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Erythropoietin falls short of neuroprotection in optic neuritis
“EPO conveyed neither functional nor structural neuroprotection in the visual pathways after optic neuritis as a clinically isolated syndrome,” said first author Wolf A. Lagreze, MD, of the University of Freiburg (Germany), in presenting the results at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
There are currently no treatments that provide neuroprotection for patients with optic neuritis, which can result in the degeneration of retinal ganglion cells, the axons of which form the optic nerve.
Although methylprednisolone, the standard treatment, can be of benefit, it has no effect in preventing neurodegeneration or subsequent vision impairment.
Importantly, optic neuritis, which can be a first sign of multiple sclerosis (MS), is considered an ideal model for an acute inflammatory attack on the nervous system and resulting neurodegeneration. Therefore, any treatment that provides neuroprotection for patients with optic neuritis could have potentially exciting broader implications.
The TONE trial
Preclinical studies have shown that EPO provides a small, potential degree of neuroprotection. To further evaluate EPO in this setting, Dr. Lagreze and colleagues conducted the TONE trial (Treatment of Optic Neuritis With Erythropoietin) in Germany between 2014 and 2017, in which they enrolled 108 patients with optic neuritis.
Inclusion criteria were having only unilateral optic neuritis as a clinically isolated syndrome that presented within 10 days of the first symptoms and having moderate to severe loss of visual acuity.
Persons with known MS were excluded; however, patients who were diagnosed with MS at the beginning of the study during the workup evaluation were included. Hence, about 20% of patients did have newly diagnosed MS, Dr. Lagreze noted.
The participants were randomly assigned in double-blind 1:1 ratio to receive treatment with either 33,000 IU EPO or placebo intravenously for 3 days as an adjunct to high-dose intravenous methylprednisolone (1,000 mg/day).
The final analysis included 52 patients who received EPO and 51 patients who received placebo. There were no significant differences between the groups in the first primary outcome of retinal nerve fiber layer atrophy, assessed with optic coherence tomography at week 26 (P = .76).
Likewise, no significant difference between groups was observed in the second primary outcome of low-contrast visual acuity at week 26, assessed using the 2.5% Sloan chart score of the affected eye (P = .38).
In addition, there were no significant differences between the groups in the rates of optic neuritis relapse.
In terms of safety measures, one patient in the EPO group developed sinus venous thrombosis, which was treated with anticoagulants and resolved without complications.
Reduced conversion to MS?
Interestingly, after 6 months, significantly fewer patients in the EPO arm (36%) had converted from clinically isolated syndrome to MS, compared with 57% in the placebo arm (P = .032). The difference became apparent as early as week 4.
Although those findings suggest that EPO provided some neuroprotection, there are notable caveats, Philippe Albrecht, MD, of the department of neurology at the University Hospital Dusseldorf (Germany), and a coauthor on the study, said.
“The significant separation of EPO and placebo group regarding MS conversion was observed very early on in the course and did not change thereafter,” Dr. Albrecht noted.
“One would expect a true disease-modifying effect of EPO on MS conversion to take longer to develop, and this early separation may very well have been due to an imbalance in the treatment groups, [for example] regarding MRI imaging findings such as gadolinium enhancement at baseline,” he said.
Dr. Lagreze said that it was a surprise to see no benefit from the drug, and a closer look at certain subgroups may still be worthwhile. Factors that could have a bearing on results include a shorter time interval for inclusion, having no concomitant use of steroids, and longer duration of treatment with EPO.
“If I could do the study again, I would do the treatment for longer than 3 days – that was based on experiences in previous EPO trials,” he said. “I would also love to do the trial without the concomitant methylprednisolone, but that is not possible from an ethical point of view.”
Trial nevertheless important
Commenting on the study, E. Anne Yeh, MD, of the division of neurology at the Hospital for Sick Children, Toronto, agreed that a challenge in evaluating therapies for optic neuritis is the potential for confounding from existing therapies that patients need to take.
“This agent could not be evaluated alone for its protective effect in comparison to no treatment at all,” she said.
In addition, improved metrics for gauging outcomes are needed to better determine the true effects, she added.
“The development of newer vision-related outcome metrics is important for future studies, and many are hard at work on both structural and functional metrics that may help us to understand the benefits of any protective therapies in a more nuanced manner than we are currently able to,” she said.
However, results of any kind – negative or positive – are valuable in improving understanding, Dr. Yeh underscored.
“Negative results can be disappointing in any trial, especially one in which alternative therapeutic pathways are being sought,” Dr. Yeh said. “I want to emphasize, however, that the fact that we are even considering and completing trials in this area is important.”
Dr. Yeh noted that she is currently involved in a trial that is evaluating the diabetes drug metformin for its remyelinating potential. “We hope to have some pilot data on MS in a few years,” she said.
Dr. Lagreze, Dr. Albrecht, and Dr. Yeh have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
“EPO conveyed neither functional nor structural neuroprotection in the visual pathways after optic neuritis as a clinically isolated syndrome,” said first author Wolf A. Lagreze, MD, of the University of Freiburg (Germany), in presenting the results at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
There are currently no treatments that provide neuroprotection for patients with optic neuritis, which can result in the degeneration of retinal ganglion cells, the axons of which form the optic nerve.
Although methylprednisolone, the standard treatment, can be of benefit, it has no effect in preventing neurodegeneration or subsequent vision impairment.
Importantly, optic neuritis, which can be a first sign of multiple sclerosis (MS), is considered an ideal model for an acute inflammatory attack on the nervous system and resulting neurodegeneration. Therefore, any treatment that provides neuroprotection for patients with optic neuritis could have potentially exciting broader implications.
The TONE trial
Preclinical studies have shown that EPO provides a small, potential degree of neuroprotection. To further evaluate EPO in this setting, Dr. Lagreze and colleagues conducted the TONE trial (Treatment of Optic Neuritis With Erythropoietin) in Germany between 2014 and 2017, in which they enrolled 108 patients with optic neuritis.
Inclusion criteria were having only unilateral optic neuritis as a clinically isolated syndrome that presented within 10 days of the first symptoms and having moderate to severe loss of visual acuity.
Persons with known MS were excluded; however, patients who were diagnosed with MS at the beginning of the study during the workup evaluation were included. Hence, about 20% of patients did have newly diagnosed MS, Dr. Lagreze noted.
The participants were randomly assigned in double-blind 1:1 ratio to receive treatment with either 33,000 IU EPO or placebo intravenously for 3 days as an adjunct to high-dose intravenous methylprednisolone (1,000 mg/day).
The final analysis included 52 patients who received EPO and 51 patients who received placebo. There were no significant differences between the groups in the first primary outcome of retinal nerve fiber layer atrophy, assessed with optic coherence tomography at week 26 (P = .76).
Likewise, no significant difference between groups was observed in the second primary outcome of low-contrast visual acuity at week 26, assessed using the 2.5% Sloan chart score of the affected eye (P = .38).
In addition, there were no significant differences between the groups in the rates of optic neuritis relapse.
In terms of safety measures, one patient in the EPO group developed sinus venous thrombosis, which was treated with anticoagulants and resolved without complications.
Reduced conversion to MS?
Interestingly, after 6 months, significantly fewer patients in the EPO arm (36%) had converted from clinically isolated syndrome to MS, compared with 57% in the placebo arm (P = .032). The difference became apparent as early as week 4.
Although those findings suggest that EPO provided some neuroprotection, there are notable caveats, Philippe Albrecht, MD, of the department of neurology at the University Hospital Dusseldorf (Germany), and a coauthor on the study, said.
“The significant separation of EPO and placebo group regarding MS conversion was observed very early on in the course and did not change thereafter,” Dr. Albrecht noted.
“One would expect a true disease-modifying effect of EPO on MS conversion to take longer to develop, and this early separation may very well have been due to an imbalance in the treatment groups, [for example] regarding MRI imaging findings such as gadolinium enhancement at baseline,” he said.
Dr. Lagreze said that it was a surprise to see no benefit from the drug, and a closer look at certain subgroups may still be worthwhile. Factors that could have a bearing on results include a shorter time interval for inclusion, having no concomitant use of steroids, and longer duration of treatment with EPO.
“If I could do the study again, I would do the treatment for longer than 3 days – that was based on experiences in previous EPO trials,” he said. “I would also love to do the trial without the concomitant methylprednisolone, but that is not possible from an ethical point of view.”
Trial nevertheless important
Commenting on the study, E. Anne Yeh, MD, of the division of neurology at the Hospital for Sick Children, Toronto, agreed that a challenge in evaluating therapies for optic neuritis is the potential for confounding from existing therapies that patients need to take.
“This agent could not be evaluated alone for its protective effect in comparison to no treatment at all,” she said.
In addition, improved metrics for gauging outcomes are needed to better determine the true effects, she added.
“The development of newer vision-related outcome metrics is important for future studies, and many are hard at work on both structural and functional metrics that may help us to understand the benefits of any protective therapies in a more nuanced manner than we are currently able to,” she said.
However, results of any kind – negative or positive – are valuable in improving understanding, Dr. Yeh underscored.
“Negative results can be disappointing in any trial, especially one in which alternative therapeutic pathways are being sought,” Dr. Yeh said. “I want to emphasize, however, that the fact that we are even considering and completing trials in this area is important.”
Dr. Yeh noted that she is currently involved in a trial that is evaluating the diabetes drug metformin for its remyelinating potential. “We hope to have some pilot data on MS in a few years,” she said.
Dr. Lagreze, Dr. Albrecht, and Dr. Yeh have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
“EPO conveyed neither functional nor structural neuroprotection in the visual pathways after optic neuritis as a clinically isolated syndrome,” said first author Wolf A. Lagreze, MD, of the University of Freiburg (Germany), in presenting the results at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
There are currently no treatments that provide neuroprotection for patients with optic neuritis, which can result in the degeneration of retinal ganglion cells, the axons of which form the optic nerve.
Although methylprednisolone, the standard treatment, can be of benefit, it has no effect in preventing neurodegeneration or subsequent vision impairment.
Importantly, optic neuritis, which can be a first sign of multiple sclerosis (MS), is considered an ideal model for an acute inflammatory attack on the nervous system and resulting neurodegeneration. Therefore, any treatment that provides neuroprotection for patients with optic neuritis could have potentially exciting broader implications.
The TONE trial
Preclinical studies have shown that EPO provides a small, potential degree of neuroprotection. To further evaluate EPO in this setting, Dr. Lagreze and colleagues conducted the TONE trial (Treatment of Optic Neuritis With Erythropoietin) in Germany between 2014 and 2017, in which they enrolled 108 patients with optic neuritis.
Inclusion criteria were having only unilateral optic neuritis as a clinically isolated syndrome that presented within 10 days of the first symptoms and having moderate to severe loss of visual acuity.
Persons with known MS were excluded; however, patients who were diagnosed with MS at the beginning of the study during the workup evaluation were included. Hence, about 20% of patients did have newly diagnosed MS, Dr. Lagreze noted.
The participants were randomly assigned in double-blind 1:1 ratio to receive treatment with either 33,000 IU EPO or placebo intravenously for 3 days as an adjunct to high-dose intravenous methylprednisolone (1,000 mg/day).
The final analysis included 52 patients who received EPO and 51 patients who received placebo. There were no significant differences between the groups in the first primary outcome of retinal nerve fiber layer atrophy, assessed with optic coherence tomography at week 26 (P = .76).
Likewise, no significant difference between groups was observed in the second primary outcome of low-contrast visual acuity at week 26, assessed using the 2.5% Sloan chart score of the affected eye (P = .38).
In addition, there were no significant differences between the groups in the rates of optic neuritis relapse.
In terms of safety measures, one patient in the EPO group developed sinus venous thrombosis, which was treated with anticoagulants and resolved without complications.
Reduced conversion to MS?
Interestingly, after 6 months, significantly fewer patients in the EPO arm (36%) had converted from clinically isolated syndrome to MS, compared with 57% in the placebo arm (P = .032). The difference became apparent as early as week 4.
Although those findings suggest that EPO provided some neuroprotection, there are notable caveats, Philippe Albrecht, MD, of the department of neurology at the University Hospital Dusseldorf (Germany), and a coauthor on the study, said.
“The significant separation of EPO and placebo group regarding MS conversion was observed very early on in the course and did not change thereafter,” Dr. Albrecht noted.
“One would expect a true disease-modifying effect of EPO on MS conversion to take longer to develop, and this early separation may very well have been due to an imbalance in the treatment groups, [for example] regarding MRI imaging findings such as gadolinium enhancement at baseline,” he said.
Dr. Lagreze said that it was a surprise to see no benefit from the drug, and a closer look at certain subgroups may still be worthwhile. Factors that could have a bearing on results include a shorter time interval for inclusion, having no concomitant use of steroids, and longer duration of treatment with EPO.
“If I could do the study again, I would do the treatment for longer than 3 days – that was based on experiences in previous EPO trials,” he said. “I would also love to do the trial without the concomitant methylprednisolone, but that is not possible from an ethical point of view.”
Trial nevertheless important
Commenting on the study, E. Anne Yeh, MD, of the division of neurology at the Hospital for Sick Children, Toronto, agreed that a challenge in evaluating therapies for optic neuritis is the potential for confounding from existing therapies that patients need to take.
“This agent could not be evaluated alone for its protective effect in comparison to no treatment at all,” she said.
In addition, improved metrics for gauging outcomes are needed to better determine the true effects, she added.
“The development of newer vision-related outcome metrics is important for future studies, and many are hard at work on both structural and functional metrics that may help us to understand the benefits of any protective therapies in a more nuanced manner than we are currently able to,” she said.
However, results of any kind – negative or positive – are valuable in improving understanding, Dr. Yeh underscored.
“Negative results can be disappointing in any trial, especially one in which alternative therapeutic pathways are being sought,” Dr. Yeh said. “I want to emphasize, however, that the fact that we are even considering and completing trials in this area is important.”
Dr. Yeh noted that she is currently involved in a trial that is evaluating the diabetes drug metformin for its remyelinating potential. “We hope to have some pilot data on MS in a few years,” she said.
Dr. Lagreze, Dr. Albrecht, and Dr. Yeh have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ACTRIMS FORUM 2021
Natalizumab postinfusion reactions rare; is monitoring necessary?
new studies show.
Collectively, the results suggest the need to rethink the drug’s mandatory 1-hour postinfusion observation period – particularly when unnecessarily spending time in medical settings is discouraged because of concerns regarding COVID-19, the researchers concluded.
Their findings “highlight a potential opportunity to improve and streamline the infusion and postinfusion monitoring process,” reported the authors of one of the studies. The findings were presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Infusion reactions were rare
“In this systematic review of almost 10,000 natalizumab infusions, all infusion-related adverse events were mild, and no clinically relevant safety concerns were associated with natalizumab infusions,” they said.
The 1-hour postinfusion observation period for natalizumab, approved for the treatment of relapsing remitting MS (RRMS), is mandated by the Food and Drug Administration, as well as the European Medicines Agency, and applies to each dose, regardless of treatment duration, owing to concerns of infusion reactions. However, previous evidence has indicated that reactions are rare and are usually mild.
In addition to adding burden to the treatment regimen for patients and providers alike, any extended time in an environment where there is concern of heightened risk for SARS-CoV-2 exposure is a concern.
To evaluate the frequency, severity, and timing of infusion reactions, Yujie Wang, MD, of the department of neurology at the University of Washington, Seattle, and colleagues reviewed medical records of all patients who received natalizumab at the University of Washington MS Center’s infusion suite between July 2012 and September 2020.
Among 333 patients with RRMS, 9,682 infusions of natalizumab were provided over the study period, with a mean of 27 infusions per patient (range, 1-174). The mean age of the patients was 41 years, and 87 (26%) were male.
Overall, 33 infusion-related adverse events were reported in 26 patients, representing 0.34% of total infusions and 7.8% of patients.
In 77% of cases, the adverse event occurred during the infusion. In 92% of cases, the adverse event occurred within the first 6 months of treatment.
All of the events were described as mild. The most common were itching, gastrointestinal problems, headache, and flushing.
None of the reactions required emergency care or hospitalization. Symptoms were either self-managed or were managed easily with standard care. The treatment was continued in all cases.
“For physicians and providers who care for patients with MS and are comfortable with infusible therapies, it is no surprise that rates of clinically significant infusion reactions were low,” Dr. Wang said. “It is indeed consistent with prior studies that reactions generally occur during rather than post infusion.”
The authors underscored the array of potential benefits in making changes to the requirement. “Anticipated benefits may include reducing SARS-CoV2 exposure risks for patients and staff, reducing patients’ treatment burden, increasing efficiency, as well as improving access to care without neglecting patient safety.”
Additional studies show consistent findings
Several other recent studies have shown similar results. In a study published in Multiple Sclerosis in October 2020, researchers with the Amsterdam University Medical Center found that, among 14,174 natalizumab infusions provided to 225 patients with RRMS between 2006 and 2018, 276 infusion-related adverse events occurred (1.95%) among 60 patients.
There were 11 severe infusion-related adverse events in nine patients (4.0%). All documented severe reactions occurred during the infusion. Among 19 moderate adverse events, 17 occurred during the infusion.
The researchers noted that the majority of patients who experienced severe infusion reactions had detectable antibodies against natalizumab. Such antibodies are associated with a higher risk for infusion-related adverse events.
Patients who did not have any symptoms of a reaction during the infusion had no clinically relevant moderate or severe reactions.
“Thus, the need for postinfusion observation will depend on the patients’ clinical status during the infusion,” they wrote. “Consequently, our data suggest that patients who do not have an infusion-related adverse event while receiving natalizumab treatment do not need to stay in the hospital for an additional observation hour.”
