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TBI Significantly Increases Mortality Rate Among Veterans With Epilepsy
, according to recent research published in Epilepsia.
In a retrospective cohort study, Ali Roghani, PhD, of the division of epidemiology at the University of Utah School of Medicine in Salt Lake City, and colleagues evaluated 938,890 veterans between 2000 and 2019 in the Defense Health Agency and the Veterans Health Administration who served in the US military after the September 11 attacks. Overall, 27,436 veterans met criteria for a diagnosis of epilepsy, 264,890 had received a diagnosis for a traumatic brain injury (TBI), and the remaining patients had neither epilepsy nor TBI.
Among the veterans with no epilepsy, 248,714 veterans had a TBI diagnosis, while in the group of patients with epilepsy, 10,358 veterans experienced a TBI before their epilepsy diagnosis, 1598 were diagnosed with a TBI within 6 months of epilepsy, and 4310 veterans had a TBI 6 months after an epilepsy diagnosis. The researchers assessed all-cause mortality in each group, calculating cumulative mortality rates compared with the group of veterans who had no TBI and no epilepsy diagnosis.
Dr. Roghani and colleagues found a significantly higher mortality rate among veterans who developed epilepsy compared with a control group with neither epilepsy nor TBI (6.26% vs. 1.12%; P < .01), with a majority of veterans in the group who died being White (67.4%) men (89.9%). Compared with veterans who were deceased, nondeceased veterans were significantly more likely to have a history of being deployed (70.7% vs. 64.8%; P < .001), were less likely to be in the army (52.2% vs. 55.0%; P < .001), and were more likely to reach the rank of officer or warrant officer (8.1% vs. 7.6%; P = .014).
There were also significant differences in clinical characteristics between nondeceased and deceased veterans, including a higher rate of substance abuse disorder, smoking history, cardiovascular disease, stroke, transient ischemic attack, cancer, liver disease, kidney disease, or other injury as well as overdose, suicidal ideation, and homelessness. “Most clinical conditions were significantly different between deceased and nondeceased in part due to the large cohort size,” the researchers said.
After performing Cox regression analyses, the researchers found a higher mortality risk in veterans with epilepsy and/or TBIs among those who developed a TBI within 6 months of an epilepsy diagnosis (hazard ratio [HR], 5.02; 95% CI, 4.21-5.99), had a TBI prior to epilepsy (HR, 4.25; 95% CI, 3.89-4.58), had epilepsy alone (HR, 4.00; 95% CI, 3.67-4.36), had a TBI more than 6 months after an epilepsy diagnosis (HR, 2.49; 95% CI, 2.17-2.85), and those who had epilepsy alone (HR, 1.30; 95% CI, 1.25-1.36) compared with veterans who had neither epilepsy nor a TBI.
“The temporal relationship with TBI that occurred within 6 months after epilepsy diagnosis may suggest an increased vulnerability to accidents, severe injuries, or TBI resulting from seizures, potentially elevating mortality risk,” Dr. Roghani and colleagues wrote.
The researchers said the results “raise concerns” about the subgroup of patients who are diagnosed with epilepsy close to experiencing a TBI.
“Our results provide information regarding the temporal relationship between epilepsy and TBI regarding mortality in a cohort of post-9/11 veterans, which highlights the need for enhanced primary prevention, such as more access to health care among people with epilepsy and TBI,” they said. “Given the rising incidence of TBI in both the military and civilian populations, these findings suggest close monitoring might be crucial to develop effective prevention strategies for long-term complications, particularly [post-traumatic epilepsy].”
Reevaluating the Treatment of Epilepsy
Juliann Paolicchi, MD, a neurologist and member of the epilepsy team at Northwell Health in New York, who was not involved with the study, said in an interview that TBIs have been studied more closely since the beginning of conflicts in the Middle East, particularly in Iran and Afghanistan, where “newer artillery causes more diffuse traumatic injury to the brain and the body than the effects of more typical weaponry.”
The study by Roghani and colleagues, she said, “is groundbreaking in that it looks at the connection and timing of these two disruptive forces, epilepsy and TBI, on the brain,” she said. “The study reveals that timing is everything: The combination of two disrupting circuitry effects in proximity can have a deadly effect. The summation is greater than either alone in veterans, and has significant effects on the brain’s ability to sustain the functions that keep us alive.”
The 6 months following either a diagnosis of epilepsy or TBI is “crucial,” Dr. Paolicchi noted. “Military and private citizens should be closely monitored during this period, and the results suggest they should refrain from activities that could predispose to further brain injury.”
In addition, current standards for treatment of epilepsy may need to be reevaluated, she said. “Patients are not always treated with a seizure medication after a first seizure, but perhaps, especially in patients at higher risk for brain injury such as the military and athletes, that policy warrants further examination.”
The findings by Roghani and colleagues may also extend to other groups, such as evaluating athletes after a concussion, patients after they are in a motor vehicle accident, and infants with traumatic brain injury, Dr. Paolicchi said. “The results suggest a reexamining of the proximity [of TBI] and epilepsy in these and other areas,” she noted.
The authors reported personal and institutional relationships in the form of research support and other financial compensation from AbbVie, Biohaven, CURE, Department of Defense, Department of Veterans Affairs (VA), Eisai, Engage, National Institutes of Health, Sanofi, SCS Consulting, Sunovion, and UCB. This study was supported by funding from the Department of Defense, VA Health Systems, and the VA HSR&D Informatics, Decision Enhancement, and Analytic Sciences Center of Innovation. Dr. Paolicchi reports no relevant conflicts of interest.
, according to recent research published in Epilepsia.
In a retrospective cohort study, Ali Roghani, PhD, of the division of epidemiology at the University of Utah School of Medicine in Salt Lake City, and colleagues evaluated 938,890 veterans between 2000 and 2019 in the Defense Health Agency and the Veterans Health Administration who served in the US military after the September 11 attacks. Overall, 27,436 veterans met criteria for a diagnosis of epilepsy, 264,890 had received a diagnosis for a traumatic brain injury (TBI), and the remaining patients had neither epilepsy nor TBI.
