User login
MDedge conference coverage features onsite reporting of the latest study results and expert perspectives from leading researchers.
COVID-19 vaccination in MS: Lower response on certain medications
The results also show a reduced response to COVID vaccination in some patients on fingolimod.
The data come from a new series of vaccinated patients with MS from Madrid, which was presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Presenting the data, Celia Oreja-Guevara, MD, Hospital Clínico San Carlos, Madrid, concluded that “currently approved COVID-19 vaccines appear safe in MS patients and are effective in most patients. However, vaccine strategy in patients treated with anti-CD20 and S1P inhibitors [such as fingolimod] need further study.”
“We showed that patients on ocrelizumab or rituximab had a very low or no antibody response to COVID vaccination,” she added. “However, some previous studies have shown some T-cell response to vaccination in these patients, and we are looking at that now.”
Assessing postvaccination antibody response
For the current study, the researchers analyzed the antibody response to COVID-19 vaccination at week 3, week 6, and month 3 after the first dose in 165 patients with MS and 200 healthy controls.
Of the patients with MS, 120 received both doses of mRNA vaccine and 42 received the AstraZeneca vaccine. The mean age of the MS patients was 45 years and 46 years in the healthy controls.
Adverse events were similar in the two groups, and no increase in relapse activity was seen in the patients with MS.
Mean antibody titers were slightly lower in the patients with MS versus the healthy controls. At 3 weeks, mean titers were 7,910 AU/mL in the patients with MS and 9,397 in the healthy controls. At 6 weeks, mean levels were 16,347 AU/mL in the patients with MS and 18,120 in the healthy controls.
Patients with MS treated with interferon-beta, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine, and natalizumab who received mRNA vaccines developed a similar postvaccination humoral response as the healthy controls at each of 3, 6, and 12 weeks after the first dose.
Patients with MS receiving the AstraZeneca vaccine mounted a lower humoral response than those receiving the mRNA vaccine, but this same effect was also seen in the healthy controls.
However, patients on the anti-CD20 drugs ocrelizumab or rituximab showed a lower humoral response to COVID vaccination. Only 3 of 20 patients who had been treated with ocrelizumab developed antibodies, but these patients had longer washout periods (at least 6 months) between receiving ocrelizumab and the COVID vaccine. All six patients treated with rituximab had no antibody response to the COVID vaccination.
Dr. Oreja-Guevara suggested that ocrelizumab-treated patients may have a worse outcome after COVID-19 infection. “In the first wave of infection in Madrid, we recorded five patients on ocrelizumab with COVID-19, four of whom were hospitalized,” she noted.
“In patients on ocrelizumab we need to try and have a long interval between giving this drug and giving the COVID vaccine. The longer the washout period, the more antibodies are seen,” she said.
She noted that two patients in the study received the COVID vaccine 1 year after ocrelizumab administration and had a normal humoral response, similar to the healthy controls.
The new anti-CD20 drug, ofatumumab, did not seem to affect the COVID vaccine antibody response as much as ocrelizumab or rituximab. In the current study, four of five patients treated with ofatumumab had an antibody response.
Dr. Oreja-Guevara suggested that this was probably because the depletion of B cells is not so strong with ofatumumab. “This drug is dosed every 4 weeks and it doesn’t deplete all the B cells and they are replaced quite quickly.”
Fingolimod is another MS drug that seems to affect the antibody response to COVID-19 vaccination.
Dr. Oreja-Guevara described the response to COVID vaccination in patients on fingolimod as “very variable.” Of 16 patients treated with fingolimod, 4 failed to develop a humoral response, 7 had a low antibody response, and 5 had a similar response to that seen in the healthy controls (three of these patients had also had a previous COVID-19 infection). The response to vaccination in fingolimod-treated patients did not appear to be related to lymphopenia.
Cellular response also impaired with fingolimod
These data are consistent with those from another cohort from Israel reported previously.
In that study, which was published earlier in 2021, a team led by Anat Achiron, MD, Sheba Medical Center, Tel Aviv, analyzed humoral immunity in 125 patients with MS 1 month after the second dose of the Pfizer COVID vaccine. A group of healthy people similarly vaccinated served as control.
Results showed that protective humoral immunity occurred in 97.9% of the control group after vaccination, compared with 100% in untreated patients and 100% in patients treated with cladribine but in just 22.7% of those treated with ocrelizumab and only 3.8% of those taking fingolimod.
For ocrelizumab-treated patients, the failure to mount appropriate IgG immune response was regardless of the absolute lymphocyte counts that were in the normal range or to the time interval from the last ocrelizumab treatment dose that ranged from 3.1 to 8.9 months, “suggesting the need to postpone the next dosing to enable an effective postvaccination humoral response,” the authors said.
They noted that the majority of the fingolimod-treated patients in the study had a low lymphocyte count (<1,000 cells/mm3), which may be the cause for failing to mount an immune response. But even in the small group of fingolimod-treated MS patients with an absolute lymphocyte count above 1,000 cells/mm3, no humoral response was detected.
At the ECTRIMS meeting, Dr. Achiron presented further results from this study on memory B-cell and T-cell responses to the COVID vaccine in these patients.
The results showed that COVID-specific B- and T-cell responses were only present in about half of healthy subjects, untreated patients with MS, and those treated with cladribine.
While the B-cell response was almost completely impaired in the ocrelizumab-treated patients, the T-cell response was present to the same extent as in the control group. But fingolimod patients showed no B- or T-cell responses.
Dr. Achiron concluded that patients on ocrelizumab should wait at least 9 months following the last dose before receiving COVID vaccination, and that patients taking fingolimod should consider a switch to a different medication.
But she pointed out that, despite the lack of humoral cellular responses in the fingolimod group, in this study there does not seem to have been an increase in COVID infection in patients taking fingolimod in a large registry study.
“This leads us to the idea that maybe lymphopenia is not the only story, and maybe innate immunity is playing a role. We still don’t really know the answer for that.”
Dr. Achiron said she was also surprised to see that even untreated and healthy subjects did not develop complete B-cell and T-cell responses after double COVID vaccination. And similar results have been seen in patients who have recovered from natural COVID infection, where the B-cell response is “not 100%,” she added.
“This points to the suggestion that everyone might need a third vaccination, MS patients or not,” she concluded.
A version of this article first appeared on Medscape.com.
The results also show a reduced response to COVID vaccination in some patients on fingolimod.
The data come from a new series of vaccinated patients with MS from Madrid, which was presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Presenting the data, Celia Oreja-Guevara, MD, Hospital Clínico San Carlos, Madrid, concluded that “currently approved COVID-19 vaccines appear safe in MS patients and are effective in most patients. However, vaccine strategy in patients treated with anti-CD20 and S1P inhibitors [such as fingolimod] need further study.”
“We showed that patients on ocrelizumab or rituximab had a very low or no antibody response to COVID vaccination,” she added. “However, some previous studies have shown some T-cell response to vaccination in these patients, and we are looking at that now.”
Assessing postvaccination antibody response
For the current study, the researchers analyzed the antibody response to COVID-19 vaccination at week 3, week 6, and month 3 after the first dose in 165 patients with MS and 200 healthy controls.
Of the patients with MS, 120 received both doses of mRNA vaccine and 42 received the AstraZeneca vaccine. The mean age of the MS patients was 45 years and 46 years in the healthy controls.
Adverse events were similar in the two groups, and no increase in relapse activity was seen in the patients with MS.
Mean antibody titers were slightly lower in the patients with MS versus the healthy controls. At 3 weeks, mean titers were 7,910 AU/mL in the patients with MS and 9,397 in the healthy controls. At 6 weeks, mean levels were 16,347 AU/mL in the patients with MS and 18,120 in the healthy controls.
Patients with MS treated with interferon-beta, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine, and natalizumab who received mRNA vaccines developed a similar postvaccination humoral response as the healthy controls at each of 3, 6, and 12 weeks after the first dose.
Patients with MS receiving the AstraZeneca vaccine mounted a lower humoral response than those receiving the mRNA vaccine, but this same effect was also seen in the healthy controls.
However, patients on the anti-CD20 drugs ocrelizumab or rituximab showed a lower humoral response to COVID vaccination. Only 3 of 20 patients who had been treated with ocrelizumab developed antibodies, but these patients had longer washout periods (at least 6 months) between receiving ocrelizumab and the COVID vaccine. All six patients treated with rituximab had no antibody response to the COVID vaccination.
Dr. Oreja-Guevara suggested that ocrelizumab-treated patients may have a worse outcome after COVID-19 infection. “In the first wave of infection in Madrid, we recorded five patients on ocrelizumab with COVID-19, four of whom were hospitalized,” she noted.
“In patients on ocrelizumab we need to try and have a long interval between giving this drug and giving the COVID vaccine. The longer the washout period, the more antibodies are seen,” she said.
She noted that two patients in the study received the COVID vaccine 1 year after ocrelizumab administration and had a normal humoral response, similar to the healthy controls.
The new anti-CD20 drug, ofatumumab, did not seem to affect the COVID vaccine antibody response as much as ocrelizumab or rituximab. In the current study, four of five patients treated with ofatumumab had an antibody response.
Dr. Oreja-Guevara suggested that this was probably because the depletion of B cells is not so strong with ofatumumab. “This drug is dosed every 4 weeks and it doesn’t deplete all the B cells and they are replaced quite quickly.”
Fingolimod is another MS drug that seems to affect the antibody response to COVID-19 vaccination.
Dr. Oreja-Guevara described the response to COVID vaccination in patients on fingolimod as “very variable.” Of 16 patients treated with fingolimod, 4 failed to develop a humoral response, 7 had a low antibody response, and 5 had a similar response to that seen in the healthy controls (three of these patients had also had a previous COVID-19 infection). The response to vaccination in fingolimod-treated patients did not appear to be related to lymphopenia.
Cellular response also impaired with fingolimod
These data are consistent with those from another cohort from Israel reported previously.
In that study, which was published earlier in 2021, a team led by Anat Achiron, MD, Sheba Medical Center, Tel Aviv, analyzed humoral immunity in 125 patients with MS 1 month after the second dose of the Pfizer COVID vaccine. A group of healthy people similarly vaccinated served as control.
Results showed that protective humoral immunity occurred in 97.9% of the control group after vaccination, compared with 100% in untreated patients and 100% in patients treated with cladribine but in just 22.7% of those treated with ocrelizumab and only 3.8% of those taking fingolimod.
For ocrelizumab-treated patients, the failure to mount appropriate IgG immune response was regardless of the absolute lymphocyte counts that were in the normal range or to the time interval from the last ocrelizumab treatment dose that ranged from 3.1 to 8.9 months, “suggesting the need to postpone the next dosing to enable an effective postvaccination humoral response,” the authors said.
They noted that the majority of the fingolimod-treated patients in the study had a low lymphocyte count (<1,000 cells/mm3), which may be the cause for failing to mount an immune response. But even in the small group of fingolimod-treated MS patients with an absolute lymphocyte count above 1,000 cells/mm3, no humoral response was detected.
At the ECTRIMS meeting, Dr. Achiron presented further results from this study on memory B-cell and T-cell responses to the COVID vaccine in these patients.
The results showed that COVID-specific B- and T-cell responses were only present in about half of healthy subjects, untreated patients with MS, and those treated with cladribine.
While the B-cell response was almost completely impaired in the ocrelizumab-treated patients, the T-cell response was present to the same extent as in the control group. But fingolimod patients showed no B- or T-cell responses.
Dr. Achiron concluded that patients on ocrelizumab should wait at least 9 months following the last dose before receiving COVID vaccination, and that patients taking fingolimod should consider a switch to a different medication.
But she pointed out that, despite the lack of humoral cellular responses in the fingolimod group, in this study there does not seem to have been an increase in COVID infection in patients taking fingolimod in a large registry study.
“This leads us to the idea that maybe lymphopenia is not the only story, and maybe innate immunity is playing a role. We still don’t really know the answer for that.”
Dr. Achiron said she was also surprised to see that even untreated and healthy subjects did not develop complete B-cell and T-cell responses after double COVID vaccination. And similar results have been seen in patients who have recovered from natural COVID infection, where the B-cell response is “not 100%,” she added.
“This points to the suggestion that everyone might need a third vaccination, MS patients or not,” she concluded.
A version of this article first appeared on Medscape.com.
The results also show a reduced response to COVID vaccination in some patients on fingolimod.
The data come from a new series of vaccinated patients with MS from Madrid, which was presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Presenting the data, Celia Oreja-Guevara, MD, Hospital Clínico San Carlos, Madrid, concluded that “currently approved COVID-19 vaccines appear safe in MS patients and are effective in most patients. However, vaccine strategy in patients treated with anti-CD20 and S1P inhibitors [such as fingolimod] need further study.”
“We showed that patients on ocrelizumab or rituximab had a very low or no antibody response to COVID vaccination,” she added. “However, some previous studies have shown some T-cell response to vaccination in these patients, and we are looking at that now.”
Assessing postvaccination antibody response
For the current study, the researchers analyzed the antibody response to COVID-19 vaccination at week 3, week 6, and month 3 after the first dose in 165 patients with MS and 200 healthy controls.
Of the patients with MS, 120 received both doses of mRNA vaccine and 42 received the AstraZeneca vaccine. The mean age of the MS patients was 45 years and 46 years in the healthy controls.
Adverse events were similar in the two groups, and no increase in relapse activity was seen in the patients with MS.
Mean antibody titers were slightly lower in the patients with MS versus the healthy controls. At 3 weeks, mean titers were 7,910 AU/mL in the patients with MS and 9,397 in the healthy controls. At 6 weeks, mean levels were 16,347 AU/mL in the patients with MS and 18,120 in the healthy controls.
Patients with MS treated with interferon-beta, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine, and natalizumab who received mRNA vaccines developed a similar postvaccination humoral response as the healthy controls at each of 3, 6, and 12 weeks after the first dose.
Patients with MS receiving the AstraZeneca vaccine mounted a lower humoral response than those receiving the mRNA vaccine, but this same effect was also seen in the healthy controls.
However, patients on the anti-CD20 drugs ocrelizumab or rituximab showed a lower humoral response to COVID vaccination. Only 3 of 20 patients who had been treated with ocrelizumab developed antibodies, but these patients had longer washout periods (at least 6 months) between receiving ocrelizumab and the COVID vaccine. All six patients treated with rituximab had no antibody response to the COVID vaccination.
Dr. Oreja-Guevara suggested that ocrelizumab-treated patients may have a worse outcome after COVID-19 infection. “In the first wave of infection in Madrid, we recorded five patients on ocrelizumab with COVID-19, four of whom were hospitalized,” she noted.
“In patients on ocrelizumab we need to try and have a long interval between giving this drug and giving the COVID vaccine. The longer the washout period, the more antibodies are seen,” she said.
She noted that two patients in the study received the COVID vaccine 1 year after ocrelizumab administration and had a normal humoral response, similar to the healthy controls.
The new anti-CD20 drug, ofatumumab, did not seem to affect the COVID vaccine antibody response as much as ocrelizumab or rituximab. In the current study, four of five patients treated with ofatumumab had an antibody response.
Dr. Oreja-Guevara suggested that this was probably because the depletion of B cells is not so strong with ofatumumab. “This drug is dosed every 4 weeks and it doesn’t deplete all the B cells and they are replaced quite quickly.”
Fingolimod is another MS drug that seems to affect the antibody response to COVID-19 vaccination.
Dr. Oreja-Guevara described the response to COVID vaccination in patients on fingolimod as “very variable.” Of 16 patients treated with fingolimod, 4 failed to develop a humoral response, 7 had a low antibody response, and 5 had a similar response to that seen in the healthy controls (three of these patients had also had a previous COVID-19 infection). The response to vaccination in fingolimod-treated patients did not appear to be related to lymphopenia.
Cellular response also impaired with fingolimod
These data are consistent with those from another cohort from Israel reported previously.
In that study, which was published earlier in 2021, a team led by Anat Achiron, MD, Sheba Medical Center, Tel Aviv, analyzed humoral immunity in 125 patients with MS 1 month after the second dose of the Pfizer COVID vaccine. A group of healthy people similarly vaccinated served as control.
Results showed that protective humoral immunity occurred in 97.9% of the control group after vaccination, compared with 100% in untreated patients and 100% in patients treated with cladribine but in just 22.7% of those treated with ocrelizumab and only 3.8% of those taking fingolimod.
For ocrelizumab-treated patients, the failure to mount appropriate IgG immune response was regardless of the absolute lymphocyte counts that were in the normal range or to the time interval from the last ocrelizumab treatment dose that ranged from 3.1 to 8.9 months, “suggesting the need to postpone the next dosing to enable an effective postvaccination humoral response,” the authors said.
They noted that the majority of the fingolimod-treated patients in the study had a low lymphocyte count (<1,000 cells/mm3), which may be the cause for failing to mount an immune response. But even in the small group of fingolimod-treated MS patients with an absolute lymphocyte count above 1,000 cells/mm3, no humoral response was detected.
At the ECTRIMS meeting, Dr. Achiron presented further results from this study on memory B-cell and T-cell responses to the COVID vaccine in these patients.
The results showed that COVID-specific B- and T-cell responses were only present in about half of healthy subjects, untreated patients with MS, and those treated with cladribine.
While the B-cell response was almost completely impaired in the ocrelizumab-treated patients, the T-cell response was present to the same extent as in the control group. But fingolimod patients showed no B- or T-cell responses.
Dr. Achiron concluded that patients on ocrelizumab should wait at least 9 months following the last dose before receiving COVID vaccination, and that patients taking fingolimod should consider a switch to a different medication.
But she pointed out that, despite the lack of humoral cellular responses in the fingolimod group, in this study there does not seem to have been an increase in COVID infection in patients taking fingolimod in a large registry study.
“This leads us to the idea that maybe lymphopenia is not the only story, and maybe innate immunity is playing a role. We still don’t really know the answer for that.”
Dr. Achiron said she was also surprised to see that even untreated and healthy subjects did not develop complete B-cell and T-cell responses after double COVID vaccination. And similar results have been seen in patients who have recovered from natural COVID infection, where the B-cell response is “not 100%,” she added.
“This points to the suggestion that everyone might need a third vaccination, MS patients or not,” she concluded.
A version of this article first appeared on Medscape.com.
FROM ECTRIMS 2021
Lower thyroid hormone levels a red flag for elevated suicide risk?
Patients with comorbid anxiety and mood disorders who have reduced, albeit “normal” serum levels of thyroid-stimulating hormone (TSH) may be at increased risk for suicidal ideation, new research suggests.
In a cross-sectional study, clinical data on diagnosis, medication use, and symptom scores were gathered, along with assessments of blood levels of thyroid axis hormones, in patients with both anxiety and mood disorders.
After investigators accounted for age, gender, symptoms, medication use, and other potential confounders, patients with suicidal ideation were 54% less likely to have higher TSH levels. There was no association found with other thyroid hormones.
Based on the results, the assessment of thyroid hormone levels “may be important for suicide prevention and might allow clinicians to evaluate the potential of the suicidal ideation risk in individuals with [anxiety and mood disorders],” co-investigator Vilma Liaugaudaite, PhD student, Neuroscience Institute of the Lithuanian University of Health Sciences, Palanga, and colleagues note.
