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The Rise of the Scribes
“We really aren’t taking care of records — we’re taking care of people.” — Dr. Lawrence Weed
What is the purpose of a progress note? Anyone? Yes, you there. “Insurance billing?” Yes, that’s a good one. Anyone else? “To remember what you did?” Excellent. Another? Yes, that’s right, for others to follow along in your care. These are all good reasons for a progress note to exist. But they aren’t the whole story. Let’s start at the beginning.
Charts were once a collection of paper sheets with handwritten notes. Sometimes illegible, sometimes beautiful, always efficient. A progress note back then could be just 10 characters, AK, LN2, X,X,X,X,X (with X’s marking nitrogen sprays). Then came the healthcare K-Pg event: the conversion to EMRs. Those doctors who survived evolved into computer programmers, creating blocks of text from a few keystrokes. But like toddler-sized Legos, the blocks made it impossible to build a note that is nuanced or precise. Worse yet, many notes consisting of blocks from one note added awkwardly to a new note, creating grotesque structures unrecognizable as anything that should exist in nature. Words and numbers, but no information.
Thanks to the eternity of EMR, these creations live on, hideous and useless. They waste not only the server’s energy but also our time. Few things are more maddening than scrolling to reach the bottom of another physician’s note only to find there is nothing there.
Whose fault is this? Anyone? Yes, that’s right, insurers. As there are probably no payers in this audience, let’s blame them. I agree, the crushing burden of documentation-to-get-reimbursed has forced us to create “notes” that add no value to us but add up points for us to get paid for them. CMS, payers, prior authorizations, and now even patients, it seems we are documenting for lots of people except for us. There isn’t time to satisfy all and this significant burden for every encounter is a proximate cause for doctors despair. Until now.
A fully formed, comprehensive, sometimes pretty note that satisfies all audiences. Dr. Larry Weed must be dancing in heaven. It was Dr. Weed who led us from the nicotine-stained logs of the 1950s to the powerful problem-based notes we use today, an innovation that rivals the stethoscope in its impact.
Professor Weed also predicted that computers would be important to capture and make sense of patient data, helping us make accurate diagnoses and efficient plans. Again, he was right. He would surely be advocating to take advantage of AI scribes’ marvelous ability to capture salient data and present it in the form of a problem-oriented medical record.
AI scribes will be ubiquitous soon; I’m fast and even for me they save time. They also allow, for the first time in a decade, to turn from the glow of a screen to actually face the patient – we no longer have to scribe and care simultaneously. Hallelujah. And yet, lest I disappoint you without a twist, it seems with AI scribes, like EMRs we lose a little something too.
Like self-driving cars or ChatGPT-generated letters, they remove cognitive loads. They are lovely when you have to multitask or are trying to recall a visit from hours (days) ago. Using them, you’ll feel faster, lighter, freer, happier. But what’s missing is the thinking. At the end, you have an exquisite note, but you didn’t write it. It has the salient points, but none of the mental work to create it. AI scribes subvert the valuable work of synthesis. That was the critical part of Dr. Weed’s discovery: writing problem-oriented notes helped us think better.
Writing allows for the friction that helps us process what is going on with a patient. It allows for the discovery of diagnoses and prompts plans. When I was an intern, one of my attendings would hand write notes, succinctly showing what he had observed and was thinking. He’d sketch diagrams in the chart, for example, to help illustrate how we’d work though the toxic, metabolic, and infectious etiologies of acute liver failure. Sublime.
The act of writing also helps remind us there is a person attached to these words. Like a handwritten sympathy card, it is intimate, human. Even using our EMR, I’d still often type sentences that help tell the patient’s story. “Her sister just died. Utterly devastated. I’ll forward chart to Bob (her PCP) to check in on her.” Or: “Scratch golfer wants to know why he is getting so many SCCs now. ‘Like bankruptcy, gradually then suddenly,’ I explained. I think I broke through.”
Since we’ve concluded the purpose of a note is mostly to capture data, AI scribes are a godsend. They do so with remarkable quality and efficiency. We’ll just have to remember if the diagnosis is unclear, then it might help to write the note out yourself. And even when done by the AI machine, we might add human touches now and again lest there be no art left in what we do.
“For sale. Sun hat. Never worn.”
Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on X. Write to him at [email protected].
“We really aren’t taking care of records — we’re taking care of people.” — Dr. Lawrence Weed
What is the purpose of a progress note? Anyone? Yes, you there. “Insurance billing?” Yes, that’s a good one. Anyone else? “To remember what you did?” Excellent. Another? Yes, that’s right, for others to follow along in your care. These are all good reasons for a progress note to exist. But they aren’t the whole story. Let’s start at the beginning.
Charts were once a collection of paper sheets with handwritten notes. Sometimes illegible, sometimes beautiful, always efficient. A progress note back then could be just 10 characters, AK, LN2, X,X,X,X,X (with X’s marking nitrogen sprays). Then came the healthcare K-Pg event: the conversion to EMRs. Those doctors who survived evolved into computer programmers, creating blocks of text from a few keystrokes. But like toddler-sized Legos, the blocks made it impossible to build a note that is nuanced or precise. Worse yet, many notes consisting of blocks from one note added awkwardly to a new note, creating grotesque structures unrecognizable as anything that should exist in nature. Words and numbers, but no information.
Thanks to the eternity of EMR, these creations live on, hideous and useless. They waste not only the server’s energy but also our time. Few things are more maddening than scrolling to reach the bottom of another physician’s note only to find there is nothing there.
Whose fault is this? Anyone? Yes, that’s right, insurers. As there are probably no payers in this audience, let’s blame them. I agree, the crushing burden of documentation-to-get-reimbursed has forced us to create “notes” that add no value to us but add up points for us to get paid for them. CMS, payers, prior authorizations, and now even patients, it seems we are documenting for lots of people except for us. There isn’t time to satisfy all and this significant burden for every encounter is a proximate cause for doctors despair. Until now.
A fully formed, comprehensive, sometimes pretty note that satisfies all audiences. Dr. Larry Weed must be dancing in heaven. It was Dr. Weed who led us from the nicotine-stained logs of the 1950s to the powerful problem-based notes we use today, an innovation that rivals the stethoscope in its impact.
Professor Weed also predicted that computers would be important to capture and make sense of patient data, helping us make accurate diagnoses and efficient plans. Again, he was right. He would surely be advocating to take advantage of AI scribes’ marvelous ability to capture salient data and present it in the form of a problem-oriented medical record.
AI scribes will be ubiquitous soon; I’m fast and even for me they save time. They also allow, for the first time in a decade, to turn from the glow of a screen to actually face the patient – we no longer have to scribe and care simultaneously. Hallelujah. And yet, lest I disappoint you without a twist, it seems with AI scribes, like EMRs we lose a little something too.
Like self-driving cars or ChatGPT-generated letters, they remove cognitive loads. They are lovely when you have to multitask or are trying to recall a visit from hours (days) ago. Using them, you’ll feel faster, lighter, freer, happier. But what’s missing is the thinking. At the end, you have an exquisite note, but you didn’t write it. It has the salient points, but none of the mental work to create it. AI scribes subvert the valuable work of synthesis. That was the critical part of Dr. Weed’s discovery: writing problem-oriented notes helped us think better.
Writing allows for the friction that helps us process what is going on with a patient. It allows for the discovery of diagnoses and prompts plans. When I was an intern, one of my attendings would hand write notes, succinctly showing what he had observed and was thinking. He’d sketch diagrams in the chart, for example, to help illustrate how we’d work though the toxic, metabolic, and infectious etiologies of acute liver failure. Sublime.
The act of writing also helps remind us there is a person attached to these words. Like a handwritten sympathy card, it is intimate, human. Even using our EMR, I’d still often type sentences that help tell the patient’s story. “Her sister just died. Utterly devastated. I’ll forward chart to Bob (her PCP) to check in on her.” Or: “Scratch golfer wants to know why he is getting so many SCCs now. ‘Like bankruptcy, gradually then suddenly,’ I explained. I think I broke through.”
Since we’ve concluded the purpose of a note is mostly to capture data, AI scribes are a godsend. They do so with remarkable quality and efficiency. We’ll just have to remember if the diagnosis is unclear, then it might help to write the note out yourself. And even when done by the AI machine, we might add human touches now and again lest there be no art left in what we do.
“For sale. Sun hat. Never worn.”
Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on X. Write to him at [email protected].
“We really aren’t taking care of records — we’re taking care of people.” — Dr. Lawrence Weed
What is the purpose of a progress note? Anyone? Yes, you there. “Insurance billing?” Yes, that’s a good one. Anyone else? “To remember what you did?” Excellent. Another? Yes, that’s right, for others to follow along in your care. These are all good reasons for a progress note to exist. But they aren’t the whole story. Let’s start at the beginning.
Charts were once a collection of paper sheets with handwritten notes. Sometimes illegible, sometimes beautiful, always efficient. A progress note back then could be just 10 characters, AK, LN2, X,X,X,X,X (with X’s marking nitrogen sprays). Then came the healthcare K-Pg event: the conversion to EMRs. Those doctors who survived evolved into computer programmers, creating blocks of text from a few keystrokes. But like toddler-sized Legos, the blocks made it impossible to build a note that is nuanced or precise. Worse yet, many notes consisting of blocks from one note added awkwardly to a new note, creating grotesque structures unrecognizable as anything that should exist in nature. Words and numbers, but no information.
Thanks to the eternity of EMR, these creations live on, hideous and useless. They waste not only the server’s energy but also our time. Few things are more maddening than scrolling to reach the bottom of another physician’s note only to find there is nothing there.
Whose fault is this? Anyone? Yes, that’s right, insurers. As there are probably no payers in this audience, let’s blame them. I agree, the crushing burden of documentation-to-get-reimbursed has forced us to create “notes” that add no value to us but add up points for us to get paid for them. CMS, payers, prior authorizations, and now even patients, it seems we are documenting for lots of people except for us. There isn’t time to satisfy all and this significant burden for every encounter is a proximate cause for doctors despair. Until now.
A fully formed, comprehensive, sometimes pretty note that satisfies all audiences. Dr. Larry Weed must be dancing in heaven. It was Dr. Weed who led us from the nicotine-stained logs of the 1950s to the powerful problem-based notes we use today, an innovation that rivals the stethoscope in its impact.
Professor Weed also predicted that computers would be important to capture and make sense of patient data, helping us make accurate diagnoses and efficient plans. Again, he was right. He would surely be advocating to take advantage of AI scribes’ marvelous ability to capture salient data and present it in the form of a problem-oriented medical record.
AI scribes will be ubiquitous soon; I’m fast and even for me they save time. They also allow, for the first time in a decade, to turn from the glow of a screen to actually face the patient – we no longer have to scribe and care simultaneously. Hallelujah. And yet, lest I disappoint you without a twist, it seems with AI scribes, like EMRs we lose a little something too.
Like self-driving cars or ChatGPT-generated letters, they remove cognitive loads. They are lovely when you have to multitask or are trying to recall a visit from hours (days) ago. Using them, you’ll feel faster, lighter, freer, happier. But what’s missing is the thinking. At the end, you have an exquisite note, but you didn’t write it. It has the salient points, but none of the mental work to create it. AI scribes subvert the valuable work of synthesis. That was the critical part of Dr. Weed’s discovery: writing problem-oriented notes helped us think better.
Writing allows for the friction that helps us process what is going on with a patient. It allows for the discovery of diagnoses and prompts plans. When I was an intern, one of my attendings would hand write notes, succinctly showing what he had observed and was thinking. He’d sketch diagrams in the chart, for example, to help illustrate how we’d work though the toxic, metabolic, and infectious etiologies of acute liver failure. Sublime.
The act of writing also helps remind us there is a person attached to these words. Like a handwritten sympathy card, it is intimate, human. Even using our EMR, I’d still often type sentences that help tell the patient’s story. “Her sister just died. Utterly devastated. I’ll forward chart to Bob (her PCP) to check in on her.” Or: “Scratch golfer wants to know why he is getting so many SCCs now. ‘Like bankruptcy, gradually then suddenly,’ I explained. I think I broke through.”
Since we’ve concluded the purpose of a note is mostly to capture data, AI scribes are a godsend. They do so with remarkable quality and efficiency. We’ll just have to remember if the diagnosis is unclear, then it might help to write the note out yourself. And even when done by the AI machine, we might add human touches now and again lest there be no art left in what we do.
“For sale. Sun hat. Never worn.”
Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on X. Write to him at [email protected].
AGA Issues Guidance on Identifying, Treating Cyclic Vomiting Syndrome
, according to a new clinical practice update from the American Gastroenterological Association.
CVS affects up to 2% of U.S. adults and is more common in women, young adults, and those with a personal or family history of migraine headaches. However, most patients don’t receive a diagnosis or often experience years of delay in receiving effective treatment.
“A diagnosis is a powerful tool. Not only does it help patients make sense of debilitating symptoms, but it allows healthcare providers to create an effective treatment plan,” said author David J. Levinthal, MD, AGAF, director of the Neurogastroenterology and Motility Center at the University of Pittsburgh Medical Center.
The update was published online in Gastroenterology.
Understanding Cyclic Vomiting Syndrome
CVS is a chronic disorder of gut-brain interaction (DGBI), which is characterized by acute episodes of nausea and vomiting, separated by time without symptoms. Patients can usually identify a pattern of symptoms that show up during and between episodes.
CVS can vary, ranging from mild — with less than four episodes per year and lasting less than 2 days — to moderate-severe — with more than four episodes per year, lasting more than 2 days, and requiring at least one emergency department visit or hospitalization.
The disorder has four distinct phases — inter-episodic, prodromal, emetic, and recovery — that align with distinct treatment and management strategies. Between episodes, patients typically don’t experience repetitive vomiting but may experience symptoms such as mild nausea, indigestion, and occasional vomiting. Although CVS episodes can happen at any time, most tend to occur in the early morning.
For diagnosis, clinicians should consider CVS in adults presenting with episodic bouts of repetitive vomiting, following criteria established by the Rome Foundation. Rome IV criteria include acute-onset vomiting lasting less than 7 days, at least three discrete episodes in a year with two in the previous 6 months, and an absence of vomiting between episodes separated by at least 1 week of baseline health.
About 65% of patients with CVS experience prodromal symptoms, which last for about an hour before the onset of vomiting and may include panic, a sense of doom, and an inability to communicate effectively. During prodromal or emetic phases, patients have also reported fatigue, brain fog, restlessness, anxiety, headache, bowel urgency, abdominal pain, flushing, or shakiness.
As with migraines, CVS episodes may often be triggered by psychological and physiological factors, particularly stress. Episodes can stem from both negative stress, such as a death or relationship conflicts, as well as positive stress, such as birthdays and vacations. Other triggers include sleep deprivation, hormonal fluctuations linked to the menstrual cycle, travel, motion sickness, or acute infections.
Adult CVS is associated with several conditions, particularly mood disorders, including anxiety, depression, and panic disorder. Patients may also experience migraines, seizure disorders, or autonomic imbalances, such as postural orthostatic tachycardia syndrome, which may indicate pathophysiological mechanisms and routes for management.
The American Neurogastroenterology and Motility Society recommends testing to rule out similar or overlapping conditions, such as Addison’s disease, hypothyroidism, and hepatic porphyria. Diagnostic workup should include blood work, urinalysis, and one-time esophagogastroduodenoscopy or upper gastrointestinal imaging. Repeated imaging and gastric emptying scans should be avoided.
Providing Treatment and Prevention
For treatment, knowing the CVS phase is “essential,” the authors wrote. For instance, during the prodromal phase, abortive therapies can halt the transition to the emetic phase, and earlier intervention is associated with a higher probability of stopping an episode. The authors recommend intranasal sumatriptan, ondansetron, antihistamines, and sedatives.
During the emetic phase, supportive therapy can help terminate the episode. This may include continuing the abortive regimen and going to the emergency department for hydration and antiemetic medications. Patients may also find relief in a quiet, darker room in the emergency department, along with IV benzodiazepines, with the goal of inducing sedation.
During the recovery phase, patients should rest and focus on rehydration and nutrition to return to the well phase.
During the well or inter-episodic phase, patients can follow lifestyle measures to identify and avoid triggers, such as taking prophylactic medication (tricyclic antidepressants, anticonvulsants, and neurokinin-1 receptor antagonists such as aprepitant), reducing stress, and implementing a good sleep routine.
As part of patient education, clinicians can discuss the four phases and rehearse the actions to take to prevent or stop an episode.
“CVS has a significant impact on patients, families, and the healthcare system. The unpredictable and disruptive nature of episodes can result in reduced health-related quality of life, job loss precipitated by work absenteeism, and even divorce,” said Rosita Frazier, MD, a gastroenterologist at Mayo Clinic Arizona in Scottsdale who specializes in DGBI and CVS. Dr. Frazier, who wasn’t involved with the clinical practice update, has previously written about CVS diagnosis and management.
“Providing an individualized care plan for all patients could potentially address this problem and improve the physician-patient interaction,” she said. “Educational efforts to raise awareness among the medical community and increase both patient and provider engagement can optimize outcomes and are needed to address this critical problem.”
The authors received no specific funding for this update. Dr. Levinthal is a consultant for Takeda Pharmaceuticals and Mahana. Dr. Frazier reported no relevant financial disclosures.
, according to a new clinical practice update from the American Gastroenterological Association.
CVS affects up to 2% of U.S. adults and is more common in women, young adults, and those with a personal or family history of migraine headaches. However, most patients don’t receive a diagnosis or often experience years of delay in receiving effective treatment.
“A diagnosis is a powerful tool. Not only does it help patients make sense of debilitating symptoms, but it allows healthcare providers to create an effective treatment plan,” said author David J. Levinthal, MD, AGAF, director of the Neurogastroenterology and Motility Center at the University of Pittsburgh Medical Center.
The update was published online in Gastroenterology.
Understanding Cyclic Vomiting Syndrome
CVS is a chronic disorder of gut-brain interaction (DGBI), which is characterized by acute episodes of nausea and vomiting, separated by time without symptoms. Patients can usually identify a pattern of symptoms that show up during and between episodes.
CVS can vary, ranging from mild — with less than four episodes per year and lasting less than 2 days — to moderate-severe — with more than four episodes per year, lasting more than 2 days, and requiring at least one emergency department visit or hospitalization.
The disorder has four distinct phases — inter-episodic, prodromal, emetic, and recovery — that align with distinct treatment and management strategies. Between episodes, patients typically don’t experience repetitive vomiting but may experience symptoms such as mild nausea, indigestion, and occasional vomiting. Although CVS episodes can happen at any time, most tend to occur in the early morning.
For diagnosis, clinicians should consider CVS in adults presenting with episodic bouts of repetitive vomiting, following criteria established by the Rome Foundation. Rome IV criteria include acute-onset vomiting lasting less than 7 days, at least three discrete episodes in a year with two in the previous 6 months, and an absence of vomiting between episodes separated by at least 1 week of baseline health.
About 65% of patients with CVS experience prodromal symptoms, which last for about an hour before the onset of vomiting and may include panic, a sense of doom, and an inability to communicate effectively. During prodromal or emetic phases, patients have also reported fatigue, brain fog, restlessness, anxiety, headache, bowel urgency, abdominal pain, flushing, or shakiness.
As with migraines, CVS episodes may often be triggered by psychological and physiological factors, particularly stress. Episodes can stem from both negative stress, such as a death or relationship conflicts, as well as positive stress, such as birthdays and vacations. Other triggers include sleep deprivation, hormonal fluctuations linked to the menstrual cycle, travel, motion sickness, or acute infections.
Adult CVS is associated with several conditions, particularly mood disorders, including anxiety, depression, and panic disorder. Patients may also experience migraines, seizure disorders, or autonomic imbalances, such as postural orthostatic tachycardia syndrome, which may indicate pathophysiological mechanisms and routes for management.
The American Neurogastroenterology and Motility Society recommends testing to rule out similar or overlapping conditions, such as Addison’s disease, hypothyroidism, and hepatic porphyria. Diagnostic workup should include blood work, urinalysis, and one-time esophagogastroduodenoscopy or upper gastrointestinal imaging. Repeated imaging and gastric emptying scans should be avoided.
Providing Treatment and Prevention
For treatment, knowing the CVS phase is “essential,” the authors wrote. For instance, during the prodromal phase, abortive therapies can halt the transition to the emetic phase, and earlier intervention is associated with a higher probability of stopping an episode. The authors recommend intranasal sumatriptan, ondansetron, antihistamines, and sedatives.
During the emetic phase, supportive therapy can help terminate the episode. This may include continuing the abortive regimen and going to the emergency department for hydration and antiemetic medications. Patients may also find relief in a quiet, darker room in the emergency department, along with IV benzodiazepines, with the goal of inducing sedation.
During the recovery phase, patients should rest and focus on rehydration and nutrition to return to the well phase.
