, they can cause tissue and organ damage over time.

Other investigators are proposing “immune exhaustion” in long COVID because of similarities to chronic fatigue syndrome, Dr. Hornig said.

“It should be ‘all hands on deck’ for research into long COVID,” she said. “The number of disabled individuals who will likely qualify for a diagnosis of [chronic fatigue syndrome] is growing by the second.”
 

Forging ahead on future research

It’s clear there is more work to do. There are investigators working on banking tissue samples from people with long COVID to learn more, for example.

Also, finding a biomarker unique to long COVID could vastly improve the precision of diagnosing long COVID, especially if the dog sniffing option does not pan out.

Of the thousands of biomarker possibilities, Dr. Hornig said, “maybe that’s one or two that ultimately make a real impact on patient care. So it’s going to be critical to find those quickly, translate them, and make them available.”

In the meantime, some answers might come from a large study sponsored by the National Institutes of Health. The NIH is funding the “Researching COVID to Enhance Recovery” project using $470 million from the American Rescue Plan. Investigators at NYU Langone Health are leading the effort and plan to share the wealth by funding more than 100 researchers at more than 30 institutions to create a “metacohort” to study long COVID. More information is available at recovercovid.org.

“Fortunately, through the global research effort, we are now really starting to expand our understanding of how long COVID manifests, how common it is, and what the underlying mechanisms may be,” Dr. Purpura said.

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

It’s a story of promise at a time of urgent need.

Scientists are optimistic about new evidence into what is causing long COVID, a panel of research experts brought together by the New York State Department of Health said.

They proposed many theories on what might be driving long COVID. A role for a virus “cryptic reservoir” that could reactivate at any time, “viral remnants” that trigger chronic inflammation, and action by “autoimmune antibodies” that cause ongoing symptoms are possibilities.

In fact, it’s likely that research will show long COVID is a condition with more than one cause, the experts said during a recent webinar.

People might experience post-infection problems, including organ damage that takes time to heal after initial COVID-19 illness. Or they may be living with post-immune factors, including ongoing immune system responses triggered by autoantibodies.

Determining the cause or causes of long COVID is essential for treatment. For example, if one person’s symptoms persist because of an overactive immune system, “we need to provide immunosuppressant therapies,” Akiko Iwasaki, PhD, said. “But we don’t want to give that to someone who has a persistent virus reservoir,” meaning remnants of the virus remain in their bodies.

Interestingly, a study preprint, which has not been peer reviewed, found dogs were accurate more than half the time in sniffing out long COVID, said Dr. Iwasaki, professor of immunobiology and developmental biology at Yale University, New Haven, Conn.

The dogs were tasked with identifying 45 people with long COVID versus 188 people without it. The findings suggest the presence of a unique chemical in the sweat of people with long COVID that could someday lead to a diagnostic test.
 

Viral persistence possible

If one of the main theories holds, it could be that the coronavirus somehow remains in the body in some form for some people after COVID-19.

Mady Hornig, MD, agreed this is a possibility that needs to be investigated further.

“A weakened immune response to an infection may mean that you have cryptic reservoirs of virus that are continuing to cause symptoms,” she said during the briefing. Dr. Hornig is a doctor-scientist specializing in epidemiology at Columbia University, New York.

“That may explain why some patients with long COVID feel better after vaccination,” because the vaccine creates a strong antibody response to fight COVID-19, Dr. Iwasaki said.

Researchers are unearthing additional potential factors contributing to long COVID.

Viral persistence could also reactivate other dormant viruses in the body, such as Epstein-Barr virus (EBV), said Lawrence Purpura, MD, MPH, an infectious disease specialist at New York Presbyterian/Columbia University. Reactivation of Epstein-Barr is one of four identifying signs of long COVID revealed in a Jan. 25 study published in the journal Cell.
 

Immune overactivation also possible?

For other people with long COVID, it’s not the virus sticking around but the body’s reaction that’s the issue.

Investigators suggest autoimmunity plays a role, and they point to the presence of autoantibodies, for example.

When these autoantibodies persist, they can cause tissue and organ damage over time.

Other investigators are proposing “immune exhaustion” in long COVID because of similarities to chronic fatigue syndrome, Dr. Hornig said.

“It should be ‘all hands on deck’ for research into long COVID,” she said. “The number of disabled individuals who will likely qualify for a diagnosis of [chronic fatigue syndrome] is growing by the second.”
 

Forging ahead on future research

It’s clear there is more work to do. There are investigators working on banking tissue samples from people with long COVID to learn more, for example.

Also, finding a biomarker unique to long COVID could vastly improve the precision of diagnosing long COVID, especially if the dog sniffing option does not pan out.

Of the thousands of biomarker possibilities, Dr. Hornig said, “maybe that’s one or two that ultimately make a real impact on patient care. So it’s going to be critical to find those quickly, translate them, and make them available.”

In the meantime, some answers might come from a large study sponsored by the National Institutes of Health. The NIH is funding the “Researching COVID to Enhance Recovery” project using $470 million from the American Rescue Plan. Investigators at NYU Langone Health are leading the effort and plan to share the wealth by funding more than 100 researchers at more than 30 institutions to create a “metacohort” to study long COVID. More information is available at recovercovid.org.

“Fortunately, through the global research effort, we are now really starting to expand our understanding of how long COVID manifests, how common it is, and what the underlying mechanisms may be,” Dr. Purpura said.

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

It’s a story of promise at a time of urgent need.

Scientists are optimistic about new evidence into what is causing long COVID, a panel of research experts brought together by the New York State Department of Health said.

They proposed many theories on what might be driving long COVID. A role for a virus “cryptic reservoir” that could reactivate at any time, “viral remnants” that trigger chronic inflammation, and action by “autoimmune antibodies” that cause ongoing symptoms are possibilities.

In fact, it’s likely that research will show long COVID is a condition with more than one cause, the experts said during a recent webinar.

People might experience post-infection problems, including organ damage that takes time to heal after initial COVID-19 illness. Or they may be living with post-immune factors, including ongoing immune system responses triggered by autoantibodies.

Determining the cause or causes of long COVID is essential for treatment. For example, if one person’s symptoms persist because of an overactive immune system, “we need to provide immunosuppressant therapies,” Akiko Iwasaki, PhD, said. “But we don’t want to give that to someone who has a persistent virus reservoir,” meaning remnants of the virus remain in their bodies.

Interestingly, a study preprint, which has not been peer reviewed, found dogs were accurate more than half the time in sniffing out long COVID, said Dr. Iwasaki, professor of immunobiology and developmental biology at Yale University, New Haven, Conn.

The dogs were tasked with identifying 45 people with long COVID versus 188 people without it. The findings suggest the presence of a unique chemical in the sweat of people with long COVID that could someday lead to a diagnostic test.
 

Viral persistence possible

If one of the main theories holds, it could be that the coronavirus somehow remains in the body in some form for some people after COVID-19.

Mady Hornig, MD, agreed this is a possibility that needs to be investigated further.

“A weakened immune response to an infection may mean that you have cryptic reservoirs of virus that are continuing to cause symptoms,” she said during the briefing. Dr. Hornig is a doctor-scientist specializing in epidemiology at Columbia University, New York.

“That may explain why some patients with long COVID feel better after vaccination,” because the vaccine creates a strong antibody response to fight COVID-19, Dr. Iwasaki said.

Researchers are unearthing additional potential factors contributing to long COVID.

Viral persistence could also reactivate other dormant viruses in the body, such as Epstein-Barr virus (EBV), said Lawrence Purpura, MD, MPH, an infectious disease specialist at New York Presbyterian/Columbia University. Reactivation of Epstein-Barr is one of four identifying signs of long COVID revealed in a Jan. 25 study published in the journal Cell.
 

Immune overactivation also possible?

For other people with long COVID, it’s not the virus sticking around but the body’s reaction that’s the issue.

Investigators suggest autoimmunity plays a role, and they point to the presence of autoantibodies, for example.

When these autoantibodies persist, they can cause tissue and organ damage over time.

Other investigators are proposing “immune exhaustion” in long COVID because of similarities to chronic fatigue syndrome, Dr. Hornig said.

“It should be ‘all hands on deck’ for research into long COVID,” she said. “The number of disabled individuals who will likely qualify for a diagnosis of [chronic fatigue syndrome] is growing by the second.”
 

Forging ahead on future research

It’s clear there is more work to do. There are investigators working on banking tissue samples from people with long COVID to learn more, for example.

Also, finding a biomarker unique to long COVID could vastly improve the precision of diagnosing long COVID, especially if the dog sniffing option does not pan out.

Of the thousands of biomarker possibilities, Dr. Hornig said, “maybe that’s one or two that ultimately make a real impact on patient care. So it’s going to be critical to find those quickly, translate them, and make them available.”

In the meantime, some answers might come from a large study sponsored by the National Institutes of Health. The NIH is funding the “Researching COVID to Enhance Recovery” project using $470 million from the American Rescue Plan. Investigators at NYU Langone Health are leading the effort and plan to share the wealth by funding more than 100 researchers at more than 30 institutions to create a “metacohort” to study long COVID. More information is available at recovercovid.org.

“Fortunately, through the global research effort, we are now really starting to expand our understanding of how long COVID manifests, how common it is, and what the underlying mechanisms may be,” Dr. Purpura said.

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

Several relatively large real-world analyses of Janus kinase inhibitors (JAKi) in patients with rheumatoid arthritis appear to show that the oral small-molecule drugs are discontinued and retained at rates similar to or better than biologic disease-modifying antirheumatic drugs (bDMARDs), including tumor necrosis factor inhibitors (TNFi), according to studies presented at the annual meeting of the Canadian Rheumatology Association.

The findings of these studies, although conducted prior to the Food and Drug Administration’s September 2021 announcement of a boxed warning for JAKi, do not lend support to the warning’s message of higher risks of major adverse cardiovascular events (MACE), blood clots, cancer, and death associated with JAKi.

In one study, discontinuation of JAKi-class drugs was less common than discontinuation of bDMARD-class drugs, including tumor necrosis factor inhibitors (TNFi), according to a multicenter team of investigators led by Janet Pope, MD, a professor in the division of rheumatology at the University of Western Ontario, London.

The greater durability of the JAKi relative to TNFi “seem to be driven by a greater loss of efficacy in bDMARDs over time,” reported Samir Magdy Iskander, a medical student at the university, who presented the data.
 

JAKi rival bDMARDs for long-term retention

In a separate but larger analysis, the retention rates with the JAKi tofacitinib (Xeljanz) and TNFi in two RA registries in Canada were about the same after a mean follow-up of 23.2 months (36.9% vs. 37.5%), but the tofacitinib group was at a relative disadvantage. Relative to the bDMARD group, patients taking JAKi were more likely to have had prior treatment with a bDMARD (66.9% vs. 33.9%), to have a higher median baseline Clinical Disease Activity Index (CDAI) score (22.1 vs. 20.0; P < .05), and to be older (59.5 vs. 57.6 years).

In this study, 1,318 patients with RA enrolled in the Ontario Best Practices Research Initiative (OBRI) or a Quebec cohort called RHUMADATA were evaluated, reported Mohammad Movahedi, MD, PhD, of the Institute of Health Policy, Management, and Evaluation at the University of Toronto.

“We have not yet analyzed the reasons for discontinuation, but the data show that retention is about the same, meaning that selection of one agent over the other should be tailored according to patient characteristics,” Dr. Movahedi said.

Reasons for discontinuation were presented in the other observational study, which included 333 adult patients with RA from two centers in Ontario. The discontinuation rate for adverse events was approximately 20% in both groups (HR, 1.0005; P = .98). However, the discontinuation rate for lack of efficacy favored the JAKi, reaching statistical significance.
 

TNFi failure for lack of efficacy is higher

“For lack of efficacy, the discontinuation rate was about 35% lower on the JAKi [HR, 0.6543; P = .029],” Mr. Iskander reported. Relative to those taking a TNFi, those on a JAKi demonstrated “greater durability regardless of gender, age, disease duration, and prior lines of therapy.”