The findings were presented at the 34th European College of Neuropsychopharmacology (ECNP) Congress.
‘Complex mechanism’
Ms. Liaugaudaite told this news organization that thyroid hormones are known to have a “profound” effect on mood and behavior.
Recent studies show “various degrees of hypothalamic-pituitary-thyroid axis dysregulation are associated with suicidal behavior” in patients with depression, she added.
Noting that disturbances in the serotonin system “constitute the most common biochemical abnormality associated with suicidal behavior,” Ms. Liaugaudaite said it is thought thyroid hormones “are involved in a complex compensatory mechanism to correct reduced central 5-hydroxytryptamine activity” via lower TSH levels.
In addition, hypersecretion of thyrotropin-releasing hormone, which stimulates the release of TSH, “has been considered a compensatory mechanism to maintain normal thyroid hormone secretion and normalize serotonin activity in depressed patients,” she said.
To investigate associations between thyroid axis hormones and suicidality in individuals with comorbid anxiety and mood disorders, the researchers assessed consecutive patients attending a stress disorders clinic.
Sociodemographic and clinical information was gathered, and patients completed the Mini International Neuropsychiatric Interview, the Patient Health Questionnaire-9 (PHQ-9), and the General Anxiety Disorder-7 (GAD-7) scale.
Fasting blood samples were also tested for free thyroxine (FT4), free triiodothyronine (FT3), and TSH levels.
Significant association
Suicidal ideation was identified in 42 participants. Serum FT4, FT3, and TSH levels were within the normal range.
There were no significant differences between patients with and without suicidal ideation in terms of age, gender, education, obesity, smoking, and medication use.
Suicidal ideation was associated with higher scores on the PHQ-9 (15.5 vs. 13.3; P = .085), and with lower TSH levels (1.54 IU/L vs. 2.04 IU/L; P = .092).
The association between serum TSH levels and suicidal ideation was significant after multivariate logistic regression analysis accounted for age, gender, PHQ-9 and GAD-7 scores, education, body mass index, smoking, and use of antidepressants, tranquilizers, mood stabilizers, and neuroleptics.
Specifically, patients with suicidal ideation were significantly less likely to have higher TSH levels than those without, at an odds ratio of 0.46 (P = .027).
There were no significant associations between serum FT4 and FT3 levels and suicidal ideation.
Interesting, but preliminary
Commenting on the findings, Sanjeev Sockalingam, MD, vice chair and professor of psychiatry at the University of Toronto, said it is an “interesting study” because the literature on trying to identify individuals at risk for suicidal ideation or behaviors is “quite mixed, in terms of the results.”
However, it was a cross-sectional study with a relatively small sample size, and studies of this nature typically include patients with hypothyroidism “who end up having suicidal thoughts,” said Dr. Sockalingam, who was not involved with the research.
“I do wonder, given the sample size and patient population, if there may be other factors that may have been related to this,” he added.
Dr. Sockalingam noted that he would like to see more data on the medications the patients were taking, and he underlined that the thyroid levels were in the normal range, “so it’s a bit difficult to untangle what that means in terms of these subtle changes in thyroid levels.”
Robert Levitan, MD, Cameron Wilson Chair in Depression Research at the Centre for Addiction and Mental Health, Toronto, also emphasized that the thyroid levels were in the normal range.
He commented that it therefore “seems unlikely that there’s going to be some biological effect that’s going to affect the brain in a significant enough way” to influence suicidal ideation.
Dr. Levitan continued, “What’s probably happening is there’s some other clinical issue here that they just haven’t picked up on that’s leading in one direction to the suicidal ideation and perhaps affecting the TSH to some extent.”
Although the study is, therefore, “preliminary,” the findings are nevertheless “interesting,” he concluded.
The study received no funding. Ms. Liaugaudaite, Dr. Sockalingam, and Dr. Levitan have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Patients with comorbid anxiety and mood disorders who have reduced, albeit “normal” serum levels of thyroid-stimulating hormone (TSH) may be at increased risk for suicidal ideation, new research suggests.
In a cross-sectional study, clinical data on diagnosis, medication use, and symptom scores were gathered, along with assessments of blood levels of thyroid axis hormones, in patients with both anxiety and mood disorders.
After investigators accounted for age, gender, symptoms, medication use, and other potential confounders, patients with suicidal ideation were 54% less likely to have higher TSH levels. There was no association found with other thyroid hormones.
Based on the results, the assessment of thyroid hormone levels “may be important for suicide prevention and might allow clinicians to evaluate the potential of the suicidal ideation risk in individuals with [anxiety and mood disorders],” co-investigator Vilma Liaugaudaite, PhD student, Neuroscience Institute of the Lithuanian University of Health Sciences, Palanga, and colleagues note.
The findings were presented at the 34th European College of Neuropsychopharmacology (ECNP) Congress.
‘Complex mechanism’
Ms. Liaugaudaite told this news organization that thyroid hormones are known to have a “profound” effect on mood and behavior.
Recent studies show “various degrees of hypothalamic-pituitary-thyroid axis dysregulation are associated with suicidal behavior” in patients with depression, she added.
Noting that disturbances in the serotonin system “constitute the most common biochemical abnormality associated with suicidal behavior,” Ms. Liaugaudaite said it is thought thyroid hormones “are involved in a complex compensatory mechanism to correct reduced central 5-hydroxytryptamine activity” via lower TSH levels.
In addition, hypersecretion of thyrotropin-releasing hormone, which stimulates the release of TSH, “has been considered a compensatory mechanism to maintain normal thyroid hormone secretion and normalize serotonin activity in depressed patients,” she said.
To investigate associations between thyroid axis hormones and suicidality in individuals with comorbid anxiety and mood disorders, the researchers assessed consecutive patients attending a stress disorders clinic.
Sociodemographic and clinical information was gathered, and patients completed the Mini International Neuropsychiatric Interview, the Patient Health Questionnaire-9 (PHQ-9), and the General Anxiety Disorder-7 (GAD-7) scale.
Fasting blood samples were also tested for free thyroxine (FT4), free triiodothyronine (FT3), and TSH levels.
Significant association
Suicidal ideation was identified in 42 participants. Serum FT4, FT3, and TSH levels were within the normal range.
There were no significant differences between patients with and without suicidal ideation in terms of age, gender, education, obesity, smoking, and medication use.
Suicidal ideation was associated with higher scores on the PHQ-9 (15.5 vs. 13.3; P = .085), and with lower TSH levels (1.54 IU/L vs. 2.04 IU/L; P = .092).
The association between serum TSH levels and suicidal ideation was significant after multivariate logistic regression analysis accounted for age, gender, PHQ-9 and GAD-7 scores, education, body mass index, smoking, and use of antidepressants, tranquilizers, mood stabilizers, and neuroleptics.
Specifically, patients with suicidal ideation were significantly less likely to have higher TSH levels than those without, at an odds ratio of 0.46 (P = .027).
There were no significant associations between serum FT4 and FT3 levels and suicidal ideation.
Interesting, but preliminary
Commenting on the findings, Sanjeev Sockalingam, MD, vice chair and professor of psychiatry at the University of Toronto, said it is an “interesting study” because the literature on trying to identify individuals at risk for suicidal ideation or behaviors is “quite mixed, in terms of the results.”
However, it was a cross-sectional study with a relatively small sample size, and studies of this nature typically include patients with hypothyroidism “who end up having suicidal thoughts,” said Dr. Sockalingam, who was not involved with the research.
“I do wonder, given the sample size and patient population, if there may be other factors that may have been related to this,” he added.
Dr. Sockalingam noted that he would like to see more data on the medications the patients were taking, and he underlined that the thyroid levels were in the normal range, “so it’s a bit difficult to untangle what that means in terms of these subtle changes in thyroid levels.”
Robert Levitan, MD, Cameron Wilson Chair in Depression Research at the Centre for Addiction and Mental Health, Toronto, also emphasized that the thyroid levels were in the normal range.
He commented that it therefore “seems unlikely that there’s going to be some biological effect that’s going to affect the brain in a significant enough way” to influence suicidal ideation.
Dr. Levitan continued, “What’s probably happening is there’s some other clinical issue here that they just haven’t picked up on that’s leading in one direction to the suicidal ideation and perhaps affecting the TSH to some extent.”
Although the study is, therefore, “preliminary,” the findings are nevertheless “interesting,” he concluded.
The study received no funding. Ms. Liaugaudaite, Dr. Sockalingam, and Dr. Levitan have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Patients with comorbid anxiety and mood disorders who have reduced, albeit “normal” serum levels of thyroid-stimulating hormone (TSH) may be at increased risk for suicidal ideation, new research suggests.
In a cross-sectional study, clinical data on diagnosis, medication use, and symptom scores were gathered, along with assessments of blood levels of thyroid axis hormones, in patients with both anxiety and mood disorders.
After investigators accounted for age, gender, symptoms, medication use, and other potential confounders, patients with suicidal ideation were 54% less likely to have higher TSH levels. There was no association found with other thyroid hormones.
Based on the results, the assessment of thyroid hormone levels “may be important for suicide prevention and might allow clinicians to evaluate the potential of the suicidal ideation risk in individuals with [anxiety and mood disorders],” co-investigator Vilma Liaugaudaite, PhD student, Neuroscience Institute of the Lithuanian University of Health Sciences, Palanga, and colleagues note.
The findings were presented at the 34th European College of Neuropsychopharmacology (ECNP) Congress.
‘Complex mechanism’
Ms. Liaugaudaite told this news organization that thyroid hormones are known to have a “profound” effect on mood and behavior.
Recent studies show “various degrees of hypothalamic-pituitary-thyroid axis dysregulation are associated with suicidal behavior” in patients with depression, she added.
Noting that disturbances in the serotonin system “constitute the most common biochemical abnormality associated with suicidal behavior,” Ms. Liaugaudaite said it is thought thyroid hormones “are involved in a complex compensatory mechanism to correct reduced central 5-hydroxytryptamine activity” via lower TSH levels.
In addition, hypersecretion of thyrotropin-releasing hormone, which stimulates the release of TSH, “has been considered a compensatory mechanism to maintain normal thyroid hormone secretion and normalize serotonin activity in depressed patients,” she said.
To investigate associations between thyroid axis hormones and suicidality in individuals with comorbid anxiety and mood disorders, the researchers assessed consecutive patients attending a stress disorders clinic.
Sociodemographic and clinical information was gathered, and patients completed the Mini International Neuropsychiatric Interview, the Patient Health Questionnaire-9 (PHQ-9), and the General Anxiety Disorder-7 (GAD-7) scale.
Fasting blood samples were also tested for free thyroxine (FT4), free triiodothyronine (FT3), and TSH levels.
Significant association
Suicidal ideation was identified in 42 participants. Serum FT4, FT3, and TSH levels were within the normal range.
There were no significant differences between patients with and without suicidal ideation in terms of age, gender, education, obesity, smoking, and medication use.
Suicidal ideation was associated with higher scores on the PHQ-9 (15.5 vs. 13.3; P = .085), and with lower TSH levels (1.54 IU/L vs. 2.04 IU/L; P = .092).
The association between serum TSH levels and suicidal ideation was significant after multivariate logistic regression analysis accounted for age, gender, PHQ-9 and GAD-7 scores, education, body mass index, smoking, and use of antidepressants, tranquilizers, mood stabilizers, and neuroleptics.
Specifically, patients with suicidal ideation were significantly less likely to have higher TSH levels than those without, at an odds ratio of 0.46 (P = .027).
There were no significant associations between serum FT4 and FT3 levels and suicidal ideation.
Interesting, but preliminary
Commenting on the findings, Sanjeev Sockalingam, MD, vice chair and professor of psychiatry at the University of Toronto, said it is an “interesting study” because the literature on trying to identify individuals at risk for suicidal ideation or behaviors is “quite mixed, in terms of the results.”
However, it was a cross-sectional study with a relatively small sample size, and studies of this nature typically include patients with hypothyroidism “who end up having suicidal thoughts,” said Dr. Sockalingam, who was not involved with the research.
“I do wonder, given the sample size and patient population, if there may be other factors that may have been related to this,” he added.
Dr. Sockalingam noted that he would like to see more data on the medications the patients were taking, and he underlined that the thyroid levels were in the normal range, “so it’s a bit difficult to untangle what that means in terms of these subtle changes in thyroid levels.”
Robert Levitan, MD, Cameron Wilson Chair in Depression Research at the Centre for Addiction and Mental Health, Toronto, also emphasized that the thyroid levels were in the normal range.
He commented that it therefore “seems unlikely that there’s going to be some biological effect that’s going to affect the brain in a significant enough way” to influence suicidal ideation.
Dr. Levitan continued, “What’s probably happening is there’s some other clinical issue here that they just haven’t picked up on that’s leading in one direction to the suicidal ideation and perhaps affecting the TSH to some extent.”
Although the study is, therefore, “preliminary,” the findings are nevertheless “interesting,” he concluded.
The study received no funding. Ms. Liaugaudaite, Dr. Sockalingam, and Dr. Levitan have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ECNP 2021
Fecal microbiota transplants may improve resistance to melanoma immunotherapy
In the fall of 2020, Hassane M. Zarour, MD, and colleagues began to pore over raw data from their
Preclinical mouse studies have demonstrated that the gut microbiota could influence the response of tumors to anti–PD-1 immunotherapy, but FMT had not been previously evaluated in human patients with malignant melanoma whose disease persisted or progressed after medical therapy. Only 30%-40% of melanoma patients respond to anti–PD-1 immunotherapy, so the researchers’ sense of anticipation was palpable. “It’s a high-risk, high-reward study, so you never know,” Dr. Zarour, a dermatologist and immunologist who is coleader of the melanoma program at the University of Pittsburgh Medical Center’s Hillman Cancer Center, said in an interview.
For the study, which was funded by the National Institutes of Health and published in Science, Dr. Zarour and a team of colleagues, including Diwakar Davar, MD, a medical oncologist/hematologist at UPMC and Giorgio Trinchieri, MD, head of the cancer immunology section at the National Cancer Institute, enrolled 16 patients with advanced melanoma whose disease had persisted or progressed with anti-PD-1 drugs; donors were 7 patients with advanced melanoma who had responded to pembrolizumab, 4 with a complete response and 3 with a partial response, with a median progression-free survival of 56 months.
After donors and patients underwent serial stool sampling and studies to stamp out the potential for transmitting infectious agents, the researchers administered the donor-derived FMT to patients via colonoscopy every 14 days for 3 weeks, followed by pembrolizumab. To their delight, 6 of the 15 evaluable recipients responded to treatment, with a reduction in tumor or long-term disease stabilization. Moreover, responders also showed increased abundance of taxa that were previously associated with response to immunotherapy, increased activation of CD8+ T cells, and decreased frequency of interleukin-8–expressing myeloid cells.
“This opens new doors for the future,” Dr. Zarour said. “It’s very encouraging, but I don’t want to overstate the data. It’s a small, nonrandomized trial, but one has to keep in mind that people were skeptical about this work; they didn’t think FMT would work. Now we see many people coming into the field to investigate the role of the microbiome as a therapeutic tool, which is great.”
Teri Greiling, MD, characterized the finding as a key development in understanding the microbiome’s potential to influence the course of melanoma and other diseases. “What’s emerging over the last decade of research is that our immune system has a close, back-and-forth relationship with our microbiota,” said Dr. Greiling, associate professor of dermatology at Oregon Health & Science University, Portland. “From day 1 of birth, we’re colonized by microbes that train our immune system how to function. In response, your immune system keeps those microbes in check and shapes which ones are allowed to colonize, and which ones are a target for attack. Thus, inflammatory responses are generated. Similarly, the goal of immunotherapy is to activate the immune system to fight cancer. This study shows that the immune system continues to need the colonizing microbes in our body to function optimally.”
Immunotherapy with checkpoint inhibitors was not an option for malignant melanoma patients until 2011, she noted, so the potential for FMT to further improve outcomes is welcome news for patients and their families. “We went from a less than 5% chance of survival with metastatic melanoma to now, with the right combination of checkpoint inhibitors, we’re up over 50%, which is amazing in a decade,” Dr. Greiling said. “Still, we’re losing half of our patients. If [FMT provides] a 30% improvement over that, that would be great, but it’s hard to extrapolate from such small numbers.”
Positive results in an Israeli study
Results from a similar, smaller phase 1 trial of 2 FMT donors and 10 recipients with metastatic melanoma who had progressed on anti-PD-1 therapy, from the Ella Lemelbaum Institute for Immuno-Oncology at Sheba Medical Center in Tel HaShomer, Israel, yielded similar results. The FMT protocol in this study included colonoscopy and oral stool capsules, followed by the reintroduction of anti–PD-1 therapy with nivolumab. The two FMT donors had previously been treated with anti–PD-1 monotherapy for metastatic melanoma and had achieved a clinical response for at least 1 year. Of the 10 FMT recipients, 1 had a complete response and 2 had a partial response.
“We expected changes in the immune system but did not expect that 3 out of the 10 patients in our study would be turned from nonresponders to responders,” the study’s lead author, Erez N. Baruch, MD, PhD, told this news organization. “Since this was a first-in-human study, we were aiming to assess safety and not clinical responses. [We found] that microbiota modulation can change the immune infiltration within melanoma tumors and by this affect response to immunotherapy.”
Dr. Baruch, an internal medicine resident in the physician-scientist track program at the University of Texas, Houston, said that the findings create a potential new therapeutic paradigm, or a new “playing ground” for drug development that can support existing immunotherapies. “It is important for dermatologists to understand that disruptions of the gut microbiota, mainly by antibiotics, may be harmful to melanoma patients,” he said. “Antibiotics in cancer patients should be used judiciously but of course should not be avoided when there’s an indication.”
As for next steps, Dr. Zarour and colleagues are recruiting more patients to boost their sample size and conducting sequential analysis of the microbiome of study participants “to better determine what the good and bad bugs are,” he said. “There are so many variables, including diet and geography. We need more data.” The hope is to develop a “microbiome signature” to identify patients likely to respond to FMT, and maybe one day, a probiotic capsule that patients take to optimize their response to immunotherapy.
“We don’t want to say that the microbiome is responsible for everything, but it’s responsible for some of the response and some of the resistance to treatment,” Dr. Zarour said. “So, we want to identify what candidate nonresponders are more likely to respond to FMT and be able to stick the right stool in the donor. This goes to better education of the microbiome signature. We are working hard on that.”
Dr. Baruch added that performing FMT for melanoma patients requires tight collaborations between oncologists, dermatologists, GI, and infectious disease experts. “These usually can be done in the setting of large cancer centers and will probably not be available in any hospital,” he said. “This is why understanding the mechanisms and developing an FMT-like drug is important. We are focusing on studying the mechanisms behind the clinical effect in order to develop a drug with an FMT-like effect without the safety and logistic issues related to FMTs.”