During the well or inter-episodic phase, patients can follow lifestyle measures to identify and avoid triggers, such as taking prophylactic medication (tricyclic antidepressants, anticonvulsants, and neurokinin-1 receptor antagonists such as aprepitant), reducing stress, and implementing a good sleep routine.
As part of patient education, clinicians can discuss the four phases and rehearse the actions to take to prevent or stop an episode.
“CVS has a significant impact on patients, families, and the healthcare system. The unpredictable and disruptive nature of episodes can result in reduced health-related quality of life, job loss precipitated by work absenteeism, and even divorce,” said Rosita Frazier, MD, a gastroenterologist at Mayo Clinic Arizona in Scottsdale who specializes in DGBI and CVS. Dr. Frazier, who wasn’t involved with the clinical practice update, has previously written about CVS diagnosis and management.
“Providing an individualized care plan for all patients could potentially address this problem and improve the physician-patient interaction,” she said. “Educational efforts to raise awareness among the medical community and increase both patient and provider engagement can optimize outcomes and are needed to address this critical problem.”
The authors received no specific funding for this update. Dr. Levinthal is a consultant for Takeda Pharmaceuticals and Mahana. Dr. Frazier reported no relevant financial disclosures.
, according to a new clinical practice update from the American Gastroenterological Association.
CVS affects up to 2% of U.S. adults and is more common in women, young adults, and those with a personal or family history of migraine headaches. However, most patients don’t receive a diagnosis or often experience years of delay in receiving effective treatment.
“A diagnosis is a powerful tool. Not only does it help patients make sense of debilitating symptoms, but it allows healthcare providers to create an effective treatment plan,” said author David J. Levinthal, MD, AGAF, director of the Neurogastroenterology and Motility Center at the University of Pittsburgh Medical Center.
The update was published online in Gastroenterology.
Understanding Cyclic Vomiting Syndrome
CVS is a chronic disorder of gut-brain interaction (DGBI), which is characterized by acute episodes of nausea and vomiting, separated by time without symptoms. Patients can usually identify a pattern of symptoms that show up during and between episodes.
CVS can vary, ranging from mild — with less than four episodes per year and lasting less than 2 days — to moderate-severe — with more than four episodes per year, lasting more than 2 days, and requiring at least one emergency department visit or hospitalization.
The disorder has four distinct phases — inter-episodic, prodromal, emetic, and recovery — that align with distinct treatment and management strategies. Between episodes, patients typically don’t experience repetitive vomiting but may experience symptoms such as mild nausea, indigestion, and occasional vomiting. Although CVS episodes can happen at any time, most tend to occur in the early morning.
For diagnosis, clinicians should consider CVS in adults presenting with episodic bouts of repetitive vomiting, following criteria established by the Rome Foundation. Rome IV criteria include acute-onset vomiting lasting less than 7 days, at least three discrete episodes in a year with two in the previous 6 months, and an absence of vomiting between episodes separated by at least 1 week of baseline health.
About 65% of patients with CVS experience prodromal symptoms, which last for about an hour before the onset of vomiting and may include panic, a sense of doom, and an inability to communicate effectively. During prodromal or emetic phases, patients have also reported fatigue, brain fog, restlessness, anxiety, headache, bowel urgency, abdominal pain, flushing, or shakiness.
As with migraines, CVS episodes may often be triggered by psychological and physiological factors, particularly stress. Episodes can stem from both negative stress, such as a death or relationship conflicts, as well as positive stress, such as birthdays and vacations. Other triggers include sleep deprivation, hormonal fluctuations linked to the menstrual cycle, travel, motion sickness, or acute infections.
Adult CVS is associated with several conditions, particularly mood disorders, including anxiety, depression, and panic disorder. Patients may also experience migraines, seizure disorders, or autonomic imbalances, such as postural orthostatic tachycardia syndrome, which may indicate pathophysiological mechanisms and routes for management.
The American Neurogastroenterology and Motility Society recommends testing to rule out similar or overlapping conditions, such as Addison’s disease, hypothyroidism, and hepatic porphyria. Diagnostic workup should include blood work, urinalysis, and one-time esophagogastroduodenoscopy or upper gastrointestinal imaging. Repeated imaging and gastric emptying scans should be avoided.
Providing Treatment and Prevention
For treatment, knowing the CVS phase is “essential,” the authors wrote. For instance, during the prodromal phase, abortive therapies can halt the transition to the emetic phase, and earlier intervention is associated with a higher probability of stopping an episode. The authors recommend intranasal sumatriptan, ondansetron, antihistamines, and sedatives.
During the emetic phase, supportive therapy can help terminate the episode. This may include continuing the abortive regimen and going to the emergency department for hydration and antiemetic medications. Patients may also find relief in a quiet, darker room in the emergency department, along with IV benzodiazepines, with the goal of inducing sedation.
During the recovery phase, patients should rest and focus on rehydration and nutrition to return to the well phase.
During the well or inter-episodic phase, patients can follow lifestyle measures to identify and avoid triggers, such as taking prophylactic medication (tricyclic antidepressants, anticonvulsants, and neurokinin-1 receptor antagonists such as aprepitant), reducing stress, and implementing a good sleep routine.
As part of patient education, clinicians can discuss the four phases and rehearse the actions to take to prevent or stop an episode.
“CVS has a significant impact on patients, families, and the healthcare system. The unpredictable and disruptive nature of episodes can result in reduced health-related quality of life, job loss precipitated by work absenteeism, and even divorce,” said Rosita Frazier, MD, a gastroenterologist at Mayo Clinic Arizona in Scottsdale who specializes in DGBI and CVS. Dr. Frazier, who wasn’t involved with the clinical practice update, has previously written about CVS diagnosis and management.
“Providing an individualized care plan for all patients could potentially address this problem and improve the physician-patient interaction,” she said. “Educational efforts to raise awareness among the medical community and increase both patient and provider engagement can optimize outcomes and are needed to address this critical problem.”
The authors received no specific funding for this update. Dr. Levinthal is a consultant for Takeda Pharmaceuticals and Mahana. Dr. Frazier reported no relevant financial disclosures.
FROM GASTROENTEROLOGY
Steroids’ 75th Anniversary: Clinicians Strive to Use Less
Now, 75 years after the first presentations were made on the “sensational” effects of cortisone in the treatment of rheumatoid arthritis (RA), glucocorticoids (GCs) are still highly relevant and widely used in the management of RA and other immune-mediated inflammatory diseases.
“It makes me smile because this is such an old drug, and we need it still so much. It still hasn’t been replaced,” Josef S. Smolen, MD, observed at annual European Congress of Rheumatology.
At low doses, GCs are highly effective as anti-inflammatory and anti-destructive agents in RA and many other diseases, said Dr. Smolen, a rheumatologist and immunologist and professor emeritus at the Medical University of Vienna, Austria.
But even after all this time, the mechanisms that lead to efficacy vs toxicity have yet to be clarified. “Such separation may provide further insights into future treatment options,” said Dr. Smolen.
His comments, made during a special session on the 75th anniversary of GCs at EULAR 2024, underscore the endless saga to manage GCs while finding better alternatives. Opinions differ on what the research says on toxicity and dosage and whether a long-term, low-dose option is viable. Alternative therapies are being studied, but those endeavors are still in the early stages of development.
While GCs are still used chronically in many patients, clinicians should always attempt to discontinue them whenever possible, Frank Buttgereit, MD, professor of rheumatology and deputy head of the Department of Rheumatology and Clinical Immunology at Charité – Universitätsmedizin Berlin, Germany, told attendees at the congress. Up to 60% of patients in registries use GCs, and many patients with early or established RA enter randomized controlled trials on GCs as maintenance therapy.
The ubiquity of GC usage stems in part from overprescribing by non-rheumatologist physicians who might not have access to or aren’t aware of newer biologics or disease-modifying antirheumatic drugs (DMARDs). “We see a lot of patients on long-term glucocorticoids, chronic use for years and years, decades of glucocorticoids,” said Giovanni Adami, MD, PhD, a rheumatologist at the University of Verona, Italy, who has coauthored several studies on the use of GCs.
Societies Agree: Discontinue as Fast as Possible
GCs have been associated with a long list of adverse events, most notably Cushing syndrome, hypertension, cardiovascular disease, osteoporosis, myopathy, peptic ulcer, adrenal insufficiency (AI), infections, mood disorders, ophthalmologic disorders such as cataracts, skin disorders, menstrual septic necrosis, and pancreatitis.
Dose matters, Dr. Smolen said, citing studies that found that cumulative GC doses of 1000 or 1100 mg increase risks. One study by German researchers found that doses above 10 mg/d significantly raised the hazard ratio for death.
Because high disease activity is also associated with an equally high mortality risk, “we have to balance this out: Active disease vs glucocorticoid use, especially in countries that have less access to modern therapies than we have in the more affluent Western regions,” Dr. Smolen said.
Rheumatology societies generally agree that clinicians should try to minimize GC use or eventually discontinue the therapy.
The American College of Rheumatology recommends not using GCs as part of the first-line treatment of RA. “And if you want to use [them], you should do that for less than 3 months, taper and discontinue as fast as possible, and use the lowest dose possible,” Dr. Adami said.
EULAR’s recommendation is more nuanced in that it allows for a lower dose but gives physicians more choice in how they want to handle GCs, Dr. Adami said. The task force added that all patients should try to taper down or discontinue as fast as possible, he said.
For GCs in the management of systemic lupus erythematosus, a EULAR task force recommended that the type and severity of organ involvement should determine dose, with a long-term goal of maintaining the dose < 5 mg/d or possibly withdrawing it.
EULAR also recommends GC bridging when initiating or changing conventional synthetic (cs) DMARDs. This effectively dismisses the use of GCs when using biologic DMARDs or targeted synthetic DMARDs. As a bridging therapy, EULAR recommends either a single parenteral dose of GC or a predefined tapering or discontinuation scheme within 3 months, when starting an oral GC.
Low-Dose Approach Gains Ground
While saying he’d be the first physician to eliminate GCs whenever possible, Dr. Buttgereit made the case before the EULAR Congress that GCs in low doses could still play a role in treatment.
Many physicians believe that very low doses between 2 and 4 mg/d are a realistic therapy option for RA, he said, adding that a mean daily usage < 5 mg could be used over a longer period with relatively low risk.
Several studies he coauthored tested the 5-mg approach. The GLORIA trial compared 5 mg/d prednisolone and placebo in 451 patients aged 65 years and older with active RA over the course of 2 years. The researchers found that patients on prednisolone had a mean Disease Activity Score in 28 joints (DAS28) that was 0.37 points lower and mean joint damage score that was 1.7 points lower than those of patients on placebo, suggesting that the GC had long-term benefits in these patients with RA.
The tradeoff was a 24% increase in the risk of having at least one adverse event of special interest, but most of these events were non-severe infections, Dr. Buttgereit said.
Another study, the SEMIRA trial, assigned 128 patients to a continued regimen of prednisone 5 mg/d for 24 weeks. Another group of 131 patients received a tapered-prednisone regimen. All patients received tocilizumab 162 mg with or without csDMARDs, maintained at stable doses.
Patients in the first cohort achieved superior disease activity control than those in the tapered regimen group. “The side effects showed that in the tapering prednisone group, there were more treatment-emergent adverse effects in this double-blind trial as compared to the continued prednisone group,” Dr. Buttgereit said.
One limitation of the SEMIRA trial was that it studied the effect of tocilizumab as a GC-sparing agent, and it didn’t consider using a tumor necrosis factor or Janus kinase (JAK) inhibitor, which might have a more potent effect on pain and GC dose reduction, Dr. Adami said. “Why do we need to use glucocorticoids if we know they might be detrimental, if we know there might be some other option in our armamentarium?”
Other studies have shown that low-dose GC protocols can be used with standard treatment, according to Sebastian E. Sattui, MD, assistant professor of medicine and director of the Vasculitis Center at the University of Pittsburgh School of Medicine.
“Examples of this are the LoVAS and PEXIVAS studies for antineutrophil cytoplasmic antibody-associated [ANCA] vasculitis. This has been highlighted in existing treatment recommendations for ANCA vasculitis and systemic lupus erythematosus nephritis,” Dr. Sattui said.
Two-year results from LoVAS showed noninferiority in remission induction rates and rates of relapse and significantly less frequent serious adverse events between a reduced-dose GC regimen at 0.5 mg/kg/d and conventional high-dose GC regimen at 1 mg/kg/d plus rituximab for ANCA vasculitis.
PEXIVAS demonstrated the noninferiority of a reduced-dose regimen of GCs vs a standard-dose regimen with respect to death or end-stage kidney disease in patients with severe disease involvement.
Debating the Toxicity Threshold
Are low GC dosages significantly associated with adverse events like mortality, cardiovascular, or diabetes risk? It depends on who you ask.
Much of the toxicity data on GCs come from inadequately powered or controlled studies and often refer to doses that currently are considered too high, Dr. Buttgereit said. His presentation highlighted a study from Hong Kong, a time-varying analysis of GC dose and incident risk for major adverse cardiovascular events (MACE) in more than 12,000 patients with RA. Researchers found that GC regimens ≥ 5 mg/d significantly increased the risk for MACE. Comparatively, doses below this threshold did not confer excessive risk, he said.
Low-dose GCs are lesser toxic than high-dose GCs, noted Joan Merrill, MD, a professor with the Arthritis and Clinical Immunology Research Program at The University of Oklahoma Health Sciences Center, Oklahoma City. “There may be less weight gain, less chance of acne, and less risk for all the slower, more organ-threatening side effects.”
Dr. Merrill, who cares for patients with lupus, said physicians can keep lupus in check for years, using constant, low-dose GCs. “The one thing we know is that steroids work.” But over many years, damage may still occur, she cautioned.
But even a low dose could present health problems to patients. The GLORIA trial of patients with RA, which showed promising results on disease control with 5 mg/d, found an association between GCs and increased risk for infection and osteoporosis. There was a higher overall risk for adverse events related to skin, infections, and bone mineral density changes. Bone mineral density loss and fractures were more common in the GC group, Adami noted.
Surprisingly, some of the trial’s authors said patients could handle such adverse events. But what is your threshold of “acceptable?” Dr. Adami asked.
Other studies have found associations between low-dose GC regimens and adverse events. Researchers of a 2023 study reported bone mineral density loss in patients with inflammatory rheumatic musculoskeletal diseases on a 2.5-mg/d regimen. Another decade-long analysis of Medicare and Optum data found a link between serious infection and low-dose GCs in patients receiving stable DMARD therapy. Investigators reported risk even at daily doses of ≤ 5 mg.
Dr. Adami acknowledged that these studies may have “confounding by indication,” a channeling bias in which people with severe RA are more likely to be treated with GCs. For this reason, it’s a challenge to disentangle the independent role of GCs from the disease activity itself, he said.
The big question is: Why don’t these observational studies show an increased risk for adverse events with biologic drugs that are given to more severe patients? “That confirms the hypothesis that confounding by indication for GCs is minimal, and most of the risk is driven by GCs,” he said.
Tapering Options Across Diseases
Rheumatologists in the field continue to navigate GC-tapering options and treatment combinations that reduce the cumulative use of GCs over time, finding their own solutions based on the conditions they treat.
In his EULAR presentation, Dr. Buttgereit suggested that current therapeutic approaches for RA may be too narrow when they don’t consider the possibility of including very low doses of GCs.
For RA, “why shouldn’t we not do a combination of something like methotrexate plus a JAK inhibitor or a biological,” plus a very low dose of GCs < 5 mg/d, he asked.
However, Dr. Adami said he generally avoids GCs if RA disease activity is not severe (based on DAS28) and if the patient has a visual analog scale pain score < 7. “Nonetheless, even in patients with more severe disease, I would avoid GCs for more than 3 months. Usually, 1 month of steroids, tapered rapidly and discontinued.”
All patients should receive an appropriate treat-to-target strategy with csDMARDs and biologics if needed, he added.
A patient coming to clinic with difficult-to-treat RA who chronically uses GCs deserves special attention. The priority is bone protection with an anti-osteoporosis medication. “I found that JAK inhibitors, in some cases, help with the discontinuation of steroids, especially in those with residual pain. Therefore, I would think of switching medication,” Dr. Adami said.
For polymyalgia rheumatica, most clinicians will likely try to taper GCs around 52 weeks, similar to ACR/EULAR guidelines, according to Robert F. Spiera, MD, director of the Scleroderma and Vasculitis Program at Hospital for Special Surgery, New York City.
“I usually challenge patients with a more rapid taper, hoping to get them off GCs in 6 or even 4 months in some patients, recognizing that many will flare, and we will have to bump up their GC dose,” Dr. Spiera said.
For patients with lupus, GCs remain the most effective treatment, Dr. Merrill said. “The toxicities are unacceptable for long-term use. So we try to get in fast when we need them and get out as soon as possible after that, tapering down as fast as the patient can tolerate it.”
Unfortunately, that’s not always as fast as the clinician or patient hopes for, she said.
“New treatments are being developed that may help us avoid the constant use of steroids. However, it would be wonderful to see how these new safer types of steroids work in lupus,” she said.
Minimizing GCs is an important goal that should be considered and aimed for in every single patient, Dr. Sattui said. “Risk of GC toxicity should be considered in all patients, assessing [them] for cardiometabolic comorbidities, bone metabolic diseases, risk of infection, among many others.” Sticking to one specific GC-tapering protocol might not be achievable for every patient, however, based on disease characteristics, response, and other factors, he added.
Monitoring for GC toxicity is important and should occur during and after every single clinical visit, he emphasized. Patient education is critical. “Different tools have been developed and employed in clinical trials, both patient- and physician-facing instruments. Implementation to clinical practice of some of these should be the next step in order to achieve a more systematic approach.”
What to Consider for AI Symptoms
Clinicians also need to address AI in patients who are coming off GCs, Dr. Sattui said. He advised that symptoms suggestive of AI, including malaise, fatigue, nausea, and muscle and/or joint pain, should guide testing.
Even in the absence of symptoms, clinicians should consider assessing patients who have been on high doses for prolonged periods or obese or older adults who might be at a high risk for AI. “Signs to consider include weight loss, hypotension, or orthostatism,” he said.
Differentiating between AI symptoms and symptoms from the underlying disease can be a challenge. This requires a physical exam and workup, including morning serum cortisol. Collaboration with endocrinology colleagues and other treating providers is important, as well as patient education of symptoms and monitoring for possible adjustments in treating AI and other acute diseases, he said.
Dr. Smolen received research grants from AbbVie, AstraZeneca, Galapagos, and Eli Lilly. Dr. Adami received speaker fees and/or was a consultant for Galapagos, Theramex, Amgen, Eli Lilly, UCB, Fresenius Kabi, Bristol Myers Squibb, Abiogen, and Pfizer. Dr. Buttgereit’s disclosures included AbbVie, AstraZeneca, Grünenthal, Horizon Therapeutics, Mundipharma, Pfizer, and Roche. Dr. Merrill had no relevant disclosures. Dr. Spiera has been a consultant for Roche-Genentech, GlaxoSmithKline, Sanofi, ChemoCentryx, Novartis, Galderma, Cytori, AstraZeneca, Amgen, and AbbVie and received research grant support from GlaxoSmithKline, Roche-Genentech, AstraZeneca, Bristol Myers Squibb, Kadmon, Boehringer Ingelheim, Cytori, ChemoCentryx, Corbus, Novartis, Amgen, and AbbVie. Dr. Sattui reported receiving research support from AstraZeneca and GlaxoSmithKline (clinical trials), receiving consulting fees from Sanofi (funds toward research support), serving on advisory boards for Sanofi and Amgen (funds toward research support), and receiving speaker fees from Fresenius Kabi (funds toward research support).
A version of this article appeared on Medscape.com.
Now, 75 years after the first presentations were made on the “sensational” effects of cortisone in the treatment of rheumatoid arthritis (RA), glucocorticoids (GCs) are still highly relevant and widely used in the management of RA and other immune-mediated inflammatory diseases.
“It makes me smile because this is such an old drug, and we need it still so much. It still hasn’t been replaced,” Josef S. Smolen, MD, observed at annual European Congress of Rheumatology.
At low doses, GCs are highly effective as anti-inflammatory and anti-destructive agents in RA and many other diseases, said Dr. Smolen, a rheumatologist and immunologist and professor emeritus at the Medical University of Vienna, Austria.
But even after all this time, the mechanisms that lead to efficacy vs toxicity have yet to be clarified. “Such separation may provide further insights into future treatment options,” said Dr. Smolen.
His comments, made during a special session on the 75th anniversary of GCs at EULAR 2024, underscore the endless saga to manage GCs while finding better alternatives. Opinions differ on what the research says on toxicity and dosage and whether a long-term, low-dose option is viable. Alternative therapies are being studied, but those endeavors are still in the early stages of development.