In a population of patients who have not achieved an adequate response to conventional synthetic DMARDs (csDMARDs), which describes the study population from the two Ontario centers, JAKi “may be considered as a preferable method of treatment,” Mr. Iskander said.

Pointing out that many clinicians have interpreted the boxed warning as a relative contraindication for use of JAKi as first-line therapy in patients with an inadequate response to csDMARDs, Marinka Twilt, MD, PhD, the moderator of the scientific session where these data were presented, questioned the conclusion. In the boxed warning, clinicians and patients are advised to consider an increased risk of serious infections, malignancy, and cardiovascular-related mortality in individuals older than 50 years.

In response, Mr. Iskander said that the data were collected and analyzed prior to the change in labeling. He acknowledged that this study was not designed to capture long-term risks, such as cardiovascular disease or malignancy. In this analysis, the safety and tolerability of JAKi and bDMARDs appeared comparable.
 

NEJM published study leading to boxed warning

Just a week prior to the CRA annual meeting, the New England Journal of Medicine published an FDA-mandated postmarketing trial of tofacitinib that was used by the agency to justify the boxed warning for JAKi with indications for artitis and other inflammatory diseases. In that open-label trial, more than 4,000 patients aged 50 years or older with at least one additional cardiovascular risk factor were randomized to 5 mg tofacitinib twice daily, 10 mg tofacitinib twice daily, or a TNFi (adalimumab or etanercept).

The efficacy of the therapies was similar, but tofacitinib failed to meet predefined noninferiority criteria for the co–primary endpoints of MACE or cancer (excluding nonmelanoma skin cancer). For tofacitinib relative to TNFi, the hazard ratio was 1.33 for MACE and 1.48 for cancers. The JAKi was also associated with higher incidences of opportunistic infections.

Mr. Iskander noted that Canadian clinical practice guidelines currently identify JAKi as a reasonable first-line alternative to bDMARDs after inadequate response to csDMARDs. While his data support that position, Dr. Twilt indicated that the benefit-to-risk ratio of JAKi might need recalculation based on the data that led the FDA to issue its boxed warning. She questioned whether the language regarding the relative role of JAKi and bDMARDs will change in coming RA guideline revisions.

Dr. Iskander reported no potential conflicts of interest. Dr. Movahedi did not list any personal conflicts of interest but acknowledged that OBRI received unrestricted grants from a variety of pharmaceutical companies, including those that manufacture bDMARDs and JAKi. Dr. Twilt reported no potential conflicts of interest.

Several relatively large real-world analyses of Janus kinase inhibitors (JAKi) in patients with rheumatoid arthritis appear to show that the oral small-molecule drugs are discontinued and retained at rates similar to or better than biologic disease-modifying antirheumatic drugs (bDMARDs), including tumor necrosis factor inhibitors (TNFi), according to studies presented at the annual meeting of the Canadian Rheumatology Association.

The findings of these studies, although conducted prior to the Food and Drug Administration’s September 2021 announcement of a boxed warning for JAKi, do not lend support to the warning’s message of higher risks of major adverse cardiovascular events (MACE), blood clots, cancer, and death associated with JAKi.

In one study, discontinuation of JAKi-class drugs was less common than discontinuation of bDMARD-class drugs, including tumor necrosis factor inhibitors (TNFi), according to a multicenter team of investigators led by Janet Pope, MD, a professor in the division of rheumatology at the University of Western Ontario, London.

The greater durability of the JAKi relative to TNFi “seem to be driven by a greater loss of efficacy in bDMARDs over time,” reported Samir Magdy Iskander, a medical student at the university, who presented the data.
 

JAKi rival bDMARDs for long-term retention

In a separate but larger analysis, the retention rates with the JAKi tofacitinib (Xeljanz) and TNFi in two RA registries in Canada were about the same after a mean follow-up of 23.2 months (36.9% vs. 37.5%), but the tofacitinib group was at a relative disadvantage. Relative to the bDMARD group, patients taking JAKi were more likely to have had prior treatment with a bDMARD (66.9% vs. 33.9%), to have a higher median baseline Clinical Disease Activity Index (CDAI) score (22.1 vs. 20.0; P < .05), and to be older (59.5 vs. 57.6 years).

In this study, 1,318 patients with RA enrolled in the Ontario Best Practices Research Initiative (OBRI) or a Quebec cohort called RHUMADATA were evaluated, reported Mohammad Movahedi, MD, PhD, of the Institute of Health Policy, Management, and Evaluation at the University of Toronto.

“We have not yet analyzed the reasons for discontinuation, but the data show that retention is about the same, meaning that selection of one agent over the other should be tailored according to patient characteristics,” Dr. Movahedi said.

Reasons for discontinuation were presented in the other observational study, which included 333 adult patients with RA from two centers in Ontario. The discontinuation rate for adverse events was approximately 20% in both groups (HR, 1.0005; P = .98). However, the discontinuation rate for lack of efficacy favored the JAKi, reaching statistical significance.
 

TNFi failure for lack of efficacy is higher

“For lack of efficacy, the discontinuation rate was about 35% lower on the JAKi [HR, 0.6543; P = .029],” Mr. Iskander reported. Relative to those taking a TNFi, those on a JAKi demonstrated “greater durability regardless of gender, age, disease duration, and prior lines of therapy.”

In a population of patients who have not achieved an adequate response to conventional synthetic DMARDs (csDMARDs), which describes the study population from the two Ontario centers, JAKi “may be considered as a preferable method of treatment,” Mr. Iskander said.

Pointing out that many clinicians have interpreted the boxed warning as a relative contraindication for use of JAKi as first-line therapy in patients with an inadequate response to csDMARDs, Marinka Twilt, MD, PhD, the moderator of the scientific session where these data were presented, questioned the conclusion. In the boxed warning, clinicians and patients are advised to consider an increased risk of serious infections, malignancy, and cardiovascular-related mortality in individuals older than 50 years.

In response, Mr. Iskander said that the data were collected and analyzed prior to the change in labeling. He acknowledged that this study was not designed to capture long-term risks, such as cardiovascular disease or malignancy. In this analysis, the safety and tolerability of JAKi and bDMARDs appeared comparable.
 

NEJM published study leading to boxed warning

Just a week prior to the CRA annual meeting, the New England Journal of Medicine published an FDA-mandated postmarketing trial of tofacitinib that was used by the agency to justify the boxed warning for JAKi with indications for artitis and other inflammatory diseases. In that open-label trial, more than 4,000 patients aged 50 years or older with at least one additional cardiovascular risk factor were randomized to 5 mg tofacitinib twice daily, 10 mg tofacitinib twice daily, or a TNFi (adalimumab or etanercept).

The efficacy of the therapies was similar, but tofacitinib failed to meet predefined noninferiority criteria for the co–primary endpoints of MACE or cancer (excluding nonmelanoma skin cancer). For tofacitinib relative to TNFi, the hazard ratio was 1.33 for MACE and 1.48 for cancers. The JAKi was also associated with higher incidences of opportunistic infections.

Mr. Iskander noted that Canadian clinical practice guidelines currently identify JAKi as a reasonable first-line alternative to bDMARDs after inadequate response to csDMARDs. While his data support that position, Dr. Twilt indicated that the benefit-to-risk ratio of JAKi might need recalculation based on the data that led the FDA to issue its boxed warning. She questioned whether the language regarding the relative role of JAKi and bDMARDs will change in coming RA guideline revisions.

Dr. Iskander reported no potential conflicts of interest. Dr. Movahedi did not list any personal conflicts of interest but acknowledged that OBRI received unrestricted grants from a variety of pharmaceutical companies, including those that manufacture bDMARDs and JAKi. Dr. Twilt reported no potential conflicts of interest.

Several relatively large real-world analyses of Janus kinase inhibitors (JAKi) in patients with rheumatoid arthritis appear to show that the oral small-molecule drugs are discontinued and retained at rates similar to or better than biologic disease-modifying antirheumatic drugs (bDMARDs), including tumor necrosis factor inhibitors (TNFi), according to studies presented at the annual meeting of the Canadian Rheumatology Association.

The findings of these studies, although conducted prior to the Food and Drug Administration’s September 2021 announcement of a boxed warning for JAKi, do not lend support to the warning’s message of higher risks of major adverse cardiovascular events (MACE), blood clots, cancer, and death associated with JAKi.

In one study, discontinuation of JAKi-class drugs was less common than discontinuation of bDMARD-class drugs, including tumor necrosis factor inhibitors (TNFi), according to a multicenter team of investigators led by Janet Pope, MD, a professor in the division of rheumatology at the University of Western Ontario, London.

The greater durability of the JAKi relative to TNFi “seem to be driven by a greater loss of efficacy in bDMARDs over time,” reported Samir Magdy Iskander, a medical student at the university, who presented the data.
 

JAKi rival bDMARDs for long-term retention

In a separate but larger analysis, the retention rates with the JAKi tofacitinib (Xeljanz) and TNFi in two RA registries in Canada were about the same after a mean follow-up of 23.2 months (36.9% vs. 37.5%), but the tofacitinib group was at a relative disadvantage. Relative to the bDMARD group, patients taking JAKi were more likely to have had prior treatment with a bDMARD (66.9% vs. 33.9%), to have a higher median baseline Clinical Disease Activity Index (CDAI) score (22.1 vs. 20.0; P < .05), and to be older (59.5 vs. 57.6 years).

In this study, 1,318 patients with RA enrolled in the Ontario Best Practices Research Initiative (OBRI) or a Quebec cohort called RHUMADATA were evaluated, reported Mohammad Movahedi, MD, PhD, of the Institute of Health Policy, Management, and Evaluation at the University of Toronto.

“We have not yet analyzed the reasons for discontinuation, but the data show that retention is about the same, meaning that selection of one agent over the other should be tailored according to patient characteristics,” Dr. Movahedi said.

Reasons for discontinuation were presented in the other observational study, which included 333 adult patients with RA from two centers in Ontario. The discontinuation rate for adverse events was approximately 20% in both groups (HR, 1.0005; P = .98). However, the discontinuation rate for lack of efficacy favored the JAKi, reaching statistical significance.
 

TNFi failure for lack of efficacy is higher

“For lack of efficacy, the discontinuation rate was about 35% lower on the JAKi [HR, 0.6543; P = .029],” Mr. Iskander reported. Relative to those taking a TNFi, those on a JAKi demonstrated “greater durability regardless of gender, age, disease duration, and prior lines of therapy.”

In a population of patients who have not achieved an adequate response to conventional synthetic DMARDs (csDMARDs), which describes the study population from the two Ontario centers, JAKi “may be considered as a preferable method of treatment,” Mr. Iskander said.

Pointing out that many clinicians have interpreted the boxed warning as a relative contraindication for use of JAKi as first-line therapy in patients with an inadequate response to csDMARDs, Marinka Twilt, MD, PhD, the moderator of the scientific session where these data were presented, questioned the conclusion. In the boxed warning, clinicians and patients are advised to consider an increased risk of serious infections, malignancy, and cardiovascular-related mortality in individuals older than 50 years.

In response, Mr. Iskander said that the data were collected and analyzed prior to the change in labeling. He acknowledged that this study was not designed to capture long-term risks, such as cardiovascular disease or malignancy. In this analysis, the safety and tolerability of JAKi and bDMARDs appeared comparable.
 

NEJM published study leading to boxed warning

Just a week prior to the CRA annual meeting, the New England Journal of Medicine published an FDA-mandated postmarketing trial of tofacitinib that was used by the agency to justify the boxed warning for JAKi with indications for artitis and other inflammatory diseases. In that open-label trial, more than 4,000 patients aged 50 years or older with at least one additional cardiovascular risk factor were randomized to 5 mg tofacitinib twice daily, 10 mg tofacitinib twice daily, or a TNFi (adalimumab or etanercept).