Among the veterans with no epilepsy, 248,714 veterans had a TBI diagnosis, while in the group of patients with epilepsy, 10,358 veterans experienced a TBI before their epilepsy diagnosis, 1598 were diagnosed with a TBI within 6 months of epilepsy, and 4310 veterans had a TBI 6 months after an epilepsy diagnosis. The researchers assessed all-cause mortality in each group, calculating cumulative mortality rates compared with the group of veterans who had no TBI and no epilepsy diagnosis.
Dr. Roghani and colleagues found a significantly higher mortality rate among veterans who developed epilepsy compared with a control group with neither epilepsy nor TBI (6.26% vs. 1.12%; P < .01), with a majority of veterans in the group who died being White (67.4%) men (89.9%). Compared with veterans who were deceased, nondeceased veterans were significantly more likely to have a history of being deployed (70.7% vs. 64.8%; P < .001), were less likely to be in the army (52.2% vs. 55.0%; P < .001), and were more likely to reach the rank of officer or warrant officer (8.1% vs. 7.6%; P = .014).
There were also significant differences in clinical characteristics between nondeceased and deceased veterans, including a higher rate of substance abuse disorder, smoking history, cardiovascular disease, stroke, transient ischemic attack, cancer, liver disease, kidney disease, or other injury as well as overdose, suicidal ideation, and homelessness. “Most clinical conditions were significantly different between deceased and nondeceased in part due to the large cohort size,” the researchers said.
After performing Cox regression analyses, the researchers found a higher mortality risk in veterans with epilepsy and/or TBIs among those who developed a TBI within 6 months of an epilepsy diagnosis (hazard ratio [HR], 5.02; 95% CI, 4.21-5.99), had a TBI prior to epilepsy (HR, 4.25; 95% CI, 3.89-4.58), had epilepsy alone (HR, 4.00; 95% CI, 3.67-4.36), had a TBI more than 6 months after an epilepsy diagnosis (HR, 2.49; 95% CI, 2.17-2.85), and those who had epilepsy alone (HR, 1.30; 95% CI, 1.25-1.36) compared with veterans who had neither epilepsy nor a TBI.
“The temporal relationship with TBI that occurred within 6 months after epilepsy diagnosis may suggest an increased vulnerability to accidents, severe injuries, or TBI resulting from seizures, potentially elevating mortality risk,” Dr. Roghani and colleagues wrote.
The researchers said the results “raise concerns” about the subgroup of patients who are diagnosed with epilepsy close to experiencing a TBI.
“Our results provide information regarding the temporal relationship between epilepsy and TBI regarding mortality in a cohort of post-9/11 veterans, which highlights the need for enhanced primary prevention, such as more access to health care among people with epilepsy and TBI,” they said. “Given the rising incidence of TBI in both the military and civilian populations, these findings suggest close monitoring might be crucial to develop effective prevention strategies for long-term complications, particularly [post-traumatic epilepsy].”
Reevaluating the Treatment of Epilepsy
Juliann Paolicchi, MD, a neurologist and member of the epilepsy team at Northwell Health in New York, who was not involved with the study, said in an interview that TBIs have been studied more closely since the beginning of conflicts in the Middle East, particularly in Iran and Afghanistan, where “newer artillery causes more diffuse traumatic injury to the brain and the body than the effects of more typical weaponry.”
The study by Roghani and colleagues, she said, “is groundbreaking in that it looks at the connection and timing of these two disruptive forces, epilepsy and TBI, on the brain,” she said. “The study reveals that timing is everything: The combination of two disrupting circuitry effects in proximity can have a deadly effect. The summation is greater than either alone in veterans, and has significant effects on the brain’s ability to sustain the functions that keep us alive.”
The 6 months following either a diagnosis of epilepsy or TBI is “crucial,” Dr. Paolicchi noted. “Military and private citizens should be closely monitored during this period, and the results suggest they should refrain from activities that could predispose to further brain injury.”
In addition, current standards for treatment of epilepsy may need to be reevaluated, she said. “Patients are not always treated with a seizure medication after a first seizure, but perhaps, especially in patients at higher risk for brain injury such as the military and athletes, that policy warrants further examination.”
The findings by Roghani and colleagues may also extend to other groups, such as evaluating athletes after a concussion, patients after they are in a motor vehicle accident, and infants with traumatic brain injury, Dr. Paolicchi said. “The results suggest a reexamining of the proximity [of TBI] and epilepsy in these and other areas,” she noted.
The authors reported personal and institutional relationships in the form of research support and other financial compensation from AbbVie, Biohaven, CURE, Department of Defense, Department of Veterans Affairs (VA), Eisai, Engage, National Institutes of Health, Sanofi, SCS Consulting, Sunovion, and UCB. This study was supported by funding from the Department of Defense, VA Health Systems, and the VA HSR&D Informatics, Decision Enhancement, and Analytic Sciences Center of Innovation. Dr. Paolicchi reports no relevant conflicts of interest.
, according to recent research published in Epilepsia.
In a retrospective cohort study, Ali Roghani, PhD, of the division of epidemiology at the University of Utah School of Medicine in Salt Lake City, and colleagues evaluated 938,890 veterans between 2000 and 2019 in the Defense Health Agency and the Veterans Health Administration who served in the US military after the September 11 attacks. Overall, 27,436 veterans met criteria for a diagnosis of epilepsy, 264,890 had received a diagnosis for a traumatic brain injury (TBI), and the remaining patients had neither epilepsy nor TBI.
Among the veterans with no epilepsy, 248,714 veterans had a TBI diagnosis, while in the group of patients with epilepsy, 10,358 veterans experienced a TBI before their epilepsy diagnosis, 1598 were diagnosed with a TBI within 6 months of epilepsy, and 4310 veterans had a TBI 6 months after an epilepsy diagnosis. The researchers assessed all-cause mortality in each group, calculating cumulative mortality rates compared with the group of veterans who had no TBI and no epilepsy diagnosis.