Rapid infusion protocol
In another recent study published in Multiple Sclerosis and Related Disorders in January 2021, researchers in Australia reported on the use of a rapid infusion protocol of natalizumab and ocrelizumab. The protocol was implemented to reduce the amount of time patients are required to spend in clinical settings during the COVID-19 pandemic.
In their analysis of 269 rapid infusions of natalizumab and 100 rapid infusions of ocrelizumab, there were two infusion-related reactions in the natalizumab group and eight in the ocrelizumab group.
All the reactions were mild to moderate, and no discontinuations were required. None of the reactions occurred during the postinfusion observation period.
“In the setting of COVID-19 pandemic, rapid infusion protocols could potentially save hospital resources and limit patient exposure to a high-risk clinical setting while still maintaining ongoing treatment of multiple sclerosis,” the authors wrote.
Under the rapid infusion protocol, patients receive three standard doses for 1 hour followed by 30 minutes of observation. In addition, infusions are reduced to 30 minutes, explained lead author Louise Rath, of clinical neurosciences, Alfred Health, in Melbourne.
“For our cohort of patients, the side effects were minimal,” she said.
“Rapid infusions allowed patients to have option of hospital in-home or office, ensuring work was not at risk by infusion,” she added. “Our governance has been very supportive, and we will be keeping rapid infusion post COVID.”
The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new studies show.
Collectively, the results suggest the need to rethink the drug’s mandatory 1-hour postinfusion observation period – particularly when unnecessarily spending time in medical settings is discouraged because of concerns regarding COVID-19, the researchers concluded.
Their findings “highlight a potential opportunity to improve and streamline the infusion and postinfusion monitoring process,” reported the authors of one of the studies. The findings were presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Infusion reactions were rare
“In this systematic review of almost 10,000 natalizumab infusions, all infusion-related adverse events were mild, and no clinically relevant safety concerns were associated with natalizumab infusions,” they said.
The 1-hour postinfusion observation period for natalizumab, approved for the treatment of relapsing remitting MS (RRMS), is mandated by the Food and Drug Administration, as well as the European Medicines Agency, and applies to each dose, regardless of treatment duration, owing to concerns of infusion reactions. However, previous evidence has indicated that reactions are rare and are usually mild.
In addition to adding burden to the treatment regimen for patients and providers alike, any extended time in an environment where there is concern of heightened risk for SARS-CoV-2 exposure is a concern.
To evaluate the frequency, severity, and timing of infusion reactions, Yujie Wang, MD, of the department of neurology at the University of Washington, Seattle, and colleagues reviewed medical records of all patients who received natalizumab at the University of Washington MS Center’s infusion suite between July 2012 and September 2020.
Among 333 patients with RRMS, 9,682 infusions of natalizumab were provided over the study period, with a mean of 27 infusions per patient (range, 1-174). The mean age of the patients was 41 years, and 87 (26%) were male.
Overall, 33 infusion-related adverse events were reported in 26 patients, representing 0.34% of total infusions and 7.8% of patients.
In 77% of cases, the adverse event occurred during the infusion. In 92% of cases, the adverse event occurred within the first 6 months of treatment.
All of the events were described as mild. The most common were itching, gastrointestinal problems, headache, and flushing.
None of the reactions required emergency care or hospitalization. Symptoms were either self-managed or were managed easily with standard care. The treatment was continued in all cases.
“For physicians and providers who care for patients with MS and are comfortable with infusible therapies, it is no surprise that rates of clinically significant infusion reactions were low,” Dr. Wang said. “It is indeed consistent with prior studies that reactions generally occur during rather than post infusion.”
The authors underscored the array of potential benefits in making changes to the requirement. “Anticipated benefits may include reducing SARS-CoV2 exposure risks for patients and staff, reducing patients’ treatment burden, increasing efficiency, as well as improving access to care without neglecting patient safety.”
Additional studies show consistent findings
Several other recent studies have shown similar results. In a study published in Multiple Sclerosis in October 2020, researchers with the Amsterdam University Medical Center found that, among 14,174 natalizumab infusions provided to 225 patients with RRMS between 2006 and 2018, 276 infusion-related adverse events occurred (1.95%) among 60 patients.
There were 11 severe infusion-related adverse events in nine patients (4.0%). All documented severe reactions occurred during the infusion. Among 19 moderate adverse events, 17 occurred during the infusion.
The researchers noted that the majority of patients who experienced severe infusion reactions had detectable antibodies against natalizumab. Such antibodies are associated with a higher risk for infusion-related adverse events.
Patients who did not have any symptoms of a reaction during the infusion had no clinically relevant moderate or severe reactions.
“Thus, the need for postinfusion observation will depend on the patients’ clinical status during the infusion,” they wrote. “Consequently, our data suggest that patients who do not have an infusion-related adverse event while receiving natalizumab treatment do not need to stay in the hospital for an additional observation hour.”
Rapid infusion protocol
In another recent study published in Multiple Sclerosis and Related Disorders in January 2021, researchers in Australia reported on the use of a rapid infusion protocol of natalizumab and ocrelizumab. The protocol was implemented to reduce the amount of time patients are required to spend in clinical settings during the COVID-19 pandemic.
In their analysis of 269 rapid infusions of natalizumab and 100 rapid infusions of ocrelizumab, there were two infusion-related reactions in the natalizumab group and eight in the ocrelizumab group.
All the reactions were mild to moderate, and no discontinuations were required. None of the reactions occurred during the postinfusion observation period.
“In the setting of COVID-19 pandemic, rapid infusion protocols could potentially save hospital resources and limit patient exposure to a high-risk clinical setting while still maintaining ongoing treatment of multiple sclerosis,” the authors wrote.
Under the rapid infusion protocol, patients receive three standard doses for 1 hour followed by 30 minutes of observation. In addition, infusions are reduced to 30 minutes, explained lead author Louise Rath, of clinical neurosciences, Alfred Health, in Melbourne.
“For our cohort of patients, the side effects were minimal,” she said.
“Rapid infusions allowed patients to have option of hospital in-home or office, ensuring work was not at risk by infusion,” she added. “Our governance has been very supportive, and we will be keeping rapid infusion post COVID.”
The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new studies show.
Collectively, the results suggest the need to rethink the drug’s mandatory 1-hour postinfusion observation period – particularly when unnecessarily spending time in medical settings is discouraged because of concerns regarding COVID-19, the researchers concluded.
Their findings “highlight a potential opportunity to improve and streamline the infusion and postinfusion monitoring process,” reported the authors of one of the studies. The findings were presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Infusion reactions were rare
“In this systematic review of almost 10,000 natalizumab infusions, all infusion-related adverse events were mild, and no clinically relevant safety concerns were associated with natalizumab infusions,” they said.
The 1-hour postinfusion observation period for natalizumab, approved for the treatment of relapsing remitting MS (RRMS), is mandated by the Food and Drug Administration, as well as the European Medicines Agency, and applies to each dose, regardless of treatment duration, owing to concerns of infusion reactions. However, previous evidence has indicated that reactions are rare and are usually mild.
In addition to adding burden to the treatment regimen for patients and providers alike, any extended time in an environment where there is concern of heightened risk for SARS-CoV-2 exposure is a concern.
To evaluate the frequency, severity, and timing of infusion reactions, Yujie Wang, MD, of the department of neurology at the University of Washington, Seattle, and colleagues reviewed medical records of all patients who received natalizumab at the University of Washington MS Center’s infusion suite between July 2012 and September 2020.
Among 333 patients with RRMS, 9,682 infusions of natalizumab were provided over the study period, with a mean of 27 infusions per patient (range, 1-174). The mean age of the patients was 41 years, and 87 (26%) were male.
Overall, 33 infusion-related adverse events were reported in 26 patients, representing 0.34% of total infusions and 7.8% of patients.
In 77% of cases, the adverse event occurred during the infusion. In 92% of cases, the adverse event occurred within the first 6 months of treatment.
All of the events were described as mild. The most common were itching, gastrointestinal problems, headache, and flushing.
None of the reactions required emergency care or hospitalization. Symptoms were either self-managed or were managed easily with standard care. The treatment was continued in all cases.
“For physicians and providers who care for patients with MS and are comfortable with infusible therapies, it is no surprise that rates of clinically significant infusion reactions were low,” Dr. Wang said. “It is indeed consistent with prior studies that reactions generally occur during rather than post infusion.”
The authors underscored the array of potential benefits in making changes to the requirement. “Anticipated benefits may include reducing SARS-CoV2 exposure risks for patients and staff, reducing patients’ treatment burden, increasing efficiency, as well as improving access to care without neglecting patient safety.”
Additional studies show consistent findings
Several other recent studies have shown similar results. In a study published in Multiple Sclerosis in October 2020, researchers with the Amsterdam University Medical Center found that, among 14,174 natalizumab infusions provided to 225 patients with RRMS between 2006 and 2018, 276 infusion-related adverse events occurred (1.95%) among 60 patients.
There were 11 severe infusion-related adverse events in nine patients (4.0%). All documented severe reactions occurred during the infusion. Among 19 moderate adverse events, 17 occurred during the infusion.
The researchers noted that the majority of patients who experienced severe infusion reactions had detectable antibodies against natalizumab. Such antibodies are associated with a higher risk for infusion-related adverse events.
Patients who did not have any symptoms of a reaction during the infusion had no clinically relevant moderate or severe reactions.
“Thus, the need for postinfusion observation will depend on the patients’ clinical status during the infusion,” they wrote. “Consequently, our data suggest that patients who do not have an infusion-related adverse event while receiving natalizumab treatment do not need to stay in the hospital for an additional observation hour.”
Rapid infusion protocol
In another recent study published in Multiple Sclerosis and Related Disorders in January 2021, researchers in Australia reported on the use of a rapid infusion protocol of natalizumab and ocrelizumab. The protocol was implemented to reduce the amount of time patients are required to spend in clinical settings during the COVID-19 pandemic.
In their analysis of 269 rapid infusions of natalizumab and 100 rapid infusions of ocrelizumab, there were two infusion-related reactions in the natalizumab group and eight in the ocrelizumab group.
All the reactions were mild to moderate, and no discontinuations were required. None of the reactions occurred during the postinfusion observation period.
“In the setting of COVID-19 pandemic, rapid infusion protocols could potentially save hospital resources and limit patient exposure to a high-risk clinical setting while still maintaining ongoing treatment of multiple sclerosis,” the authors wrote.
Under the rapid infusion protocol, patients receive three standard doses for 1 hour followed by 30 minutes of observation. In addition, infusions are reduced to 30 minutes, explained lead author Louise Rath, of clinical neurosciences, Alfred Health, in Melbourne.
“For our cohort of patients, the side effects were minimal,” she said.
“Rapid infusions allowed patients to have option of hospital in-home or office, ensuring work was not at risk by infusion,” she added. “Our governance has been very supportive, and we will be keeping rapid infusion post COVID.”
The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ACTRIMS 2021
NfL levels linked to worse disability in real-world MS
according to new findings from a large, diverse population of patients with MS. “This is one of the largest studies to evaluate serum neurofilament light chain levels in people with MS,” said lead author Elias S. Sotirchos, MD, an assistant professor of neurology at Johns Hopkins University, Baltimore.
“An important strength of this cohort is that it is a real-world cohort of patients followed in U.S. and European MS centers,” he said. “The study captures the diversity of the MS population, including demographics, comorbidities, lifestyle factors, and clinical characteristics that may otherwise not be captured in a clinical trial population.”
The research was presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Scrutinizing serum neurofilament light chain levels in a real-world cohort
Neurofilaments – neuron-specific proteins that release in response to neuroaxonal injury – have been observed to be elevated in a variety of neurologic disorders, and with a need for biomarkers in MS, there is high interest of their role in the disease. But studies involving real-world, heterogeneous MS populations are lacking, the researchers noted.
To take a broader look at the issue, Dr. Sotirchos and colleagues conducted a cross-sectional evaluation of 6,968 people with MS in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS), a large network of MS centers in the United States and Europe.
Participants’ baseline serum neurofilament light chain levels were compared with those of 201 healthy controls in the cohort using a novel, high-throughput immunoassay (Siemens Healthineers).
Of those with MS, 1,202 (17.2%) showed elevated serum neurofilament light chain levels, above the age-specific 97.5th percentile derived from the healthy controls.
A look at key factors associated with elevations showed significant links to having progressive MS (odds ratio, 1.63), non-White race (OR, 1.43), type 2 diabetes (OR, 1.89), and smoking (current vs. never smoker; OR, 1.49).
Associations with age and symptom duration were somewhat complex, but overall, younger patients and those with shorter disease duration had the highest frequency of elevated serum neurofilament light chain levels.
Interestingly, those with a higher body mass index (BMI) showed a reduced odds of having elevated serum neurofilament light chain levels (OR, 0.83 per 5 kg/m2 increase in BMI).
Evaluation of neuroperformance measures – including walking speed, manual dexterity and processing speed, and MRI data – showed that those with elevated serum neurofilament light chain levels had worse neurologic function, lower brain parenchymal fraction, lower thalamic volume, and higher T2 lesion volume (P < .001 for all).
Dr. Sotirchos noted that the higher rates of elevations in younger people, also observed in previous clinical trials, may reflect higher early-stage disease activity. “Generally, people who are younger and earlier in the course of disease tend to have more inflammatory disease activity in MS, and that could be what we’re capturing here, but we need to better understand the pathologic correlates of elevated serum neurofilament light chain levels.”
The lower levels of neurofilament light chain with higher BMI, also recently reported in another study, likewise need further investigation, including in healthy controls, Dr. Sotirchos added. “Having lower serum neurofilament light chain levels with increasing BMI could have to do with effects of blood volume and how the serum neurofilament light chain levels is distributed in the body,” he explained.
The findings suggest that interpretation of serum neurofilament light chain levels without accounting for BMI could result in false-negative or false-positive results, Dr. Sotirchos noted. “It will be important to further evaluate this observation in control populations and account for BMI in neurofilament light chain reference ranges.”
Dr. Sotirchos added that the 17% rate of elevated serum neurofilament light chain levels seen in people with MS in the study is likely an underestimate.
“This is a cross-sectional study and represents one sample per patient, so it is a snapshot in time,” he said. “With the nature of MS, we know that people’s levels fluctuate over time.” In addition, most patients were on disease-modifying therapy for MS, so serum neurofilament light chain elevations could have been suppressed.
Applying the findings to individual patients
Commenting on the findings, Jennifer Graves, MD, PhD, director of the neuroimmunology research program at the University of California, San Diego, said the study is an important addition to the ongoing evidence on serum neurofilament light chain in MS.
“The current presented research importantly addresses the gaps we have in understanding how best to apply serum filament light chain levels to individual patients and not just using them to assess group level means of outcome measures,” she said.
“The MS PATHS collaborative is looking at multiple factors (in addition to MS activity) that drive serum neurofilament light chain levels so meaningful and practical cutoffs for what’s abnormal can be created,” said Dr. Graves, who also directs the Rady Children’s Pediatric MS Clinic in San Diego.
Dr. Graves noted that the findings on BMI were unexpected. “Elevated BMI has been shown to be associated with greater brain atrophy and greater relapses and disability in MS participants, so to have an opposite effect with serum neurofilament light chain is interesting.
“My thoughts would be that obesity is somehow affecting measurable blood levels of this marker. I think it less likely BMI has a protective effect against neurodegeneration given the observations with other MS outcome measures,” she added.
Future research
In terms of future directions, Dr. Sotirchos noted that the researchers are following the group longitudinally to further assess changes in neurofilament light chain over time, and will be looking at associations with longitudinal, clinical, and radiologic outcomes.
The current research, meanwhile, offers important insights in terms of developing precision reference ranges, he noted.
“It appears that reference ranges may need to account for sex, race, BMI, and comorbid/lifestyle factors,” Dr. Sotirchos said, “in order to potentially improve the performance of serum neurofilament light chain as a biomarker in MS and other neurological diseases.”
The study received funding from Biogen and the MS PATHS network receives funding from Biogen. Dr. Sotirchos has served on scientific advisory boards for Alexion, Viela Bio, and Genentech, and has received speaker honoraria from Viela Bio and Biogen. Dr. Graves has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
according to new findings from a large, diverse population of patients with MS. “This is one of the largest studies to evaluate serum neurofilament light chain levels in people with MS,” said lead author Elias S. Sotirchos, MD, an assistant professor of neurology at Johns Hopkins University, Baltimore.
“An important strength of this cohort is that it is a real-world cohort of patients followed in U.S. and European MS centers,” he said. “The study captures the diversity of the MS population, including demographics, comorbidities, lifestyle factors, and clinical characteristics that may otherwise not be captured in a clinical trial population.”
The research was presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Scrutinizing serum neurofilament light chain levels in a real-world cohort
Neurofilaments – neuron-specific proteins that release in response to neuroaxonal injury – have been observed to be elevated in a variety of neurologic disorders, and with a need for biomarkers in MS, there is high interest of their role in the disease. But studies involving real-world, heterogeneous MS populations are lacking, the researchers noted.
To take a broader look at the issue, Dr. Sotirchos and colleagues conducted a cross-sectional evaluation of 6,968 people with MS in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS), a large network of MS centers in the United States and Europe.
Participants’ baseline serum neurofilament light chain levels were compared with those of 201 healthy controls in the cohort using a novel, high-throughput immunoassay (Siemens Healthineers).
Of those with MS, 1,202 (17.2%) showed elevated serum neurofilament light chain levels, above the age-specific 97.5th percentile derived from the healthy controls.
A look at key factors associated with elevations showed significant links to having progressive MS (odds ratio, 1.63), non-White race (OR, 1.43), type 2 diabetes (OR, 1.89), and smoking (current vs. never smoker; OR, 1.49).
Associations with age and symptom duration were somewhat complex, but overall, younger patients and those with shorter disease duration had the highest frequency of elevated serum neurofilament light chain levels.