The efficacy of the therapies was similar, but tofacitinib failed to meet predefined noninferiority criteria for the co–primary endpoints of MACE or cancer (excluding nonmelanoma skin cancer). For tofacitinib relative to TNFi, the hazard ratio was 1.33 for MACE and 1.48 for cancers. The JAKi was also associated with higher incidences of opportunistic infections.

Mr. Iskander noted that Canadian clinical practice guidelines currently identify JAKi as a reasonable first-line alternative to bDMARDs after inadequate response to csDMARDs. While his data support that position, Dr. Twilt indicated that the benefit-to-risk ratio of JAKi might need recalculation based on the data that led the FDA to issue its boxed warning. She questioned whether the language regarding the relative role of JAKi and bDMARDs will change in coming RA guideline revisions.

Dr. Iskander reported no potential conflicts of interest. Dr. Movahedi did not list any personal conflicts of interest but acknowledged that OBRI received unrestricted grants from a variety of pharmaceutical companies, including those that manufacture bDMARDs and JAKi. Dr. Twilt reported no potential conflicts of interest.

In the clinical experience of George Han, MD, PhD, treatment of psoriasis currently is often taxing for patients, with wait times to see a dermatologist exceeding 30 days in many markets and patients who present to him having cycled through many providers seeking relief from their disease.

“They come in with bags of topical products to show you what they’ve tried,” Dr. Han, associate professor of dermatology at Hofstra University, Hempstead, N.Y., said during the ODAC Dermatology, Aesthetic & Surgical Conference. “And you’re supposed to see this patient, talk to them, and counsel them in about 10 minutes. How do you make time to conduct an efficient psoriasis visit?”

Patients have a long-term battle to get clear, and spending a little longer on the initial visit “pays a lot of dividends,” he said. “Some of these patients are the most thankful patients in our practices, and it truly is gratifying” to see how much they can improve.
 

Questions about diet

Dr. Han said that psoriasis patients often ask him if, what, or how much they’re eating affects their disease. “But how do you counsel patients about diet when we’re not dietitians? We can at least give some guidance based on available data.”

He referred to a nationwide study of psoriasis patient-reported outcomes and dietary behaviors, which found that the percentage of patients who reported skin improvement was greatest after reducing intake of alcohol (53.8%); gluten (53.4%); and nightshade vegetables, such as tomatoes, potatoes, and peppers (52.1%); and after adding fish oil/omega-3 (44.6%), vegetables (42.5%), and oral vitamin D (41%). He noted that there is a threefold increased incidence of celiac disease in patients with psoriasis.

As for nightshade vegetables, intake leads to increased alkaloids, “which have been known to worsen bowel inflammation such as in IBD [inflammatory bowel disease], but there is a lack of controlled trials examining this in the overall psoriasis population,” Dr. Han said. The Mediterranean diet, he added, “is sensible, and adding olive oil to your diet seems to have a positive effect on ... PASI, while fish oil seems to reduce C-reactive protein.” The data on the effect of vitamin D supplements are mixed, he said.

A separate randomized study evaluated the impact of weight loss in overweight or obese patients with psoriasis, who had not achieved clearance after 4 weeks of systemic treatment. Significantly more of those in the dietary intervention arm reached the weight loss goal of 5% at 20 weeks, and patients in this arm had a median reduction in the Psoriasis Area and Severity Index (PASI) score of almost 50%, compared with almost 26% among those without an active dietary intervention.
 

Joint pain, PsA

For psoriasis patients who complain of joint pain, he recommends administering quick measures like the five-question Psoriasis Epidemiology Screening Test (PEST) to screen for psoriatic arthritis (PsA), which is available on the National Psoriasis Foundation web site. “I ask patients about swollen, tender joints – specifically hands, wrists, ankles, feet, and toes,” Dr. Han said. Joint stiffness in the morning is a “concerning finding,” which is “more indicative of psoriatic arthritis than vague knee or back pain that worsens with use. If you have a younger patient with back pain who has a reduced ability to flex their spine, think axial disease.”

Tumor necrosis factor (TNF)–alpha inhibitors are considered first- and second-line treatment for PsA, but interleukin (IL)–17 inhibitors are generally considered just as effective overall. “The IL-23 inhibitors have mixed signals,” said Dr. Han, who is also on the NPF’s medical board. “We know that guselkumab is effective against psoriatic arthritis, but there is no inhibition of joint progression at the approved dosage on the label – though it was pretty close.”

Risankizumab (Skyrizi), an IL-23 inhibitor, was approved in January 2022 for adults with PsA and while the American College of Rheumatology response data “look reasonably good, the results for inhibition of radiographic progression are quite far off and it’s not in the label,” he said. Tildrakizumab (Ilumya), an IL-23 inhibitor, “looks impressive in phase 2b trials. It will be interesting to see if there is differentiation between the IL-23 agents in treating joint disease going forward.”

Dr. Han considers biologic therapy a good option for patients with questionable joint involvement or very limited joint disease. “If the patient has some evidence of PsA, as long as it’s a medication that has approval for that, I’m OK with starting it,” he said. “However, for patients whose joint pain dominates over the skin, or [who] have severe joint disease at presentation, I would prioritize the TNF-alpha inhibitors and IL-17s and refer them to rheumatology for shared management.”
 

Topical, oral treatments

As for topical approaches to treating psoriasis, adding halobetasol propionate 0.01% to tazarotene 0.045% may have a synergistic effect, while tapinarof 1% cream holds promise, he said. Tapinarof, which is expected to be approved this year, is an investigative aryl hydrocarbon agonist that inhibits an array of proinflammatory cytokines, including interferon-gamma and TNF-alpha. “It has been shown to have inhibitory effects both on Th17 cytokines and Th2 cytokines,” Dr. Han said. “What’s nice about this is that patients still appear to have treatment effect 1-2 months after stopping the drug.”

Another topical agent now under FDA review for psoriasis, is roflumilast, a phosphodiesterase type 4 (PDE4) inhibitor, which has been shown to have a treatment efficacy of 30% or more. “We’ll see how this works into our treatment regimen for psoriasis,” he said, as strategies targeting PDE4 have already been reported to help treat psoriasis.

With regards to oral therapies, he said that there are concerns about the efficacy of the oral PDE4 inhibitor apremilast, approved for psoriasis, compared with other biologics. Deucravacitinib, an oral selective tyrosine kinase 2 (TYK2) inhibitor also under FDA review for psoriasis, “may fill this gap, because its efficacy seems much stronger and really capitalizes on blocking IL-23, which we know is a central pathway in the pathogenesis of psoriasis.”

Phototherapy is another treatment option. Home narrowband-UVB devices cost $3,000-$5,000, “which is a fraction of 1 year of biologic treatment,” Dr. Han said. Older data on phototherapy suggest that “lesions can clear within 2-3 months, depending on how often you do the phototherapy, while newer data suggest that 75% of patients can achieve clear or minimal disease” with phototherapy.

Biologic therapy

If patients meet criteria for treatment with a biologic, he begins the conversation by saying, “I don’t want to give you an immunosuppressant, but your psoriasis represents an overactivation of inflammation in your body, so in some way we have to bring that down. Ideally, we would target your immune system in a way that targets psoriasis very narrowly, while leaving it to do what it needs to: protecting against infections and neoplasia.”

XXXIL-17 inhibitors generally have the fastest onset of action, Dr. Han noted. Authors of a review paper found that achievement of Psoriasis Area and Severity Index (PASI) 50 was 1.8 weeks with brodalumab, 1.9 weeks for ixekizumab, 3 weeks for high-dose secukinumab, 3.5 weeks for adalimumab, 3.7 weeks for infliximab, 5.1 weeks for low-dose ustekinumab, 6.5 weeks for high-dose etanercept, and 10.9 weeks with low-dose etanercept, while achievement of PASI 50 was closer to 1 month for IL-23 inhibitors.

“The conversation I have with patients on IL-23 inhibitors is, ‘we’re in this for the long haul,’ otherwise they come in 2 months later,” he said. “They may have gotten clearer but we’re talking about getting well over half of our patients to PASI 100, or to clear or minimal disease, and they may not have gotten there yet. It helps to frame expectations.”

Dr. Han disclosed that he is a consultant to, a speaker for, or has received research support from Beiersdorf, CeraVe, Celgene, Janssen, Lilly, MC2, Pfizer, UCB, Boehringer Ingelheim, Bond Avillion, Athenex, Amgen, AbbVie, Regeneron/Sanofi, LEO Pharma, Ortho Dermatologics, BMS, Sun Pharma, Dermavant, Dermtech, MedX, Novartis, and Castle Biosciences.

In the clinical experience of George Han, MD, PhD, treatment of psoriasis currently is often taxing for patients, with wait times to see a dermatologist exceeding 30 days in many markets and patients who present to him having cycled through many providers seeking relief from their disease.

“They come in with bags of topical products to show you what they’ve tried,” Dr. Han, associate professor of dermatology at Hofstra University, Hempstead, N.Y., said during the ODAC Dermatology, Aesthetic & Surgical Conference. “And you’re supposed to see this patient, talk to them, and counsel them in about 10 minutes. How do you make time to conduct an efficient psoriasis visit?”

Patients have a long-term battle to get clear, and spending a little longer on the initial visit “pays a lot of dividends,” he said. “Some of these patients are the most thankful patients in our practices, and it truly is gratifying” to see how much they can improve.
 

Questions about diet

Dr. Han said that psoriasis patients often ask him if, what, or how much they’re eating affects their disease. “But how do you counsel patients about diet when we’re not dietitians? We can at least give some guidance based on available data.”

He referred to a nationwide study of psoriasis patient-reported outcomes and dietary behaviors, which found that the percentage of patients who reported skin improvement was greatest after reducing intake of alcohol (53.8%); gluten (53.4%); and nightshade vegetables, such as tomatoes, potatoes, and peppers (52.1%); and after adding fish oil/omega-3 (44.6%), vegetables (42.5%), and oral vitamin D (41%). He noted that there is a threefold increased incidence of celiac disease in patients with psoriasis.

As for nightshade vegetables, intake leads to increased alkaloids, “which have been known to worsen bowel inflammation such as in IBD [inflammatory bowel disease], but there is a lack of controlled trials examining this in the overall psoriasis population,” Dr. Han said. The Mediterranean diet, he added, “is sensible, and adding olive oil to your diet seems to have a positive effect on ... PASI, while fish oil seems to reduce C-reactive protein.” The data on the effect of vitamin D supplements are mixed, he said.

A separate randomized study evaluated the impact of weight loss in overweight or obese patients with psoriasis, who had not achieved clearance after 4 weeks of systemic treatment. Significantly more of those in the dietary intervention arm reached the weight loss goal of 5% at 20 weeks, and patients in this arm had a median reduction in the Psoriasis Area and Severity Index (PASI) score of almost 50%, compared with almost 26% among those without an active dietary intervention.
 

Joint pain, PsA

For psoriasis patients who complain of joint pain, he recommends administering quick measures like the five-question Psoriasis Epidemiology Screening Test (PEST) to screen for psoriatic arthritis (PsA), which is available on the National Psoriasis Foundation web site. “I ask patients about swollen, tender joints – specifically hands, wrists, ankles, feet, and toes,” Dr. Han said. Joint stiffness in the morning is a “concerning finding,” which is “more indicative of psoriatic arthritis than vague knee or back pain that worsens with use. If you have a younger patient with back pain who has a reduced ability to flex their spine, think axial disease.”

Tumor necrosis factor (TNF)–alpha inhibitors are considered first- and second-line treatment for PsA, but interleukin (IL)–17 inhibitors are generally considered just as effective overall. “The IL-23 inhibitors have mixed signals,” said Dr. Han, who is also on the NPF’s medical board. “We know that guselkumab is effective against psoriatic arthritis, but there is no inhibition of joint progression at the approved dosage on the label – though it was pretty close.”

Risankizumab (Skyrizi), an IL-23 inhibitor, was approved in January 2022 for adults with PsA and while the American College of Rheumatology response data “look reasonably good, the results for inhibition of radiographic progression are quite far off and it’s not in the label,” he said. Tildrakizumab (Ilumya), an IL-23 inhibitor, “looks impressive in phase 2b trials. It will be interesting to see if there is differentiation between the IL-23 agents in treating joint disease going forward.”