Dr. Roghani and colleagues found a significantly higher mortality rate among veterans who developed epilepsy compared with a control group with neither epilepsy nor TBI (6.26% vs. 1.12%; P < .01), with a majority of veterans in the group who died being White (67.4%) men (89.9%). Compared with veterans who were deceased, nondeceased veterans were significantly more likely to have a history of being deployed (70.7% vs. 64.8%; P < .001), were less likely to be in the army (52.2% vs. 55.0%; P < .001), and were more likely to reach the rank of officer or warrant officer (8.1% vs. 7.6%; P = .014).
There were also significant differences in clinical characteristics between nondeceased and deceased veterans, including a higher rate of substance abuse disorder, smoking history, cardiovascular disease, stroke, transient ischemic attack, cancer, liver disease, kidney disease, or other injury as well as overdose, suicidal ideation, and homelessness. “Most clinical conditions were significantly different between deceased and nondeceased in part due to the large cohort size,” the researchers said.
After performing Cox regression analyses, the researchers found a higher mortality risk in veterans with epilepsy and/or TBIs among those who developed a TBI within 6 months of an epilepsy diagnosis (hazard ratio [HR], 5.02; 95% CI, 4.21-5.99), had a TBI prior to epilepsy (HR, 4.25; 95% CI, 3.89-4.58), had epilepsy alone (HR, 4.00; 95% CI, 3.67-4.36), had a TBI more than 6 months after an epilepsy diagnosis (HR, 2.49; 95% CI, 2.17-2.85), and those who had epilepsy alone (HR, 1.30; 95% CI, 1.25-1.36) compared with veterans who had neither epilepsy nor a TBI.
“The temporal relationship with TBI that occurred within 6 months after epilepsy diagnosis may suggest an increased vulnerability to accidents, severe injuries, or TBI resulting from seizures, potentially elevating mortality risk,” Dr. Roghani and colleagues wrote.
The researchers said the results “raise concerns” about the subgroup of patients who are diagnosed with epilepsy close to experiencing a TBI.
“Our results provide information regarding the temporal relationship between epilepsy and TBI regarding mortality in a cohort of post-9/11 veterans, which highlights the need for enhanced primary prevention, such as more access to health care among people with epilepsy and TBI,” they said. “Given the rising incidence of TBI in both the military and civilian populations, these findings suggest close monitoring might be crucial to develop effective prevention strategies for long-term complications, particularly [post-traumatic epilepsy].”
Reevaluating the Treatment of Epilepsy
Juliann Paolicchi, MD, a neurologist and member of the epilepsy team at Northwell Health in New York, who was not involved with the study, said in an interview that TBIs have been studied more closely since the beginning of conflicts in the Middle East, particularly in Iran and Afghanistan, where “newer artillery causes more diffuse traumatic injury to the brain and the body than the effects of more typical weaponry.”
The study by Roghani and colleagues, she said, “is groundbreaking in that it looks at the connection and timing of these two disruptive forces, epilepsy and TBI, on the brain,” she said. “The study reveals that timing is everything: The combination of two disrupting circuitry effects in proximity can have a deadly effect. The summation is greater than either alone in veterans, and has significant effects on the brain’s ability to sustain the functions that keep us alive.”
The 6 months following either a diagnosis of epilepsy or TBI is “crucial,” Dr. Paolicchi noted. “Military and private citizens should be closely monitored during this period, and the results suggest they should refrain from activities that could predispose to further brain injury.”
In addition, current standards for treatment of epilepsy may need to be reevaluated, she said. “Patients are not always treated with a seizure medication after a first seizure, but perhaps, especially in patients at higher risk for brain injury such as the military and athletes, that policy warrants further examination.”
The findings by Roghani and colleagues may also extend to other groups, such as evaluating athletes after a concussion, patients after they are in a motor vehicle accident, and infants with traumatic brain injury, Dr. Paolicchi said. “The results suggest a reexamining of the proximity [of TBI] and epilepsy in these and other areas,” she noted.
The authors reported personal and institutional relationships in the form of research support and other financial compensation from AbbVie, Biohaven, CURE, Department of Defense, Department of Veterans Affairs (VA), Eisai, Engage, National Institutes of Health, Sanofi, SCS Consulting, Sunovion, and UCB. This study was supported by funding from the Department of Defense, VA Health Systems, and the VA HSR&D Informatics, Decision Enhancement, and Analytic Sciences Center of Innovation. Dr. Paolicchi reports no relevant conflicts of interest.
FROM EPILEPSIA
COMBAT-MS: Therapy Choice for Relapsing-Remitting MS Has ‘Small’ Impact on Disability Progression, Patient-Reported Outcomes
, according to recent research published in Annals of Neurology.
Fredrik Piehl, MD, PhD, of the department of clinical neuroscience at Karolinska Institutet in Stockholm, and colleagues analyzed results from a cohort study in Sweden of 2449 patients with relapsing-remitting MS who started an initial disease-modifying therapy (DMT), and 2463 patients who switched from their first therapy between 2011 and 2018, with 1148 patients overlapping in both groups. DMTs evaluated in the group that started an initial treatment included rituximab (591 patients), natalizumab (334 patients), dimethyl fumarate (416 patients), interferon (992 patients), and glatiramer acetate (116 patients), while DMTs included in the group switching therapies were rituximab (748 patients), natalizumab (541 patients), dimethyl fumarate (570 patients), fingolimod (443 patients), and teriflunomide (161 patients).
The researchers compared patients receiving low-dose rituximab with other MS therapies, with confirmed disability worsening (CDW) over 12 months and change in disease-related impact on daily life as measured by MS Impact Scale-29 (MSIS-29) subscales as primary outcomes at 3 years after therapy initiation or switching. They also assessed the rate of relapse, discontinuation of therapy, and serious adverse events as secondary outcomes.
At 3 years, among patients who received rituximab, 9.1% of patients who initiated therapy and 5.1% who switched therapy experienced CDW, and there were no significant differences in disease worsening between patients who received rituximab and those who received other MS therapies. “Most instances of CDW on rituximab were in subjects with no relapse within 3 years of treatment start,” the researchers said.