Interestingly, those with a higher body mass index (BMI) showed a reduced odds of having elevated serum neurofilament light chain levels (OR, 0.83 per 5 kg/m2 increase in BMI).
Evaluation of neuroperformance measures – including walking speed, manual dexterity and processing speed, and MRI data – showed that those with elevated serum neurofilament light chain levels had worse neurologic function, lower brain parenchymal fraction, lower thalamic volume, and higher T2 lesion volume (P < .001 for all).
Dr. Sotirchos noted that the higher rates of elevations in younger people, also observed in previous clinical trials, may reflect higher early-stage disease activity. “Generally, people who are younger and earlier in the course of disease tend to have more inflammatory disease activity in MS, and that could be what we’re capturing here, but we need to better understand the pathologic correlates of elevated serum neurofilament light chain levels.”
The lower levels of neurofilament light chain with higher BMI, also recently reported in another study, likewise need further investigation, including in healthy controls, Dr. Sotirchos added. “Having lower serum neurofilament light chain levels with increasing BMI could have to do with effects of blood volume and how the serum neurofilament light chain levels is distributed in the body,” he explained.
The findings suggest that interpretation of serum neurofilament light chain levels without accounting for BMI could result in false-negative or false-positive results, Dr. Sotirchos noted. “It will be important to further evaluate this observation in control populations and account for BMI in neurofilament light chain reference ranges.”
Dr. Sotirchos added that the 17% rate of elevated serum neurofilament light chain levels seen in people with MS in the study is likely an underestimate.
“This is a cross-sectional study and represents one sample per patient, so it is a snapshot in time,” he said. “With the nature of MS, we know that people’s levels fluctuate over time.” In addition, most patients were on disease-modifying therapy for MS, so serum neurofilament light chain elevations could have been suppressed.
Applying the findings to individual patients
Commenting on the findings, Jennifer Graves, MD, PhD, director of the neuroimmunology research program at the University of California, San Diego, said the study is an important addition to the ongoing evidence on serum neurofilament light chain in MS.
“The current presented research importantly addresses the gaps we have in understanding how best to apply serum filament light chain levels to individual patients and not just using them to assess group level means of outcome measures,” she said.
“The MS PATHS collaborative is looking at multiple factors (in addition to MS activity) that drive serum neurofilament light chain levels so meaningful and practical cutoffs for what’s abnormal can be created,” said Dr. Graves, who also directs the Rady Children’s Pediatric MS Clinic in San Diego.
Dr. Graves noted that the findings on BMI were unexpected. “Elevated BMI has been shown to be associated with greater brain atrophy and greater relapses and disability in MS participants, so to have an opposite effect with serum neurofilament light chain is interesting.
“My thoughts would be that obesity is somehow affecting measurable blood levels of this marker. I think it less likely BMI has a protective effect against neurodegeneration given the observations with other MS outcome measures,” she added.
Future research
In terms of future directions, Dr. Sotirchos noted that the researchers are following the group longitudinally to further assess changes in neurofilament light chain over time, and will be looking at associations with longitudinal, clinical, and radiologic outcomes.
The current research, meanwhile, offers important insights in terms of developing precision reference ranges, he noted.
“It appears that reference ranges may need to account for sex, race, BMI, and comorbid/lifestyle factors,” Dr. Sotirchos said, “in order to potentially improve the performance of serum neurofilament light chain as a biomarker in MS and other neurological diseases.”
The study received funding from Biogen and the MS PATHS network receives funding from Biogen. Dr. Sotirchos has served on scientific advisory boards for Alexion, Viela Bio, and Genentech, and has received speaker honoraria from Viela Bio and Biogen. Dr. Graves has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
according to new findings from a large, diverse population of patients with MS. “This is one of the largest studies to evaluate serum neurofilament light chain levels in people with MS,” said lead author Elias S. Sotirchos, MD, an assistant professor of neurology at Johns Hopkins University, Baltimore.
“An important strength of this cohort is that it is a real-world cohort of patients followed in U.S. and European MS centers,” he said. “The study captures the diversity of the MS population, including demographics, comorbidities, lifestyle factors, and clinical characteristics that may otherwise not be captured in a clinical trial population.”
The research was presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Scrutinizing serum neurofilament light chain levels in a real-world cohort
Neurofilaments – neuron-specific proteins that release in response to neuroaxonal injury – have been observed to be elevated in a variety of neurologic disorders, and with a need for biomarkers in MS, there is high interest of their role in the disease. But studies involving real-world, heterogeneous MS populations are lacking, the researchers noted.
To take a broader look at the issue, Dr. Sotirchos and colleagues conducted a cross-sectional evaluation of 6,968 people with MS in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS), a large network of MS centers in the United States and Europe.
Participants’ baseline serum neurofilament light chain levels were compared with those of 201 healthy controls in the cohort using a novel, high-throughput immunoassay (Siemens Healthineers).
Of those with MS, 1,202 (17.2%) showed elevated serum neurofilament light chain levels, above the age-specific 97.5th percentile derived from the healthy controls.
A look at key factors associated with elevations showed significant links to having progressive MS (odds ratio, 1.63), non-White race (OR, 1.43), type 2 diabetes (OR, 1.89), and smoking (current vs. never smoker; OR, 1.49).
Associations with age and symptom duration were somewhat complex, but overall, younger patients and those with shorter disease duration had the highest frequency of elevated serum neurofilament light chain levels.
Interestingly, those with a higher body mass index (BMI) showed a reduced odds of having elevated serum neurofilament light chain levels (OR, 0.83 per 5 kg/m2 increase in BMI).
Evaluation of neuroperformance measures – including walking speed, manual dexterity and processing speed, and MRI data – showed that those with elevated serum neurofilament light chain levels had worse neurologic function, lower brain parenchymal fraction, lower thalamic volume, and higher T2 lesion volume (P < .001 for all).
Dr. Sotirchos noted that the higher rates of elevations in younger people, also observed in previous clinical trials, may reflect higher early-stage disease activity. “Generally, people who are younger and earlier in the course of disease tend to have more inflammatory disease activity in MS, and that could be what we’re capturing here, but we need to better understand the pathologic correlates of elevated serum neurofilament light chain levels.”
The lower levels of neurofilament light chain with higher BMI, also recently reported in another study, likewise need further investigation, including in healthy controls, Dr. Sotirchos added. “Having lower serum neurofilament light chain levels with increasing BMI could have to do with effects of blood volume and how the serum neurofilament light chain levels is distributed in the body,” he explained.
The findings suggest that interpretation of serum neurofilament light chain levels without accounting for BMI could result in false-negative or false-positive results, Dr. Sotirchos noted. “It will be important to further evaluate this observation in control populations and account for BMI in neurofilament light chain reference ranges.”
Dr. Sotirchos added that the 17% rate of elevated serum neurofilament light chain levels seen in people with MS in the study is likely an underestimate.
“This is a cross-sectional study and represents one sample per patient, so it is a snapshot in time,” he said. “With the nature of MS, we know that people’s levels fluctuate over time.” In addition, most patients were on disease-modifying therapy for MS, so serum neurofilament light chain elevations could have been suppressed.
Applying the findings to individual patients
Commenting on the findings, Jennifer Graves, MD, PhD, director of the neuroimmunology research program at the University of California, San Diego, said the study is an important addition to the ongoing evidence on serum neurofilament light chain in MS.
“The current presented research importantly addresses the gaps we have in understanding how best to apply serum filament light chain levels to individual patients and not just using them to assess group level means of outcome measures,” she said.
“The MS PATHS collaborative is looking at multiple factors (in addition to MS activity) that drive serum neurofilament light chain levels so meaningful and practical cutoffs for what’s abnormal can be created,” said Dr. Graves, who also directs the Rady Children’s Pediatric MS Clinic in San Diego.
Dr. Graves noted that the findings on BMI were unexpected. “Elevated BMI has been shown to be associated with greater brain atrophy and greater relapses and disability in MS participants, so to have an opposite effect with serum neurofilament light chain is interesting.
“My thoughts would be that obesity is somehow affecting measurable blood levels of this marker. I think it less likely BMI has a protective effect against neurodegeneration given the observations with other MS outcome measures,” she added.
Future research
In terms of future directions, Dr. Sotirchos noted that the researchers are following the group longitudinally to further assess changes in neurofilament light chain over time, and will be looking at associations with longitudinal, clinical, and radiologic outcomes.
The current research, meanwhile, offers important insights in terms of developing precision reference ranges, he noted.
“It appears that reference ranges may need to account for sex, race, BMI, and comorbid/lifestyle factors,” Dr. Sotirchos said, “in order to potentially improve the performance of serum neurofilament light chain as a biomarker in MS and other neurological diseases.”
The study received funding from Biogen and the MS PATHS network receives funding from Biogen. Dr. Sotirchos has served on scientific advisory boards for Alexion, Viela Bio, and Genentech, and has received speaker honoraria from Viela Bio and Biogen. Dr. Graves has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ACTRIMS 2021
Vitamin D deficiency linked to early cognitive impairment in MS
according to new research that adds to the known adverse relationship between low vitamin D and MS.
“We confirmed that low vitamin D may affect not only early disability but also cognition in newly MS diagnosed patients,” said lead author Eleonora Virgilio, MD, of the MS Center, neurology unit, at the University of Eastern Piedmont, Novara, Italy.
“The possible effects of vitamin D on both cognition (in particular, information processing speed) and early disability in newly diagnosed MS patients needs to be further investigated because this association might represent a marker of future disability, supporting the need for prompt supplementation,” she said.
The findings were presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Low vitamin D and MS
Previous studies have linked insufficient serum vitamin D with everything from the development of MS to activity and disease progression, but less has been reported on a specific link to the impairment of cognitive function, an important complication of MS.
“Cognitive impairment, and, in particular, slowed information processing speed, is very frequent in the MS population from the early stages of disease, and frequently underestimated,” Dr. Virgilio noted. “It has yet to be completely elucidated what the exact underlying mechanisms are.”
To evaluate the relationship, Dr. Virgilio and colleagues enrolled 60 patients in Italy with MS who were newly diagnosed and had serum vitamin D levels collected upon diagnosis. The participants were also tested at diagnosis with the Symbol Digit Modalities Test (SDMT) for information processing speed, which is a hallmark of the cognitive impairment that can occur in MS and is typically the first cognitive domain to show effects of the disease.
Among the patients, 40 were female and the mean age at diagnosis was 39.5 years; 90% had relapsing remitting MS at baseline and 10% had progressive MS. Their median Expanded Disability Status Scale score at diagnosis was 1.5.
At baseline, as many as 85% of the participants (51) had low serum vitamin D levels, defined as below 30 ng/mL, which Dr. Virgilio noted is consistent with other rates reported among people with MS in the Lombardy region of Italy, where the study was conducted.
The patients had a mean vitamin D level of 21.17 ng/mL (± 10.02), with 51.7% considered to have a deficiency (less than 20 ng/mL) and 33.3% with an insufficiency (20-30 ng/mL).
Of the patients, 16 (27%) had cognitive impairment, defined as a z score of 1.5 or less. Their mean raw SDMT score was 46.50 (± 14.73) and mean z score was –0.62 (± 1.29).
Importantly, those with cognitive impairment were significantly more likely to have severe hypovitaminosis D, compared with those with sufficient vitamin D levels, none of whom showed cognitive impairment (P = .02).
Furthermore, vitamin D levels positively correlated with SDMT raw values (P = .001) and z score (P = .008).
Over a mean follow-up of 2 years, a significant correlation was observed between serum vitamin D levels at diagnosis and early disability on the MS severity score (MSSS; P = .02) and a weak correlation with age-related MSSS (ARMSS; P = .08) at the last clinical follow-up.
Dr. Virgilio noted that factors including disease treatment effects or other factors could have played a role in the weaker results. “It is possible that the linear correlation we found was not as strong as expected [because of] an effect of treatment with disease-modifying therapies or vitamin D supplementation, or because of the short follow-up available at the moment for our population – only for a mean period of 2 years after MS diagnosis.”
The mechanisms for vitamin D deficiency in the MS population are likely multifactorial, with genetic as well as environmental links, she noted.
“The immunomodulatory effects of vitamin D are well known,” Dr. Virgilio said.
“Vitamin D was already linked to cognitive function in other neurodegenerative diseases, [including] Alzheimer’s disease, but more importantly, also in other autoimmune diseases, such as systemic lupus erythematosus,” she explained.
Vitamin D also linked to long-term cognitive function
The study adds to recent research showing longer-term effects of vitamin D deficiency and cognitive impairment in MS: In the longitudinal BENEFIT trial published in 2020, researchers following 278 patients with MS over the course of 11 years found that a 50 ng/L higher mean vitamin D level in the first 2 years of the study was associated with a 65% lower odds of a poor performance on Paced Auditory Serial Addition Test scores at the 11-year follow-up.
That study also looked at neurofilament light chain concentrations, which are associated with MS disease activity, and found they were 20% lower among those with higher vitamin D at baseline. Smokers also had lower cognitive scores.
“Lower vitamin D and smoking after clinical onset predicted worse long-term cognitive function and neuronal integrity in patients with MS,” the authors concluded.
The authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
according to new research that adds to the known adverse relationship between low vitamin D and MS.
“We confirmed that low vitamin D may affect not only early disability but also cognition in newly MS diagnosed patients,” said lead author Eleonora Virgilio, MD, of the MS Center, neurology unit, at the University of Eastern Piedmont, Novara, Italy.
“The possible effects of vitamin D on both cognition (in particular, information processing speed) and early disability in newly diagnosed MS patients needs to be further investigated because this association might represent a marker of future disability, supporting the need for prompt supplementation,” she said.
The findings were presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Low vitamin D and MS
Previous studies have linked insufficient serum vitamin D with everything from the development of MS to activity and disease progression, but less has been reported on a specific link to the impairment of cognitive function, an important complication of MS.
“Cognitive impairment, and, in particular, slowed information processing speed, is very frequent in the MS population from the early stages of disease, and frequently underestimated,” Dr. Virgilio noted. “It has yet to be completely elucidated what the exact underlying mechanisms are.”
To evaluate the relationship, Dr. Virgilio and colleagues enrolled 60 patients in Italy with MS who were newly diagnosed and had serum vitamin D levels collected upon diagnosis. The participants were also tested at diagnosis with the Symbol Digit Modalities Test (SDMT) for information processing speed, which is a hallmark of the cognitive impairment that can occur in MS and is typically the first cognitive domain to show effects of the disease.
Among the patients, 40 were female and the mean age at diagnosis was 39.5 years; 90% had relapsing remitting MS at baseline and 10% had progressive MS. Their median Expanded Disability Status Scale score at diagnosis was 1.5.
At baseline, as many as 85% of the participants (51) had low serum vitamin D levels, defined as below 30 ng/mL, which Dr. Virgilio noted is consistent with other rates reported among people with MS in the Lombardy region of Italy, where the study was conducted.
The patients had a mean vitamin D level of 21.17 ng/mL (± 10.02), with 51.7% considered to have a deficiency (less than 20 ng/mL) and 33.3% with an insufficiency (20-30 ng/mL).
Of the patients, 16 (27%) had cognitive impairment, defined as a z score of 1.5 or less. Their mean raw SDMT score was 46.50 (± 14.73) and mean z score was –0.62 (± 1.29).
Importantly, those with cognitive impairment were significantly more likely to have severe hypovitaminosis D, compared with those with sufficient vitamin D levels, none of whom showed cognitive impairment (P = .02).
Furthermore, vitamin D levels positively correlated with SDMT raw values (P = .001) and z score (P = .008).
Over a mean follow-up of 2 years, a significant correlation was observed between serum vitamin D levels at diagnosis and early disability on the MS severity score (MSSS; P = .02) and a weak correlation with age-related MSSS (ARMSS; P = .08) at the last clinical follow-up.
Dr. Virgilio noted that factors including disease treatment effects or other factors could have played a role in the weaker results. “It is possible that the linear correlation we found was not as strong as expected [because of] an effect of treatment with disease-modifying therapies or vitamin D supplementation, or because of the short follow-up available at the moment for our population – only for a mean period of 2 years after MS diagnosis.”
The mechanisms for vitamin D deficiency in the MS population are likely multifactorial, with genetic as well as environmental links, she noted.
“The immunomodulatory effects of vitamin D are well known,” Dr. Virgilio said.
“Vitamin D was already linked to cognitive function in other neurodegenerative diseases, [including] Alzheimer’s disease, but more importantly, also in other autoimmune diseases, such as systemic lupus erythematosus,” she explained.
Vitamin D also linked to long-term cognitive function
The study adds to recent research showing longer-term effects of vitamin D deficiency and cognitive impairment in MS: In the longitudinal BENEFIT trial published in 2020, researchers following 278 patients with MS over the course of 11 years found that a 50 ng/L higher mean vitamin D level in the first 2 years of the study was associated with a 65% lower odds of a poor performance on Paced Auditory Serial Addition Test scores at the 11-year follow-up.
That study also looked at neurofilament light chain concentrations, which are associated with MS disease activity, and found they were 20% lower among those with higher vitamin D at baseline. Smokers also had lower cognitive scores.
“Lower vitamin D and smoking after clinical onset predicted worse long-term cognitive function and neuronal integrity in patients with MS,” the authors concluded.
The authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
according to new research that adds to the known adverse relationship between low vitamin D and MS.
“We confirmed that low vitamin D may affect not only early disability but also cognition in newly MS diagnosed patients,” said lead author Eleonora Virgilio, MD, of the MS Center, neurology unit, at the University of Eastern Piedmont, Novara, Italy.