Dr. Han considers biologic therapy a good option for patients with questionable joint involvement or very limited joint disease. “If the patient has some evidence of PsA, as long as it’s a medication that has approval for that, I’m OK with starting it,” he said. “However, for patients whose joint pain dominates over the skin, or [who] have severe joint disease at presentation, I would prioritize the TNF-alpha inhibitors and IL-17s and refer them to rheumatology for shared management.”
 

Topical, oral treatments

As for topical approaches to treating psoriasis, adding halobetasol propionate 0.01% to tazarotene 0.045% may have a synergistic effect, while tapinarof 1% cream holds promise, he said. Tapinarof, which is expected to be approved this year, is an investigative aryl hydrocarbon agonist that inhibits an array of proinflammatory cytokines, including interferon-gamma and TNF-alpha. “It has been shown to have inhibitory effects both on Th17 cytokines and Th2 cytokines,” Dr. Han said. “What’s nice about this is that patients still appear to have treatment effect 1-2 months after stopping the drug.”

Another topical agent now under FDA review for psoriasis, is roflumilast, a phosphodiesterase type 4 (PDE4) inhibitor, which has been shown to have a treatment efficacy of 30% or more. “We’ll see how this works into our treatment regimen for psoriasis,” he said, as strategies targeting PDE4 have already been reported to help treat psoriasis.

With regards to oral therapies, he said that there are concerns about the efficacy of the oral PDE4 inhibitor apremilast, approved for psoriasis, compared with other biologics. Deucravacitinib, an oral selective tyrosine kinase 2 (TYK2) inhibitor also under FDA review for psoriasis, “may fill this gap, because its efficacy seems much stronger and really capitalizes on blocking IL-23, which we know is a central pathway in the pathogenesis of psoriasis.”

Phototherapy is another treatment option. Home narrowband-UVB devices cost $3,000-$5,000, “which is a fraction of 1 year of biologic treatment,” Dr. Han said. Older data on phototherapy suggest that “lesions can clear within 2-3 months, depending on how often you do the phototherapy, while newer data suggest that 75% of patients can achieve clear or minimal disease” with phototherapy.

Biologic therapy

If patients meet criteria for treatment with a biologic, he begins the conversation by saying, “I don’t want to give you an immunosuppressant, but your psoriasis represents an overactivation of inflammation in your body, so in some way we have to bring that down. Ideally, we would target your immune system in a way that targets psoriasis very narrowly, while leaving it to do what it needs to: protecting against infections and neoplasia.”

XXXIL-17 inhibitors generally have the fastest onset of action, Dr. Han noted. Authors of a review paper found that achievement of Psoriasis Area and Severity Index (PASI) 50 was 1.8 weeks with brodalumab, 1.9 weeks for ixekizumab, 3 weeks for high-dose secukinumab, 3.5 weeks for adalimumab, 3.7 weeks for infliximab, 5.1 weeks for low-dose ustekinumab, 6.5 weeks for high-dose etanercept, and 10.9 weeks with low-dose etanercept, while achievement of PASI 50 was closer to 1 month for IL-23 inhibitors.

“The conversation I have with patients on IL-23 inhibitors is, ‘we’re in this for the long haul,’ otherwise they come in 2 months later,” he said. “They may have gotten clearer but we’re talking about getting well over half of our patients to PASI 100, or to clear or minimal disease, and they may not have gotten there yet. It helps to frame expectations.”

Dr. Han disclosed that he is a consultant to, a speaker for, or has received research support from Beiersdorf, CeraVe, Celgene, Janssen, Lilly, MC2, Pfizer, UCB, Boehringer Ingelheim, Bond Avillion, Athenex, Amgen, AbbVie, Regeneron/Sanofi, LEO Pharma, Ortho Dermatologics, BMS, Sun Pharma, Dermavant, Dermtech, MedX, Novartis, and Castle Biosciences.

In the clinical experience of George Han, MD, PhD, treatment of psoriasis currently is often taxing for patients, with wait times to see a dermatologist exceeding 30 days in many markets and patients who present to him having cycled through many providers seeking relief from their disease.

“They come in with bags of topical products to show you what they’ve tried,” Dr. Han, associate professor of dermatology at Hofstra University, Hempstead, N.Y., said during the ODAC Dermatology, Aesthetic & Surgical Conference. “And you’re supposed to see this patient, talk to them, and counsel them in about 10 minutes. How do you make time to conduct an efficient psoriasis visit?”

Patients have a long-term battle to get clear, and spending a little longer on the initial visit “pays a lot of dividends,” he said. “Some of these patients are the most thankful patients in our practices, and it truly is gratifying” to see how much they can improve.
 

Questions about diet

Dr. Han said that psoriasis patients often ask him if, what, or how much they’re eating affects their disease. “But how do you counsel patients about diet when we’re not dietitians? We can at least give some guidance based on available data.”

He referred to a nationwide study of psoriasis patient-reported outcomes and dietary behaviors, which found that the percentage of patients who reported skin improvement was greatest after reducing intake of alcohol (53.8%); gluten (53.4%); and nightshade vegetables, such as tomatoes, potatoes, and peppers (52.1%); and after adding fish oil/omega-3 (44.6%), vegetables (42.5%), and oral vitamin D (41%). He noted that there is a threefold increased incidence of celiac disease in patients with psoriasis.

As for nightshade vegetables, intake leads to increased alkaloids, “which have been known to worsen bowel inflammation such as in IBD [inflammatory bowel disease], but there is a lack of controlled trials examining this in the overall psoriasis population,” Dr. Han said. The Mediterranean diet, he added, “is sensible, and adding olive oil to your diet seems to have a positive effect on ... PASI, while fish oil seems to reduce C-reactive protein.” The data on the effect of vitamin D supplements are mixed, he said.

A separate randomized study evaluated the impact of weight loss in overweight or obese patients with psoriasis, who had not achieved clearance after 4 weeks of systemic treatment. Significantly more of those in the dietary intervention arm reached the weight loss goal of 5% at 20 weeks, and patients in this arm had a median reduction in the Psoriasis Area and Severity Index (PASI) score of almost 50%, compared with almost 26% among those without an active dietary intervention.
 

Joint pain, PsA

For psoriasis patients who complain of joint pain, he recommends administering quick measures like the five-question Psoriasis Epidemiology Screening Test (PEST) to screen for psoriatic arthritis (PsA), which is available on the National Psoriasis Foundation web site. “I ask patients about swollen, tender joints – specifically hands, wrists, ankles, feet, and toes,” Dr. Han said. Joint stiffness in the morning is a “concerning finding,” which is “more indicative of psoriatic arthritis than vague knee or back pain that worsens with use. If you have a younger patient with back pain who has a reduced ability to flex their spine, think axial disease.”

Tumor necrosis factor (TNF)–alpha inhibitors are considered first- and second-line treatment for PsA, but interleukin (IL)–17 inhibitors are generally considered just as effective overall. “The IL-23 inhibitors have mixed signals,” said Dr. Han, who is also on the NPF’s medical board. “We know that guselkumab is effective against psoriatic arthritis, but there is no inhibition of joint progression at the approved dosage on the label – though it was pretty close.”

Risankizumab (Skyrizi), an IL-23 inhibitor, was approved in January 2022 for adults with PsA and while the American College of Rheumatology response data “look reasonably good, the results for inhibition of radiographic progression are quite far off and it’s not in the label,” he said. Tildrakizumab (Ilumya), an IL-23 inhibitor, “looks impressive in phase 2b trials. It will be interesting to see if there is differentiation between the IL-23 agents in treating joint disease going forward.”

Dr. Han considers biologic therapy a good option for patients with questionable joint involvement or very limited joint disease. “If the patient has some evidence of PsA, as long as it’s a medication that has approval for that, I’m OK with starting it,” he said. “However, for patients whose joint pain dominates over the skin, or [who] have severe joint disease at presentation, I would prioritize the TNF-alpha inhibitors and IL-17s and refer them to rheumatology for shared management.”
 

Topical, oral treatments

As for topical approaches to treating psoriasis, adding halobetasol propionate 0.01% to tazarotene 0.045% may have a synergistic effect, while tapinarof 1% cream holds promise, he said. Tapinarof, which is expected to be approved this year, is an investigative aryl hydrocarbon agonist that inhibits an array of proinflammatory cytokines, including interferon-gamma and TNF-alpha. “It has been shown to have inhibitory effects both on Th17 cytokines and Th2 cytokines,” Dr. Han said. “What’s nice about this is that patients still appear to have treatment effect 1-2 months after stopping the drug.”

Another topical agent now under FDA review for psoriasis, is roflumilast, a phosphodiesterase type 4 (PDE4) inhibitor, which has been shown to have a treatment efficacy of 30% or more. “We’ll see how this works into our treatment regimen for psoriasis,” he said, as strategies targeting PDE4 have already been reported to help treat psoriasis.

With regards to oral therapies, he said that there are concerns about the efficacy of the oral PDE4 inhibitor apremilast, approved for psoriasis, compared with other biologics. Deucravacitinib, an oral selective tyrosine kinase 2 (TYK2) inhibitor also under FDA review for psoriasis, “may fill this gap, because its efficacy seems much stronger and really capitalizes on blocking IL-23, which we know is a central pathway in the pathogenesis of psoriasis.”

Phototherapy is another treatment option. Home narrowband-UVB devices cost $3,000-$5,000, “which is a fraction of 1 year of biologic treatment,” Dr. Han said. Older data on phototherapy suggest that “lesions can clear within 2-3 months, depending on how often you do the phototherapy, while newer data suggest that 75% of patients can achieve clear or minimal disease” with phototherapy.

Biologic therapy

If patients meet criteria for treatment with a biologic, he begins the conversation by saying, “I don’t want to give you an immunosuppressant, but your psoriasis represents an overactivation of inflammation in your body, so in some way we have to bring that down. Ideally, we would target your immune system in a way that targets psoriasis very narrowly, while leaving it to do what it needs to: protecting against infections and neoplasia.”

XXXIL-17 inhibitors generally have the fastest onset of action, Dr. Han noted. Authors of a review paper found that achievement of Psoriasis Area and Severity Index (PASI) 50 was 1.8 weeks with brodalumab, 1.9 weeks for ixekizumab, 3 weeks for high-dose secukinumab, 3.5 weeks for adalimumab, 3.7 weeks for infliximab, 5.1 weeks for low-dose ustekinumab, 6.5 weeks for high-dose etanercept, and 10.9 weeks with low-dose etanercept, while achievement of PASI 50 was closer to 1 month for IL-23 inhibitors.

“The conversation I have with patients on IL-23 inhibitors is, ‘we’re in this for the long haul,’ otherwise they come in 2 months later,” he said. “They may have gotten clearer but we’re talking about getting well over half of our patients to PASI 100, or to clear or minimal disease, and they may not have gotten there yet. It helps to frame expectations.”

Dr. Han disclosed that he is a consultant to, a speaker for, or has received research support from Beiersdorf, CeraVe, Celgene, Janssen, Lilly, MC2, Pfizer, UCB, Boehringer Ingelheim, Bond Avillion, Athenex, Amgen, AbbVie, Regeneron/Sanofi, LEO Pharma, Ortho Dermatologics, BMS, Sun Pharma, Dermavant, Dermtech, MedX, Novartis, and Castle Biosciences.

Current selection criteria for autologous hematopoietic stem cell transplant (AHSCT) in patients with rapidly progressing systemic sclerosis were validated in a study presented at the annual meeting of the Canadian Rheumatology Association.

The study, which associated AHSCT with improvement in overall survival and an acceptable risk of adverse events, “provides valuable real-world, long-term data pertaining to key clinical outcomes to support the use of AHSCT in patients with rapidly progressing systemic sclerosis,” reported Nancy Maltez, MD, a rheumatologist and clinical investigator who is on the faculty of the University of Ottawa.

