AUSTIN, TEX – Treatment with ubrogepant (Ubrelvy, Abbvie) during the prodromal phase of a migraine led to a reduction in both prodromal symptoms and ensuing migraine frequency, according to results from a new randomized, crossover study. Researchers took pains to identify migraineurs who could predict an ensuing headache 75% of the time based on prodromal symptoms. Those who could make such predictions were allowed into the randomized study.

Patients are quite good at predicting ensuing headaches when encouraged to do so, according to Peter J. Goadsby, MBBS, MD, PhD, who presented the study findings at the annual meeting of the American Headache Society.

“I find it quite useful to ask patients about these [symptoms]: Have you got cognitive clouding? Do you pass more urine? Have you got mood change? Do you feel fatigue? Associated with the attack, is how I phrase it. Get them first into the idea of thinking about the symptoms, and then get them to think about when they’re occurring. Certainly with things like brain fog, many patients will tell you that it happens. If you ask them whether they’re 100% [certain] when that’s happening, they will tell you [they’re] not. This is part of taking a history and building a relationship with the patient,” Dr. Goadsby, professor of neurology at the University of California, Los Angeles, said during the Q&A after his presentation.
 

‘Significant’ finding

“This is a significant finding because what patients really want is not to develop their headache and no medication has been shown to prevent a headache during the prodrome,” said Alan M. Rapoport, MD, a board certified neurologist and headache expert, as well as clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews. Successful treatment during the prodrome treatment could eliminate the need for use of preventive medication, which might decrease the patient’s adverse effects, he said.

Session comoderator Jason J. Sico, MD, took note of the patient experience during the prodrome period. “One of many noteworthy things is the large percentage of people that reported disability during prodrome before the headache. I just find that staggering, though not surprising to many of us,” he said during the session. Dr. Sico is associate professor of neurology and internal medicine at Yale University, New Haven, Conn.

Dr. Rapoport and Dr. Sico were not involved in the study.
 

Probing the prodrome

The study included a 60-day screening period, which had to include between 3 and 16 recorded prodrome events. Headaches had to occur within 1-6 hours in at least 75% of prodrome events. Study subjects were then randomized to 100 mg ubrogepant or placebo for up to 60 days. After their first prodrome event, they entered a 7-day washout period, and then crossed over to the other group until they experienced a second prodrome event.

During the screening period, 81.5% of prodromal events identified by patients were followed by a headache within 1-6 hours of onset. Nearly 10% of the time headache occurred in 1 hour or less, 81.5% between 1 and 6 hours, and 4.5% between 6 and 24 hours after prodrome. Commonly reported prodromal symptoms included sensitivity to light (57.2%), fatigue (50.1%), neck pain (41.9%), sensitivity to sound (33.9%), and dizziness (27.8%).

The study included 247 patients in the first sequence, and 233 in the second sequence. Patient characteristics were similar in both. Ubrogepant treatment led to a greater absence of moderate- or severe-intensity headache within 24 hours of the dose (45.5% vs. 28.6% headache-free; odds ratio [OR], 2.09; P < .0001). They were also more likely to report normal functioning over 24 hours (OR, 1.66; P < .0001) and to have absence of headache within 24 hours (23.7% vs. 13.9%; OR, 1.93; P < .0001).

Between 73% and 75% of participants reported at least mild functional disability before taking medication. Two hours after a dose, ubrogepant led to a higher rate of normal functioning (37.0% vs. 26.1%; P < .001). Ubrogepant had a similar positive effect on sensitivity to light, fatigue, neck pain, sensitivity to sound, and dizziness. Adverse events were higher during ubrogepant treatment (13.2% vs. 9.1%), and included nausea, dizziness, fatigue, and somnolence, all of which were mild. “One is really scraping the barrel [to identify adverse events]. There were no serious adverse events,” said Dr. Goadsby.
 

A unique result?

One questioner asked if other medications used during the prodrome might yield similar results. Dr. Goadsby expressed doubt. “I think the evidence for other treatments is not terribly good. The triptan evidence is really poor. There is no randomized, placebo-controlled trial of a triptan explicitly in promontory symptomatology. There are randomized placebo controlled trials of triptans during the aura phase. The best one was the injected sumatriptan study, and it failed. So, as far as I can see from the randomized-controlled data, triptans don’t do this, and we don’t have good data for nonsteroidals and other therapies,” said Dr. Goadsby.

The researchers showed that you could treat a patient in advance of the headache to actually prevent the headache a significant number of times; it also reduced the prodromal events and it got patients back to normal functioning to a greater extent.

Dr. Goadsby was asked how many patients are typically able to identify prodrome periods on their own. He estimated that about one in three can do it initially. “I think if you teach people how to do this, it becomes very common. I would say four out of five people in my practice are able to talk about this, but you have to introduce the topic. They’ve had [prodrome symptoms], but they haven’t thought about it for a while. This is one of the things where headache doctors can offer real benefit in helping educate patients,” said Dr. Goadsby.

Dr. Sico did not disclose any conflicts of interest. Dr. Rapoport advises AbbVie, Biohaven, Cala Health, Dr. Reddy’s, Pfizer, Satsuma, Teva Pharmaceutical Industries, and Theranica. He is on the speakers bureau of AbbVie, Dr. Reddy’s, Impel, Pfizer and Teva Pharmaceutical Industries. He is editor-in-chief of Neurology Reviews and on the Editorial Board of CNS Drugs. Dr. Goadsby has financial ties to Amgen, Eli Lilly, Alder Biopharmaceuticals, Allergan, Autonomic Technologies Inc., Biohaven Pharmaceuticals Inc., Dr. Reddy’s Laboratories, Electrocore, eNeura, Massachusetts Medical Society, MedicoLegal work, Novartis, Oxford University Press, Teva Pharmaceuticals, Trigemina, Up-to-Date, and Wolters Kluwer. He has a patent for headache assigned to eNeura without fee.

AUSTIN, TEX – Treatment with ubrogepant (Ubrelvy, Abbvie) during the prodromal phase of a migraine led to a reduction in both prodromal symptoms and ensuing migraine frequency, according to results from a new randomized, crossover study. Researchers took pains to identify migraineurs who could predict an ensuing headache 75% of the time based on prodromal symptoms. Those who could make such predictions were allowed into the randomized study.

Patients are quite good at predicting ensuing headaches when encouraged to do so, according to Peter J. Goadsby, MBBS, MD, PhD, who presented the study findings at the annual meeting of the American Headache Society.

“I find it quite useful to ask patients about these [symptoms]: Have you got cognitive clouding? Do you pass more urine? Have you got mood change? Do you feel fatigue? Associated with the attack, is how I phrase it. Get them first into the idea of thinking about the symptoms, and then get them to think about when they’re occurring. Certainly with things like brain fog, many patients will tell you that it happens. If you ask them whether they’re 100% [certain] when that’s happening, they will tell you [they’re] not. This is part of taking a history and building a relationship with the patient,” Dr. Goadsby, professor of neurology at the University of California, Los Angeles, said during the Q&A after his presentation.
 

‘Significant’ finding

“This is a significant finding because what patients really want is not to develop their headache and no medication has been shown to prevent a headache during the prodrome,” said Alan M. Rapoport, MD, a board certified neurologist and headache expert, as well as clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews. Successful treatment during the prodrome treatment could eliminate the need for use of preventive medication, which might decrease the patient’s adverse effects, he said.

Session comoderator Jason J. Sico, MD, took note of the patient experience during the prodrome period. “One of many noteworthy things is the large percentage of people that reported disability during prodrome before the headache. I just find that staggering, though not surprising to many of us,” he said during the session. Dr. Sico is associate professor of neurology and internal medicine at Yale University, New Haven, Conn.

Dr. Rapoport and Dr. Sico were not involved in the study.
 

Probing the prodrome

The study included a 60-day screening period, which had to include between 3 and 16 recorded prodrome events. Headaches had to occur within 1-6 hours in at least 75% of prodrome events. Study subjects were then randomized to 100 mg ubrogepant or placebo for up to 60 days. After their first prodrome event, they entered a 7-day washout period, and then crossed over to the other group until they experienced a second prodrome event.

During the screening period, 81.5% of prodromal events identified by patients were followed by a headache within 1-6 hours of onset. Nearly 10% of the time headache occurred in 1 hour or less, 81.5% between 1 and 6 hours, and 4.5% between 6 and 24 hours after prodrome. Commonly reported prodromal symptoms included sensitivity to light (57.2%), fatigue (50.1%), neck pain (41.9%), sensitivity to sound (33.9%), and dizziness (27.8%).

The study included 247 patients in the first sequence, and 233 in the second sequence. Patient characteristics were similar in both. Ubrogepant treatment led to a greater absence of moderate- or severe-intensity headache within 24 hours of the dose (45.5% vs. 28.6% headache-free; odds ratio [OR], 2.09; P < .0001). They were also more likely to report normal functioning over 24 hours (OR, 1.66; P < .0001) and to have absence of headache within 24 hours (23.7% vs. 13.9%; OR, 1.93; P < .0001).

Between 73% and 75% of participants reported at least mild functional disability before taking medication. Two hours after a dose, ubrogepant led to a higher rate of normal functioning (37.0% vs. 26.1%; P < .001). Ubrogepant had a similar positive effect on sensitivity to light, fatigue, neck pain, sensitivity to sound, and dizziness. Adverse events were higher during ubrogepant treatment (13.2% vs. 9.1%), and included nausea, dizziness, fatigue, and somnolence, all of which were mild. “One is really scraping the barrel [to identify adverse events]. There were no serious adverse events,” said Dr. Goadsby.
 

A unique result?

One questioner asked if other medications used during the prodrome might yield similar results. Dr. Goadsby expressed doubt. “I think the evidence for other treatments is not terribly good. The triptan evidence is really poor. There is no randomized, placebo-controlled trial of a triptan explicitly in promontory symptomatology. There are randomized placebo controlled trials of triptans during the aura phase. The best one was the injected sumatriptan study, and it failed. So, as far as I can see from the randomized-controlled data, triptans don’t do this, and we don’t have good data for nonsteroidals and other therapies,” said Dr. Goadsby.

The researchers showed that you could treat a patient in advance of the headache to actually prevent the headache a significant number of times; it also reduced the prodromal events and it got patients back to normal functioning to a greater extent.

Dr. Goadsby was asked how many patients are typically able to identify prodrome periods on their own. He estimated that about one in three can do it initially. “I think if you teach people how to do this, it becomes very common. I would say four out of five people in my practice are able to talk about this, but you have to introduce the topic. They’ve had [prodrome symptoms], but they haven’t thought about it for a while. This is one of the things where headache doctors can offer real benefit in helping educate patients,” said Dr. Goadsby.

Dr. Sico did not disclose any conflicts of interest. Dr. Rapoport advises AbbVie, Biohaven, Cala Health, Dr. Reddy’s, Pfizer, Satsuma, Teva Pharmaceutical Industries, and Theranica. He is on the speakers bureau of AbbVie, Dr. Reddy’s, Impel, Pfizer and Teva Pharmaceutical Industries. He is editor-in-chief of Neurology Reviews and on the Editorial Board of CNS Drugs. Dr. Goadsby has financial ties to Amgen, Eli Lilly, Alder Biopharmaceuticals, Allergan, Autonomic Technologies Inc., Biohaven Pharmaceuticals Inc., Dr. Reddy’s Laboratories, Electrocore, eNeura, Massachusetts Medical Society, MedicoLegal work, Novartis, Oxford University Press, Teva Pharmaceuticals, Trigemina, Up-to-Date, and Wolters Kluwer. He has a patent for headache assigned to eNeura without fee.

AUSTIN, TEX – Treatment with ubrogepant (Ubrelvy, Abbvie) during the prodromal phase of a migraine led to a reduction in both prodromal symptoms and ensuing migraine frequency, according to results from a new randomized, crossover study. Researchers took pains to identify migraineurs who could predict an ensuing headache 75% of the time based on prodromal symptoms. Those who could make such predictions were allowed into the randomized study.

Patients are quite good at predicting ensuing headaches when encouraged to do so, according to Peter J. Goadsby, MBBS, MD, PhD, who presented the study findings at the annual meeting of the American Headache Society.

“I find it quite useful to ask patients about these [symptoms]: Have you got cognitive clouding? Do you pass more urine? Have you got mood change? Do you feel fatigue? Associated with the attack, is how I phrase it. Get them first into the idea of thinking about the symptoms, and then get them to think about when they’re occurring. Certainly with things like brain fog, many patients will tell you that it happens. If you ask them whether they’re 100% [certain] when that’s happening, they will tell you [they’re] not. This is part of taking a history and building a relationship with the patient,” Dr. Goadsby, professor of neurology at the University of California, Los Angeles, said during the Q&A after his presentation.
 

‘Significant’ finding

“This is a significant finding because what patients really want is not to develop their headache and no medication has been shown to prevent a headache during the prodrome,” said Alan M. Rapoport, MD, a board certified neurologist and headache expert, as well as clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews. Successful treatment during the prodrome treatment could eliminate the need for use of preventive medication, which might decrease the patient’s adverse effects, he said.

Session comoderator Jason J. Sico, MD, took note of the patient experience during the prodrome period. “One of many noteworthy things is the large percentage of people that reported disability during prodrome before the headache. I just find that staggering, though not surprising to many of us,” he said during the session. Dr. Sico is associate professor of neurology and internal medicine at Yale University, New Haven, Conn.

Dr. Rapoport and Dr. Sico were not involved in the study.
 

Probing the prodrome

The study included a 60-day screening period, which had to include between 3 and 16 recorded prodrome events. Headaches had to occur within 1-6 hours in at least 75% of prodrome events. Study subjects were then randomized to 100 mg ubrogepant or placebo for up to 60 days. After their first prodrome event, they entered a 7-day washout period, and then crossed over to the other group until they experienced a second prodrome event.

During the screening period, 81.5% of prodromal events identified by patients were followed by a headache within 1-6 hours of onset. Nearly 10% of the time headache occurred in 1 hour or less, 81.5% between 1 and 6 hours, and 4.5% between 6 and 24 hours after prodrome. Commonly reported prodromal symptoms included sensitivity to light (57.2%), fatigue (50.1%), neck pain (41.9%), sensitivity to sound (33.9%), and dizziness (27.8%).

The study included 247 patients in the first sequence, and 233 in the second sequence. Patient characteristics were similar in both. Ubrogepant treatment led to a greater absence of moderate- or severe-intensity headache within 24 hours of the dose (45.5% vs. 28.6% headache-free; odds ratio [OR], 2.09; P < .0001). They were also more likely to report normal functioning over 24 hours (OR, 1.66; P < .0001) and to have absence of headache within 24 hours (23.7% vs. 13.9%; OR, 1.93; P < .0001).

Between 73% and 75% of participants reported at least mild functional disability before taking medication. Two hours after a dose, ubrogepant led to a higher rate of normal functioning (37.0% vs. 26.1%; P < .001). Ubrogepant had a similar positive effect on sensitivity to light, fatigue, neck pain, sensitivity to sound, and dizziness. Adverse events were higher during ubrogepant treatment (13.2% vs. 9.1%), and included nausea, dizziness, fatigue, and somnolence, all of which were mild. “One is really scraping the barrel [to identify adverse events]. There were no serious adverse events,” said Dr. Goadsby.
 

A unique result?

One questioner asked if other medications used during the prodrome might yield similar results. Dr. Goadsby expressed doubt. “I think the evidence for other treatments is not terribly good. The triptan evidence is really poor. There is no randomized, placebo-controlled trial of a triptan explicitly in promontory symptomatology. There are randomized placebo controlled trials of triptans during the aura phase. The best one was the injected sumatriptan study, and it failed. So, as far as I can see from the randomized-controlled data, triptans don’t do this, and we don’t have good data for nonsteroidals and other therapies,” said Dr. Goadsby.

The researchers showed that you could treat a patient in advance of the headache to actually prevent the headache a significant number of times; it also reduced the prodromal events and it got patients back to normal functioning to a greater extent.

Dr. Goadsby was asked how many patients are typically able to identify prodrome periods on their own. He estimated that about one in three can do it initially. “I think if you teach people how to do this, it becomes very common. I would say four out of five people in my practice are able to talk about this, but you have to introduce the topic. They’ve had [prodrome symptoms], but they haven’t thought about it for a while. This is one of the things where headache doctors can offer real benefit in helping educate patients,” said Dr. Goadsby.

Dr. Sico did not disclose any conflicts of interest. Dr. Rapoport advises AbbVie, Biohaven, Cala Health, Dr. Reddy’s, Pfizer, Satsuma, Teva Pharmaceutical Industries, and Theranica. He is on the speakers bureau of AbbVie, Dr. Reddy’s, Impel, Pfizer and Teva Pharmaceutical Industries. He is editor-in-chief of Neurology Reviews and on the Editorial Board of CNS Drugs. Dr. Goadsby has financial ties to Amgen, Eli Lilly, Alder Biopharmaceuticals, Allergan, Autonomic Technologies Inc., Biohaven Pharmaceuticals Inc., Dr. Reddy’s Laboratories, Electrocore, eNeura, Massachusetts Medical Society, MedicoLegal work, Novartis, Oxford University Press, Teva Pharmaceuticals, Trigemina, Up-to-Date, and Wolters Kluwer. He has a patent for headache assigned to eNeura without fee.

Family physicians are the only providers of care for most patients with several chronic diseases, according to new research.

A population-based retrospective cohort study examined data from nearly 1 million patients with common chronic conditions in Alberta, Canada. Family doctors were the sole providers of care for 85.7% of patients with hypertension and 70.9% of those with diabetes.

The study is part of efforts to encourage more research “by primary care, for primary care,” study author Jessica Kirkwood, MD, family physician and assistant professor of family medicine at the University of Alberta, Edmonton, said in an interview. The prevalence of primary care involvement demonstrates the importance of involving family physicians in creating guidelines for management and developing clinical trials, Dr. Kirkwood said.

The study was published in Canadian Family Physician.
 

Who provides care?