Tamia A. Harris-Tryon, MD, PhD, whose lab at the University of Texas Southwestern Medical Center at Dallas is studying how diet and the microbiota impact skin immunity, underscored the importance of evaluating the characteristics of the diet of patients as trials of FMT in melanoma patients carry on. “We know that the diet impacts the repertoire of microbes that colonize the gut,” said Dr. Harris-Tryon, assistant professor in the department of dermatology at the medical center. “The diet of the recipient likely has an impact” on the success of donor FMT.
She also noted that other skin conditions have been linked to a disrupted gut microbiome, such as psoriasis. “Given the safety of FMT in both of these studies, trials of FMT in psoriasis and other systemic skin conditions should be considered,” she said.
According to Dr. Zarour, mounting data from separate studies show that some gut microbiota play a role in adverse events experienced by melanoma patients on immunotherapy. “That is very important, especially with combination therapy,” he said. “There are also microbes involved in resistance to treatment, so the idea would be to identify these microbes.”
Studies raise more questions
In the opinion of Dr. Greiling, results from these two studies raise more questions than they answer. “The big question ... is why and how does FMT work, and how can we make the response better?” she said. “Is there one particular gene product from one microbe that is the key magic ingredient, and we can harness this as a drug? More likely it’s a complex interplay between multiple bacterial species needed to direct the immune response. Is there a group of microbes that is the same from person to person, or is it more complex?”
Then there are pending regulatory concerns. “We know that FMT works for [Clostridioides] difficile colitis but it’s not officially [Food and Drug Administration] approved,” Dr. Greiling said. “The FDA is really struggling with how to approve or regulate using bacteria as a drug. Where is that crossover? That inhibits things moving forward, for good reason. You want to balance safety with live microbes.”
The UPMC clinical trial was supported by Merck. Dr. Zarour disclosed that he is supported by grants from the National Cancer Institute and the James W. and Frances G. McGlothlin Chair in Melanoma Immunotherapy Research at UPMC. The Israeli study was funded by the Ella Lemelbaum Institute for Immuno-Oncology. Dr. Baruch was supported by the Allen Berg Fund for Excellence in Immuno-Oncology Research. Dr. Greiling and Dr. Harris-Tryon reported having no relevant financial disclosures.
In the fall of 2020, Hassane M. Zarour, MD, and colleagues began to pore over raw data from their
Preclinical mouse studies have demonstrated that the gut microbiota could influence the response of tumors to anti–PD-1 immunotherapy, but FMT had not been previously evaluated in human patients with malignant melanoma whose disease persisted or progressed after medical therapy. Only 30%-40% of melanoma patients respond to anti–PD-1 immunotherapy, so the researchers’ sense of anticipation was palpable. “It’s a high-risk, high-reward study, so you never know,” Dr. Zarour, a dermatologist and immunologist who is coleader of the melanoma program at the University of Pittsburgh Medical Center’s Hillman Cancer Center, said in an interview.
For the study, which was funded by the National Institutes of Health and published in Science, Dr. Zarour and a team of colleagues, including Diwakar Davar, MD, a medical oncologist/hematologist at UPMC and Giorgio Trinchieri, MD, head of the cancer immunology section at the National Cancer Institute, enrolled 16 patients with advanced melanoma whose disease had persisted or progressed with anti-PD-1 drugs; donors were 7 patients with advanced melanoma who had responded to pembrolizumab, 4 with a complete response and 3 with a partial response, with a median progression-free survival of 56 months.
After donors and patients underwent serial stool sampling and studies to stamp out the potential for transmitting infectious agents, the researchers administered the donor-derived FMT to patients via colonoscopy every 14 days for 3 weeks, followed by pembrolizumab. To their delight, 6 of the 15 evaluable recipients responded to treatment, with a reduction in tumor or long-term disease stabilization. Moreover, responders also showed increased abundance of taxa that were previously associated with response to immunotherapy, increased activation of CD8+ T cells, and decreased frequency of interleukin-8–expressing myeloid cells.
“This opens new doors for the future,” Dr. Zarour said. “It’s very encouraging, but I don’t want to overstate the data. It’s a small, nonrandomized trial, but one has to keep in mind that people were skeptical about this work; they didn’t think FMT would work. Now we see many people coming into the field to investigate the role of the microbiome as a therapeutic tool, which is great.”
Teri Greiling, MD, characterized the finding as a key development in understanding the microbiome’s potential to influence the course of melanoma and other diseases. “What’s emerging over the last decade of research is that our immune system has a close, back-and-forth relationship with our microbiota,” said Dr. Greiling, associate professor of dermatology at Oregon Health & Science University, Portland. “From day 1 of birth, we’re colonized by microbes that train our immune system how to function. In response, your immune system keeps those microbes in check and shapes which ones are allowed to colonize, and which ones are a target for attack. Thus, inflammatory responses are generated. Similarly, the goal of immunotherapy is to activate the immune system to fight cancer. This study shows that the immune system continues to need the colonizing microbes in our body to function optimally.”
Immunotherapy with checkpoint inhibitors was not an option for malignant melanoma patients until 2011, she noted, so the potential for FMT to further improve outcomes is welcome news for patients and their families. “We went from a less than 5% chance of survival with metastatic melanoma to now, with the right combination of checkpoint inhibitors, we’re up over 50%, which is amazing in a decade,” Dr. Greiling said. “Still, we’re losing half of our patients. If [FMT provides] a 30% improvement over that, that would be great, but it’s hard to extrapolate from such small numbers.”
Positive results in an Israeli study
Results from a similar, smaller phase 1 trial of 2 FMT donors and 10 recipients with metastatic melanoma who had progressed on anti-PD-1 therapy, from the Ella Lemelbaum Institute for Immuno-Oncology at Sheba Medical Center in Tel HaShomer, Israel, yielded similar results. The FMT protocol in this study included colonoscopy and oral stool capsules, followed by the reintroduction of anti–PD-1 therapy with nivolumab. The two FMT donors had previously been treated with anti–PD-1 monotherapy for metastatic melanoma and had achieved a clinical response for at least 1 year. Of the 10 FMT recipients, 1 had a complete response and 2 had a partial response.
“We expected changes in the immune system but did not expect that 3 out of the 10 patients in our study would be turned from nonresponders to responders,” the study’s lead author, Erez N. Baruch, MD, PhD, told this news organization. “Since this was a first-in-human study, we were aiming to assess safety and not clinical responses. [We found] that microbiota modulation can change the immune infiltration within melanoma tumors and by this affect response to immunotherapy.”
Dr. Baruch, an internal medicine resident in the physician-scientist track program at the University of Texas, Houston, said that the findings create a potential new therapeutic paradigm, or a new “playing ground” for drug development that can support existing immunotherapies. “It is important for dermatologists to understand that disruptions of the gut microbiota, mainly by antibiotics, may be harmful to melanoma patients,” he said. “Antibiotics in cancer patients should be used judiciously but of course should not be avoided when there’s an indication.”
As for next steps, Dr. Zarour and colleagues are recruiting more patients to boost their sample size and conducting sequential analysis of the microbiome of study participants “to better determine what the good and bad bugs are,” he said. “There are so many variables, including diet and geography. We need more data.” The hope is to develop a “microbiome signature” to identify patients likely to respond to FMT, and maybe one day, a probiotic capsule that patients take to optimize their response to immunotherapy.
“We don’t want to say that the microbiome is responsible for everything, but it’s responsible for some of the response and some of the resistance to treatment,” Dr. Zarour said. “So, we want to identify what candidate nonresponders are more likely to respond to FMT and be able to stick the right stool in the donor. This goes to better education of the microbiome signature. We are working hard on that.”
Dr. Baruch added that performing FMT for melanoma patients requires tight collaborations between oncologists, dermatologists, GI, and infectious disease experts. “These usually can be done in the setting of large cancer centers and will probably not be available in any hospital,” he said. “This is why understanding the mechanisms and developing an FMT-like drug is important. We are focusing on studying the mechanisms behind the clinical effect in order to develop a drug with an FMT-like effect without the safety and logistic issues related to FMTs.”
Tamia A. Harris-Tryon, MD, PhD, whose lab at the University of Texas Southwestern Medical Center at Dallas is studying how diet and the microbiota impact skin immunity, underscored the importance of evaluating the characteristics of the diet of patients as trials of FMT in melanoma patients carry on. “We know that the diet impacts the repertoire of microbes that colonize the gut,” said Dr. Harris-Tryon, assistant professor in the department of dermatology at the medical center. “The diet of the recipient likely has an impact” on the success of donor FMT.
She also noted that other skin conditions have been linked to a disrupted gut microbiome, such as psoriasis. “Given the safety of FMT in both of these studies, trials of FMT in psoriasis and other systemic skin conditions should be considered,” she said.
According to Dr. Zarour, mounting data from separate studies show that some gut microbiota play a role in adverse events experienced by melanoma patients on immunotherapy. “That is very important, especially with combination therapy,” he said. “There are also microbes involved in resistance to treatment, so the idea would be to identify these microbes.”
Studies raise more questions
In the opinion of Dr. Greiling, results from these two studies raise more questions than they answer. “The big question ... is why and how does FMT work, and how can we make the response better?” she said. “Is there one particular gene product from one microbe that is the key magic ingredient, and we can harness this as a drug? More likely it’s a complex interplay between multiple bacterial species needed to direct the immune response. Is there a group of microbes that is the same from person to person, or is it more complex?”
Then there are pending regulatory concerns. “We know that FMT works for [Clostridioides] difficile colitis but it’s not officially [Food and Drug Administration] approved,” Dr. Greiling said. “The FDA is really struggling with how to approve or regulate using bacteria as a drug. Where is that crossover? That inhibits things moving forward, for good reason. You want to balance safety with live microbes.”
The UPMC clinical trial was supported by Merck. Dr. Zarour disclosed that he is supported by grants from the National Cancer Institute and the James W. and Frances G. McGlothlin Chair in Melanoma Immunotherapy Research at UPMC. The Israeli study was funded by the Ella Lemelbaum Institute for Immuno-Oncology. Dr. Baruch was supported by the Allen Berg Fund for Excellence in Immuno-Oncology Research. Dr. Greiling and Dr. Harris-Tryon reported having no relevant financial disclosures.
In the fall of 2020, Hassane M. Zarour, MD, and colleagues began to pore over raw data from their
Preclinical mouse studies have demonstrated that the gut microbiota could influence the response of tumors to anti–PD-1 immunotherapy, but FMT had not been previously evaluated in human patients with malignant melanoma whose disease persisted or progressed after medical therapy. Only 30%-40% of melanoma patients respond to anti–PD-1 immunotherapy, so the researchers’ sense of anticipation was palpable. “It’s a high-risk, high-reward study, so you never know,” Dr. Zarour, a dermatologist and immunologist who is coleader of the melanoma program at the University of Pittsburgh Medical Center’s Hillman Cancer Center, said in an interview.
For the study, which was funded by the National Institutes of Health and published in Science, Dr. Zarour and a team of colleagues, including Diwakar Davar, MD, a medical oncologist/hematologist at UPMC and Giorgio Trinchieri, MD, head of the cancer immunology section at the National Cancer Institute, enrolled 16 patients with advanced melanoma whose disease had persisted or progressed with anti-PD-1 drugs; donors were 7 patients with advanced melanoma who had responded to pembrolizumab, 4 with a complete response and 3 with a partial response, with a median progression-free survival of 56 months.
After donors and patients underwent serial stool sampling and studies to stamp out the potential for transmitting infectious agents, the researchers administered the donor-derived FMT to patients via colonoscopy every 14 days for 3 weeks, followed by pembrolizumab. To their delight, 6 of the 15 evaluable recipients responded to treatment, with a reduction in tumor or long-term disease stabilization. Moreover, responders also showed increased abundance of taxa that were previously associated with response to immunotherapy, increased activation of CD8+ T cells, and decreased frequency of interleukin-8–expressing myeloid cells.
“This opens new doors for the future,” Dr. Zarour said. “It’s very encouraging, but I don’t want to overstate the data. It’s a small, nonrandomized trial, but one has to keep in mind that people were skeptical about this work; they didn’t think FMT would work. Now we see many people coming into the field to investigate the role of the microbiome as a therapeutic tool, which is great.”
Teri Greiling, MD, characterized the finding as a key development in understanding the microbiome’s potential to influence the course of melanoma and other diseases. “What’s emerging over the last decade of research is that our immune system has a close, back-and-forth relationship with our microbiota,” said Dr. Greiling, associate professor of dermatology at Oregon Health & Science University, Portland. “From day 1 of birth, we’re colonized by microbes that train our immune system how to function. In response, your immune system keeps those microbes in check and shapes which ones are allowed to colonize, and which ones are a target for attack. Thus, inflammatory responses are generated. Similarly, the goal of immunotherapy is to activate the immune system to fight cancer. This study shows that the immune system continues to need the colonizing microbes in our body to function optimally.”
Immunotherapy with checkpoint inhibitors was not an option for malignant melanoma patients until 2011, she noted, so the potential for FMT to further improve outcomes is welcome news for patients and their families. “We went from a less than 5% chance of survival with metastatic melanoma to now, with the right combination of checkpoint inhibitors, we’re up over 50%, which is amazing in a decade,” Dr. Greiling said. “Still, we’re losing half of our patients. If [FMT provides] a 30% improvement over that, that would be great, but it’s hard to extrapolate from such small numbers.”
Positive results in an Israeli study
Results from a similar, smaller phase 1 trial of 2 FMT donors and 10 recipients with metastatic melanoma who had progressed on anti-PD-1 therapy, from the Ella Lemelbaum Institute for Immuno-Oncology at Sheba Medical Center in Tel HaShomer, Israel, yielded similar results. The FMT protocol in this study included colonoscopy and oral stool capsules, followed by the reintroduction of anti–PD-1 therapy with nivolumab. The two FMT donors had previously been treated with anti–PD-1 monotherapy for metastatic melanoma and had achieved a clinical response for at least 1 year. Of the 10 FMT recipients, 1 had a complete response and 2 had a partial response.
“We expected changes in the immune system but did not expect that 3 out of the 10 patients in our study would be turned from nonresponders to responders,” the study’s lead author, Erez N. Baruch, MD, PhD, told this news organization. “Since this was a first-in-human study, we were aiming to assess safety and not clinical responses. [We found] that microbiota modulation can change the immune infiltration within melanoma tumors and by this affect response to immunotherapy.”
Dr. Baruch, an internal medicine resident in the physician-scientist track program at the University of Texas, Houston, said that the findings create a potential new therapeutic paradigm, or a new “playing ground” for drug development that can support existing immunotherapies. “It is important for dermatologists to understand that disruptions of the gut microbiota, mainly by antibiotics, may be harmful to melanoma patients,” he said. “Antibiotics in cancer patients should be used judiciously but of course should not be avoided when there’s an indication.”
As for next steps, Dr. Zarour and colleagues are recruiting more patients to boost their sample size and conducting sequential analysis of the microbiome of study participants “to better determine what the good and bad bugs are,” he said. “There are so many variables, including diet and geography. We need more data.” The hope is to develop a “microbiome signature” to identify patients likely to respond to FMT, and maybe one day, a probiotic capsule that patients take to optimize their response to immunotherapy.
“We don’t want to say that the microbiome is responsible for everything, but it’s responsible for some of the response and some of the resistance to treatment,” Dr. Zarour said. “So, we want to identify what candidate nonresponders are more likely to respond to FMT and be able to stick the right stool in the donor. This goes to better education of the microbiome signature. We are working hard on that.”
Dr. Baruch added that performing FMT for melanoma patients requires tight collaborations between oncologists, dermatologists, GI, and infectious disease experts. “These usually can be done in the setting of large cancer centers and will probably not be available in any hospital,” he said. “This is why understanding the mechanisms and developing an FMT-like drug is important. We are focusing on studying the mechanisms behind the clinical effect in order to develop a drug with an FMT-like effect without the safety and logistic issues related to FMTs.”
Tamia A. Harris-Tryon, MD, PhD, whose lab at the University of Texas Southwestern Medical Center at Dallas is studying how diet and the microbiota impact skin immunity, underscored the importance of evaluating the characteristics of the diet of patients as trials of FMT in melanoma patients carry on. “We know that the diet impacts the repertoire of microbes that colonize the gut,” said Dr. Harris-Tryon, assistant professor in the department of dermatology at the medical center. “The diet of the recipient likely has an impact” on the success of donor FMT.
She also noted that other skin conditions have been linked to a disrupted gut microbiome, such as psoriasis. “Given the safety of FMT in both of these studies, trials of FMT in psoriasis and other systemic skin conditions should be considered,” she said.
According to Dr. Zarour, mounting data from separate studies show that some gut microbiota play a role in adverse events experienced by melanoma patients on immunotherapy. “That is very important, especially with combination therapy,” he said. “There are also microbes involved in resistance to treatment, so the idea would be to identify these microbes.”
Studies raise more questions
In the opinion of Dr. Greiling, results from these two studies raise more questions than they answer. “The big question ... is why and how does FMT work, and how can we make the response better?” she said. “Is there one particular gene product from one microbe that is the key magic ingredient, and we can harness this as a drug? More likely it’s a complex interplay between multiple bacterial species needed to direct the immune response. Is there a group of microbes that is the same from person to person, or is it more complex?”
Then there are pending regulatory concerns. “We know that FMT works for [Clostridioides] difficile colitis but it’s not officially [Food and Drug Administration] approved,” Dr. Greiling said. “The FDA is really struggling with how to approve or regulate using bacteria as a drug. Where is that crossover? That inhibits things moving forward, for good reason. You want to balance safety with live microbes.”
The UPMC clinical trial was supported by Merck. Dr. Zarour disclosed that he is supported by grants from the National Cancer Institute and the James W. and Frances G. McGlothlin Chair in Melanoma Immunotherapy Research at UPMC. The Israeli study was funded by the Ella Lemelbaum Institute for Immuno-Oncology. Dr. Baruch was supported by the Allen Berg Fund for Excellence in Immuno-Oncology Research. Dr. Greiling and Dr. Harris-Tryon reported having no relevant financial disclosures.
No short-term death risk in elderly after COVID-19 vaccines
and launched an investigation into the safety of the BNT162b2 vaccine (Comirnaty; Pfizer-BioNTech).
Now, the results of that investigation and of a subsequent larger study of nursing home residents in Norway have shown no increased risk for short-term mortality following COVID-19 vaccination in the overall population of elderly patients. The new research also showed clear evidence of a survival benefit compared with the unvaccinated population, Anette Hylen Ranhoff, MD, PhD, said at the annual meeting of the European Geriatric Medicine Society, held in a hybrid format in Athens, Greece, and online.
“We found no evidence of increased short-term mortality among vaccinated older individuals, and particularly not among the nursing home patients,” said Dr. Ranhoff, a senior researcher at the Norwegian Institute of Public Health and professor at University of Bergen, Norway. “But we think that this [lower] mortality risk was most likely a sort of ‘healthy-vaccinee’ effect, which means that people who were a bit more healthy were vaccinated, and not those who were the very, very most frail.”
“We have more or less the same data in France about events, with very high rates of vaccination,” said session moderator Athanase Benetos MD, PhD, professor and chairman of geriatric medicine at the University Hospital of Nancy in France, who was not involved in the study.