Patient MSIS-29 physical subscores at 3 years improved by 1.3 points in the initial DMT group and by 0.4 points in the DMT-switching group, while MSIS-29 psychological scores improved by 8.4 points in the initial DMT and by 3.6 points in the DMT-switching group. “Adjusted for baseline characteristics, MSIS-29 physical subscale scores decreased more with natalizumab, both as a first DMT and after a DMT switch, compared with rituximab, although absolute differences were small,” Dr. Piehl and colleagues said.
With regard to secondary outcomes, there was a reduction in mean overall Expanded Disability Status Scale (EDSS) score compared with baseline in the initial rituximab group at 3 years (–0.2 points), with 28.7% of patients experiencing improvement and 19.0% experiencing worsening, while there was no overall change in mean EDSS score in the rituximab-switching group. At 5 years, mean EDSS scores decreased compared with baseline in the initial rituximab group (–0.1 point), with 27.1% patients experiencing improvement and 20.8% experiencing worsening, and there was an increase in overall EDSS score (0.1 point) at 5 years for the rituximab-switching group, with improvement in 17.9% of patients and worsening in 26.4% of patients. However, there were no significant differences between rituximab and other DMTs.
Patients in both initial and switching rituximab groups had a lower annualized relapse rate (ARR) compared with other DMTs, with the exception of natalizumab in the initial DMT group (3 vs 2 additional relapses per 100 patients per year). The highest ARR in the initial DMT group belonged to interferon (13 additional relapses per 100 patients per year) and teriflunomide (8 additional relapses per 100 patients per year). “Similar differences were evident also at 5 years, with significantly higher ARRs with all other DMTs compared with rituximab, except for natalizumab, in both the first DMT and DMT switch groups,” Dr. Piehl and colleagues said.
In the group of patients who received rituximab, 75.7% of patients had no evidence of disease activity (NEDA-3) at 3 years in the initial DMT group and 82.1% of patients in the DMT-switching group, which was “greater than for all comparators, except natalizumab as a first DMT,” the researchers said. “Proportions fulfilling NEDA-3 status at 5 years were higher with rituximab than with all comparators in both cohorts,” they noted.
Concerning safety, the researchers said there were minor differences in safety outcomes between rituximab and comparators, but patients in the DMT-switching group who received rituximab had a higher risk of severe infections compared with other groups.
Unanswered Questions About MS Therapies
In an interview, Mark Gudesblatt, MD, a neurologist at South Shore Neurologic Associates, New York, who was not involved in the study, emphasized the importance of high-potency DMTs and adherence for treatment success.
“Lower-efficacy DMT might result in insufficient suppression of disease activity that might not be clinically apparent,” he said. “Routine examination is not sufficient to detect cognitive impairment or change in cognitive impact of disease. Adherence is critical to therapy success, and infusion therapies or treatment not self-administered have higher likelihood of higher adherence rates.”
Commenting on the study by Piehl et al, Dr. Gudesblatt said it “provides important real-world information” on how infusion therapies are tolerated, their effectiveness, and their adherence compared with oral or self-administered treatments. For rituximab, “just as importantly, this therapy provides effective disease control with less accumulated disability and disability related health care costs,” he said.
Dr. Gudesblatt said there are several unanswered issues in the study, including the uncertain nature of the incidence and development of rituximab-blocking antibodies, which could potentially differ by biosimilar. “[H]ow this impacts therapy efficacy is unclear,” he said. “The presence of blocking antibodies should be routinely monitored.”
Another issue is the between-patient variation in degree of B-cell depletion and speed of B-cell repletion, which might differ based on therapy duration. “The timing and frequency of dosing is an issue that also needs further critical analysis and improved guidelines,” he noted.
Dr. Gudesblatt said up to 25% of patients with MS might have unrecognized immune deficiency. “[I]mmune deficiency unrelated to DMT as well as the development of immune deficiency related to DMT are issues of concern, as the rate of infections in B-cell depleting agents are higher than other class of DMT,” he explained. Patients with MS who develop infections carry significant risk of morbidity and mortality, he added.
“Lastly, the issue of vaccination failure is extremely high in B-cell depleting agents, and with the recent viral pandemic and lingering concerns about recurrent similar scenarios, this is another issue of great concern with use of this highly adherent and effective DMT choice,” Dr. Gudesblatt said.
Several authors reported personal and institutional relationships in the form of grants, consultancies, research support, honoraria, advisory board positions, travel support, and other fees for Bayer, Biogen, Merck, Novartis, Roche, and Teva. Dr. Gudesblatt reports no relevant conflicts of interest.
, according to recent research published in Annals of Neurology.
Fredrik Piehl, MD, PhD, of the department of clinical neuroscience at Karolinska Institutet in Stockholm, and colleagues analyzed results from a cohort study in Sweden of 2449 patients with relapsing-remitting MS who started an initial disease-modifying therapy (DMT), and 2463 patients who switched from their first therapy between 2011 and 2018, with 1148 patients overlapping in both groups. DMTs evaluated in the group that started an initial treatment included rituximab (591 patients), natalizumab (334 patients), dimethyl fumarate (416 patients), interferon (992 patients), and glatiramer acetate (116 patients), while DMTs included in the group switching therapies were rituximab (748 patients), natalizumab (541 patients), dimethyl fumarate (570 patients), fingolimod (443 patients), and teriflunomide (161 patients).
The researchers compared patients receiving low-dose rituximab with other MS therapies, with confirmed disability worsening (CDW) over 12 months and change in disease-related impact on daily life as measured by MS Impact Scale-29 (MSIS-29) subscales as primary outcomes at 3 years after therapy initiation or switching. They also assessed the rate of relapse, discontinuation of therapy, and serious adverse events as secondary outcomes.
At 3 years, among patients who received rituximab, 9.1% of patients who initiated therapy and 5.1% who switched therapy experienced CDW, and there were no significant differences in disease worsening between patients who received rituximab and those who received other MS therapies. “Most instances of CDW on rituximab were in subjects with no relapse within 3 years of treatment start,” the researchers said.
Patient MSIS-29 physical subscores at 3 years improved by 1.3 points in the initial DMT group and by 0.4 points in the DMT-switching group, while MSIS-29 psychological scores improved by 8.4 points in the initial DMT and by 3.6 points in the DMT-switching group. “Adjusted for baseline characteristics, MSIS-29 physical subscale scores decreased more with natalizumab, both as a first DMT and after a DMT switch, compared with rituximab, although absolute differences were small,” Dr. Piehl and colleagues said.