While GCs are still used chronically in many patients, clinicians should always attempt to discontinue them whenever possible, Frank Buttgereit, MD, professor of rheumatology and deputy head of the Department of Rheumatology and Clinical Immunology at Charité – Universitätsmedizin Berlin, Germany, told attendees at the congress. Up to 60% of patients in registries use GCs, and many patients with early or established RA enter randomized controlled trials on GCs as maintenance therapy.
The ubiquity of GC usage stems in part from overprescribing by non-rheumatologist physicians who might not have access to or aren’t aware of newer biologics or disease-modifying antirheumatic drugs (DMARDs). “We see a lot of patients on long-term glucocorticoids, chronic use for years and years, decades of glucocorticoids,” said Giovanni Adami, MD, PhD, a rheumatologist at the University of Verona, Italy, who has coauthored several studies on the use of GCs.
Societies Agree: Discontinue as Fast as Possible
GCs have been associated with a long list of adverse events, most notably Cushing syndrome, hypertension, cardiovascular disease, osteoporosis, myopathy, peptic ulcer, adrenal insufficiency (AI), infections, mood disorders, ophthalmologic disorders such as cataracts, skin disorders, menstrual septic necrosis, and pancreatitis.
Dose matters, Dr. Smolen said, citing studies that found that cumulative GC doses of 1000 or 1100 mg increase risks. One study by German researchers found that doses above 10 mg/d significantly raised the hazard ratio for death.
Because high disease activity is also associated with an equally high mortality risk, “we have to balance this out: Active disease vs glucocorticoid use, especially in countries that have less access to modern therapies than we have in the more affluent Western regions,” Dr. Smolen said.
Rheumatology societies generally agree that clinicians should try to minimize GC use or eventually discontinue the therapy.
The American College of Rheumatology recommends not using GCs as part of the first-line treatment of RA. “And if you want to use [them], you should do that for less than 3 months, taper and discontinue as fast as possible, and use the lowest dose possible,” Dr. Adami said.
EULAR’s recommendation is more nuanced in that it allows for a lower dose but gives physicians more choice in how they want to handle GCs, Dr. Adami said. The task force added that all patients should try to taper down or discontinue as fast as possible, he said.
For GCs in the management of systemic lupus erythematosus, a EULAR task force recommended that the type and severity of organ involvement should determine dose, with a long-term goal of maintaining the dose < 5 mg/d or possibly withdrawing it.
EULAR also recommends GC bridging when initiating or changing conventional synthetic (cs) DMARDs. This effectively dismisses the use of GCs when using biologic DMARDs or targeted synthetic DMARDs. As a bridging therapy, EULAR recommends either a single parenteral dose of GC or a predefined tapering or discontinuation scheme within 3 months, when starting an oral GC.
Low-Dose Approach Gains Ground
While saying he’d be the first physician to eliminate GCs whenever possible, Dr. Buttgereit made the case before the EULAR Congress that GCs in low doses could still play a role in treatment.
Many physicians believe that very low doses between 2 and 4 mg/d are a realistic therapy option for RA, he said, adding that a mean daily usage < 5 mg could be used over a longer period with relatively low risk.
Several studies he coauthored tested the 5-mg approach. The GLORIA trial compared 5 mg/d prednisolone and placebo in 451 patients aged 65 years and older with active RA over the course of 2 years. The researchers found that patients on prednisolone had a mean Disease Activity Score in 28 joints (DAS28) that was 0.37 points lower and mean joint damage score that was 1.7 points lower than those of patients on placebo, suggesting that the GC had long-term benefits in these patients with RA.
The tradeoff was a 24% increase in the risk of having at least one adverse event of special interest, but most of these events were non-severe infections, Dr. Buttgereit said.
Another study, the SEMIRA trial, assigned 128 patients to a continued regimen of prednisone 5 mg/d for 24 weeks. Another group of 131 patients received a tapered-prednisone regimen. All patients received tocilizumab 162 mg with or without csDMARDs, maintained at stable doses.
Patients in the first cohort achieved superior disease activity control than those in the tapered regimen group. “The side effects showed that in the tapering prednisone group, there were more treatment-emergent adverse effects in this double-blind trial as compared to the continued prednisone group,” Dr. Buttgereit said.
One limitation of the SEMIRA trial was that it studied the effect of tocilizumab as a GC-sparing agent, and it didn’t consider using a tumor necrosis factor or Janus kinase (JAK) inhibitor, which might have a more potent effect on pain and GC dose reduction, Dr. Adami said. “Why do we need to use glucocorticoids if we know they might be detrimental, if we know there might be some other option in our armamentarium?”
Other studies have shown that low-dose GC protocols can be used with standard treatment, according to Sebastian E. Sattui, MD, assistant professor of medicine and director of the Vasculitis Center at the University of Pittsburgh School of Medicine.
“Examples of this are the LoVAS and PEXIVAS studies for antineutrophil cytoplasmic antibody-associated [ANCA] vasculitis. This has been highlighted in existing treatment recommendations for ANCA vasculitis and systemic lupus erythematosus nephritis,” Dr. Sattui said.
Two-year results from LoVAS showed noninferiority in remission induction rates and rates of relapse and significantly less frequent serious adverse events between a reduced-dose GC regimen at 0.5 mg/kg/d and conventional high-dose GC regimen at 1 mg/kg/d plus rituximab for ANCA vasculitis.
PEXIVAS demonstrated the noninferiority of a reduced-dose regimen of GCs vs a standard-dose regimen with respect to death or end-stage kidney disease in patients with severe disease involvement.
Debating the Toxicity Threshold
Are low GC dosages significantly associated with adverse events like mortality, cardiovascular, or diabetes risk? It depends on who you ask.
Much of the toxicity data on GCs come from inadequately powered or controlled studies and often refer to doses that currently are considered too high, Dr. Buttgereit said. His presentation highlighted a study from Hong Kong, a time-varying analysis of GC dose and incident risk for major adverse cardiovascular events (MACE) in more than 12,000 patients with RA. Researchers found that GC regimens ≥ 5 mg/d significantly increased the risk for MACE. Comparatively, doses below this threshold did not confer excessive risk, he said.
Low-dose GCs are lesser toxic than high-dose GCs, noted Joan Merrill, MD, a professor with the Arthritis and Clinical Immunology Research Program at The University of Oklahoma Health Sciences Center, Oklahoma City. “There may be less weight gain, less chance of acne, and less risk for all the slower, more organ-threatening side effects.”
Dr. Merrill, who cares for patients with lupus, said physicians can keep lupus in check for years, using constant, low-dose GCs. “The one thing we know is that steroids work.” But over many years, damage may still occur, she cautioned.
But even a low dose could present health problems to patients. The GLORIA trial of patients with RA, which showed promising results on disease control with 5 mg/d, found an association between GCs and increased risk for infection and osteoporosis. There was a higher overall risk for adverse events related to skin, infections, and bone mineral density changes. Bone mineral density loss and fractures were more common in the GC group, Adami noted.
Surprisingly, some of the trial’s authors said patients could handle such adverse events. But what is your threshold of “acceptable?” Dr. Adami asked.
Other studies have found associations between low-dose GC regimens and adverse events. Researchers of a 2023 study reported bone mineral density loss in patients with inflammatory rheumatic musculoskeletal diseases on a 2.5-mg/d regimen. Another decade-long analysis of Medicare and Optum data found a link between serious infection and low-dose GCs in patients receiving stable DMARD therapy. Investigators reported risk even at daily doses of ≤ 5 mg.
Dr. Adami acknowledged that these studies may have “confounding by indication,” a channeling bias in which people with severe RA are more likely to be treated with GCs. For this reason, it’s a challenge to disentangle the independent role of GCs from the disease activity itself, he said.
The big question is: Why don’t these observational studies show an increased risk for adverse events with biologic drugs that are given to more severe patients? “That confirms the hypothesis that confounding by indication for GCs is minimal, and most of the risk is driven by GCs,” he said.
Tapering Options Across Diseases
Rheumatologists in the field continue to navigate GC-tapering options and treatment combinations that reduce the cumulative use of GCs over time, finding their own solutions based on the conditions they treat.
In his EULAR presentation, Dr. Buttgereit suggested that current therapeutic approaches for RA may be too narrow when they don’t consider the possibility of including very low doses of GCs.
For RA, “why shouldn’t we not do a combination of something like methotrexate plus a JAK inhibitor or a biological,” plus a very low dose of GCs < 5 mg/d, he asked.
However, Dr. Adami said he generally avoids GCs if RA disease activity is not severe (based on DAS28) and if the patient has a visual analog scale pain score < 7. “Nonetheless, even in patients with more severe disease, I would avoid GCs for more than 3 months. Usually, 1 month of steroids, tapered rapidly and discontinued.”
All patients should receive an appropriate treat-to-target strategy with csDMARDs and biologics if needed, he added.
A patient coming to clinic with difficult-to-treat RA who chronically uses GCs deserves special attention. The priority is bone protection with an anti-osteoporosis medication. “I found that JAK inhibitors, in some cases, help with the discontinuation of steroids, especially in those with residual pain. Therefore, I would think of switching medication,” Dr. Adami said.
For polymyalgia rheumatica, most clinicians will likely try to taper GCs around 52 weeks, similar to ACR/EULAR guidelines, according to Robert F. Spiera, MD, director of the Scleroderma and Vasculitis Program at Hospital for Special Surgery, New York City.
“I usually challenge patients with a more rapid taper, hoping to get them off GCs in 6 or even 4 months in some patients, recognizing that many will flare, and we will have to bump up their GC dose,” Dr. Spiera said.
For patients with lupus, GCs remain the most effective treatment, Dr. Merrill said. “The toxicities are unacceptable for long-term use. So we try to get in fast when we need them and get out as soon as possible after that, tapering down as fast as the patient can tolerate it.”
Unfortunately, that’s not always as fast as the clinician or patient hopes for, she said.
“New treatments are being developed that may help us avoid the constant use of steroids. However, it would be wonderful to see how these new safer types of steroids work in lupus,” she said.
Minimizing GCs is an important goal that should be considered and aimed for in every single patient, Dr. Sattui said. “Risk of GC toxicity should be considered in all patients, assessing [them] for cardiometabolic comorbidities, bone metabolic diseases, risk of infection, among many others.” Sticking to one specific GC-tapering protocol might not be achievable for every patient, however, based on disease characteristics, response, and other factors, he added.
Monitoring for GC toxicity is important and should occur during and after every single clinical visit, he emphasized. Patient education is critical. “Different tools have been developed and employed in clinical trials, both patient- and physician-facing instruments. Implementation to clinical practice of some of these should be the next step in order to achieve a more systematic approach.”
What to Consider for AI Symptoms
Clinicians also need to address AI in patients who are coming off GCs, Dr. Sattui said. He advised that symptoms suggestive of AI, including malaise, fatigue, nausea, and muscle and/or joint pain, should guide testing.
Even in the absence of symptoms, clinicians should consider assessing patients who have been on high doses for prolonged periods or obese or older adults who might be at a high risk for AI. “Signs to consider include weight loss, hypotension, or orthostatism,” he said.
Differentiating between AI symptoms and symptoms from the underlying disease can be a challenge. This requires a physical exam and workup, including morning serum cortisol. Collaboration with endocrinology colleagues and other treating providers is important, as well as patient education of symptoms and monitoring for possible adjustments in treating AI and other acute diseases, he said.
Dr. Smolen received research grants from AbbVie, AstraZeneca, Galapagos, and Eli Lilly. Dr. Adami received speaker fees and/or was a consultant for Galapagos, Theramex, Amgen, Eli Lilly, UCB, Fresenius Kabi, Bristol Myers Squibb, Abiogen, and Pfizer. Dr. Buttgereit’s disclosures included AbbVie, AstraZeneca, Grünenthal, Horizon Therapeutics, Mundipharma, Pfizer, and Roche. Dr. Merrill had no relevant disclosures. Dr. Spiera has been a consultant for Roche-Genentech, GlaxoSmithKline, Sanofi, ChemoCentryx, Novartis, Galderma, Cytori, AstraZeneca, Amgen, and AbbVie and received research grant support from GlaxoSmithKline, Roche-Genentech, AstraZeneca, Bristol Myers Squibb, Kadmon, Boehringer Ingelheim, Cytori, ChemoCentryx, Corbus, Novartis, Amgen, and AbbVie. Dr. Sattui reported receiving research support from AstraZeneca and GlaxoSmithKline (clinical trials), receiving consulting fees from Sanofi (funds toward research support), serving on advisory boards for Sanofi and Amgen (funds toward research support), and receiving speaker fees from Fresenius Kabi (funds toward research support).
A version of this article appeared on Medscape.com.
Now, 75 years after the first presentations were made on the “sensational” effects of cortisone in the treatment of rheumatoid arthritis (RA), glucocorticoids (GCs) are still highly relevant and widely used in the management of RA and other immune-mediated inflammatory diseases.
“It makes me smile because this is such an old drug, and we need it still so much. It still hasn’t been replaced,” Josef S. Smolen, MD, observed at annual European Congress of Rheumatology.
At low doses, GCs are highly effective as anti-inflammatory and anti-destructive agents in RA and many other diseases, said Dr. Smolen, a rheumatologist and immunologist and professor emeritus at the Medical University of Vienna, Austria.
But even after all this time, the mechanisms that lead to efficacy vs toxicity have yet to be clarified. “Such separation may provide further insights into future treatment options,” said Dr. Smolen.
His comments, made during a special session on the 75th anniversary of GCs at EULAR 2024, underscore the endless saga to manage GCs while finding better alternatives. Opinions differ on what the research says on toxicity and dosage and whether a long-term, low-dose option is viable. Alternative therapies are being studied, but those endeavors are still in the early stages of development.
While GCs are still used chronically in many patients, clinicians should always attempt to discontinue them whenever possible, Frank Buttgereit, MD, professor of rheumatology and deputy head of the Department of Rheumatology and Clinical Immunology at Charité – Universitätsmedizin Berlin, Germany, told attendees at the congress. Up to 60% of patients in registries use GCs, and many patients with early or established RA enter randomized controlled trials on GCs as maintenance therapy.
The ubiquity of GC usage stems in part from overprescribing by non-rheumatologist physicians who might not have access to or aren’t aware of newer biologics or disease-modifying antirheumatic drugs (DMARDs). “We see a lot of patients on long-term glucocorticoids, chronic use for years and years, decades of glucocorticoids,” said Giovanni Adami, MD, PhD, a rheumatologist at the University of Verona, Italy, who has coauthored several studies on the use of GCs.
Societies Agree: Discontinue as Fast as Possible
GCs have been associated with a long list of adverse events, most notably Cushing syndrome, hypertension, cardiovascular disease, osteoporosis, myopathy, peptic ulcer, adrenal insufficiency (AI), infections, mood disorders, ophthalmologic disorders such as cataracts, skin disorders, menstrual septic necrosis, and pancreatitis.
Dose matters, Dr. Smolen said, citing studies that found that cumulative GC doses of 1000 or 1100 mg increase risks. One study by German researchers found that doses above 10 mg/d significantly raised the hazard ratio for death.
Because high disease activity is also associated with an equally high mortality risk, “we have to balance this out: Active disease vs glucocorticoid use, especially in countries that have less access to modern therapies than we have in the more affluent Western regions,” Dr. Smolen said.
Rheumatology societies generally agree that clinicians should try to minimize GC use or eventually discontinue the therapy.
The American College of Rheumatology recommends not using GCs as part of the first-line treatment of RA. “And if you want to use [them], you should do that for less than 3 months, taper and discontinue as fast as possible, and use the lowest dose possible,” Dr. Adami said.
EULAR’s recommendation is more nuanced in that it allows for a lower dose but gives physicians more choice in how they want to handle GCs, Dr. Adami said. The task force added that all patients should try to taper down or discontinue as fast as possible, he said.
For GCs in the management of systemic lupus erythematosus, a EULAR task force recommended that the type and severity of organ involvement should determine dose, with a long-term goal of maintaining the dose < 5 mg/d or possibly withdrawing it.
EULAR also recommends GC bridging when initiating or changing conventional synthetic (cs) DMARDs. This effectively dismisses the use of GCs when using biologic DMARDs or targeted synthetic DMARDs. As a bridging therapy, EULAR recommends either a single parenteral dose of GC or a predefined tapering or discontinuation scheme within 3 months, when starting an oral GC.
Low-Dose Approach Gains Ground
While saying he’d be the first physician to eliminate GCs whenever possible, Dr. Buttgereit made the case before the EULAR Congress that GCs in low doses could still play a role in treatment.
Many physicians believe that very low doses between 2 and 4 mg/d are a realistic therapy option for RA, he said, adding that a mean daily usage < 5 mg could be used over a longer period with relatively low risk.
Several studies he coauthored tested the 5-mg approach. The GLORIA trial compared 5 mg/d prednisolone and placebo in 451 patients aged 65 years and older with active RA over the course of 2 years. The researchers found that patients on prednisolone had a mean Disease Activity Score in 28 joints (DAS28) that was 0.37 points lower and mean joint damage score that was 1.7 points lower than those of patients on placebo, suggesting that the GC had long-term benefits in these patients with RA.
The tradeoff was a 24% increase in the risk of having at least one adverse event of special interest, but most of these events were non-severe infections, Dr. Buttgereit said.
Another study, the SEMIRA trial, assigned 128 patients to a continued regimen of prednisone 5 mg/d for 24 weeks. Another group of 131 patients received a tapered-prednisone regimen. All patients received tocilizumab 162 mg with or without csDMARDs, maintained at stable doses.
Patients in the first cohort achieved superior disease activity control than those in the tapered regimen group. “The side effects showed that in the tapering prednisone group, there were more treatment-emergent adverse effects in this double-blind trial as compared to the continued prednisone group,” Dr. Buttgereit said.
One limitation of the SEMIRA trial was that it studied the effect of tocilizumab as a GC-sparing agent, and it didn’t consider using a tumor necrosis factor or Janus kinase (JAK) inhibitor, which might have a more potent effect on pain and GC dose reduction, Dr. Adami said. “Why do we need to use glucocorticoids if we know they might be detrimental, if we know there might be some other option in our armamentarium?”
Other studies have shown that low-dose GC protocols can be used with standard treatment, according to Sebastian E. Sattui, MD, assistant professor of medicine and director of the Vasculitis Center at the University of Pittsburgh School of Medicine.
“Examples of this are the LoVAS and PEXIVAS studies for antineutrophil cytoplasmic antibody-associated [ANCA] vasculitis. This has been highlighted in existing treatment recommendations for ANCA vasculitis and systemic lupus erythematosus nephritis,” Dr. Sattui said.
Two-year results from LoVAS showed noninferiority in remission induction rates and rates of relapse and significantly less frequent serious adverse events between a reduced-dose GC regimen at 0.5 mg/kg/d and conventional high-dose GC regimen at 1 mg/kg/d plus rituximab for ANCA vasculitis.
PEXIVAS demonstrated the noninferiority of a reduced-dose regimen of GCs vs a standard-dose regimen with respect to death or end-stage kidney disease in patients with severe disease involvement.
Debating the Toxicity Threshold
Are low GC dosages significantly associated with adverse events like mortality, cardiovascular, or diabetes risk? It depends on who you ask.
Much of the toxicity data on GCs come from inadequately powered or controlled studies and often refer to doses that currently are considered too high, Dr. Buttgereit said. His presentation highlighted a study from Hong Kong, a time-varying analysis of GC dose and incident risk for major adverse cardiovascular events (MACE) in more than 12,000 patients with RA. Researchers found that GC regimens ≥ 5 mg/d significantly increased the risk for MACE. Comparatively, doses below this threshold did not confer excessive risk, he said.
Low-dose GCs are lesser toxic than high-dose GCs, noted Joan Merrill, MD, a professor with the Arthritis and Clinical Immunology Research Program at The University of Oklahoma Health Sciences Center, Oklahoma City. “There may be less weight gain, less chance of acne, and less risk for all the slower, more organ-threatening side effects.”
Dr. Merrill, who cares for patients with lupus, said physicians can keep lupus in check for years, using constant, low-dose GCs. “The one thing we know is that steroids work.” But over many years, damage may still occur, she cautioned.
But even a low dose could present health problems to patients. The GLORIA trial of patients with RA, which showed promising results on disease control with 5 mg/d, found an association between GCs and increased risk for infection and osteoporosis. There was a higher overall risk for adverse events related to skin, infections, and bone mineral density changes. Bone mineral density loss and fractures were more common in the GC group, Adami noted.
Surprisingly, some of the trial’s authors said patients could handle such adverse events. But what is your threshold of “acceptable?” Dr. Adami asked.
Other studies have found associations between low-dose GC regimens and adverse events. Researchers of a 2023 study reported bone mineral density loss in patients with inflammatory rheumatic musculoskeletal diseases on a 2.5-mg/d regimen. Another decade-long analysis of Medicare and Optum data found a link between serious infection and low-dose GCs in patients receiving stable DMARD therapy. Investigators reported risk even at daily doses of ≤ 5 mg.