Fnaq / Wikimedia Commons / CC BY-SA 4.0

The prospective study enrolled 85 patients in Canada and 41 patients in France with rapidly progressing systemic sclerosis. The patients in both countries were enrolled with the same eligibility criteria for AHSCT, but patients in France underwent AHSCT while the patients in Canada were treated with conventional therapies, such as cyclophosphamide.

On the primary outcome of overall survival, the Kaplan-Meier curve split almost immediately in favor of AHSCT. At 4 years, more than 25% of patients in the conventional therapy group had died versus less than 5% of those who underwent AHSCT. Although the mortality curve did slope downwards in the AHSCT group over the subsequent 6 years of follow-up, it largely paralleled and remained superior to convention therapy.
 

About 50% survival advantage seen for AHSCT

In this nonrandomized study, the statistical survival advantage of AHSCT was not provided, but the survival graph showed about 75% survival at 8 years of follow-up in the AHSCT group, compared with about 50% survival in the conventional-therapy group.

Many of the secondary outcomes, including those evaluating skin involvement, preservation of lung function, and absence of renal complications also favored AHSCT, according to Dr. Maltez.

On the modified Rodnan skin score, a significant difference (P < .001) observed at 12 months was sustained at 36 months, when the score was 4.48 points lower among patients treated with AHSCT. The difference in forced vital capacity (FVC) was about 10% higher (P < .0001) in the AHSCT group.

Over long-term follow-up, the incidence of scleroderma renal crisis per 100 person-years was 6.02 cases in the conventional therapy group versus 0.58 cases (P < .001) in the AHSCT group. There was no significant difference in the proportion of patients in the two groups receiving a pacemaker over the course of follow-up, but the rate of new malignancies per 100 person-years was 3.71 in the conventional care group versus 0.58 (P < .001) in the AHSCT group.

Significant complications attributed to AHSCT were uncommon. This is important, because AHSCT was not uniformly well tolerated in the initial trials. The first of three randomized trials with AHSCT in progressive systemic sclerosis was published more than 10 years ago after a series of promising early phase trials. Each associated AHSCT with benefit, but patient selection appeared to be important.

In the ASSIST trial of 2011, AHSCT was associated with significant reductions in skin involvement and improvements in pulmonary function relative to cyclophosphamide, but enrollment was stopped after only 19 patients, and follow-up extended to only 2 years.

Substantial AHSCT-related mortality in ASTIS

In the second trial, called ASTIS, AHSCT was associated with a higher rate of mortality than cyclophosphamide after 1 year of follow-up, although there was a significantly greater long-term event-free survival for AHSCT when patients were followed out to 4 years. This study reinforced the need for cardiac screening because of because of concern that severe cardiac compromise contributed to the increased risk of AHSCT-related mortality.

The SCOT trial employed a high-intensity myeloablative conditioning regimen and total body irradiation prior to AHSCT. It is not clear that these contributed to improved survival, particularly because of the risk for irradiation to exacerbate complications in the lung and kidney, but AHSCT-related mortality was only 3% at 54 months. Patient enrollment criteria in this trial were also suspected of having played a role in the favorable results.

In the Canadian-French collaborative study, patients were considered eligible for AHSCT if they met the enrollment criteria used in the ASTIS trial, according to Dr. Maltez. She attributed the low rates of early mortality and relative absence of transplant-related death to the lessons learned in the published trials.

Overall, the data support the routine but selective use of AHSCT in rapidly progressing systemic sclerosis, Dr. Maltez concluded.

Maria Carolina Oliveira, MD, of the department of internal medicine at the University of São Paulo, generally agreed. A coauthor of a recent review of AHSCT for systemic sclerosis, Dr. Oliveira emphasized that patient selection is critical.

“AHSCT for systemic sclerosis has very specific inclusion criteria. Indeed, it is indicated for patients with severe and progressive disease but under two specific conditions: severe and progressive diffuse skin involvement and/or progressive interstitial lung disease,” she said in an interview.

Because of the thin line between benefit and risk according to disease subtypes and comorbidities, she said that it is important to be aware of relative contraindications and to recognize the risks of AHSCT.

At this time, and in the absence of better biomarkers to identify those most likely to benefit, “patients with other forms of severe scleroderma, such as those with pulmonary hypertension, scleroderma renal crisis, or severe cardiac involvement, for example, are not eligible,” she said.

Dr. Maltez and Dr. Oliveira reported having no potential conflicts of interest.

Current selection criteria for autologous hematopoietic stem cell transplant (AHSCT) in patients with rapidly progressing systemic sclerosis were validated in a study presented at the annual meeting of the Canadian Rheumatology Association.

The study, which associated AHSCT with improvement in overall survival and an acceptable risk of adverse events, “provides valuable real-world, long-term data pertaining to key clinical outcomes to support the use of AHSCT in patients with rapidly progressing systemic sclerosis,” reported Nancy Maltez, MD, a rheumatologist and clinical investigator who is on the faculty of the University of Ottawa.

Fnaq / Wikimedia Commons / CC BY-SA 4.0

The prospective study enrolled 85 patients in Canada and 41 patients in France with rapidly progressing systemic sclerosis. The patients in both countries were enrolled with the same eligibility criteria for AHSCT, but patients in France underwent AHSCT while the patients in Canada were treated with conventional therapies, such as cyclophosphamide.

On the primary outcome of overall survival, the Kaplan-Meier curve split almost immediately in favor of AHSCT. At 4 years, more than 25% of patients in the conventional therapy group had died versus less than 5% of those who underwent AHSCT. Although the mortality curve did slope downwards in the AHSCT group over the subsequent 6 years of follow-up, it largely paralleled and remained superior to convention therapy.
 

About 50% survival advantage seen for AHSCT

In this nonrandomized study, the statistical survival advantage of AHSCT was not provided, but the survival graph showed about 75% survival at 8 years of follow-up in the AHSCT group, compared with about 50% survival in the conventional-therapy group.

Many of the secondary outcomes, including those evaluating skin involvement, preservation of lung function, and absence of renal complications also favored AHSCT, according to Dr. Maltez.

On the modified Rodnan skin score, a significant difference (P < .001) observed at 12 months was sustained at 36 months, when the score was 4.48 points lower among patients treated with AHSCT. The difference in forced vital capacity (FVC) was about 10% higher (P < .0001) in the AHSCT group.

Over long-term follow-up, the incidence of scleroderma renal crisis per 100 person-years was 6.02 cases in the conventional therapy group versus 0.58 cases (P < .001) in the AHSCT group. There was no significant difference in the proportion of patients in the two groups receiving a pacemaker over the course of follow-up, but the rate of new malignancies per 100 person-years was 3.71 in the conventional care group versus 0.58 (P < .001) in the AHSCT group.

Significant complications attributed to AHSCT were uncommon. This is important, because AHSCT was not uniformly well tolerated in the initial trials. The first of three randomized trials with AHSCT in progressive systemic sclerosis was published more than 10 years ago after a series of promising early phase trials. Each associated AHSCT with benefit, but patient selection appeared to be important.

In the ASSIST trial of 2011, AHSCT was associated with significant reductions in skin involvement and improvements in pulmonary function relative to cyclophosphamide, but enrollment was stopped after only 19 patients, and follow-up extended to only 2 years.

Substantial AHSCT-related mortality in ASTIS

In the second trial, called ASTIS, AHSCT was associated with a higher rate of mortality than cyclophosphamide after 1 year of follow-up, although there was a significantly greater long-term event-free survival for AHSCT when patients were followed out to 4 years. This study reinforced the need for cardiac screening because of because of concern that severe cardiac compromise contributed to the increased risk of AHSCT-related mortality.

The SCOT trial employed a high-intensity myeloablative conditioning regimen and total body irradiation prior to AHSCT. It is not clear that these contributed to improved survival, particularly because of the risk for irradiation to exacerbate complications in the lung and kidney, but AHSCT-related mortality was only 3% at 54 months. Patient enrollment criteria in this trial were also suspected of having played a role in the favorable results.

In the Canadian-French collaborative study, patients were considered eligible for AHSCT if they met the enrollment criteria used in the ASTIS trial, according to Dr. Maltez. She attributed the low rates of early mortality and relative absence of transplant-related death to the lessons learned in the published trials.

Overall, the data support the routine but selective use of AHSCT in rapidly progressing systemic sclerosis, Dr. Maltez concluded.

Maria Carolina Oliveira, MD, of the department of internal medicine at the University of São Paulo, generally agreed. A coauthor of a recent review of AHSCT for systemic sclerosis, Dr. Oliveira emphasized that patient selection is critical.

“AHSCT for systemic sclerosis has very specific inclusion criteria. Indeed, it is indicated for patients with severe and progressive disease but under two specific conditions: severe and progressive diffuse skin involvement and/or progressive interstitial lung disease,” she said in an interview.

Because of the thin line between benefit and risk according to disease subtypes and comorbidities, she said that it is important to be aware of relative contraindications and to recognize the risks of AHSCT.

At this time, and in the absence of better biomarkers to identify those most likely to benefit, “patients with other forms of severe scleroderma, such as those with pulmonary hypertension, scleroderma renal crisis, or severe cardiac involvement, for example, are not eligible,” she said.

Dr. Maltez and Dr. Oliveira reported having no potential conflicts of interest.

Current selection criteria for autologous hematopoietic stem cell transplant (AHSCT) in patients with rapidly progressing systemic sclerosis were validated in a study presented at the annual meeting of the Canadian Rheumatology Association.

The study, which associated AHSCT with improvement in overall survival and an acceptable risk of adverse events, “provides valuable real-world, long-term data pertaining to key clinical outcomes to support the use of AHSCT in patients with rapidly progressing systemic sclerosis,” reported Nancy Maltez, MD, a rheumatologist and clinical investigator who is on the faculty of the University of Ottawa.

Fnaq / Wikimedia Commons / CC BY-SA 4.0

The prospective study enrolled 85 patients in Canada and 41 patients in France with rapidly progressing systemic sclerosis. The patients in both countries were enrolled with the same eligibility criteria for AHSCT, but patients in France underwent AHSCT while the patients in Canada were treated with conventional therapies, such as cyclophosphamide.

On the primary outcome of overall survival, the Kaplan-Meier curve split almost immediately in favor of AHSCT. At 4 years, more than 25% of patients in the conventional therapy group had died versus less than 5% of those who underwent AHSCT. Although the mortality curve did slope downwards in the AHSCT group over the subsequent 6 years of follow-up, it largely paralleled and remained superior to convention therapy.
 

About 50% survival advantage seen for AHSCT

In this nonrandomized study, the statistical survival advantage of AHSCT was not provided, but the survival graph showed about 75% survival at 8 years of follow-up in the AHSCT group, compared with about 50% survival in the conventional-therapy group.

Many of the secondary outcomes, including those evaluating skin involvement, preservation of lung function, and absence of renal complications also favored AHSCT, according to Dr. Maltez.

On the modified Rodnan skin score, a significant difference (P < .001) observed at 12 months was sustained at 36 months, when the score was 4.48 points lower among patients treated with AHSCT. The difference in forced vital capacity (FVC) was about 10% higher (P < .0001) in the AHSCT group.

Over long-term follow-up, the incidence of scleroderma renal crisis per 100 person-years was 6.02 cases in the conventional therapy group versus 0.58 cases (P < .001) in the AHSCT group. There was no significant difference in the proportion of patients in the two groups receiving a pacemaker over the course of follow-up, but the rate of new malignancies per 100 person-years was 3.71 in the conventional care group versus 0.58 (P < .001) in the AHSCT group.

Significant complications attributed to AHSCT were uncommon. This is important, because AHSCT was not uniformly well tolerated in the initial trials. The first of three randomized trials with AHSCT in progressive systemic sclerosis was published more than 10 years ago after a series of promising early phase trials. Each associated AHSCT with benefit, but patient selection appeared to be important.