The study focused on care provided from 2013 to 2017 for seven chronic conditions. The information collected consisted of data from administrative health databases, which track medical services provided by Alberta’s government-funded universal health care system.

Most patients’ care was managed by family physicians alone in four of the conditions studied: hypertension (85.7%), diabetes (70.9%), chronic obstructive pulmonary disease (59.8%), and asthma (65.5%).

Specialists were more involved in the remaining three diseases. They provided the sole management in 49.1% of patients with ischemic heart disease, 42.2% of those with chronic kidney disease, and 35.6% of those with heart failure. For these conditions, family physicians remained involved in the care for a large proportion of patients. Specialist involvement may be more common with these diseases because they sometimes involve interventions that only specialists offer, like angiography and dialysis, said Dr. Kirkwood.

The study also found that nurse practitioners were involved in care for very few patients (less than 1%), in accordance with the small number of nurse practitioners working in primary care settings.

Dr. Kirkwood acknowledged that the data come with certain limitations because they were not intended for research purposes. One limitation is that some conditions may not have been recorded because of “shadow billing.” Salaried physicians and practitioners do not have an incentive to include all diagnostic codes in their records. By comparison, clinicians operating under a fee-for-service model would be likely to indicate all diagnoses.
 

Developing guidelines

Despite the widespread management of chronic conditions by family physicians, these doctors represented about 17% of the experts who contribute to guidelines and recommendations, according to a 2015 study that the investigators cited.

“Frankly, that’s concerning,” said Dr. Kirkwood, regarding the disconnect between the people creating the recommendations and the people using them. The guidelines should include the perspective of clinicians who regularly work with patients, she said. Providing that perspective would also make the design of clinical trials on interventions more informative, the researchers concluded.

“I know as a family doctor myself that some recommendations are completely overwhelming,” especially given the range of issues that primary care clinicians see, said Dr. Kirkwood. Including primary care representatives who are familiar with the demands of the position “hopefully will make the recommendations much more applicable to the people that they will affect,” she said.

Dr. Kirkwood also noted the need for sufficient support for family doctors to contribute to guideline creation and research, especially for doctors in rural communities who are not already affiliated with a university.

The involvement of primary care providers in research settings is a primary goal of Patients, Experience, Evidence and Research (PEER), a primary care-led group that collaborates with the College of Family Physicians of Canada. The current investigators are members of PEER.
 

Additional conditions

Commenting on the study, Martin Fortin, MD, clinical teaching professor at the University of Sherbrooke, Quebec, said, “This is a good opportunity to advocate for more studies to be done in the primary care context, where the majority of chronic disease management is done.”

However, Dr. Fortin wishes that more diagnoses had been included in the study, such as mental health and musculoskeletal conditions like back pain and osteoarthritis. These conditions are also commonly seen by primary care clinicians, according to Dr. Fortin.

Because the number of conditions studied is limited, the data may not reflect the true prevalence of multimorbidity, Dr. Fortin added.

Primary care doctors provide a broad perspective on the overall health of patients, compared with specialists who focus on particular conditions. Similarly, during drug trials, pharmaceutical companies aim to reduce complicating factors, even though the medications are prescribed for conditions where multimorbidity is common. “Medication should be tested in the real environment,” said Dr. Fortin.

Ultimately, he added, the study cannot address the complexity of the patients, but it nevertheless sheds light on who is providing care and where the research on these conditions should be done.

The study was conducted without outside funding. Dr. Kirkwood and Dr. Fortin reported no relevant financial relationships.

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

Family physicians are the only providers of care for most patients with several chronic diseases, according to new research.

A population-based retrospective cohort study examined data from nearly 1 million patients with common chronic conditions in Alberta, Canada. Family doctors were the sole providers of care for 85.7% of patients with hypertension and 70.9% of those with diabetes.

The study is part of efforts to encourage more research “by primary care, for primary care,” study author Jessica Kirkwood, MD, family physician and assistant professor of family medicine at the University of Alberta, Edmonton, said in an interview. The prevalence of primary care involvement demonstrates the importance of involving family physicians in creating guidelines for management and developing clinical trials, Dr. Kirkwood said.

The study was published in Canadian Family Physician.
 

Who provides care?

The study focused on care provided from 2013 to 2017 for seven chronic conditions. The information collected consisted of data from administrative health databases, which track medical services provided by Alberta’s government-funded universal health care system.

Most patients’ care was managed by family physicians alone in four of the conditions studied: hypertension (85.7%), diabetes (70.9%), chronic obstructive pulmonary disease (59.8%), and asthma (65.5%).

Specialists were more involved in the remaining three diseases. They provided the sole management in 49.1% of patients with ischemic heart disease, 42.2% of those with chronic kidney disease, and 35.6% of those with heart failure. For these conditions, family physicians remained involved in the care for a large proportion of patients. Specialist involvement may be more common with these diseases because they sometimes involve interventions that only specialists offer, like angiography and dialysis, said Dr. Kirkwood.

The study also found that nurse practitioners were involved in care for very few patients (less than 1%), in accordance with the small number of nurse practitioners working in primary care settings.

Dr. Kirkwood acknowledged that the data come with certain limitations because they were not intended for research purposes. One limitation is that some conditions may not have been recorded because of “shadow billing.” Salaried physicians and practitioners do not have an incentive to include all diagnostic codes in their records. By comparison, clinicians operating under a fee-for-service model would be likely to indicate all diagnoses.
 

Developing guidelines

Despite the widespread management of chronic conditions by family physicians, these doctors represented about 17% of the experts who contribute to guidelines and recommendations, according to a 2015 study that the investigators cited.

“Frankly, that’s concerning,” said Dr. Kirkwood, regarding the disconnect between the people creating the recommendations and the people using them. The guidelines should include the perspective of clinicians who regularly work with patients, she said. Providing that perspective would also make the design of clinical trials on interventions more informative, the researchers concluded.

“I know as a family doctor myself that some recommendations are completely overwhelming,” especially given the range of issues that primary care clinicians see, said Dr. Kirkwood. Including primary care representatives who are familiar with the demands of the position “hopefully will make the recommendations much more applicable to the people that they will affect,” she said.

Dr. Kirkwood also noted the need for sufficient support for family doctors to contribute to guideline creation and research, especially for doctors in rural communities who are not already affiliated with a university.

The involvement of primary care providers in research settings is a primary goal of Patients, Experience, Evidence and Research (PEER), a primary care-led group that collaborates with the College of Family Physicians of Canada. The current investigators are members of PEER.
 

Additional conditions

Commenting on the study, Martin Fortin, MD, clinical teaching professor at the University of Sherbrooke, Quebec, said, “This is a good opportunity to advocate for more studies to be done in the primary care context, where the majority of chronic disease management is done.”

However, Dr. Fortin wishes that more diagnoses had been included in the study, such as mental health and musculoskeletal conditions like back pain and osteoarthritis. These conditions are also commonly seen by primary care clinicians, according to Dr. Fortin.

Because the number of conditions studied is limited, the data may not reflect the true prevalence of multimorbidity, Dr. Fortin added.

Primary care doctors provide a broad perspective on the overall health of patients, compared with specialists who focus on particular conditions. Similarly, during drug trials, pharmaceutical companies aim to reduce complicating factors, even though the medications are prescribed for conditions where multimorbidity is common. “Medication should be tested in the real environment,” said Dr. Fortin.

Ultimately, he added, the study cannot address the complexity of the patients, but it nevertheless sheds light on who is providing care and where the research on these conditions should be done.

The study was conducted without outside funding. Dr. Kirkwood and Dr. Fortin reported no relevant financial relationships.

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

Family physicians are the only providers of care for most patients with several chronic diseases, according to new research.

A population-based retrospective cohort study examined data from nearly 1 million patients with common chronic conditions in Alberta, Canada. Family doctors were the sole providers of care for 85.7% of patients with hypertension and 70.9% of those with diabetes.

The study is part of efforts to encourage more research “by primary care, for primary care,” study author Jessica Kirkwood, MD, family physician and assistant professor of family medicine at the University of Alberta, Edmonton, said in an interview. The prevalence of primary care involvement demonstrates the importance of involving family physicians in creating guidelines for management and developing clinical trials, Dr. Kirkwood said.

The study was published in Canadian Family Physician.
 

Who provides care?

The study focused on care provided from 2013 to 2017 for seven chronic conditions. The information collected consisted of data from administrative health databases, which track medical services provided by Alberta’s government-funded universal health care system.

Most patients’ care was managed by family physicians alone in four of the conditions studied: hypertension (85.7%), diabetes (70.9%), chronic obstructive pulmonary disease (59.8%), and asthma (65.5%).

Specialists were more involved in the remaining three diseases. They provided the sole management in 49.1% of patients with ischemic heart disease, 42.2% of those with chronic kidney disease, and 35.6% of those with heart failure. For these conditions, family physicians remained involved in the care for a large proportion of patients. Specialist involvement may be more common with these diseases because they sometimes involve interventions that only specialists offer, like angiography and dialysis, said Dr. Kirkwood.

The study also found that nurse practitioners were involved in care for very few patients (less than 1%), in accordance with the small number of nurse practitioners working in primary care settings.

Dr. Kirkwood acknowledged that the data come with certain limitations because they were not intended for research purposes. One limitation is that some conditions may not have been recorded because of “shadow billing.” Salaried physicians and practitioners do not have an incentive to include all diagnostic codes in their records. By comparison, clinicians operating under a fee-for-service model would be likely to indicate all diagnoses.
 

Developing guidelines

Despite the widespread management of chronic conditions by family physicians, these doctors represented about 17% of the experts who contribute to guidelines and recommendations, according to a 2015 study that the investigators cited.

“Frankly, that’s concerning,” said Dr. Kirkwood, regarding the disconnect between the people creating the recommendations and the people using them. The guidelines should include the perspective of clinicians who regularly work with patients, she said. Providing that perspective would also make the design of clinical trials on interventions more informative, the researchers concluded.

“I know as a family doctor myself that some recommendations are completely overwhelming,” especially given the range of issues that primary care clinicians see, said Dr. Kirkwood. Including primary care representatives who are familiar with the demands of the position “hopefully will make the recommendations much more applicable to the people that they will affect,” she said.

Dr. Kirkwood also noted the need for sufficient support for family doctors to contribute to guideline creation and research, especially for doctors in rural communities who are not already affiliated with a university.

The involvement of primary care providers in research settings is a primary goal of Patients, Experience, Evidence and Research (PEER), a primary care-led group that collaborates with the College of Family Physicians of Canada. The current investigators are members of PEER.
 

Additional conditions

Commenting on the study, Martin Fortin, MD, clinical teaching professor at the University of Sherbrooke, Quebec, said, “This is a good opportunity to advocate for more studies to be done in the primary care context, where the majority of chronic disease management is done.”

However, Dr. Fortin wishes that more diagnoses had been included in the study, such as mental health and musculoskeletal conditions like back pain and osteoarthritis. These conditions are also commonly seen by primary care clinicians, according to Dr. Fortin.

Because the number of conditions studied is limited, the data may not reflect the true prevalence of multimorbidity, Dr. Fortin added.

Primary care doctors provide a broad perspective on the overall health of patients, compared with specialists who focus on particular conditions. Similarly, during drug trials, pharmaceutical companies aim to reduce complicating factors, even though the medications are prescribed for conditions where multimorbidity is common. “Medication should be tested in the real environment,” said Dr. Fortin.

Ultimately, he added, the study cannot address the complexity of the patients, but it nevertheless sheds light on who is providing care and where the research on these conditions should be done.

The study was conducted without outside funding. Dr. Kirkwood and Dr. Fortin reported no relevant financial relationships.

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

Adults aged 60 or older who took high monthly doses of vitamin D for 5 years failed to show a significant drop in risk for cardiovascular (CV) events in general but may have benefited for other CV outcomes in an analysis from a large prospective randomized trial.

Risk reductions on vitamin D in the mixed primary- and secondary-prevention population were slight in absolute terms but reached a significant 19% in the case of myocardial infarction (MI).

Over 5 years, 6.6% of those in placebo group experienced major CV events, the primary endpoint, compared with 6% in the vitamin D group. The difference, which corresponded to 5.8 fewer events per 1,000 participants, was short of significance in adjusted analysis.

Benefits minimal

The 21,302 patients in the D-Health trial, conducted in Australia from 2014 to 2020, were randomly assigned double-blind to receive either placebo or vitamin D3 supplements for a planned 5 years. They were instructed to take one placebo or vitamin D capsule per month, each active capsule containing 60,000 IU of the vitamin.

People with self-reported hypercalcemia, hyperparathyroidism, kidney stones, osteomalacia, or sarcoidosis, and those taking greater than 500 IU/day vitamin D supplements were excluded from enrollment. Participants ranged in age from 60 to 84 at randomization and 46% were women.

With 80% of the 10,658 participants assigned to vitamin D and 78% of the 10,644 control subjects completing the 5-year intervention, 6% and 6.6%, respectively, met the primary endpoint of a major CV event, defined as MI, stroke, or coronary revascularization.

The hazard ratio for a vitamin-D effect on the primary endpoint was 0.91 (95% confidence interval, 0.81-1.01). The number needed to treat to avoid one major CV event was 172.

The HR for MI was 0.81 (95% CI, 0.67-0.98), for coronary intervention was 0.89 (0.78-1.01), and for stroke was 0.99 (0.80-1.23).

Adverse event rates were similar at about 16% in both groups and included hypercalcemia, kidney stones, gastrointestinal issues, and skin rash.

Vitamin D at moderate dosages has low toxicity, Dr. Neale said, “so I think it would be reasonable for clinicians to consider supplementing elderly people who do not have contraindications, particularly those who have underlying risk factors for CV disease,” Dr. Neale said. But patients should be told that the evidence for such a recommendation is not strong, so they can make an informed decision, she added.

Also, in general “we would be cautious about extrapolating to formulations other than those used in the study,” Dr. Neale said. “However, in this case, I think it would be reasonable to extrapolate to the use of 2,000 IU per day taken orally, provided that the same adherence can be maintained for a lengthy period.”
 

Chance findings?

Based on the current study and in light of prior research, “it is premature to recommend vitamin D supplementation for cardiovascular disease prevention specifically,” Nour Makarem, PhD, of the Mailman School of Public Health, Columbia University, New York, said in an interview.

“Prior clinical trials did not show an association between vitamin D supplementation and cardiovascular events,” observed Dr. Makarem, who is not affiliated with the current study. Also, she agreed, it looked at “multiple outcomes, which increases the likelihood that findings may be due to chance.”

She added that the study’s authors observed a possible vitamin-D protective effect “among people who were vitamin D sufficient at baseline but not among those who were insufficient. It is important to interpret this finding with caution because they used predicted, not measured, vitamin D status for these analyses.”

There’s a need for studies in other populations, including younger persons and “particularly populations with higher rates of vitamin D deficiency,” Dr. Makarem observed. Also, further research should aim to “understand the interactions between vitamin D supplementation and cardiovascular medications, including statins.” 

The D-Health Trial is funded by National Health and Medical Research Council project grants. Dr. Neale was supported by fellowships from the NHMRC. Neither she nor Dr. Makarem reported any relevant financial relationships.

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

Adults aged 60 or older who took high monthly doses of vitamin D for 5 years failed to show a significant drop in risk for cardiovascular (CV) events in general but may have benefited for other CV outcomes in an analysis from a large prospective randomized trial.

Risk reductions on vitamin D in the mixed primary- and secondary-prevention population were slight in absolute terms but reached a significant 19% in the case of myocardial infarction (MI).

Over 5 years, 6.6% of those in placebo group experienced major CV events, the primary endpoint, compared with 6% in the vitamin D group. The difference, which corresponded to 5.8 fewer events per 1,000 participants, was short of significance in adjusted analysis.

Benefits minimal

The 21,302 patients in the D-Health trial, conducted in Australia from 2014 to 2020, were randomly assigned double-blind to receive either placebo or vitamin D3 supplements for a planned 5 years. They were instructed to take one placebo or vitamin D capsule per month, each active capsule containing 60,000 IU of the vitamin.

People with self-reported hypercalcemia, hyperparathyroidism, kidney stones, osteomalacia, or sarcoidosis, and those taking greater than 500 IU/day vitamin D supplements were excluded from enrollment. Participants ranged in age from 60 to 84 at randomization and 46% were women.

With 80% of the 10,658 participants assigned to vitamin D and 78% of the 10,644 control subjects completing the 5-year intervention, 6% and 6.6%, respectively, met the primary endpoint of a major CV event, defined as MI, stroke, or coronary revascularization.

The hazard ratio for a vitamin-D effect on the primary endpoint was 0.91 (95% confidence interval, 0.81-1.01). The number needed to treat to avoid one major CV event was 172.

The HR for MI was 0.81 (95% CI, 0.67-0.98), for coronary intervention was 0.89 (0.78-1.01), and for stroke was 0.99 (0.80-1.23).

Adverse event rates were similar at about 16% in both groups and included hypercalcemia, kidney stones, gastrointestinal issues, and skin rash.

Vitamin D at moderate dosages has low toxicity, Dr. Neale said, “so I think it would be reasonable for clinicians to consider supplementing elderly people who do not have contraindications, particularly those who have underlying risk factors for CV disease,” Dr. Neale said. But patients should be told that the evidence for such a recommendation is not strong, so they can make an informed decision, she added.

Also, in general “we would be cautious about extrapolating to formulations other than those used in the study,” Dr. Neale said. “However, in this case, I think it would be reasonable to extrapolate to the use of 2,000 IU per day taken orally, provided that the same adherence can be maintained for a lengthy period.”
 

Chance findings?

Based on the current study and in light of prior research, “it is premature to recommend vitamin D supplementation for cardiovascular disease prevention specifically,” Nour Makarem, PhD, of the Mailman School of Public Health, Columbia University, New York, said in an interview.

“Prior clinical trials did not show an association between vitamin D supplementation and cardiovascular events,” observed Dr. Makarem, who is not affiliated with the current study. Also, she agreed, it looked at “multiple outcomes, which increases the likelihood that findings may be due to chance.”