Dr. Adami acknowledged that these studies may have “confounding by indication,” a channeling bias in which people with severe RA are more likely to be treated with GCs. For this reason, it’s a challenge to disentangle the independent role of GCs from the disease activity itself, he said.
The big question is: Why don’t these observational studies show an increased risk for adverse events with biologic drugs that are given to more severe patients? “That confirms the hypothesis that confounding by indication for GCs is minimal, and most of the risk is driven by GCs,” he said.
Tapering Options Across Diseases
Rheumatologists in the field continue to navigate GC-tapering options and treatment combinations that reduce the cumulative use of GCs over time, finding their own solutions based on the conditions they treat.
In his EULAR presentation, Dr. Buttgereit suggested that current therapeutic approaches for RA may be too narrow when they don’t consider the possibility of including very low doses of GCs.
For RA, “why shouldn’t we not do a combination of something like methotrexate plus a JAK inhibitor or a biological,” plus a very low dose of GCs < 5 mg/d, he asked.
However, Dr. Adami said he generally avoids GCs if RA disease activity is not severe (based on DAS28) and if the patient has a visual analog scale pain score < 7. “Nonetheless, even in patients with more severe disease, I would avoid GCs for more than 3 months. Usually, 1 month of steroids, tapered rapidly and discontinued.”
All patients should receive an appropriate treat-to-target strategy with csDMARDs and biologics if needed, he added.
A patient coming to clinic with difficult-to-treat RA who chronically uses GCs deserves special attention. The priority is bone protection with an anti-osteoporosis medication. “I found that JAK inhibitors, in some cases, help with the discontinuation of steroids, especially in those with residual pain. Therefore, I would think of switching medication,” Dr. Adami said.
For polymyalgia rheumatica, most clinicians will likely try to taper GCs around 52 weeks, similar to ACR/EULAR guidelines, according to Robert F. Spiera, MD, director of the Scleroderma and Vasculitis Program at Hospital for Special Surgery, New York City.
“I usually challenge patients with a more rapid taper, hoping to get them off GCs in 6 or even 4 months in some patients, recognizing that many will flare, and we will have to bump up their GC dose,” Dr. Spiera said.
For patients with lupus, GCs remain the most effective treatment, Dr. Merrill said. “The toxicities are unacceptable for long-term use. So we try to get in fast when we need them and get out as soon as possible after that, tapering down as fast as the patient can tolerate it.”
Unfortunately, that’s not always as fast as the clinician or patient hopes for, she said.
“New treatments are being developed that may help us avoid the constant use of steroids. However, it would be wonderful to see how these new safer types of steroids work in lupus,” she said.
Minimizing GCs is an important goal that should be considered and aimed for in every single patient, Dr. Sattui said. “Risk of GC toxicity should be considered in all patients, assessing [them] for cardiometabolic comorbidities, bone metabolic diseases, risk of infection, among many others.” Sticking to one specific GC-tapering protocol might not be achievable for every patient, however, based on disease characteristics, response, and other factors, he added.
Monitoring for GC toxicity is important and should occur during and after every single clinical visit, he emphasized. Patient education is critical. “Different tools have been developed and employed in clinical trials, both patient- and physician-facing instruments. Implementation to clinical practice of some of these should be the next step in order to achieve a more systematic approach.”
What to Consider for AI Symptoms
Clinicians also need to address AI in patients who are coming off GCs, Dr. Sattui said. He advised that symptoms suggestive of AI, including malaise, fatigue, nausea, and muscle and/or joint pain, should guide testing.
Even in the absence of symptoms, clinicians should consider assessing patients who have been on high doses for prolonged periods or obese or older adults who might be at a high risk for AI. “Signs to consider include weight loss, hypotension, or orthostatism,” he said.
Differentiating between AI symptoms and symptoms from the underlying disease can be a challenge. This requires a physical exam and workup, including morning serum cortisol. Collaboration with endocrinology colleagues and other treating providers is important, as well as patient education of symptoms and monitoring for possible adjustments in treating AI and other acute diseases, he said.
Dr. Smolen received research grants from AbbVie, AstraZeneca, Galapagos, and Eli Lilly. Dr. Adami received speaker fees and/or was a consultant for Galapagos, Theramex, Amgen, Eli Lilly, UCB, Fresenius Kabi, Bristol Myers Squibb, Abiogen, and Pfizer. Dr. Buttgereit’s disclosures included AbbVie, AstraZeneca, Grünenthal, Horizon Therapeutics, Mundipharma, Pfizer, and Roche. Dr. Merrill had no relevant disclosures. Dr. Spiera has been a consultant for Roche-Genentech, GlaxoSmithKline, Sanofi, ChemoCentryx, Novartis, Galderma, Cytori, AstraZeneca, Amgen, and AbbVie and received research grant support from GlaxoSmithKline, Roche-Genentech, AstraZeneca, Bristol Myers Squibb, Kadmon, Boehringer Ingelheim, Cytori, ChemoCentryx, Corbus, Novartis, Amgen, and AbbVie. Dr. Sattui reported receiving research support from AstraZeneca and GlaxoSmithKline (clinical trials), receiving consulting fees from Sanofi (funds toward research support), serving on advisory boards for Sanofi and Amgen (funds toward research support), and receiving speaker fees from Fresenius Kabi (funds toward research support).
A version of this article appeared on Medscape.com.
FROM EULAR 2024
New Drugs, Treatment Strategies Aim to Lessen Rheumatic Diseases’ Reliance on Steroids
. Selective GC receptor agonists and modulators and GC plus hydroxysteroid dehydrogenase inhibitor combination therapy are some of the approaches under consideration.
“There is growing observational data that confirms the GC-sparing effect seen in some of these clinical trials in real-world data,” said Sebastian E. Sattui, MD, assistant professor of medicine and director of the Vasculitis Center at the University of Pittsburgh Medical Center, Pittsburgh.
GC minimization is an important goal, “and the data emerging from these trials should be reassuring for rheumatology providers,” Dr. Sattui said.
HSD-1 Inhibitors Under Study
11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a tissue-specific intracellular modulator of GC action that’s been trialed for a number of rheumatic conditions. “HSD-1 deficiency or inhibition has been consistently associated with reduced GC side effects in mouse and human,” wrote the authors of a study testing the coadministration of HSD-1 inhibitor SPI-62 (clofutriben) with prednisolone in patients with polymyalgia rheumatica (PMR) to measure its impact on efficacy and toxicity.
Lead study author David Katz, PhD, chief scientific officer at Sparrow Pharmaceuticals, presented results at the at the annual European Congress of Rheumatology.
GCs are often the first-line therapy with PMR. However, it’s very difficult for patients to stop taking GCs once they start taking them. The study included patients with PMR who were taking 10 mg/d prednisolone and didn’t require a dose increase. For the study, they continued prednisolone without dose reduction for 4 weeks, receiving either SPI-62 6 mg/d or a matching placebo for 2 weeks.
During SPI-62 treatment, researchers in sequential cohorts maintained daily prednisolone doses at 10 mg, adjusted to 15 mg or adjusted to 20 mg.
A 10-mg dose of prednisolone combined with 6 mg of SPI-62 demonstrated less efficacy compared with placebo but improved upon prednisolone toxicities such as bone formation and resorption biomarkers, lipidemia, and insulin resistance. Doubling the dose to 20 mg prednisolone combined with SPI-62 achieved similar efficacy and maintained improvement of prednisolone toxicity markers.
“In patients with PMR, when we double the dose of prednisolone during coadministration with a potent HSD-1 inhibitor, we are able to have similar stability of symptoms, physical function, and systemic inflammation. At the same time, we are able to show improvements on biomarkers of bone turnover and insulin resistance,” Dr. Katz informed the EULAR 2024 audience.
An ongoing phase 2 clinical trial is testing SPI-62 in patients with endogenous Cushing syndrome. “It’s a longer-term trial, so we’re able to see at least an individual patient’s more clinical outcomes such as reversal of Cushing’s-associated myopathy and the ability of patients to discontinue all of their antidiabetic medications and yet still have good glycemic control,” he said.
Another research team from the United Kingdom explored whether AZD4017, an inhibitor of human 11ß-HSD1, could mitigate GC effects. The researchers randomly assigned 32 healthy male volunteers to AZD4017 or placebo, along with prednisolone. They reported a worsening of hepatic insulin sensitivity in the placebo group but not in the AZD4017 group, and protective effects of AZD4017 on markers of lipid metabolism and bone turnover, as well as lowered nighttime blood pressure. The results signified that coadministration of AZD4017 with prednisolone in men could be a way to reduce GC side effects.
In a Japanese phase 1/2 study, 11ß-HSD1 inhibitor S-707106 proved useful as an insulin sensitizer and antisarcopenic and anti-obesity medication in 16 patients with Cushing syndrome and autonomous cortisol secretion.
Novel Antitumor Necrosis Factor (TNF) Antibody Plus GC Receptor Modulator Conjugate
A novel antibody-drug conjugate comprising the anti-TNF monoclonal antibody adalimumab (ABBV-3373) linked to a GC receptor modulator shows promise as a GC alternative.
A notable 2022 study authored by Frank Buttgereit, MD, and other researchers assessed its safety and efficacy in a randomized, double-blind, active-controlled, proof-of-concept trial.
ABBV-3373 “was designed to potentially allow precise targeting of activated immune cells while significantly dampening inflammation and minimizing the systemic side effects associated with glucocorticoids,” according to AbbVie, its manufacturer.
A total of 48 adults with moderate to severe rheumatoid arthritis receiving background methotrexate were randomized to receive either ABBV-3373 (n = 31) or adalimumab (n = 17). The novel drug at 12 weeks showed a −2.65 reduction in the Disease Activity Score in 28 joints using C-reactive protein, compared with −2.13 for adalimumab. Researchers also predicted ABBV-3373 to be more effective than adalimumab based on in-trial and historical adalimumab data.
“We have great expectations for this molecule,” said Giovanni Adami, MD, PhD, a rheumatologist at the University of Verona, Verona, Italy, who has coauthored several studies on the use of GCs. Plans are underway for a phase 3 study with ABBV-3373.
C5a and Interleukin (IL)-6 Receptor Inhibitors as GC-Sparing Drugs
Investigators in a 2021 paper explored whether the C5a receptor inhibitor avacopan could effectively treat patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis without the need for daily GCs, following treatment with either cyclophosphamide or rituximab. They randomized 331 patients to receive avacopan or prednisone given on a tapering schedule for 20 weeks (60 mg/d tapered to discontinuation by week 21). “Avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52,” the investigators summarized.
A longer trial should test avacopan’s safety and durability in patients with ANCA-associated vasculitis, they recommended.
Sarilumab, a human monoclonal antibody that binds IL-6 receptor alpha and blocks the IL-6 pathway, yielded good results in the phase 3 SAPHYR trial as an alternative for patients with PMR who relapse while tapering prednisone therapy.
Researchers in the SAPHYR trial randomly assigned 118 patients 1:1 to receive a twice-monthly subcutaneous injection of sarilumab over 52 weeks plus a 14-week prednisone taper or placebo plus a 52-week prednisone taper. Patients in each group received a tapered GC dose initially at 15 mg/d for 2 weeks in a blinded fashion to control for disease at baseline.
Sarilumab effectively sustained remission in patients, significantly reducing the GC dose compared with placebo.
Disease flare after clinical remission took place in 57% of patients in the placebo group, vs 24% in the sarilumab group. “The placebo-treated patients had a fairly traditional 52-week GC taper. The patients treated with sarilumab had a very rapid GC taper,” said lead study author Robert Spiera, MD, director of the Scleroderma, Vasculitis and Myositis Center at the Hospital for Special Surgery, New York City.
In his own practice, Dr. Spiera often treats his patients with new-onset PMR with a fairly rapid GC taper, akin to what was used in SAPHYR, recognizing that a portion of these patients can be successfully treated with a relatively brief course of GCs, although the majority will need to have “rescue” therapy for flares with that approach.
In SAPHYR, everyone had previously flared and started at 15 mg/d prednisone at study entry. “In my practice, I don’t always raise the prednisone to 15 mg for a PMR flare. I raise it to whatever dose is necessary to capture control of polymyalgia rheumatica symptoms as I add sarilumab. Often, that is less than 15 mg,” he clarified.
Patients with giant cell arteritis (GCA) also struggle to taper or stop using GCs. For these patients, the IL-6 receptor alpha inhibitor tocilizumab has demonstrated benefits in shortening the GC-tapering period.
In the GiACTA trial, researchers randomly assigned 251 patients in a 2:1:1:1 ratio with GCA to receive subcutaneous tocilizumab weekly or every other week, combined with a 26-week prednisone taper, or placebo combined with a prednisone taper over a period of either 26 weeks or 52 weeks. Patients in the tocilizumab arms combined with a 26-week prednisone taper had superior results with GC-free remission compared with those who underwent prednisone tapering plus placebo.
Subsequent studies have investigated the use of tocilizumab in shortening GC tapers. One pilot clinical trial assessed the use of tocilizumab monotherapy following ultrashort-term GC treatment (three pulses of 500 mg of methylprednisolone) in 18 patients with new-onset GCA. Researchers found that approximately 70% of patients were able to achieve and maintain disease remission for 52 weeks. One patient developed anterior ischemic optic neuropathy.
Another pilot study of 30 patients with GCA (50% new-onset disease, 50% relapsing disease) concluded that a year of tocilizumab combined with 8 weeks of prednisone could lead to remission. The majority of patients (77% of 30) maintained prednisone-free remission at 52 weeks, and no cases of anterior ischemic optic neuropathy were observed.
“The results of the studies mentioned above are encouraging and suggest that in the setting of IL-6 blockade treatment with tocilizumab, GC tapers shorter than 6 months may be possible. However, in order to be able to recommend short prednisone tapers in GCA, clinical trials comparing the efficacy and safety of different prednisone tapers [such as 8 vs 26 weeks] are required,” said Sebastian H. Unizony, MD, the study’s lead author and an assistant professor at Harvard Medical School and codirector of the Massachusetts General Hospital Rheumatology Vasculitis Program, Boston.
“The last several years have been a breakthrough period in GCA, which started with addition of tocilizumab to the therapeutic armamentarium against this disease and continued with several other agents showing promising results in phase 2 trials [of abatacept, mavrilimumab, and secukinumab] and a recently successful phase 3 trial with upadacitinib,” Dr. Unizony said.
Dr. Katz is a corporate officer and stockholder of Sparrow Pharmaceuticals. Dr. Adami has received speaker fees and/or has consulted for Galapagos, Theramex, Amgen, Eli Lilly, UCB, Fresenius Kabi, Bristol Myers Squibb, Abiogen, and Pfizer. Dr. Spiera has been a consultant for Roche-Genentech, GlaxoSmithKline, Sanofi, ChemoCentryx, Novartis, Galderma, Cytori, AstraZeneca, Amgen, and AbbVie, and has received research grant support from GlaxoSmithKline, Roche-Genentech, AstraZeneca, Bristol Myers Squibb, Kadmon, Boehringer Ingelheim, Cytori, ChemoCentryx, Corbus, Novartis, Amgen, and AbbVie.
A version of this article appeared on Medscape.com.
. Selective GC receptor agonists and modulators and GC plus hydroxysteroid dehydrogenase inhibitor combination therapy are some of the approaches under consideration.
“There is growing observational data that confirms the GC-sparing effect seen in some of these clinical trials in real-world data,” said Sebastian E. Sattui, MD, assistant professor of medicine and director of the Vasculitis Center at the University of Pittsburgh Medical Center, Pittsburgh.
GC minimization is an important goal, “and the data emerging from these trials should be reassuring for rheumatology providers,” Dr. Sattui said.
HSD-1 Inhibitors Under Study
11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a tissue-specific intracellular modulator of GC action that’s been trialed for a number of rheumatic conditions. “HSD-1 deficiency or inhibition has been consistently associated with reduced GC side effects in mouse and human,” wrote the authors of a study testing the coadministration of HSD-1 inhibitor SPI-62 (clofutriben) with prednisolone in patients with polymyalgia rheumatica (PMR) to measure its impact on efficacy and toxicity.
Lead study author David Katz, PhD, chief scientific officer at Sparrow Pharmaceuticals, presented results at the at the annual European Congress of Rheumatology.
GCs are often the first-line therapy with PMR. However, it’s very difficult for patients to stop taking GCs once they start taking them. The study included patients with PMR who were taking 10 mg/d prednisolone and didn’t require a dose increase. For the study, they continued prednisolone without dose reduction for 4 weeks, receiving either SPI-62 6 mg/d or a matching placebo for 2 weeks.
During SPI-62 treatment, researchers in sequential cohorts maintained daily prednisolone doses at 10 mg, adjusted to 15 mg or adjusted to 20 mg.
A 10-mg dose of prednisolone combined with 6 mg of SPI-62 demonstrated less efficacy compared with placebo but improved upon prednisolone toxicities such as bone formation and resorption biomarkers, lipidemia, and insulin resistance. Doubling the dose to 20 mg prednisolone combined with SPI-62 achieved similar efficacy and maintained improvement of prednisolone toxicity markers.
“In patients with PMR, when we double the dose of prednisolone during coadministration with a potent HSD-1 inhibitor, we are able to have similar stability of symptoms, physical function, and systemic inflammation. At the same time, we are able to show improvements on biomarkers of bone turnover and insulin resistance,” Dr. Katz informed the EULAR 2024 audience.
An ongoing phase 2 clinical trial is testing SPI-62 in patients with endogenous Cushing syndrome. “It’s a longer-term trial, so we’re able to see at least an individual patient’s more clinical outcomes such as reversal of Cushing’s-associated myopathy and the ability of patients to discontinue all of their antidiabetic medications and yet still have good glycemic control,” he said.
Another research team from the United Kingdom explored whether AZD4017, an inhibitor of human 11ß-HSD1, could mitigate GC effects. The researchers randomly assigned 32 healthy male volunteers to AZD4017 or placebo, along with prednisolone. They reported a worsening of hepatic insulin sensitivity in the placebo group but not in the AZD4017 group, and protective effects of AZD4017 on markers of lipid metabolism and bone turnover, as well as lowered nighttime blood pressure. The results signified that coadministration of AZD4017 with prednisolone in men could be a way to reduce GC side effects.
In a Japanese phase 1/2 study, 11ß-HSD1 inhibitor S-707106 proved useful as an insulin sensitizer and antisarcopenic and anti-obesity medication in 16 patients with Cushing syndrome and autonomous cortisol secretion.
Novel Antitumor Necrosis Factor (TNF) Antibody Plus GC Receptor Modulator Conjugate
A novel antibody-drug conjugate comprising the anti-TNF monoclonal antibody adalimumab (ABBV-3373) linked to a GC receptor modulator shows promise as a GC alternative.
A notable 2022 study authored by Frank Buttgereit, MD, and other researchers assessed its safety and efficacy in a randomized, double-blind, active-controlled, proof-of-concept trial.
ABBV-3373 “was designed to potentially allow precise targeting of activated immune cells while significantly dampening inflammation and minimizing the systemic side effects associated with glucocorticoids,” according to AbbVie, its manufacturer.
A total of 48 adults with moderate to severe rheumatoid arthritis receiving background methotrexate were randomized to receive either ABBV-3373 (n = 31) or adalimumab (n = 17). The novel drug at 12 weeks showed a −2.65 reduction in the Disease Activity Score in 28 joints using C-reactive protein, compared with −2.13 for adalimumab. Researchers also predicted ABBV-3373 to be more effective than adalimumab based on in-trial and historical adalimumab data.
“We have great expectations for this molecule,” said Giovanni Adami, MD, PhD, a rheumatologist at the University of Verona, Verona, Italy, who has coauthored several studies on the use of GCs. Plans are underway for a phase 3 study with ABBV-3373.
C5a and Interleukin (IL)-6 Receptor Inhibitors as GC-Sparing Drugs
Investigators in a 2021 paper explored whether the C5a receptor inhibitor avacopan could effectively treat patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis without the need for daily GCs, following treatment with either cyclophosphamide or rituximab. They randomized 331 patients to receive avacopan or prednisone given on a tapering schedule for 20 weeks (60 mg/d tapered to discontinuation by week 21). “Avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52,” the investigators summarized.
A longer trial should test avacopan’s safety and durability in patients with ANCA-associated vasculitis, they recommended.
Sarilumab, a human monoclonal antibody that binds IL-6 receptor alpha and blocks the IL-6 pathway, yielded good results in the phase 3 SAPHYR trial as an alternative for patients with PMR who relapse while tapering prednisone therapy.
Researchers in the SAPHYR trial randomly assigned 118 patients 1:1 to receive a twice-monthly subcutaneous injection of sarilumab over 52 weeks plus a 14-week prednisone taper or placebo plus a 52-week prednisone taper. Patients in each group received a tapered GC dose initially at 15 mg/d for 2 weeks in a blinded fashion to control for disease at baseline.