With regard to secondary outcomes, there was a reduction in mean overall Expanded Disability Status Scale (EDSS) score compared with baseline in the initial rituximab group at 3 years (–0.2 points), with 28.7% of patients experiencing improvement and 19.0% experiencing worsening, while there was no overall change in mean EDSS score in the rituximab-switching group. At 5 years, mean EDSS scores decreased compared with baseline in the initial rituximab group (–0.1 point), with 27.1% patients experiencing improvement and 20.8% experiencing worsening, and there was an increase in overall EDSS score (0.1 point) at 5 years for the rituximab-switching group, with improvement in 17.9% of patients and worsening in 26.4% of patients. However, there were no significant differences between rituximab and other DMTs.
Patients in both initial and switching rituximab groups had a lower annualized relapse rate (ARR) compared with other DMTs, with the exception of natalizumab in the initial DMT group (3 vs 2 additional relapses per 100 patients per year). The highest ARR in the initial DMT group belonged to interferon (13 additional relapses per 100 patients per year) and teriflunomide (8 additional relapses per 100 patients per year). “Similar differences were evident also at 5 years, with significantly higher ARRs with all other DMTs compared with rituximab, except for natalizumab, in both the first DMT and DMT switch groups,” Dr. Piehl and colleagues said.
In the group of patients who received rituximab, 75.7% of patients had no evidence of disease activity (NEDA-3) at 3 years in the initial DMT group and 82.1% of patients in the DMT-switching group, which was “greater than for all comparators, except natalizumab as a first DMT,” the researchers said. “Proportions fulfilling NEDA-3 status at 5 years were higher with rituximab than with all comparators in both cohorts,” they noted.
Concerning safety, the researchers said there were minor differences in safety outcomes between rituximab and comparators, but patients in the DMT-switching group who received rituximab had a higher risk of severe infections compared with other groups.
Unanswered Questions About MS Therapies
In an interview, Mark Gudesblatt, MD, a neurologist at South Shore Neurologic Associates, New York, who was not involved in the study, emphasized the importance of high-potency DMTs and adherence for treatment success.
“Lower-efficacy DMT might result in insufficient suppression of disease activity that might not be clinically apparent,” he said. “Routine examination is not sufficient to detect cognitive impairment or change in cognitive impact of disease. Adherence is critical to therapy success, and infusion therapies or treatment not self-administered have higher likelihood of higher adherence rates.”
Commenting on the study by Piehl et al, Dr. Gudesblatt said it “provides important real-world information” on how infusion therapies are tolerated, their effectiveness, and their adherence compared with oral or self-administered treatments. For rituximab, “just as importantly, this therapy provides effective disease control with less accumulated disability and disability related health care costs,” he said.
Dr. Gudesblatt said there are several unanswered issues in the study, including the uncertain nature of the incidence and development of rituximab-blocking antibodies, which could potentially differ by biosimilar. “[H]ow this impacts therapy efficacy is unclear,” he said. “The presence of blocking antibodies should be routinely monitored.”
Another issue is the between-patient variation in degree of B-cell depletion and speed of B-cell repletion, which might differ based on therapy duration. “The timing and frequency of dosing is an issue that also needs further critical analysis and improved guidelines,” he noted.
Dr. Gudesblatt said up to 25% of patients with MS might have unrecognized immune deficiency. “[I]mmune deficiency unrelated to DMT as well as the development of immune deficiency related to DMT are issues of concern, as the rate of infections in B-cell depleting agents are higher than other class of DMT,” he explained. Patients with MS who develop infections carry significant risk of morbidity and mortality, he added.
“Lastly, the issue of vaccination failure is extremely high in B-cell depleting agents, and with the recent viral pandemic and lingering concerns about recurrent similar scenarios, this is another issue of great concern with use of this highly adherent and effective DMT choice,” Dr. Gudesblatt said.
Several authors reported personal and institutional relationships in the form of grants, consultancies, research support, honoraria, advisory board positions, travel support, and other fees for Bayer, Biogen, Merck, Novartis, Roche, and Teva. Dr. Gudesblatt reports no relevant conflicts of interest.
, according to recent research published in Annals of Neurology.
Fredrik Piehl, MD, PhD, of the department of clinical neuroscience at Karolinska Institutet in Stockholm, and colleagues analyzed results from a cohort study in Sweden of 2449 patients with relapsing-remitting MS who started an initial disease-modifying therapy (DMT), and 2463 patients who switched from their first therapy between 2011 and 2018, with 1148 patients overlapping in both groups. DMTs evaluated in the group that started an initial treatment included rituximab (591 patients), natalizumab (334 patients), dimethyl fumarate (416 patients), interferon (992 patients), and glatiramer acetate (116 patients), while DMTs included in the group switching therapies were rituximab (748 patients), natalizumab (541 patients), dimethyl fumarate (570 patients), fingolimod (443 patients), and teriflunomide (161 patients).
The researchers compared patients receiving low-dose rituximab with other MS therapies, with confirmed disability worsening (CDW) over 12 months and change in disease-related impact on daily life as measured by MS Impact Scale-29 (MSIS-29) subscales as primary outcomes at 3 years after therapy initiation or switching. They also assessed the rate of relapse, discontinuation of therapy, and serious adverse events as secondary outcomes.
At 3 years, among patients who received rituximab, 9.1% of patients who initiated therapy and 5.1% who switched therapy experienced CDW, and there were no significant differences in disease worsening between patients who received rituximab and those who received other MS therapies. “Most instances of CDW on rituximab were in subjects with no relapse within 3 years of treatment start,” the researchers said.
Patient MSIS-29 physical subscores at 3 years improved by 1.3 points in the initial DMT group and by 0.4 points in the DMT-switching group, while MSIS-29 psychological scores improved by 8.4 points in the initial DMT and by 3.6 points in the DMT-switching group. “Adjusted for baseline characteristics, MSIS-29 physical subscale scores decreased more with natalizumab, both as a first DMT and after a DMT switch, compared with rituximab, although absolute differences were small,” Dr. Piehl and colleagues said.