She added that the study’s authors observed a possible vitamin-D protective effect “among people who were vitamin D sufficient at baseline but not among those who were insufficient. It is important to interpret this finding with caution because they used predicted, not measured, vitamin D status for these analyses.”

There’s a need for studies in other populations, including younger persons and “particularly populations with higher rates of vitamin D deficiency,” Dr. Makarem observed. Also, further research should aim to “understand the interactions between vitamin D supplementation and cardiovascular medications, including statins.” 

The D-Health Trial is funded by National Health and Medical Research Council project grants. Dr. Neale was supported by fellowships from the NHMRC. Neither she nor Dr. Makarem reported any relevant financial relationships.

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

Adults aged 60 or older who took high monthly doses of vitamin D for 5 years failed to show a significant drop in risk for cardiovascular (CV) events in general but may have benefited for other CV outcomes in an analysis from a large prospective randomized trial.

Risk reductions on vitamin D in the mixed primary- and secondary-prevention population were slight in absolute terms but reached a significant 19% in the case of myocardial infarction (MI).

Over 5 years, 6.6% of those in placebo group experienced major CV events, the primary endpoint, compared with 6% in the vitamin D group. The difference, which corresponded to 5.8 fewer events per 1,000 participants, was short of significance in adjusted analysis.

Benefits minimal

The 21,302 patients in the D-Health trial, conducted in Australia from 2014 to 2020, were randomly assigned double-blind to receive either placebo or vitamin D3 supplements for a planned 5 years. They were instructed to take one placebo or vitamin D capsule per month, each active capsule containing 60,000 IU of the vitamin.

People with self-reported hypercalcemia, hyperparathyroidism, kidney stones, osteomalacia, or sarcoidosis, and those taking greater than 500 IU/day vitamin D supplements were excluded from enrollment. Participants ranged in age from 60 to 84 at randomization and 46% were women.

With 80% of the 10,658 participants assigned to vitamin D and 78% of the 10,644 control subjects completing the 5-year intervention, 6% and 6.6%, respectively, met the primary endpoint of a major CV event, defined as MI, stroke, or coronary revascularization.

The hazard ratio for a vitamin-D effect on the primary endpoint was 0.91 (95% confidence interval, 0.81-1.01). The number needed to treat to avoid one major CV event was 172.

The HR for MI was 0.81 (95% CI, 0.67-0.98), for coronary intervention was 0.89 (0.78-1.01), and for stroke was 0.99 (0.80-1.23).

Adverse event rates were similar at about 16% in both groups and included hypercalcemia, kidney stones, gastrointestinal issues, and skin rash.

Vitamin D at moderate dosages has low toxicity, Dr. Neale said, “so I think it would be reasonable for clinicians to consider supplementing elderly people who do not have contraindications, particularly those who have underlying risk factors for CV disease,” Dr. Neale said. But patients should be told that the evidence for such a recommendation is not strong, so they can make an informed decision, she added.

Also, in general “we would be cautious about extrapolating to formulations other than those used in the study,” Dr. Neale said. “However, in this case, I think it would be reasonable to extrapolate to the use of 2,000 IU per day taken orally, provided that the same adherence can be maintained for a lengthy period.”
 

Chance findings?

Based on the current study and in light of prior research, “it is premature to recommend vitamin D supplementation for cardiovascular disease prevention specifically,” Nour Makarem, PhD, of the Mailman School of Public Health, Columbia University, New York, said in an interview.

“Prior clinical trials did not show an association between vitamin D supplementation and cardiovascular events,” observed Dr. Makarem, who is not affiliated with the current study. Also, she agreed, it looked at “multiple outcomes, which increases the likelihood that findings may be due to chance.”

She added that the study’s authors observed a possible vitamin-D protective effect “among people who were vitamin D sufficient at baseline but not among those who were insufficient. It is important to interpret this finding with caution because they used predicted, not measured, vitamin D status for these analyses.”

There’s a need for studies in other populations, including younger persons and “particularly populations with higher rates of vitamin D deficiency,” Dr. Makarem observed. Also, further research should aim to “understand the interactions between vitamin D supplementation and cardiovascular medications, including statins.” 

The D-Health Trial is funded by National Health and Medical Research Council project grants. Dr. Neale was supported by fellowships from the NHMRC. Neither she nor Dr. Makarem reported any relevant financial relationships.

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

SAN DIEGO – Survodutide, a dual glucagonlike peptide–1 (GLP-1) and glucagon receptor agonist, led to “striking” weight loss in a phase 2 dosing trial in people with overweight/obesity but without type 2 diabetes.

Close to 40% of people who were taking the highest dose lost 20% or more of their starting weight at 46 weeks, Carel Le Roux, MBChB, PhD, reported at the annual scientific sessions of the American Diabetes Association.

Boehringer Ingelheim and Zealand Pharma are developing survodutide (formerly BI 456906) to treat obesity and nonalcoholic fatty liver disease (NAFLD), according to a company press release.

Glucagon receptor agonism increases energy expenditure, and GLP-1 receptor agonism inhibits appetite, both part of the mechanism of action, Dr. Le Roux, a professor at University College in Dublin, explained.

The trial showed a “striking” and clear dose-response in terms of weight loss, with no new unexpected safety signals, he reported.

Invited to comment, session moderator Elisabetta Patorno, MD, DrPH, noted that “Obesity is one of the main risk factors for [type 2] diabetes.”

“It’s very stimulating to see this new medication class make such a big impact on weight loss in such a short amount of time,” Dr. Patorno, associate professor of medicine at Harvard Medical School, Boston, said in an interview. However, whether the weight loss can be maintained over time remains to be determined in further research, she said.

Head-to-head weight-loss studies of the dual agonist survodutide versus the mono GLP-1 agonist semaglutide (Ozempic, Wegovy, Novo Nordisk) have not been conducted, Dr. Le Roux said during a press briefing.

“What we don’t know is if somebody doesn’t respond to [weight-loss drug] product A, will they respond to product B?” he said. Because survodutide acts on two types of receptors, “you could argue that you would not only increase the absolute amount of weight but you might also increase the number of patients who would respond, but that’s theoretical at the moment,” he explained.
 

Close to 400 patients, five doses, 46-week endpoint

The researchers randomized 387 adults aged 18-75 who had a body mass index (BMI) ≥ 27 kg/m² (overweight or obesity) without type 2 diabetes at sites in North America, Europe, Australia/New Zealand, and Asia.

On average, patients were 49 years old with a body weight of 106 kg (234 lb) and a BMI of 37 kg/m², and 68% were women.

They were randomized to receive a planned weekly subcutaneous maintenance survodutide dose of 0.6 mg (76 patients), 2.4 mg (78 patients), 3.6 mg (76 patients), or 4.8 mg (76 patients), or placebo (77 patients).

The dose was escalated rapidly (monthly) during a 20-week dose-escalation phase, followed by a 26-week maintenance phase.

Patients who did not reach the planned dose remained on a lower dose during the maintenance phase.

In terms of actual treatment, during the maintenance phase, 76 patients were taking placebo, 88 patients were taking 0.6 mg survodutide, 92 were taking 2.4 mg survodutide, 71 were taking 3.6 mg survodutide, and 54 were taking 4.8 mg survodutide, all given as weekly subcutaneous injections.

Primary outcome was the percentage change in body weight from baseline to week 46.

Secondary outcomes included the percentage of patients who reached a body weight reduction of ≥ 5%, ≥ 10%, and ≥ 15% from baseline to week 46.

Mean weight loss at 46 weeks in the planned treatment analysis (where some patients in each group were taking a lower than planned dose during maintenance) was 6.2% in the 0.6-mg survodutide group, 12.5% in the 2.4-mg group, 13.2% in the 3.6-mg group, 14.9% in the 4.8-mg group, and 2.8% in the placebo group.

Among participants who did reach and stay on their assigned dose during the maintenance phase, average weight loss was 6.8% in the 0.6-mg survodutide group,13.6% with 2.4 mg survodutide,16.7% with 3.6 mg survodutide, 18.6% with 4.8 mg survodutide, and 2.0% with placebo.

That is, patients reaching and staying on a weekly subcutaneous dose of 4.8 mg survodutide lost 18.6% of their body weight at 46 weeks, Dr. Le Roux emphasized.

In terms of secondary outcomes, in the group of patients with a planned weekly dose of 4.8 mg survodutide, 83%, 69%, and 55% attained weight loss of ≥ 5%, ≥ 10%, and ≥ 15% of their initial weight, respectively, at 46 weeks.

In the group of patients with an actual weekly dose of 4.8 mg survodutide, 98%, 82%, and 67% attained weight loss of ≥ 5%, ≥ 10%, and ≥ 15% of their initial weight, respectively, at 46 weeks.

Moreover, 33% of patients in the group with a planned weekly dose of 4.8 mg survodutide and 38% of patients with an actual weekly dose of 4.8 mg survodutide lost ≥ 20% of their baseline body weight by week 46.

Adverse events occurred in 91% of patients in the survodutide groups and 75% in the placebo group. The most common side effects were nausea, vomiting, diarrhea, and constipation, which were mostly mild to moderate and mainly occurred during dose escalation. These effects may potentially be mitigated by more gradual dose escalation, Dr. Le Roux said.

There were no unexpected safety or tolerability concerns, and no serious drug-related adverse events.

These “encouraging data” support further study of survodutide for weight loss in larger phase 3 trials, Dr. Le Roux and colleagues conclude.
 

Survodutide has FDA fast track designation for NASH

Survodutide has received U.S. Food and Drug Administration Fast Track Designation for adults with NASH. The drug is currently being evaluated in a phase 2 study in adults with NASH and stages F1/F2/F3 liver fibrosis, with trial completion expected in the last quarter of 2023.

The current trial was funded by Boehringer Ingelheim. Dr. Le Roux has reported being on an advisory panel for Boehringer Ingelheim and being on advisory panels and receiving research funding from multiple other pharmaceutical companies. Two study authors are Boehringer Ingelheim employees.

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

SAN DIEGO – Survodutide, a dual glucagonlike peptide–1 (GLP-1) and glucagon receptor agonist, led to “striking” weight loss in a phase 2 dosing trial in people with overweight/obesity but without type 2 diabetes.

Close to 40% of people who were taking the highest dose lost 20% or more of their starting weight at 46 weeks, Carel Le Roux, MBChB, PhD, reported at the annual scientific sessions of the American Diabetes Association.

Boehringer Ingelheim and Zealand Pharma are developing survodutide (formerly BI 456906) to treat obesity and nonalcoholic fatty liver disease (NAFLD), according to a company press release.

Glucagon receptor agonism increases energy expenditure, and GLP-1 receptor agonism inhibits appetite, both part of the mechanism of action, Dr. Le Roux, a professor at University College in Dublin, explained.

The trial showed a “striking” and clear dose-response in terms of weight loss, with no new unexpected safety signals, he reported.

Invited to comment, session moderator Elisabetta Patorno, MD, DrPH, noted that “Obesity is one of the main risk factors for [type 2] diabetes.”

“It’s very stimulating to see this new medication class make such a big impact on weight loss in such a short amount of time,” Dr. Patorno, associate professor of medicine at Harvard Medical School, Boston, said in an interview. However, whether the weight loss can be maintained over time remains to be determined in further research, she said.

Head-to-head weight-loss studies of the dual agonist survodutide versus the mono GLP-1 agonist semaglutide (Ozempic, Wegovy, Novo Nordisk) have not been conducted, Dr. Le Roux said during a press briefing.

“What we don’t know is if somebody doesn’t respond to [weight-loss drug] product A, will they respond to product B?” he said. Because survodutide acts on two types of receptors, “you could argue that you would not only increase the absolute amount of weight but you might also increase the number of patients who would respond, but that’s theoretical at the moment,” he explained.
 

Close to 400 patients, five doses, 46-week endpoint

The researchers randomized 387 adults aged 18-75 who had a body mass index (BMI) ≥ 27 kg/m² (overweight or obesity) without type 2 diabetes at sites in North America, Europe, Australia/New Zealand, and Asia.

On average, patients were 49 years old with a body weight of 106 kg (234 lb) and a BMI of 37 kg/m², and 68% were women.

They were randomized to receive a planned weekly subcutaneous maintenance survodutide dose of 0.6 mg (76 patients), 2.4 mg (78 patients), 3.6 mg (76 patients), or 4.8 mg (76 patients), or placebo (77 patients).

The dose was escalated rapidly (monthly) during a 20-week dose-escalation phase, followed by a 26-week maintenance phase.

Patients who did not reach the planned dose remained on a lower dose during the maintenance phase.

In terms of actual treatment, during the maintenance phase, 76 patients were taking placebo, 88 patients were taking 0.6 mg survodutide, 92 were taking 2.4 mg survodutide, 71 were taking 3.6 mg survodutide, and 54 were taking 4.8 mg survodutide, all given as weekly subcutaneous injections.

Primary outcome was the percentage change in body weight from baseline to week 46.

Secondary outcomes included the percentage of patients who reached a body weight reduction of ≥ 5%, ≥ 10%, and ≥ 15% from baseline to week 46.

Mean weight loss at 46 weeks in the planned treatment analysis (where some patients in each group were taking a lower than planned dose during maintenance) was 6.2% in the 0.6-mg survodutide group, 12.5% in the 2.4-mg group, 13.2% in the 3.6-mg group, 14.9% in the 4.8-mg group, and 2.8% in the placebo group.

Among participants who did reach and stay on their assigned dose during the maintenance phase, average weight loss was 6.8% in the 0.6-mg survodutide group,13.6% with 2.4 mg survodutide,16.7% with 3.6 mg survodutide, 18.6% with 4.8 mg survodutide, and 2.0% with placebo.

That is, patients reaching and staying on a weekly subcutaneous dose of 4.8 mg survodutide lost 18.6% of their body weight at 46 weeks, Dr. Le Roux emphasized.

In terms of secondary outcomes, in the group of patients with a planned weekly dose of 4.8 mg survodutide, 83%, 69%, and 55% attained weight loss of ≥ 5%, ≥ 10%, and ≥ 15% of their initial weight, respectively, at 46 weeks.

In the group of patients with an actual weekly dose of 4.8 mg survodutide, 98%, 82%, and 67% attained weight loss of ≥ 5%, ≥ 10%, and ≥ 15% of their initial weight, respectively, at 46 weeks.

Moreover, 33% of patients in the group with a planned weekly dose of 4.8 mg survodutide and 38% of patients with an actual weekly dose of 4.8 mg survodutide lost ≥ 20% of their baseline body weight by week 46.

Adverse events occurred in 91% of patients in the survodutide groups and 75% in the placebo group. The most common side effects were nausea, vomiting, diarrhea, and constipation, which were mostly mild to moderate and mainly occurred during dose escalation. These effects may potentially be mitigated by more gradual dose escalation, Dr. Le Roux said.

There were no unexpected safety or tolerability concerns, and no serious drug-related adverse events.

These “encouraging data” support further study of survodutide for weight loss in larger phase 3 trials, Dr. Le Roux and colleagues conclude.
 

Survodutide has FDA fast track designation for NASH

Survodutide has received U.S. Food and Drug Administration Fast Track Designation for adults with NASH. The drug is currently being evaluated in a phase 2 study in adults with NASH and stages F1/F2/F3 liver fibrosis, with trial completion expected in the last quarter of 2023.

The current trial was funded by Boehringer Ingelheim. Dr. Le Roux has reported being on an advisory panel for Boehringer Ingelheim and being on advisory panels and receiving research funding from multiple other pharmaceutical companies. Two study authors are Boehringer Ingelheim employees.

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

SAN DIEGO – Survodutide, a dual glucagonlike peptide–1 (GLP-1) and glucagon receptor agonist, led to “striking” weight loss in a phase 2 dosing trial in people with overweight/obesity but without type 2 diabetes.

Close to 40% of people who were taking the highest dose lost 20% or more of their starting weight at 46 weeks, Carel Le Roux, MBChB, PhD, reported at the annual scientific sessions of the American Diabetes Association.

Boehringer Ingelheim and Zealand Pharma are developing survodutide (formerly BI 456906) to treat obesity and nonalcoholic fatty liver disease (NAFLD), according to a company press release.

Glucagon receptor agonism increases energy expenditure, and GLP-1 receptor agonism inhibits appetite, both part of the mechanism of action, Dr. Le Roux, a professor at University College in Dublin, explained.

The trial showed a “striking” and clear dose-response in terms of weight loss, with no new unexpected safety signals, he reported.

Invited to comment, session moderator Elisabetta Patorno, MD, DrPH, noted that “Obesity is one of the main risk factors for [type 2] diabetes.”

“It’s very stimulating to see this new medication class make such a big impact on weight loss in such a short amount of time,” Dr. Patorno, associate professor of medicine at Harvard Medical School, Boston, said in an interview. However, whether the weight loss can be maintained over time remains to be determined in further research, she said.

Head-to-head weight-loss studies of the dual agonist survodutide versus the mono GLP-1 agonist semaglutide (Ozempic, Wegovy, Novo Nordisk) have not been conducted, Dr. Le Roux said during a press briefing.

“What we don’t know is if somebody doesn’t respond to [weight-loss drug] product A, will they respond to product B?” he said. Because survodutide acts on two types of receptors, “you could argue that you would not only increase the absolute amount of weight but you might also increase the number of patients who would respond, but that’s theoretical at the moment,” he explained.
 

Close to 400 patients, five doses, 46-week endpoint

The researchers randomized 387 adults aged 18-75 who had a body mass index (BMI) ≥ 27 kg/m² (overweight or obesity) without type 2 diabetes at sites in North America, Europe, Australia/New Zealand, and Asia.

On average, patients were 49 years old with a body weight of 106 kg (234 lb) and a BMI of 37 kg/m², and 68% were women.

They were randomized to receive a planned weekly subcutaneous maintenance survodutide dose of 0.6 mg (76 patients), 2.4 mg (78 patients), 3.6 mg (76 patients), or 4.8 mg (76 patients), or placebo (77 patients).