Sarilumab effectively sustained remission in patients, significantly reducing the GC dose compared with placebo.
Disease flare after clinical remission took place in 57% of patients in the placebo group, vs 24% in the sarilumab group. “The placebo-treated patients had a fairly traditional 52-week GC taper. The patients treated with sarilumab had a very rapid GC taper,” said lead study author Robert Spiera, MD, director of the Scleroderma, Vasculitis and Myositis Center at the Hospital for Special Surgery, New York City.
In his own practice, Dr. Spiera often treats his patients with new-onset PMR with a fairly rapid GC taper, akin to what was used in SAPHYR, recognizing that a portion of these patients can be successfully treated with a relatively brief course of GCs, although the majority will need to have “rescue” therapy for flares with that approach.
In SAPHYR, everyone had previously flared and started at 15 mg/d prednisone at study entry. “In my practice, I don’t always raise the prednisone to 15 mg for a PMR flare. I raise it to whatever dose is necessary to capture control of polymyalgia rheumatica symptoms as I add sarilumab. Often, that is less than 15 mg,” he clarified.
Patients with giant cell arteritis (GCA) also struggle to taper or stop using GCs. For these patients, the IL-6 receptor alpha inhibitor tocilizumab has demonstrated benefits in shortening the GC-tapering period.
In the GiACTA trial, researchers randomly assigned 251 patients in a 2:1:1:1 ratio with GCA to receive subcutaneous tocilizumab weekly or every other week, combined with a 26-week prednisone taper, or placebo combined with a prednisone taper over a period of either 26 weeks or 52 weeks. Patients in the tocilizumab arms combined with a 26-week prednisone taper had superior results with GC-free remission compared with those who underwent prednisone tapering plus placebo.
Subsequent studies have investigated the use of tocilizumab in shortening GC tapers. One pilot clinical trial assessed the use of tocilizumab monotherapy following ultrashort-term GC treatment (three pulses of 500 mg of methylprednisolone) in 18 patients with new-onset GCA. Researchers found that approximately 70% of patients were able to achieve and maintain disease remission for 52 weeks. One patient developed anterior ischemic optic neuropathy.
Another pilot study of 30 patients with GCA (50% new-onset disease, 50% relapsing disease) concluded that a year of tocilizumab combined with 8 weeks of prednisone could lead to remission. The majority of patients (77% of 30) maintained prednisone-free remission at 52 weeks, and no cases of anterior ischemic optic neuropathy were observed.
“The results of the studies mentioned above are encouraging and suggest that in the setting of IL-6 blockade treatment with tocilizumab, GC tapers shorter than 6 months may be possible. However, in order to be able to recommend short prednisone tapers in GCA, clinical trials comparing the efficacy and safety of different prednisone tapers [such as 8 vs 26 weeks] are required,” said Sebastian H. Unizony, MD, the study’s lead author and an assistant professor at Harvard Medical School and codirector of the Massachusetts General Hospital Rheumatology Vasculitis Program, Boston.
“The last several years have been a breakthrough period in GCA, which started with addition of tocilizumab to the therapeutic armamentarium against this disease and continued with several other agents showing promising results in phase 2 trials [of abatacept, mavrilimumab, and secukinumab] and a recently successful phase 3 trial with upadacitinib,” Dr. Unizony said.
Dr. Katz is a corporate officer and stockholder of Sparrow Pharmaceuticals. Dr. Adami has received speaker fees and/or has consulted for Galapagos, Theramex, Amgen, Eli Lilly, UCB, Fresenius Kabi, Bristol Myers Squibb, Abiogen, and Pfizer. Dr. Spiera has been a consultant for Roche-Genentech, GlaxoSmithKline, Sanofi, ChemoCentryx, Novartis, Galderma, Cytori, AstraZeneca, Amgen, and AbbVie, and has received research grant support from GlaxoSmithKline, Roche-Genentech, AstraZeneca, Bristol Myers Squibb, Kadmon, Boehringer Ingelheim, Cytori, ChemoCentryx, Corbus, Novartis, Amgen, and AbbVie.
A version of this article appeared on Medscape.com.
. Selective GC receptor agonists and modulators and GC plus hydroxysteroid dehydrogenase inhibitor combination therapy are some of the approaches under consideration.
“There is growing observational data that confirms the GC-sparing effect seen in some of these clinical trials in real-world data,” said Sebastian E. Sattui, MD, assistant professor of medicine and director of the Vasculitis Center at the University of Pittsburgh Medical Center, Pittsburgh.
GC minimization is an important goal, “and the data emerging from these trials should be reassuring for rheumatology providers,” Dr. Sattui said.
HSD-1 Inhibitors Under Study
11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a tissue-specific intracellular modulator of GC action that’s been trialed for a number of rheumatic conditions. “HSD-1 deficiency or inhibition has been consistently associated with reduced GC side effects in mouse and human,” wrote the authors of a study testing the coadministration of HSD-1 inhibitor SPI-62 (clofutriben) with prednisolone in patients with polymyalgia rheumatica (PMR) to measure its impact on efficacy and toxicity.
Lead study author David Katz, PhD, chief scientific officer at Sparrow Pharmaceuticals, presented results at the at the annual European Congress of Rheumatology.
GCs are often the first-line therapy with PMR. However, it’s very difficult for patients to stop taking GCs once they start taking them. The study included patients with PMR who were taking 10 mg/d prednisolone and didn’t require a dose increase. For the study, they continued prednisolone without dose reduction for 4 weeks, receiving either SPI-62 6 mg/d or a matching placebo for 2 weeks.
During SPI-62 treatment, researchers in sequential cohorts maintained daily prednisolone doses at 10 mg, adjusted to 15 mg or adjusted to 20 mg.
A 10-mg dose of prednisolone combined with 6 mg of SPI-62 demonstrated less efficacy compared with placebo but improved upon prednisolone toxicities such as bone formation and resorption biomarkers, lipidemia, and insulin resistance. Doubling the dose to 20 mg prednisolone combined with SPI-62 achieved similar efficacy and maintained improvement of prednisolone toxicity markers.
“In patients with PMR, when we double the dose of prednisolone during coadministration with a potent HSD-1 inhibitor, we are able to have similar stability of symptoms, physical function, and systemic inflammation. At the same time, we are able to show improvements on biomarkers of bone turnover and insulin resistance,” Dr. Katz informed the EULAR 2024 audience.
An ongoing phase 2 clinical trial is testing SPI-62 in patients with endogenous Cushing syndrome. “It’s a longer-term trial, so we’re able to see at least an individual patient’s more clinical outcomes such as reversal of Cushing’s-associated myopathy and the ability of patients to discontinue all of their antidiabetic medications and yet still have good glycemic control,” he said.
Another research team from the United Kingdom explored whether AZD4017, an inhibitor of human 11ß-HSD1, could mitigate GC effects. The researchers randomly assigned 32 healthy male volunteers to AZD4017 or placebo, along with prednisolone. They reported a worsening of hepatic insulin sensitivity in the placebo group but not in the AZD4017 group, and protective effects of AZD4017 on markers of lipid metabolism and bone turnover, as well as lowered nighttime blood pressure. The results signified that coadministration of AZD4017 with prednisolone in men could be a way to reduce GC side effects.
In a Japanese phase 1/2 study, 11ß-HSD1 inhibitor S-707106 proved useful as an insulin sensitizer and antisarcopenic and anti-obesity medication in 16 patients with Cushing syndrome and autonomous cortisol secretion.
Novel Antitumor Necrosis Factor (TNF) Antibody Plus GC Receptor Modulator Conjugate
A novel antibody-drug conjugate comprising the anti-TNF monoclonal antibody adalimumab (ABBV-3373) linked to a GC receptor modulator shows promise as a GC alternative.
A notable 2022 study authored by Frank Buttgereit, MD, and other researchers assessed its safety and efficacy in a randomized, double-blind, active-controlled, proof-of-concept trial.
ABBV-3373 “was designed to potentially allow precise targeting of activated immune cells while significantly dampening inflammation and minimizing the systemic side effects associated with glucocorticoids,” according to AbbVie, its manufacturer.
A total of 48 adults with moderate to severe rheumatoid arthritis receiving background methotrexate were randomized to receive either ABBV-3373 (n = 31) or adalimumab (n = 17). The novel drug at 12 weeks showed a −2.65 reduction in the Disease Activity Score in 28 joints using C-reactive protein, compared with −2.13 for adalimumab. Researchers also predicted ABBV-3373 to be more effective than adalimumab based on in-trial and historical adalimumab data.
“We have great expectations for this molecule,” said Giovanni Adami, MD, PhD, a rheumatologist at the University of Verona, Verona, Italy, who has coauthored several studies on the use of GCs. Plans are underway for a phase 3 study with ABBV-3373.
C5a and Interleukin (IL)-6 Receptor Inhibitors as GC-Sparing Drugs
Investigators in a 2021 paper explored whether the C5a receptor inhibitor avacopan could effectively treat patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis without the need for daily GCs, following treatment with either cyclophosphamide or rituximab. They randomized 331 patients to receive avacopan or prednisone given on a tapering schedule for 20 weeks (60 mg/d tapered to discontinuation by week 21). “Avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52,” the investigators summarized.
A longer trial should test avacopan’s safety and durability in patients with ANCA-associated vasculitis, they recommended.
Sarilumab, a human monoclonal antibody that binds IL-6 receptor alpha and blocks the IL-6 pathway, yielded good results in the phase 3 SAPHYR trial as an alternative for patients with PMR who relapse while tapering prednisone therapy.
Researchers in the SAPHYR trial randomly assigned 118 patients 1:1 to receive a twice-monthly subcutaneous injection of sarilumab over 52 weeks plus a 14-week prednisone taper or placebo plus a 52-week prednisone taper. Patients in each group received a tapered GC dose initially at 15 mg/d for 2 weeks in a blinded fashion to control for disease at baseline.
Sarilumab effectively sustained remission in patients, significantly reducing the GC dose compared with placebo.
Disease flare after clinical remission took place in 57% of patients in the placebo group, vs 24% in the sarilumab group. “The placebo-treated patients had a fairly traditional 52-week GC taper. The patients treated with sarilumab had a very rapid GC taper,” said lead study author Robert Spiera, MD, director of the Scleroderma, Vasculitis and Myositis Center at the Hospital for Special Surgery, New York City.
In his own practice, Dr. Spiera often treats his patients with new-onset PMR with a fairly rapid GC taper, akin to what was used in SAPHYR, recognizing that a portion of these patients can be successfully treated with a relatively brief course of GCs, although the majority will need to have “rescue” therapy for flares with that approach.
In SAPHYR, everyone had previously flared and started at 15 mg/d prednisone at study entry. “In my practice, I don’t always raise the prednisone to 15 mg for a PMR flare. I raise it to whatever dose is necessary to capture control of polymyalgia rheumatica symptoms as I add sarilumab. Often, that is less than 15 mg,” he clarified.
Patients with giant cell arteritis (GCA) also struggle to taper or stop using GCs. For these patients, the IL-6 receptor alpha inhibitor tocilizumab has demonstrated benefits in shortening the GC-tapering period.
In the GiACTA trial, researchers randomly assigned 251 patients in a 2:1:1:1 ratio with GCA to receive subcutaneous tocilizumab weekly or every other week, combined with a 26-week prednisone taper, or placebo combined with a prednisone taper over a period of either 26 weeks or 52 weeks. Patients in the tocilizumab arms combined with a 26-week prednisone taper had superior results with GC-free remission compared with those who underwent prednisone tapering plus placebo.
Subsequent studies have investigated the use of tocilizumab in shortening GC tapers. One pilot clinical trial assessed the use of tocilizumab monotherapy following ultrashort-term GC treatment (three pulses of 500 mg of methylprednisolone) in 18 patients with new-onset GCA. Researchers found that approximately 70% of patients were able to achieve and maintain disease remission for 52 weeks. One patient developed anterior ischemic optic neuropathy.
Another pilot study of 30 patients with GCA (50% new-onset disease, 50% relapsing disease) concluded that a year of tocilizumab combined with 8 weeks of prednisone could lead to remission. The majority of patients (77% of 30) maintained prednisone-free remission at 52 weeks, and no cases of anterior ischemic optic neuropathy were observed.
“The results of the studies mentioned above are encouraging and suggest that in the setting of IL-6 blockade treatment with tocilizumab, GC tapers shorter than 6 months may be possible. However, in order to be able to recommend short prednisone tapers in GCA, clinical trials comparing the efficacy and safety of different prednisone tapers [such as 8 vs 26 weeks] are required,” said Sebastian H. Unizony, MD, the study’s lead author and an assistant professor at Harvard Medical School and codirector of the Massachusetts General Hospital Rheumatology Vasculitis Program, Boston.
“The last several years have been a breakthrough period in GCA, which started with addition of tocilizumab to the therapeutic armamentarium against this disease and continued with several other agents showing promising results in phase 2 trials [of abatacept, mavrilimumab, and secukinumab] and a recently successful phase 3 trial with upadacitinib,” Dr. Unizony said.
Dr. Katz is a corporate officer and stockholder of Sparrow Pharmaceuticals. Dr. Adami has received speaker fees and/or has consulted for Galapagos, Theramex, Amgen, Eli Lilly, UCB, Fresenius Kabi, Bristol Myers Squibb, Abiogen, and Pfizer. Dr. Spiera has been a consultant for Roche-Genentech, GlaxoSmithKline, Sanofi, ChemoCentryx, Novartis, Galderma, Cytori, AstraZeneca, Amgen, and AbbVie, and has received research grant support from GlaxoSmithKline, Roche-Genentech, AstraZeneca, Bristol Myers Squibb, Kadmon, Boehringer Ingelheim, Cytori, ChemoCentryx, Corbus, Novartis, Amgen, and AbbVie.
A version of this article appeared on Medscape.com.
How the New Vitamin D Guidelines Will, and Won’t, Change My Practice
Hi, everyone. I’m Dr. Kenny Lin. I am a family physician and associate director of the Lancaster General Hospital Family Medicine Residency, and I blog at Common Sense Family Doctor.
A few months ago, my health system added a clinical decision support function to our electronic health record to reduce inappropriate ordering of vitamin D levels. Clinicians are now required to select from a list of approved indications or diagnoses (including a history of vitamin D deficiency) before ordering the test.
Although I don’t know yet whether this process has had the desired effect, I felt that it was long overdue. Several years ago, I wrote an editorial that questioned the dramatic increase in vitamin D testing given the uncertainty about what level is adequate for good health and clinical trials showing that supplementing people with lower levels has no benefits for a variety of medical conditions. A more recent review of prospective studies of vitamin D supplements concluded that most correlations between vitamin D levels and outcomes in common and high-mortality conditions are unlikely to be causal.
A new Endocrine Society guideline recommends against routine measurement of vitamin D levels in healthy individuals. The guideline reinforces my current practice of not screening for vitamin D deficiency except in special situations, such as an individual with dark skin who works the night shift and rarely goes outdoors during daytime hours. But I haven’t been offering empirical vitamin D supplements to the four at-risk groups identified by the Endocrine Society: children, adults older than 75 years, pregnant patients, and adults with prediabetes. The evidence behind these recommendations merits a closer look.
In exclusively or primarily breastfed infants, I follow the American Academy of Pediatrics recommendation to prescribe a daily supplement containing 400 IU of vitamin D. However, the Endocrine Society found evidence from several studies conducted in other countries that continuing supplementation throughout childhood reduces the risk for rickets and possibly reduces the incidence of respiratory infections, with few adverse effects.
Many older women, and some older men, choose to take a calcium and vitamin D supplement for bone health, even though there is scant evidence that doing so prevents fractures in community-dwelling adults without osteoporosis. The Endocrine Society’s meta-analysis, however, found that 1000 adults aged 75 years or older who took an average of 900 IU of vitamin D daily for 2 years could expect to experience six fewer deaths than an identical group not taking supplements.
A typical prenatal vitamin contains 400 IU of vitamin D. Placebo-controlled trials reviewed by the Endocrine Society that gave an average of 2500 IU daily found statistically insignificant reductions in preeclampsia, intrauterine death, preterm birth, small for gestation age birth, and neonatal deaths.
Finally, the Endocrine Society’s recommendation for adults with prediabetes was based on 11 trials (three conducted in the United States) that tested a daily average of 3500 IU and found a slightly lower risk for progression to diabetes (24 fewer diagnoses of type 2 diabetes per 1000 persons) in the group who took supplements.
Of the four groups highlighted by the guideline, the strongest case for vitamin D supplements is in older adults — it’s hard to argue with lower mortality, even if the difference is small. Therefore, I will start suggesting that my patients over age 75 take a daily vitamin D supplement containing at least 800 IU if they aren’t already doing so.
On the other hand, I don’t plan to change my approach to pregnant patients (whose benefits in studies could have been due to chance), children after age 1 year (studies of children in other countries with different nutritional status may not apply to the United States), or adults with prediabetes (where we already have proven lifestyle interventions with much greater effects). In these cases, either I am unconvinced that the data support benefits for my patients, or I feel that the benefits of vitamin D supplements are small enough to be outweighed by potential harms, such as increased kidney stones.
Kenneth W. Lin, Associate Director, Family Medicine Residency Program, Lancaster General Hospital, Lancaster, Pennsylvania, has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Hi, everyone. I’m Dr. Kenny Lin. I am a family physician and associate director of the Lancaster General Hospital Family Medicine Residency, and I blog at Common Sense Family Doctor.
A few months ago, my health system added a clinical decision support function to our electronic health record to reduce inappropriate ordering of vitamin D levels. Clinicians are now required to select from a list of approved indications or diagnoses (including a history of vitamin D deficiency) before ordering the test.
Although I don’t know yet whether this process has had the desired effect, I felt that it was long overdue. Several years ago, I wrote an editorial that questioned the dramatic increase in vitamin D testing given the uncertainty about what level is adequate for good health and clinical trials showing that supplementing people with lower levels has no benefits for a variety of medical conditions. A more recent review of prospective studies of vitamin D supplements concluded that most correlations between vitamin D levels and outcomes in common and high-mortality conditions are unlikely to be causal.
A new Endocrine Society guideline recommends against routine measurement of vitamin D levels in healthy individuals. The guideline reinforces my current practice of not screening for vitamin D deficiency except in special situations, such as an individual with dark skin who works the night shift and rarely goes outdoors during daytime hours. But I haven’t been offering empirical vitamin D supplements to the four at-risk groups identified by the Endocrine Society: children, adults older than 75 years, pregnant patients, and adults with prediabetes. The evidence behind these recommendations merits a closer look.
In exclusively or primarily breastfed infants, I follow the American Academy of Pediatrics recommendation to prescribe a daily supplement containing 400 IU of vitamin D. However, the Endocrine Society found evidence from several studies conducted in other countries that continuing supplementation throughout childhood reduces the risk for rickets and possibly reduces the incidence of respiratory infections, with few adverse effects.
Many older women, and some older men, choose to take a calcium and vitamin D supplement for bone health, even though there is scant evidence that doing so prevents fractures in community-dwelling adults without osteoporosis. The Endocrine Society’s meta-analysis, however, found that 1000 adults aged 75 years or older who took an average of 900 IU of vitamin D daily for 2 years could expect to experience six fewer deaths than an identical group not taking supplements.
A typical prenatal vitamin contains 400 IU of vitamin D. Placebo-controlled trials reviewed by the Endocrine Society that gave an average of 2500 IU daily found statistically insignificant reductions in preeclampsia, intrauterine death, preterm birth, small for gestation age birth, and neonatal deaths.
Finally, the Endocrine Society’s recommendation for adults with prediabetes was based on 11 trials (three conducted in the United States) that tested a daily average of 3500 IU and found a slightly lower risk for progression to diabetes (24 fewer diagnoses of type 2 diabetes per 1000 persons) in the group who took supplements.
Of the four groups highlighted by the guideline, the strongest case for vitamin D supplements is in older adults — it’s hard to argue with lower mortality, even if the difference is small. Therefore, I will start suggesting that my patients over age 75 take a daily vitamin D supplement containing at least 800 IU if they aren’t already doing so.
On the other hand, I don’t plan to change my approach to pregnant patients (whose benefits in studies could have been due to chance), children after age 1 year (studies of children in other countries with different nutritional status may not apply to the United States), or adults with prediabetes (where we already have proven lifestyle interventions with much greater effects). In these cases, either I am unconvinced that the data support benefits for my patients, or I feel that the benefits of vitamin D supplements are small enough to be outweighed by potential harms, such as increased kidney stones.
Kenneth W. Lin, Associate Director, Family Medicine Residency Program, Lancaster General Hospital, Lancaster, Pennsylvania, has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Hi, everyone. I’m Dr. Kenny Lin. I am a family physician and associate director of the Lancaster General Hospital Family Medicine Residency, and I blog at Common Sense Family Doctor.