With regard to secondary outcomes, there was a reduction in mean overall Expanded Disability Status Scale (EDSS) score compared with baseline in the initial rituximab group at 3 years (–0.2 points), with 28.7% of patients experiencing improvement and 19.0% experiencing worsening, while there was no overall change in mean EDSS score in the rituximab-switching group. At 5 years, mean EDSS scores decreased compared with baseline in the initial rituximab group (–0.1 point), with 27.1% patients experiencing improvement and 20.8% experiencing worsening, and there was an increase in overall EDSS score (0.1 point) at 5 years for the rituximab-switching group, with improvement in 17.9% of patients and worsening in 26.4% of patients. However, there were no significant differences between rituximab and other DMTs.
Patients in both initial and switching rituximab groups had a lower annualized relapse rate (ARR) compared with other DMTs, with the exception of natalizumab in the initial DMT group (3 vs 2 additional relapses per 100 patients per year). The highest ARR in the initial DMT group belonged to interferon (13 additional relapses per 100 patients per year) and teriflunomide (8 additional relapses per 100 patients per year). “Similar differences were evident also at 5 years, with significantly higher ARRs with all other DMTs compared with rituximab, except for natalizumab, in both the first DMT and DMT switch groups,” Dr. Piehl and colleagues said.
In the group of patients who received rituximab, 75.7% of patients had no evidence of disease activity (NEDA-3) at 3 years in the initial DMT group and 82.1% of patients in the DMT-switching group, which was “greater than for all comparators, except natalizumab as a first DMT,” the researchers said. “Proportions fulfilling NEDA-3 status at 5 years were higher with rituximab than with all comparators in both cohorts,” they noted.
Concerning safety, the researchers said there were minor differences in safety outcomes between rituximab and comparators, but patients in the DMT-switching group who received rituximab had a higher risk of severe infections compared with other groups.
Unanswered Questions About MS Therapies
In an interview, Mark Gudesblatt, MD, a neurologist at South Shore Neurologic Associates, New York, who was not involved in the study, emphasized the importance of high-potency DMTs and adherence for treatment success.
“Lower-efficacy DMT might result in insufficient suppression of disease activity that might not be clinically apparent,” he said. “Routine examination is not sufficient to detect cognitive impairment or change in cognitive impact of disease. Adherence is critical to therapy success, and infusion therapies or treatment not self-administered have higher likelihood of higher adherence rates.”
Commenting on the study by Piehl et al, Dr. Gudesblatt said it “provides important real-world information” on how infusion therapies are tolerated, their effectiveness, and their adherence compared with oral or self-administered treatments. For rituximab, “just as importantly, this therapy provides effective disease control with less accumulated disability and disability related health care costs,” he said.
Dr. Gudesblatt said there are several unanswered issues in the study, including the uncertain nature of the incidence and development of rituximab-blocking antibodies, which could potentially differ by biosimilar. “[H]ow this impacts therapy efficacy is unclear,” he said. “The presence of blocking antibodies should be routinely monitored.”
Another issue is the between-patient variation in degree of B-cell depletion and speed of B-cell repletion, which might differ based on therapy duration. “The timing and frequency of dosing is an issue that also needs further critical analysis and improved guidelines,” he noted.
Dr. Gudesblatt said up to 25% of patients with MS might have unrecognized immune deficiency. “[I]mmune deficiency unrelated to DMT as well as the development of immune deficiency related to DMT are issues of concern, as the rate of infections in B-cell depleting agents are higher than other class of DMT,” he explained. Patients with MS who develop infections carry significant risk of morbidity and mortality, he added.
“Lastly, the issue of vaccination failure is extremely high in B-cell depleting agents, and with the recent viral pandemic and lingering concerns about recurrent similar scenarios, this is another issue of great concern with use of this highly adherent and effective DMT choice,” Dr. Gudesblatt said.
Several authors reported personal and institutional relationships in the form of grants, consultancies, research support, honoraria, advisory board positions, travel support, and other fees for Bayer, Biogen, Merck, Novartis, Roche, and Teva. Dr. Gudesblatt reports no relevant conflicts of interest.
FROM ANNALS OF NEUROLOGY
Interictal Burden, Disability, Allodynia Linked to Increased Likelihood of Seeking Migraine Care
, according to recent research published in the journal Headache.
“[T]he burden and impact of migraine on the individual both during and between attacks were identified through supervised machine learning models to be strongly associated with seeking care,” Sait Ashina, MD, of the department of neurology at Harvard Medical School in Boston, and colleagues wrote in their study.
Dr. Ashina and colleagues performed a cross-sectional study of 61,826 patients from the web-based ObserVational survey of the Epidemiology, tReatment and Care Of MigrainE (OVERCOME) study with migraine who visited a primary care, specialty care, or urgent care, or emergency setting for headache between 2018 and 2020.
The patients recruited for OBSERVE were a mean of 41.7 years old and had experienced migraines for an average of 19.0 years; 59.4% had between 0 and 3 average headache days per month, 74.5% were women, 78.8% were White, and 85.4% had health insurance; and they were demographically representative of the US population.
Researchers used a machine learning model, which consisted of random forest and least absolute shrinkage and selection operator (LASSO) algorithms, to identify the relationship between patients who sought care for migraine and 54 different clinical, sociodemographic, and migraine-associated factors, which included age, years with migraine, symptom scores, pain intensity scores, disability score, comorbidities, vomiting, presence and severity of allodynia, and other factors.
The results showed 31,529 patients (51.0%) had an in-person or e-visit encounter with a primary care, specialty care, or urgent care, or emergency care location within 12 months of the survey, and were mostly White (76.5%) women (73.3%) with health insurance (88.9%). Of the patients who sought care, 52.8% had severe interictal burden measured by Migraine Interictal Burden Scale-4 score, compared with 23.1% of patients who did not seek care. Compared with patients who did not seek care, those who did visit a health care setting for migraine had a higher percentage of severe migraine-related disability as measured by the Migraine Disability Assessment Scale (36.7% vs 14.6%) and severe ictal cutaneous allodynia as measured by the Allodynia Symptom Checklist (21.0% vs 7.4%).