The dose was escalated rapidly (monthly) during a 20-week dose-escalation phase, followed by a 26-week maintenance phase.

Patients who did not reach the planned dose remained on a lower dose during the maintenance phase.

In terms of actual treatment, during the maintenance phase, 76 patients were taking placebo, 88 patients were taking 0.6 mg survodutide, 92 were taking 2.4 mg survodutide, 71 were taking 3.6 mg survodutide, and 54 were taking 4.8 mg survodutide, all given as weekly subcutaneous injections.

Primary outcome was the percentage change in body weight from baseline to week 46.

Secondary outcomes included the percentage of patients who reached a body weight reduction of ≥ 5%, ≥ 10%, and ≥ 15% from baseline to week 46.

Mean weight loss at 46 weeks in the planned treatment analysis (where some patients in each group were taking a lower than planned dose during maintenance) was 6.2% in the 0.6-mg survodutide group, 12.5% in the 2.4-mg group, 13.2% in the 3.6-mg group, 14.9% in the 4.8-mg group, and 2.8% in the placebo group.

Among participants who did reach and stay on their assigned dose during the maintenance phase, average weight loss was 6.8% in the 0.6-mg survodutide group,13.6% with 2.4 mg survodutide,16.7% with 3.6 mg survodutide, 18.6% with 4.8 mg survodutide, and 2.0% with placebo.

That is, patients reaching and staying on a weekly subcutaneous dose of 4.8 mg survodutide lost 18.6% of their body weight at 46 weeks, Dr. Le Roux emphasized.

In terms of secondary outcomes, in the group of patients with a planned weekly dose of 4.8 mg survodutide, 83%, 69%, and 55% attained weight loss of ≥ 5%, ≥ 10%, and ≥ 15% of their initial weight, respectively, at 46 weeks.

In the group of patients with an actual weekly dose of 4.8 mg survodutide, 98%, 82%, and 67% attained weight loss of ≥ 5%, ≥ 10%, and ≥ 15% of their initial weight, respectively, at 46 weeks.

Moreover, 33% of patients in the group with a planned weekly dose of 4.8 mg survodutide and 38% of patients with an actual weekly dose of 4.8 mg survodutide lost ≥ 20% of their baseline body weight by week 46.

Adverse events occurred in 91% of patients in the survodutide groups and 75% in the placebo group. The most common side effects were nausea, vomiting, diarrhea, and constipation, which were mostly mild to moderate and mainly occurred during dose escalation. These effects may potentially be mitigated by more gradual dose escalation, Dr. Le Roux said.

There were no unexpected safety or tolerability concerns, and no serious drug-related adverse events.

These “encouraging data” support further study of survodutide for weight loss in larger phase 3 trials, Dr. Le Roux and colleagues conclude.
 

Survodutide has FDA fast track designation for NASH

Survodutide has received U.S. Food and Drug Administration Fast Track Designation for adults with NASH. The drug is currently being evaluated in a phase 2 study in adults with NASH and stages F1/F2/F3 liver fibrosis, with trial completion expected in the last quarter of 2023.

The current trial was funded by Boehringer Ingelheim. Dr. Le Roux has reported being on an advisory panel for Boehringer Ingelheim and being on advisory panels and receiving research funding from multiple other pharmaceutical companies. Two study authors are Boehringer Ingelheim employees.

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

TOPLINE:

The availability of medical cannabis has little effect on prescription rates of opioids, nonopioid pain medicines, and other pain interventions, according to a new study published in Annals of Internal Medicine.

METHODOLOGY:

• Cannabis advocates suggest that legal medical cannabis can be a partial solution to the opioid overdose crisis in the United States, which claimed more than 80,000 lives in 2021.
• Current research on how legalized cannabis reduces dependence on prescription pain medication is inconclusive.
• Researchers examined insurance data for the period 2010-2022 from 583,820 adults with chronic noncancer pain.
• They drew from 12 states in which medical cannabis is legal and from 17 in which it is not legal to create a hypothetical randomized trial. The control group simulated prescription rates where medical cannabis was not available.
• Authors evaluated prescription rates for opioids, nonopioid painkillers, and pain interventions, such as physical therapy.

TAKEAWAY:

In a given month during the first 3 years after legalization, for states with medical cannabis, the investigators found the following:

• There was an average decrease of 1.07 percentage points in the proportion of patients who received any opioid prescription, compared to a 1.12 percentage point decrease in the control group.
• There was an average increase of 1.14 percentage points in the proportion of patients who received any nonopioid prescription painkiller, compared to a 1.19 percentage point increase in the control group.
• There was a 0.17 percentage point decrease in the proportion of patients who received any pain procedure, compared to a 0.001 percentage point decrease in the control group.

IN PRACTICE:

“This study did not identify important effects of medical cannabis laws on receipt of opioid or nonopioid pain treatment among patients with chronic noncancer pain,” according to the researchers.

SOURCE:

The study was led by Emma E. McGinty, PhD, of Weill Cornell Medicine, New York, and was funded by the National Institute on Drug Abuse.

LIMITATIONS:

The investigators used a simulated, hypothetical control group that was based on untestable assumptions. They also drew data solely from insured individuals, so the study does not necessarily represent uninsured populations.

DISCLOSURES:

Dr. McGinty reports receiving a grant from NIDA. Her coauthors reported receiving support from NIDA and the National Institutes of Health.

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

TOPLINE:

The availability of medical cannabis has little effect on prescription rates of opioids, nonopioid pain medicines, and other pain interventions, according to a new study published in Annals of Internal Medicine.

METHODOLOGY:

• Cannabis advocates suggest that legal medical cannabis can be a partial solution to the opioid overdose crisis in the United States, which claimed more than 80,000 lives in 2021.
• Current research on how legalized cannabis reduces dependence on prescription pain medication is inconclusive.
• Researchers examined insurance data for the period 2010-2022 from 583,820 adults with chronic noncancer pain.
• They drew from 12 states in which medical cannabis is legal and from 17 in which it is not legal to create a hypothetical randomized trial. The control group simulated prescription rates where medical cannabis was not available.
• Authors evaluated prescription rates for opioids, nonopioid painkillers, and pain interventions, such as physical therapy.

TAKEAWAY:

In a given month during the first 3 years after legalization, for states with medical cannabis, the investigators found the following:

• There was an average decrease of 1.07 percentage points in the proportion of patients who received any opioid prescription, compared to a 1.12 percentage point decrease in the control group.
• There was an average increase of 1.14 percentage points in the proportion of patients who received any nonopioid prescription painkiller, compared to a 1.19 percentage point increase in the control group.
• There was a 0.17 percentage point decrease in the proportion of patients who received any pain procedure, compared to a 0.001 percentage point decrease in the control group.

IN PRACTICE:

“This study did not identify important effects of medical cannabis laws on receipt of opioid or nonopioid pain treatment among patients with chronic noncancer pain,” according to the researchers.

SOURCE:

The study was led by Emma E. McGinty, PhD, of Weill Cornell Medicine, New York, and was funded by the National Institute on Drug Abuse.

LIMITATIONS:

The investigators used a simulated, hypothetical control group that was based on untestable assumptions. They also drew data solely from insured individuals, so the study does not necessarily represent uninsured populations.

DISCLOSURES:

Dr. McGinty reports receiving a grant from NIDA. Her coauthors reported receiving support from NIDA and the National Institutes of Health.

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

TOPLINE:

The availability of medical cannabis has little effect on prescription rates of opioids, nonopioid pain medicines, and other pain interventions, according to a new study published in Annals of Internal Medicine.

METHODOLOGY:

• Cannabis advocates suggest that legal medical cannabis can be a partial solution to the opioid overdose crisis in the United States, which claimed more than 80,000 lives in 2021.
• Current research on how legalized cannabis reduces dependence on prescription pain medication is inconclusive.
• Researchers examined insurance data for the period 2010-2022 from 583,820 adults with chronic noncancer pain.
• They drew from 12 states in which medical cannabis is legal and from 17 in which it is not legal to create a hypothetical randomized trial. The control group simulated prescription rates where medical cannabis was not available.
• Authors evaluated prescription rates for opioids, nonopioid painkillers, and pain interventions, such as physical therapy.

TAKEAWAY:

In a given month during the first 3 years after legalization, for states with medical cannabis, the investigators found the following:

• There was an average decrease of 1.07 percentage points in the proportion of patients who received any opioid prescription, compared to a 1.12 percentage point decrease in the control group.
• There was an average increase of 1.14 percentage points in the proportion of patients who received any nonopioid prescription painkiller, compared to a 1.19 percentage point increase in the control group.
• There was a 0.17 percentage point decrease in the proportion of patients who received any pain procedure, compared to a 0.001 percentage point decrease in the control group.

IN PRACTICE:

“This study did not identify important effects of medical cannabis laws on receipt of opioid or nonopioid pain treatment among patients with chronic noncancer pain,” according to the researchers.

SOURCE:

The study was led by Emma E. McGinty, PhD, of Weill Cornell Medicine, New York, and was funded by the National Institute on Drug Abuse.

LIMITATIONS:

The investigators used a simulated, hypothetical control group that was based on untestable assumptions. They also drew data solely from insured individuals, so the study does not necessarily represent uninsured populations.

DISCLOSURES:

Dr. McGinty reports receiving a grant from NIDA. Her coauthors reported receiving support from NIDA and the National Institutes of Health.

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

Lean muscle mass may offer protection against the development of Alzheimer’s disease (AD), new research suggests.

Investigators analyzed data on more than 450,000 participants in the UK Biobank as well as two independent samples of more than 320,000 individuals with and without AD, and more than 260,000 individuals participating in a separate genes and intelligence study.

They estimated lean muscle and fat tissue in the arms and legs and found, in adjusted analyses, over 500 genetic variants associated with lean mass.

On average, higher genetically lean mass was associated with a “modest but statistically robust” reduction in AD risk and with superior performance on cognitive tasks.

“Using human genetic data, we found evidence for a protective effect of lean mass on risk of Alzheimer’s disease,” study investigators Iyas Daghlas, MD, a resident in the department of neurology, University of California, San Francisco, said in an interview.

Although “clinical intervention studies are needed to confirm this effect, this study supports current recommendations to maintain a healthy lifestyle to prevent dementia,” he said.

The study was published online in BMJ Medicine.
 

Naturally randomized research

Several measures of body composition have been investigated for their potential association with AD. Lean mass – a “proxy for muscle mass, defined as the difference between total mass and fat mass” – has been shown to be reduced in patients with AD compared with controls, the researchers noted.

“Previous research studies have tested the relationship of body mass index with Alzheimer’s disease and did not find evidence for a causal effect,” Dr. Daghlas said. “We wondered whether BMI was an insufficiently granular measure and hypothesized that disaggregating body mass into lean mass and fat mass could reveal novel associations with disease.”

Most studies have used case-control designs, which might be biased by “residual confounding or reverse causality.” Naturally randomized data “may be used as an alternative to conventional observational studies to investigate causal relations between risk factors and diseases,” the researchers wrote.

In particular, the Mendelian randomization (MR) paradigm randomly allocates germline genetic variants and uses them as proxies for a specific risk factor.

MR “is a technique that permits researchers to investigate cause-and-effect relationships using human genetic data,” Dr. Daghlas explained. “In effect, we’re studying the results of a naturally randomized experiment whereby some individuals are genetically allocated to carry more lean mass.” 

The current study used MR to investigate the effect of genetically proxied lean mass on the risk of AD and the “related phenotype” of cognitive performance.
 

Genetic proxy

As genetic proxies for lean mass, the researchers chose single nucleotide polymorphisms (genetic variants) that were associated, in a genome-wide association study (GWAS), with appendicular lean mass.

Appendicular lean mass “more accurately reflects the effects of lean mass than whole body lean mass, which includes smooth and cardiac muscle,” the authors explained.

This GWAS used phenotypic and genetic data from 450,243 participants in the UK Biobank cohort (mean age 57 years). All participants were of European ancestry.

The researchers adjusted for age, sex, and genetic ancestry. They measured appendicular lean mass using bioimpedance – an electric current that flows at different rates through the body, depending on its composition.

In addition to the UK Biobank participants, the researchers drew on an independent sample of 21,982 people with AD; a control group of 41,944 people without AD; a replication sample of 7,329 people with and 252,879 people without AD to validate the findings; and 269,867 people taking part in a genome-wide study of cognitive performance.

The researchers identified 584 variants that met criteria for use as genetic proxies for lean mass. None were located within the APOE gene region. In the aggregate, these variants explained 10.3% of the variance in appendicular lean mass.

Each standard deviation increase in genetically proxied lean mass was associated with a 12% reduction in AD risk (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.82-0.95; P < .001). This finding was replicated in the independent consortium (OR, 0.91; 95% CI, 0.83-0.99; P = .02).

The findings remained “consistent” in sensitivity analyses.
 

A modifiable risk factor?

Higher appendicular lean mass was associated with higher levels of cognitive performance, with each SD increase in lean mass associated with an SD increase in cognitive performance (OR, 0.09; 95% CI, 0.06-0.11; P = .001).

“Adjusting for potential mediation through performance did not reduce the association between appendicular lean mass and risk of AD,” the authors wrote.

They obtained similar results using genetically proxied trunk and whole-body lean mass, after adjusting for fat mass.

The authors noted several limitations. The bioimpedance measures “only predict, but do not directly measure, lean mass.” Moreover, the approach didn’t examine whether a “critical window of risk factor timing” exists, during which lean mass might play a role in influencing AD risk and after which “interventions would no longer be effective.” Nor could the study determine whether increasing lean mass could reverse AD pathology in patients with preclinical disease or mild cognitive impairment.

Nevertheless, the findings suggest “that lean mass might be a possible modifiable protective factor for Alzheimer’s disease,” the authors wrote. “The mechanisms underlying this finding, as well as the clinical and public health implications, warrant further investigation.”
 

Novel strategies

In a comment, Iva Miljkovic, MD, PhD, associate professor, department of epidemiology, University of Pittsburgh, said the investigators used “very rigorous methodology.”

The finding suggesting that lean mass is associated with better cognitive function is “important, as cognitive impairment can become stable rather than progress to a pathological state; and, in some cases, can even be reversed.”

In those cases, “identifying the underlying cause – e.g., low lean mass – can significantly improve cognitive function,” said Dr. Miljkovic, senior author of a study showing muscle fat as a risk factor for cognitive decline.

More research will enable us to “expand our understanding” of the mechanisms involved and determine whether interventions aimed at preventing muscle loss and/or increasing muscle fat may have a beneficial effect on cognitive function,” she said. “This might lead to novel strategies to prevent AD.”

Dr. Daghlas is supported by the British Heart Foundation Centre of Research Excellence at Imperial College, London, and is employed part-time by Novo Nordisk. Dr. Miljkovic reports no relevant financial relationships.

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

Lean muscle mass may offer protection against the development of Alzheimer’s disease (AD), new research suggests.

Investigators analyzed data on more than 450,000 participants in the UK Biobank as well as two independent samples of more than 320,000 individuals with and without AD, and more than 260,000 individuals participating in a separate genes and intelligence study.

They estimated lean muscle and fat tissue in the arms and legs and found, in adjusted analyses, over 500 genetic variants associated with lean mass.

On average, higher genetically lean mass was associated with a “modest but statistically robust” reduction in AD risk and with superior performance on cognitive tasks.

“Using human genetic data, we found evidence for a protective effect of lean mass on risk of Alzheimer’s disease,” study investigators Iyas Daghlas, MD, a resident in the department of neurology, University of California, San Francisco, said in an interview.

Although “clinical intervention studies are needed to confirm this effect, this study supports current recommendations to maintain a healthy lifestyle to prevent dementia,” he said.

The study was published online in BMJ Medicine.
 

Naturally randomized research

Several measures of body composition have been investigated for their potential association with AD. Lean mass – a “proxy for muscle mass, defined as the difference between total mass and fat mass” – has been shown to be reduced in patients with AD compared with controls, the researchers noted.

“Previous research studies have tested the relationship of body mass index with Alzheimer’s disease and did not find evidence for a causal effect,” Dr. Daghlas said. “We wondered whether BMI was an insufficiently granular measure and hypothesized that disaggregating body mass into lean mass and fat mass could reveal novel associations with disease.”

Most studies have used case-control designs, which might be biased by “residual confounding or reverse causality.” Naturally randomized data “may be used as an alternative to conventional observational studies to investigate causal relations between risk factors and diseases,” the researchers wrote.

In particular, the Mendelian randomization (MR) paradigm randomly allocates germline genetic variants and uses them as proxies for a specific risk factor.

MR “is a technique that permits researchers to investigate cause-and-effect relationships using human genetic data,” Dr. Daghlas explained. “In effect, we’re studying the results of a naturally randomized experiment whereby some individuals are genetically allocated to carry more lean mass.” 

The current study used MR to investigate the effect of genetically proxied lean mass on the risk of AD and the “related phenotype” of cognitive performance.
 

Genetic proxy

As genetic proxies for lean mass, the researchers chose single nucleotide polymorphisms (genetic variants) that were associated, in a genome-wide association study (GWAS), with appendicular lean mass.

Appendicular lean mass “more accurately reflects the effects of lean mass than whole body lean mass, which includes smooth and cardiac muscle,” the authors explained.

This GWAS used phenotypic and genetic data from 450,243 participants in the UK Biobank cohort (mean age 57 years). All participants were of European ancestry.

The researchers adjusted for age, sex, and genetic ancestry. They measured appendicular lean mass using bioimpedance – an electric current that flows at different rates through the body, depending on its composition.

In addition to the UK Biobank participants, the researchers drew on an independent sample of 21,982 people with AD; a control group of 41,944 people without AD; a replication sample of 7,329 people with and 252,879 people without AD to validate the findings; and 269,867 people taking part in a genome-wide study of cognitive performance.

The researchers identified 584 variants that met criteria for use as genetic proxies for lean mass. None were located within the APOE gene region. In the aggregate, these variants explained 10.3% of the variance in appendicular lean mass.