A few months ago, my health system added a clinical decision support function to our electronic health record to reduce inappropriate ordering of vitamin D levels. Clinicians are now required to select from a list of approved indications or diagnoses (including a history of vitamin D deficiency) before ordering the test.
Although I don’t know yet whether this process has had the desired effect, I felt that it was long overdue. Several years ago, I wrote an editorial that questioned the dramatic increase in vitamin D testing given the uncertainty about what level is adequate for good health and clinical trials showing that supplementing people with lower levels has no benefits for a variety of medical conditions. A more recent review of prospective studies of vitamin D supplements concluded that most correlations between vitamin D levels and outcomes in common and high-mortality conditions are unlikely to be causal.
A new Endocrine Society guideline recommends against routine measurement of vitamin D levels in healthy individuals. The guideline reinforces my current practice of not screening for vitamin D deficiency except in special situations, such as an individual with dark skin who works the night shift and rarely goes outdoors during daytime hours. But I haven’t been offering empirical vitamin D supplements to the four at-risk groups identified by the Endocrine Society: children, adults older than 75 years, pregnant patients, and adults with prediabetes. The evidence behind these recommendations merits a closer look.
In exclusively or primarily breastfed infants, I follow the American Academy of Pediatrics recommendation to prescribe a daily supplement containing 400 IU of vitamin D. However, the Endocrine Society found evidence from several studies conducted in other countries that continuing supplementation throughout childhood reduces the risk for rickets and possibly reduces the incidence of respiratory infections, with few adverse effects.
Many older women, and some older men, choose to take a calcium and vitamin D supplement for bone health, even though there is scant evidence that doing so prevents fractures in community-dwelling adults without osteoporosis. The Endocrine Society’s meta-analysis, however, found that 1000 adults aged 75 years or older who took an average of 900 IU of vitamin D daily for 2 years could expect to experience six fewer deaths than an identical group not taking supplements.
A typical prenatal vitamin contains 400 IU of vitamin D. Placebo-controlled trials reviewed by the Endocrine Society that gave an average of 2500 IU daily found statistically insignificant reductions in preeclampsia, intrauterine death, preterm birth, small for gestation age birth, and neonatal deaths.
Finally, the Endocrine Society’s recommendation for adults with prediabetes was based on 11 trials (three conducted in the United States) that tested a daily average of 3500 IU and found a slightly lower risk for progression to diabetes (24 fewer diagnoses of type 2 diabetes per 1000 persons) in the group who took supplements.
Of the four groups highlighted by the guideline, the strongest case for vitamin D supplements is in older adults — it’s hard to argue with lower mortality, even if the difference is small. Therefore, I will start suggesting that my patients over age 75 take a daily vitamin D supplement containing at least 800 IU if they aren’t already doing so.
On the other hand, I don’t plan to change my approach to pregnant patients (whose benefits in studies could have been due to chance), children after age 1 year (studies of children in other countries with different nutritional status may not apply to the United States), or adults with prediabetes (where we already have proven lifestyle interventions with much greater effects). In these cases, either I am unconvinced that the data support benefits for my patients, or I feel that the benefits of vitamin D supplements are small enough to be outweighed by potential harms, such as increased kidney stones.
Kenneth W. Lin, Associate Director, Family Medicine Residency Program, Lancaster General Hospital, Lancaster, Pennsylvania, has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Dangers of Intramuscular Fat Tissue Are Often Underestimated
The health consequences of excess visceral fat tissue are well known. But there is another type of fat accumulation in the body that increases the risk for type 2 diabetes and cardiovascular diseases. In Molecular Aspects of Medicine, researchers warned that the dangers arising from intramuscular fat tissue are often underestimated.
“Everyone knows the dangers of abdominal fat or that the deposition of fat in the coronary arteries can cause a heart attack,” said lead author Osvaldo Contreras, PhD, from the School of Clinical Medicine at the University of New South Wales in Sydney, Australia. “But hardly anyone has ever heard of fat accumulation in skeletal muscles, even though they are associated with a whole range of life-threatening diseases.”
“The work emphasizes that muscles are not only good for standing, walking, or lifting a box. They are metabolically active, produce hormones, communicate in the body, and can positively or negatively affect a person’s health,” Yurdagül Zopf, MD, PhD, professor of integrative medicine specializing in nutritional medicine and director of the Hector Center for Nutrition, Exercise, and Sports at the University Hospital Erlangen, Erlangen, Germany, said in an interview.
Associated With Diseases
Increased intramuscular fat is found in various conditions where muscle mass is increasingly lost and replaced by fat and connective tissue. Intramuscular fat has been observed, for example, in patients with chronic muscle diseases, sarcopenia, hormonal disorders, and metabolic diseases such as insulin resistance and type 2 diabetes, as well as in patients with cardiovascular problems such as hypertension and heart failure.
Fat accumulation in the muscles, like all fat deposits in the body, can result from an unhealthy lifestyle with excessive calorie intake and, especially, lack of exercise. “If the body has more energy available than it can use, it will initially store it as subcutaneous fat,” said Dr. Zopf. “Once these storage capacities are depleted, more and more visceral fat is deposited, and then more and more fat is stored in the organs and the muscles.”
Movement plays a particularly important role in intramuscular fat. “We know that the less physically active someone is, the higher the risk that fat will be stored in the muscles,” said Dr. Zopf.
Arising From Injuries
Unlike other fat tissues in the body, intramuscular fat can also accumulate in higher amounts when there are injuries to the muscles. The group led by Dr. Contreras and lead author Marcelo Flores-Opazo from the Universidad de O’Higgins in Rancagua, Chile, emphasized the role of fibroadipogenic progenitor (FAP) cells in their review. “FAPs play a crucial role in preserving and repairing muscle tissue injuries. They can differentiate into fibroblasts and adipocytes and are responsible for depositing fat and connective tissue in response to muscle injuries.”
Studies suggest that exercise can prevent FAPs from differentiating into fat and connective tissue cells. Metformin can achieve a similar effect in vitro. Dr. Contreras and colleagues hope that drug-based ways to reduce muscle fat will emerge in the future.
But how do you determine whether a patient has too much intramuscular fat? Although MRI and CT can be used for quantification, these are not routine examinations. There is currently no simple way to determine the fat content in muscles, according to the authors. The study authors hope that advances in molecular testing, imaging, and biopsies will improve diagnostic capabilities in the future.
Training Crucial
Until then, Dr. Contreras and colleagues advise close monitoring of one’s body weight and the maintenance of a healthy lifestyle. Excessive fat accumulation in the muscles can be prevented and reversed through adequate exercise and healthy nutrition, they emphasized.
The important message is that these measures are possible. “With healthy nutrition and exercise, excess fat can be reduced. We have observed a reduction in muscle fat in obese individuals with just two sessions of 15-minute high-intensity workouts per week,” Dr. Zopf reported, citing her own research. The more obese a person is and the higher the inflammation in the body, the more likely additional medication may be needed.
Dr. Zopf also pointed out a peculiarity of intramuscular fat tissue. “Muscle fat can only be trained off.” A fatty liver or too much fat under the skin can be combated well with a diet, but muscles are different. “For that, you have to exercise to counteract the inflammatory cascade in the muscles.”
This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
The health consequences of excess visceral fat tissue are well known. But there is another type of fat accumulation in the body that increases the risk for type 2 diabetes and cardiovascular diseases. In Molecular Aspects of Medicine, researchers warned that the dangers arising from intramuscular fat tissue are often underestimated.
“Everyone knows the dangers of abdominal fat or that the deposition of fat in the coronary arteries can cause a heart attack,” said lead author Osvaldo Contreras, PhD, from the School of Clinical Medicine at the University of New South Wales in Sydney, Australia. “But hardly anyone has ever heard of fat accumulation in skeletal muscles, even though they are associated with a whole range of life-threatening diseases.”
“The work emphasizes that muscles are not only good for standing, walking, or lifting a box. They are metabolically active, produce hormones, communicate in the body, and can positively or negatively affect a person’s health,” Yurdagül Zopf, MD, PhD, professor of integrative medicine specializing in nutritional medicine and director of the Hector Center for Nutrition, Exercise, and Sports at the University Hospital Erlangen, Erlangen, Germany, said in an interview.
Associated With Diseases
Increased intramuscular fat is found in various conditions where muscle mass is increasingly lost and replaced by fat and connective tissue. Intramuscular fat has been observed, for example, in patients with chronic muscle diseases, sarcopenia, hormonal disorders, and metabolic diseases such as insulin resistance and type 2 diabetes, as well as in patients with cardiovascular problems such as hypertension and heart failure.
Fat accumulation in the muscles, like all fat deposits in the body, can result from an unhealthy lifestyle with excessive calorie intake and, especially, lack of exercise. “If the body has more energy available than it can use, it will initially store it as subcutaneous fat,” said Dr. Zopf. “Once these storage capacities are depleted, more and more visceral fat is deposited, and then more and more fat is stored in the organs and the muscles.”
Movement plays a particularly important role in intramuscular fat. “We know that the less physically active someone is, the higher the risk that fat will be stored in the muscles,” said Dr. Zopf.
Arising From Injuries
Unlike other fat tissues in the body, intramuscular fat can also accumulate in higher amounts when there are injuries to the muscles. The group led by Dr. Contreras and lead author Marcelo Flores-Opazo from the Universidad de O’Higgins in Rancagua, Chile, emphasized the role of fibroadipogenic progenitor (FAP) cells in their review. “FAPs play a crucial role in preserving and repairing muscle tissue injuries. They can differentiate into fibroblasts and adipocytes and are responsible for depositing fat and connective tissue in response to muscle injuries.”
Studies suggest that exercise can prevent FAPs from differentiating into fat and connective tissue cells. Metformin can achieve a similar effect in vitro. Dr. Contreras and colleagues hope that drug-based ways to reduce muscle fat will emerge in the future.
But how do you determine whether a patient has too much intramuscular fat? Although MRI and CT can be used for quantification, these are not routine examinations. There is currently no simple way to determine the fat content in muscles, according to the authors. The study authors hope that advances in molecular testing, imaging, and biopsies will improve diagnostic capabilities in the future.
Training Crucial
Until then, Dr. Contreras and colleagues advise close monitoring of one’s body weight and the maintenance of a healthy lifestyle. Excessive fat accumulation in the muscles can be prevented and reversed through adequate exercise and healthy nutrition, they emphasized.
The important message is that these measures are possible. “With healthy nutrition and exercise, excess fat can be reduced. We have observed a reduction in muscle fat in obese individuals with just two sessions of 15-minute high-intensity workouts per week,” Dr. Zopf reported, citing her own research. The more obese a person is and the higher the inflammation in the body, the more likely additional medication may be needed.
Dr. Zopf also pointed out a peculiarity of intramuscular fat tissue. “Muscle fat can only be trained off.” A fatty liver or too much fat under the skin can be combated well with a diet, but muscles are different. “For that, you have to exercise to counteract the inflammatory cascade in the muscles.”
This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
The health consequences of excess visceral fat tissue are well known. But there is another type of fat accumulation in the body that increases the risk for type 2 diabetes and cardiovascular diseases. In Molecular Aspects of Medicine, researchers warned that the dangers arising from intramuscular fat tissue are often underestimated.
“Everyone knows the dangers of abdominal fat or that the deposition of fat in the coronary arteries can cause a heart attack,” said lead author Osvaldo Contreras, PhD, from the School of Clinical Medicine at the University of New South Wales in Sydney, Australia. “But hardly anyone has ever heard of fat accumulation in skeletal muscles, even though they are associated with a whole range of life-threatening diseases.”
“The work emphasizes that muscles are not only good for standing, walking, or lifting a box. They are metabolically active, produce hormones, communicate in the body, and can positively or negatively affect a person’s health,” Yurdagül Zopf, MD, PhD, professor of integrative medicine specializing in nutritional medicine and director of the Hector Center for Nutrition, Exercise, and Sports at the University Hospital Erlangen, Erlangen, Germany, said in an interview.
Associated With Diseases
Increased intramuscular fat is found in various conditions where muscle mass is increasingly lost and replaced by fat and connective tissue. Intramuscular fat has been observed, for example, in patients with chronic muscle diseases, sarcopenia, hormonal disorders, and metabolic diseases such as insulin resistance and type 2 diabetes, as well as in patients with cardiovascular problems such as hypertension and heart failure.
Fat accumulation in the muscles, like all fat deposits in the body, can result from an unhealthy lifestyle with excessive calorie intake and, especially, lack of exercise. “If the body has more energy available than it can use, it will initially store it as subcutaneous fat,” said Dr. Zopf. “Once these storage capacities are depleted, more and more visceral fat is deposited, and then more and more fat is stored in the organs and the muscles.”
Movement plays a particularly important role in intramuscular fat. “We know that the less physically active someone is, the higher the risk that fat will be stored in the muscles,” said Dr. Zopf.
Arising From Injuries
Unlike other fat tissues in the body, intramuscular fat can also accumulate in higher amounts when there are injuries to the muscles. The group led by Dr. Contreras and lead author Marcelo Flores-Opazo from the Universidad de O’Higgins in Rancagua, Chile, emphasized the role of fibroadipogenic progenitor (FAP) cells in their review. “FAPs play a crucial role in preserving and repairing muscle tissue injuries. They can differentiate into fibroblasts and adipocytes and are responsible for depositing fat and connective tissue in response to muscle injuries.”
Studies suggest that exercise can prevent FAPs from differentiating into fat and connective tissue cells. Metformin can achieve a similar effect in vitro. Dr. Contreras and colleagues hope that drug-based ways to reduce muscle fat will emerge in the future.
But how do you determine whether a patient has too much intramuscular fat? Although MRI and CT can be used for quantification, these are not routine examinations. There is currently no simple way to determine the fat content in muscles, according to the authors. The study authors hope that advances in molecular testing, imaging, and biopsies will improve diagnostic capabilities in the future.
Training Crucial
Until then, Dr. Contreras and colleagues advise close monitoring of one’s body weight and the maintenance of a healthy lifestyle. Excessive fat accumulation in the muscles can be prevented and reversed through adequate exercise and healthy nutrition, they emphasized.
The important message is that these measures are possible. “With healthy nutrition and exercise, excess fat can be reduced. We have observed a reduction in muscle fat in obese individuals with just two sessions of 15-minute high-intensity workouts per week,” Dr. Zopf reported, citing her own research. The more obese a person is and the higher the inflammation in the body, the more likely additional medication may be needed.
Dr. Zopf also pointed out a peculiarity of intramuscular fat tissue. “Muscle fat can only be trained off.” A fatty liver or too much fat under the skin can be combated well with a diet, but muscles are different. “For that, you have to exercise to counteract the inflammatory cascade in the muscles.”
This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
FROM MOLECULAR ASPECTS OF MEDICINE
New Criteria Distinguish Memory Disorder Often Misdiagnosed as Alzheimer’s
Proposed clinical criteria for a memory loss disorder that is often misdiagnosed as Alzheimer’s disease (AD) have been published.
The new criteria for limbic-predominant amnestic neurodegenerative syndrome (LANS) provide a framework for neurologists and other experts to classify the condition and offer a more precise diagnosis and potential treatments.
“In our clinical work, we see patients whose memory symptoms appear to mimic Alzheimer’s disease, but when you look at their brain imaging or biomarkers, it’s clear they don’t have Alzheimer’s. Until now, there has not been a specific medical diagnosis to point to, but now we can offer them some answers,” senior investigator David T. Jones, MD, said in a release.
The proposed criteria and the research behind it were published online in Brain Communications and will be presented at the Alzheimer›s Association International Conference in Philadelphia.
Already in Use
Predominant limbic degeneration has been linked to various underlying etiologies, older age, predominant impairment of episodic memory, and slow clinical progression, the investigators noted. However, they added, the neurologic syndrome associated with predominant limbic degeneration is undefined.
Developing clinical criteria and validating them “is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying etiology, disease course, and therapeutic needs,” the investigators wrote.
The newly proposed clinical criteria apply to LANS, which is “highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities.”
The criteria incorporate core, standard, and advanced features including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of endocortical degeneration, and low likelihood of neocortical tau with highest, high, moderate, and low degrees of certainty.
“A detailed history of the clinical symptoms, which may be supported by neuropsychological testing, with the observation of disproportionate hippocampal atrophy and limbic degeneration on MRI/FDG yields a high confidence in a diagnosis of LANS, where the most likely symptom-driving proteinopathy is TDP-43 and not Alzheimer’s associated proteins,” the first author, Nick Corriveau-Lecavalier, PhD, assistant professor of neurology and psychology at Mayo Clinic, Rochester, Minnesota, told this news organization.
To validate the criteria, the investigators screened autopsied patients from Mayo Clinic and Alzheimer’s Disease Neuroimaging Initiative cohorts and applied the criteria to those with a predominant amnestic syndrome and those who had AD neuropathologic change, limbic-predominant age-related TDP-43 encephalopathy, or both pathologies at autopsy.
“The criteria effectively categorized these cases, with Alzheimer’s disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods, and patients with both pathologies having intermediate likelihoods,” the investigators reported.
“Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods,” they added.
Dr. Corriveau-Lecavalier said the team is currently analyzing longitudinal cognitive and imaging trajectories in LANS over several years. “This will help us better understand how LANS and Alzheimer’s differ in their sequence of symptoms over time.”
It is important to understand that memory symptoms in old age are not “unequivocally” driven by Alzheimer’s and that LANS progresses more slowly and has a better prognosis than AD, he noted.
In addition, in vivo markers of TDP-43 are “on the horizon and can hopefully make their way to human research settings soon. This will help better understand the underlying molecular etiologies causing LANS and associated symptoms,” he said.
Dr. Corriveau-Lecavalier said the LANS criteria are ready for clinical use by experts in neurologic care. These criteria can be used to inform not only diagnosis but also prognosis, where this syndrome is associated with slow and mild progression and a memory-dominant profile.
He added that “the new criteria are also routinely used in our practice to make decisions about anti-amyloid treatment eligibility.”
Commenting on the research for this news organization, Rebecca M. Edelmayer, PhD, Alzheimer’s Association senior director of scientific engagement, said the research “exemplifies the great need to develop objective criteria for diagnosis and staging of Alzheimer’s and all other types of dementia and to create an integrated biological and clinical staging scheme that can be used effectively by physicians.”
“Advances in biomarkers will help to differentiate all types of dementia when incorporated into the diagnostic workup, but until those tools are available, a more succinct clinical criteria for diagnosis can be used to support a more personalized medicine approach to treatment, care, and enrollment into clinical studies,” said Dr. Edelmayer, who wasn’t involved in the research.
The research was funded in part by the National Institutes of Health and by the Robert Wood Johnson Foundation, the Elsie & Marvin Dekelboum Family Foundation, the Liston Family Foundation, the Edson Family, the Gerald A. and Henrietta Rauenhorst Foundation, and the Foundation Dr Corinne Schuler. Dr. Corriveau-Lecavalier and Dr. Edelmayer had no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Proposed clinical criteria for a memory loss disorder that is often misdiagnosed as Alzheimer’s disease (AD) have been published.
The new criteria for limbic-predominant amnestic neurodegenerative syndrome (LANS) provide a framework for neurologists and other experts to classify the condition and offer a more precise diagnosis and potential treatments.
“In our clinical work, we see patients whose memory symptoms appear to mimic Alzheimer’s disease, but when you look at their brain imaging or biomarkers, it’s clear they don’t have Alzheimer’s. Until now, there has not been a specific medical diagnosis to point to, but now we can offer them some answers,” senior investigator David T. Jones, MD, said in a release.
The proposed criteria and the research behind it were published online in Brain Communications and will be presented at the Alzheimer›s Association International Conference in Philadelphia.
Already in Use
Predominant limbic degeneration has been linked to various underlying etiologies, older age, predominant impairment of episodic memory, and slow clinical progression, the investigators noted. However, they added, the neurologic syndrome associated with predominant limbic degeneration is undefined.
Developing clinical criteria and validating them “is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying etiology, disease course, and therapeutic needs,” the investigators wrote.
The newly proposed clinical criteria apply to LANS, which is “highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities.”
The criteria incorporate core, standard, and advanced features including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of endocortical degeneration, and low likelihood of neocortical tau with highest, high, moderate, and low degrees of certainty.
“A detailed history of the clinical symptoms, which may be supported by neuropsychological testing, with the observation of disproportionate hippocampal atrophy and limbic degeneration on MRI/FDG yields a high confidence in a diagnosis of LANS, where the most likely symptom-driving proteinopathy is TDP-43 and not Alzheimer’s associated proteins,” the first author, Nick Corriveau-Lecavalier, PhD, assistant professor of neurology and psychology at Mayo Clinic, Rochester, Minnesota, told this news organization.
To validate the criteria, the investigators screened autopsied patients from Mayo Clinic and Alzheimer’s Disease Neuroimaging Initiative cohorts and applied the criteria to those with a predominant amnestic syndrome and those who had AD neuropathologic change, limbic-predominant age-related TDP-43 encephalopathy, or both pathologies at autopsy.