“The possible effects of vitamin D on both cognition (in particular, information processing speed) and early disability in newly diagnosed MS patients needs to be further investigated because this association might represent a marker of future disability, supporting the need for prompt supplementation,” she said.
The findings were presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Low vitamin D and MS
Previous studies have linked insufficient serum vitamin D with everything from the development of MS to activity and disease progression, but less has been reported on a specific link to the impairment of cognitive function, an important complication of MS.
“Cognitive impairment, and, in particular, slowed information processing speed, is very frequent in the MS population from the early stages of disease, and frequently underestimated,” Dr. Virgilio noted. “It has yet to be completely elucidated what the exact underlying mechanisms are.”
To evaluate the relationship, Dr. Virgilio and colleagues enrolled 60 patients in Italy with MS who were newly diagnosed and had serum vitamin D levels collected upon diagnosis. The participants were also tested at diagnosis with the Symbol Digit Modalities Test (SDMT) for information processing speed, which is a hallmark of the cognitive impairment that can occur in MS and is typically the first cognitive domain to show effects of the disease.
Among the patients, 40 were female and the mean age at diagnosis was 39.5 years; 90% had relapsing remitting MS at baseline and 10% had progressive MS. Their median Expanded Disability Status Scale score at diagnosis was 1.5.
At baseline, as many as 85% of the participants (51) had low serum vitamin D levels, defined as below 30 ng/mL, which Dr. Virgilio noted is consistent with other rates reported among people with MS in the Lombardy region of Italy, where the study was conducted.
The patients had a mean vitamin D level of 21.17 ng/mL (± 10.02), with 51.7% considered to have a deficiency (less than 20 ng/mL) and 33.3% with an insufficiency (20-30 ng/mL).
Of the patients, 16 (27%) had cognitive impairment, defined as a z score of 1.5 or less. Their mean raw SDMT score was 46.50 (± 14.73) and mean z score was –0.62 (± 1.29).
Importantly, those with cognitive impairment were significantly more likely to have severe hypovitaminosis D, compared with those with sufficient vitamin D levels, none of whom showed cognitive impairment (P = .02).
Furthermore, vitamin D levels positively correlated with SDMT raw values (P = .001) and z score (P = .008).
Over a mean follow-up of 2 years, a significant correlation was observed between serum vitamin D levels at diagnosis and early disability on the MS severity score (MSSS; P = .02) and a weak correlation with age-related MSSS (ARMSS; P = .08) at the last clinical follow-up.
Dr. Virgilio noted that factors including disease treatment effects or other factors could have played a role in the weaker results. “It is possible that the linear correlation we found was not as strong as expected [because of] an effect of treatment with disease-modifying therapies or vitamin D supplementation, or because of the short follow-up available at the moment for our population – only for a mean period of 2 years after MS diagnosis.”
The mechanisms for vitamin D deficiency in the MS population are likely multifactorial, with genetic as well as environmental links, she noted.
“The immunomodulatory effects of vitamin D are well known,” Dr. Virgilio said.
“Vitamin D was already linked to cognitive function in other neurodegenerative diseases, [including] Alzheimer’s disease, but more importantly, also in other autoimmune diseases, such as systemic lupus erythematosus,” she explained.
Vitamin D also linked to long-term cognitive function
The study adds to recent research showing longer-term effects of vitamin D deficiency and cognitive impairment in MS: In the longitudinal BENEFIT trial published in 2020, researchers following 278 patients with MS over the course of 11 years found that a 50 ng/L higher mean vitamin D level in the first 2 years of the study was associated with a 65% lower odds of a poor performance on Paced Auditory Serial Addition Test scores at the 11-year follow-up.
That study also looked at neurofilament light chain concentrations, which are associated with MS disease activity, and found they were 20% lower among those with higher vitamin D at baseline. Smokers also had lower cognitive scores.
“Lower vitamin D and smoking after clinical onset predicted worse long-term cognitive function and neuronal integrity in patients with MS,” the authors concluded.
The authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ACTRIMS FORUM 2021
Opioid use common for pain in multiple sclerosis
, new research shows.
“This high level of opioid use supports that better pain management treatment options, including nonpharmacological options, are needed for people with MS and pain,” wrote the authors of the study, which was presented at ACTRIMS Forum 2021, held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Previous research has shown that more than 50% of people with MS report chronic pain that is serious enough to interfere with daily activities, employment, and quality of life. Many with MS report that pain is one of their worst symptoms, the authors noted.
With surprisingly few studies evaluating opioid use in the MS population, Cinda L. Hugos, PT, associate professor of neurology with the VA Portland Health Care System and the department of neurology, Oregon Health and Science University, Portland, and colleagues investigated the issue in a sample of patients participating in a U.S. multisite MS fatigue management trial conducted between 2013 and 2014.
Of the 281 participants with MS in the study, 58 patients (20.6%) reported using prescription opioids. Among them, most – 44 (76%) – reported regular daily use, 10 (17%) reported using the drugs only as needed, 3 (5%) reported only short-term use, including after recent injury or dental surgery, and 1 provided incomplete information.
Those who reported opioid use had significantly worse fatigue scores on the Modified Fatigue Impact Scale (P = .015) and worse pain scores (P < .0001).
There were no significant differences in terms of age (mean age, 53 years), gender (69% were female), or race (in both groups, about 76% were White). No significant differences were seen in disability or depression scores in the opioid users versus nonusers.
“In this sample of people with multiple sclerosis who self-reported fatigue and volunteered to join an MS fatigue management research study, more than one in five reported using prescription opioids and nearly one in six used opioids daily,” the authors wrote. “Opioid users had more pain and fatigue than nonusers.”
Commenting on the study, Jeffrey Cohen, MD, president of ACTRIMS, said that the findings are consistent with his observations that “in the general population, opioids often are used to treat chronic pain in people with MS.”
But they’re not getting the drugs from his clinic. “We do not prescribe opioids in our clinic, referring such patients to a chronic pain program,” Dr. Cohen said. “However, there clearly is need for better treatment options.”
A previous study on opioid use by people with MS, published in 2015, found even higher rates – 42% reported having ever used opioids, and 38% reported currently using opioids.
Although reports of opioid use by patients with MS have been lacking, more has been published on the emerging use of cannabis-related products. One recent study showed that nearly half of people with MS reported using a cannabis-based therapy for nerve-based pain and sleep disturbances.
Although cannabis is considered safer than opioids, the authors noted that it has its own significant drawback – a “paucity of provider guidance.”
“The range of perceived benefits and potential differential effects of THC and cannabinoid highlight the need for personalized, evidence-based guidelines regarding cannabinoid use,” they wrote.
Stretching program for spasticity shows benefits
With spasticity representing a key contributor to MS pain and affecting more than 80% of people with MS, Ms. Hugos and colleagues are developing an alternative to medication – a nonpharmacologic stretching regimen called Spasticity: Take Control” (STC).
Based on evidence-based strategies for the treatment of spasticity in MS, the program involves exercises with daily routines of 15-20 minutes over 6 months.
In a pilot study of 66 patients, also presented at the ACTRIMS meeting, the investigators reported that the program showed significant reductions in pain severity and interference, measured with the Brief Pain Inventory–Short Form, compared with a control consisting of range of motion instruction over 6 months.
The study also offered insights on the specific areas of pain. Among those who reported chronic pain (42% in the STC group and 63.3% in the range-of-motion group), the pain was most frequently reported in the lower back (74.3%), legs (68.6%), or lower back and legs (88.6%).
Ms. Hugos noted that the findings suggest a potentially important nonpharmacologic alternative to spasticity-related pain in MS.
“Stretching is the cornerstone treatment for spasticity from all causes, but there is very little information on stretching exercises in MS or any other conditions,” Ms. Hugos said. “[Our] pilot study is the first and only study using a standardized, daily stretching exercise program to treat MS spasticity,” she said.
“A fully powered study is needed to better understand the impact of different types of exercise on pain severity and interference in multiple sclerosis,” she noted.
Ms. Hugos has received consulting fees from Greenwich Biosciences, Evidera, and Techspert.io. Dr. Cohen has received personal compensation for consulting for Adamas, Atara, Bristol-Myers Squibb, Convelo, MedDay, and Mylan.
A version of this article first appeared on Medscape.com.
, new research shows.
“This high level of opioid use supports that better pain management treatment options, including nonpharmacological options, are needed for people with MS and pain,” wrote the authors of the study, which was presented at ACTRIMS Forum 2021, held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Previous research has shown that more than 50% of people with MS report chronic pain that is serious enough to interfere with daily activities, employment, and quality of life. Many with MS report that pain is one of their worst symptoms, the authors noted.
With surprisingly few studies evaluating opioid use in the MS population, Cinda L. Hugos, PT, associate professor of neurology with the VA Portland Health Care System and the department of neurology, Oregon Health and Science University, Portland, and colleagues investigated the issue in a sample of patients participating in a U.S. multisite MS fatigue management trial conducted between 2013 and 2014.
Of the 281 participants with MS in the study, 58 patients (20.6%) reported using prescription opioids. Among them, most – 44 (76%) – reported regular daily use, 10 (17%) reported using the drugs only as needed, 3 (5%) reported only short-term use, including after recent injury or dental surgery, and 1 provided incomplete information.
Those who reported opioid use had significantly worse fatigue scores on the Modified Fatigue Impact Scale (P = .015) and worse pain scores (P < .0001).
There were no significant differences in terms of age (mean age, 53 years), gender (69% were female), or race (in both groups, about 76% were White). No significant differences were seen in disability or depression scores in the opioid users versus nonusers.
“In this sample of people with multiple sclerosis who self-reported fatigue and volunteered to join an MS fatigue management research study, more than one in five reported using prescription opioids and nearly one in six used opioids daily,” the authors wrote. “Opioid users had more pain and fatigue than nonusers.”
Commenting on the study, Jeffrey Cohen, MD, president of ACTRIMS, said that the findings are consistent with his observations that “in the general population, opioids often are used to treat chronic pain in people with MS.”
But they’re not getting the drugs from his clinic. “We do not prescribe opioids in our clinic, referring such patients to a chronic pain program,” Dr. Cohen said. “However, there clearly is need for better treatment options.”
A previous study on opioid use by people with MS, published in 2015, found even higher rates – 42% reported having ever used opioids, and 38% reported currently using opioids.
Although reports of opioid use by patients with MS have been lacking, more has been published on the emerging use of cannabis-related products. One recent study showed that nearly half of people with MS reported using a cannabis-based therapy for nerve-based pain and sleep disturbances.
Although cannabis is considered safer than opioids, the authors noted that it has its own significant drawback – a “paucity of provider guidance.”
“The range of perceived benefits and potential differential effects of THC and cannabinoid highlight the need for personalized, evidence-based guidelines regarding cannabinoid use,” they wrote.
Stretching program for spasticity shows benefits
With spasticity representing a key contributor to MS pain and affecting more than 80% of people with MS, Ms. Hugos and colleagues are developing an alternative to medication – a nonpharmacologic stretching regimen called Spasticity: Take Control” (STC).
Based on evidence-based strategies for the treatment of spasticity in MS, the program involves exercises with daily routines of 15-20 minutes over 6 months.
In a pilot study of 66 patients, also presented at the ACTRIMS meeting, the investigators reported that the program showed significant reductions in pain severity and interference, measured with the Brief Pain Inventory–Short Form, compared with a control consisting of range of motion instruction over 6 months.
The study also offered insights on the specific areas of pain. Among those who reported chronic pain (42% in the STC group and 63.3% in the range-of-motion group), the pain was most frequently reported in the lower back (74.3%), legs (68.6%), or lower back and legs (88.6%).
Ms. Hugos noted that the findings suggest a potentially important nonpharmacologic alternative to spasticity-related pain in MS.
“Stretching is the cornerstone treatment for spasticity from all causes, but there is very little information on stretching exercises in MS or any other conditions,” Ms. Hugos said. “[Our] pilot study is the first and only study using a standardized, daily stretching exercise program to treat MS spasticity,” she said.
“A fully powered study is needed to better understand the impact of different types of exercise on pain severity and interference in multiple sclerosis,” she noted.
Ms. Hugos has received consulting fees from Greenwich Biosciences, Evidera, and Techspert.io. Dr. Cohen has received personal compensation for consulting for Adamas, Atara, Bristol-Myers Squibb, Convelo, MedDay, and Mylan.
A version of this article first appeared on Medscape.com.
, new research shows.
“This high level of opioid use supports that better pain management treatment options, including nonpharmacological options, are needed for people with MS and pain,” wrote the authors of the study, which was presented at ACTRIMS Forum 2021, held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Previous research has shown that more than 50% of people with MS report chronic pain that is serious enough to interfere with daily activities, employment, and quality of life. Many with MS report that pain is one of their worst symptoms, the authors noted.
With surprisingly few studies evaluating opioid use in the MS population, Cinda L. Hugos, PT, associate professor of neurology with the VA Portland Health Care System and the department of neurology, Oregon Health and Science University, Portland, and colleagues investigated the issue in a sample of patients participating in a U.S. multisite MS fatigue management trial conducted between 2013 and 2014.
Of the 281 participants with MS in the study, 58 patients (20.6%) reported using prescription opioids. Among them, most – 44 (76%) – reported regular daily use, 10 (17%) reported using the drugs only as needed, 3 (5%) reported only short-term use, including after recent injury or dental surgery, and 1 provided incomplete information.
Those who reported opioid use had significantly worse fatigue scores on the Modified Fatigue Impact Scale (P = .015) and worse pain scores (P < .0001).
There were no significant differences in terms of age (mean age, 53 years), gender (69% were female), or race (in both groups, about 76% were White). No significant differences were seen in disability or depression scores in the opioid users versus nonusers.
“In this sample of people with multiple sclerosis who self-reported fatigue and volunteered to join an MS fatigue management research study, more than one in five reported using prescription opioids and nearly one in six used opioids daily,” the authors wrote. “Opioid users had more pain and fatigue than nonusers.”
Commenting on the study, Jeffrey Cohen, MD, president of ACTRIMS, said that the findings are consistent with his observations that “in the general population, opioids often are used to treat chronic pain in people with MS.”
But they’re not getting the drugs from his clinic. “We do not prescribe opioids in our clinic, referring such patients to a chronic pain program,” Dr. Cohen said. “However, there clearly is need for better treatment options.”
A previous study on opioid use by people with MS, published in 2015, found even higher rates – 42% reported having ever used opioids, and 38% reported currently using opioids.
Although reports of opioid use by patients with MS have been lacking, more has been published on the emerging use of cannabis-related products. One recent study showed that nearly half of people with MS reported using a cannabis-based therapy for nerve-based pain and sleep disturbances.
Although cannabis is considered safer than opioids, the authors noted that it has its own significant drawback – a “paucity of provider guidance.”
“The range of perceived benefits and potential differential effects of THC and cannabinoid highlight the need for personalized, evidence-based guidelines regarding cannabinoid use,” they wrote.
Stretching program for spasticity shows benefits
With spasticity representing a key contributor to MS pain and affecting more than 80% of people with MS, Ms. Hugos and colleagues are developing an alternative to medication – a nonpharmacologic stretching regimen called Spasticity: Take Control” (STC).
Based on evidence-based strategies for the treatment of spasticity in MS, the program involves exercises with daily routines of 15-20 minutes over 6 months.
In a pilot study of 66 patients, also presented at the ACTRIMS meeting, the investigators reported that the program showed significant reductions in pain severity and interference, measured with the Brief Pain Inventory–Short Form, compared with a control consisting of range of motion instruction over 6 months.
The study also offered insights on the specific areas of pain. Among those who reported chronic pain (42% in the STC group and 63.3% in the range-of-motion group), the pain was most frequently reported in the lower back (74.3%), legs (68.6%), or lower back and legs (88.6%).
Ms. Hugos noted that the findings suggest a potentially important nonpharmacologic alternative to spasticity-related pain in MS.
“Stretching is the cornerstone treatment for spasticity from all causes, but there is very little information on stretching exercises in MS or any other conditions,” Ms. Hugos said. “[Our] pilot study is the first and only study using a standardized, daily stretching exercise program to treat MS spasticity,” she said.
“A fully powered study is needed to better understand the impact of different types of exercise on pain severity and interference in multiple sclerosis,” she noted.
Ms. Hugos has received consulting fees from Greenwich Biosciences, Evidera, and Techspert.io. Dr. Cohen has received personal compensation for consulting for Adamas, Atara, Bristol-Myers Squibb, Convelo, MedDay, and Mylan.
A version of this article first appeared on Medscape.com.
FROM ACTRIMS FORUM 2021
Breast cancer surgeries deemed ‘low value’ continue, increase
“This is the first study to [evaluate] all four of the low-value breast cancer procedures at the same time and try to draw some conclusions on practice patterns across facilities,” said senior author Lesly A. Dossett, MD, MPH, Center for Health Outcomes and Policy, the University of Michigan, Ann Arbor.
The two low-value procedures that have increased in use are contralateral prophylactic mastectomy for average-risk women with unilateral cancer and sentinel lymph node biopsy for clinically node-negative women aged 70 years and older with hormone receptor–positive (HR+) cancer.
“This suggests that formal efforts to reduce low value care through dissemination of guidelines, education of patients or providers, or alignment of incentives will be necessary to achieve full deimplementation,” she told this news organization.
The researchers emphasize that the providing of services that have no clinically meaningful benefit is a national epidemic, costing the United States more than $100 billion dollars annually.
These trends are notable and likely reflect a broad range of factors, commented Katharine Yao, MD, chief of the division of surgical oncology at the NorthShore University HealthSystem, Evanston, Ill.
“I think the better message here is not so much that facilities are doing too many low-value procedures but more that these procedures are still being performed, and the trends show increased rates over the years – why is that?”