Each standard deviation increase in genetically proxied lean mass was associated with a 12% reduction in AD risk (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.82-0.95; P < .001). This finding was replicated in the independent consortium (OR, 0.91; 95% CI, 0.83-0.99; P = .02).

The findings remained “consistent” in sensitivity analyses.
 

A modifiable risk factor?

Higher appendicular lean mass was associated with higher levels of cognitive performance, with each SD increase in lean mass associated with an SD increase in cognitive performance (OR, 0.09; 95% CI, 0.06-0.11; P = .001).

“Adjusting for potential mediation through performance did not reduce the association between appendicular lean mass and risk of AD,” the authors wrote.

They obtained similar results using genetically proxied trunk and whole-body lean mass, after adjusting for fat mass.

The authors noted several limitations. The bioimpedance measures “only predict, but do not directly measure, lean mass.” Moreover, the approach didn’t examine whether a “critical window of risk factor timing” exists, during which lean mass might play a role in influencing AD risk and after which “interventions would no longer be effective.” Nor could the study determine whether increasing lean mass could reverse AD pathology in patients with preclinical disease or mild cognitive impairment.

Nevertheless, the findings suggest “that lean mass might be a possible modifiable protective factor for Alzheimer’s disease,” the authors wrote. “The mechanisms underlying this finding, as well as the clinical and public health implications, warrant further investigation.”
 

Novel strategies

In a comment, Iva Miljkovic, MD, PhD, associate professor, department of epidemiology, University of Pittsburgh, said the investigators used “very rigorous methodology.”

The finding suggesting that lean mass is associated with better cognitive function is “important, as cognitive impairment can become stable rather than progress to a pathological state; and, in some cases, can even be reversed.”

In those cases, “identifying the underlying cause – e.g., low lean mass – can significantly improve cognitive function,” said Dr. Miljkovic, senior author of a study showing muscle fat as a risk factor for cognitive decline.

More research will enable us to “expand our understanding” of the mechanisms involved and determine whether interventions aimed at preventing muscle loss and/or increasing muscle fat may have a beneficial effect on cognitive function,” she said. “This might lead to novel strategies to prevent AD.”

Dr. Daghlas is supported by the British Heart Foundation Centre of Research Excellence at Imperial College, London, and is employed part-time by Novo Nordisk. Dr. Miljkovic reports no relevant financial relationships.

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

Lean muscle mass may offer protection against the development of Alzheimer’s disease (AD), new research suggests.

Investigators analyzed data on more than 450,000 participants in the UK Biobank as well as two independent samples of more than 320,000 individuals with and without AD, and more than 260,000 individuals participating in a separate genes and intelligence study.

They estimated lean muscle and fat tissue in the arms and legs and found, in adjusted analyses, over 500 genetic variants associated with lean mass.

On average, higher genetically lean mass was associated with a “modest but statistically robust” reduction in AD risk and with superior performance on cognitive tasks.

“Using human genetic data, we found evidence for a protective effect of lean mass on risk of Alzheimer’s disease,” study investigators Iyas Daghlas, MD, a resident in the department of neurology, University of California, San Francisco, said in an interview.

Although “clinical intervention studies are needed to confirm this effect, this study supports current recommendations to maintain a healthy lifestyle to prevent dementia,” he said.

The study was published online in BMJ Medicine.
 

Naturally randomized research

Several measures of body composition have been investigated for their potential association with AD. Lean mass – a “proxy for muscle mass, defined as the difference between total mass and fat mass” – has been shown to be reduced in patients with AD compared with controls, the researchers noted.

“Previous research studies have tested the relationship of body mass index with Alzheimer’s disease and did not find evidence for a causal effect,” Dr. Daghlas said. “We wondered whether BMI was an insufficiently granular measure and hypothesized that disaggregating body mass into lean mass and fat mass could reveal novel associations with disease.”

Most studies have used case-control designs, which might be biased by “residual confounding or reverse causality.” Naturally randomized data “may be used as an alternative to conventional observational studies to investigate causal relations between risk factors and diseases,” the researchers wrote.

In particular, the Mendelian randomization (MR) paradigm randomly allocates germline genetic variants and uses them as proxies for a specific risk factor.

MR “is a technique that permits researchers to investigate cause-and-effect relationships using human genetic data,” Dr. Daghlas explained. “In effect, we’re studying the results of a naturally randomized experiment whereby some individuals are genetically allocated to carry more lean mass.” 

The current study used MR to investigate the effect of genetically proxied lean mass on the risk of AD and the “related phenotype” of cognitive performance.
 

Genetic proxy

As genetic proxies for lean mass, the researchers chose single nucleotide polymorphisms (genetic variants) that were associated, in a genome-wide association study (GWAS), with appendicular lean mass.

Appendicular lean mass “more accurately reflects the effects of lean mass than whole body lean mass, which includes smooth and cardiac muscle,” the authors explained.

This GWAS used phenotypic and genetic data from 450,243 participants in the UK Biobank cohort (mean age 57 years). All participants were of European ancestry.

The researchers adjusted for age, sex, and genetic ancestry. They measured appendicular lean mass using bioimpedance – an electric current that flows at different rates through the body, depending on its composition.

In addition to the UK Biobank participants, the researchers drew on an independent sample of 21,982 people with AD; a control group of 41,944 people without AD; a replication sample of 7,329 people with and 252,879 people without AD to validate the findings; and 269,867 people taking part in a genome-wide study of cognitive performance.

The researchers identified 584 variants that met criteria for use as genetic proxies for lean mass. None were located within the APOE gene region. In the aggregate, these variants explained 10.3% of the variance in appendicular lean mass.

Each standard deviation increase in genetically proxied lean mass was associated with a 12% reduction in AD risk (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.82-0.95; P < .001). This finding was replicated in the independent consortium (OR, 0.91; 95% CI, 0.83-0.99; P = .02).

The findings remained “consistent” in sensitivity analyses.
 

A modifiable risk factor?

Higher appendicular lean mass was associated with higher levels of cognitive performance, with each SD increase in lean mass associated with an SD increase in cognitive performance (OR, 0.09; 95% CI, 0.06-0.11; P = .001).

“Adjusting for potential mediation through performance did not reduce the association between appendicular lean mass and risk of AD,” the authors wrote.

They obtained similar results using genetically proxied trunk and whole-body lean mass, after adjusting for fat mass.

The authors noted several limitations. The bioimpedance measures “only predict, but do not directly measure, lean mass.” Moreover, the approach didn’t examine whether a “critical window of risk factor timing” exists, during which lean mass might play a role in influencing AD risk and after which “interventions would no longer be effective.” Nor could the study determine whether increasing lean mass could reverse AD pathology in patients with preclinical disease or mild cognitive impairment.

Nevertheless, the findings suggest “that lean mass might be a possible modifiable protective factor for Alzheimer’s disease,” the authors wrote. “The mechanisms underlying this finding, as well as the clinical and public health implications, warrant further investigation.”
 

Novel strategies

In a comment, Iva Miljkovic, MD, PhD, associate professor, department of epidemiology, University of Pittsburgh, said the investigators used “very rigorous methodology.”

The finding suggesting that lean mass is associated with better cognitive function is “important, as cognitive impairment can become stable rather than progress to a pathological state; and, in some cases, can even be reversed.”

In those cases, “identifying the underlying cause – e.g., low lean mass – can significantly improve cognitive function,” said Dr. Miljkovic, senior author of a study showing muscle fat as a risk factor for cognitive decline.

More research will enable us to “expand our understanding” of the mechanisms involved and determine whether interventions aimed at preventing muscle loss and/or increasing muscle fat may have a beneficial effect on cognitive function,” she said. “This might lead to novel strategies to prevent AD.”

Dr. Daghlas is supported by the British Heart Foundation Centre of Research Excellence at Imperial College, London, and is employed part-time by Novo Nordisk. Dr. Miljkovic reports no relevant financial relationships.

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

Oral contraceptive (OC) use has been linked to increased depression risk, especially within the first 2 years following initiation, new research shows.

In addition, OC use in adolescence has been tied to an increased risk for depression later in life. However, some experts believe the study’s methodology may be flawed.

The investigators tracked more than 250,000 women from birth to menopause, gathering information about their use of combined contraceptive pills (progesterone and estrogen), the timing of the initial depression diagnosis, and the onset of depressive symptoms that were not formally diagnosed.

areeya_ann/Thinkstock

Women who began using these OCs before or at the age of 20 experienced a 130% higher incidence of depressive symptoms, whereas adult users saw a 92% increase. But the higher occurrence of depression tended to decline after the first 2 years of use, except in teenagers, who maintained an increased incidence of depression even after discontinuation.

This effect remained, even after analysis of potential familial confounding.

“Our findings suggest that the use of OCs, particularly during the first 2 years, increases the risk of depression. Additionally, OC use during adolescence might increase the risk of depression later in life,” Therese Johansson, of the department of immunology, genetics, and pathology, Science for Life Laboratory, Uppsala (Sweden) University, and colleagues wrote.

The study was published online in Epidemiology and Psychiatric Sciences.
 

Inconsistent findings

Previous studies suggest an association between adolescent use of hormonal contraceptives (HCs) and increased depression risk, but it’s “less clear” whether these effects are similar in adults, the authors wrote. Randomized clinical trials have “shown little or no effect” of HCs on mood. However, most of these studies didn’t consider previous use of HC.

The researchers wanted to estimate the incidence rate of depression associated with first initiation of OC use as well as the lifetime risk associated with use.

They studied 264,557 female participants in the UK Biobank (aged 37-71 years), collecting data from questionnaires, interviews, physical health measures, biological samples, imaging, and linked health records.

Most participants taking OCs had initiated use during the 1970s/early 1980s when second-generation OCs were predominantly used, consisting of levonorgestrel and ethinyl estradiol.

The researchers conducted a secondary outcome analysis on women who completed the UK Biobank Mental Health Questionnaire (MHQ) to evaluate depressive symptoms.

They estimated the associated risk for depression within 2 years after starting OCs in all women, as well as in groups stratified by age at initiation: before age 20 (adolescents) and age 20 and older (adults). In addition, the investigators estimated the lifetime risk for depression.

Time-dependent analysis compared the effect of OC use at initiation to the effect during the remaining years of use in recent and previous users.

They analyzed a subcohort of female siblings, utilizing “inference about causation from examination of familial confounding,” defined by the authors as a “regression-based approach for determining causality through the use of paired observational data collected from related individuals.”
 

Adolescents at highest risk

Of the participants, 80.6% had used OCs at some point.

The first 2 years of use were associated with a higher rate of depression among users, compared with never-users (hazard ration, 1.79; 95% confidence interval, 1.63-1.96). Although the risk became less pronounced after that, ever-use was still associated with increased lifetime risk for depression (HR, 1.05; 95% CI, 1.01-1.09).

Adolescents and adult OC users both experienced higher rates of depression during the first 2 years, with a more marked effect in adolescents than in adults (HR, 1.95; 95% CI, 1.64-2.32; and HR, 1.74; 95% CI, 1.54-1.95, respectively).

Previous users of OCs had a higher lifetime risk for depression, compared with never-users (HR, 1.05; 95% CI, 1.01-1.09).

Of the subcohort of women who completed the MHQ (n = 82,232), about half reported experiencing at least one of the core depressive symptoms.

OC initiation was associated with an increased risk for depressive symptoms during the first 2 years in ever- versus never-users (HR, 2.00; 95% CI, 1.91-2.10).

Those who began using OCs during adolescence had a dramatically higher rate of depressive symptoms, compared with never-users (HR, 2.30; 95% CI, 2.11-2.51), as did adult initiators (HR, 1.92; 95% CI, 2.11-2.51).

In the analysis of 7,354 first-degree sister pairs, 81% had initiated OCs. A sibling’s OC use was positively associated with a depression diagnosis, and the cosibling’s OC use was also associated with the sibling’s depression diagnosis. “These results support the hypothesis of a causal relationship between OC use and depression, such that OC use increases the risk of depression,” the authors wrote.

The main limitation is the potential for recall bias in the self-reported data, and that the UK Biobank sample consists of a healthier population than the overall U.K. population, which “hampers the generalizability” of the findings, the authors stated.
 

Flawed study

In a comment, Natalie Rasgon, MD, founder and director of the Stanford (Calif.) Center for Neuroscience in Women’s Health, said the study was “well researched” and “well written” but had “methodological issues.”

She questioned the sibling component, “which the researchers regard as confirming causality.” The effect may be “important but not causative.” Causality in people who are recalling retrospectively “is highly questionable by any adept researcher because it’s subject to memory. Different siblings may have different recall.”

The authors also didn’t study the indication for OC use. Several medical conditions are treated with OCs, including premenstrual dysphoric disorder, the “number one mood disorder among women of reproductive age.” Including this “could have made a huge difference in outcome data,” said Dr. Rasgon, who was not involved with the study.

Anne-Marie Amies Oelschlager, MD, professor of obstetrics and gynecology, University of Washington, Seattle, noted participants were asked to recall depressive symptoms and OC use as far back as 20-30 years ago, which lends itself to inaccurate recall.

And the researchers didn’t ascertain whether the contraceptives had been used continuously or had been started, stopped, and restarted. Nor did they look at different formulations and doses. And the observational nature of the study “limits the ability to infer causation,” continued Dr. Oelschlager, chair of the American College of Obstetrics and Gynecology Clinical Consensus Gynecology Committee. She was not involved with the study.

“This study is too flawed to use meaningfully in clinical practice,” Dr. Oelschlager concluded.

The study was primarily funded by the Swedish Research Council, the Swedish Brain Foundation, and the Uppsala University Center for Women ‘s Mental Health during the Reproductive Lifespan. The authors, Dr. Rasgon, and Dr. Oelschlager declared no relevant financial relationships.

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

Oral contraceptive (OC) use has been linked to increased depression risk, especially within the first 2 years following initiation, new research shows.

In addition, OC use in adolescence has been tied to an increased risk for depression later in life. However, some experts believe the study’s methodology may be flawed.

The investigators tracked more than 250,000 women from birth to menopause, gathering information about their use of combined contraceptive pills (progesterone and estrogen), the timing of the initial depression diagnosis, and the onset of depressive symptoms that were not formally diagnosed.

areeya_ann/Thinkstock

Women who began using these OCs before or at the age of 20 experienced a 130% higher incidence of depressive symptoms, whereas adult users saw a 92% increase. But the higher occurrence of depression tended to decline after the first 2 years of use, except in teenagers, who maintained an increased incidence of depression even after discontinuation.

This effect remained, even after analysis of potential familial confounding.

“Our findings suggest that the use of OCs, particularly during the first 2 years, increases the risk of depression. Additionally, OC use during adolescence might increase the risk of depression later in life,” Therese Johansson, of the department of immunology, genetics, and pathology, Science for Life Laboratory, Uppsala (Sweden) University, and colleagues wrote.

The study was published online in Epidemiology and Psychiatric Sciences.
 

Inconsistent findings

Previous studies suggest an association between adolescent use of hormonal contraceptives (HCs) and increased depression risk, but it’s “less clear” whether these effects are similar in adults, the authors wrote. Randomized clinical trials have “shown little or no effect” of HCs on mood. However, most of these studies didn’t consider previous use of HC.

The researchers wanted to estimate the incidence rate of depression associated with first initiation of OC use as well as the lifetime risk associated with use.

They studied 264,557 female participants in the UK Biobank (aged 37-71 years), collecting data from questionnaires, interviews, physical health measures, biological samples, imaging, and linked health records.

Most participants taking OCs had initiated use during the 1970s/early 1980s when second-generation OCs were predominantly used, consisting of levonorgestrel and ethinyl estradiol.

The researchers conducted a secondary outcome analysis on women who completed the UK Biobank Mental Health Questionnaire (MHQ) to evaluate depressive symptoms.

They estimated the associated risk for depression within 2 years after starting OCs in all women, as well as in groups stratified by age at initiation: before age 20 (adolescents) and age 20 and older (adults). In addition, the investigators estimated the lifetime risk for depression.

Time-dependent analysis compared the effect of OC use at initiation to the effect during the remaining years of use in recent and previous users.

They analyzed a subcohort of female siblings, utilizing “inference about causation from examination of familial confounding,” defined by the authors as a “regression-based approach for determining causality through the use of paired observational data collected from related individuals.”
 

Adolescents at highest risk

Of the participants, 80.6% had used OCs at some point.

The first 2 years of use were associated with a higher rate of depression among users, compared with never-users (hazard ration, 1.79; 95% confidence interval, 1.63-1.96). Although the risk became less pronounced after that, ever-use was still associated with increased lifetime risk for depression (HR, 1.05; 95% CI, 1.01-1.09).

Adolescents and adult OC users both experienced higher rates of depression during the first 2 years, with a more marked effect in adolescents than in adults (HR, 1.95; 95% CI, 1.64-2.32; and HR, 1.74; 95% CI, 1.54-1.95, respectively).

Previous users of OCs had a higher lifetime risk for depression, compared with never-users (HR, 1.05; 95% CI, 1.01-1.09).

Of the subcohort of women who completed the MHQ (n = 82,232), about half reported experiencing at least one of the core depressive symptoms.

OC initiation was associated with an increased risk for depressive symptoms during the first 2 years in ever- versus never-users (HR, 2.00; 95% CI, 1.91-2.10).

Those who began using OCs during adolescence had a dramatically higher rate of depressive symptoms, compared with never-users (HR, 2.30; 95% CI, 2.11-2.51), as did adult initiators (HR, 1.92; 95% CI, 2.11-2.51).

In the analysis of 7,354 first-degree sister pairs, 81% had initiated OCs. A sibling’s OC use was positively associated with a depression diagnosis, and the cosibling’s OC use was also associated with the sibling’s depression diagnosis. “These results support the hypothesis of a causal relationship between OC use and depression, such that OC use increases the risk of depression,” the authors wrote.

The main limitation is the potential for recall bias in the self-reported data, and that the UK Biobank sample consists of a healthier population than the overall U.K. population, which “hampers the generalizability” of the findings, the authors stated.
 