“The criteria effectively categorized these cases, with Alzheimer’s disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods, and patients with both pathologies having intermediate likelihoods,” the investigators reported.
“Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods,” they added.
Dr. Corriveau-Lecavalier said the team is currently analyzing longitudinal cognitive and imaging trajectories in LANS over several years. “This will help us better understand how LANS and Alzheimer’s differ in their sequence of symptoms over time.”
It is important to understand that memory symptoms in old age are not “unequivocally” driven by Alzheimer’s and that LANS progresses more slowly and has a better prognosis than AD, he noted.
In addition, in vivo markers of TDP-43 are “on the horizon and can hopefully make their way to human research settings soon. This will help better understand the underlying molecular etiologies causing LANS and associated symptoms,” he said.
Dr. Corriveau-Lecavalier said the LANS criteria are ready for clinical use by experts in neurologic care. These criteria can be used to inform not only diagnosis but also prognosis, where this syndrome is associated with slow and mild progression and a memory-dominant profile.
He added that “the new criteria are also routinely used in our practice to make decisions about anti-amyloid treatment eligibility.”
Commenting on the research for this news organization, Rebecca M. Edelmayer, PhD, Alzheimer’s Association senior director of scientific engagement, said the research “exemplifies the great need to develop objective criteria for diagnosis and staging of Alzheimer’s and all other types of dementia and to create an integrated biological and clinical staging scheme that can be used effectively by physicians.”
“Advances in biomarkers will help to differentiate all types of dementia when incorporated into the diagnostic workup, but until those tools are available, a more succinct clinical criteria for diagnosis can be used to support a more personalized medicine approach to treatment, care, and enrollment into clinical studies,” said Dr. Edelmayer, who wasn’t involved in the research.
The research was funded in part by the National Institutes of Health and by the Robert Wood Johnson Foundation, the Elsie & Marvin Dekelboum Family Foundation, the Liston Family Foundation, the Edson Family, the Gerald A. and Henrietta Rauenhorst Foundation, and the Foundation Dr Corinne Schuler. Dr. Corriveau-Lecavalier and Dr. Edelmayer had no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Proposed clinical criteria for a memory loss disorder that is often misdiagnosed as Alzheimer’s disease (AD) have been published.
The new criteria for limbic-predominant amnestic neurodegenerative syndrome (LANS) provide a framework for neurologists and other experts to classify the condition and offer a more precise diagnosis and potential treatments.
“In our clinical work, we see patients whose memory symptoms appear to mimic Alzheimer’s disease, but when you look at their brain imaging or biomarkers, it’s clear they don’t have Alzheimer’s. Until now, there has not been a specific medical diagnosis to point to, but now we can offer them some answers,” senior investigator David T. Jones, MD, said in a release.
The proposed criteria and the research behind it were published online in Brain Communications and will be presented at the Alzheimer›s Association International Conference in Philadelphia.
Already in Use
Predominant limbic degeneration has been linked to various underlying etiologies, older age, predominant impairment of episodic memory, and slow clinical progression, the investigators noted. However, they added, the neurologic syndrome associated with predominant limbic degeneration is undefined.
Developing clinical criteria and validating them “is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying etiology, disease course, and therapeutic needs,” the investigators wrote.
The newly proposed clinical criteria apply to LANS, which is “highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities.”
The criteria incorporate core, standard, and advanced features including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of endocortical degeneration, and low likelihood of neocortical tau with highest, high, moderate, and low degrees of certainty.
“A detailed history of the clinical symptoms, which may be supported by neuropsychological testing, with the observation of disproportionate hippocampal atrophy and limbic degeneration on MRI/FDG yields a high confidence in a diagnosis of LANS, where the most likely symptom-driving proteinopathy is TDP-43 and not Alzheimer’s associated proteins,” the first author, Nick Corriveau-Lecavalier, PhD, assistant professor of neurology and psychology at Mayo Clinic, Rochester, Minnesota, told this news organization.
To validate the criteria, the investigators screened autopsied patients from Mayo Clinic and Alzheimer’s Disease Neuroimaging Initiative cohorts and applied the criteria to those with a predominant amnestic syndrome and those who had AD neuropathologic change, limbic-predominant age-related TDP-43 encephalopathy, or both pathologies at autopsy.
“The criteria effectively categorized these cases, with Alzheimer’s disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods, and patients with both pathologies having intermediate likelihoods,” the investigators reported.
“Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods,” they added.
Dr. Corriveau-Lecavalier said the team is currently analyzing longitudinal cognitive and imaging trajectories in LANS over several years. “This will help us better understand how LANS and Alzheimer’s differ in their sequence of symptoms over time.”
It is important to understand that memory symptoms in old age are not “unequivocally” driven by Alzheimer’s and that LANS progresses more slowly and has a better prognosis than AD, he noted.
In addition, in vivo markers of TDP-43 are “on the horizon and can hopefully make their way to human research settings soon. This will help better understand the underlying molecular etiologies causing LANS and associated symptoms,” he said.
Dr. Corriveau-Lecavalier said the LANS criteria are ready for clinical use by experts in neurologic care. These criteria can be used to inform not only diagnosis but also prognosis, where this syndrome is associated with slow and mild progression and a memory-dominant profile.
He added that “the new criteria are also routinely used in our practice to make decisions about anti-amyloid treatment eligibility.”
Commenting on the research for this news organization, Rebecca M. Edelmayer, PhD, Alzheimer’s Association senior director of scientific engagement, said the research “exemplifies the great need to develop objective criteria for diagnosis and staging of Alzheimer’s and all other types of dementia and to create an integrated biological and clinical staging scheme that can be used effectively by physicians.”
“Advances in biomarkers will help to differentiate all types of dementia when incorporated into the diagnostic workup, but until those tools are available, a more succinct clinical criteria for diagnosis can be used to support a more personalized medicine approach to treatment, care, and enrollment into clinical studies,” said Dr. Edelmayer, who wasn’t involved in the research.
The research was funded in part by the National Institutes of Health and by the Robert Wood Johnson Foundation, the Elsie & Marvin Dekelboum Family Foundation, the Liston Family Foundation, the Edson Family, the Gerald A. and Henrietta Rauenhorst Foundation, and the Foundation Dr Corinne Schuler. Dr. Corriveau-Lecavalier and Dr. Edelmayer had no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
New, Near-to-Market PCSK9s Could Help Patients Meet Cholesterol Targets
, experts said.
One new anti-PCSK9 agent — lerodalcibep from LIB Therapeutics — is a small protein molecule, which is expected to reach the market by early 2026. It is being positioned as a step forward from the two monoclonal antibody products already available — evolocumab (Repatha; Amgen) and alirocumab (Praluent; Sanofi/Regeneron).
The new option can be given less frequently than the antibodies with a once-a-month injection instead of every 2 weeks. It also does not need to be kept refrigerated like the antibodies, Evan Stein, MD, chief scientific and operating officer of LIB Therapeutics, said in an interview.
Two phase 3 trials have recently been reported, showing impressive reductions in LDL in patients already taking statins.
The LIBerate Trials
The LIBerate-HR trial, published in JAMA Cardiology, involved 922 patients who still had LDL above target despite taking maximally tolerated statin therapy plus other lipid-lowering agents in some cases.
The trial found a time-averaged mean reduction in LDL cholesterol of 62%.
“This large reduction resulted in more than 90% of patients reaching the new lower LDL targets set in recent guidelines of less than 55 mg/dL for patients with cardiovascular disease or at very high risk, and less than 70 mg/dL in patients at risk,” said Stein.
Another phase 3 trial, LIBerate-CVD, has also shown reductions in LDL cholesterol levels of more than 60% in patients at high risk for cardiovascular disease on maximally tolerated statins.
LIB Therapeutics plans to file approval applications for lerodalcibep in the United States and Europe later this year.
A Crowded Field
Dr. Stein said PCSK9 inhibitors have been underused so far, but this is starting to change.
“The monoclonal antibodies were way overpriced costing around $14,000 per year when they were first introduced, which resulted in huge pushback from insurance companies,” Dr. Stein said, which made the drugs difficult to prescribe. “Then a few years ago, the price dropped a bit, and now they’re probably running at about $4000 per year, which made them more accessible.”
He said the market is now rapidly taking off. Lerodalcibep will compete in the anti-PCSK9 market with not only the two monoclonal antibodies but also with the new short-interfering RNA agent, inclisiran (Leqvio; Novartis) , a novel injectable agent that is given just twice a year but has to be administered at a medical facility.
Despite the crowded field, there appears to be plenty of room in the market. “Last year, growth was just under 40%. The first quarter of this year, it has increased by 44%. While the introduction of inclisiran has added to this growth, it hasn’t dented the sales of the existing monoclonal antibodies,” said Dr. Stein.
He estimates that the anti-PCSK9 market will reach $3 billion globally this year, and by the time lerodalcibep is launched, it could be worth $5 billion.
As well as inclisiran and lerodalcibep, there are other innovations in the anti-PCSK9 field in development, with oral drugs now also in the pipeline. The first one of these, in development by Merck, is in early phase 3 trials, and AstraZeneca has an oral agent in earlier development.
Enthusiastic Response
Other experts in the lipid field are also enthusiastic about new developments in the PCSK9s.
Jorge Plutzky, MD, director of preventive cardiology at Brigham and Women’s Hospital in Boston, said he welcomes the prospect of new approaches to PCSK9 inhibition.
“The increase in the number of safe, effective tools for LDL lowering, whether through PCSK9 or other targets, is inevitably beneficial for patients and the field,” he said during an interview.
Dr. Plutzky pointed out that although the current agents are effective, cost and coverage remain issues despite some recent progress in these areas, and new agents will increase competition and should hopefully drive prices down. Having a variety of dosing methods and frequencies provides more options for patients to find the one that works best for them.
Lerodalcibep’s once-monthly dosing schedule and the lack of need for refrigeration may be appreciated by some patients, he said, particularly those who need to travel for long periods.
Connie Newman, MD, adjunct professor of medicine at NYU School of Medicine, New York City, said there is plenty of room in the market to accommodate patient’s needs and preferences.
“Despite the US FDA approval of three medications that target PCSK9, there is a need for more anti-PCSK9 agents that reduce LDL and cardiovascular events,” she said. “In the US alone, 25% of adults have LDL levels of 130 mg/dL and above. Of all the non-statin therapies, medications targeting PCSK9 produce the greatest reduction in LDL. However, some patients may not tolerate one or more of the medications available or may prefer a monthly injection of lower volume.”
Dr. Newman said she believes there will still be a market for injectable formulations of PCSK9 inhibitors in the future, even if oral formulations are approved.
“Oral formulations usually require more frequent administration. Some people prefer longer-acting medications that can be taken less often. This might lead to better adherence,” she said.
Dr. Stein said he agrees there will always be room for different options. “And you only have to look at what is happening with the weight loss drugs to see that there is a market for injectables.” The ability to get patients to the new, more aggressive LDL goals is what is important, he added. “These drugs do that, and offering patients a choice of agents and delivery mechanisms is helpful.”
A version of this article appeared on Medscape.com.
, experts said.
One new anti-PCSK9 agent — lerodalcibep from LIB Therapeutics — is a small protein molecule, which is expected to reach the market by early 2026. It is being positioned as a step forward from the two monoclonal antibody products already available — evolocumab (Repatha; Amgen) and alirocumab (Praluent; Sanofi/Regeneron).
The new option can be given less frequently than the antibodies with a once-a-month injection instead of every 2 weeks. It also does not need to be kept refrigerated like the antibodies, Evan Stein, MD, chief scientific and operating officer of LIB Therapeutics, said in an interview.
Two phase 3 trials have recently been reported, showing impressive reductions in LDL in patients already taking statins.
The LIBerate Trials
The LIBerate-HR trial, published in JAMA Cardiology, involved 922 patients who still had LDL above target despite taking maximally tolerated statin therapy plus other lipid-lowering agents in some cases.
The trial found a time-averaged mean reduction in LDL cholesterol of 62%.
“This large reduction resulted in more than 90% of patients reaching the new lower LDL targets set in recent guidelines of less than 55 mg/dL for patients with cardiovascular disease or at very high risk, and less than 70 mg/dL in patients at risk,” said Stein.
Another phase 3 trial, LIBerate-CVD, has also shown reductions in LDL cholesterol levels of more than 60% in patients at high risk for cardiovascular disease on maximally tolerated statins.
LIB Therapeutics plans to file approval applications for lerodalcibep in the United States and Europe later this year.
A Crowded Field
Dr. Stein said PCSK9 inhibitors have been underused so far, but this is starting to change.
“The monoclonal antibodies were way overpriced costing around $14,000 per year when they were first introduced, which resulted in huge pushback from insurance companies,” Dr. Stein said, which made the drugs difficult to prescribe. “Then a few years ago, the price dropped a bit, and now they’re probably running at about $4000 per year, which made them more accessible.”
He said the market is now rapidly taking off. Lerodalcibep will compete in the anti-PCSK9 market with not only the two monoclonal antibodies but also with the new short-interfering RNA agent, inclisiran (Leqvio; Novartis) , a novel injectable agent that is given just twice a year but has to be administered at a medical facility.
Despite the crowded field, there appears to be plenty of room in the market. “Last year, growth was just under 40%. The first quarter of this year, it has increased by 44%. While the introduction of inclisiran has added to this growth, it hasn’t dented the sales of the existing monoclonal antibodies,” said Dr. Stein.
He estimates that the anti-PCSK9 market will reach $3 billion globally this year, and by the time lerodalcibep is launched, it could be worth $5 billion.
As well as inclisiran and lerodalcibep, there are other innovations in the anti-PCSK9 field in development, with oral drugs now also in the pipeline. The first one of these, in development by Merck, is in early phase 3 trials, and AstraZeneca has an oral agent in earlier development.
Enthusiastic Response
Other experts in the lipid field are also enthusiastic about new developments in the PCSK9s.
Jorge Plutzky, MD, director of preventive cardiology at Brigham and Women’s Hospital in Boston, said he welcomes the prospect of new approaches to PCSK9 inhibition.
“The increase in the number of safe, effective tools for LDL lowering, whether through PCSK9 or other targets, is inevitably beneficial for patients and the field,” he said during an interview.
Dr. Plutzky pointed out that although the current agents are effective, cost and coverage remain issues despite some recent progress in these areas, and new agents will increase competition and should hopefully drive prices down. Having a variety of dosing methods and frequencies provides more options for patients to find the one that works best for them.
Lerodalcibep’s once-monthly dosing schedule and the lack of need for refrigeration may be appreciated by some patients, he said, particularly those who need to travel for long periods.
Connie Newman, MD, adjunct professor of medicine at NYU School of Medicine, New York City, said there is plenty of room in the market to accommodate patient’s needs and preferences.
“Despite the US FDA approval of three medications that target PCSK9, there is a need for more anti-PCSK9 agents that reduce LDL and cardiovascular events,” she said. “In the US alone, 25% of adults have LDL levels of 130 mg/dL and above. Of all the non-statin therapies, medications targeting PCSK9 produce the greatest reduction in LDL. However, some patients may not tolerate one or more of the medications available or may prefer a monthly injection of lower volume.”
Dr. Newman said she believes there will still be a market for injectable formulations of PCSK9 inhibitors in the future, even if oral formulations are approved.
“Oral formulations usually require more frequent administration. Some people prefer longer-acting medications that can be taken less often. This might lead to better adherence,” she said.
Dr. Stein said he agrees there will always be room for different options. “And you only have to look at what is happening with the weight loss drugs to see that there is a market for injectables.” The ability to get patients to the new, more aggressive LDL goals is what is important, he added. “These drugs do that, and offering patients a choice of agents and delivery mechanisms is helpful.”
A version of this article appeared on Medscape.com.
, experts said.
One new anti-PCSK9 agent — lerodalcibep from LIB Therapeutics — is a small protein molecule, which is expected to reach the market by early 2026. It is being positioned as a step forward from the two monoclonal antibody products already available — evolocumab (Repatha; Amgen) and alirocumab (Praluent; Sanofi/Regeneron).
The new option can be given less frequently than the antibodies with a once-a-month injection instead of every 2 weeks. It also does not need to be kept refrigerated like the antibodies, Evan Stein, MD, chief scientific and operating officer of LIB Therapeutics, said in an interview.
Two phase 3 trials have recently been reported, showing impressive reductions in LDL in patients already taking statins.
The LIBerate Trials
The LIBerate-HR trial, published in JAMA Cardiology, involved 922 patients who still had LDL above target despite taking maximally tolerated statin therapy plus other lipid-lowering agents in some cases.
The trial found a time-averaged mean reduction in LDL cholesterol of 62%.
“This large reduction resulted in more than 90% of patients reaching the new lower LDL targets set in recent guidelines of less than 55 mg/dL for patients with cardiovascular disease or at very high risk, and less than 70 mg/dL in patients at risk,” said Stein.
Another phase 3 trial, LIBerate-CVD, has also shown reductions in LDL cholesterol levels of more than 60% in patients at high risk for cardiovascular disease on maximally tolerated statins.
LIB Therapeutics plans to file approval applications for lerodalcibep in the United States and Europe later this year.
A Crowded Field
Dr. Stein said PCSK9 inhibitors have been underused so far, but this is starting to change.
“The monoclonal antibodies were way overpriced costing around $14,000 per year when they were first introduced, which resulted in huge pushback from insurance companies,” Dr. Stein said, which made the drugs difficult to prescribe. “Then a few years ago, the price dropped a bit, and now they’re probably running at about $4000 per year, which made them more accessible.”
He said the market is now rapidly taking off. Lerodalcibep will compete in the anti-PCSK9 market with not only the two monoclonal antibodies but also with the new short-interfering RNA agent, inclisiran (Leqvio; Novartis) , a novel injectable agent that is given just twice a year but has to be administered at a medical facility.
Despite the crowded field, there appears to be plenty of room in the market. “Last year, growth was just under 40%. The first quarter of this year, it has increased by 44%. While the introduction of inclisiran has added to this growth, it hasn’t dented the sales of the existing monoclonal antibodies,” said Dr. Stein.
He estimates that the anti-PCSK9 market will reach $3 billion globally this year, and by the time lerodalcibep is launched, it could be worth $5 billion.
As well as inclisiran and lerodalcibep, there are other innovations in the anti-PCSK9 field in development, with oral drugs now also in the pipeline. The first one of these, in development by Merck, is in early phase 3 trials, and AstraZeneca has an oral agent in earlier development.
Enthusiastic Response
Other experts in the lipid field are also enthusiastic about new developments in the PCSK9s.
Jorge Plutzky, MD, director of preventive cardiology at Brigham and Women’s Hospital in Boston, said he welcomes the prospect of new approaches to PCSK9 inhibition.
“The increase in the number of safe, effective tools for LDL lowering, whether through PCSK9 or other targets, is inevitably beneficial for patients and the field,” he said during an interview.
Dr. Plutzky pointed out that although the current agents are effective, cost and coverage remain issues despite some recent progress in these areas, and new agents will increase competition and should hopefully drive prices down. Having a variety of dosing methods and frequencies provides more options for patients to find the one that works best for them.
Lerodalcibep’s once-monthly dosing schedule and the lack of need for refrigeration may be appreciated by some patients, he said, particularly those who need to travel for long periods.
Connie Newman, MD, adjunct professor of medicine at NYU School of Medicine, New York City, said there is plenty of room in the market to accommodate patient’s needs and preferences.
“Despite the US FDA approval of three medications that target PCSK9, there is a need for more anti-PCSK9 agents that reduce LDL and cardiovascular events,” she said. “In the US alone, 25% of adults have LDL levels of 130 mg/dL and above. Of all the non-statin therapies, medications targeting PCSK9 produce the greatest reduction in LDL. However, some patients may not tolerate one or more of the medications available or may prefer a monthly injection of lower volume.”
Dr. Newman said she believes there will still be a market for injectable formulations of PCSK9 inhibitors in the future, even if oral formulations are approved.
“Oral formulations usually require more frequent administration. Some people prefer longer-acting medications that can be taken less often. This might lead to better adherence,” she said.
Dr. Stein said he agrees there will always be room for different options. “And you only have to look at what is happening with the weight loss drugs to see that there is a market for injectables.” The ability to get patients to the new, more aggressive LDL goals is what is important, he added. “These drugs do that, and offering patients a choice of agents and delivery mechanisms is helpful.”
A version of this article appeared on Medscape.com.
Less Invasive, Overlooked Option in Cardiac Surgery May Offer Benefit
Compared with traditional replacement valves, sutureless valves placed through minimally invasive cardiac surgery have less data supporting their use but offer unique features that might make them the preferred option for certain patients, reported specialists.
The sutureless device known as Perceval (Corcym) and a rapidly deployed device called Intuity (Edwards Lifesciences) are used as an alternative to surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR). But despite being commercially available since 2016, the devices are still not being used much.