“Perhaps there are other factors here we need to explore: why do these procedures persist, and why, despite the Choosing Wisely campaign, [do] they continue to increase?” she said in an interview. “Maybe there is something we can learn here about patient and physician preferences that perhaps we should be paying more attention to.”
The study was published on Feb. 3 in JAMA Surgery.
For the analysis, Dr. Dossett and her colleagues evaluated surgical data from the National Cancer Database. They examined data from more than 1,500 surgical facilities and from surgeries involving 920,256 women in the United States who were diagnosed with breast cancer between 2004 and 2016.
The team focused on four procedures that have been determined to be of low value by Choosing Wisely, a campaign of the American Board of Internal Medicine Foundation, on the basis of recommendations of the American College of Surgeons, the Society for Surgical Oncology, and the American Society for Breast Surgeons.
The results show that, for two of the four low-value procedures, use declined significantly over the study period. These two procedures were axillary lymph node dissection for limited nodal disease, for patients undergoing lumpectomy and radiotherapy, and lumpectomy re-excision for patients whose surgical margins were close but were negative for invasive cancer.
Axillary lymph node dissection declined from 63% in 2004 to 14% in 2016. The steepest reduction was seen soon after data from the Z0011 study were published in 2010. The rates for this procedure halved in the following year, from 62% in 2010 to 31% in 2011 (P < .001).
Likewise, reoperation rates after lumpectomy dropped from 19% in 2004 to 15% in 2016. The sharpest decline, from 18% in 2013 to 16% in 2014, corresponded to the publishing of the SSO/ASTRO consensus statement, which designated a negative margin as having “no tumor on ink.”
Two of the four low-value procedures increased in use during the study period.
Rates of contralateral prophylactic mastectomy increased nearly 2.5-fold among women with unilateral breast cancer undergoing mastectomy, from 11% in 2004 to 26% in 2016, despite SSO guidelines issued in 2007 recommending that the procedure not be used for women at average risk.
In addition, rates of sentinel lymph node biopsy among women aged 70 years and older with clinically node-negative HR+ breast cancer increased from 78% in 2004 to 87% in 2012. There was no significant decline in the use of this procedure, even after the CALGB 9343 trial from the Cancer and Leukemia Group B showed no survival benefit in 2013.
Patterns at hospitals vary
The authors of the study also examined hospital factors, which can heavily influence choice of procedure.
These results showed that the greatest reductions of the low-value breast cancer procedures occurred at academic research programs and high-volume surgical facilities. Elsewhere, the rates varied widely.
Interfacility rates of axillary lymph node dissection ranged from 7% to 47%; lumpectomy reoperation rates ranged from 3% to 62%; contralateral prophylactic mastectomy rates ranged from 9% to 67%; and sentinel lymph node biopsy rates ranged from 25% to 97%.
Being an outlier for use of one procedure did not necessarily translate to nonconformity for others. Factors such as a hospital’s volume of breast cancer cases or the type of facility did not appear to influence rates of axillary lymph node dissection or lumpectomy reoperation.
However, the rates of contralateral prophylactic mastectomy were significantly higher in high-volume centers and integrated network cancer programs, compared with community cancer programs (23% vs. 2%; P < .001).
Dr. Dossett said the lack of consistency was somewhat unexpected.
“We expected we would find some facilities were constantly good or bad at deimplementation or that there would be stronger associations between certain facility characteristics and performance,” she said. “That really wasn’t the case, and most facilities had mixed performance.”
Evidence may or may not influence trends
The authors speculate on why the low-value designation is in some cases being ignored.
The evidence regarding the risk for lymphedema related to axillary lymph node dissection procedure appears to have helped reduce its use, they note.
However, surgeons have been much less convinced of benefits in omitting sentinel lymph node biopsy, either because they are unfamiliar with the recommendations to avoid the procedure, or they may feel the procedure adds only minimal time and risk to a patient’s operation, the authors explain.
Patients may be convinced to opt to omit sentinel lymph node biopsy if they are properly counseled regarding the risks and benefits of the procedure, Dr. Dossett commented.
Dr. Yao added that, for elderly patients, age can play an important role in sentinel node biopsy.
“Patients’ life expectancy has increased over the years, and node status may impact adjuvant therapy decisions for these patients, even chemotherapy decisions,” she said.
Pressure to continue to perform contralateral prophylactic mastectomy is believed to be significantly patient driven, Dr. Dossett noted.
“I ultimately think the best way to reduce contralateral prophylactic mastectomy is to encourage women with small cancers to undergo breast-conserving surgery, i.e., lumpectomy, instead of mastectomy,” she explained.
“Once the decision for mastectomy is made, there is often a great deal of momentum towards a contralateral prophylactic mastectomy.”
“Contralateral prophylactic mastectomy is a personal preference that many surgeons are willing to do for their patients,” Dr. Yao explained.
“Although no survival benefit has been demonstrated for this procedure, patients find many other benefits that have nothing to do with survival.”
The authors and Dr. Yao have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
“This is the first study to [evaluate] all four of the low-value breast cancer procedures at the same time and try to draw some conclusions on practice patterns across facilities,” said senior author Lesly A. Dossett, MD, MPH, Center for Health Outcomes and Policy, the University of Michigan, Ann Arbor.
The two low-value procedures that have increased in use are contralateral prophylactic mastectomy for average-risk women with unilateral cancer and sentinel lymph node biopsy for clinically node-negative women aged 70 years and older with hormone receptor–positive (HR+) cancer.
“This suggests that formal efforts to reduce low value care through dissemination of guidelines, education of patients or providers, or alignment of incentives will be necessary to achieve full deimplementation,” she told this news organization.
The researchers emphasize that the providing of services that have no clinically meaningful benefit is a national epidemic, costing the United States more than $100 billion dollars annually.
These trends are notable and likely reflect a broad range of factors, commented Katharine Yao, MD, chief of the division of surgical oncology at the NorthShore University HealthSystem, Evanston, Ill.
“I think the better message here is not so much that facilities are doing too many low-value procedures but more that these procedures are still being performed, and the trends show increased rates over the years – why is that?”
“Perhaps there are other factors here we need to explore: why do these procedures persist, and why, despite the Choosing Wisely campaign, [do] they continue to increase?” she said in an interview. “Maybe there is something we can learn here about patient and physician preferences that perhaps we should be paying more attention to.”
The study was published on Feb. 3 in JAMA Surgery.
For the analysis, Dr. Dossett and her colleagues evaluated surgical data from the National Cancer Database. They examined data from more than 1,500 surgical facilities and from surgeries involving 920,256 women in the United States who were diagnosed with breast cancer between 2004 and 2016.
The team focused on four procedures that have been determined to be of low value by Choosing Wisely, a campaign of the American Board of Internal Medicine Foundation, on the basis of recommendations of the American College of Surgeons, the Society for Surgical Oncology, and the American Society for Breast Surgeons.
The results show that, for two of the four low-value procedures, use declined significantly over the study period. These two procedures were axillary lymph node dissection for limited nodal disease, for patients undergoing lumpectomy and radiotherapy, and lumpectomy re-excision for patients whose surgical margins were close but were negative for invasive cancer.
Axillary lymph node dissection declined from 63% in 2004 to 14% in 2016. The steepest reduction was seen soon after data from the Z0011 study were published in 2010. The rates for this procedure halved in the following year, from 62% in 2010 to 31% in 2011 (P < .001).
Likewise, reoperation rates after lumpectomy dropped from 19% in 2004 to 15% in 2016. The sharpest decline, from 18% in 2013 to 16% in 2014, corresponded to the publishing of the SSO/ASTRO consensus statement, which designated a negative margin as having “no tumor on ink.”
Two of the four low-value procedures increased in use during the study period.
Rates of contralateral prophylactic mastectomy increased nearly 2.5-fold among women with unilateral breast cancer undergoing mastectomy, from 11% in 2004 to 26% in 2016, despite SSO guidelines issued in 2007 recommending that the procedure not be used for women at average risk.
In addition, rates of sentinel lymph node biopsy among women aged 70 years and older with clinically node-negative HR+ breast cancer increased from 78% in 2004 to 87% in 2012. There was no significant decline in the use of this procedure, even after the CALGB 9343 trial from the Cancer and Leukemia Group B showed no survival benefit in 2013.
Patterns at hospitals vary
The authors of the study also examined hospital factors, which can heavily influence choice of procedure.
These results showed that the greatest reductions of the low-value breast cancer procedures occurred at academic research programs and high-volume surgical facilities. Elsewhere, the rates varied widely.
Interfacility rates of axillary lymph node dissection ranged from 7% to 47%; lumpectomy reoperation rates ranged from 3% to 62%; contralateral prophylactic mastectomy rates ranged from 9% to 67%; and sentinel lymph node biopsy rates ranged from 25% to 97%.
Being an outlier for use of one procedure did not necessarily translate to nonconformity for others. Factors such as a hospital’s volume of breast cancer cases or the type of facility did not appear to influence rates of axillary lymph node dissection or lumpectomy reoperation.
However, the rates of contralateral prophylactic mastectomy were significantly higher in high-volume centers and integrated network cancer programs, compared with community cancer programs (23% vs. 2%; P < .001).
Dr. Dossett said the lack of consistency was somewhat unexpected.
“We expected we would find some facilities were constantly good or bad at deimplementation or that there would be stronger associations between certain facility characteristics and performance,” she said. “That really wasn’t the case, and most facilities had mixed performance.”
Evidence may or may not influence trends
The authors speculate on why the low-value designation is in some cases being ignored.
The evidence regarding the risk for lymphedema related to axillary lymph node dissection procedure appears to have helped reduce its use, they note.
However, surgeons have been much less convinced of benefits in omitting sentinel lymph node biopsy, either because they are unfamiliar with the recommendations to avoid the procedure, or they may feel the procedure adds only minimal time and risk to a patient’s operation, the authors explain.
Patients may be convinced to opt to omit sentinel lymph node biopsy if they are properly counseled regarding the risks and benefits of the procedure, Dr. Dossett commented.
Dr. Yao added that, for elderly patients, age can play an important role in sentinel node biopsy.
“Patients’ life expectancy has increased over the years, and node status may impact adjuvant therapy decisions for these patients, even chemotherapy decisions,” she said.
Pressure to continue to perform contralateral prophylactic mastectomy is believed to be significantly patient driven, Dr. Dossett noted.
“I ultimately think the best way to reduce contralateral prophylactic mastectomy is to encourage women with small cancers to undergo breast-conserving surgery, i.e., lumpectomy, instead of mastectomy,” she explained.
“Once the decision for mastectomy is made, there is often a great deal of momentum towards a contralateral prophylactic mastectomy.”
“Contralateral prophylactic mastectomy is a personal preference that many surgeons are willing to do for their patients,” Dr. Yao explained.
“Although no survival benefit has been demonstrated for this procedure, patients find many other benefits that have nothing to do with survival.”
The authors and Dr. Yao have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
“This is the first study to [evaluate] all four of the low-value breast cancer procedures at the same time and try to draw some conclusions on practice patterns across facilities,” said senior author Lesly A. Dossett, MD, MPH, Center for Health Outcomes and Policy, the University of Michigan, Ann Arbor.
The two low-value procedures that have increased in use are contralateral prophylactic mastectomy for average-risk women with unilateral cancer and sentinel lymph node biopsy for clinically node-negative women aged 70 years and older with hormone receptor–positive (HR+) cancer.
“This suggests that formal efforts to reduce low value care through dissemination of guidelines, education of patients or providers, or alignment of incentives will be necessary to achieve full deimplementation,” she told this news organization.
The researchers emphasize that the providing of services that have no clinically meaningful benefit is a national epidemic, costing the United States more than $100 billion dollars annually.
These trends are notable and likely reflect a broad range of factors, commented Katharine Yao, MD, chief of the division of surgical oncology at the NorthShore University HealthSystem, Evanston, Ill.
“I think the better message here is not so much that facilities are doing too many low-value procedures but more that these procedures are still being performed, and the trends show increased rates over the years – why is that?”
“Perhaps there are other factors here we need to explore: why do these procedures persist, and why, despite the Choosing Wisely campaign, [do] they continue to increase?” she said in an interview. “Maybe there is something we can learn here about patient and physician preferences that perhaps we should be paying more attention to.”
The study was published on Feb. 3 in JAMA Surgery.
For the analysis, Dr. Dossett and her colleagues evaluated surgical data from the National Cancer Database. They examined data from more than 1,500 surgical facilities and from surgeries involving 920,256 women in the United States who were diagnosed with breast cancer between 2004 and 2016.
The team focused on four procedures that have been determined to be of low value by Choosing Wisely, a campaign of the American Board of Internal Medicine Foundation, on the basis of recommendations of the American College of Surgeons, the Society for Surgical Oncology, and the American Society for Breast Surgeons.
The results show that, for two of the four low-value procedures, use declined significantly over the study period. These two procedures were axillary lymph node dissection for limited nodal disease, for patients undergoing lumpectomy and radiotherapy, and lumpectomy re-excision for patients whose surgical margins were close but were negative for invasive cancer.
Axillary lymph node dissection declined from 63% in 2004 to 14% in 2016. The steepest reduction was seen soon after data from the Z0011 study were published in 2010. The rates for this procedure halved in the following year, from 62% in 2010 to 31% in 2011 (P < .001).
Likewise, reoperation rates after lumpectomy dropped from 19% in 2004 to 15% in 2016. The sharpest decline, from 18% in 2013 to 16% in 2014, corresponded to the publishing of the SSO/ASTRO consensus statement, which designated a negative margin as having “no tumor on ink.”
Two of the four low-value procedures increased in use during the study period.
Rates of contralateral prophylactic mastectomy increased nearly 2.5-fold among women with unilateral breast cancer undergoing mastectomy, from 11% in 2004 to 26% in 2016, despite SSO guidelines issued in 2007 recommending that the procedure not be used for women at average risk.
In addition, rates of sentinel lymph node biopsy among women aged 70 years and older with clinically node-negative HR+ breast cancer increased from 78% in 2004 to 87% in 2012. There was no significant decline in the use of this procedure, even after the CALGB 9343 trial from the Cancer and Leukemia Group B showed no survival benefit in 2013.
Patterns at hospitals vary
The authors of the study also examined hospital factors, which can heavily influence choice of procedure.
These results showed that the greatest reductions of the low-value breast cancer procedures occurred at academic research programs and high-volume surgical facilities. Elsewhere, the rates varied widely.
Interfacility rates of axillary lymph node dissection ranged from 7% to 47%; lumpectomy reoperation rates ranged from 3% to 62%; contralateral prophylactic mastectomy rates ranged from 9% to 67%; and sentinel lymph node biopsy rates ranged from 25% to 97%.
Being an outlier for use of one procedure did not necessarily translate to nonconformity for others. Factors such as a hospital’s volume of breast cancer cases or the type of facility did not appear to influence rates of axillary lymph node dissection or lumpectomy reoperation.
However, the rates of contralateral prophylactic mastectomy were significantly higher in high-volume centers and integrated network cancer programs, compared with community cancer programs (23% vs. 2%; P < .001).
Dr. Dossett said the lack of consistency was somewhat unexpected.
“We expected we would find some facilities were constantly good or bad at deimplementation or that there would be stronger associations between certain facility characteristics and performance,” she said. “That really wasn’t the case, and most facilities had mixed performance.”
Evidence may or may not influence trends
The authors speculate on why the low-value designation is in some cases being ignored.
The evidence regarding the risk for lymphedema related to axillary lymph node dissection procedure appears to have helped reduce its use, they note.
However, surgeons have been much less convinced of benefits in omitting sentinel lymph node biopsy, either because they are unfamiliar with the recommendations to avoid the procedure, or they may feel the procedure adds only minimal time and risk to a patient’s operation, the authors explain.
Patients may be convinced to opt to omit sentinel lymph node biopsy if they are properly counseled regarding the risks and benefits of the procedure, Dr. Dossett commented.
Dr. Yao added that, for elderly patients, age can play an important role in sentinel node biopsy.
“Patients’ life expectancy has increased over the years, and node status may impact adjuvant therapy decisions for these patients, even chemotherapy decisions,” she said.
Pressure to continue to perform contralateral prophylactic mastectomy is believed to be significantly patient driven, Dr. Dossett noted.
“I ultimately think the best way to reduce contralateral prophylactic mastectomy is to encourage women with small cancers to undergo breast-conserving surgery, i.e., lumpectomy, instead of mastectomy,” she explained.
“Once the decision for mastectomy is made, there is often a great deal of momentum towards a contralateral prophylactic mastectomy.”
“Contralateral prophylactic mastectomy is a personal preference that many surgeons are willing to do for their patients,” Dr. Yao explained.
“Although no survival benefit has been demonstrated for this procedure, patients find many other benefits that have nothing to do with survival.”
The authors and Dr. Yao have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A third discontinuing levothyroxine have normal thyroid levels
Approximately a third of patients treated for hypothyroidism continue to maintain normal thyroid levels after discontinuing thyroid hormone replacement therapy.
Those who were treated for overt hypothyroidism were less likely to maintain normal hormone levels than those with subclinical disease, the new meta-analysis shows.
“This analysis is the first to summarize the limited evidence regarding successful thyroid hormone discontinuation, but unfortunately more research is needed to develop an evidenced-based strategy for deprescribing thyroid hormone replacement,” Nydia Burgos, MD, and colleagues write in their article published online in Thyroid.
Nevertheless, the main findings were somewhat surprising, Dr. Burgos of the division of endocrinology, diabetes and metabolism, University of Puerto Rico, told this news organization.
“I expected that a considerable portion of patients would remain euthyroid, but up to a third of patients was an impressive number,” she said.
The finding could be an indicator of people who may not have had much benefit from the treatment in the first place, she noted.