“In my department, a month after the end of the vaccination and at the same time while the pandemic in the city was going up, we had a 90% decrease in mortality from COVID in the nursing homes,” he told Dr. Ranhoff.
Potential risks
Frail elderly patients were not included in clinical trials of COVID-19 vaccines, and although previous studies have shown a low incidence of local or systemic reactions to vaccination among older people, “we think that quite mild adverse events following vaccination could trigger and destabilize a frail person,” Dr. Ranhoff said.
As reported Jan. 15, 2021, in BMJ, investigation by the Norwegian Medicines Agency (NOMA) into 13 of the 23 reported cases concluded that common adverse reactions associated with mRNA vaccines could have contributed to the deaths of some of the frail elderly patients
Steinar Madsen, MD, NOMA medical director, told BMJ “we are not alarmed or worried about this, because these are very rare occurrences and they occurred in very frail patients with very serious disease.”
Health authorities investigate
In response to the report and at the request of the Norwegian Public Health Institute and NOMA, Dr. Ranhoff and colleagues investigated the first 100 deaths among nursing-home residents who received the vaccine. The team consisted of three geriatricians and an infectious disease specialist who sees patients in nursing homes.
They looked at each patient’s clinical course before and after vaccination, their health trajectory and life expectancy at the time of vaccination, new symptoms following vaccination, and the time from vaccination to new symptoms and to death.
In addition, the investigators evaluated Clinical Frailty Scale (CFS) scores for each patient. CFS scores range from 1 (very fit) to 9 (terminally ill, with a life expectancy of less than 6 months who are otherwise evidently frail).
The initial investigation found that among 95 evaluable patients, the association between vaccination and death was “probable” in 10, “possible” in 26, and “unlikely” in 59.
The mean time from vaccination to symptoms was 1.4 days in the probable cases, 2.5 days in the possible cases, and 4.7 days in the unlikely cases.
The mean time from vaccination to death was 3.1, 8.3, and 8.2 days, respectively.
In all three categories, the patients had mean CFS scores ranging from 7.6 to 7.9, putting them in the “severely frail” category, defined as people who are completely dependent for personal care but seem stable and not at high risk for dying.
“We have quite many nursing home residents in Norway, 35,000; more than 80% have dementia, and the mean age is 85 years. We know that approximately 45 people die every day in these nursing homes, and their mean age of death is 87.5 years,” Dr. Ranhoff said.
Population-wide study
Dr. Ranhoff and colleagues also looked more broadly into the question of potential vaccine-related mortality in the total population of older people in Norway from the day of vaccination to follow-up at 3 weeks.
They conducted a matched cohort study to investigate the relationship between the mRNA SARS-CoV-2 vaccine and overall death among persons aged 65 and older in the general population, and across four groups: patients receiving home-based care, long-term nursing home patients, short-term nursing home patients, and those not receiving health services.
The researchers identified a total of 967,786 residents of Norway aged 65 and over at the start of the country’s vaccination campaign at the end of December, 2020, and they matched vaccinated individuals with unvaccinated persons based on demographic, geographic, and clinical risk group factors.
Dr. Ranhoff showed Kaplan-Meier survival curves for the total population and for each of the health-service states. In all cases there was a clear survival benefit for vaccinated vs. unvaccinated patients. She did not, however, provide specific numbers or hazard ratios for the differences between vaccinated and unvaccinated individuals in each of the comparisons.
The study was supported by the Norwegian Institute of Public Health. Dr. Ranhoff and Dr. Benetos reported no conflicts of interest.
and launched an investigation into the safety of the BNT162b2 vaccine (Comirnaty; Pfizer-BioNTech).
Now, the results of that investigation and of a subsequent larger study of nursing home residents in Norway have shown no increased risk for short-term mortality following COVID-19 vaccination in the overall population of elderly patients. The new research also showed clear evidence of a survival benefit compared with the unvaccinated population, Anette Hylen Ranhoff, MD, PhD, said at the annual meeting of the European Geriatric Medicine Society, held in a hybrid format in Athens, Greece, and online.
“We found no evidence of increased short-term mortality among vaccinated older individuals, and particularly not among the nursing home patients,” said Dr. Ranhoff, a senior researcher at the Norwegian Institute of Public Health and professor at University of Bergen, Norway. “But we think that this [lower] mortality risk was most likely a sort of ‘healthy-vaccinee’ effect, which means that people who were a bit more healthy were vaccinated, and not those who were the very, very most frail.”
“We have more or less the same data in France about events, with very high rates of vaccination,” said session moderator Athanase Benetos MD, PhD, professor and chairman of geriatric medicine at the University Hospital of Nancy in France, who was not involved in the study.
“In my department, a month after the end of the vaccination and at the same time while the pandemic in the city was going up, we had a 90% decrease in mortality from COVID in the nursing homes,” he told Dr. Ranhoff.
Potential risks
Frail elderly patients were not included in clinical trials of COVID-19 vaccines, and although previous studies have shown a low incidence of local or systemic reactions to vaccination among older people, “we think that quite mild adverse events following vaccination could trigger and destabilize a frail person,” Dr. Ranhoff said.
As reported Jan. 15, 2021, in BMJ, investigation by the Norwegian Medicines Agency (NOMA) into 13 of the 23 reported cases concluded that common adverse reactions associated with mRNA vaccines could have contributed to the deaths of some of the frail elderly patients
Steinar Madsen, MD, NOMA medical director, told BMJ “we are not alarmed or worried about this, because these are very rare occurrences and they occurred in very frail patients with very serious disease.”
Health authorities investigate
In response to the report and at the request of the Norwegian Public Health Institute and NOMA, Dr. Ranhoff and colleagues investigated the first 100 deaths among nursing-home residents who received the vaccine. The team consisted of three geriatricians and an infectious disease specialist who sees patients in nursing homes.
They looked at each patient’s clinical course before and after vaccination, their health trajectory and life expectancy at the time of vaccination, new symptoms following vaccination, and the time from vaccination to new symptoms and to death.
In addition, the investigators evaluated Clinical Frailty Scale (CFS) scores for each patient. CFS scores range from 1 (very fit) to 9 (terminally ill, with a life expectancy of less than 6 months who are otherwise evidently frail).
The initial investigation found that among 95 evaluable patients, the association between vaccination and death was “probable” in 10, “possible” in 26, and “unlikely” in 59.
The mean time from vaccination to symptoms was 1.4 days in the probable cases, 2.5 days in the possible cases, and 4.7 days in the unlikely cases.
The mean time from vaccination to death was 3.1, 8.3, and 8.2 days, respectively.
In all three categories, the patients had mean CFS scores ranging from 7.6 to 7.9, putting them in the “severely frail” category, defined as people who are completely dependent for personal care but seem stable and not at high risk for dying.
“We have quite many nursing home residents in Norway, 35,000; more than 80% have dementia, and the mean age is 85 years. We know that approximately 45 people die every day in these nursing homes, and their mean age of death is 87.5 years,” Dr. Ranhoff said.
Population-wide study
Dr. Ranhoff and colleagues also looked more broadly into the question of potential vaccine-related mortality in the total population of older people in Norway from the day of vaccination to follow-up at 3 weeks.
They conducted a matched cohort study to investigate the relationship between the mRNA SARS-CoV-2 vaccine and overall death among persons aged 65 and older in the general population, and across four groups: patients receiving home-based care, long-term nursing home patients, short-term nursing home patients, and those not receiving health services.
The researchers identified a total of 967,786 residents of Norway aged 65 and over at the start of the country’s vaccination campaign at the end of December, 2020, and they matched vaccinated individuals with unvaccinated persons based on demographic, geographic, and clinical risk group factors.
Dr. Ranhoff showed Kaplan-Meier survival curves for the total population and for each of the health-service states. In all cases there was a clear survival benefit for vaccinated vs. unvaccinated patients. She did not, however, provide specific numbers or hazard ratios for the differences between vaccinated and unvaccinated individuals in each of the comparisons.
The study was supported by the Norwegian Institute of Public Health. Dr. Ranhoff and Dr. Benetos reported no conflicts of interest.
and launched an investigation into the safety of the BNT162b2 vaccine (Comirnaty; Pfizer-BioNTech).
Now, the results of that investigation and of a subsequent larger study of nursing home residents in Norway have shown no increased risk for short-term mortality following COVID-19 vaccination in the overall population of elderly patients. The new research also showed clear evidence of a survival benefit compared with the unvaccinated population, Anette Hylen Ranhoff, MD, PhD, said at the annual meeting of the European Geriatric Medicine Society, held in a hybrid format in Athens, Greece, and online.
“We found no evidence of increased short-term mortality among vaccinated older individuals, and particularly not among the nursing home patients,” said Dr. Ranhoff, a senior researcher at the Norwegian Institute of Public Health and professor at University of Bergen, Norway. “But we think that this [lower] mortality risk was most likely a sort of ‘healthy-vaccinee’ effect, which means that people who were a bit more healthy were vaccinated, and not those who were the very, very most frail.”
“We have more or less the same data in France about events, with very high rates of vaccination,” said session moderator Athanase Benetos MD, PhD, professor and chairman of geriatric medicine at the University Hospital of Nancy in France, who was not involved in the study.
“In my department, a month after the end of the vaccination and at the same time while the pandemic in the city was going up, we had a 90% decrease in mortality from COVID in the nursing homes,” he told Dr. Ranhoff.
Potential risks
Frail elderly patients were not included in clinical trials of COVID-19 vaccines, and although previous studies have shown a low incidence of local or systemic reactions to vaccination among older people, “we think that quite mild adverse events following vaccination could trigger and destabilize a frail person,” Dr. Ranhoff said.
As reported Jan. 15, 2021, in BMJ, investigation by the Norwegian Medicines Agency (NOMA) into 13 of the 23 reported cases concluded that common adverse reactions associated with mRNA vaccines could have contributed to the deaths of some of the frail elderly patients
Steinar Madsen, MD, NOMA medical director, told BMJ “we are not alarmed or worried about this, because these are very rare occurrences and they occurred in very frail patients with very serious disease.”
Health authorities investigate
In response to the report and at the request of the Norwegian Public Health Institute and NOMA, Dr. Ranhoff and colleagues investigated the first 100 deaths among nursing-home residents who received the vaccine. The team consisted of three geriatricians and an infectious disease specialist who sees patients in nursing homes.
They looked at each patient’s clinical course before and after vaccination, their health trajectory and life expectancy at the time of vaccination, new symptoms following vaccination, and the time from vaccination to new symptoms and to death.
In addition, the investigators evaluated Clinical Frailty Scale (CFS) scores for each patient. CFS scores range from 1 (very fit) to 9 (terminally ill, with a life expectancy of less than 6 months who are otherwise evidently frail).
The initial investigation found that among 95 evaluable patients, the association between vaccination and death was “probable” in 10, “possible” in 26, and “unlikely” in 59.
The mean time from vaccination to symptoms was 1.4 days in the probable cases, 2.5 days in the possible cases, and 4.7 days in the unlikely cases.
The mean time from vaccination to death was 3.1, 8.3, and 8.2 days, respectively.
In all three categories, the patients had mean CFS scores ranging from 7.6 to 7.9, putting them in the “severely frail” category, defined as people who are completely dependent for personal care but seem stable and not at high risk for dying.
“We have quite many nursing home residents in Norway, 35,000; more than 80% have dementia, and the mean age is 85 years. We know that approximately 45 people die every day in these nursing homes, and their mean age of death is 87.5 years,” Dr. Ranhoff said.
Population-wide study
Dr. Ranhoff and colleagues also looked more broadly into the question of potential vaccine-related mortality in the total population of older people in Norway from the day of vaccination to follow-up at 3 weeks.
They conducted a matched cohort study to investigate the relationship between the mRNA SARS-CoV-2 vaccine and overall death among persons aged 65 and older in the general population, and across four groups: patients receiving home-based care, long-term nursing home patients, short-term nursing home patients, and those not receiving health services.
The researchers identified a total of 967,786 residents of Norway aged 65 and over at the start of the country’s vaccination campaign at the end of December, 2020, and they matched vaccinated individuals with unvaccinated persons based on demographic, geographic, and clinical risk group factors.
Dr. Ranhoff showed Kaplan-Meier survival curves for the total population and for each of the health-service states. In all cases there was a clear survival benefit for vaccinated vs. unvaccinated patients. She did not, however, provide specific numbers or hazard ratios for the differences between vaccinated and unvaccinated individuals in each of the comparisons.
The study was supported by the Norwegian Institute of Public Health. Dr. Ranhoff and Dr. Benetos reported no conflicts of interest.
FROM EUGMS 2021
Oral PTH shows promise for osteoporosis in early phase 2 study
An investigational oral form of parathyroid hormone (PTH 1-34), EB 613 (Entera Bio) met its primary efficacy outcome in a phase 2 dosing study involving postmenopausal women with low bone mineral density (BMD).
The adverse effect profile of the drug was similar to that of the injectable PTH 1-34 teriparatide (Forteo), which is approved for osteoporosis.
Arthur C. Santora, MD, chief medical officer, Entera Bio, presented 6-month findings from the study during an oral session at the annual meeting of the American Society of Bone and Mineral Research. The 3-month findings from the study were reported as a poster.
If the drug demonstrates efficacy and safety in larger phase 3 trials, it could be the first oral bone-building (anabolic) therapy for osteoporosis.
Clifford J. Rosen, MD, PhD, who was not involved with the research, told this news organization: “I think this is an intriguing study.” The most likely patients for oral PTH, he added, “are those that have osteoporosis, previous fracture, or very low BMD, particularly those unlikely or unwilling to take bisphosphonates.”
However, “this is very early in the process before this drug could come to market,” cautioned Dr. Rosen, who is director of the Center for Clinical and Translational Research, Maine Medical Research Institute, Scarborough.
“Much more data on efficacy are required at 12 and 24 months for phase 2, and then a full phase 3 [clinical trial] with high-risk fracture patients,” he said.
The company is seeking input from the Food and Drug Administration to develop the protocol for a phase 3 trial. They expect to start this trial in 2022 at sites in the United States, Europe, and Israel, Dr. Santora said.
Primary outcome met
The study randomly assigned 161 postmenopausal women with osteoporosis or low BMD to receive placebo or the investigational oral PTH for 6 months.
Compared with women who received placebo, those who received the study drug experienced a significantly greater increase in the bone formation marker procollagen type I N-terminal propeptide (P1NP) from baseline to 3 months, thereby meeting the study’s primary outcome.
In secondary outcomes, women who received the 2.5-mg/d dose experienced a similar 6-month increase in BMD at the spine and greater increases in BMD at the total hip and femoral neck than those who received injectable teriparatide, Dr. Santora reported.
“The study’s key takeaway is that a once-daily oral PTH [tablet] has the potential to produce the same BMD effects as subcutaneous injections of PTH,” he said in an interview.
Additionally, “the drug was well tolerated when the dose was titrated by adding additional tablets, which suggests that the dose can be tailored to each patient,” he said.
Other study findings
Injectable teriparatide reduces the risk for vertebral fractures by up to 80%, Dr. Santora noted, but the fact that the drug must be administered by injection may deter some older patients from using it.
The company developed an oral form of biosynthetic human PTH with a proprietary drug delivery.
The researchers conducted the phase 2 study at four sites in Israel between June 2019 and May 2021. They enrolled women aged 50 years and older who had entered menopause at least 3 years earlier and who had osteoporosis or low BMD.
Forty-three women received placebo, and the others received oral PTH at doses of 0.5 mg/d (n = 25), 1.0 mg/d (n = 29), 1.5 mg/d (n = 28), 2.5 mg/d (n = 19), or at a dose that was titrated up to 2.5 mg/d starting at 1.5 mg/d for month 1, then 2 mg/d for month 2, and then 2.5 mg/d for months 3 to 6 (n = 17).
The mean age of the patients was 61 years, the mean body mass index was 25-27 kg/m2, and the mean T score at the spine of –2.2 to –2.45.
Among the women who received 2.5 mg/d of oral PTH for the full 6 months, serum levels of the bone resorption marker C-terminal telopeptide of type I collagen (CTX) decreased 21% from baseline to 6 months, and serum levels of P1NP increased at month 1 and then decreased to baseline by month 6.
The women who received 2.5 mg/d of oral PTH for the full 6 months also demonstrated significantly greater increases in BMD at the lumbar spine (3.8%), total hip (1.4%), and femoral neck (2.4%), compared with women who received placebo.
The safety profile of oral PTH was consistent with that of subcutaneous PTH. Patients experienced headache, nausea, presyncope, and dizziness; there were no treatment-emergent hypercalcemia adverse events.
A few ‘unexpected findings’
Suzanne M. Jan De Beur, MD, outgoing ASBMR president, said, “Oral PTH appeared to increase BMD by [dual-energy x-ray absorptiometry] at the lumbar spine effectively and to a similar degree as teriparatide in previous studies.”
She identified two unexpected findings.
“There were increases in BMD by DXA at the femoral neck and total hip at 6 months that were [greater than those] seen in previous trials of teriparatide. Second, markers of bone resorption (CTX) decreased at 6 months, and this is in stark contrast to the increases observed with teriparatide treatment,” she noted in an interview.
Dr. Rosen also noted that “the decrease in CTX is very unusual for PTH and difficult to explain.” He added: “P1NP, a marker of bone formation, was not increased.”
Dr. Jan de Beur continued: “Teriparatide (PTH1-34) and abaloparatide are effective anabolic agents that we use to treat patients with high risk of osteoporotic fracture. Although effective, the burden of daily subcutaneous injection can be a barrier for older individuals, those with poor dexterity, and those that are averse to self-injection.
“Taken together, these results appear promising, that oral PTH may prove to be an effective anabolic agent for osteoporosis treatment,” she summarized.
She stressed that a larger phase 3 study is needed to demonstrate safety and efficacy.
The study was funded by Entera Bio. Dr. Santora is chief medical officer of Entera Bio.
A version of this article first appeared on Medscape.com .
An investigational oral form of parathyroid hormone (PTH 1-34), EB 613 (Entera Bio) met its primary efficacy outcome in a phase 2 dosing study involving postmenopausal women with low bone mineral density (BMD).
The adverse effect profile of the drug was similar to that of the injectable PTH 1-34 teriparatide (Forteo), which is approved for osteoporosis.
Arthur C. Santora, MD, chief medical officer, Entera Bio, presented 6-month findings from the study during an oral session at the annual meeting of the American Society of Bone and Mineral Research. The 3-month findings from the study were reported as a poster.
If the drug demonstrates efficacy and safety in larger phase 3 trials, it could be the first oral bone-building (anabolic) therapy for osteoporosis.
Clifford J. Rosen, MD, PhD, who was not involved with the research, told this news organization: “I think this is an intriguing study.” The most likely patients for oral PTH, he added, “are those that have osteoporosis, previous fracture, or very low BMD, particularly those unlikely or unwilling to take bisphosphonates.”
However, “this is very early in the process before this drug could come to market,” cautioned Dr. Rosen, who is director of the Center for Clinical and Translational Research, Maine Medical Research Institute, Scarborough.