The devices are not discussed in substantial detail in either the joint guidelines from the American College of Cardiology and American Heart Association issued in 2020 or guidelines from the European Society of Cardiology issued in 2022.
Cristiano Spadaccio, MD, PhD, a cardiothoracic surgeon associated with Lancashire Cardiac Centre in Blackpool, England, and his colleagues reviewed the small number of studies evaluating the alternate approach to “make the cardiology world aware” of alternatives “that can relieve the surgical burden by minimizing the implantation time and length of the operation,” he said.
The comprehensive review is published in the Journal of the American College of Cardiology.
A Neglected Alternative
The sutureless Perceval device is held in place by a stent frame that self-expands. The Intuity device also relies primarily on its framework to anchor the valve in place but does involve three sutures. Both devices are still referred to as sutureless in the new review of them.
Only a small number of centers perform minimally invasive cardiac surgeries, and the main advantage of the devices — rapid deployment — has been eroded with the advent of automated knotting which has significantly reduced the time to implant and sutured valve.
The underuse of these devices is largely caused by the limited amount of comparative and prospective data, said Dr. Spadaccio. “The entire literature on sutureless aortic valve replacement with the exception of one randomized controlled trial is observational.”
That trial, PERSIST-AVR, found that the sutureless valves were just as good as conventional ones when it comes to major adverse cardiovascular events including all-cause death, myocardial infarction, stroke, or valve reintervention at 1 year.
In a subanalysis limited to patients who had isolated aortic valve replacement, the sutureless procedure was associated with lower adverse events (5.2% vs 10.8%) at the cost of a higher rate of pacemaker implantation (11% vs 1.6%).
There are also multiple retrospective studies and registries that have generated observational data comparing sutureless aortic valve replacement with SAVR and TAVR in various patient populations, said Dr. Spadaccio, and the review was based on more than a dozen studies published since 2015. Long-term follow-up data for sutureless aortic valve replacements, which now exceeds 10 years, suggest rates of structural valve deterioration and reintervention have been acceptably low.
The minimally invasive procedures have other advantages too. For example, relative to the greater trauma associated with open heart surgery, minimally invasive surgeries typically involve faster recovery, an advantage likely to appeal to many patients who are candidates for either.
Quicker Recovery
Collectively, these data suggest that sutureless aortic valve replacement might be a reasonable or even a more appropriate alternative to either SAVR or TAVR when considering specific patient characteristics and goals, according to the review, which included an algorithm identifying specifically where sutureless aortic valve replacement fits with SAVR and TAVR.
“The algorithm is based on different clinical scenarios and reflects current guidelines for SAVR,” said Dr. Spadaccio. For example, current guidelines identify SAVR as preferred in patients younger than 65 years and in older patients with a low Society of Thoracic Surgeons (STS) score, but there are many instances in which sutureless aortic valve replacement might be more attractive, such as in those also undergoing mitral valve repair, coronary artery bypass grafting, or another surgical procedure.
Dr. Spadaccio said that the STS score should not be considered in isolation when evaluating a patient for SAVR or TAVR. Other features such as mobility, frailty score, and comorbid liver or renal disease should also be considered when discussing the three options with patients. As a result, the algorithm emphasizes a detailed evaluation of patient characteristics in selecting one procedure over another.
“The treatment should be really tailored on the individual patient basis,” said Dr. Spadaccio.
Dr. Spadaccio acknowledged that there is a need for more comparative trials, particularly in regard to sutureless aortic valve replacement as an alternative to TAVR. “I really think that a 1:1 RCT on sutureless aortic valve replacement vs TAVR could give better answers to all of these interrogatives.”
But despite the limitations outlined in this review, Dr. Spadaccio and colleagues challenged the perception that current data are not sufficient to allow clinicians to consider sutureless aortic valve replacement in the mix of options.
A Viable Option
This comprehensive summary of what is known about sutureless aortic valve replacement compared with the other options addresses an important knowledge gap, said S. Chris Malaisrie, MD, a cardiac surgeon at Northwestern University Feinberg School of Medicine, Chicago, Illinois.
He said he agrees this option has unique qualities. “Minimally invasive surgery has been largely ignored by guideline writers, but patients certainly demand options that are less invasive than standard open heart surgery. Sutureless and rapid deployment valves facilitate minimally invasive surgery and offer an advantageous option for younger patients.”
Dr. Malaisrie said the review is generating discussion about a potentially valuable option within the cardiology community. And that is exactly what Dr. Spadaccio was hoping for. “This paper was meant to educate as much as possible on these details to assist and inform decision-making,” he said.
A version of this article first appeared on Medscape.com.
Compared with traditional replacement valves, sutureless valves placed through minimally invasive cardiac surgery have less data supporting their use but offer unique features that might make them the preferred option for certain patients, reported specialists.
The sutureless device known as Perceval (Corcym) and a rapidly deployed device called Intuity (Edwards Lifesciences) are used as an alternative to surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR). But despite being commercially available since 2016, the devices are still not being used much.
The devices are not discussed in substantial detail in either the joint guidelines from the American College of Cardiology and American Heart Association issued in 2020 or guidelines from the European Society of Cardiology issued in 2022.
Cristiano Spadaccio, MD, PhD, a cardiothoracic surgeon associated with Lancashire Cardiac Centre in Blackpool, England, and his colleagues reviewed the small number of studies evaluating the alternate approach to “make the cardiology world aware” of alternatives “that can relieve the surgical burden by minimizing the implantation time and length of the operation,” he said.
The comprehensive review is published in the Journal of the American College of Cardiology.
A Neglected Alternative
The sutureless Perceval device is held in place by a stent frame that self-expands. The Intuity device also relies primarily on its framework to anchor the valve in place but does involve three sutures. Both devices are still referred to as sutureless in the new review of them.
Only a small number of centers perform minimally invasive cardiac surgeries, and the main advantage of the devices — rapid deployment — has been eroded with the advent of automated knotting which has significantly reduced the time to implant and sutured valve.
The underuse of these devices is largely caused by the limited amount of comparative and prospective data, said Dr. Spadaccio. “The entire literature on sutureless aortic valve replacement with the exception of one randomized controlled trial is observational.”
That trial, PERSIST-AVR, found that the sutureless valves were just as good as conventional ones when it comes to major adverse cardiovascular events including all-cause death, myocardial infarction, stroke, or valve reintervention at 1 year.
In a subanalysis limited to patients who had isolated aortic valve replacement, the sutureless procedure was associated with lower adverse events (5.2% vs 10.8%) at the cost of a higher rate of pacemaker implantation (11% vs 1.6%).
There are also multiple retrospective studies and registries that have generated observational data comparing sutureless aortic valve replacement with SAVR and TAVR in various patient populations, said Dr. Spadaccio, and the review was based on more than a dozen studies published since 2015. Long-term follow-up data for sutureless aortic valve replacements, which now exceeds 10 years, suggest rates of structural valve deterioration and reintervention have been acceptably low.
The minimally invasive procedures have other advantages too. For example, relative to the greater trauma associated with open heart surgery, minimally invasive surgeries typically involve faster recovery, an advantage likely to appeal to many patients who are candidates for either.
Quicker Recovery
Collectively, these data suggest that sutureless aortic valve replacement might be a reasonable or even a more appropriate alternative to either SAVR or TAVR when considering specific patient characteristics and goals, according to the review, which included an algorithm identifying specifically where sutureless aortic valve replacement fits with SAVR and TAVR.
“The algorithm is based on different clinical scenarios and reflects current guidelines for SAVR,” said Dr. Spadaccio. For example, current guidelines identify SAVR as preferred in patients younger than 65 years and in older patients with a low Society of Thoracic Surgeons (STS) score, but there are many instances in which sutureless aortic valve replacement might be more attractive, such as in those also undergoing mitral valve repair, coronary artery bypass grafting, or another surgical procedure.
Dr. Spadaccio said that the STS score should not be considered in isolation when evaluating a patient for SAVR or TAVR. Other features such as mobility, frailty score, and comorbid liver or renal disease should also be considered when discussing the three options with patients. As a result, the algorithm emphasizes a detailed evaluation of patient characteristics in selecting one procedure over another.
“The treatment should be really tailored on the individual patient basis,” said Dr. Spadaccio.
Dr. Spadaccio acknowledged that there is a need for more comparative trials, particularly in regard to sutureless aortic valve replacement as an alternative to TAVR. “I really think that a 1:1 RCT on sutureless aortic valve replacement vs TAVR could give better answers to all of these interrogatives.”
But despite the limitations outlined in this review, Dr. Spadaccio and colleagues challenged the perception that current data are not sufficient to allow clinicians to consider sutureless aortic valve replacement in the mix of options.
A Viable Option
This comprehensive summary of what is known about sutureless aortic valve replacement compared with the other options addresses an important knowledge gap, said S. Chris Malaisrie, MD, a cardiac surgeon at Northwestern University Feinberg School of Medicine, Chicago, Illinois.
He said he agrees this option has unique qualities. “Minimally invasive surgery has been largely ignored by guideline writers, but patients certainly demand options that are less invasive than standard open heart surgery. Sutureless and rapid deployment valves facilitate minimally invasive surgery and offer an advantageous option for younger patients.”
Dr. Malaisrie said the review is generating discussion about a potentially valuable option within the cardiology community. And that is exactly what Dr. Spadaccio was hoping for. “This paper was meant to educate as much as possible on these details to assist and inform decision-making,” he said.
A version of this article first appeared on Medscape.com.
Compared with traditional replacement valves, sutureless valves placed through minimally invasive cardiac surgery have less data supporting their use but offer unique features that might make them the preferred option for certain patients, reported specialists.
The sutureless device known as Perceval (Corcym) and a rapidly deployed device called Intuity (Edwards Lifesciences) are used as an alternative to surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR). But despite being commercially available since 2016, the devices are still not being used much.
The devices are not discussed in substantial detail in either the joint guidelines from the American College of Cardiology and American Heart Association issued in 2020 or guidelines from the European Society of Cardiology issued in 2022.
Cristiano Spadaccio, MD, PhD, a cardiothoracic surgeon associated with Lancashire Cardiac Centre in Blackpool, England, and his colleagues reviewed the small number of studies evaluating the alternate approach to “make the cardiology world aware” of alternatives “that can relieve the surgical burden by minimizing the implantation time and length of the operation,” he said.
The comprehensive review is published in the Journal of the American College of Cardiology.
A Neglected Alternative
The sutureless Perceval device is held in place by a stent frame that self-expands. The Intuity device also relies primarily on its framework to anchor the valve in place but does involve three sutures. Both devices are still referred to as sutureless in the new review of them.
Only a small number of centers perform minimally invasive cardiac surgeries, and the main advantage of the devices — rapid deployment — has been eroded with the advent of automated knotting which has significantly reduced the time to implant and sutured valve.
The underuse of these devices is largely caused by the limited amount of comparative and prospective data, said Dr. Spadaccio. “The entire literature on sutureless aortic valve replacement with the exception of one randomized controlled trial is observational.”
That trial, PERSIST-AVR, found that the sutureless valves were just as good as conventional ones when it comes to major adverse cardiovascular events including all-cause death, myocardial infarction, stroke, or valve reintervention at 1 year.
In a subanalysis limited to patients who had isolated aortic valve replacement, the sutureless procedure was associated with lower adverse events (5.2% vs 10.8%) at the cost of a higher rate of pacemaker implantation (11% vs 1.6%).
There are also multiple retrospective studies and registries that have generated observational data comparing sutureless aortic valve replacement with SAVR and TAVR in various patient populations, said Dr. Spadaccio, and the review was based on more than a dozen studies published since 2015. Long-term follow-up data for sutureless aortic valve replacements, which now exceeds 10 years, suggest rates of structural valve deterioration and reintervention have been acceptably low.
The minimally invasive procedures have other advantages too. For example, relative to the greater trauma associated with open heart surgery, minimally invasive surgeries typically involve faster recovery, an advantage likely to appeal to many patients who are candidates for either.
Quicker Recovery
Collectively, these data suggest that sutureless aortic valve replacement might be a reasonable or even a more appropriate alternative to either SAVR or TAVR when considering specific patient characteristics and goals, according to the review, which included an algorithm identifying specifically where sutureless aortic valve replacement fits with SAVR and TAVR.
“The algorithm is based on different clinical scenarios and reflects current guidelines for SAVR,” said Dr. Spadaccio. For example, current guidelines identify SAVR as preferred in patients younger than 65 years and in older patients with a low Society of Thoracic Surgeons (STS) score, but there are many instances in which sutureless aortic valve replacement might be more attractive, such as in those also undergoing mitral valve repair, coronary artery bypass grafting, or another surgical procedure.
Dr. Spadaccio said that the STS score should not be considered in isolation when evaluating a patient for SAVR or TAVR. Other features such as mobility, frailty score, and comorbid liver or renal disease should also be considered when discussing the three options with patients. As a result, the algorithm emphasizes a detailed evaluation of patient characteristics in selecting one procedure over another.
“The treatment should be really tailored on the individual patient basis,” said Dr. Spadaccio.
Dr. Spadaccio acknowledged that there is a need for more comparative trials, particularly in regard to sutureless aortic valve replacement as an alternative to TAVR. “I really think that a 1:1 RCT on sutureless aortic valve replacement vs TAVR could give better answers to all of these interrogatives.”
But despite the limitations outlined in this review, Dr. Spadaccio and colleagues challenged the perception that current data are not sufficient to allow clinicians to consider sutureless aortic valve replacement in the mix of options.
A Viable Option
This comprehensive summary of what is known about sutureless aortic valve replacement compared with the other options addresses an important knowledge gap, said S. Chris Malaisrie, MD, a cardiac surgeon at Northwestern University Feinberg School of Medicine, Chicago, Illinois.
He said he agrees this option has unique qualities. “Minimally invasive surgery has been largely ignored by guideline writers, but patients certainly demand options that are less invasive than standard open heart surgery. Sutureless and rapid deployment valves facilitate minimally invasive surgery and offer an advantageous option for younger patients.”
Dr. Malaisrie said the review is generating discussion about a potentially valuable option within the cardiology community. And that is exactly what Dr. Spadaccio was hoping for. “This paper was meant to educate as much as possible on these details to assist and inform decision-making,” he said.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
A young adult with a 1-year history of erythema, papules, and pustules on her cheeks and skin
. It typically presents with a sudden onset of papules, pustules, cysts, painful inflammatory nodules, and erythema on the centrofacial areas. The etiology is unknown but has been speculated to be hormone-related as it is more common in women and can be triggered by acute changes such as stress or medications.
Because of overlapping symptoms with other conditions, an accurate clinical assessment is crucial. Typically, there are no comedones and about half of the patients have a history of acne. Some cases have shown a possible link between pyoderma faciale with inflammatory bowel disease, thyroid disease and liver disease, highlighting the importance of considering these associations in treatment decisions.
Treatment options for pyoderma faciale include isotretinoin, corticosteroids, dapsone, and antibiotics such as doxycycline. Isotretinoin is usually the first-line treatment, with dapsone reserved for cases where other methods have failed. Despite concerns about isotretinoin exacerbating inflammatory bowel disease (IBD), there has been at least one reported case where a patient with ulcerative colitis who had pyoderma faciale that was successfully treated with isotretinoin with no adverse effects.
Isotretinoin has been shown to be effective in treating pyoderma faciale by significantly reducing inflammation and scarring. This is imperative because the scarring from pyoderma faciale can be disfiguring and psychologically harmful for patients. Therefore, an early diagnosis and effective treatment method are essential in preventing these scars and improving patients’ confidence and overall dermatological care.
This patient’s initial bacterial culture was negative. She was treated with a course of low dose isotretinoin. Prednisone was initiated two weeks before starting isotretinoin and then was tapered off during the first month of isotretinoin treatment. The patient was also started on spironolactone. The course of isotretinoin was 9 months. She has remained clear and still takes oral contraceptive pills and low dose spironolactone.
This case and the photos were submitted by Ms. Towe, Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Florida, and Donna Bilu Martin, MD, of Premier Dermatology, MD, Aventura, Florida. The column was edited by Dr. Bilu Martin.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].
References
Angileri L et al. J Dermatolog Treat. 2021 Feb;32(1):110-3. doi: 10.1080/09546634.2019.1628175.
Coutinho JC et al. An Bras Dermatol. 2016 Sep-Oct;91(5 suppl 1):151-3. doi: 10.1590/abd1806-4841.20164943.
Rosen T and Unkefer RP. Cutis. 1999 Aug;64(2):107-9.
. It typically presents with a sudden onset of papules, pustules, cysts, painful inflammatory nodules, and erythema on the centrofacial areas. The etiology is unknown but has been speculated to be hormone-related as it is more common in women and can be triggered by acute changes such as stress or medications.
Because of overlapping symptoms with other conditions, an accurate clinical assessment is crucial. Typically, there are no comedones and about half of the patients have a history of acne. Some cases have shown a possible link between pyoderma faciale with inflammatory bowel disease, thyroid disease and liver disease, highlighting the importance of considering these associations in treatment decisions.
Treatment options for pyoderma faciale include isotretinoin, corticosteroids, dapsone, and antibiotics such as doxycycline. Isotretinoin is usually the first-line treatment, with dapsone reserved for cases where other methods have failed. Despite concerns about isotretinoin exacerbating inflammatory bowel disease (IBD), there has been at least one reported case where a patient with ulcerative colitis who had pyoderma faciale that was successfully treated with isotretinoin with no adverse effects.
Isotretinoin has been shown to be effective in treating pyoderma faciale by significantly reducing inflammation and scarring. This is imperative because the scarring from pyoderma faciale can be disfiguring and psychologically harmful for patients. Therefore, an early diagnosis and effective treatment method are essential in preventing these scars and improving patients’ confidence and overall dermatological care.
This patient’s initial bacterial culture was negative. She was treated with a course of low dose isotretinoin. Prednisone was initiated two weeks before starting isotretinoin and then was tapered off during the first month of isotretinoin treatment. The patient was also started on spironolactone. The course of isotretinoin was 9 months. She has remained clear and still takes oral contraceptive pills and low dose spironolactone.
This case and the photos were submitted by Ms. Towe, Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Florida, and Donna Bilu Martin, MD, of Premier Dermatology, MD, Aventura, Florida. The column was edited by Dr. Bilu Martin.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].
References
Angileri L et al. J Dermatolog Treat. 2021 Feb;32(1):110-3. doi: 10.1080/09546634.2019.1628175.
Coutinho JC et al. An Bras Dermatol. 2016 Sep-Oct;91(5 suppl 1):151-3. doi: 10.1590/abd1806-4841.20164943.
Rosen T and Unkefer RP. Cutis. 1999 Aug;64(2):107-9.
. It typically presents with a sudden onset of papules, pustules, cysts, painful inflammatory nodules, and erythema on the centrofacial areas. The etiology is unknown but has been speculated to be hormone-related as it is more common in women and can be triggered by acute changes such as stress or medications.
Because of overlapping symptoms with other conditions, an accurate clinical assessment is crucial. Typically, there are no comedones and about half of the patients have a history of acne. Some cases have shown a possible link between pyoderma faciale with inflammatory bowel disease, thyroid disease and liver disease, highlighting the importance of considering these associations in treatment decisions.
Treatment options for pyoderma faciale include isotretinoin, corticosteroids, dapsone, and antibiotics such as doxycycline. Isotretinoin is usually the first-line treatment, with dapsone reserved for cases where other methods have failed. Despite concerns about isotretinoin exacerbating inflammatory bowel disease (IBD), there has been at least one reported case where a patient with ulcerative colitis who had pyoderma faciale that was successfully treated with isotretinoin with no adverse effects.
Isotretinoin has been shown to be effective in treating pyoderma faciale by significantly reducing inflammation and scarring. This is imperative because the scarring from pyoderma faciale can be disfiguring and psychologically harmful for patients. Therefore, an early diagnosis and effective treatment method are essential in preventing these scars and improving patients’ confidence and overall dermatological care.
This patient’s initial bacterial culture was negative. She was treated with a course of low dose isotretinoin. Prednisone was initiated two weeks before starting isotretinoin and then was tapered off during the first month of isotretinoin treatment. The patient was also started on spironolactone. The course of isotretinoin was 9 months. She has remained clear and still takes oral contraceptive pills and low dose spironolactone.
This case and the photos were submitted by Ms. Towe, Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Florida, and Donna Bilu Martin, MD, of Premier Dermatology, MD, Aventura, Florida. The column was edited by Dr. Bilu Martin.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].
References
Angileri L et al. J Dermatolog Treat. 2021 Feb;32(1):110-3. doi: 10.1080/09546634.2019.1628175.
Coutinho JC et al. An Bras Dermatol. 2016 Sep-Oct;91(5 suppl 1):151-3. doi: 10.1590/abd1806-4841.20164943.
Rosen T and Unkefer RP. Cutis. 1999 Aug;64(2):107-9.