In the ASSIST trial of 2011, AHSCT was associated with significant reductions in skin involvement and improvements in pulmonary function relative to cyclophosphamide, but enrollment was stopped after only 19 patients, and follow-up extended to only 2 years.

Substantial AHSCT-related mortality in ASTIS

In the second trial, called ASTIS, AHSCT was associated with a higher rate of mortality than cyclophosphamide after 1 year of follow-up, although there was a significantly greater long-term event-free survival for AHSCT when patients were followed out to 4 years. This study reinforced the need for cardiac screening because of because of concern that severe cardiac compromise contributed to the increased risk of AHSCT-related mortality.

The SCOT trial employed a high-intensity myeloablative conditioning regimen and total body irradiation prior to AHSCT. It is not clear that these contributed to improved survival, particularly because of the risk for irradiation to exacerbate complications in the lung and kidney, but AHSCT-related mortality was only 3% at 54 months. Patient enrollment criteria in this trial were also suspected of having played a role in the favorable results.

In the Canadian-French collaborative study, patients were considered eligible for AHSCT if they met the enrollment criteria used in the ASTIS trial, according to Dr. Maltez. She attributed the low rates of early mortality and relative absence of transplant-related death to the lessons learned in the published trials.

Overall, the data support the routine but selective use of AHSCT in rapidly progressing systemic sclerosis, Dr. Maltez concluded.

Maria Carolina Oliveira, MD, of the department of internal medicine at the University of São Paulo, generally agreed. A coauthor of a recent review of AHSCT for systemic sclerosis, Dr. Oliveira emphasized that patient selection is critical.

“AHSCT for systemic sclerosis has very specific inclusion criteria. Indeed, it is indicated for patients with severe and progressive disease but under two specific conditions: severe and progressive diffuse skin involvement and/or progressive interstitial lung disease,” she said in an interview.

Because of the thin line between benefit and risk according to disease subtypes and comorbidities, she said that it is important to be aware of relative contraindications and to recognize the risks of AHSCT.

At this time, and in the absence of better biomarkers to identify those most likely to benefit, “patients with other forms of severe scleroderma, such as those with pulmonary hypertension, scleroderma renal crisis, or severe cardiac involvement, for example, are not eligible,” she said.

Dr. Maltez and Dr. Oliveira reported having no potential conflicts of interest.

Aggressive up-front combination therapy, more lofty treatment goals, and earlier and more frequent reassessments to guide treatment are improving care of patients with pulmonary arterial hypertension (PAH) while at the same time making it more complex.

A larger number of oral and generic treatment options have in some respects ushered in more management ease. But overall, “I don’t know if management of these patients has ever been more complicated, given the treatment options and strategies,” said Murali M. Chakinala, MD, professor of medicine at Washington University, St. Louis. “We’re always thinking through approaches.”

Diagnosis continues to be challenging given the rarity of PAH and its nonspecific presentation – and in some cases it’s now harder. Experts such as Dr. Chakinala are seeing increasing number of aging patients with left heart disease, chronic kidney disease, and other comorbidities who have significant precapillary pulmonary hypertension and who exhibit hemodynamics consistent with PAH, or group 1 PH.

The question experts face is, do such patients have “true PAH,” as do a reported 25-50 people per million, or do they have another type of PH in the classification schema – or a mixture?

Deciding which patients “really fit into group 1 and should be managed like group 1,” Dr. Chakinala said, requires clinical acumen and has important implications, as patients with PAH are the main beneficiaries of vasodilator therapy. Most other patients with PH will not respond to or tolerate such treatment.

“These older patients may be getting PAH through different mechanisms than our younger patients, but because we define PAH through hemodynamic criteria and by ruling out other obvious explanations, they all get lumped together,” said Dr. Chakinala. “We need to parse these patients out better in the future, much like our oncology colleagues are doing.”

Yale Rosen/Wikimedia Commons/Creative Commons Attribution-Share Alike 2.0 Generi

Personalized medicine hopefully is the next horizon for this condition, characterized by severe remodeling of the distal pulmonary arteries. Researchers are pushing to achieve deep phenotyping, identify biomarkers and improve risk assessment tools.

And with 80 or so centers now accredited by the Pulmonary Hypertension Association as Pulmonary Hypertension Care Centers, referred patients are accessing clinical trials of new nonvasodilatory drugs. Currently available therapies improve hemodynamics and symptoms, and can slow disease progression, but are not truly disease modifying, sources say.

“The endothelin, nitric oxide, and prostacyclin pathways have been exhaustively studied and we now have great drugs for those pathways,” said Dr. Chakinala, who leads the PHA’s scientific leadership council. But “we’re not going to put a greater dent into this disease until we have new drugs that work on different biologic pathways.”
 

Diagnostic challenges

The diagnosis of PAH – a remarkably heterogeneous condition that encompasses heritable forms and idiopathic forms, and that comprises a broad mix of predisposing conditions and exposures, from scleroderma to methamphetamine use – is still too often missed or delayed. Delayed diagnoses and misdiagnoses of PAH and other types of PH have been reported in up to 85% of at-risk patients, according to a 2016 literature review.

Being able to pivot from thinking about common pulmonary ailments or heart failure to considering PAH is a key part of earlier diagnosis and better treatment outcomes. “If someone has unexplained dyspnea or if they’re treated for other lung diseases and are not improving, think about a screening echocardiogram,” said Timothy L. Williamson, MD, vice president of quality and safety and a pulmonary and critical care physician at the University of Kansas Health Center, Kansas City.

One of the most common reasons Dr. Chakinala sees for missed diagnoses are right heart catheterizations that are incomplete or misinterpreted. (Right heart catheterizations are required to confirm the diagnosis.) “One can’t simply measure pressures and stop,” he said. “We need the full hemodynamic profile to know that it’s truly precapillary PAH ... and we need proper interpretation of [elements like] the waveforms.”

The 2019 World Symposium on Pulmonary Hypertension shifted the definition of PH from an arbitrarily defined mean pulmonary arterial pressure of at least 25 mm Hg at rest (as measured by right heart catheterization) to a more scientifically determined mPAP of at least 20 mm Hg.

The classification document also requires pulmonary vascular resistance (PVR) of at least 3 Wood units in the definition of all forms of precapillary PH. PAH specifically is defined as the presence of mPAP of at least 20 mm Hg, PVR of at least 3 Wood units, and pulmonary arterial wedge pressure 15 mm Hg or less.
 

Trends in treatment

The value of initial combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 (PDE5) inhibitor in treatment-naive PAH was cemented in 2015 by the AMBITION trial. The primary endpoint (death, PAH hospitalization, or unsatisfactory clinical response) occurred in 18%, 34%, and 28% of patients who were randomized, respectively, to combination therapy, monotherapy with the ERA ambrisentan, or monotherapy with the PDE-5 inhibitor tadalafil – and in 31% of the two monotherapy groups combined.

The trial reported a 50% reduction in the primary endpoint in the combination-therapy group versus the pooled monotherapy group, as well as greater reductions in N-terminal of the prohormone brain natriuretic peptide levels, more satisfactory clinical response and greater improvement in 6-minute walking distance.

In practice, a minority of patients – typically older patients with multiple comorbidities – still receive initial monotherapy with sequential add-on therapies based on tolerance, but “for the most part PAH patients will start on combination therapy, most commonly with a ERA and PDE5 inhibitor,” Dr. Chakinala said.

For patients who are not improving on the ERA-PDE5 inhibitor approach – typically those who remain in the intermediate-risk category for intermediate-term mortality – substitution of the PDE5 inhibitor with the soluble guanylate cyclase stimulator riociguat may be considered, he and Dr. Williamson said. Clinical improvement with this substitution was demonstrated in the REPLACE trial.

Experts at PH care centers are also utilizing triple therapy for patients who do not improve to low-risk status after 2-4 months of dual combination therapy. The availability of oral prostacyclin analogues (selexipag and treprostinil) makes it easier to consider adding these agents early on, Dr. Chakinala and Dr. Richardson said.

Patients who fall into the high-risk category, at any point, are still best managed with parenteral prostacyclin analogues, Dr. Chakinala said.

In general, said Dr. Williamson, who also directs the University of Kansas Pulmonary Hypertension Comprehensive Care Center, “the PH community tends to be fairly aggressive up front, and with a low threshold for using prostacyclin analogues.”

The agents are “always part of the picture for someone who is really ill, in functional class IV, or has really impaired right ventricular function,” he said. “And we’re finding increased roles in patients who are not as ill but still have decompensated right ventricular dysfunction. It’s something we now consider.”

Recently published research on up-front oral triple therapy suggests possible benefit for some patients – but it’s far from conclusive, said Dr. Chakinala. The TRITON study randomized treatment-naive patients to the traditional ERA-PDE5 combination and either oral selexipag (a selective prostacyclin receptor agonist) or placebo as a third agent. It found no significant difference in reduction in PVR, the primary outcome, at week 26. However, the authors reported a “possible signal” for improved long-term outcomes with triple therapy.

“Based on this best evidence from a randomized clinical trial, I think it’s unfair to say that all patients should be on triple combination therapy right out of the gate,” he said. “Having said that, more recent [European] data showed that two drugs fell short of the mark in some patients, with high rates of clinical progression. And even in AMBITION, there were a number of patients in the combination arm who didn’t have a robust response.”

A 2021 retrospective analysis from the French Pulmonary Hypertension Registry – one of the European studies – assessed survival with monotherapy, dual therapy, or triple-combination therapy (two orals with a parenteral prostacyclin), and found no difference between monotherapy and dual therapy in high-risk patients.

Experts have been upping the ante, therefore, on early assessment and frequent reassessment of treatment response. Not long ago, patients were typically reassessed 6-12 months after the initiation of treatment. Now, experts at the PH care centers want to assess patients at 3-4 months and adjust or intensify treatment regimens for those who don’t yet qualify as low risk using a multidimensional risk score calculator.

The REVEAL (Registry to Evaluate Early and Long-Term PAH Management) risk score calculator, for instance, predicts the probability of 1-year survival and assigns patients to a strata of risk level based on either 12 or 6 variables (for the full or “lite” versions).]

Even better monitoring and risk assessment is needed, however, to “help sift out which patients are not improving enough on initial therapy or who are starting to fall off after being on a regimen for a period of time,” Dr. Chakinala said.

Today, with a network of accredited centers of expertise and a desire and need for many patients to remain close to home, Dr. Chakinala encourages finding a balance. Well-resourced clinicians can strive for early diagnosis and management – potentially initiating ERA–PDE-5 inhibitor combination therapy – but still should collaborate with PH experts.

“It’s a good idea to comanage these patients and let the experts see them periodically to help you determine when your patient may be declining,” he said. “The timetable for reassessment, the complexity of the reassessment, and the need to escalate to more advanced therapies has never been more important.”
 

Research highlights

Therapies that target inflammation and altered metabolism – including metformin – are among those being investigated for PAH. So are therapies targeting dysfunctional bone morphogenetic protein pathway signaling, which has been shown to be associated with hereditary, idiopathic, and likely other forms of PAH; one such drug, called sotatercept, is currently at the phase 3 trial stage.

Most promising for PAH may be the research efforts involving deep phenotyping, said Andrew J. Sweatt, MD, of Stanford (Calif.) University and the Vera Moulton Wall Center for Pulmonary Vascular Disease.

“It’s where a lot of research is headed – deep phenotyping to deconstruct the molecular and clinical heterogeneity that exists within PAH ... to detect distinct subphenotypes of patients who would respond to particular therapies,” said Dr. Sweatt, who led a review of PH clinical research presented at the 2020 American Thoracic Society International Conference

“Right now, we largely treat all patients the same ... [while] we know that patients have a wide response to therapies and there’s a lot of clinical heterogeneity in how their disease evolves over time,” he said.

Data from a large National Institutes of Health–funded multicenter phenotyping study of PH is being analyzed and should yield findings and publications starting this year, said Anna R. Hemnes, MD, associate professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn., and an investigator with the initiative, coined “Redefining Pulmonary Hypertension through Pulmonary Disease Phenomics (PVDOMICS).”