“Much more data on efficacy are required at 12 and 24 months for phase 2, and then a full phase 3 [clinical trial] with high-risk fracture patients,” he said.
The company is seeking input from the Food and Drug Administration to develop the protocol for a phase 3 trial. They expect to start this trial in 2022 at sites in the United States, Europe, and Israel, Dr. Santora said.
Primary outcome met
The study randomly assigned 161 postmenopausal women with osteoporosis or low BMD to receive placebo or the investigational oral PTH for 6 months.
Compared with women who received placebo, those who received the study drug experienced a significantly greater increase in the bone formation marker procollagen type I N-terminal propeptide (P1NP) from baseline to 3 months, thereby meeting the study’s primary outcome.
In secondary outcomes, women who received the 2.5-mg/d dose experienced a similar 6-month increase in BMD at the spine and greater increases in BMD at the total hip and femoral neck than those who received injectable teriparatide, Dr. Santora reported.
“The study’s key takeaway is that a once-daily oral PTH [tablet] has the potential to produce the same BMD effects as subcutaneous injections of PTH,” he said in an interview.
Additionally, “the drug was well tolerated when the dose was titrated by adding additional tablets, which suggests that the dose can be tailored to each patient,” he said.
Other study findings
Injectable teriparatide reduces the risk for vertebral fractures by up to 80%, Dr. Santora noted, but the fact that the drug must be administered by injection may deter some older patients from using it.
The company developed an oral form of biosynthetic human PTH with a proprietary drug delivery.
The researchers conducted the phase 2 study at four sites in Israel between June 2019 and May 2021. They enrolled women aged 50 years and older who had entered menopause at least 3 years earlier and who had osteoporosis or low BMD.
Forty-three women received placebo, and the others received oral PTH at doses of 0.5 mg/d (n = 25), 1.0 mg/d (n = 29), 1.5 mg/d (n = 28), 2.5 mg/d (n = 19), or at a dose that was titrated up to 2.5 mg/d starting at 1.5 mg/d for month 1, then 2 mg/d for month 2, and then 2.5 mg/d for months 3 to 6 (n = 17).
The mean age of the patients was 61 years, the mean body mass index was 25-27 kg/m2, and the mean T score at the spine of –2.2 to –2.45.
Among the women who received 2.5 mg/d of oral PTH for the full 6 months, serum levels of the bone resorption marker C-terminal telopeptide of type I collagen (CTX) decreased 21% from baseline to 6 months, and serum levels of P1NP increased at month 1 and then decreased to baseline by month 6.
The women who received 2.5 mg/d of oral PTH for the full 6 months also demonstrated significantly greater increases in BMD at the lumbar spine (3.8%), total hip (1.4%), and femoral neck (2.4%), compared with women who received placebo.
The safety profile of oral PTH was consistent with that of subcutaneous PTH. Patients experienced headache, nausea, presyncope, and dizziness; there were no treatment-emergent hypercalcemia adverse events.
A few ‘unexpected findings’
Suzanne M. Jan De Beur, MD, outgoing ASBMR president, said, “Oral PTH appeared to increase BMD by [dual-energy x-ray absorptiometry] at the lumbar spine effectively and to a similar degree as teriparatide in previous studies.”
She identified two unexpected findings.
“There were increases in BMD by DXA at the femoral neck and total hip at 6 months that were [greater than those] seen in previous trials of teriparatide. Second, markers of bone resorption (CTX) decreased at 6 months, and this is in stark contrast to the increases observed with teriparatide treatment,” she noted in an interview.
Dr. Rosen also noted that “the decrease in CTX is very unusual for PTH and difficult to explain.” He added: “P1NP, a marker of bone formation, was not increased.”
Dr. Jan de Beur continued: “Teriparatide (PTH1-34) and abaloparatide are effective anabolic agents that we use to treat patients with high risk of osteoporotic fracture. Although effective, the burden of daily subcutaneous injection can be a barrier for older individuals, those with poor dexterity, and those that are averse to self-injection.
“Taken together, these results appear promising, that oral PTH may prove to be an effective anabolic agent for osteoporosis treatment,” she summarized.
She stressed that a larger phase 3 study is needed to demonstrate safety and efficacy.
The study was funded by Entera Bio. Dr. Santora is chief medical officer of Entera Bio.
A version of this article first appeared on Medscape.com .
An investigational oral form of parathyroid hormone (PTH 1-34), EB 613 (Entera Bio) met its primary efficacy outcome in a phase 2 dosing study involving postmenopausal women with low bone mineral density (BMD).
The adverse effect profile of the drug was similar to that of the injectable PTH 1-34 teriparatide (Forteo), which is approved for osteoporosis.
Arthur C. Santora, MD, chief medical officer, Entera Bio, presented 6-month findings from the study during an oral session at the annual meeting of the American Society of Bone and Mineral Research. The 3-month findings from the study were reported as a poster.
If the drug demonstrates efficacy and safety in larger phase 3 trials, it could be the first oral bone-building (anabolic) therapy for osteoporosis.
Clifford J. Rosen, MD, PhD, who was not involved with the research, told this news organization: “I think this is an intriguing study.” The most likely patients for oral PTH, he added, “are those that have osteoporosis, previous fracture, or very low BMD, particularly those unlikely or unwilling to take bisphosphonates.”
However, “this is very early in the process before this drug could come to market,” cautioned Dr. Rosen, who is director of the Center for Clinical and Translational Research, Maine Medical Research Institute, Scarborough.
“Much more data on efficacy are required at 12 and 24 months for phase 2, and then a full phase 3 [clinical trial] with high-risk fracture patients,” he said.
The company is seeking input from the Food and Drug Administration to develop the protocol for a phase 3 trial. They expect to start this trial in 2022 at sites in the United States, Europe, and Israel, Dr. Santora said.
Primary outcome met
The study randomly assigned 161 postmenopausal women with osteoporosis or low BMD to receive placebo or the investigational oral PTH for 6 months.
Compared with women who received placebo, those who received the study drug experienced a significantly greater increase in the bone formation marker procollagen type I N-terminal propeptide (P1NP) from baseline to 3 months, thereby meeting the study’s primary outcome.
In secondary outcomes, women who received the 2.5-mg/d dose experienced a similar 6-month increase in BMD at the spine and greater increases in BMD at the total hip and femoral neck than those who received injectable teriparatide, Dr. Santora reported.
“The study’s key takeaway is that a once-daily oral PTH [tablet] has the potential to produce the same BMD effects as subcutaneous injections of PTH,” he said in an interview.
Additionally, “the drug was well tolerated when the dose was titrated by adding additional tablets, which suggests that the dose can be tailored to each patient,” he said.
Other study findings
Injectable teriparatide reduces the risk for vertebral fractures by up to 80%, Dr. Santora noted, but the fact that the drug must be administered by injection may deter some older patients from using it.
The company developed an oral form of biosynthetic human PTH with a proprietary drug delivery.
The researchers conducted the phase 2 study at four sites in Israel between June 2019 and May 2021. They enrolled women aged 50 years and older who had entered menopause at least 3 years earlier and who had osteoporosis or low BMD.
Forty-three women received placebo, and the others received oral PTH at doses of 0.5 mg/d (n = 25), 1.0 mg/d (n = 29), 1.5 mg/d (n = 28), 2.5 mg/d (n = 19), or at a dose that was titrated up to 2.5 mg/d starting at 1.5 mg/d for month 1, then 2 mg/d for month 2, and then 2.5 mg/d for months 3 to 6 (n = 17).
The mean age of the patients was 61 years, the mean body mass index was 25-27 kg/m2, and the mean T score at the spine of –2.2 to –2.45.
Among the women who received 2.5 mg/d of oral PTH for the full 6 months, serum levels of the bone resorption marker C-terminal telopeptide of type I collagen (CTX) decreased 21% from baseline to 6 months, and serum levels of P1NP increased at month 1 and then decreased to baseline by month 6.
The women who received 2.5 mg/d of oral PTH for the full 6 months also demonstrated significantly greater increases in BMD at the lumbar spine (3.8%), total hip (1.4%), and femoral neck (2.4%), compared with women who received placebo.
The safety profile of oral PTH was consistent with that of subcutaneous PTH. Patients experienced headache, nausea, presyncope, and dizziness; there were no treatment-emergent hypercalcemia adverse events.
A few ‘unexpected findings’
Suzanne M. Jan De Beur, MD, outgoing ASBMR president, said, “Oral PTH appeared to increase BMD by [dual-energy x-ray absorptiometry] at the lumbar spine effectively and to a similar degree as teriparatide in previous studies.”
She identified two unexpected findings.
“There were increases in BMD by DXA at the femoral neck and total hip at 6 months that were [greater than those] seen in previous trials of teriparatide. Second, markers of bone resorption (CTX) decreased at 6 months, and this is in stark contrast to the increases observed with teriparatide treatment,” she noted in an interview.
Dr. Rosen also noted that “the decrease in CTX is very unusual for PTH and difficult to explain.” He added: “P1NP, a marker of bone formation, was not increased.”
Dr. Jan de Beur continued: “Teriparatide (PTH1-34) and abaloparatide are effective anabolic agents that we use to treat patients with high risk of osteoporotic fracture. Although effective, the burden of daily subcutaneous injection can be a barrier for older individuals, those with poor dexterity, and those that are averse to self-injection.
“Taken together, these results appear promising, that oral PTH may prove to be an effective anabolic agent for osteoporosis treatment,” she summarized.
She stressed that a larger phase 3 study is needed to demonstrate safety and efficacy.
The study was funded by Entera Bio. Dr. Santora is chief medical officer of Entera Bio.
A version of this article first appeared on Medscape.com .
Omega-3s tame inflammation in elderly COVID-19 patients
results of a small randomized controlled trial suggest.
Results of the study, which included 22 patients with multiple comorbidities, were presented at the European Geriatric Medicine Society annual congress, a hybrid live and online meeting.
The patients, who had a median age of 81 years, were randomized to receive an intravenous infusion of an omega-3 polyunsaturated fatty acid (PUFA) emulsion containing 10 g of fish oil per 100 mL or a saline placebo.
Those who received the intravenous infusion had significant decreases from baseline to end of treatment in the neutrophil-to-lymphocyte ratio (NLR), indicating marked reductions in systemic inflammation.
In contrast, patients randomized to a saline placebo had no significant improvements in NLR, Magnus Bäck, MD, PhD, from the Karolinska Institute in Stockholm reported at the meeting.
“Our lipidomic analysis also showed that omega-3 treatment skewed the lipid response, with reduced levels of proinflammatory lipid mediators, and increased levels of proresolving mediators,” according to a late-breaking abstract, which Dr. Bäck presented during the session.
Omega-3 treatment was not significantly associated with reduction in either C-reactive protein (CRP) or the proinflammatory cytokine interleukin-6, however.
‘Eicosanoid storm’
In a review article published in January 2021 in the open-access journal Frontiers in Physiology, Dr. Bäck and colleagues outlined the rationale for their randomized trial.
“Excessive inflammation has been reported in severe cases with respiratory failure and cardiovascular complications,” they wrote. “In addition to the release of cytokines, referred to as cytokine release syndrome or ‘cytokine storm,’ increased proinflammatory lipid mediators derived from the omega-6 polyunsaturated fatty acid (PUFA) arachidonic acid may cause an ‘eicosanoid storm,’ which contributes to the uncontrolled systemic inflammation.”
Omega-3 PUFA contains proresolving mediators that can limit inflammatory reactions, suggesting the possibility of an inflammation-resolving benefit in patients with COVID-19 without concerns about immunosuppression, the authors hypothesized.
Trial details
In the trial, COVID-Omega-F, they enrolled patients with a COVID-19 diagnosis requiring hospitalization. Patients with an allergy to fish oil or who had contraindications to intravenous PUFA administration (for example, risk for bleeding, shock, or emboli) were excluded.
Ten patients were randomly assigned to receive infusions of the omega-3 PUFA and 12 were assigned to receive infusions of the placebo, once daily for 5 days. The primary outcome measure was change in inflammatory biomarkers, including white blood cell counts, CRP, cytokines, and lipid mediators.
Baseline demographic and clinical characteristics were similar between the two study arms, with a median of about 7 days since the onset of symptoms, and 3.5 days since a diagnosis of COVID-19.
All patients had low lymphocyte responses reflected by a high NLR, a prognostic measure for worse outcomes in patients with COVID-19 infections, Dr. Bäck said.
Inflammation was moderate, with a CRP of 65 mg/L in the placebo group and 62 mg/L in the omega-3 group.
Seven patients in each study arm received concomitant corticoid treatment. Two patients in each arm died in hospital, but there were no serious treatment-related adverse events.
Inflammatory markers improve
As noted before, there was a significant decline in NLR from baseline among patients randomized to omega-3 (P = .02) but no corresponding decrease in patients assigned to placebo infusions.
“The significant decrease was largely driven by an increase in the lymphocyte count in the omega-3 treated group (P = .004), whereas lymphocytes did not significantly change,” Dr. Bäck said.
As expected, patients in the omega-3 group had pronounced increases in omega-3 fatty acids, including eicosapentaenoic acid and docosahexaenoic acid.
The metabolism of fatty acids also differed markedly between the groups, with a significant decrease in the omega-3 group but not the placebo group in proinflammatory mediators, and an increase in precursors to proresolving mediators, Dr. Bäck noted.
AFib concerns
In a question-and-answer part of the session, a physician who identified herself as “Senya from Russia” questioned the safety of omega-3 treatment in this population, “because recently there was a meta-analysis which showed that omega-3 fatty acids will increase the risk of atrial fibrillation in older adults especially.”
The systematic review and meta-analysis she referred to, published in Circulation and reported on by this news organization, showed that, among 81,210 patients with a mean age of 65 enrolled in seven randomized controlled trials, omega-3 fatty acid supplementation was associated with a 25% increase in risk for atrial fibrillation. This risk appeared to be higher in trials testing doses greater than 1 g/day, according to the paper.
“This was not monitored in this study,” Dr. Bäck replied. “It is true that the meta-analysis showed an increased incidence of atrial fibrillation, so it would be something to monitor in case this trial would be expanded to a larger population.”
The study was supported by the Karolinska Institute. Dr. Bäck disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
results of a small randomized controlled trial suggest.
Results of the study, which included 22 patients with multiple comorbidities, were presented at the European Geriatric Medicine Society annual congress, a hybrid live and online meeting.
The patients, who had a median age of 81 years, were randomized to receive an intravenous infusion of an omega-3 polyunsaturated fatty acid (PUFA) emulsion containing 10 g of fish oil per 100 mL or a saline placebo.
Those who received the intravenous infusion had significant decreases from baseline to end of treatment in the neutrophil-to-lymphocyte ratio (NLR), indicating marked reductions in systemic inflammation.
In contrast, patients randomized to a saline placebo had no significant improvements in NLR, Magnus Bäck, MD, PhD, from the Karolinska Institute in Stockholm reported at the meeting.
“Our lipidomic analysis also showed that omega-3 treatment skewed the lipid response, with reduced levels of proinflammatory lipid mediators, and increased levels of proresolving mediators,” according to a late-breaking abstract, which Dr. Bäck presented during the session.
Omega-3 treatment was not significantly associated with reduction in either C-reactive protein (CRP) or the proinflammatory cytokine interleukin-6, however.
‘Eicosanoid storm’
In a review article published in January 2021 in the open-access journal Frontiers in Physiology, Dr. Bäck and colleagues outlined the rationale for their randomized trial.
“Excessive inflammation has been reported in severe cases with respiratory failure and cardiovascular complications,” they wrote. “In addition to the release of cytokines, referred to as cytokine release syndrome or ‘cytokine storm,’ increased proinflammatory lipid mediators derived from the omega-6 polyunsaturated fatty acid (PUFA) arachidonic acid may cause an ‘eicosanoid storm,’ which contributes to the uncontrolled systemic inflammation.”
Omega-3 PUFA contains proresolving mediators that can limit inflammatory reactions, suggesting the possibility of an inflammation-resolving benefit in patients with COVID-19 without concerns about immunosuppression, the authors hypothesized.
Trial details
In the trial, COVID-Omega-F, they enrolled patients with a COVID-19 diagnosis requiring hospitalization. Patients with an allergy to fish oil or who had contraindications to intravenous PUFA administration (for example, risk for bleeding, shock, or emboli) were excluded.
Ten patients were randomly assigned to receive infusions of the omega-3 PUFA and 12 were assigned to receive infusions of the placebo, once daily for 5 days. The primary outcome measure was change in inflammatory biomarkers, including white blood cell counts, CRP, cytokines, and lipid mediators.
Baseline demographic and clinical characteristics were similar between the two study arms, with a median of about 7 days since the onset of symptoms, and 3.5 days since a diagnosis of COVID-19.
All patients had low lymphocyte responses reflected by a high NLR, a prognostic measure for worse outcomes in patients with COVID-19 infections, Dr. Bäck said.
Inflammation was moderate, with a CRP of 65 mg/L in the placebo group and 62 mg/L in the omega-3 group.
Seven patients in each study arm received concomitant corticoid treatment. Two patients in each arm died in hospital, but there were no serious treatment-related adverse events.
Inflammatory markers improve
As noted before, there was a significant decline in NLR from baseline among patients randomized to omega-3 (P = .02) but no corresponding decrease in patients assigned to placebo infusions.
“The significant decrease was largely driven by an increase in the lymphocyte count in the omega-3 treated group (P = .004), whereas lymphocytes did not significantly change,” Dr. Bäck said.
As expected, patients in the omega-3 group had pronounced increases in omega-3 fatty acids, including eicosapentaenoic acid and docosahexaenoic acid.
The metabolism of fatty acids also differed markedly between the groups, with a significant decrease in the omega-3 group but not the placebo group in proinflammatory mediators, and an increase in precursors to proresolving mediators, Dr. Bäck noted.
AFib concerns
In a question-and-answer part of the session, a physician who identified herself as “Senya from Russia” questioned the safety of omega-3 treatment in this population, “because recently there was a meta-analysis which showed that omega-3 fatty acids will increase the risk of atrial fibrillation in older adults especially.”
The systematic review and meta-analysis she referred to, published in Circulation and reported on by this news organization, showed that, among 81,210 patients with a mean age of 65 enrolled in seven randomized controlled trials, omega-3 fatty acid supplementation was associated with a 25% increase in risk for atrial fibrillation. This risk appeared to be higher in trials testing doses greater than 1 g/day, according to the paper.
“This was not monitored in this study,” Dr. Bäck replied. “It is true that the meta-analysis showed an increased incidence of atrial fibrillation, so it would be something to monitor in case this trial would be expanded to a larger population.”
The study was supported by the Karolinska Institute. Dr. Bäck disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
results of a small randomized controlled trial suggest.
Results of the study, which included 22 patients with multiple comorbidities, were presented at the European Geriatric Medicine Society annual congress, a hybrid live and online meeting.
The patients, who had a median age of 81 years, were randomized to receive an intravenous infusion of an omega-3 polyunsaturated fatty acid (PUFA) emulsion containing 10 g of fish oil per 100 mL or a saline placebo.