Flawed study

In a comment, Natalie Rasgon, MD, founder and director of the Stanford (Calif.) Center for Neuroscience in Women’s Health, said the study was “well researched” and “well written” but had “methodological issues.”

She questioned the sibling component, “which the researchers regard as confirming causality.” The effect may be “important but not causative.” Causality in people who are recalling retrospectively “is highly questionable by any adept researcher because it’s subject to memory. Different siblings may have different recall.”

The authors also didn’t study the indication for OC use. Several medical conditions are treated with OCs, including premenstrual dysphoric disorder, the “number one mood disorder among women of reproductive age.” Including this “could have made a huge difference in outcome data,” said Dr. Rasgon, who was not involved with the study.

Anne-Marie Amies Oelschlager, MD, professor of obstetrics and gynecology, University of Washington, Seattle, noted participants were asked to recall depressive symptoms and OC use as far back as 20-30 years ago, which lends itself to inaccurate recall.

And the researchers didn’t ascertain whether the contraceptives had been used continuously or had been started, stopped, and restarted. Nor did they look at different formulations and doses. And the observational nature of the study “limits the ability to infer causation,” continued Dr. Oelschlager, chair of the American College of Obstetrics and Gynecology Clinical Consensus Gynecology Committee. She was not involved with the study.

“This study is too flawed to use meaningfully in clinical practice,” Dr. Oelschlager concluded.

The study was primarily funded by the Swedish Research Council, the Swedish Brain Foundation, and the Uppsala University Center for Women ‘s Mental Health during the Reproductive Lifespan. The authors, Dr. Rasgon, and Dr. Oelschlager declared no relevant financial relationships.

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

Oral contraceptive (OC) use has been linked to increased depression risk, especially within the first 2 years following initiation, new research shows.

In addition, OC use in adolescence has been tied to an increased risk for depression later in life. However, some experts believe the study’s methodology may be flawed.

The investigators tracked more than 250,000 women from birth to menopause, gathering information about their use of combined contraceptive pills (progesterone and estrogen), the timing of the initial depression diagnosis, and the onset of depressive symptoms that were not formally diagnosed.

areeya_ann/Thinkstock

Women who began using these OCs before or at the age of 20 experienced a 130% higher incidence of depressive symptoms, whereas adult users saw a 92% increase. But the higher occurrence of depression tended to decline after the first 2 years of use, except in teenagers, who maintained an increased incidence of depression even after discontinuation.

This effect remained, even after analysis of potential familial confounding.

“Our findings suggest that the use of OCs, particularly during the first 2 years, increases the risk of depression. Additionally, OC use during adolescence might increase the risk of depression later in life,” Therese Johansson, of the department of immunology, genetics, and pathology, Science for Life Laboratory, Uppsala (Sweden) University, and colleagues wrote.

The study was published online in Epidemiology and Psychiatric Sciences.
 

Inconsistent findings

Previous studies suggest an association between adolescent use of hormonal contraceptives (HCs) and increased depression risk, but it’s “less clear” whether these effects are similar in adults, the authors wrote. Randomized clinical trials have “shown little or no effect” of HCs on mood. However, most of these studies didn’t consider previous use of HC.

The researchers wanted to estimate the incidence rate of depression associated with first initiation of OC use as well as the lifetime risk associated with use.

They studied 264,557 female participants in the UK Biobank (aged 37-71 years), collecting data from questionnaires, interviews, physical health measures, biological samples, imaging, and linked health records.

Most participants taking OCs had initiated use during the 1970s/early 1980s when second-generation OCs were predominantly used, consisting of levonorgestrel and ethinyl estradiol.

The researchers conducted a secondary outcome analysis on women who completed the UK Biobank Mental Health Questionnaire (MHQ) to evaluate depressive symptoms.

They estimated the associated risk for depression within 2 years after starting OCs in all women, as well as in groups stratified by age at initiation: before age 20 (adolescents) and age 20 and older (adults). In addition, the investigators estimated the lifetime risk for depression.

Time-dependent analysis compared the effect of OC use at initiation to the effect during the remaining years of use in recent and previous users.

They analyzed a subcohort of female siblings, utilizing “inference about causation from examination of familial confounding,” defined by the authors as a “regression-based approach for determining causality through the use of paired observational data collected from related individuals.”
 

Adolescents at highest risk

Of the participants, 80.6% had used OCs at some point.

The first 2 years of use were associated with a higher rate of depression among users, compared with never-users (hazard ration, 1.79; 95% confidence interval, 1.63-1.96). Although the risk became less pronounced after that, ever-use was still associated with increased lifetime risk for depression (HR, 1.05; 95% CI, 1.01-1.09).

Adolescents and adult OC users both experienced higher rates of depression during the first 2 years, with a more marked effect in adolescents than in adults (HR, 1.95; 95% CI, 1.64-2.32; and HR, 1.74; 95% CI, 1.54-1.95, respectively).

Previous users of OCs had a higher lifetime risk for depression, compared with never-users (HR, 1.05; 95% CI, 1.01-1.09).

Of the subcohort of women who completed the MHQ (n = 82,232), about half reported experiencing at least one of the core depressive symptoms.

OC initiation was associated with an increased risk for depressive symptoms during the first 2 years in ever- versus never-users (HR, 2.00; 95% CI, 1.91-2.10).

Those who began using OCs during adolescence had a dramatically higher rate of depressive symptoms, compared with never-users (HR, 2.30; 95% CI, 2.11-2.51), as did adult initiators (HR, 1.92; 95% CI, 2.11-2.51).

In the analysis of 7,354 first-degree sister pairs, 81% had initiated OCs. A sibling’s OC use was positively associated with a depression diagnosis, and the cosibling’s OC use was also associated with the sibling’s depression diagnosis. “These results support the hypothesis of a causal relationship between OC use and depression, such that OC use increases the risk of depression,” the authors wrote.

The main limitation is the potential for recall bias in the self-reported data, and that the UK Biobank sample consists of a healthier population than the overall U.K. population, which “hampers the generalizability” of the findings, the authors stated.
 

Flawed study

In a comment, Natalie Rasgon, MD, founder and director of the Stanford (Calif.) Center for Neuroscience in Women’s Health, said the study was “well researched” and “well written” but had “methodological issues.”

She questioned the sibling component, “which the researchers regard as confirming causality.” The effect may be “important but not causative.” Causality in people who are recalling retrospectively “is highly questionable by any adept researcher because it’s subject to memory. Different siblings may have different recall.”

The authors also didn’t study the indication for OC use. Several medical conditions are treated with OCs, including premenstrual dysphoric disorder, the “number one mood disorder among women of reproductive age.” Including this “could have made a huge difference in outcome data,” said Dr. Rasgon, who was not involved with the study.

Anne-Marie Amies Oelschlager, MD, professor of obstetrics and gynecology, University of Washington, Seattle, noted participants were asked to recall depressive symptoms and OC use as far back as 20-30 years ago, which lends itself to inaccurate recall.

And the researchers didn’t ascertain whether the contraceptives had been used continuously or had been started, stopped, and restarted. Nor did they look at different formulations and doses. And the observational nature of the study “limits the ability to infer causation,” continued Dr. Oelschlager, chair of the American College of Obstetrics and Gynecology Clinical Consensus Gynecology Committee. She was not involved with the study.

“This study is too flawed to use meaningfully in clinical practice,” Dr. Oelschlager concluded.

The study was primarily funded by the Swedish Research Council, the Swedish Brain Foundation, and the Uppsala University Center for Women ‘s Mental Health during the Reproductive Lifespan. The authors, Dr. Rasgon, and Dr. Oelschlager declared no relevant financial relationships.

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

While the typical dose of methotrexate (MTX) for inflammatory disease in pediatric patients varies in published studies, the maximum dose is considered to be 1 mg/kg and not to exceed 25 mg/week. In addition, test doses are not necessary for pediatric patients starting low dose (1 mg/kg or less) MTX for inflammatory skin disease, and the onset of efficacy with MTX may take 8-16 weeks.

Those are among 46 evidence- and consensus-based recommendations about the use of MTX for inflammatory skin disease in pediatric patients that were developed by a committee of 23 experts and published online in Pediatric Dermatology.

“Methotrexate is a cost-effective, readily accessible, well-tolerated, useful, and time-honored option for children with a spectrum of inflammatory skin diseases,” project cochair Elaine C. Siegfried, MD, professor of pediatrics and dermatology at Saint Louis University, told this news organization. “Although considered an ‘immune suppressant’ by some, it is more accurately classified as an immune modulator and has been widely used for more than 50 years, and remains the standard of care when administered at very high doses and intrathecally in children with acute lymphoblastic leukemia – a practice that supports safety. But many details that support optimized treatment are not widely appreciated.”

• MTX can be discontinued abruptly without adverse effects, other than the risk of disease worsening.
• Folic acid supplementation (starting at 1 mg/day, regardless of weight) is an effective approach to minimizing associated gastrointestinal adverse effects.
• Concomitant use of MTX and antibiotics (including trimethoprim-sulfamethoxazole) and NSAIDS are not contraindicated for most pediatric patients treated for inflammatory skin disease.
• Live virus vaccine boosters such as varicella-zoster virus (VZV) and measles, mumps, and rubella (MMR) are not contraindicated in patients taking MTX; there are insufficient data to make recommendations for or against primary immunization with MMR vaccine in patients taking MTX; inactivated vaccines should be given to patients taking MTX.
• Routine surveillance laboratory monitoring (i.e., CBC with differential, alanine transaminase, aspartate aminotransferase, creatinine) is recommended at baseline, after 1 month of treatment, and every 3-4 months thereafter.
• Transient transaminase elevation (≤ 3 upper limit normal for < 3 months) is not uncommon with low-dose MTX and does not usually require interruption of MTX. The most likely causes are concomitant viral infection, MTX dosing within 24 hours prior to phlebotomy, recent administration of other medications (such as acetaminophen), and/or recent alcohol consumption.
• Liver biopsy is not indicated for routine monitoring of pediatric patients taking low-dose MTX.

According to Dr. Siegfried, consensus of the committee members was lowest on the need for a test dose of MTX.

Overall, she said in the interview, helping to craft the guidelines caused her to reflect on how her approach to using MTX has evolved over the past 35 years, after treating “many hundreds” of patients. “I was gratified to confirm similar practice patterns among my colleagues,” she added.

The project’s other cochair was Heather Brandling-Bennett, MD, a dermatologist at Seattle Children’s Hospital. This work was supported by a grant from the Pediatric Dermatology Research Alliance (PeDRA), with additional funding from the National Eczema Association and the National Psoriasis Foundation. Dr. Siegfried disclosed ties with AbbVie, Boehringer Ingelheim, Incyte, LEO Pharma, Novan, Novartis, Pierre Fabre, Pfizer, Regeneron, Sanofi Genzyme, UCB, and Verrica. She has participated in contracted research for AI Therapeutics, and has served as principal investigator for Janssen. Many of the guideline coauthors disclosed having received grant support and other funding from pharmaceutical companies.

While the typical dose of methotrexate (MTX) for inflammatory disease in pediatric patients varies in published studies, the maximum dose is considered to be 1 mg/kg and not to exceed 25 mg/week. In addition, test doses are not necessary for pediatric patients starting low dose (1 mg/kg or less) MTX for inflammatory skin disease, and the onset of efficacy with MTX may take 8-16 weeks.

Those are among 46 evidence- and consensus-based recommendations about the use of MTX for inflammatory skin disease in pediatric patients that were developed by a committee of 23 experts and published online in Pediatric Dermatology.

“Methotrexate is a cost-effective, readily accessible, well-tolerated, useful, and time-honored option for children with a spectrum of inflammatory skin diseases,” project cochair Elaine C. Siegfried, MD, professor of pediatrics and dermatology at Saint Louis University, told this news organization. “Although considered an ‘immune suppressant’ by some, it is more accurately classified as an immune modulator and has been widely used for more than 50 years, and remains the standard of care when administered at very high doses and intrathecally in children with acute lymphoblastic leukemia – a practice that supports safety. But many details that support optimized treatment are not widely appreciated.”

• MTX can be discontinued abruptly without adverse effects, other than the risk of disease worsening.
• Folic acid supplementation (starting at 1 mg/day, regardless of weight) is an effective approach to minimizing associated gastrointestinal adverse effects.
• Concomitant use of MTX and antibiotics (including trimethoprim-sulfamethoxazole) and NSAIDS are not contraindicated for most pediatric patients treated for inflammatory skin disease.
• Live virus vaccine boosters such as varicella-zoster virus (VZV) and measles, mumps, and rubella (MMR) are not contraindicated in patients taking MTX; there are insufficient data to make recommendations for or against primary immunization with MMR vaccine in patients taking MTX; inactivated vaccines should be given to patients taking MTX.
• Routine surveillance laboratory monitoring (i.e., CBC with differential, alanine transaminase, aspartate aminotransferase, creatinine) is recommended at baseline, after 1 month of treatment, and every 3-4 months thereafter.
• Transient transaminase elevation (≤ 3 upper limit normal for < 3 months) is not uncommon with low-dose MTX and does not usually require interruption of MTX. The most likely causes are concomitant viral infection, MTX dosing within 24 hours prior to phlebotomy, recent administration of other medications (such as acetaminophen), and/or recent alcohol consumption.
• Liver biopsy is not indicated for routine monitoring of pediatric patients taking low-dose MTX.

According to Dr. Siegfried, consensus of the committee members was lowest on the need for a test dose of MTX.

Overall, she said in the interview, helping to craft the guidelines caused her to reflect on how her approach to using MTX has evolved over the past 35 years, after treating “many hundreds” of patients. “I was gratified to confirm similar practice patterns among my colleagues,” she added.

The project’s other cochair was Heather Brandling-Bennett, MD, a dermatologist at Seattle Children’s Hospital. This work was supported by a grant from the Pediatric Dermatology Research Alliance (PeDRA), with additional funding from the National Eczema Association and the National Psoriasis Foundation. Dr. Siegfried disclosed ties with AbbVie, Boehringer Ingelheim, Incyte, LEO Pharma, Novan, Novartis, Pierre Fabre, Pfizer, Regeneron, Sanofi Genzyme, UCB, and Verrica. She has participated in contracted research for AI Therapeutics, and has served as principal investigator for Janssen. Many of the guideline coauthors disclosed having received grant support and other funding from pharmaceutical companies.

While the typical dose of methotrexate (MTX) for inflammatory disease in pediatric patients varies in published studies, the maximum dose is considered to be 1 mg/kg and not to exceed 25 mg/week. In addition, test doses are not necessary for pediatric patients starting low dose (1 mg/kg or less) MTX for inflammatory skin disease, and the onset of efficacy with MTX may take 8-16 weeks.

Those are among 46 evidence- and consensus-based recommendations about the use of MTX for inflammatory skin disease in pediatric patients that were developed by a committee of 23 experts and published online in Pediatric Dermatology.

“Methotrexate is a cost-effective, readily accessible, well-tolerated, useful, and time-honored option for children with a spectrum of inflammatory skin diseases,” project cochair Elaine C. Siegfried, MD, professor of pediatrics and dermatology at Saint Louis University, told this news organization. “Although considered an ‘immune suppressant’ by some, it is more accurately classified as an immune modulator and has been widely used for more than 50 years, and remains the standard of care when administered at very high doses and intrathecally in children with acute lymphoblastic leukemia – a practice that supports safety. But many details that support optimized treatment are not widely appreciated.”

• MTX can be discontinued abruptly without adverse effects, other than the risk of disease worsening.
• Folic acid supplementation (starting at 1 mg/day, regardless of weight) is an effective approach to minimizing associated gastrointestinal adverse effects.
• Concomitant use of MTX and antibiotics (including trimethoprim-sulfamethoxazole) and NSAIDS are not contraindicated for most pediatric patients treated for inflammatory skin disease.
• Live virus vaccine boosters such as varicella-zoster virus (VZV) and measles, mumps, and rubella (MMR) are not contraindicated in patients taking MTX; there are insufficient data to make recommendations for or against primary immunization with MMR vaccine in patients taking MTX; inactivated vaccines should be given to patients taking MTX.
• Routine surveillance laboratory monitoring (i.e., CBC with differential, alanine transaminase, aspartate aminotransferase, creatinine) is recommended at baseline, after 1 month of treatment, and every 3-4 months thereafter.
• Transient transaminase elevation (≤ 3 upper limit normal for < 3 months) is not uncommon with low-dose MTX and does not usually require interruption of MTX. The most likely causes are concomitant viral infection, MTX dosing within 24 hours prior to phlebotomy, recent administration of other medications (such as acetaminophen), and/or recent alcohol consumption.
• Liver biopsy is not indicated for routine monitoring of pediatric patients taking low-dose MTX.

According to Dr. Siegfried, consensus of the committee members was lowest on the need for a test dose of MTX.

Overall, she said in the interview, helping to craft the guidelines caused her to reflect on how her approach to using MTX has evolved over the past 35 years, after treating “many hundreds” of patients. “I was gratified to confirm similar practice patterns among my colleagues,” she added.

The project’s other cochair was Heather Brandling-Bennett, MD, a dermatologist at Seattle Children’s Hospital. This work was supported by a grant from the Pediatric Dermatology Research Alliance (PeDRA), with additional funding from the National Eczema Association and the National Psoriasis Foundation. Dr. Siegfried disclosed ties with AbbVie, Boehringer Ingelheim, Incyte, LEO Pharma, Novan, Novartis, Pierre Fabre, Pfizer, Regeneron, Sanofi Genzyme, UCB, and Verrica. She has participated in contracted research for AI Therapeutics, and has served as principal investigator for Janssen. Many of the guideline coauthors disclosed having received grant support and other funding from pharmaceutical companies.

In 1927, American gynecologist John Sampson published his theory of the etiology of endometriosis, postulating that retrograde flow of endometrial debris flows backward through the fallopian tubes during menses into the peritoneal cavity. Dr. Sampson’s notion remains the main paradigm today, mentioned still in recent articles on the topic, but it has a flaw: Although the theory may account for how endometrial tissue escapes the uterus, a 1984 study revealed that this phenomenon occurs in 90% of women. Why, then, do only 10% of women suffer from endometriosis?