Patients have undergone advanced imaging (for example, echocardiography, cardiac MRI, chest CT, ventilation/perfusion scans), advanced testing through right heart catheterization, body composition testing, quality of life questionnaires, and blood draws that have been analyzed for DNA and RNA expression, proteomics, and metabolomics, said Dr. Hemnes, assistant director of Vanderbilt’s Pulmonary Vascular Center.

The initiative aims to refine the classification of all kinds of PH and “to bring precision medicine to the field so we’re no longer characterizing somebody [based on imaging] and right heart catheterization, but we also incorporating molecular pieces and biomarkers into the diagnostic evaluation,” she said.

In the short term, the results of deep phenotyping should “allow us to be more effective with our therapy recommendations,” Dr. Hemnes said. “Then hopefully in the longer term, [identified biomarkers] will help us to develop new, more effective therapies.”

Dr. Sweatt and Dr. Williamson reported that they have no relevant financial disclosures. Dr. Hemnes reported that she holds stock in Tenax (which is studying a tyrosine kinase inhibitor for PAH) and serves as a consultant for Acceleron, Bayer, GossamerBio, United Therapeutics, and Janssen. She also receives research funding from Imara. Dr. Chakinala reported that he is an investigator on clinical trials for a number of pharmaceutical companies. He also serves on advisory boards for Phase Bio, Liquidia/Rare Gen, Bayer, Janssen, Trio Health Analytics, and Aerovate.

Aggressive up-front combination therapy, more lofty treatment goals, and earlier and more frequent reassessments to guide treatment are improving care of patients with pulmonary arterial hypertension (PAH) while at the same time making it more complex.

A larger number of oral and generic treatment options have in some respects ushered in more management ease. But overall, “I don’t know if management of these patients has ever been more complicated, given the treatment options and strategies,” said Murali M. Chakinala, MD, professor of medicine at Washington University, St. Louis. “We’re always thinking through approaches.”

Diagnosis continues to be challenging given the rarity of PAH and its nonspecific presentation – and in some cases it’s now harder. Experts such as Dr. Chakinala are seeing increasing number of aging patients with left heart disease, chronic kidney disease, and other comorbidities who have significant precapillary pulmonary hypertension and who exhibit hemodynamics consistent with PAH, or group 1 PH.

The question experts face is, do such patients have “true PAH,” as do a reported 25-50 people per million, or do they have another type of PH in the classification schema – or a mixture?

Deciding which patients “really fit into group 1 and should be managed like group 1,” Dr. Chakinala said, requires clinical acumen and has important implications, as patients with PAH are the main beneficiaries of vasodilator therapy. Most other patients with PH will not respond to or tolerate such treatment.

“These older patients may be getting PAH through different mechanisms than our younger patients, but because we define PAH through hemodynamic criteria and by ruling out other obvious explanations, they all get lumped together,” said Dr. Chakinala. “We need to parse these patients out better in the future, much like our oncology colleagues are doing.”

Yale Rosen/Wikimedia Commons/Creative Commons Attribution-Share Alike 2.0 Generi

Personalized medicine hopefully is the next horizon for this condition, characterized by severe remodeling of the distal pulmonary arteries. Researchers are pushing to achieve deep phenotyping, identify biomarkers and improve risk assessment tools.

And with 80 or so centers now accredited by the Pulmonary Hypertension Association as Pulmonary Hypertension Care Centers, referred patients are accessing clinical trials of new nonvasodilatory drugs. Currently available therapies improve hemodynamics and symptoms, and can slow disease progression, but are not truly disease modifying, sources say.

“The endothelin, nitric oxide, and prostacyclin pathways have been exhaustively studied and we now have great drugs for those pathways,” said Dr. Chakinala, who leads the PHA’s scientific leadership council. But “we’re not going to put a greater dent into this disease until we have new drugs that work on different biologic pathways.”
 

Diagnostic challenges

The diagnosis of PAH – a remarkably heterogeneous condition that encompasses heritable forms and idiopathic forms, and that comprises a broad mix of predisposing conditions and exposures, from scleroderma to methamphetamine use – is still too often missed or delayed. Delayed diagnoses and misdiagnoses of PAH and other types of PH have been reported in up to 85% of at-risk patients, according to a 2016 literature review.

Being able to pivot from thinking about common pulmonary ailments or heart failure to considering PAH is a key part of earlier diagnosis and better treatment outcomes. “If someone has unexplained dyspnea or if they’re treated for other lung diseases and are not improving, think about a screening echocardiogram,” said Timothy L. Williamson, MD, vice president of quality and safety and a pulmonary and critical care physician at the University of Kansas Health Center, Kansas City.

One of the most common reasons Dr. Chakinala sees for missed diagnoses are right heart catheterizations that are incomplete or misinterpreted. (Right heart catheterizations are required to confirm the diagnosis.) “One can’t simply measure pressures and stop,” he said. “We need the full hemodynamic profile to know that it’s truly precapillary PAH ... and we need proper interpretation of [elements like] the waveforms.”

The 2019 World Symposium on Pulmonary Hypertension shifted the definition of PH from an arbitrarily defined mean pulmonary arterial pressure of at least 25 mm Hg at rest (as measured by right heart catheterization) to a more scientifically determined mPAP of at least 20 mm Hg.

The classification document also requires pulmonary vascular resistance (PVR) of at least 3 Wood units in the definition of all forms of precapillary PH. PAH specifically is defined as the presence of mPAP of at least 20 mm Hg, PVR of at least 3 Wood units, and pulmonary arterial wedge pressure 15 mm Hg or less.
 

Trends in treatment

The value of initial combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 (PDE5) inhibitor in treatment-naive PAH was cemented in 2015 by the AMBITION trial. The primary endpoint (death, PAH hospitalization, or unsatisfactory clinical response) occurred in 18%, 34%, and 28% of patients who were randomized, respectively, to combination therapy, monotherapy with the ERA ambrisentan, or monotherapy with the PDE-5 inhibitor tadalafil – and in 31% of the two monotherapy groups combined.

The trial reported a 50% reduction in the primary endpoint in the combination-therapy group versus the pooled monotherapy group, as well as greater reductions in N-terminal of the prohormone brain natriuretic peptide levels, more satisfactory clinical response and greater improvement in 6-minute walking distance.

In practice, a minority of patients – typically older patients with multiple comorbidities – still receive initial monotherapy with sequential add-on therapies based on tolerance, but “for the most part PAH patients will start on combination therapy, most commonly with a ERA and PDE5 inhibitor,” Dr. Chakinala said.

For patients who are not improving on the ERA-PDE5 inhibitor approach – typically those who remain in the intermediate-risk category for intermediate-term mortality – substitution of the PDE5 inhibitor with the soluble guanylate cyclase stimulator riociguat may be considered, he and Dr. Williamson said. Clinical improvement with this substitution was demonstrated in the REPLACE trial.

Experts at PH care centers are also utilizing triple therapy for patients who do not improve to low-risk status after 2-4 months of dual combination therapy. The availability of oral prostacyclin analogues (selexipag and treprostinil) makes it easier to consider adding these agents early on, Dr. Chakinala and Dr. Richardson said.

Patients who fall into the high-risk category, at any point, are still best managed with parenteral prostacyclin analogues, Dr. Chakinala said.

In general, said Dr. Williamson, who also directs the University of Kansas Pulmonary Hypertension Comprehensive Care Center, “the PH community tends to be fairly aggressive up front, and with a low threshold for using prostacyclin analogues.”

The agents are “always part of the picture for someone who is really ill, in functional class IV, or has really impaired right ventricular function,” he said. “And we’re finding increased roles in patients who are not as ill but still have decompensated right ventricular dysfunction. It’s something we now consider.”

Recently published research on up-front oral triple therapy suggests possible benefit for some patients – but it’s far from conclusive, said Dr. Chakinala. The TRITON study randomized treatment-naive patients to the traditional ERA-PDE5 combination and either oral selexipag (a selective prostacyclin receptor agonist) or placebo as a third agent. It found no significant difference in reduction in PVR, the primary outcome, at week 26. However, the authors reported a “possible signal” for improved long-term outcomes with triple therapy.

“Based on this best evidence from a randomized clinical trial, I think it’s unfair to say that all patients should be on triple combination therapy right out of the gate,” he said. “Having said that, more recent [European] data showed that two drugs fell short of the mark in some patients, with high rates of clinical progression. And even in AMBITION, there were a number of patients in the combination arm who didn’t have a robust response.”

A 2021 retrospective analysis from the French Pulmonary Hypertension Registry – one of the European studies – assessed survival with monotherapy, dual therapy, or triple-combination therapy (two orals with a parenteral prostacyclin), and found no difference between monotherapy and dual therapy in high-risk patients.

Experts have been upping the ante, therefore, on early assessment and frequent reassessment of treatment response. Not long ago, patients were typically reassessed 6-12 months after the initiation of treatment. Now, experts at the PH care centers want to assess patients at 3-4 months and adjust or intensify treatment regimens for those who don’t yet qualify as low risk using a multidimensional risk score calculator.

The REVEAL (Registry to Evaluate Early and Long-Term PAH Management) risk score calculator, for instance, predicts the probability of 1-year survival and assigns patients to a strata of risk level based on either 12 or 6 variables (for the full or “lite” versions).]

Even better monitoring and risk assessment is needed, however, to “help sift out which patients are not improving enough on initial therapy or who are starting to fall off after being on a regimen for a period of time,” Dr. Chakinala said.

Today, with a network of accredited centers of expertise and a desire and need for many patients to remain close to home, Dr. Chakinala encourages finding a balance. Well-resourced clinicians can strive for early diagnosis and management – potentially initiating ERA–PDE-5 inhibitor combination therapy – but still should collaborate with PH experts.

“It’s a good idea to comanage these patients and let the experts see them periodically to help you determine when your patient may be declining,” he said. “The timetable for reassessment, the complexity of the reassessment, and the need to escalate to more advanced therapies has never been more important.”
 

Research highlights

Therapies that target inflammation and altered metabolism – including metformin – are among those being investigated for PAH. So are therapies targeting dysfunctional bone morphogenetic protein pathway signaling, which has been shown to be associated with hereditary, idiopathic, and likely other forms of PAH; one such drug, called sotatercept, is currently at the phase 3 trial stage.

Most promising for PAH may be the research efforts involving deep phenotyping, said Andrew J. Sweatt, MD, of Stanford (Calif.) University and the Vera Moulton Wall Center for Pulmonary Vascular Disease.

“It’s where a lot of research is headed – deep phenotyping to deconstruct the molecular and clinical heterogeneity that exists within PAH ... to detect distinct subphenotypes of patients who would respond to particular therapies,” said Dr. Sweatt, who led a review of PH clinical research presented at the 2020 American Thoracic Society International Conference

“Right now, we largely treat all patients the same ... [while] we know that patients have a wide response to therapies and there’s a lot of clinical heterogeneity in how their disease evolves over time,” he said.

Data from a large National Institutes of Health–funded multicenter phenotyping study of PH is being analyzed and should yield findings and publications starting this year, said Anna R. Hemnes, MD, associate professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn., and an investigator with the initiative, coined “Redefining Pulmonary Hypertension through Pulmonary Disease Phenomics (PVDOMICS).”

Patients have undergone advanced imaging (for example, echocardiography, cardiac MRI, chest CT, ventilation/perfusion scans), advanced testing through right heart catheterization, body composition testing, quality of life questionnaires, and blood draws that have been analyzed for DNA and RNA expression, proteomics, and metabolomics, said Dr. Hemnes, assistant director of Vanderbilt’s Pulmonary Vascular Center.

The initiative aims to refine the classification of all kinds of PH and “to bring precision medicine to the field so we’re no longer characterizing somebody [based on imaging] and right heart catheterization, but we also incorporating molecular pieces and biomarkers into the diagnostic evaluation,” she said.