Those who received the intravenous infusion had significant decreases from baseline to end of treatment in the neutrophil-to-lymphocyte ratio (NLR), indicating marked reductions in systemic inflammation.
In contrast, patients randomized to a saline placebo had no significant improvements in NLR, Magnus Bäck, MD, PhD, from the Karolinska Institute in Stockholm reported at the meeting.
“Our lipidomic analysis also showed that omega-3 treatment skewed the lipid response, with reduced levels of proinflammatory lipid mediators, and increased levels of proresolving mediators,” according to a late-breaking abstract, which Dr. Bäck presented during the session.
Omega-3 treatment was not significantly associated with reduction in either C-reactive protein (CRP) or the proinflammatory cytokine interleukin-6, however.
‘Eicosanoid storm’
In a review article published in January 2021 in the open-access journal Frontiers in Physiology, Dr. Bäck and colleagues outlined the rationale for their randomized trial.
“Excessive inflammation has been reported in severe cases with respiratory failure and cardiovascular complications,” they wrote. “In addition to the release of cytokines, referred to as cytokine release syndrome or ‘cytokine storm,’ increased proinflammatory lipid mediators derived from the omega-6 polyunsaturated fatty acid (PUFA) arachidonic acid may cause an ‘eicosanoid storm,’ which contributes to the uncontrolled systemic inflammation.”
Omega-3 PUFA contains proresolving mediators that can limit inflammatory reactions, suggesting the possibility of an inflammation-resolving benefit in patients with COVID-19 without concerns about immunosuppression, the authors hypothesized.
Trial details
In the trial, COVID-Omega-F, they enrolled patients with a COVID-19 diagnosis requiring hospitalization. Patients with an allergy to fish oil or who had contraindications to intravenous PUFA administration (for example, risk for bleeding, shock, or emboli) were excluded.
Ten patients were randomly assigned to receive infusions of the omega-3 PUFA and 12 were assigned to receive infusions of the placebo, once daily for 5 days. The primary outcome measure was change in inflammatory biomarkers, including white blood cell counts, CRP, cytokines, and lipid mediators.
Baseline demographic and clinical characteristics were similar between the two study arms, with a median of about 7 days since the onset of symptoms, and 3.5 days since a diagnosis of COVID-19.
All patients had low lymphocyte responses reflected by a high NLR, a prognostic measure for worse outcomes in patients with COVID-19 infections, Dr. Bäck said.
Inflammation was moderate, with a CRP of 65 mg/L in the placebo group and 62 mg/L in the omega-3 group.
Seven patients in each study arm received concomitant corticoid treatment. Two patients in each arm died in hospital, but there were no serious treatment-related adverse events.
Inflammatory markers improve
As noted before, there was a significant decline in NLR from baseline among patients randomized to omega-3 (P = .02) but no corresponding decrease in patients assigned to placebo infusions.
“The significant decrease was largely driven by an increase in the lymphocyte count in the omega-3 treated group (P = .004), whereas lymphocytes did not significantly change,” Dr. Bäck said.
As expected, patients in the omega-3 group had pronounced increases in omega-3 fatty acids, including eicosapentaenoic acid and docosahexaenoic acid.
The metabolism of fatty acids also differed markedly between the groups, with a significant decrease in the omega-3 group but not the placebo group in proinflammatory mediators, and an increase in precursors to proresolving mediators, Dr. Bäck noted.
AFib concerns
In a question-and-answer part of the session, a physician who identified herself as “Senya from Russia” questioned the safety of omega-3 treatment in this population, “because recently there was a meta-analysis which showed that omega-3 fatty acids will increase the risk of atrial fibrillation in older adults especially.”
The systematic review and meta-analysis she referred to, published in Circulation and reported on by this news organization, showed that, among 81,210 patients with a mean age of 65 enrolled in seven randomized controlled trials, omega-3 fatty acid supplementation was associated with a 25% increase in risk for atrial fibrillation. This risk appeared to be higher in trials testing doses greater than 1 g/day, according to the paper.
“This was not monitored in this study,” Dr. Bäck replied. “It is true that the meta-analysis showed an increased incidence of atrial fibrillation, so it would be something to monitor in case this trial would be expanded to a larger population.”
The study was supported by the Karolinska Institute. Dr. Bäck disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM EUGMS
Pandemic data challenges infection link to Guillain-Barré syndrome
While pediatric cases of various types of infections fell by 45%-95% during the early months of the pandemic, cases of acute inflammatory demyelinating polyneuropathy (AIDP), an inflammatory neuropathy belonging to the clinical spectrum of Guillain-Barré syndrome, only fell by about 32%-37%, a rate that’s similar to the 35.1% decline in overall hospital admissions over that time period, researchers found. There was also no apparent link between the appearance of COVID-19 and the number of reported AIDP cases.
“There was no clear association between respiratory or gastrointestinal infections and rates of AIDP. Further, we found that AIDP did not have the expected dramatic reduction when community-acquired infections decreased during the pandemic,” Children’s Hospital of Philadelphia neurologist Craig A. Press, MD, PhD, said in an interview.
Dr. Press and colleagues presented their findings in a poster at the 50th annual meeting of the Child Neurology Society.
According to Dr. Press, the cause of AIDP in most patients is unclear, although infections and vaccinations are often linked to cases. “However, the data supporting this link is often weak. Infections with Campylobacter jejuni [bacteria that causes food poisoning] are known to be associated with AIDP, while rates of AIDP in the general population and in those with influenza are similar.”
For the new multicenter, cross-sectional study, researchers tracked AIDP data from the 47 pediatric hospitals that provide statistics to the Pediatric Health Information System. They focused on the period from January 2017 to September 2020, which included the first months of the COVID-19 pandemic in the United States.
“Social distancing, masks, and increased hand hygiene decrease community-acquired infectious rates in a dramatic way,” Dr. Press said. “If these infections were causing AIDP, we hypothesized that the cases of AIDP would drop substantially as a result.”
But this didn’t appear to happen. Researchers found that the numbers of various types of infections declined from April to September 2020: Respiratory infections dipped by 73%-78%, gastrointestinal infections fell by 45%-61%, and influenza infections dipped by 88%-95%. But AIDP cases didn’t fall as precipitously. In fact, their levels were about the same as they were in April 2017, a month when rates of gastrointestinal, respiratory disease and influenza infections were at seasonally low – but not abnormal – ebbs.
“While we must be cautious interpreting the results,” Dr. Press said, “this makes the link between infections as the main driver of pediatric AIDP less likely.”
However, he said, “this study does not exclude the possibility that rare infections cause AIDP – the data supporting that some more rare infections like campylobacter have a connection to AIDP are more robust – or that common infections very rarely lead to AIDP. While we look for triggers causing inflammatory disorders, AIDP maybe an autoinflammatory disorder without a clear trigger.”
Going forward, Dr. Press said, “we hope to look at infectious data in a more granular way to identify if specific viral or bacterial infectious may be associated with this or other inflammatory disorders. We believe that the use of data like this and the natural experiment that COVID-19 provided may help us to explore the impact of infections on disorders thought to be postinfectious.”
No study funding is reported, and the authors report no relevant disclosures.
While pediatric cases of various types of infections fell by 45%-95% during the early months of the pandemic, cases of acute inflammatory demyelinating polyneuropathy (AIDP), an inflammatory neuropathy belonging to the clinical spectrum of Guillain-Barré syndrome, only fell by about 32%-37%, a rate that’s similar to the 35.1% decline in overall hospital admissions over that time period, researchers found. There was also no apparent link between the appearance of COVID-19 and the number of reported AIDP cases.
“There was no clear association between respiratory or gastrointestinal infections and rates of AIDP. Further, we found that AIDP did not have the expected dramatic reduction when community-acquired infections decreased during the pandemic,” Children’s Hospital of Philadelphia neurologist Craig A. Press, MD, PhD, said in an interview.
Dr. Press and colleagues presented their findings in a poster at the 50th annual meeting of the Child Neurology Society.
According to Dr. Press, the cause of AIDP in most patients is unclear, although infections and vaccinations are often linked to cases. “However, the data supporting this link is often weak. Infections with Campylobacter jejuni [bacteria that causes food poisoning] are known to be associated with AIDP, while rates of AIDP in the general population and in those with influenza are similar.”
For the new multicenter, cross-sectional study, researchers tracked AIDP data from the 47 pediatric hospitals that provide statistics to the Pediatric Health Information System. They focused on the period from January 2017 to September 2020, which included the first months of the COVID-19 pandemic in the United States.
“Social distancing, masks, and increased hand hygiene decrease community-acquired infectious rates in a dramatic way,” Dr. Press said. “If these infections were causing AIDP, we hypothesized that the cases of AIDP would drop substantially as a result.”
But this didn’t appear to happen. Researchers found that the numbers of various types of infections declined from April to September 2020: Respiratory infections dipped by 73%-78%, gastrointestinal infections fell by 45%-61%, and influenza infections dipped by 88%-95%. But AIDP cases didn’t fall as precipitously. In fact, their levels were about the same as they were in April 2017, a month when rates of gastrointestinal, respiratory disease and influenza infections were at seasonally low – but not abnormal – ebbs.
“While we must be cautious interpreting the results,” Dr. Press said, “this makes the link between infections as the main driver of pediatric AIDP less likely.”
However, he said, “this study does not exclude the possibility that rare infections cause AIDP – the data supporting that some more rare infections like campylobacter have a connection to AIDP are more robust – or that common infections very rarely lead to AIDP. While we look for triggers causing inflammatory disorders, AIDP maybe an autoinflammatory disorder without a clear trigger.”
Going forward, Dr. Press said, “we hope to look at infectious data in a more granular way to identify if specific viral or bacterial infectious may be associated with this or other inflammatory disorders. We believe that the use of data like this and the natural experiment that COVID-19 provided may help us to explore the impact of infections on disorders thought to be postinfectious.”
No study funding is reported, and the authors report no relevant disclosures.
While pediatric cases of various types of infections fell by 45%-95% during the early months of the pandemic, cases of acute inflammatory demyelinating polyneuropathy (AIDP), an inflammatory neuropathy belonging to the clinical spectrum of Guillain-Barré syndrome, only fell by about 32%-37%, a rate that’s similar to the 35.1% decline in overall hospital admissions over that time period, researchers found. There was also no apparent link between the appearance of COVID-19 and the number of reported AIDP cases.
“There was no clear association between respiratory or gastrointestinal infections and rates of AIDP. Further, we found that AIDP did not have the expected dramatic reduction when community-acquired infections decreased during the pandemic,” Children’s Hospital of Philadelphia neurologist Craig A. Press, MD, PhD, said in an interview.
Dr. Press and colleagues presented their findings in a poster at the 50th annual meeting of the Child Neurology Society.
According to Dr. Press, the cause of AIDP in most patients is unclear, although infections and vaccinations are often linked to cases. “However, the data supporting this link is often weak. Infections with Campylobacter jejuni [bacteria that causes food poisoning] are known to be associated with AIDP, while rates of AIDP in the general population and in those with influenza are similar.”
For the new multicenter, cross-sectional study, researchers tracked AIDP data from the 47 pediatric hospitals that provide statistics to the Pediatric Health Information System. They focused on the period from January 2017 to September 2020, which included the first months of the COVID-19 pandemic in the United States.
“Social distancing, masks, and increased hand hygiene decrease community-acquired infectious rates in a dramatic way,” Dr. Press said. “If these infections were causing AIDP, we hypothesized that the cases of AIDP would drop substantially as a result.”
But this didn’t appear to happen. Researchers found that the numbers of various types of infections declined from April to September 2020: Respiratory infections dipped by 73%-78%, gastrointestinal infections fell by 45%-61%, and influenza infections dipped by 88%-95%. But AIDP cases didn’t fall as precipitously. In fact, their levels were about the same as they were in April 2017, a month when rates of gastrointestinal, respiratory disease and influenza infections were at seasonally low – but not abnormal – ebbs.
“While we must be cautious interpreting the results,” Dr. Press said, “this makes the link between infections as the main driver of pediatric AIDP less likely.”
However, he said, “this study does not exclude the possibility that rare infections cause AIDP – the data supporting that some more rare infections like campylobacter have a connection to AIDP are more robust – or that common infections very rarely lead to AIDP. While we look for triggers causing inflammatory disorders, AIDP maybe an autoinflammatory disorder without a clear trigger.”
Going forward, Dr. Press said, “we hope to look at infectious data in a more granular way to identify if specific viral or bacterial infectious may be associated with this or other inflammatory disorders. We believe that the use of data like this and the natural experiment that COVID-19 provided may help us to explore the impact of infections on disorders thought to be postinfectious.”
No study funding is reported, and the authors report no relevant disclosures.
FROM CNS 2021
Epidiolex plus THC lowers seizures in pediatric epilepsy
the component of cannabis that makes people high in larger quantities, researchers reported.
“THC can contribute to seizure control and mitigation some of the side effects of CBD,” said study coauthor and Austin, Tex., child neurologist Karen Keough, MD, in an interview. Dr. Keough and colleagues presented their findings at the 50th annual meeting of the Child Neurology Society.
In a landmark move, the Food and Drug Administration approved Epidiolex in 2018 for the treatment of seizures in two rare forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome. The agency had never before approved a drug with a purified ingredient derived from marijuana.
CBD, the active ingredient in Epidiolex, is nonpsychoactive. The use in medicine of THC, the main driver of marijuana’s ability to make people stoned, is much more controversial.
Dr. Keough said she had treated 60-70 children with CBD, at the same strength as in Epidiolex (100 mg), and 5 mg of THC before the drug was approved. “I was seeing some very impressive results, and some became seizure free who’d always been refractory,” she said.
When the Epidiolex became available, she said, some patients transitioned to it and stopped taking THC. According to her, some patients fared well. But others immediately experienced worse seizures, she said, and some developed side effects to Epidiolex in the absence of THC, such as agitation and appetite suppression.
Combination therapy
For the new study, a retrospective, unblinded cohort analysis, Dr. Keough and colleagues tracked patients who received various doses of CBD, in some cases as Epidiolex, and various doses of THC prescribed by the Texas Original Compassionate Cultivation dispensary, where she serves as chief medical officer.
The initial number of patients was 212; 135 consented to review and 10 were excluded for various reasons leaving a total of 74 subjects in the study. The subjects, whose median age at the start of the study was 12 years (range, 2-25 years), were tracked from 2018 to2021. Just over half (55%) were male, and they remained on the regimen for a median of 805 days (range, 400-1,141).
Of the 74 subjects, 45.9% had a reduction of seizures of more than 75%, and 20.3% had a reduction of 50%-75%. Only 4.1% saw their seizures worsen.
The THC doses varied from none to more than 12 mg/day; CBD doses varied from none to more than 26 mg/kg per day. O the 74 patients, 18 saw their greatest seizure reduction from baseline when they received no THC; 12 saw their greatest seizure reduction from baseline when they received 0-2 mg/kg per day of CBD.
Still controversial
Did the patients get high? In some cases they did, Dr. Keough said. However, “a lot of these patients are either too young or too cognitively limited to describe whether they’re feeling intoxicated. That’s one of the many reasons why this is so controversial. You have to go into this with eyes wide open. We’re working in an environment with limited information as to what an intoxicating dose is for a small kid.”
However, she said, it seems clear that “THC can enhance the effect of CBD in children with epilepsy” and reduce CBD side effects. It’s not surprising that the substances work differently since they interact with brain cells in different ways, she said.
For neurologists, she said, “the challenge is to find a reliable source of THC that you can count on and verify so you aren’t overdosing the patients.”
University of Saskatchewan, Saskatoon, child neurologist and cannabinoid researcher Richard Huntsman, MD, who’s familiar with the study findings, said in an interview that they “provide another strong signal that the addition of THC provides benefit, at least in some patients.”
But it’s still unclear “why some children respond best in regards to seizure reduction and side effect profile with combination CBD:THC therapy, and others seemed to do better with CBD alone,” he said. Also unknown: “the ideal THC:CBD ratio that allows optimal seizure control while preventing the potential harmful effects of THC.”
As for the future, he said, “as we are just scratching the surface of our knowledge about the use of cannabis-based therapies in children with neurological disorders, I suspect that the use of these therapies will expand over time.”
No study funding is reported. Dr. Keough disclosed serving as chief medical officer of Texas Original Compassionate Cultivation. Dr. Huntsman disclosed serving as lead investigator of the Cannabidiol in Children with Refractory Epileptic Encephalopathy study and serving on the boards of the Cannabinoid Research Initiative of Saskatchewan (University of Saskatchewan) and Canadian Childhood Cannabinoid Clinical Trials Consortium. He is also cochair of Health Canada’s Scientific Advisory Committee on Cannabinoids for Health Purposes.
the component of cannabis that makes people high in larger quantities, researchers reported.
“THC can contribute to seizure control and mitigation some of the side effects of CBD,” said study coauthor and Austin, Tex., child neurologist Karen Keough, MD, in an interview. Dr. Keough and colleagues presented their findings at the 50th annual meeting of the Child Neurology Society.
In a landmark move, the Food and Drug Administration approved Epidiolex in 2018 for the treatment of seizures in two rare forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome. The agency had never before approved a drug with a purified ingredient derived from marijuana.
CBD, the active ingredient in Epidiolex, is nonpsychoactive. The use in medicine of THC, the main driver of marijuana’s ability to make people stoned, is much more controversial.
Dr. Keough said she had treated 60-70 children with CBD, at the same strength as in Epidiolex (100 mg), and 5 mg of THC before the drug was approved. “I was seeing some very impressive results, and some became seizure free who’d always been refractory,” she said.
When the Epidiolex became available, she said, some patients transitioned to it and stopped taking THC. According to her, some patients fared well. But others immediately experienced worse seizures, she said, and some developed side effects to Epidiolex in the absence of THC, such as agitation and appetite suppression.
Combination therapy
For the new study, a retrospective, unblinded cohort analysis, Dr. Keough and colleagues tracked patients who received various doses of CBD, in some cases as Epidiolex, and various doses of THC prescribed by the Texas Original Compassionate Cultivation dispensary, where she serves as chief medical officer.
The initial number of patients was 212; 135 consented to review and 10 were excluded for various reasons leaving a total of 74 subjects in the study. The subjects, whose median age at the start of the study was 12 years (range, 2-25 years), were tracked from 2018 to2021. Just over half (55%) were male, and they remained on the regimen for a median of 805 days (range, 400-1,141).
Of the 74 subjects, 45.9% had a reduction of seizures of more than 75%, and 20.3% had a reduction of 50%-75%. Only 4.1% saw their seizures worsen.
The THC doses varied from none to more than 12 mg/day; CBD doses varied from none to more than 26 mg/kg per day. O the 74 patients, 18 saw their greatest seizure reduction from baseline when they received no THC; 12 saw their greatest seizure reduction from baseline when they received 0-2 mg/kg per day of CBD.
Still controversial
Did the patients get high? In some cases they did, Dr. Keough said. However, “a lot of these patients are either too young or too cognitively limited to describe whether they’re feeling intoxicated. That’s one of the many reasons why this is so controversial. You have to go into this with eyes wide open. We’re working in an environment with limited information as to what an intoxicating dose is for a small kid.”