In a multivariable logistic regression model analysis, Dr. Ashina and colleagues said the factors most associated with seeking care included severe interictal burden (odds ratio [OR], 2.64; 95% confidence interval [CI], 2.5-2.8), severe migraine-related disability (OR, 2.2; 95% CI, 2.0-2.3), and severe ictal allodynia (OR, 1.7; 95% CI, 1.6-1.8), compared with less severe factors.
The researchers said their results have “significant implications for public health and advocacy efforts.”
“As seen through three decades of epidemiological research in the United States, rates of care-seeking have not improved dramatically over time despite significant additions to scientific knowledge and the therapeutic armamentarium, leaving a significant unmet need. This is also important from a clinical perspective,” they explained. “Health care professionals in primary care and internal medicine most likely see patients with migraine who do not discuss it during visits. This underscores the importance of maintaining vigilance for migraine, especially among those who may experience greater disability, impact, and interictal burden.”
Asking the Right Questions
Asked to comment on the research, Robert P. Cowan, MD, a neurologist and professor in the Stanford University School of Medicine department of neurology and neurological sciences in Palo Alto, California, said in an interview that the value of the paper is in what it does not say about the main reasons patients seek care.
“Most clinicians readily acknowledge that the average number of migraine headache days per month is, at best, a weak predictor of which patients seek care and when,” he said.
Dr. Cowan said that most patients are referred to him by other providers, and when he asks them why they did not seek care for migraine sooner, the answer is usually because the migraine was not severe enough or because over-the-counter medication had previously worked for them. He noted that change in frequency is, in his experience, a primary reason why patients will seek care. “[F]or new (or increasing) headache, it is the concern that the headaches are something more ‘serious,’ and once that is ruled out, the conversation often stops,” he said. “For long-standing migraine sufferers, it is the perception that the headache is a ‘fact of life’ and does not rise to the bar of seeking medical advice.”
The questions a survey or a provider asks matters, Dr. Cowan said. “Often, when we ask a patient how many headache (or migraine) days per month, the answer is in single digits. But if we follow-up with a question about the number of headache-free days [per] month, the answer is ‘never’ or ‘hardly ever,’” he explained. “The point here is that what questions a survey (or a provider) asks introduces a clear bias. The use of machine learning instruments, especially when utilizing supervised learning, only reinforces and amplifies the bias of the designers of the categories.”
Epidemiologic studies are interesting but “often ask the wrong questions,” Dr. Cowan said. “I am less worried about the ... 49% of migraine or possible migraine patients who do not seek care and do [not] progress to more disabling ‘chronic’ migraine than I am with identifying the subpopulations of migraine patients who seek care from providers who do not have adequate tools to match patients to the best treatments.”
The authors reported personal and institutional relationships in the form of advisory board memberships, consultancies, employment, honoraria, research support, speakers bureau positions, stock ownership, and teaching services with AbbVie, Aeon, Alder, Allay Lamp, Allergan, Amgen, Axon, Biohaven Pharmaceuticals, Collegium, CoolTech, Currax, Dr. Reddy’s Laboratories (Promius), electroCore, GlaxoSmithKline, Impel NeuroPharma, Informa, Eli Lilly and Company, Lundbeck, Mainistee, Merck, National Headache Foundation, National Institutes of Health, Novartis, Pfizer, Satsuma, Supernus, Percept, Teva, Theranica, UpsherSmith, the US Food and Drug Administration, Vector, Vedanta Research, and Wolff’s Headache. The study was supported by Eli Lilly. Dr. Cowan reports no relevant conflicts of interest.
, according to recent research published in the journal Headache.
“[T]he burden and impact of migraine on the individual both during and between attacks were identified through supervised machine learning models to be strongly associated with seeking care,” Sait Ashina, MD, of the department of neurology at Harvard Medical School in Boston, and colleagues wrote in their study.
Dr. Ashina and colleagues performed a cross-sectional study of 61,826 patients from the web-based ObserVational survey of the Epidemiology, tReatment and Care Of MigrainE (OVERCOME) study with migraine who visited a primary care, specialty care, or urgent care, or emergency setting for headache between 2018 and 2020.
The patients recruited for OBSERVE were a mean of 41.7 years old and had experienced migraines for an average of 19.0 years; 59.4% had between 0 and 3 average headache days per month, 74.5% were women, 78.8% were White, and 85.4% had health insurance; and they were demographically representative of the US population.
Researchers used a machine learning model, which consisted of random forest and least absolute shrinkage and selection operator (LASSO) algorithms, to identify the relationship between patients who sought care for migraine and 54 different clinical, sociodemographic, and migraine-associated factors, which included age, years with migraine, symptom scores, pain intensity scores, disability score, comorbidities, vomiting, presence and severity of allodynia, and other factors.
The results showed 31,529 patients (51.0%) had an in-person or e-visit encounter with a primary care, specialty care, or urgent care, or emergency care location within 12 months of the survey, and were mostly White (76.5%) women (73.3%) with health insurance (88.9%). Of the patients who sought care, 52.8% had severe interictal burden measured by Migraine Interictal Burden Scale-4 score, compared with 23.1% of patients who did not seek care. Compared with patients who did not seek care, those who did visit a health care setting for migraine had a higher percentage of severe migraine-related disability as measured by the Migraine Disability Assessment Scale (36.7% vs 14.6%) and severe ictal cutaneous allodynia as measured by the Allodynia Symptom Checklist (21.0% vs 7.4%).
In a multivariable logistic regression model analysis, Dr. Ashina and colleagues said the factors most associated with seeking care included severe interictal burden (odds ratio [OR], 2.64; 95% confidence interval [CI], 2.5-2.8), severe migraine-related disability (OR, 2.2; 95% CI, 2.0-2.3), and severe ictal allodynia (OR, 1.7; 95% CI, 1.6-1.8), compared with less severe factors.
The researchers said their results have “significant implications for public health and advocacy efforts.”