In the short term, the results of deep phenotyping should “allow us to be more effective with our therapy recommendations,” Dr. Hemnes said. “Then hopefully in the longer term, [identified biomarkers] will help us to develop new, more effective therapies.”

Dr. Sweatt and Dr. Williamson reported that they have no relevant financial disclosures. Dr. Hemnes reported that she holds stock in Tenax (which is studying a tyrosine kinase inhibitor for PAH) and serves as a consultant for Acceleron, Bayer, GossamerBio, United Therapeutics, and Janssen. She also receives research funding from Imara. Dr. Chakinala reported that he is an investigator on clinical trials for a number of pharmaceutical companies. He also serves on advisory boards for Phase Bio, Liquidia/Rare Gen, Bayer, Janssen, Trio Health Analytics, and Aerovate.

Aggressive up-front combination therapy, more lofty treatment goals, and earlier and more frequent reassessments to guide treatment are improving care of patients with pulmonary arterial hypertension (PAH) while at the same time making it more complex.

A larger number of oral and generic treatment options have in some respects ushered in more management ease. But overall, “I don’t know if management of these patients has ever been more complicated, given the treatment options and strategies,” said Murali M. Chakinala, MD, professor of medicine at Washington University, St. Louis. “We’re always thinking through approaches.”

Diagnosis continues to be challenging given the rarity of PAH and its nonspecific presentation – and in some cases it’s now harder. Experts such as Dr. Chakinala are seeing increasing number of aging patients with left heart disease, chronic kidney disease, and other comorbidities who have significant precapillary pulmonary hypertension and who exhibit hemodynamics consistent with PAH, or group 1 PH.

The question experts face is, do such patients have “true PAH,” as do a reported 25-50 people per million, or do they have another type of PH in the classification schema – or a mixture?

Deciding which patients “really fit into group 1 and should be managed like group 1,” Dr. Chakinala said, requires clinical acumen and has important implications, as patients with PAH are the main beneficiaries of vasodilator therapy. Most other patients with PH will not respond to or tolerate such treatment.

“These older patients may be getting PAH through different mechanisms than our younger patients, but because we define PAH through hemodynamic criteria and by ruling out other obvious explanations, they all get lumped together,” said Dr. Chakinala. “We need to parse these patients out better in the future, much like our oncology colleagues are doing.”

Yale Rosen/Wikimedia Commons/Creative Commons Attribution-Share Alike 2.0 Generi

Personalized medicine hopefully is the next horizon for this condition, characterized by severe remodeling of the distal pulmonary arteries. Researchers are pushing to achieve deep phenotyping, identify biomarkers and improve risk assessment tools.

And with 80 or so centers now accredited by the Pulmonary Hypertension Association as Pulmonary Hypertension Care Centers, referred patients are accessing clinical trials of new nonvasodilatory drugs. Currently available therapies improve hemodynamics and symptoms, and can slow disease progression, but are not truly disease modifying, sources say.

“The endothelin, nitric oxide, and prostacyclin pathways have been exhaustively studied and we now have great drugs for those pathways,” said Dr. Chakinala, who leads the PHA’s scientific leadership council. But “we’re not going to put a greater dent into this disease until we have new drugs that work on different biologic pathways.”
 

Diagnostic challenges

The diagnosis of PAH – a remarkably heterogeneous condition that encompasses heritable forms and idiopathic forms, and that comprises a broad mix of predisposing conditions and exposures, from scleroderma to methamphetamine use – is still too often missed or delayed. Delayed diagnoses and misdiagnoses of PAH and other types of PH have been reported in up to 85% of at-risk patients, according to a 2016 literature review.

Being able to pivot from thinking about common pulmonary ailments or heart failure to considering PAH is a key part of earlier diagnosis and better treatment outcomes. “If someone has unexplained dyspnea or if they’re treated for other lung diseases and are not improving, think about a screening echocardiogram,” said Timothy L. Williamson, MD, vice president of quality and safety and a pulmonary and critical care physician at the University of Kansas Health Center, Kansas City.

One of the most common reasons Dr. Chakinala sees for missed diagnoses are right heart catheterizations that are incomplete or misinterpreted. (Right heart catheterizations are required to confirm the diagnosis.) “One can’t simply measure pressures and stop,” he said. “We need the full hemodynamic profile to know that it’s truly precapillary PAH ... and we need proper interpretation of [elements like] the waveforms.”

The 2019 World Symposium on Pulmonary Hypertension shifted the definition of PH from an arbitrarily defined mean pulmonary arterial pressure of at least 25 mm Hg at rest (as measured by right heart catheterization) to a more scientifically determined mPAP of at least 20 mm Hg.

The classification document also requires pulmonary vascular resistance (PVR) of at least 3 Wood units in the definition of all forms of precapillary PH. PAH specifically is defined as the presence of mPAP of at least 20 mm Hg, PVR of at least 3 Wood units, and pulmonary arterial wedge pressure 15 mm Hg or less.
 

Trends in treatment

The value of initial combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 (PDE5) inhibitor in treatment-naive PAH was cemented in 2015 by the AMBITION trial. The primary endpoint (death, PAH hospitalization, or unsatisfactory clinical response) occurred in 18%, 34%, and 28% of patients who were randomized, respectively, to combination therapy, monotherapy with the ERA ambrisentan, or monotherapy with the PDE-5 inhibitor tadalafil – and in 31% of the two monotherapy groups combined.

The trial reported a 50% reduction in the primary endpoint in the combination-therapy group versus the pooled monotherapy group, as well as greater reductions in N-terminal of the prohormone brain natriuretic peptide levels, more satisfactory clinical response and greater improvement in 6-minute walking distance.

In practice, a minority of patients – typically older patients with multiple comorbidities – still receive initial monotherapy with sequential add-on therapies based on tolerance, but “for the most part PAH patients will start on combination therapy, most commonly with a ERA and PDE5 inhibitor,” Dr. Chakinala said.

For patients who are not improving on the ERA-PDE5 inhibitor approach – typically those who remain in the intermediate-risk category for intermediate-term mortality – substitution of the PDE5 inhibitor with the soluble guanylate cyclase stimulator riociguat may be considered, he and Dr. Williamson said. Clinical improvement with this substitution was demonstrated in the REPLACE trial.

Experts at PH care centers are also utilizing triple therapy for patients who do not improve to low-risk status after 2-4 months of dual combination therapy. The availability of oral prostacyclin analogues (selexipag and treprostinil) makes it easier to consider adding these agents early on, Dr. Chakinala and Dr. Richardson said.

Patients who fall into the high-risk category, at any point, are still best managed with parenteral prostacyclin analogues, Dr. Chakinala said.

In general, said Dr. Williamson, who also directs the University of Kansas Pulmonary Hypertension Comprehensive Care Center, “the PH community tends to be fairly aggressive up front, and with a low threshold for using prostacyclin analogues.”

The agents are “always part of the picture for someone who is really ill, in functional class IV, or has really impaired right ventricular function,” he said. “And we’re finding increased roles in patients who are not as ill but still have decompensated right ventricular dysfunction. It’s something we now consider.”

Recently published research on up-front oral triple therapy suggests possible benefit for some patients – but it’s far from conclusive, said Dr. Chakinala. The TRITON study randomized treatment-naive patients to the traditional ERA-PDE5 combination and either oral selexipag (a selective prostacyclin receptor agonist) or placebo as a third agent. It found no significant difference in reduction in PVR, the primary outcome, at week 26. However, the authors reported a “possible signal” for improved long-term outcomes with triple therapy.

“Based on this best evidence from a randomized clinical trial, I think it’s unfair to say that all patients should be on triple combination therapy right out of the gate,” he said. “Having said that, more recent [European] data showed that two drugs fell short of the mark in some patients, with high rates of clinical progression. And even in AMBITION, there were a number of patients in the combination arm who didn’t have a robust response.”

A 2021 retrospective analysis from the French Pulmonary Hypertension Registry – one of the European studies – assessed survival with monotherapy, dual therapy, or triple-combination therapy (two orals with a parenteral prostacyclin), and found no difference between monotherapy and dual therapy in high-risk patients.

Experts have been upping the ante, therefore, on early assessment and frequent reassessment of treatment response. Not long ago, patients were typically reassessed 6-12 months after the initiation of treatment. Now, experts at the PH care centers want to assess patients at 3-4 months and adjust or intensify treatment regimens for those who don’t yet qualify as low risk using a multidimensional risk score calculator.

The REVEAL (Registry to Evaluate Early and Long-Term PAH Management) risk score calculator, for instance, predicts the probability of 1-year survival and assigns patients to a strata of risk level based on either 12 or 6 variables (for the full or “lite” versions).]

Even better monitoring and risk assessment is needed, however, to “help sift out which patients are not improving enough on initial therapy or who are starting to fall off after being on a regimen for a period of time,” Dr. Chakinala said.

Today, with a network of accredited centers of expertise and a desire and need for many patients to remain close to home, Dr. Chakinala encourages finding a balance. Well-resourced clinicians can strive for early diagnosis and management – potentially initiating ERA–PDE-5 inhibitor combination therapy – but still should collaborate with PH experts.

“It’s a good idea to comanage these patients and let the experts see them periodically to help you determine when your patient may be declining,” he said. “The timetable for reassessment, the complexity of the reassessment, and the need to escalate to more advanced therapies has never been more important.”
 

Research highlights

Therapies that target inflammation and altered metabolism – including metformin – are among those being investigated for PAH. So are therapies targeting dysfunctional bone morphogenetic protein pathway signaling, which has been shown to be associated with hereditary, idiopathic, and likely other forms of PAH; one such drug, called sotatercept, is currently at the phase 3 trial stage.

Most promising for PAH may be the research efforts involving deep phenotyping, said Andrew J. Sweatt, MD, of Stanford (Calif.) University and the Vera Moulton Wall Center for Pulmonary Vascular Disease.

“It’s where a lot of research is headed – deep phenotyping to deconstruct the molecular and clinical heterogeneity that exists within PAH ... to detect distinct subphenotypes of patients who would respond to particular therapies,” said Dr. Sweatt, who led a review of PH clinical research presented at the 2020 American Thoracic Society International Conference

“Right now, we largely treat all patients the same ... [while] we know that patients have a wide response to therapies and there’s a lot of clinical heterogeneity in how their disease evolves over time,” he said.

Data from a large National Institutes of Health–funded multicenter phenotyping study of PH is being analyzed and should yield findings and publications starting this year, said Anna R. Hemnes, MD, associate professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn., and an investigator with the initiative, coined “Redefining Pulmonary Hypertension through Pulmonary Disease Phenomics (PVDOMICS).”

Patients have undergone advanced imaging (for example, echocardiography, cardiac MRI, chest CT, ventilation/perfusion scans), advanced testing through right heart catheterization, body composition testing, quality of life questionnaires, and blood draws that have been analyzed for DNA and RNA expression, proteomics, and metabolomics, said Dr. Hemnes, assistant director of Vanderbilt’s Pulmonary Vascular Center.

The initiative aims to refine the classification of all kinds of PH and “to bring precision medicine to the field so we’re no longer characterizing somebody [based on imaging] and right heart catheterization, but we also incorporating molecular pieces and biomarkers into the diagnostic evaluation,” she said.

In the short term, the results of deep phenotyping should “allow us to be more effective with our therapy recommendations,” Dr. Hemnes said. “Then hopefully in the longer term, [identified biomarkers] will help us to develop new, more effective therapies.”

Dr. Sweatt and Dr. Williamson reported that they have no relevant financial disclosures. Dr. Hemnes reported that she holds stock in Tenax (which is studying a tyrosine kinase inhibitor for PAH) and serves as a consultant for Acceleron, Bayer, GossamerBio, United Therapeutics, and Janssen. She also receives research funding from Imara. Dr. Chakinala reported that he is an investigator on clinical trials for a number of pharmaceutical companies. He also serves on advisory boards for Phase Bio, Liquidia/Rare Gen, Bayer, Janssen, Trio Health Analytics, and Aerovate.