However, she said, it seems clear that “THC can enhance the effect of CBD in children with epilepsy” and reduce CBD side effects. It’s not surprising that the substances work differently since they interact with brain cells in different ways, she said.
For neurologists, she said, “the challenge is to find a reliable source of THC that you can count on and verify so you aren’t overdosing the patients.”
University of Saskatchewan, Saskatoon, child neurologist and cannabinoid researcher Richard Huntsman, MD, who’s familiar with the study findings, said in an interview that they “provide another strong signal that the addition of THC provides benefit, at least in some patients.”
But it’s still unclear “why some children respond best in regards to seizure reduction and side effect profile with combination CBD:THC therapy, and others seemed to do better with CBD alone,” he said. Also unknown: “the ideal THC:CBD ratio that allows optimal seizure control while preventing the potential harmful effects of THC.”
As for the future, he said, “as we are just scratching the surface of our knowledge about the use of cannabis-based therapies in children with neurological disorders, I suspect that the use of these therapies will expand over time.”
No study funding is reported. Dr. Keough disclosed serving as chief medical officer of Texas Original Compassionate Cultivation. Dr. Huntsman disclosed serving as lead investigator of the Cannabidiol in Children with Refractory Epileptic Encephalopathy study and serving on the boards of the Cannabinoid Research Initiative of Saskatchewan (University of Saskatchewan) and Canadian Childhood Cannabinoid Clinical Trials Consortium. He is also cochair of Health Canada’s Scientific Advisory Committee on Cannabinoids for Health Purposes.
the component of cannabis that makes people high in larger quantities, researchers reported.
“THC can contribute to seizure control and mitigation some of the side effects of CBD,” said study coauthor and Austin, Tex., child neurologist Karen Keough, MD, in an interview. Dr. Keough and colleagues presented their findings at the 50th annual meeting of the Child Neurology Society.
In a landmark move, the Food and Drug Administration approved Epidiolex in 2018 for the treatment of seizures in two rare forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome. The agency had never before approved a drug with a purified ingredient derived from marijuana.
CBD, the active ingredient in Epidiolex, is nonpsychoactive. The use in medicine of THC, the main driver of marijuana’s ability to make people stoned, is much more controversial.
Dr. Keough said she had treated 60-70 children with CBD, at the same strength as in Epidiolex (100 mg), and 5 mg of THC before the drug was approved. “I was seeing some very impressive results, and some became seizure free who’d always been refractory,” she said.
When the Epidiolex became available, she said, some patients transitioned to it and stopped taking THC. According to her, some patients fared well. But others immediately experienced worse seizures, she said, and some developed side effects to Epidiolex in the absence of THC, such as agitation and appetite suppression.
Combination therapy
For the new study, a retrospective, unblinded cohort analysis, Dr. Keough and colleagues tracked patients who received various doses of CBD, in some cases as Epidiolex, and various doses of THC prescribed by the Texas Original Compassionate Cultivation dispensary, where she serves as chief medical officer.
The initial number of patients was 212; 135 consented to review and 10 were excluded for various reasons leaving a total of 74 subjects in the study. The subjects, whose median age at the start of the study was 12 years (range, 2-25 years), were tracked from 2018 to2021. Just over half (55%) were male, and they remained on the regimen for a median of 805 days (range, 400-1,141).
Of the 74 subjects, 45.9% had a reduction of seizures of more than 75%, and 20.3% had a reduction of 50%-75%. Only 4.1% saw their seizures worsen.
The THC doses varied from none to more than 12 mg/day; CBD doses varied from none to more than 26 mg/kg per day. O the 74 patients, 18 saw their greatest seizure reduction from baseline when they received no THC; 12 saw their greatest seizure reduction from baseline when they received 0-2 mg/kg per day of CBD.
Still controversial
Did the patients get high? In some cases they did, Dr. Keough said. However, “a lot of these patients are either too young or too cognitively limited to describe whether they’re feeling intoxicated. That’s one of the many reasons why this is so controversial. You have to go into this with eyes wide open. We’re working in an environment with limited information as to what an intoxicating dose is for a small kid.”
However, she said, it seems clear that “THC can enhance the effect of CBD in children with epilepsy” and reduce CBD side effects. It’s not surprising that the substances work differently since they interact with brain cells in different ways, she said.
For neurologists, she said, “the challenge is to find a reliable source of THC that you can count on and verify so you aren’t overdosing the patients.”
University of Saskatchewan, Saskatoon, child neurologist and cannabinoid researcher Richard Huntsman, MD, who’s familiar with the study findings, said in an interview that they “provide another strong signal that the addition of THC provides benefit, at least in some patients.”
But it’s still unclear “why some children respond best in regards to seizure reduction and side effect profile with combination CBD:THC therapy, and others seemed to do better with CBD alone,” he said. Also unknown: “the ideal THC:CBD ratio that allows optimal seizure control while preventing the potential harmful effects of THC.”
As for the future, he said, “as we are just scratching the surface of our knowledge about the use of cannabis-based therapies in children with neurological disorders, I suspect that the use of these therapies will expand over time.”
No study funding is reported. Dr. Keough disclosed serving as chief medical officer of Texas Original Compassionate Cultivation. Dr. Huntsman disclosed serving as lead investigator of the Cannabidiol in Children with Refractory Epileptic Encephalopathy study and serving on the boards of the Cannabinoid Research Initiative of Saskatchewan (University of Saskatchewan) and Canadian Childhood Cannabinoid Clinical Trials Consortium. He is also cochair of Health Canada’s Scientific Advisory Committee on Cannabinoids for Health Purposes.
FROM CNS 2021
Lupus may confer higher risk of death from COVID-19
There is a significantly increased risk for acute respiratory distress syndrome (ARDS)–related death from COVID-19 among people with systemic lupus erythematous (SLE), compared with the general population, according to data collected in Brazil in 2020.
“Special care is therefore necessary for these patients, as well as reinforcement of the importance of preventive measures during a pandemic for this population,” said Eloisa Bonfá, MD, PhD, at the 14th International Congress on Systemic Lupus Erythematosus, which was held together with the 6th International Congress on Controversies in Rheumatology and Autoimmunity.
“We know that lupus patients have an increased susceptibility to infections due to autoimmune dysregulation and use of immunosuppressive therapy,” explained Dr. Bonfá, who is clinical director of the largest tertiary referral center for autoimmune rheumatic diseases in Latin America, the University of São Paulo Faculty of Medicine Hospital Clinics.
“Our study demonstrates for the first time that lupus patients have an increased ARDS severity,” she added.
Prior to the meeting, the study was published in ACR Open Rheumatology.
Collating the evidence
Since the COVID-19 pandemic began, there have been more than 20 million confirmed cases of SARS-CoV-2 infection in Brazil and more than half a million deaths.
Dr. Bonfá presented the results of a cross-sectional study that was part of the country’s national Influenza Epidemiological Reporting Surveillance System. Data from 2020 were used, which included just over 252,000 individuals who had polymerase chain reaction–confirmed SARS-CoV-2 infection. Of these individuals, there were 319 consecutively recruited patients with SLE.
The aim was to look at the effect of being hospitalized for COVID-19–related ARDS on outcomes in people with SLE versus the general population.
ARDS was defined as a positive polymerase chain reaction test and accompanying flu-like symptoms with dyspnea, respiratory discomfort, persistent pressure in the chest, or desaturation less than 95% in room air or having a bluish tinge to the lips or face.
Other telling signs of a serious respiratory infection that were evaluated, but not mandatory for study eligibility, were loss of smell, impaired taste, typical CT findings, or having had contact with a confirmed COVID-19 case in the preceding 2 weeks.
Key findings
The risk for death from COVID-19–related ARDS was “more than double” in patients with SLE, compared with the general population, Dr. Bonfá reported. The relative risk in the fully adjusted, propensity-scored analysis was approximately 2.25.
That analysis did not account for other comorbidities but was fully adjusted for individuals’ age, sex, and region of Brazil where they lived. The latter was important, Dr. Bonfá said, because “we have a high disparity regarding health access and treatment among regions.”
Comorbidities considered as part of the analyses included arterial hypertension, diabetes, malignancies, neurologic disease, and diseases affecting the heart, lung, liver, and kidneys. Researchers also adjusted for smoking, alcohol intake, body weight, pregnancy, and transplantation.
SLE had a greater impact on individuals’ outcomes than all other comorbidities considered.
“We evaluated lupus as one comorbidity compared to all other comorbidities,” Dr. Bonfá explained.
SLE “more than doubled the chances” of dying from ARDS, she said. “This is [a] very impressive finding.”
They found that SLE was associated with an RR for death of 1.73, compared with non-SLE patients, when propensity-score matching without adjustment for comorbidities was used. The RR for death dropped to 1.40 but was still significant when researchers included comorbidities.
Dr. Bonfá and her team also looked at a combined endpoint of death, ICU admission, and need for mechanical ventilation. They found an increased risk in patients with SLE versus the general population in all their analyses, ranging from 1.70 if comorbidities were included in the model to 1.27 if they weren’t to 1.39 if propensity-score matching alone was used.
Got lupus? ‘Get vaccinated’
“The data we have are in nonvaccinated patients,” Dr. Bonfá said. “We didn’t have vaccines in 2020.”
Whether being vaccinated might make a different to the risks found in this study is an “interesting question,” and one that may be examined in the future.
Certainly, other work Dr. Bonfá has been involved in seems to point to a likely benefit of vaccination in patients with autoimmune diseases in terms of reducing mortality from COVID-19, even when rates of infection may be on the rise.
“There’s considerable vaccine hesitancy in SLE patients,” Chi-Chiu Mok, MD, of Tuen Mun Hospital in Hong Kong, observed in a separate presentation at the congress.
This may be for several reasons, such as worry that their disease may flare or the vaccine might compromise their drug treatment or result in uncommon complications.
However, “we should encourage our SLE patients to receive COVID-19 vaccination at a time of clinical remission or low disease activity state,” Dr. Mok advised.
“Physical distancing, protective masks, and personal hygiene [measures]” should also continue.
The bottom line for those with SLE is to get vaccinated, stressed Sandra Navarra, MD, of the University of Santo Tomas Hospital in Manila, the Philippines, during the discussion.
“There’s still so much out there that we do not know about,” she said. “Just get yourself vaccinated.”
The study had no outside funding. Dr. Bonfá, Dr. Mok, and Dr. Navarra reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
There is a significantly increased risk for acute respiratory distress syndrome (ARDS)–related death from COVID-19 among people with systemic lupus erythematous (SLE), compared with the general population, according to data collected in Brazil in 2020.
“Special care is therefore necessary for these patients, as well as reinforcement of the importance of preventive measures during a pandemic for this population,” said Eloisa Bonfá, MD, PhD, at the 14th International Congress on Systemic Lupus Erythematosus, which was held together with the 6th International Congress on Controversies in Rheumatology and Autoimmunity.
“We know that lupus patients have an increased susceptibility to infections due to autoimmune dysregulation and use of immunosuppressive therapy,” explained Dr. Bonfá, who is clinical director of the largest tertiary referral center for autoimmune rheumatic diseases in Latin America, the University of São Paulo Faculty of Medicine Hospital Clinics.
“Our study demonstrates for the first time that lupus patients have an increased ARDS severity,” she added.
Prior to the meeting, the study was published in ACR Open Rheumatology.
Collating the evidence
Since the COVID-19 pandemic began, there have been more than 20 million confirmed cases of SARS-CoV-2 infection in Brazil and more than half a million deaths.
Dr. Bonfá presented the results of a cross-sectional study that was part of the country’s national Influenza Epidemiological Reporting Surveillance System. Data from 2020 were used, which included just over 252,000 individuals who had polymerase chain reaction–confirmed SARS-CoV-2 infection. Of these individuals, there were 319 consecutively recruited patients with SLE.
The aim was to look at the effect of being hospitalized for COVID-19–related ARDS on outcomes in people with SLE versus the general population.
ARDS was defined as a positive polymerase chain reaction test and accompanying flu-like symptoms with dyspnea, respiratory discomfort, persistent pressure in the chest, or desaturation less than 95% in room air or having a bluish tinge to the lips or face.
Other telling signs of a serious respiratory infection that were evaluated, but not mandatory for study eligibility, were loss of smell, impaired taste, typical CT findings, or having had contact with a confirmed COVID-19 case in the preceding 2 weeks.
Key findings
The risk for death from COVID-19–related ARDS was “more than double” in patients with SLE, compared with the general population, Dr. Bonfá reported. The relative risk in the fully adjusted, propensity-scored analysis was approximately 2.25.
That analysis did not account for other comorbidities but was fully adjusted for individuals’ age, sex, and region of Brazil where they lived. The latter was important, Dr. Bonfá said, because “we have a high disparity regarding health access and treatment among regions.”
Comorbidities considered as part of the analyses included arterial hypertension, diabetes, malignancies, neurologic disease, and diseases affecting the heart, lung, liver, and kidneys. Researchers also adjusted for smoking, alcohol intake, body weight, pregnancy, and transplantation.
SLE had a greater impact on individuals’ outcomes than all other comorbidities considered.
“We evaluated lupus as one comorbidity compared to all other comorbidities,” Dr. Bonfá explained.
SLE “more than doubled the chances” of dying from ARDS, she said. “This is [a] very impressive finding.”
They found that SLE was associated with an RR for death of 1.73, compared with non-SLE patients, when propensity-score matching without adjustment for comorbidities was used. The RR for death dropped to 1.40 but was still significant when researchers included comorbidities.
Dr. Bonfá and her team also looked at a combined endpoint of death, ICU admission, and need for mechanical ventilation. They found an increased risk in patients with SLE versus the general population in all their analyses, ranging from 1.70 if comorbidities were included in the model to 1.27 if they weren’t to 1.39 if propensity-score matching alone was used.
Got lupus? ‘Get vaccinated’
“The data we have are in nonvaccinated patients,” Dr. Bonfá said. “We didn’t have vaccines in 2020.”
Whether being vaccinated might make a different to the risks found in this study is an “interesting question,” and one that may be examined in the future.
Certainly, other work Dr. Bonfá has been involved in seems to point to a likely benefit of vaccination in patients with autoimmune diseases in terms of reducing mortality from COVID-19, even when rates of infection may be on the rise.
“There’s considerable vaccine hesitancy in SLE patients,” Chi-Chiu Mok, MD, of Tuen Mun Hospital in Hong Kong, observed in a separate presentation at the congress.
This may be for several reasons, such as worry that their disease may flare or the vaccine might compromise their drug treatment or result in uncommon complications.
However, “we should encourage our SLE patients to receive COVID-19 vaccination at a time of clinical remission or low disease activity state,” Dr. Mok advised.
“Physical distancing, protective masks, and personal hygiene [measures]” should also continue.
The bottom line for those with SLE is to get vaccinated, stressed Sandra Navarra, MD, of the University of Santo Tomas Hospital in Manila, the Philippines, during the discussion.
“There’s still so much out there that we do not know about,” she said. “Just get yourself vaccinated.”
The study had no outside funding. Dr. Bonfá, Dr. Mok, and Dr. Navarra reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
There is a significantly increased risk for acute respiratory distress syndrome (ARDS)–related death from COVID-19 among people with systemic lupus erythematous (SLE), compared with the general population, according to data collected in Brazil in 2020.
“Special care is therefore necessary for these patients, as well as reinforcement of the importance of preventive measures during a pandemic for this population,” said Eloisa Bonfá, MD, PhD, at the 14th International Congress on Systemic Lupus Erythematosus, which was held together with the 6th International Congress on Controversies in Rheumatology and Autoimmunity.
“We know that lupus patients have an increased susceptibility to infections due to autoimmune dysregulation and use of immunosuppressive therapy,” explained Dr. Bonfá, who is clinical director of the largest tertiary referral center for autoimmune rheumatic diseases in Latin America, the University of São Paulo Faculty of Medicine Hospital Clinics.
“Our study demonstrates for the first time that lupus patients have an increased ARDS severity,” she added.
Prior to the meeting, the study was published in ACR Open Rheumatology.
Collating the evidence
Since the COVID-19 pandemic began, there have been more than 20 million confirmed cases of SARS-CoV-2 infection in Brazil and more than half a million deaths.
Dr. Bonfá presented the results of a cross-sectional study that was part of the country’s national Influenza Epidemiological Reporting Surveillance System. Data from 2020 were used, which included just over 252,000 individuals who had polymerase chain reaction–confirmed SARS-CoV-2 infection. Of these individuals, there were 319 consecutively recruited patients with SLE.
The aim was to look at the effect of being hospitalized for COVID-19–related ARDS on outcomes in people with SLE versus the general population.
ARDS was defined as a positive polymerase chain reaction test and accompanying flu-like symptoms with dyspnea, respiratory discomfort, persistent pressure in the chest, or desaturation less than 95% in room air or having a bluish tinge to the lips or face.
Other telling signs of a serious respiratory infection that were evaluated, but not mandatory for study eligibility, were loss of smell, impaired taste, typical CT findings, or having had contact with a confirmed COVID-19 case in the preceding 2 weeks.
Key findings
The risk for death from COVID-19–related ARDS was “more than double” in patients with SLE, compared with the general population, Dr. Bonfá reported. The relative risk in the fully adjusted, propensity-scored analysis was approximately 2.25.
That analysis did not account for other comorbidities but was fully adjusted for individuals’ age, sex, and region of Brazil where they lived. The latter was important, Dr. Bonfá said, because “we have a high disparity regarding health access and treatment among regions.”
Comorbidities considered as part of the analyses included arterial hypertension, diabetes, malignancies, neurologic disease, and diseases affecting the heart, lung, liver, and kidneys. Researchers also adjusted for smoking, alcohol intake, body weight, pregnancy, and transplantation.
SLE had a greater impact on individuals’ outcomes than all other comorbidities considered.
“We evaluated lupus as one comorbidity compared to all other comorbidities,” Dr. Bonfá explained.
SLE “more than doubled the chances” of dying from ARDS, she said. “This is [a] very impressive finding.”
They found that SLE was associated with an RR for death of 1.73, compared with non-SLE patients, when propensity-score matching without adjustment for comorbidities was used. The RR for death dropped to 1.40 but was still significant when researchers included comorbidities.
Dr. Bonfá and her team also looked at a combined endpoint of death, ICU admission, and need for mechanical ventilation. They found an increased risk in patients with SLE versus the general population in all their analyses, ranging from 1.70 if comorbidities were included in the model to 1.27 if they weren’t to 1.39 if propensity-score matching alone was used.
Got lupus? ‘Get vaccinated’
“The data we have are in nonvaccinated patients,” Dr. Bonfá said. “We didn’t have vaccines in 2020.”
Whether being vaccinated might make a different to the risks found in this study is an “interesting question,” and one that may be examined in the future.
Certainly, other work Dr. Bonfá has been involved in seems to point to a likely benefit of vaccination in patients with autoimmune diseases in terms of reducing mortality from COVID-19, even when rates of infection may be on the rise.
“There’s considerable vaccine hesitancy in SLE patients,” Chi-Chiu Mok, MD, of Tuen Mun Hospital in Hong Kong, observed in a separate presentation at the congress.