Endometriosis describes a condition in which endometrial tissue lining the uterus is found outside the uterus. The disease can be painful, even crippling. As many as 30% of women in their reproductive years who have endometriosis are infertile as a consequence. The hallmarks of the condition are superficial peritoneal lesions of varying color, cysts in the ovaries, deeper nodules accompanied by scarring and adhesion, primarily in the pelvis but sometimes appearing outside the pelvis. The syndrome can be challenging to identify, requiring laparoscopy for definitive diagnosis.

John Sampson aside, scientists have struggled for the past century to identify the cause, or causes, of endometriosis. Hormones clearly play a role in its development, and women with endometriosis have an elevated risk of clear-cell and endometrioid ovarian cancer and autoimmune diseases. Immunodeficiency also could be to blame, if a faulty immune system fails to find and remove endometrial tissue outside of the uterus. A class of chemicals known as endocrine disruptors have been linked to endometriosis, but not definitively. Twin studies have demonstrated that as many as 50% of cases have a genetic basis, while mice with surgically induced endometriosis have been found to have a higher ratio of harmful to beneficial bacteria in their gut.

Several studies published this year point to new insights into the old mystery – with possible implications for ways to treat the disorder.

Perhaps the most surprising came out earlier this year in Science Translational Medicine, as a team of researchers in Japan reported that invasive infection by bacteria of the genus Fusobacterium may cause at least some cases of endometriosis.

Is Fusobacterium the new Helicobacter pylori?

The researchers, from Nagoya University, are the first to suggest that not only might a single bacterial genus cause endometriosis, but that antibiotic treatment could prevent progression of the disease. Using endometrial tissue obtained from 79 women undergoing hysterectomy for endometriosis and 76 women undergoing hysterectomy for other reasons (such as cervical cancer), the team started with gene expression profiling to explore differences between the two sets of samples. 

They uncovered an interesting chain of cellular events:  macrophages found in endometriotic lesions were secreting transforming growth factor-beta (TGF-beta). TGF-beta in turn stimulated high levels of expression of a gene called TAGLN in fibroblast cells from women with endometriosis but not in fibroblasts from women without endometriosis. 

Turning on TAGLN transformed these previously inactive cells into active myofibroblasts, leading to increased proliferation, mobility, and attachment to mesothelial cells, the layer of cells that line body cavities and internal organs. In short, they identified some key players in an environment that seemed very favorable to the development of endometriosis.

“So, the question is: Why are macrophages activated?” said Yutaka Kondo, MD, PhD, the senior author of the study and a professor in the division of cancer biology at the Nagoya (Japan) University Graduate School of Medicine. “We think that there are always bacteria in the endometrium.”

After reviewing data from a previously published study, they used quantitative polymerase chain reaction to rule out one candidate, Erysipelothrix, but scored on their next attempt, identifying Fusobacterium species in endometrial tissue from 64% of the women with endometriosis, compared with fewer than 10% of the controls.

To confirm that the bacteria could cause disease and were not simply bystanders, Dr. Kondo’s team turned to a mouse model for endometriosis, in which endometrial cells are surgically removed from the uteri of mice and injected into the peritoneum of recipient mice, leading to the formation of endometriotic lesions. When mice received further injections of uterine tissue from mice that were infected with F. nucleatum, their lesions were more numerous when compared with mice that received injections of uninfected uterine tissue. Furthermore, antibiotic treatment with metronidazole or chloramphenicol immediately after surgery largely prevented progression to endometriosis, Dr. Kondo and his colleagues reported.

Dr. Kondo likened this relationship between Fusobacterium and endometriosis to that of the link between Helicobacter pylori and peptic ulcers but acknowledged that he doesn’t have all the answers.

“We need more clinical trials, and also we have to know what kind of treatment might be the most effective for the treatment of endometriosis,” Dr. Kondo said, pointing out that other therapies should still be pursued in addition to antibiotics, as not all the samples from women with endometriosis harbored Fusobacterium. “It might be possible that other mechanisms are also involved.”

Don’t write off gut microbiota

Ramakrishna Kommagani, PhD, associate professor of pathology and immunology at Baylor College of Medicine in Houston, agreed. “Endometriosis is a complex disease, which appears to be impacted by many factors, including genetic, epigenetic, and environmental factors,” Dr. Kommagani said.

Dr. Ramakrishna Kommagani, Baylor College of Medicine Photography Services

Clues in genetic variants

Krina Zondervan, DPhil, professor and head of the department of reproductive and genomic epidemiology at the University of Oxford (England), focuses on genomic, molecular, and epidemiologic approaches to understanding endometriosis.

What’s next?

The chief limitation of human studies looking at mechanisms of endometriosis is that they are correlational: Tissue samples are collected from women with and without endometriosis, often through an invasive procedure such as laparoscopy or biopsy, at one point in time. If a researcher identifies a factor that is more common in women with endometriosis – a particular bacterium or environmental exposure – proving causality is difficult. Currently, the best tools for proving causation are animal models of endometriosis, such as the those used by Dr. Kondo’s and Dr. Kommagani’s teams.

Better diagnostic tools would solve that problem. The ultimate goal is a noninvasive test for endometriosis that would allow clinicians to follow women over time and permit the monitoring of disease progression, or regression, without the need for painful procedures. Such a diagnostic tool would facilitate rigorous longitudinal studies evaluating mechanisms of disease, as well as monitoring outcomes of clinical trials of new treatments.

Could stool samples be the answer?

The Japanese team found that women harboring Fusobacterium in endometrial tissue also had Fusobacterium in vaginal samples taken at the time of their hysterectomy – and stool samples can pick up changes in the gut microbiome.

“Vaginal swab or stool tests are probably the best and easiest for noninvasive early detection,” Dr. Kommagani said. 

Spit tests for DNA would be even easier to obtain. Polygenic risk scores could be developed to estimate an individual’s risk of disease based on the number of variants, but Dr. Zondervan cautioned that not all the genes that account for endometriosis are known.

“The things that we found altogether explain about 5% of disease variability, basically – which is still not an awful lot,” she said.

Dr. Kondo’s work was supported by the Grant-in-Aid for Scientific Research, the Japan Society for the Promotion of Science, and the Research Grant of the Princess Takamatsu Cancer Research Fund. A patent method for detecting bacteria of genus Fusobacterium in order to diagnose endometriosis (WO2023/ 042714), was submitted (international publication date, March 23, 2023).

Dr. Kommagani’s work was funded, in part, by National Institutes of Health/National Institute of Child Health and Human Development grants R01HD102680, R01HD065435, and R00HD080742. He has no other conflicts of interest. Dr. Zondervan received funding from the Wellcome Trust (216767; 104036; 084766; 212904; 076113 and 085475) and also reported grants from Bayer AG, AbbVie, Volition Rx, MDNA Life Sciences, and Roche Diagnostics outside the submitted work.

Dr. Thomas is a pediatrician and epidemiologist living in Portland, Ore.

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

In 1927, American gynecologist John Sampson published his theory of the etiology of endometriosis, postulating that retrograde flow of endometrial debris flows backward through the fallopian tubes during menses into the peritoneal cavity. Dr. Sampson’s notion remains the main paradigm today, mentioned still in recent articles on the topic, but it has a flaw: Although the theory may account for how endometrial tissue escapes the uterus, a 1984 study revealed that this phenomenon occurs in 90% of women. Why, then, do only 10% of women suffer from endometriosis?

Endometriosis describes a condition in which endometrial tissue lining the uterus is found outside the uterus. The disease can be painful, even crippling. As many as 30% of women in their reproductive years who have endometriosis are infertile as a consequence. The hallmarks of the condition are superficial peritoneal lesions of varying color, cysts in the ovaries, deeper nodules accompanied by scarring and adhesion, primarily in the pelvis but sometimes appearing outside the pelvis. The syndrome can be challenging to identify, requiring laparoscopy for definitive diagnosis.

John Sampson aside, scientists have struggled for the past century to identify the cause, or causes, of endometriosis. Hormones clearly play a role in its development, and women with endometriosis have an elevated risk of clear-cell and endometrioid ovarian cancer and autoimmune diseases. Immunodeficiency also could be to blame, if a faulty immune system fails to find and remove endometrial tissue outside of the uterus. A class of chemicals known as endocrine disruptors have been linked to endometriosis, but not definitively. Twin studies have demonstrated that as many as 50% of cases have a genetic basis, while mice with surgically induced endometriosis have been found to have a higher ratio of harmful to beneficial bacteria in their gut.

Several studies published this year point to new insights into the old mystery – with possible implications for ways to treat the disorder.

Perhaps the most surprising came out earlier this year in Science Translational Medicine, as a team of researchers in Japan reported that invasive infection by bacteria of the genus Fusobacterium may cause at least some cases of endometriosis.

Is Fusobacterium the new Helicobacter pylori?

The researchers, from Nagoya University, are the first to suggest that not only might a single bacterial genus cause endometriosis, but that antibiotic treatment could prevent progression of the disease. Using endometrial tissue obtained from 79 women undergoing hysterectomy for endometriosis and 76 women undergoing hysterectomy for other reasons (such as cervical cancer), the team started with gene expression profiling to explore differences between the two sets of samples. 

They uncovered an interesting chain of cellular events:  macrophages found in endometriotic lesions were secreting transforming growth factor-beta (TGF-beta). TGF-beta in turn stimulated high levels of expression of a gene called TAGLN in fibroblast cells from women with endometriosis but not in fibroblasts from women without endometriosis. 

Turning on TAGLN transformed these previously inactive cells into active myofibroblasts, leading to increased proliferation, mobility, and attachment to mesothelial cells, the layer of cells that line body cavities and internal organs. In short, they identified some key players in an environment that seemed very favorable to the development of endometriosis.

“So, the question is: Why are macrophages activated?” said Yutaka Kondo, MD, PhD, the senior author of the study and a professor in the division of cancer biology at the Nagoya (Japan) University Graduate School of Medicine. “We think that there are always bacteria in the endometrium.”

After reviewing data from a previously published study, they used quantitative polymerase chain reaction to rule out one candidate, Erysipelothrix, but scored on their next attempt, identifying Fusobacterium species in endometrial tissue from 64% of the women with endometriosis, compared with fewer than 10% of the controls.

To confirm that the bacteria could cause disease and were not simply bystanders, Dr. Kondo’s team turned to a mouse model for endometriosis, in which endometrial cells are surgically removed from the uteri of mice and injected into the peritoneum of recipient mice, leading to the formation of endometriotic lesions. When mice received further injections of uterine tissue from mice that were infected with F. nucleatum, their lesions were more numerous when compared with mice that received injections of uninfected uterine tissue. Furthermore, antibiotic treatment with metronidazole or chloramphenicol immediately after surgery largely prevented progression to endometriosis, Dr. Kondo and his colleagues reported.

Dr. Kondo likened this relationship between Fusobacterium and endometriosis to that of the link between Helicobacter pylori and peptic ulcers but acknowledged that he doesn’t have all the answers.

“We need more clinical trials, and also we have to know what kind of treatment might be the most effective for the treatment of endometriosis,” Dr. Kondo said, pointing out that other therapies should still be pursued in addition to antibiotics, as not all the samples from women with endometriosis harbored Fusobacterium. “It might be possible that other mechanisms are also involved.”

Don’t write off gut microbiota

Ramakrishna Kommagani, PhD, associate professor of pathology and immunology at Baylor College of Medicine in Houston, agreed. “Endometriosis is a complex disease, which appears to be impacted by many factors, including genetic, epigenetic, and environmental factors,” Dr. Kommagani said.

Dr. Ramakrishna Kommagani, Baylor College of Medicine Photography Services

Clues in genetic variants

Krina Zondervan, DPhil, professor and head of the department of reproductive and genomic epidemiology at the University of Oxford (England), focuses on genomic, molecular, and epidemiologic approaches to understanding endometriosis.

What’s next?

The chief limitation of human studies looking at mechanisms of endometriosis is that they are correlational: Tissue samples are collected from women with and without endometriosis, often through an invasive procedure such as laparoscopy or biopsy, at one point in time. If a researcher identifies a factor that is more common in women with endometriosis – a particular bacterium or environmental exposure – proving causality is difficult. Currently, the best tools for proving causation are animal models of endometriosis, such as the those used by Dr. Kondo’s and Dr. Kommagani’s teams.

Better diagnostic tools would solve that problem. The ultimate goal is a noninvasive test for endometriosis that would allow clinicians to follow women over time and permit the monitoring of disease progression, or regression, without the need for painful procedures. Such a diagnostic tool would facilitate rigorous longitudinal studies evaluating mechanisms of disease, as well as monitoring outcomes of clinical trials of new treatments.

Could stool samples be the answer?

The Japanese team found that women harboring Fusobacterium in endometrial tissue also had Fusobacterium in vaginal samples taken at the time of their hysterectomy – and stool samples can pick up changes in the gut microbiome.

“Vaginal swab or stool tests are probably the best and easiest for noninvasive early detection,” Dr. Kommagani said. 

Spit tests for DNA would be even easier to obtain. Polygenic risk scores could be developed to estimate an individual’s risk of disease based on the number of variants, but Dr. Zondervan cautioned that not all the genes that account for endometriosis are known.

“The things that we found altogether explain about 5% of disease variability, basically – which is still not an awful lot,” she said.

Dr. Kondo’s work was supported by the Grant-in-Aid for Scientific Research, the Japan Society for the Promotion of Science, and the Research Grant of the Princess Takamatsu Cancer Research Fund. A patent method for detecting bacteria of genus Fusobacterium in order to diagnose endometriosis (WO2023/ 042714), was submitted (international publication date, March 23, 2023).

Dr. Kommagani’s work was funded, in part, by National Institutes of Health/National Institute of Child Health and Human Development grants R01HD102680, R01HD065435, and R00HD080742. He has no other conflicts of interest. Dr. Zondervan received funding from the Wellcome Trust (216767; 104036; 084766; 212904; 076113 and 085475) and also reported grants from Bayer AG, AbbVie, Volition Rx, MDNA Life Sciences, and Roche Diagnostics outside the submitted work.

Dr. Thomas is a pediatrician and epidemiologist living in Portland, Ore.

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

In 1927, American gynecologist John Sampson published his theory of the etiology of endometriosis, postulating that retrograde flow of endometrial debris flows backward through the fallopian tubes during menses into the peritoneal cavity. Dr. Sampson’s notion remains the main paradigm today, mentioned still in recent articles on the topic, but it has a flaw: Although the theory may account for how endometrial tissue escapes the uterus, a 1984 study revealed that this phenomenon occurs in 90% of women. Why, then, do only 10% of women suffer from endometriosis?

Endometriosis describes a condition in which endometrial tissue lining the uterus is found outside the uterus. The disease can be painful, even crippling. As many as 30% of women in their reproductive years who have endometriosis are infertile as a consequence. The hallmarks of the condition are superficial peritoneal lesions of varying color, cysts in the ovaries, deeper nodules accompanied by scarring and adhesion, primarily in the pelvis but sometimes appearing outside the pelvis. The syndrome can be challenging to identify, requiring laparoscopy for definitive diagnosis.

John Sampson aside, scientists have struggled for the past century to identify the cause, or causes, of endometriosis. Hormones clearly play a role in its development, and women with endometriosis have an elevated risk of clear-cell and endometrioid ovarian cancer and autoimmune diseases. Immunodeficiency also could be to blame, if a faulty immune system fails to find and remove endometrial tissue outside of the uterus. A class of chemicals known as endocrine disruptors have been linked to endometriosis, but not definitively. Twin studies have demonstrated that as many as 50% of cases have a genetic basis, while mice with surgically induced endometriosis have been found to have a higher ratio of harmful to beneficial bacteria in their gut.

Several studies published this year point to new insights into the old mystery – with possible implications for ways to treat the disorder.

Perhaps the most surprising came out earlier this year in Science Translational Medicine, as a team of researchers in Japan reported that invasive infection by bacteria of the genus Fusobacterium may cause at least some cases of endometriosis.

Is Fusobacterium the new Helicobacter pylori?

The researchers, from Nagoya University, are the first to suggest that not only might a single bacterial genus cause endometriosis, but that antibiotic treatment could prevent progression of the disease. Using endometrial tissue obtained from 79 women undergoing hysterectomy for endometriosis and 76 women undergoing hysterectomy for other reasons (such as cervical cancer), the team started with gene expression profiling to explore differences between the two sets of samples. 

They uncovered an interesting chain of cellular events:  macrophages found in endometriotic lesions were secreting transforming growth factor-beta (TGF-beta). TGF-beta in turn stimulated high levels of expression of a gene called TAGLN in fibroblast cells from women with endometriosis but not in fibroblasts from women without endometriosis. 

Turning on TAGLN transformed these previously inactive cells into active myofibroblasts, leading to increased proliferation, mobility, and attachment to mesothelial cells, the layer of cells that line body cavities and internal organs. In short, they identified some key players in an environment that seemed very favorable to the development of endometriosis.

“So, the question is: Why are macrophages activated?” said Yutaka Kondo, MD, PhD, the senior author of the study and a professor in the division of cancer biology at the Nagoya (Japan) University Graduate School of Medicine. “We think that there are always bacteria in the endometrium.”

After reviewing data from a previously published study, they used quantitative polymerase chain reaction to rule out one candidate, Erysipelothrix, but scored on their next attempt, identifying Fusobacterium species in endometrial tissue from 64% of the women with endometriosis, compared with fewer than 10% of the controls.

To confirm that the bacteria could cause disease and were not simply bystanders, Dr. Kondo’s team turned to a mouse model for endometriosis, in which endometrial cells are surgically removed from the uteri of mice and injected into the peritoneum of recipient mice, leading to the formation of endometriotic lesions. When mice received further injections of uterine tissue from mice that were infected with F. nucleatum, their lesions were more numerous when compared with mice that received injections of uninfected uterine tissue. Furthermore, antibiotic treatment with metronidazole or chloramphenicol immediately after surgery largely prevented progression to endometriosis, Dr. Kondo and his colleagues reported.