“The truth of the matter is that levothyroxine (LT4) is among the top-prescribed drugs in the United States, and every day in clinics we encounter patients that were started on thyroid hormone replacement therapy for unclear reasons, as a therapeutic trial that was never reassessed, or as treatment for subclinical hypothyroidism without having convincing criteria for treatment,” she observed.
Meta-analysis of 17 studies examining LT4 discontinuation
Known to be highly effective in the treatment of overt hypothyroidism, LT4 is often prescribed long term; however, it is also commonly prescribed for patients with subclinical hypothyroidism, despite research suggesting no benefits in these patients.
With a guideline panel underscoring the lack of evidence and issuing a “strong recommendation” in May 2019 against treatment with thyroid hormones in adults with subclinical hypothyroidism (elevated thyroid-stimulating hormone [TSH] levels and normal free T4 levels), clinicians may increasingly be considering discontinuation strategies.
To examine the evidence to date on the clinical outcomes of discontinuing LT4, Dr. Burgos and colleagues conducted a meta-analysis in which they identified 17 observational studies that met the inclusion criteria. Of a total of 1,103 patients in the studies, 86% were women. Most studies included only adults.
With a median follow-up of 5 years, the pooled estimate of patients maintaining euthyroidism after treatment discontinuation was 37.2%.
The estimated rate of remaining euthyroid was significantly lower among those with overt hypothyroidism (11.8%) compared with those with subclinical hypothyroidism (35.6%).
Meanwhile, as many as 65.8% of patients ended up restarting thyroid hormone treatment during the follow-up period, according to pooled estimates, and the rate was as high as 87.2% in patients with overt hypothyroidism. The mean increase in TSH from time of LT4 discontinuation to follow-up was 9.4 mIU/L.
Among specific factors shown to be linked to a lower likelihood of euthyroidism at follow-up were inconsistent echogenicity on thyroid ultrasound, elevated TSH (8-9 mIU/L), and the presence of thyroid antibodies.
Only a few of the studies evaluated thyroid hormones other than synthetic LT4 (such as the commonly used desiccated thyroid), and so the analysis did not compare differences between therapies, Dr. Burgos noted.
Despite the lack of evidence of benefits of LT4 treatment for subclinical hypothyroidism, the finding that, even among those patients, approximately two-thirds were not euthyroid at follow-up was not unexpected, she added.
“I am not surprised that, even in the subclinical hypothyroidism group about two-thirds of participants were not euthyroid, because when looking at the natural history of subclinical hypothyroidism in other studies, only a fifth had normalized thyroid hormone tests, while the majority continue with mild subclinical hypothyroidism and a fifth progress to overt hypothyroidism,” she explained.
More work needed to determine best way to taper down LT4
The specific regimens for discontinuing LT4 were detailed in only three studies and reflected varying approaches, ranging from tapering down the dose over 2 weeks to reducing the dose over several more weeks, or even months, Dr. Burgos noted
“We need more studies to figure out which tapering regimen will promote a more favorable outcome,” she said.
“The ideal regimen will be one in which patients can comply with follow-up visits and have thyroid function testing done before symptoms of hypothyroidism develop.”
In addition to likely offering no benefit to people with subclinical hypothyroidism, other reasons for discontinuing LT4 in patients who are considered appropriate candidates include concerns about side effects in older patients.
The authors say there is evidence indicating that as many as 50% of patients older than 65 who take thyroid hormones develop iatrogenic hyperthyroidism, which can have detrimental effects including an increased risk for cardiac arrhythmias, angina pectoris, bone loss, and fractures.
Collaborative approach to ‘deprescribing’ suggested
To get patients off LT4, the authors suggest a collaborative approach of “deprescribing,” whereby the health care professional supervises with a goal of managing polypharmacy and improving outcomes.
“This systematic process starts with an accurate evaluation of the medication list, followed by identification of potentially inappropriate medications, collaboration between patients and clinicians to decide whether deprescribing would be appropriate, and establishing a supportive plan to safely deprescribe the medication,” they write.
When decision-making is shared, patients are more likely to consider discontinuation if they understand why the medication is inappropriate, have their concerns related to the discontinuation addressed, understand the process, and feel that they have the support of the clinical team, the authors conclude.
The authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Approximately a third of patients treated for hypothyroidism continue to maintain normal thyroid levels after discontinuing thyroid hormone replacement therapy.
Those who were treated for overt hypothyroidism were less likely to maintain normal hormone levels than those with subclinical disease, the new meta-analysis shows.
“This analysis is the first to summarize the limited evidence regarding successful thyroid hormone discontinuation, but unfortunately more research is needed to develop an evidenced-based strategy for deprescribing thyroid hormone replacement,” Nydia Burgos, MD, and colleagues write in their article published online in Thyroid.
Nevertheless, the main findings were somewhat surprising, Dr. Burgos of the division of endocrinology, diabetes and metabolism, University of Puerto Rico, told this news organization.
“I expected that a considerable portion of patients would remain euthyroid, but up to a third of patients was an impressive number,” she said.
The finding could be an indicator of people who may not have had much benefit from the treatment in the first place, she noted.
“The truth of the matter is that levothyroxine (LT4) is among the top-prescribed drugs in the United States, and every day in clinics we encounter patients that were started on thyroid hormone replacement therapy for unclear reasons, as a therapeutic trial that was never reassessed, or as treatment for subclinical hypothyroidism without having convincing criteria for treatment,” she observed.
Meta-analysis of 17 studies examining LT4 discontinuation
Known to be highly effective in the treatment of overt hypothyroidism, LT4 is often prescribed long term; however, it is also commonly prescribed for patients with subclinical hypothyroidism, despite research suggesting no benefits in these patients.
With a guideline panel underscoring the lack of evidence and issuing a “strong recommendation” in May 2019 against treatment with thyroid hormones in adults with subclinical hypothyroidism (elevated thyroid-stimulating hormone [TSH] levels and normal free T4 levels), clinicians may increasingly be considering discontinuation strategies.
To examine the evidence to date on the clinical outcomes of discontinuing LT4, Dr. Burgos and colleagues conducted a meta-analysis in which they identified 17 observational studies that met the inclusion criteria. Of a total of 1,103 patients in the studies, 86% were women. Most studies included only adults.
With a median follow-up of 5 years, the pooled estimate of patients maintaining euthyroidism after treatment discontinuation was 37.2%.
The estimated rate of remaining euthyroid was significantly lower among those with overt hypothyroidism (11.8%) compared with those with subclinical hypothyroidism (35.6%).
Meanwhile, as many as 65.8% of patients ended up restarting thyroid hormone treatment during the follow-up period, according to pooled estimates, and the rate was as high as 87.2% in patients with overt hypothyroidism. The mean increase in TSH from time of LT4 discontinuation to follow-up was 9.4 mIU/L.
Among specific factors shown to be linked to a lower likelihood of euthyroidism at follow-up were inconsistent echogenicity on thyroid ultrasound, elevated TSH (8-9 mIU/L), and the presence of thyroid antibodies.
Only a few of the studies evaluated thyroid hormones other than synthetic LT4 (such as the commonly used desiccated thyroid), and so the analysis did not compare differences between therapies, Dr. Burgos noted.
Despite the lack of evidence of benefits of LT4 treatment for subclinical hypothyroidism, the finding that, even among those patients, approximately two-thirds were not euthyroid at follow-up was not unexpected, she added.
“I am not surprised that, even in the subclinical hypothyroidism group about two-thirds of participants were not euthyroid, because when looking at the natural history of subclinical hypothyroidism in other studies, only a fifth had normalized thyroid hormone tests, while the majority continue with mild subclinical hypothyroidism and a fifth progress to overt hypothyroidism,” she explained.
More work needed to determine best way to taper down LT4
The specific regimens for discontinuing LT4 were detailed in only three studies and reflected varying approaches, ranging from tapering down the dose over 2 weeks to reducing the dose over several more weeks, or even months, Dr. Burgos noted
“We need more studies to figure out which tapering regimen will promote a more favorable outcome,” she said.
“The ideal regimen will be one in which patients can comply with follow-up visits and have thyroid function testing done before symptoms of hypothyroidism develop.”
In addition to likely offering no benefit to people with subclinical hypothyroidism, other reasons for discontinuing LT4 in patients who are considered appropriate candidates include concerns about side effects in older patients.
The authors say there is evidence indicating that as many as 50% of patients older than 65 who take thyroid hormones develop iatrogenic hyperthyroidism, which can have detrimental effects including an increased risk for cardiac arrhythmias, angina pectoris, bone loss, and fractures.
Collaborative approach to ‘deprescribing’ suggested
To get patients off LT4, the authors suggest a collaborative approach of “deprescribing,” whereby the health care professional supervises with a goal of managing polypharmacy and improving outcomes.
“This systematic process starts with an accurate evaluation of the medication list, followed by identification of potentially inappropriate medications, collaboration between patients and clinicians to decide whether deprescribing would be appropriate, and establishing a supportive plan to safely deprescribe the medication,” they write.
When decision-making is shared, patients are more likely to consider discontinuation if they understand why the medication is inappropriate, have their concerns related to the discontinuation addressed, understand the process, and feel that they have the support of the clinical team, the authors conclude.
The authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Approximately a third of patients treated for hypothyroidism continue to maintain normal thyroid levels after discontinuing thyroid hormone replacement therapy.
Those who were treated for overt hypothyroidism were less likely to maintain normal hormone levels than those with subclinical disease, the new meta-analysis shows.
“This analysis is the first to summarize the limited evidence regarding successful thyroid hormone discontinuation, but unfortunately more research is needed to develop an evidenced-based strategy for deprescribing thyroid hormone replacement,” Nydia Burgos, MD, and colleagues write in their article published online in Thyroid.
Nevertheless, the main findings were somewhat surprising, Dr. Burgos of the division of endocrinology, diabetes and metabolism, University of Puerto Rico, told this news organization.
“I expected that a considerable portion of patients would remain euthyroid, but up to a third of patients was an impressive number,” she said.
The finding could be an indicator of people who may not have had much benefit from the treatment in the first place, she noted.
“The truth of the matter is that levothyroxine (LT4) is among the top-prescribed drugs in the United States, and every day in clinics we encounter patients that were started on thyroid hormone replacement therapy for unclear reasons, as a therapeutic trial that was never reassessed, or as treatment for subclinical hypothyroidism without having convincing criteria for treatment,” she observed.
Meta-analysis of 17 studies examining LT4 discontinuation
Known to be highly effective in the treatment of overt hypothyroidism, LT4 is often prescribed long term; however, it is also commonly prescribed for patients with subclinical hypothyroidism, despite research suggesting no benefits in these patients.
With a guideline panel underscoring the lack of evidence and issuing a “strong recommendation” in May 2019 against treatment with thyroid hormones in adults with subclinical hypothyroidism (elevated thyroid-stimulating hormone [TSH] levels and normal free T4 levels), clinicians may increasingly be considering discontinuation strategies.
To examine the evidence to date on the clinical outcomes of discontinuing LT4, Dr. Burgos and colleagues conducted a meta-analysis in which they identified 17 observational studies that met the inclusion criteria. Of a total of 1,103 patients in the studies, 86% were women. Most studies included only adults.
With a median follow-up of 5 years, the pooled estimate of patients maintaining euthyroidism after treatment discontinuation was 37.2%.
The estimated rate of remaining euthyroid was significantly lower among those with overt hypothyroidism (11.8%) compared with those with subclinical hypothyroidism (35.6%).
Meanwhile, as many as 65.8% of patients ended up restarting thyroid hormone treatment during the follow-up period, according to pooled estimates, and the rate was as high as 87.2% in patients with overt hypothyroidism. The mean increase in TSH from time of LT4 discontinuation to follow-up was 9.4 mIU/L.
Among specific factors shown to be linked to a lower likelihood of euthyroidism at follow-up were inconsistent echogenicity on thyroid ultrasound, elevated TSH (8-9 mIU/L), and the presence of thyroid antibodies.
Only a few of the studies evaluated thyroid hormones other than synthetic LT4 (such as the commonly used desiccated thyroid), and so the analysis did not compare differences between therapies, Dr. Burgos noted.
Despite the lack of evidence of benefits of LT4 treatment for subclinical hypothyroidism, the finding that, even among those patients, approximately two-thirds were not euthyroid at follow-up was not unexpected, she added.
“I am not surprised that, even in the subclinical hypothyroidism group about two-thirds of participants were not euthyroid, because when looking at the natural history of subclinical hypothyroidism in other studies, only a fifth had normalized thyroid hormone tests, while the majority continue with mild subclinical hypothyroidism and a fifth progress to overt hypothyroidism,” she explained.
More work needed to determine best way to taper down LT4
The specific regimens for discontinuing LT4 were detailed in only three studies and reflected varying approaches, ranging from tapering down the dose over 2 weeks to reducing the dose over several more weeks, or even months, Dr. Burgos noted
“We need more studies to figure out which tapering regimen will promote a more favorable outcome,” she said.
“The ideal regimen will be one in which patients can comply with follow-up visits and have thyroid function testing done before symptoms of hypothyroidism develop.”
In addition to likely offering no benefit to people with subclinical hypothyroidism, other reasons for discontinuing LT4 in patients who are considered appropriate candidates include concerns about side effects in older patients.
The authors say there is evidence indicating that as many as 50% of patients older than 65 who take thyroid hormones develop iatrogenic hyperthyroidism, which can have detrimental effects including an increased risk for cardiac arrhythmias, angina pectoris, bone loss, and fractures.
Collaborative approach to ‘deprescribing’ suggested
To get patients off LT4, the authors suggest a collaborative approach of “deprescribing,” whereby the health care professional supervises with a goal of managing polypharmacy and improving outcomes.
“This systematic process starts with an accurate evaluation of the medication list, followed by identification of potentially inappropriate medications, collaboration between patients and clinicians to decide whether deprescribing would be appropriate, and establishing a supportive plan to safely deprescribe the medication,” they write.
When decision-making is shared, patients are more likely to consider discontinuation if they understand why the medication is inappropriate, have their concerns related to the discontinuation addressed, understand the process, and feel that they have the support of the clinical team, the authors conclude.
The authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Global thyroid cancer overdiagnosis in children and adolescents
Global patterns of the incidence of thyroid cancer in children and adolescents closely correspond to the increases seen in recent decades in adults. The patterns point to the same culprit in both groups – overdiagnosis. The finding underscores recommendations to limit screening.
“Our findings suggest that recommendations against screening for thyroid cancer in the asymptomatic adult population who are free from risk factors should be extended to explicitly recommend against screening for thyroid cancer in similar populations of children and adolescents,” say the authors, led by Salvatore Vaccarella, PhD, of the International Agency for Research on Cancer, in Lyon, France.
The study was published online Jan. 19 in The Lancet Diabetes and Endocrinology.
In an accompanying comment, Livia Lamartina and colleagues from the department of nuclear medicine and endocrine oncology, Institut Gustave Roussy and the University Paris-Saclay, Villejuif, France, emphasize that unnecessary screening of thyroid cancer in children can have substantial implications.
“Overdiagnosis might transform a child into a thyroid cancer patient for the rest of their life, and overtreatment might induce complications and possibly lead to the requirement of lifelong thyroid hormone treatment,” they write.
“Therefore, screening with ultrasonography should not be recommended in asymptomatic children and adolescents,” they conclude.
Study findings
For the study, Dr. Vaccarella and colleagues evaluated the incidence of thyroid cancer in 49 countries and territories and mortality in 27 countries, using the most up-to-date data from the International Incidence of Childhood Cancer Volume 3 study, the Cancer in Five Continents database, and the World Health Organization mortality database.
Although there was considerable variability between countries, the incidence of thyroid cancer in children and adolescents aged 0-19 years increased rapidly between 1998 and 2002 and again between 2008 and 2012 in nearly all countries.
Country-specific incidence rates strongly correlated with rates in adults (r > 0.8), including the temporal aspects of the incidence rates (r > .0.6).
Of the 8049 thyroid cancers that were detected, 6935 (86.2%) were papillary carcinomas, 682 (8.5%) were follicular carcinomas, and 307 (3.8%) were medullary carcinomas, as determined on the basis of the WHO classification of thyroid carcinomas. Sixty-four tumors (0.8%) were of unspecified subtype. As is commonly observed in adults, rates were higher in girls than in boys and increased with older age for both sexes.
The strong correlation between children and adults in the timing of the increases in incidence was especially notable in countries where overdiagnosis has been identified as having a major role in the increasing thyroid cancer rates. Those countries are South Korea, the United States, Italy, France, and Australia, where 60%-90% of thyroid cancer diagnoses are attributable to overdiagnosis. Overall, the incidence of thyroid cancer was less than 1.5 per one million person-years in children younger than 10 years. There were small variations by country and sex.
Thyroid cancer mortalities remain low
Overall, the rate of thyroid cancer mortality among those younger than 20 years in each country was less than 0.1 per 10 million person-years, “corresponding to less than 10 deaths per year in all of the included countries collectively,” note Dr. Vaccarella and colleagues.
“The epidemiological pattern seen in children and adolescents mirrored that seen in adults. These findings suggest that, in affected countries and territories, there might be overdiagnosis in children and adolescents, as has been observed in adults,” they write.
The incidence of thyroid cancer in children and adolescents between 2008 and 2012 ranged from 0.4 per one million person-years in Uganda and Kenya and 13.4 per 1 million person-years in Belarus, where the increase is believed to be related to the Chernobyl nuclear power plant accident and to increased screening in the years following the accident.
Subclinical discoveries may lead to unnecessary measures
Thyroid cancer was once a rare condition. Rates began to increase steadily in the 1990s, corresponding with rapid advances in noninvasive diagnostic imaging. Currently, thyroid cancer is the fifth most diagnosed cancer worldwide in adult women and the third most common in women aged 50 years and younger.