This may be for several reasons, such as worry that their disease may flare or the vaccine might compromise their drug treatment or result in uncommon complications.
However, “we should encourage our SLE patients to receive COVID-19 vaccination at a time of clinical remission or low disease activity state,” Dr. Mok advised.
“Physical distancing, protective masks, and personal hygiene [measures]” should also continue.
The bottom line for those with SLE is to get vaccinated, stressed Sandra Navarra, MD, of the University of Santo Tomas Hospital in Manila, the Philippines, during the discussion.
“There’s still so much out there that we do not know about,” she said. “Just get yourself vaccinated.”
The study had no outside funding. Dr. Bonfá, Dr. Mok, and Dr. Navarra reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Double antiglutamatergic therapy is ‘promising’ for super-refractory status epilepticus
(SRSE), new research suggests.
In a retrospective cohort study of survivors of cardiac arrest with postanoxic sustained SRSE, resolution of the condition was achieved by 81% of those who received intensive treatment of ketamine plus perampanel, versus 41% of those who received standard care.
The novelty of the new treatment approach is the duration of therapy as well as the dual antiglutamate drugs, researchers note.
“So the logic is to continue treatment until resolution of refractory status epilepticus under continuous EEG [electroencephalographic] monitoring,” reported lead investigator Simone Beretta, MD, San Gerardo University Hospital, Monza, Italy.
Therapy was guided by data on brainstem reflexes, N20 cortical responses, neuronal serum enolase levels, and neuroimaging.
If all or most of these indicators are favorable, “we continue to treat without any time limit,” Dr. Beretta said. However, if the indicators become unfavorable, clinicians should consider lowering the intensity of care, he added.
The findings were presented at the 2021 World Congress of Neurology (WCN).
SUPER-CAT trial
In SRSE, epileptic seizures occur one after another without patients recovering consciousness in between. Standard aggressive therapy for the condition does not include antiglutamatergic drugs, the researchers noted.
In the Super-Refractory Status Epilepticus After Cardiac Arrest: Aggressive Treatment Guided by Multimodal Prognostic Indicators (SUPER-CAT) study, researchers assessed the combination of two such medications.
The first was the anti-NMDA receptor drug ketamine, which was given by intravenous bolus and then continuous infusion for 3 days guided by continuous EEG to reach a ketamine EEG pattern, as evidenced by alpha and beta waves. It was combined with the anti-AMPA receptor antiepileptic perampanel via nasogastric tube for 5 days, followed by slow tapering.
Dr. Beretta noted that in the ongoing TELSTAR trial, which involved a similar patient population, a different drug combination is being used. A major difference between the two trials is that in the TELSTAR trial, aggressive therapy continues for only 2 days if there is no response.
“In the SUPER-CAT study, we continue far beyond 2 days in the majority of patients,” he said. In addition, ketamine and perampanel were not assessed in TELSTAR.
In SUPER-CAT, 489 survivors of cardiac arrest were recruited over 10 years. Of these, 101 had refractory status epilepticus. After excluding those with more than two indicators of poor prognosis (n = 31) or whose status epilepticus resolved (n = 14), 56 patients were determined to have SRSE. All had experienced relapse after undergoing one cycle of anesthetic.
The 56 participants received one of three treatment regimens: double antiglutamate (DAG) therapy of ketamine and perampanel (n = 26), single antiglutamate therapy with either agent (n = 8), or aggressive nonantiglutamate (NAG) therapy with antiepilepsy drugs and anesthetics other than ketamine or perampanel (n = 22).
The single-antiglutamate group was not included in the analysis of patient outcomes.
The DAG and NAG groups were well balanced at baseline. There were no significant differences in median age (60 years vs. 66 years), gender, low cerebral blood flow, presence of bilateral pupillary or corneal reflexes, neuron-specific enolase levels, cortical N20 somatosenory evoked potentials, moderate to severe postanoxic brain injury, and hypothermia/targeted temperature management.
Primary outcome met
More patients in the DAG group (42%) had moderate to severe postanoxic brain injury than in the NAG group (28%). However, the difference was not statistically significant (P = .08), possibly because of the small sample sizes. The number of antiepileptic drugs and the number of cycles of anesthetics did not differ between the groups.
Results showed that efficacy and safety outcomes favored DAG therapy.
The primary efficacy outcome was resolution of status epilepticus within 3 days after initiation of treatments. Status epilepticus resolved for 21 of 26 patients in the DAG group (81%), versus 9 of 22 patients in the NAG group (41%; odds ratio, 6.06; 95% confidence interval, 1.66-22.12; P = .005).
For secondary efficacy outcomes, there was a trend in favor of DAG, but differences from the NAG group were not statistically significant. In the groups, 46% versus 32% awakened and responded to commands before discharge from the intensive care unit, and 32% versus 23% showed good neurologic outcome at 6 months.
The primary safety outcome of all-cause mortality risk in the ICU was 90% lower for patients treated with DAG than for those treated with NAG (15% vs. 64%; OR, 0.1; 95% CI, 0.02-0.41; P < .01). Dr. Beretta explained that the high mortality rate in the NAG group was presumably a result of unresolved status epilepticus.
The secondary safety outcome of a transitory rise of gamma-glutamyl transferase greater than three times the upper limit of normal in the DAG group was expected with high-dose perampanel, the investigators noted. This outcome occurred in 77% of the DAG group versus 27% of the NAG group (OR, 9.88; 95% CI, 2.4-32.9; P < .001).
There was no statistically significant difference in incidence of recurrent cardiac arrest during therapy. This occurred in one member of the DAG group and in none in the NAG group.
Dr. Beretta reported that their investigations are still in a retrospective phase, but the researchers plan to move the work into a prospective phase and possibly a randomized trial soon.
Fascinating, promising
Commenting on the findings, Jaysingh Singh, MD, co-director of the Epilepsy Surgery Center at the Ohio State University Wexner Medical Center, Columbus, said the study provides “fascinating, very helpful data” about a condition that has responded well to current treatment options.
He added that his center has used “the innovative treatments” discussed in the study for a few patients.
“More concrete evidence will push us to use it more uniformly across all our patient population [that] has refractory status. So I’m very optimistic, and the data were very promising,” said Dr. Singh, who was not involved with the research.
He cautioned that the study was retrospective, not randomized or controlled, and that it involved a small number of patients but said that the data were “heading in the right direction.”
Although resolution of status epilepticus was better among patients in the DAG group than in the NAG group, the awakenings and neurologic outcomes were “pretty much same as standard medical therapy, which we commonly give to our patients,” said Dr. Singh. “We see this phenomenon all the time in our patients.”
He noted that other factors can determine how patients respond, such as conditions of the heart or kidneys, the presence of sepsis, and multiorgan dysfunction. These factors were not controlled for in the study.
Nonetheless, he said the study achieved its primary endpoint of better resolution of status epilepticus “because that’s the first thing you want to see: whether the treatment is taking care of that.”
The study received no outside funding. Dr. Beretta and Dr. Singh have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
(SRSE), new research suggests.
In a retrospective cohort study of survivors of cardiac arrest with postanoxic sustained SRSE, resolution of the condition was achieved by 81% of those who received intensive treatment of ketamine plus perampanel, versus 41% of those who received standard care.
The novelty of the new treatment approach is the duration of therapy as well as the dual antiglutamate drugs, researchers note.
“So the logic is to continue treatment until resolution of refractory status epilepticus under continuous EEG [electroencephalographic] monitoring,” reported lead investigator Simone Beretta, MD, San Gerardo University Hospital, Monza, Italy.
Therapy was guided by data on brainstem reflexes, N20 cortical responses, neuronal serum enolase levels, and neuroimaging.
If all or most of these indicators are favorable, “we continue to treat without any time limit,” Dr. Beretta said. However, if the indicators become unfavorable, clinicians should consider lowering the intensity of care, he added.
The findings were presented at the 2021 World Congress of Neurology (WCN).
SUPER-CAT trial
In SRSE, epileptic seizures occur one after another without patients recovering consciousness in between. Standard aggressive therapy for the condition does not include antiglutamatergic drugs, the researchers noted.
In the Super-Refractory Status Epilepticus After Cardiac Arrest: Aggressive Treatment Guided by Multimodal Prognostic Indicators (SUPER-CAT) study, researchers assessed the combination of two such medications.
The first was the anti-NMDA receptor drug ketamine, which was given by intravenous bolus and then continuous infusion for 3 days guided by continuous EEG to reach a ketamine EEG pattern, as evidenced by alpha and beta waves. It was combined with the anti-AMPA receptor antiepileptic perampanel via nasogastric tube for 5 days, followed by slow tapering.
Dr. Beretta noted that in the ongoing TELSTAR trial, which involved a similar patient population, a different drug combination is being used. A major difference between the two trials is that in the TELSTAR trial, aggressive therapy continues for only 2 days if there is no response.
“In the SUPER-CAT study, we continue far beyond 2 days in the majority of patients,” he said. In addition, ketamine and perampanel were not assessed in TELSTAR.
In SUPER-CAT, 489 survivors of cardiac arrest were recruited over 10 years. Of these, 101 had refractory status epilepticus. After excluding those with more than two indicators of poor prognosis (n = 31) or whose status epilepticus resolved (n = 14), 56 patients were determined to have SRSE. All had experienced relapse after undergoing one cycle of anesthetic.
The 56 participants received one of three treatment regimens: double antiglutamate (DAG) therapy of ketamine and perampanel (n = 26), single antiglutamate therapy with either agent (n = 8), or aggressive nonantiglutamate (NAG) therapy with antiepilepsy drugs and anesthetics other than ketamine or perampanel (n = 22).
The single-antiglutamate group was not included in the analysis of patient outcomes.
The DAG and NAG groups were well balanced at baseline. There were no significant differences in median age (60 years vs. 66 years), gender, low cerebral blood flow, presence of bilateral pupillary or corneal reflexes, neuron-specific enolase levels, cortical N20 somatosenory evoked potentials, moderate to severe postanoxic brain injury, and hypothermia/targeted temperature management.
Primary outcome met
More patients in the DAG group (42%) had moderate to severe postanoxic brain injury than in the NAG group (28%). However, the difference was not statistically significant (P = .08), possibly because of the small sample sizes. The number of antiepileptic drugs and the number of cycles of anesthetics did not differ between the groups.
Results showed that efficacy and safety outcomes favored DAG therapy.
The primary efficacy outcome was resolution of status epilepticus within 3 days after initiation of treatments. Status epilepticus resolved for 21 of 26 patients in the DAG group (81%), versus 9 of 22 patients in the NAG group (41%; odds ratio, 6.06; 95% confidence interval, 1.66-22.12; P = .005).
For secondary efficacy outcomes, there was a trend in favor of DAG, but differences from the NAG group were not statistically significant. In the groups, 46% versus 32% awakened and responded to commands before discharge from the intensive care unit, and 32% versus 23% showed good neurologic outcome at 6 months.
The primary safety outcome of all-cause mortality risk in the ICU was 90% lower for patients treated with DAG than for those treated with NAG (15% vs. 64%; OR, 0.1; 95% CI, 0.02-0.41; P < .01). Dr. Beretta explained that the high mortality rate in the NAG group was presumably a result of unresolved status epilepticus.
The secondary safety outcome of a transitory rise of gamma-glutamyl transferase greater than three times the upper limit of normal in the DAG group was expected with high-dose perampanel, the investigators noted. This outcome occurred in 77% of the DAG group versus 27% of the NAG group (OR, 9.88; 95% CI, 2.4-32.9; P < .001).
There was no statistically significant difference in incidence of recurrent cardiac arrest during therapy. This occurred in one member of the DAG group and in none in the NAG group.
Dr. Beretta reported that their investigations are still in a retrospective phase, but the researchers plan to move the work into a prospective phase and possibly a randomized trial soon.
Fascinating, promising
Commenting on the findings, Jaysingh Singh, MD, co-director of the Epilepsy Surgery Center at the Ohio State University Wexner Medical Center, Columbus, said the study provides “fascinating, very helpful data” about a condition that has responded well to current treatment options.
He added that his center has used “the innovative treatments” discussed in the study for a few patients.
“More concrete evidence will push us to use it more uniformly across all our patient population [that] has refractory status. So I’m very optimistic, and the data were very promising,” said Dr. Singh, who was not involved with the research.
He cautioned that the study was retrospective, not randomized or controlled, and that it involved a small number of patients but said that the data were “heading in the right direction.”
Although resolution of status epilepticus was better among patients in the DAG group than in the NAG group, the awakenings and neurologic outcomes were “pretty much same as standard medical therapy, which we commonly give to our patients,” said Dr. Singh. “We see this phenomenon all the time in our patients.”
He noted that other factors can determine how patients respond, such as conditions of the heart or kidneys, the presence of sepsis, and multiorgan dysfunction. These factors were not controlled for in the study.
Nonetheless, he said the study achieved its primary endpoint of better resolution of status epilepticus “because that’s the first thing you want to see: whether the treatment is taking care of that.”
The study received no outside funding. Dr. Beretta and Dr. Singh have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
(SRSE), new research suggests.
In a retrospective cohort study of survivors of cardiac arrest with postanoxic sustained SRSE, resolution of the condition was achieved by 81% of those who received intensive treatment of ketamine plus perampanel, versus 41% of those who received standard care.
The novelty of the new treatment approach is the duration of therapy as well as the dual antiglutamate drugs, researchers note.
“So the logic is to continue treatment until resolution of refractory status epilepticus under continuous EEG [electroencephalographic] monitoring,” reported lead investigator Simone Beretta, MD, San Gerardo University Hospital, Monza, Italy.
Therapy was guided by data on brainstem reflexes, N20 cortical responses, neuronal serum enolase levels, and neuroimaging.
If all or most of these indicators are favorable, “we continue to treat without any time limit,” Dr. Beretta said. However, if the indicators become unfavorable, clinicians should consider lowering the intensity of care, he added.
The findings were presented at the 2021 World Congress of Neurology (WCN).
SUPER-CAT trial
In SRSE, epileptic seizures occur one after another without patients recovering consciousness in between. Standard aggressive therapy for the condition does not include antiglutamatergic drugs, the researchers noted.
In the Super-Refractory Status Epilepticus After Cardiac Arrest: Aggressive Treatment Guided by Multimodal Prognostic Indicators (SUPER-CAT) study, researchers assessed the combination of two such medications.
The first was the anti-NMDA receptor drug ketamine, which was given by intravenous bolus and then continuous infusion for 3 days guided by continuous EEG to reach a ketamine EEG pattern, as evidenced by alpha and beta waves. It was combined with the anti-AMPA receptor antiepileptic perampanel via nasogastric tube for 5 days, followed by slow tapering.
Dr. Beretta noted that in the ongoing TELSTAR trial, which involved a similar patient population, a different drug combination is being used. A major difference between the two trials is that in the TELSTAR trial, aggressive therapy continues for only 2 days if there is no response.
“In the SUPER-CAT study, we continue far beyond 2 days in the majority of patients,” he said. In addition, ketamine and perampanel were not assessed in TELSTAR.
In SUPER-CAT, 489 survivors of cardiac arrest were recruited over 10 years. Of these, 101 had refractory status epilepticus. After excluding those with more than two indicators of poor prognosis (n = 31) or whose status epilepticus resolved (n = 14), 56 patients were determined to have SRSE. All had experienced relapse after undergoing one cycle of anesthetic.
The 56 participants received one of three treatment regimens: double antiglutamate (DAG) therapy of ketamine and perampanel (n = 26), single antiglutamate therapy with either agent (n = 8), or aggressive nonantiglutamate (NAG) therapy with antiepilepsy drugs and anesthetics other than ketamine or perampanel (n = 22).
The single-antiglutamate group was not included in the analysis of patient outcomes.
The DAG and NAG groups were well balanced at baseline. There were no significant differences in median age (60 years vs. 66 years), gender, low cerebral blood flow, presence of bilateral pupillary or corneal reflexes, neuron-specific enolase levels, cortical N20 somatosenory evoked potentials, moderate to severe postanoxic brain injury, and hypothermia/targeted temperature management.
Primary outcome met
More patients in the DAG group (42%) had moderate to severe postanoxic brain injury than in the NAG group (28%). However, the difference was not statistically significant (P = .08), possibly because of the small sample sizes. The number of antiepileptic drugs and the number of cycles of anesthetics did not differ between the groups.
Results showed that efficacy and safety outcomes favored DAG therapy.
The primary efficacy outcome was resolution of status epilepticus within 3 days after initiation of treatments. Status epilepticus resolved for 21 of 26 patients in the DAG group (81%), versus 9 of 22 patients in the NAG group (41%; odds ratio, 6.06; 95% confidence interval, 1.66-22.12; P = .005).
For secondary efficacy outcomes, there was a trend in favor of DAG, but differences from the NAG group were not statistically significant. In the groups, 46% versus 32% awakened and responded to commands before discharge from the intensive care unit, and 32% versus 23% showed good neurologic outcome at 6 months.
The primary safety outcome of all-cause mortality risk in the ICU was 90% lower for patients treated with DAG than for those treated with NAG (15% vs. 64%; OR, 0.1; 95% CI, 0.02-0.41; P < .01). Dr. Beretta explained that the high mortality rate in the NAG group was presumably a result of unresolved status epilepticus.
The secondary safety outcome of a transitory rise of gamma-glutamyl transferase greater than three times the upper limit of normal in the DAG group was expected with high-dose perampanel, the investigators noted. This outcome occurred in 77% of the DAG group versus 27% of the NAG group (OR, 9.88; 95% CI, 2.4-32.9; P < .001).
There was no statistically significant difference in incidence of recurrent cardiac arrest during therapy. This occurred in one member of the DAG group and in none in the NAG group.
Dr. Beretta reported that their investigations are still in a retrospective phase, but the researchers plan to move the work into a prospective phase and possibly a randomized trial soon.
Fascinating, promising
Commenting on the findings, Jaysingh Singh, MD, co-director of the Epilepsy Surgery Center at the Ohio State University Wexner Medical Center, Columbus, said the study provides “fascinating, very helpful data” about a condition that has responded well to current treatment options.
He added that his center has used “the innovative treatments” discussed in the study for a few patients.
“More concrete evidence will push us to use it more uniformly across all our patient population [that] has refractory status. So I’m very optimistic, and the data were very promising,” said Dr. Singh, who was not involved with the research.
He cautioned that the study was retrospective, not randomized or controlled, and that it involved a small number of patients but said that the data were “heading in the right direction.”
Although resolution of status epilepticus was better among patients in the DAG group than in the NAG group, the awakenings and neurologic outcomes were “pretty much same as standard medical therapy, which we commonly give to our patients,” said Dr. Singh. “We see this phenomenon all the time in our patients.”
He noted that other factors can determine how patients respond, such as conditions of the heart or kidneys, the presence of sepsis, and multiorgan dysfunction. These factors were not controlled for in the study.
Nonetheless, he said the study achieved its primary endpoint of better resolution of status epilepticus “because that’s the first thing you want to see: whether the treatment is taking care of that.”
The study received no outside funding. Dr. Beretta and Dr. Singh have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
From WCN 2021