Dr. Kondo likened this relationship between Fusobacterium and endometriosis to that of the link between Helicobacter pylori and peptic ulcers but acknowledged that he doesn’t have all the answers.

“We need more clinical trials, and also we have to know what kind of treatment might be the most effective for the treatment of endometriosis,” Dr. Kondo said, pointing out that other therapies should still be pursued in addition to antibiotics, as not all the samples from women with endometriosis harbored Fusobacterium. “It might be possible that other mechanisms are also involved.”

Don’t write off gut microbiota

Ramakrishna Kommagani, PhD, associate professor of pathology and immunology at Baylor College of Medicine in Houston, agreed. “Endometriosis is a complex disease, which appears to be impacted by many factors, including genetic, epigenetic, and environmental factors,” Dr. Kommagani said.

Dr. Ramakrishna Kommagani, Baylor College of Medicine Photography Services

Clues in genetic variants

Krina Zondervan, DPhil, professor and head of the department of reproductive and genomic epidemiology at the University of Oxford (England), focuses on genomic, molecular, and epidemiologic approaches to understanding endometriosis.

What’s next?

The chief limitation of human studies looking at mechanisms of endometriosis is that they are correlational: Tissue samples are collected from women with and without endometriosis, often through an invasive procedure such as laparoscopy or biopsy, at one point in time. If a researcher identifies a factor that is more common in women with endometriosis – a particular bacterium or environmental exposure – proving causality is difficult. Currently, the best tools for proving causation are animal models of endometriosis, such as the those used by Dr. Kondo’s and Dr. Kommagani’s teams.

Better diagnostic tools would solve that problem. The ultimate goal is a noninvasive test for endometriosis that would allow clinicians to follow women over time and permit the monitoring of disease progression, or regression, without the need for painful procedures. Such a diagnostic tool would facilitate rigorous longitudinal studies evaluating mechanisms of disease, as well as monitoring outcomes of clinical trials of new treatments.

Could stool samples be the answer?

The Japanese team found that women harboring Fusobacterium in endometrial tissue also had Fusobacterium in vaginal samples taken at the time of their hysterectomy – and stool samples can pick up changes in the gut microbiome.

“Vaginal swab or stool tests are probably the best and easiest for noninvasive early detection,” Dr. Kommagani said. 

Spit tests for DNA would be even easier to obtain. Polygenic risk scores could be developed to estimate an individual’s risk of disease based on the number of variants, but Dr. Zondervan cautioned that not all the genes that account for endometriosis are known.

“The things that we found altogether explain about 5% of disease variability, basically – which is still not an awful lot,” she said.

Dr. Kondo’s work was supported by the Grant-in-Aid for Scientific Research, the Japan Society for the Promotion of Science, and the Research Grant of the Princess Takamatsu Cancer Research Fund. A patent method for detecting bacteria of genus Fusobacterium in order to diagnose endometriosis (WO2023/ 042714), was submitted (international publication date, March 23, 2023).

Dr. Kommagani’s work was funded, in part, by National Institutes of Health/National Institute of Child Health and Human Development grants R01HD102680, R01HD065435, and R00HD080742. He has no other conflicts of interest. Dr. Zondervan received funding from the Wellcome Trust (216767; 104036; 084766; 212904; 076113 and 085475) and also reported grants from Bayer AG, AbbVie, Volition Rx, MDNA Life Sciences, and Roche Diagnostics outside the submitted work.

Dr. Thomas is a pediatrician and epidemiologist living in Portland, Ore.

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

SAN DIEGO – An investigational allogeneic stem cell–derived pancreatic islet cell replacement therapy (VX-880, Vertex Pharmaceuticals) continues to show promise as a treatment for type 1 diabetes, according to the latest data, from six patients thus far.

Two of the six are insulin-independent beyond 1 year after receiving the VX-880 infusions, and three others who received them more recently are on a similar trajectory. One dropped out because of reasons unrelated to the therapy. The remaining five are continuing to receive immunosuppressive treatment to prevent rejection of the islets. The six all had undetectable insulin secretion, impaired hypoglycemic awareness, and severe hypoglycemia as the criterion to enter the phase 1/2 study.

“These new findings demonstrate the potential of stem cell–derived islets as a future treatment for patients with type 1 diabetes, signaling a new era that could potentially remove the need for exogenously administered insulin to achieve glycemic control,” said lead investigator Trevor W. Reichman, MD, PhD, surgical director of Pancreas and Islet Cell Transplantation at the University of Toronto.

Dr. Reichman presented the data at the annual scientific sessions of the American Diabetes Association, as an update to the report of the first two patients at last year’s ADA meeting. “We are hopeful that this first-of-its-kind research could be a game-changer for the treatment of type 1 diabetes,” he emphasized.

Co-investigator Maria Cristina Nostro, PhD, senior scientist at McEwen Stem Cell Institute, Toronto, told this news organization: “The clinical trial data are extremely exciting ... I think what was very beautiful is the glucose tolerance test where the insulin secretion was almost like a person without type 1 diabetes. For someone who is in the lab doing basic science research ... all the work we’ve put into this, it’s a labor of love. We’ve been trying to generate the cells for so long, and now to see this, it’s fantastic.”  
 

Two meet primary endpoint, three more on the right path

The six patients had a mean age of 44 years and mean 23 years’ diabetes duration. Three each were male and female. Their mean baseline A1c was 8.1%, and fasting C-peptide was undetectable. They had experienced a mean of 3.3 severe hypoglycemia episodes in the year prior to receiving the infusion, which was delivered to the portal vein similarly to the procedure with cadaveric donor islets, Dr. Reichman said.

The first two patients, including the one who dropped out, received half target doses of VX-880 (trial part A), while the rest, enrolled sequentially (part B), were each administered the full target dose of VX-880 given as a single infusion.

Induction with anti-thymocyte globulin and maintenance immunosuppressants, tacrolimus/sirolimus, was used to protect the cells from the recipient’s immune system. After the infusion, all six participants had C-peptide production, reduction in A1c despite reduced insulin use, and no severe hypoglycemia episodes from day 90 onwards.

Both participants with at least a year of follow-up met the criteria for the primary endpoint of A1c less than 7% with no severe hypoglycemic episodes. The first participant had an A1c of 5.3% at month 21, and the second 6.0% at 12 months. Both had sustained glucose-responsive insulin production with a mixed-meal tolerance test and exceeded the ADA target of more than 70% time-in blood glucose range assessed with continuous glucose monitoring.  
 

Safety: No major concerns thus far

Among all six, adverse events included elevations in the liver enzyme transaminase, occurring shortly after VX-880 infusion that were transient and resolved. No serious adverse events were considered related to the therapy.

Regarding safety, Dr. Nostro said, “With this trial, I have no concerns, because they’re using immunosuppression, so should anything go bad, you remove immunosuppression and the cells would be destroyed by the immune system. So it’s a perfect trial in a way.”

However, she noted, “Moving forward, as we develop something that will be genetically modified ... I think this is the future, because if you’re going to treat people with type 1 diabetes, we have to eliminate the immune suppression. I think the concern would be making sure the genetically modified cells are safe.”

Dr. Nostro, who gave an introductory presentation at the beginning of the symposium where the VX-880 data were presented, explained that in a current trial of genetically modified cells, “they’re placing the product inside a device so that the cells would be retrievable. It might not be perfect, but at least it’s going to tell us whether the genetically modified product is safe, which I think is what we need to use.”

In her talk, Dr. Nostro also summarized ongoing work in this field involving efforts to improve the generation of stem cell–derived islets with no “off target” non-beta cells to ensure consistency, optimization of engraftment, and elimination of immunosuppression. “[VX-880] is the beginning. This is the first product that’s going to be in the clinic, but I can imagine how 5, 10 years from now we will have different and more enhanced solutions for type 1 diabetes and who knows, maybe even for type 2.” 

Based on the data so far, the VX-880 trial is now moving to part C, in which 10 concurrently enrolled participants will receive the full target dose of the product. The trial, previously exclusively in the United States, has now expanded to additional sites in Norway, Switzerland, and the Netherlands. 

The study was funded by Vertex. Dr. Reichman is on advisory boards for Vertex and Sernova. Dr. Nostro was a consultant for Sigilon Therapeutics from 2018-2022, currently receives research support from Universal Cells, and has a patent licensed to Sernova.

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

SAN DIEGO – An investigational allogeneic stem cell–derived pancreatic islet cell replacement therapy (VX-880, Vertex Pharmaceuticals) continues to show promise as a treatment for type 1 diabetes, according to the latest data, from six patients thus far.

Two of the six are insulin-independent beyond 1 year after receiving the VX-880 infusions, and three others who received them more recently are on a similar trajectory. One dropped out because of reasons unrelated to the therapy. The remaining five are continuing to receive immunosuppressive treatment to prevent rejection of the islets. The six all had undetectable insulin secretion, impaired hypoglycemic awareness, and severe hypoglycemia as the criterion to enter the phase 1/2 study.

“These new findings demonstrate the potential of stem cell–derived islets as a future treatment for patients with type 1 diabetes, signaling a new era that could potentially remove the need for exogenously administered insulin to achieve glycemic control,” said lead investigator Trevor W. Reichman, MD, PhD, surgical director of Pancreas and Islet Cell Transplantation at the University of Toronto.

Dr. Reichman presented the data at the annual scientific sessions of the American Diabetes Association, as an update to the report of the first two patients at last year’s ADA meeting. “We are hopeful that this first-of-its-kind research could be a game-changer for the treatment of type 1 diabetes,” he emphasized.

Co-investigator Maria Cristina Nostro, PhD, senior scientist at McEwen Stem Cell Institute, Toronto, told this news organization: “The clinical trial data are extremely exciting ... I think what was very beautiful is the glucose tolerance test where the insulin secretion was almost like a person without type 1 diabetes. For someone who is in the lab doing basic science research ... all the work we’ve put into this, it’s a labor of love. We’ve been trying to generate the cells for so long, and now to see this, it’s fantastic.”  
 

Two meet primary endpoint, three more on the right path

The six patients had a mean age of 44 years and mean 23 years’ diabetes duration. Three each were male and female. Their mean baseline A1c was 8.1%, and fasting C-peptide was undetectable. They had experienced a mean of 3.3 severe hypoglycemia episodes in the year prior to receiving the infusion, which was delivered to the portal vein similarly to the procedure with cadaveric donor islets, Dr. Reichman said.

The first two patients, including the one who dropped out, received half target doses of VX-880 (trial part A), while the rest, enrolled sequentially (part B), were each administered the full target dose of VX-880 given as a single infusion.

Induction with anti-thymocyte globulin and maintenance immunosuppressants, tacrolimus/sirolimus, was used to protect the cells from the recipient’s immune system. After the infusion, all six participants had C-peptide production, reduction in A1c despite reduced insulin use, and no severe hypoglycemia episodes from day 90 onwards.

Both participants with at least a year of follow-up met the criteria for the primary endpoint of A1c less than 7% with no severe hypoglycemic episodes. The first participant had an A1c of 5.3% at month 21, and the second 6.0% at 12 months. Both had sustained glucose-responsive insulin production with a mixed-meal tolerance test and exceeded the ADA target of more than 70% time-in blood glucose range assessed with continuous glucose monitoring.  
 

Safety: No major concerns thus far

Among all six, adverse events included elevations in the liver enzyme transaminase, occurring shortly after VX-880 infusion that were transient and resolved. No serious adverse events were considered related to the therapy.

Regarding safety, Dr. Nostro said, “With this trial, I have no concerns, because they’re using immunosuppression, so should anything go bad, you remove immunosuppression and the cells would be destroyed by the immune system. So it’s a perfect trial in a way.”

However, she noted, “Moving forward, as we develop something that will be genetically modified ... I think this is the future, because if you’re going to treat people with type 1 diabetes, we have to eliminate the immune suppression. I think the concern would be making sure the genetically modified cells are safe.”

Dr. Nostro, who gave an introductory presentation at the beginning of the symposium where the VX-880 data were presented, explained that in a current trial of genetically modified cells, “they’re placing the product inside a device so that the cells would be retrievable. It might not be perfect, but at least it’s going to tell us whether the genetically modified product is safe, which I think is what we need to use.”

In her talk, Dr. Nostro also summarized ongoing work in this field involving efforts to improve the generation of stem cell–derived islets with no “off target” non-beta cells to ensure consistency, optimization of engraftment, and elimination of immunosuppression. “[VX-880] is the beginning. This is the first product that’s going to be in the clinic, but I can imagine how 5, 10 years from now we will have different and more enhanced solutions for type 1 diabetes and who knows, maybe even for type 2.” 

Based on the data so far, the VX-880 trial is now moving to part C, in which 10 concurrently enrolled participants will receive the full target dose of the product. The trial, previously exclusively in the United States, has now expanded to additional sites in Norway, Switzerland, and the Netherlands. 

The study was funded by Vertex. Dr. Reichman is on advisory boards for Vertex and Sernova. Dr. Nostro was a consultant for Sigilon Therapeutics from 2018-2022, currently receives research support from Universal Cells, and has a patent licensed to Sernova.

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

SAN DIEGO – An investigational allogeneic stem cell–derived pancreatic islet cell replacement therapy (VX-880, Vertex Pharmaceuticals) continues to show promise as a treatment for type 1 diabetes, according to the latest data, from six patients thus far.

Two of the six are insulin-independent beyond 1 year after receiving the VX-880 infusions, and three others who received them more recently are on a similar trajectory. One dropped out because of reasons unrelated to the therapy. The remaining five are continuing to receive immunosuppressive treatment to prevent rejection of the islets. The six all had undetectable insulin secretion, impaired hypoglycemic awareness, and severe hypoglycemia as the criterion to enter the phase 1/2 study.

“These new findings demonstrate the potential of stem cell–derived islets as a future treatment for patients with type 1 diabetes, signaling a new era that could potentially remove the need for exogenously administered insulin to achieve glycemic control,” said lead investigator Trevor W. Reichman, MD, PhD, surgical director of Pancreas and Islet Cell Transplantation at the University of Toronto.

Dr. Reichman presented the data at the annual scientific sessions of the American Diabetes Association, as an update to the report of the first two patients at last year’s ADA meeting. “We are hopeful that this first-of-its-kind research could be a game-changer for the treatment of type 1 diabetes,” he emphasized.

Co-investigator Maria Cristina Nostro, PhD, senior scientist at McEwen Stem Cell Institute, Toronto, told this news organization: “The clinical trial data are extremely exciting ... I think what was very beautiful is the glucose tolerance test where the insulin secretion was almost like a person without type 1 diabetes. For someone who is in the lab doing basic science research ... all the work we’ve put into this, it’s a labor of love. We’ve been trying to generate the cells for so long, and now to see this, it’s fantastic.”  
 

Two meet primary endpoint, three more on the right path

The six patients had a mean age of 44 years and mean 23 years’ diabetes duration. Three each were male and female. Their mean baseline A1c was 8.1%, and fasting C-peptide was undetectable. They had experienced a mean of 3.3 severe hypoglycemia episodes in the year prior to receiving the infusion, which was delivered to the portal vein similarly to the procedure with cadaveric donor islets, Dr. Reichman said.

The first two patients, including the one who dropped out, received half target doses of VX-880 (trial part A), while the rest, enrolled sequentially (part B), were each administered the full target dose of VX-880 given as a single infusion.

Induction with anti-thymocyte globulin and maintenance immunosuppressants, tacrolimus/sirolimus, was used to protect the cells from the recipient’s immune system. After the infusion, all six participants had C-peptide production, reduction in A1c despite reduced insulin use, and no severe hypoglycemia episodes from day 90 onwards.

Both participants with at least a year of follow-up met the criteria for the primary endpoint of A1c less than 7% with no severe hypoglycemic episodes. The first participant had an A1c of 5.3% at month 21, and the second 6.0% at 12 months. Both had sustained glucose-responsive insulin production with a mixed-meal tolerance test and exceeded the ADA target of more than 70% time-in blood glucose range assessed with continuous glucose monitoring.  
 

Safety: No major concerns thus far

Among all six, adverse events included elevations in the liver enzyme transaminase, occurring shortly after VX-880 infusion that were transient and resolved. No serious adverse events were considered related to the therapy.

Regarding safety, Dr. Nostro said, “With this trial, I have no concerns, because they’re using immunosuppression, so should anything go bad, you remove immunosuppression and the cells would be destroyed by the immune system. So it’s a perfect trial in a way.”

However, she noted, “Moving forward, as we develop something that will be genetically modified ... I think this is the future, because if you’re going to treat people with type 1 diabetes, we have to eliminate the immune suppression. I think the concern would be making sure the genetically modified cells are safe.”

Dr. Nostro, who gave an introductory presentation at the beginning of the symposium where the VX-880 data were presented, explained that in a current trial of genetically modified cells, “they’re placing the product inside a device so that the cells would be retrievable. It might not be perfect, but at least it’s going to tell us whether the genetically modified product is safe, which I think is what we need to use.”

In her talk, Dr. Nostro also summarized ongoing work in this field involving efforts to improve the generation of stem cell–derived islets with no “off target” non-beta cells to ensure consistency, optimization of engraftment, and elimination of immunosuppression. “[VX-880] is the beginning. This is the first product that’s going to be in the clinic, but I can imagine how 5, 10 years from now we will have different and more enhanced solutions for type 1 diabetes and who knows, maybe even for type 2.” 

Based on the data so far, the VX-880 trial is now moving to part C, in which 10 concurrently enrolled participants will receive the full target dose of the product. The trial, previously exclusively in the United States, has now expanded to additional sites in Norway, Switzerland, and the Netherlands. 

The study was funded by Vertex. Dr. Reichman is on advisory boards for Vertex and Sernova. Dr. Nostro was a consultant for Sigilon Therapeutics from 2018-2022, currently receives research support from Universal Cells, and has a patent licensed to Sernova.

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