Diagnostic measures ranging from ultrasound and MRI to fine-needle aspiration biopsy have played a large role in the increase in diagnoses. The diagnostic techniques are revealing subclinical cancers in thyroid glands that previously went undetected and that usually do not cause harm over a person’s lifetime. According to Dr. Vaccarella and colleagues, such discoveries can open the door to a wide range of unnecessary measures.
The possible consequences of overdiagnosis include unnecessary treatments, the need to undergo lifelong medical care, and potential adverse effects, which could negatively affect quality of life.
Recent research from the International Agency for Research on Cancer has indicated that there has been an “epidemic of overdiagnosis” of thyroid cancer. The pattern has even reached less affluent regions as diagnostic technologies have become widely available.
“What is surprising is the magnitude of this,” Dr. Vaccarella said in an interview.
“Without overdiagnosis, thyroid cancer would probably still be a relatively rare cancer,” he said.
The study authors have disclosed no relevant financial relationships. Dr. Lamartina has received personal, advisory board, and clinical trial principal investigator fees from Bayer, personal fees from Eisai, and clinical trial principal investigator fees from AstraZeneca. The other editorialists’ financial relationships are listed in the original article.
A version of this article first appeared on Medscape.com.
Global patterns of the incidence of thyroid cancer in children and adolescents closely correspond to the increases seen in recent decades in adults. The patterns point to the same culprit in both groups – overdiagnosis. The finding underscores recommendations to limit screening.
“Our findings suggest that recommendations against screening for thyroid cancer in the asymptomatic adult population who are free from risk factors should be extended to explicitly recommend against screening for thyroid cancer in similar populations of children and adolescents,” say the authors, led by Salvatore Vaccarella, PhD, of the International Agency for Research on Cancer, in Lyon, France.
The study was published online Jan. 19 in The Lancet Diabetes and Endocrinology.
In an accompanying comment, Livia Lamartina and colleagues from the department of nuclear medicine and endocrine oncology, Institut Gustave Roussy and the University Paris-Saclay, Villejuif, France, emphasize that unnecessary screening of thyroid cancer in children can have substantial implications.
“Overdiagnosis might transform a child into a thyroid cancer patient for the rest of their life, and overtreatment might induce complications and possibly lead to the requirement of lifelong thyroid hormone treatment,” they write.
“Therefore, screening with ultrasonography should not be recommended in asymptomatic children and adolescents,” they conclude.
Study findings
For the study, Dr. Vaccarella and colleagues evaluated the incidence of thyroid cancer in 49 countries and territories and mortality in 27 countries, using the most up-to-date data from the International Incidence of Childhood Cancer Volume 3 study, the Cancer in Five Continents database, and the World Health Organization mortality database.
Although there was considerable variability between countries, the incidence of thyroid cancer in children and adolescents aged 0-19 years increased rapidly between 1998 and 2002 and again between 2008 and 2012 in nearly all countries.
Country-specific incidence rates strongly correlated with rates in adults (r > 0.8), including the temporal aspects of the incidence rates (r > .0.6).
Of the 8049 thyroid cancers that were detected, 6935 (86.2%) were papillary carcinomas, 682 (8.5%) were follicular carcinomas, and 307 (3.8%) were medullary carcinomas, as determined on the basis of the WHO classification of thyroid carcinomas. Sixty-four tumors (0.8%) were of unspecified subtype. As is commonly observed in adults, rates were higher in girls than in boys and increased with older age for both sexes.
The strong correlation between children and adults in the timing of the increases in incidence was especially notable in countries where overdiagnosis has been identified as having a major role in the increasing thyroid cancer rates. Those countries are South Korea, the United States, Italy, France, and Australia, where 60%-90% of thyroid cancer diagnoses are attributable to overdiagnosis. Overall, the incidence of thyroid cancer was less than 1.5 per one million person-years in children younger than 10 years. There were small variations by country and sex.
Thyroid cancer mortalities remain low
Overall, the rate of thyroid cancer mortality among those younger than 20 years in each country was less than 0.1 per 10 million person-years, “corresponding to less than 10 deaths per year in all of the included countries collectively,” note Dr. Vaccarella and colleagues.
“The epidemiological pattern seen in children and adolescents mirrored that seen in adults. These findings suggest that, in affected countries and territories, there might be overdiagnosis in children and adolescents, as has been observed in adults,” they write.
The incidence of thyroid cancer in children and adolescents between 2008 and 2012 ranged from 0.4 per one million person-years in Uganda and Kenya and 13.4 per 1 million person-years in Belarus, where the increase is believed to be related to the Chernobyl nuclear power plant accident and to increased screening in the years following the accident.
Subclinical discoveries may lead to unnecessary measures
Thyroid cancer was once a rare condition. Rates began to increase steadily in the 1990s, corresponding with rapid advances in noninvasive diagnostic imaging. Currently, thyroid cancer is the fifth most diagnosed cancer worldwide in adult women and the third most common in women aged 50 years and younger.
Diagnostic measures ranging from ultrasound and MRI to fine-needle aspiration biopsy have played a large role in the increase in diagnoses. The diagnostic techniques are revealing subclinical cancers in thyroid glands that previously went undetected and that usually do not cause harm over a person’s lifetime. According to Dr. Vaccarella and colleagues, such discoveries can open the door to a wide range of unnecessary measures.
The possible consequences of overdiagnosis include unnecessary treatments, the need to undergo lifelong medical care, and potential adverse effects, which could negatively affect quality of life.
Recent research from the International Agency for Research on Cancer has indicated that there has been an “epidemic of overdiagnosis” of thyroid cancer. The pattern has even reached less affluent regions as diagnostic technologies have become widely available.
“What is surprising is the magnitude of this,” Dr. Vaccarella said in an interview.
“Without overdiagnosis, thyroid cancer would probably still be a relatively rare cancer,” he said.
The study authors have disclosed no relevant financial relationships. Dr. Lamartina has received personal, advisory board, and clinical trial principal investigator fees from Bayer, personal fees from Eisai, and clinical trial principal investigator fees from AstraZeneca. The other editorialists’ financial relationships are listed in the original article.
A version of this article first appeared on Medscape.com.
Global patterns of the incidence of thyroid cancer in children and adolescents closely correspond to the increases seen in recent decades in adults. The patterns point to the same culprit in both groups – overdiagnosis. The finding underscores recommendations to limit screening.
“Our findings suggest that recommendations against screening for thyroid cancer in the asymptomatic adult population who are free from risk factors should be extended to explicitly recommend against screening for thyroid cancer in similar populations of children and adolescents,” say the authors, led by Salvatore Vaccarella, PhD, of the International Agency for Research on Cancer, in Lyon, France.
The study was published online Jan. 19 in The Lancet Diabetes and Endocrinology.
In an accompanying comment, Livia Lamartina and colleagues from the department of nuclear medicine and endocrine oncology, Institut Gustave Roussy and the University Paris-Saclay, Villejuif, France, emphasize that unnecessary screening of thyroid cancer in children can have substantial implications.
“Overdiagnosis might transform a child into a thyroid cancer patient for the rest of their life, and overtreatment might induce complications and possibly lead to the requirement of lifelong thyroid hormone treatment,” they write.
“Therefore, screening with ultrasonography should not be recommended in asymptomatic children and adolescents,” they conclude.
Study findings
For the study, Dr. Vaccarella and colleagues evaluated the incidence of thyroid cancer in 49 countries and territories and mortality in 27 countries, using the most up-to-date data from the International Incidence of Childhood Cancer Volume 3 study, the Cancer in Five Continents database, and the World Health Organization mortality database.
Although there was considerable variability between countries, the incidence of thyroid cancer in children and adolescents aged 0-19 years increased rapidly between 1998 and 2002 and again between 2008 and 2012 in nearly all countries.
Country-specific incidence rates strongly correlated with rates in adults (r > 0.8), including the temporal aspects of the incidence rates (r > .0.6).
Of the 8049 thyroid cancers that were detected, 6935 (86.2%) were papillary carcinomas, 682 (8.5%) were follicular carcinomas, and 307 (3.8%) were medullary carcinomas, as determined on the basis of the WHO classification of thyroid carcinomas. Sixty-four tumors (0.8%) were of unspecified subtype. As is commonly observed in adults, rates were higher in girls than in boys and increased with older age for both sexes.
The strong correlation between children and adults in the timing of the increases in incidence was especially notable in countries where overdiagnosis has been identified as having a major role in the increasing thyroid cancer rates. Those countries are South Korea, the United States, Italy, France, and Australia, where 60%-90% of thyroid cancer diagnoses are attributable to overdiagnosis. Overall, the incidence of thyroid cancer was less than 1.5 per one million person-years in children younger than 10 years. There were small variations by country and sex.
Thyroid cancer mortalities remain low
Overall, the rate of thyroid cancer mortality among those younger than 20 years in each country was less than 0.1 per 10 million person-years, “corresponding to less than 10 deaths per year in all of the included countries collectively,” note Dr. Vaccarella and colleagues.
“The epidemiological pattern seen in children and adolescents mirrored that seen in adults. These findings suggest that, in affected countries and territories, there might be overdiagnosis in children and adolescents, as has been observed in adults,” they write.
The incidence of thyroid cancer in children and adolescents between 2008 and 2012 ranged from 0.4 per one million person-years in Uganda and Kenya and 13.4 per 1 million person-years in Belarus, where the increase is believed to be related to the Chernobyl nuclear power plant accident and to increased screening in the years following the accident.
Subclinical discoveries may lead to unnecessary measures
Thyroid cancer was once a rare condition. Rates began to increase steadily in the 1990s, corresponding with rapid advances in noninvasive diagnostic imaging. Currently, thyroid cancer is the fifth most diagnosed cancer worldwide in adult women and the third most common in women aged 50 years and younger.
Diagnostic measures ranging from ultrasound and MRI to fine-needle aspiration biopsy have played a large role in the increase in diagnoses. The diagnostic techniques are revealing subclinical cancers in thyroid glands that previously went undetected and that usually do not cause harm over a person’s lifetime. According to Dr. Vaccarella and colleagues, such discoveries can open the door to a wide range of unnecessary measures.
The possible consequences of overdiagnosis include unnecessary treatments, the need to undergo lifelong medical care, and potential adverse effects, which could negatively affect quality of life.
Recent research from the International Agency for Research on Cancer has indicated that there has been an “epidemic of overdiagnosis” of thyroid cancer. The pattern has even reached less affluent regions as diagnostic technologies have become widely available.
“What is surprising is the magnitude of this,” Dr. Vaccarella said in an interview.
“Without overdiagnosis, thyroid cancer would probably still be a relatively rare cancer,” he said.
The study authors have disclosed no relevant financial relationships. Dr. Lamartina has received personal, advisory board, and clinical trial principal investigator fees from Bayer, personal fees from Eisai, and clinical trial principal investigator fees from AstraZeneca. The other editorialists’ financial relationships are listed in the original article.
A version of this article first appeared on Medscape.com.
Adding liothyronine for hypothyroidism doesn’t up breast cancer risk
“An increasing number of patients ask their physicians for a prescription of combination therapy, often causing tensions. Thus, the question of whether combination therapy does any harm to patients is crucial,” say Tereza Planck, MD, PhD, of Skane University Hospital, Malmo, Sweden, and colleagues, in their article published online Jan. 5 in Thyroid.
“Our data provide reassuring evidence regarding the risk of cancer and mortality,” they stress.
Asked to comment, Caroline T. Nguyen, MD, agrees that the study results are welcome in light of some previous evidence.
“The findings of these [prior] studies were concerning as they suggested an association between T3 and breast cancer, breast cancer-specific mortality, and poorer prognosis with potential estrogen-like activity of T3 on the estrogen receptor,” Dr. Nguyen of the division of endocrinology, diabetes & metabolism at Keck Medical Center of University of Southern California, Los Angeles, told this news organization.
“Therefore, the findings of this paper provide some reassurance, which is important because, as the paper states, the use of T3 is becoming increasingly common.”
Many patients with hypothyroidism opt to add liothyronine
Although the standard treatment for hypothyroidism, levothyroxine, increases free thyroxine (T4) to high-normal levels, it may potentially lower triiodothyronine (T3) to relatively low levels. There is speculation that the imbalance in a subset of patients could explain why some fail to have an adequate reduction of symptoms with levothyroxine alone.
To offset the effect, some add liothyronine (a synthetic version of T3) to levothyroxine treatment as so-called “combination therapy.” However, a long-term study conducted in Scotland showed a borderline significant increase in breast cancer risk with the combination, raising concern.
To further investigate, Dr. Planck and coauthors used Swedish adult population data, identifying 575,461 individuals who had made at least three purchases of thyroid hormone therapy between July 2005 and December 2017, and had no history of breast cancer at the time of their first prescription.
Among the individuals, 11,147 had made at least three purchases of LT3, including combinations with LT4. LT4-only users were an average age of 54.4 years, and the average age of those who also took LT3 was 44.7 years.
Over a median follow-up of 8.1 years, there was no significantly increased risk of breast cancer among women treated with LT3 plus LT4 versus LT4 alone (hazard ratio, 0.93), after adjusting for differences in age, sex, previous thyroid cancer, previous other cancer, use of antithyroid preparations, use of sex hormones, and dose.
Further evaluation of women as well as men showed those treated with LT3 also had no increased incidence of any cancer (HR, 0.97).
In dose-adjusted models, LT3 treatment did, surprisingly, appear to have a protective effect in terms of all-cause mortality (HR, 0.69) and any cancer mortality (HR, 0.78) for men and women.
However, the implications of these latter results remain uncertain, first author Dr. Planck said in an interview.
“We think the data on reduced mortality should be interpreted with caution, as we only observe the differences in the models adjusting for dose,” she noted.
LT3 treatment still considered ‘experimental’
Despite the dramatic increase in LT3 prescribing in recent years noted by the authors, as many as five systematic reviews/meta-analyses have shown no superiority of combination therapy over LT4 alone in terms of hypothyroid symptoms, quality of life, or patient preference.
As a result, many international guidelines still consider the combination-treatment approach to be experimental.
Other trials that have raised concerns about the combination include previous large, prospective Swedish studies that have linked higher endogenous T3 levels to breast cancer in postmenopausal women.
As for the mechanism, some small experimental studies have suggested an estrogenlike effect whereby T3 could enhance the proliferation of breast cancer cells.
On a broader level, thyroid hormones, in general, have been extensively studied in cancer research as possibly promoting cancer cell proliferation in a variety of cancer types.
However, the current findings should lay some of those concerns to rest, Dr. Planck reiterated: “Our data provide reassuring evidence regarding the risk of cancer and mortality.”
“We did not identify any increase in breast cancer incidence, any cancer incidence, all-cause mortality, any cancer mortality, or breast cancer mortality between individuals using LT3 and LT4 treatment.”
The authors and Nguyen have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
“An increasing number of patients ask their physicians for a prescription of combination therapy, often causing tensions. Thus, the question of whether combination therapy does any harm to patients is crucial,” say Tereza Planck, MD, PhD, of Skane University Hospital, Malmo, Sweden, and colleagues, in their article published online Jan. 5 in Thyroid.
“Our data provide reassuring evidence regarding the risk of cancer and mortality,” they stress.
Asked to comment, Caroline T. Nguyen, MD, agrees that the study results are welcome in light of some previous evidence.
“The findings of these [prior] studies were concerning as they suggested an association between T3 and breast cancer, breast cancer-specific mortality, and poorer prognosis with potential estrogen-like activity of T3 on the estrogen receptor,” Dr. Nguyen of the division of endocrinology, diabetes & metabolism at Keck Medical Center of University of Southern California, Los Angeles, told this news organization.
“Therefore, the findings of this paper provide some reassurance, which is important because, as the paper states, the use of T3 is becoming increasingly common.”
Many patients with hypothyroidism opt to add liothyronine
Although the standard treatment for hypothyroidism, levothyroxine, increases free thyroxine (T4) to high-normal levels, it may potentially lower triiodothyronine (T3) to relatively low levels. There is speculation that the imbalance in a subset of patients could explain why some fail to have an adequate reduction of symptoms with levothyroxine alone.
To offset the effect, some add liothyronine (a synthetic version of T3) to levothyroxine treatment as so-called “combination therapy.” However, a long-term study conducted in Scotland showed a borderline significant increase in breast cancer risk with the combination, raising concern.
To further investigate, Dr. Planck and coauthors used Swedish adult population data, identifying 575,461 individuals who had made at least three purchases of thyroid hormone therapy between July 2005 and December 2017, and had no history of breast cancer at the time of their first prescription.
Among the individuals, 11,147 had made at least three purchases of LT3, including combinations with LT4. LT4-only users were an average age of 54.4 years, and the average age of those who also took LT3 was 44.7 years.
Over a median follow-up of 8.1 years, there was no significantly increased risk of breast cancer among women treated with LT3 plus LT4 versus LT4 alone (hazard ratio, 0.93), after adjusting for differences in age, sex, previous thyroid cancer, previous other cancer, use of antithyroid preparations, use of sex hormones, and dose.
Further evaluation of women as well as men showed those treated with LT3 also had no increased incidence of any cancer (HR, 0.97).
In dose-adjusted models, LT3 treatment did, surprisingly, appear to have a protective effect in terms of all-cause mortality (HR, 0.69) and any cancer mortality (HR, 0.78) for men and women.
However, the implications of these latter results remain uncertain, first author Dr. Planck said in an interview.
“We think the data on reduced mortality should be interpreted with caution, as we only observe the differences in the models adjusting for dose,” she noted.
LT3 treatment still considered ‘experimental’
Despite the dramatic increase in LT3 prescribing in recent years noted by the authors, as many as five systematic reviews/meta-analyses have shown no superiority of combination therapy over LT4 alone in terms of hypothyroid symptoms, quality of life, or patient preference.
As a result, many international guidelines still consider the combination-treatment approach to be experimental.
Other trials that have raised concerns about the combination include previous large, prospective Swedish studies that have linked higher endogenous T3 levels to breast cancer in postmenopausal women.
As for the mechanism, some small experimental studies have suggested an estrogenlike effect whereby T3 could enhance the proliferation of breast cancer cells.
On a broader level, thyroid hormones, in general, have been extensively studied in cancer research as possibly promoting cancer cell proliferation in a variety of cancer types.
However, the current findings should lay some of those concerns to rest, Dr. Planck reiterated: “Our data provide reassuring evidence regarding the risk of cancer and mortality.”
“We did not identify any increase in breast cancer incidence, any cancer incidence, all-cause mortality, any cancer mortality, or breast cancer mortality between individuals using LT3 and LT4 treatment.”
The authors and Nguyen have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
“An increasing number of patients ask their physicians for a prescription of combination therapy, often causing tensions. Thus, the question of whether combination therapy does any harm to patients is crucial,” say Tereza Planck, MD, PhD, of Skane University Hospital, Malmo, Sweden, and colleagues, in their article published online Jan. 5 in Thyroid.
“Our data provide reassuring evidence regarding the risk of cancer and mortality,” they stress.
Asked to comment, Caroline T. Nguyen, MD, agrees that the study results are welcome in light of some previous evidence.
“The findings of these [prior] studies were concerning as they suggested an association between T3 and breast cancer, breast cancer-specific mortality, and poorer prognosis with potential estrogen-like activity of T3 on the estrogen receptor,” Dr. Nguyen of the division of endocrinology, diabetes & metabolism at Keck Medical Center of University of Southern California, Los Angeles, told this news organization.
“Therefore, the findings of this paper provide some reassurance, which is important because, as the paper states, the use of T3 is becoming increasingly common.”
Many patients with hypothyroidism opt to add liothyronine
Although the standard treatment for hypothyroidism, levothyroxine, increases free thyroxine (T4) to high-normal levels, it may potentially lower triiodothyronine (T3) to relatively low levels. There is speculation that the imbalance in a subset of patients could explain why some fail to have an adequate reduction of symptoms with levothyroxine alone.
To offset the effect, some add liothyronine (a synthetic version of T3) to levothyroxine treatment as so-called “combination therapy.” However, a long-term study conducted in Scotland showed a borderline significant increase in breast cancer risk with the combination, raising concern.
To further investigate, Dr. Planck and coauthors used Swedish adult population data, identifying 575,461 individuals who had made at least three purchases of thyroid hormone therapy between July 2005 and December 2017, and had no history of breast cancer at the time of their first prescription.
Among the individuals, 11,147 had made at least three purchases of LT3, including combinations with LT4. LT4-only users were an average age of 54.4 years, and the average age of those who also took LT3 was 44.7 years.
Over a median follow-up of 8.1 years, there was no significantly increased risk of breast cancer among women treated with LT3 plus LT4 versus LT4 alone (hazard ratio, 0.93), after adjusting for differences in age, sex, previous thyroid cancer, previous other cancer, use of antithyroid preparations, use of sex hormones, and dose.
Further evaluation of women as well as men showed those treated with LT3 also had no increased incidence of any cancer (HR, 0.97).
In dose-adjusted models, LT3 treatment did, surprisingly, appear to have a protective effect in terms of all-cause mortality (HR, 0.69) and any cancer mortality (HR, 0.78) for men and women.
However, the implications of these latter results remain uncertain, first author Dr. Planck said in an interview.
“We think the data on reduced mortality should be interpreted with caution, as we only observe the differences in the models adjusting for dose,” she noted.
LT3 treatment still considered ‘experimental’
Despite the dramatic increase in LT3 prescribing in recent years noted by the authors, as many as five systematic reviews/meta-analyses have shown no superiority of combination therapy over LT4 alone in terms of hypothyroid symptoms, quality of life, or patient preference.
As a result, many international guidelines still consider the combination-treatment approach to be experimental.
Other trials that have raised concerns about the combination include previous large, prospective Swedish studies that have linked higher endogenous T3 levels to breast cancer in postmenopausal women.
As for the mechanism, some small experimental studies have suggested an estrogenlike effect whereby T3 could enhance the proliferation of breast cancer cells.
On a broader level, thyroid hormones, in general, have been extensively studied in cancer research as possibly promoting cancer cell proliferation in a variety of cancer types.
However, the current findings should lay some of those concerns to rest, Dr. Planck reiterated: “Our data provide reassuring evidence regarding the risk of cancer and mortality.”
“We did not identify any increase in breast cancer incidence, any cancer incidence, all-cause mortality, any cancer mortality, or breast cancer mortality between individuals using LT3 and LT4 treatment.”
The authors and Nguyen have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Metformin treatment again linked to fewer deaths from COVID-19
People with type 2 diabetes who develop COVID-19 show a substantially reduced risk of dying if they are taking metformin, shows a study that adds to prior research indicating the drug might somehow play a role in reducing the severity of infection.
“Unlike several previous analyses, this was a study in a racially diverse population with a high proportion of Blacks/African Americans and [it] revealed that metformin treatment of diabetes prior to diagnosis with COVID-19 was associated with a dramatic threefold reduced mortality in subjects with type 2 diabetes, even after correcting for multiple covariates,” first author Anath Shalev, MD, of the Comprehensive Diabetes Center at the University of Alabama at Birmingham, said in an interview.
But Anne Peters, MD, a professor of clinical medicine at the University of Southern California, Los Angeles, said caution is needed when interpreting these findings.
“It’s hard to tease out the true effects because, for instance, those treated with insulin may be a sicker subset of patients with diabetes than those on metformin, or those with comorbidities such as renal insufficiency may not be treated with metformin” she said in an interview.
“In general, though, treatment obviously matters and people who are better treated tend to do better, so while I think this study raises the question of what role metformin plays in the risk of mortality and COVID-19, I don’t think it necessarily proves the association,” Dr. Peters asserted.
Diverse population
The new study, published this month in Frontiers of Endocrinology, included 25,326 individuals who were tested for COVID-19 at the University of Alabama at Birmingham Hospital between February and June 2020.
Overall, 2.4% tested positive for COVID-19 (n = 604), which the authors note is likely a low figure because screening included asymptomatic hospital staff and patients having elective procedures.
Black/African American patients had a significantly higher risk of COVID-19 positivity, compared with White patients (odds ratio, 2.6; P < .0001). Rates were also higher among those with hypertension (OR, 2.46), diabetes (OR, 2.11), and obesity (OR, 1.93), compared with those without each condition (all P < .0001).
The overall mortality rate in COVID-19-positive patients was 11%. Diabetes was associated with a dramatically increased risk of death (OR, 3.62; P < .0001), and remained an independent risk factor even after adjusting for age, race, sex, obesity, and hypertension.
Notably, the reduction in mortality among those with diabetes taking metformin prior to COVID-19 diagnosis was significant: 11% of those patients died, compared with 23% of those with diabetes not taking metformin (OR, 0.33; P = .021).
Similar findings reported across varied populations
The study adds to mounting research suggesting metformin could have a protective effect on COVID-19 mortality, including an early report from Wuhan, China, findings from the French CORONADO study, and a U.S. study linking treatment with decreased mortality among women with COVID-19.
Of note, the effects of metformin on mortality in the current study were observed in men and women alike, as well as in high-risk subgroups including African Americans.
“The fact that such similar results were obtained in different populations from around the world suggests that the observed reduction in mortality risk, associated with metformin use in subjects with type 2 diabetes and COVID-19, might be generalizable,” the authors wrote.
“Furthermore, these findings underline the importance of following general diabetes treatment and prevention guidelines and not delaying or discontinuing any metformin treatment,” they add.
Speculation of mechanisms includes anti-inflammatory effects
While the mechanisms behind metformin’s potential role in reducing mortality risk in COVID-19 are unknown, the authors note that the most obvious assumption – that improved glycemic control may be a key factor – is disputed by the study’s finding that blood glucose levels and hemoglobin A1c were not significantly different among COVID-19 survivors taking versus not taking metformin.
They point instead to metformin’s known anti-inflammatory and antithrombotic properties.
“We therefore hypothesize that, by exerting some of these effects, metformin might improve outcomes and we are now in the process of investigating this possibility further,” Dr. Shalev said.
Dr. Peters noted that anti-inflammatory properties, themselves, are not necessarily unique to metformin in the treatment of diabetes.
“Many other agents, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors can reduce inflammation, so I don’t know if that would explain it, but it certainly could help,” she said. “[Reducing inflammation] is a hypothesis you see commonly with diabetes drugs, but I think there are also a lot of metabolic benefits from metformin.”
“It was fascinating that they had the A1c data and that survival with metformin didn’t appear to be as related to A1c levels as one might think,” she added.
Notably, a key advantage, should the effects and mechanisms be validated, is metformin’s high accessibility, Dr. Peters added.
“This doesn’t necessarily tell us what we can do to reduce the health care disparities surrounding COVID-19, but the fact that metformin is low cost and easily available is very important, so maybe it will help as we try to grapple with other risk factors.”
The authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
People with type 2 diabetes who develop COVID-19 show a substantially reduced risk of dying if they are taking metformin, shows a study that adds to prior research indicating the drug might somehow play a role in reducing the severity of infection.
“Unlike several previous analyses, this was a study in a racially diverse population with a high proportion of Blacks/African Americans and [it] revealed that metformin treatment of diabetes prior to diagnosis with COVID-19 was associated with a dramatic threefold reduced mortality in subjects with type 2 diabetes, even after correcting for multiple covariates,” first author Anath Shalev, MD, of the Comprehensive Diabetes Center at the University of Alabama at Birmingham, said in an interview.
But Anne Peters, MD, a professor of clinical medicine at the University of Southern California, Los Angeles, said caution is needed when interpreting these findings.
“It’s hard to tease out the true effects because, for instance, those treated with insulin may be a sicker subset of patients with diabetes than those on metformin, or those with comorbidities such as renal insufficiency may not be treated with metformin” she said in an interview.
“In general, though, treatment obviously matters and people who are better treated tend to do better, so while I think this study raises the question of what role metformin plays in the risk of mortality and COVID-19, I don’t think it necessarily proves the association,” Dr. Peters asserted.
Diverse population
The new study, published this month in Frontiers of Endocrinology, included 25,326 individuals who were tested for COVID-19 at the University of Alabama at Birmingham Hospital between February and June 2020.
Overall, 2.4% tested positive for COVID-19 (n = 604), which the authors note is likely a low figure because screening included asymptomatic hospital staff and patients having elective procedures.
Black/African American patients had a significantly higher risk of COVID-19 positivity, compared with White patients (odds ratio, 2.6; P < .0001). Rates were also higher among those with hypertension (OR, 2.46), diabetes (OR, 2.11), and obesity (OR, 1.93), compared with those without each condition (all P < .0001).
The overall mortality rate in COVID-19-positive patients was 11%. Diabetes was associated with a dramatically increased risk of death (OR, 3.62; P < .0001), and remained an independent risk factor even after adjusting for age, race, sex, obesity, and hypertension.
Notably, the reduction in mortality among those with diabetes taking metformin prior to COVID-19 diagnosis was significant: 11% of those patients died, compared with 23% of those with diabetes not taking metformin (OR, 0.33; P = .021).
Similar findings reported across varied populations
The study adds to mounting research suggesting metformin could have a protective effect on COVID-19 mortality, including an early report from Wuhan, China, findings from the French CORONADO study, and a U.S. study linking treatment with decreased mortality among women with COVID-19.
Of note, the effects of metformin on mortality in the current study were observed in men and women alike, as well as in high-risk subgroups including African Americans.
“The fact that such similar results were obtained in different populations from around the world suggests that the observed reduction in mortality risk, associated with metformin use in subjects with type 2 diabetes and COVID-19, might be generalizable,” the authors wrote.
“Furthermore, these findings underline the importance of following general diabetes treatment and prevention guidelines and not delaying or discontinuing any metformin treatment,” they add.
Speculation of mechanisms includes anti-inflammatory effects
While the mechanisms behind metformin’s potential role in reducing mortality risk in COVID-19 are unknown, the authors note that the most obvious assumption – that improved glycemic control may be a key factor – is disputed by the study’s finding that blood glucose levels and hemoglobin A1c were not significantly different among COVID-19 survivors taking versus not taking metformin.
They point instead to metformin’s known anti-inflammatory and antithrombotic properties.
“We therefore hypothesize that, by exerting some of these effects, metformin might improve outcomes and we are now in the process of investigating this possibility further,” Dr. Shalev said.
Dr. Peters noted that anti-inflammatory properties, themselves, are not necessarily unique to metformin in the treatment of diabetes.
“Many other agents, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors can reduce inflammation, so I don’t know if that would explain it, but it certainly could help,” she said. “[Reducing inflammation] is a hypothesis you see commonly with diabetes drugs, but I think there are also a lot of metabolic benefits from metformin.”
“It was fascinating that they had the A1c data and that survival with metformin didn’t appear to be as related to A1c levels as one might think,” she added.
Notably, a key advantage, should the effects and mechanisms be validated, is metformin’s high accessibility, Dr. Peters added.
“This doesn’t necessarily tell us what we can do to reduce the health care disparities surrounding COVID-19, but the fact that metformin is low cost and easily available is very important, so maybe it will help as we try to grapple with other risk factors.”
The authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
People with type 2 diabetes who develop COVID-19 show a substantially reduced risk of dying if they are taking metformin, shows a study that adds to prior research indicating the drug might somehow play a role in reducing the severity of infection.
“Unlike several previous analyses, this was a study in a racially diverse population with a high proportion of Blacks/African Americans and [it] revealed that metformin treatment of diabetes prior to diagnosis with COVID-19 was associated with a dramatic threefold reduced mortality in subjects with type 2 diabetes, even after correcting for multiple covariates,” first author Anath Shalev, MD, of the Comprehensive Diabetes Center at the University of Alabama at Birmingham, said in an interview.
But Anne Peters, MD, a professor of clinical medicine at the University of Southern California, Los Angeles, said caution is needed when interpreting these findings.
“It’s hard to tease out the true effects because, for instance, those treated with insulin may be a sicker subset of patients with diabetes than those on metformin, or those with comorbidities such as renal insufficiency may not be treated with metformin” she said in an interview.
“In general, though, treatment obviously matters and people who are better treated tend to do better, so while I think this study raises the question of what role metformin plays in the risk of mortality and COVID-19, I don’t think it necessarily proves the association,” Dr. Peters asserted.
Diverse population
The new study, published this month in Frontiers of Endocrinology, included 25,326 individuals who were tested for COVID-19 at the University of Alabama at Birmingham Hospital between February and June 2020.
Overall, 2.4% tested positive for COVID-19 (n = 604), which the authors note is likely a low figure because screening included asymptomatic hospital staff and patients having elective procedures.
Black/African American patients had a significantly higher risk of COVID-19 positivity, compared with White patients (odds ratio, 2.6; P < .0001). Rates were also higher among those with hypertension (OR, 2.46), diabetes (OR, 2.11), and obesity (OR, 1.93), compared with those without each condition (all P < .0001).
The overall mortality rate in COVID-19-positive patients was 11%. Diabetes was associated with a dramatically increased risk of death (OR, 3.62; P < .0001), and remained an independent risk factor even after adjusting for age, race, sex, obesity, and hypertension.
Notably, the reduction in mortality among those with diabetes taking metformin prior to COVID-19 diagnosis was significant: 11% of those patients died, compared with 23% of those with diabetes not taking metformin (OR, 0.33; P = .021).
Similar findings reported across varied populations
The study adds to mounting research suggesting metformin could have a protective effect on COVID-19 mortality, including an early report from Wuhan, China, findings from the French CORONADO study, and a U.S. study linking treatment with decreased mortality among women with COVID-19.
Of note, the effects of metformin on mortality in the current study were observed in men and women alike, as well as in high-risk subgroups including African Americans.
“The fact that such similar results were obtained in different populations from around the world suggests that the observed reduction in mortality risk, associated with metformin use in subjects with type 2 diabetes and COVID-19, might be generalizable,” the authors wrote.
“Furthermore, these findings underline the importance of following general diabetes treatment and prevention guidelines and not delaying or discontinuing any metformin treatment,” they add.
Speculation of mechanisms includes anti-inflammatory effects
While the mechanisms behind metformin’s potential role in reducing mortality risk in COVID-19 are unknown, the authors note that the most obvious assumption – that improved glycemic control may be a key factor – is disputed by the study’s finding that blood glucose levels and hemoglobin A1c were not significantly different among COVID-19 survivors taking versus not taking metformin.
They point instead to metformin’s known anti-inflammatory and antithrombotic properties.
“We therefore hypothesize that, by exerting some of these effects, metformin might improve outcomes and we are now in the process of investigating this possibility further,” Dr. Shalev said.
Dr. Peters noted that anti-inflammatory properties, themselves, are not necessarily unique to metformin in the treatment of diabetes.
“Many other agents, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors can reduce inflammation, so I don’t know if that would explain it, but it certainly could help,” she said. “[Reducing inflammation] is a hypothesis you see commonly with diabetes drugs, but I think there are also a lot of metabolic benefits from metformin.”
“It was fascinating that they had the A1c data and that survival with metformin didn’t appear to be as related to A1c levels as one might think,” she added.
Notably, a key advantage, should the effects and mechanisms be validated, is metformin’s high accessibility, Dr. Peters added.
“This doesn’t necessarily tell us what we can do to reduce the health care disparities surrounding COVID-19, but the fact that metformin is low cost and easily available is very important, so maybe it will help as we try to grapple with other risk factors.”
The authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.