“As seen through three decades of epidemiological research in the United States, rates of care-seeking have not improved dramatically over time despite significant additions to scientific knowledge and the therapeutic armamentarium, leaving a significant unmet need. This is also important from a clinical perspective,” they explained. “Health care professionals in primary care and internal medicine most likely see patients with migraine who do not discuss it during visits. This underscores the importance of maintaining vigilance for migraine, especially among those who may experience greater disability, impact, and interictal burden.”
Asking the Right Questions
Asked to comment on the research, Robert P. Cowan, MD, a neurologist and professor in the Stanford University School of Medicine department of neurology and neurological sciences in Palo Alto, California, said in an interview that the value of the paper is in what it does not say about the main reasons patients seek care.
“Most clinicians readily acknowledge that the average number of migraine headache days per month is, at best, a weak predictor of which patients seek care and when,” he said.
Dr. Cowan said that most patients are referred to him by other providers, and when he asks them why they did not seek care for migraine sooner, the answer is usually because the migraine was not severe enough or because over-the-counter medication had previously worked for them. He noted that change in frequency is, in his experience, a primary reason why patients will seek care. “[F]or new (or increasing) headache, it is the concern that the headaches are something more ‘serious,’ and once that is ruled out, the conversation often stops,” he said. “For long-standing migraine sufferers, it is the perception that the headache is a ‘fact of life’ and does not rise to the bar of seeking medical advice.”
The questions a survey or a provider asks matters, Dr. Cowan said. “Often, when we ask a patient how many headache (or migraine) days per month, the answer is in single digits. But if we follow-up with a question about the number of headache-free days [per] month, the answer is ‘never’ or ‘hardly ever,’” he explained. “The point here is that what questions a survey (or a provider) asks introduces a clear bias. The use of machine learning instruments, especially when utilizing supervised learning, only reinforces and amplifies the bias of the designers of the categories.”
Epidemiologic studies are interesting but “often ask the wrong questions,” Dr. Cowan said. “I am less worried about the ... 49% of migraine or possible migraine patients who do not seek care and do [not] progress to more disabling ‘chronic’ migraine than I am with identifying the subpopulations of migraine patients who seek care from providers who do not have adequate tools to match patients to the best treatments.”
The authors reported personal and institutional relationships in the form of advisory board memberships, consultancies, employment, honoraria, research support, speakers bureau positions, stock ownership, and teaching services with AbbVie, Aeon, Alder, Allay Lamp, Allergan, Amgen, Axon, Biohaven Pharmaceuticals, Collegium, CoolTech, Currax, Dr. Reddy’s Laboratories (Promius), electroCore, GlaxoSmithKline, Impel NeuroPharma, Informa, Eli Lilly and Company, Lundbeck, Mainistee, Merck, National Headache Foundation, National Institutes of Health, Novartis, Pfizer, Satsuma, Supernus, Percept, Teva, Theranica, UpsherSmith, the US Food and Drug Administration, Vector, Vedanta Research, and Wolff’s Headache. The study was supported by Eli Lilly. Dr. Cowan reports no relevant conflicts of interest.
, according to recent research published in the journal Headache.
“[T]he burden and impact of migraine on the individual both during and between attacks were identified through supervised machine learning models to be strongly associated with seeking care,” Sait Ashina, MD, of the department of neurology at Harvard Medical School in Boston, and colleagues wrote in their study.
Dr. Ashina and colleagues performed a cross-sectional study of 61,826 patients from the web-based ObserVational survey of the Epidemiology, tReatment and Care Of MigrainE (OVERCOME) study with migraine who visited a primary care, specialty care, or urgent care, or emergency setting for headache between 2018 and 2020.
The patients recruited for OBSERVE were a mean of 41.7 years old and had experienced migraines for an average of 19.0 years; 59.4% had between 0 and 3 average headache days per month, 74.5% were women, 78.8% were White, and 85.4% had health insurance; and they were demographically representative of the US population.
Researchers used a machine learning model, which consisted of random forest and least absolute shrinkage and selection operator (LASSO) algorithms, to identify the relationship between patients who sought care for migraine and 54 different clinical, sociodemographic, and migraine-associated factors, which included age, years with migraine, symptom scores, pain intensity scores, disability score, comorbidities, vomiting, presence and severity of allodynia, and other factors.
The results showed 31,529 patients (51.0%) had an in-person or e-visit encounter with a primary care, specialty care, or urgent care, or emergency care location within 12 months of the survey, and were mostly White (76.5%) women (73.3%) with health insurance (88.9%). Of the patients who sought care, 52.8% had severe interictal burden measured by Migraine Interictal Burden Scale-4 score, compared with 23.1% of patients who did not seek care. Compared with patients who did not seek care, those who did visit a health care setting for migraine had a higher percentage of severe migraine-related disability as measured by the Migraine Disability Assessment Scale (36.7% vs 14.6%) and severe ictal cutaneous allodynia as measured by the Allodynia Symptom Checklist (21.0% vs 7.4%).
In a multivariable logistic regression model analysis, Dr. Ashina and colleagues said the factors most associated with seeking care included severe interictal burden (odds ratio [OR], 2.64; 95% confidence interval [CI], 2.5-2.8), severe migraine-related disability (OR, 2.2; 95% CI, 2.0-2.3), and severe ictal allodynia (OR, 1.7; 95% CI, 1.6-1.8), compared with less severe factors.
The researchers said their results have “significant implications for public health and advocacy efforts.”
“As seen through three decades of epidemiological research in the United States, rates of care-seeking have not improved dramatically over time despite significant additions to scientific knowledge and the therapeutic armamentarium, leaving a significant unmet need. This is also important from a clinical perspective,” they explained. “Health care professionals in primary care and internal medicine most likely see patients with migraine who do not discuss it during visits. This underscores the importance of maintaining vigilance for migraine, especially among those who may experience greater disability, impact, and interictal burden.”
Asking the Right Questions
Asked to comment on the research, Robert P. Cowan, MD, a neurologist and professor in the Stanford University School of Medicine department of neurology and neurological sciences in Palo Alto, California, said in an interview that the value of the paper is in what it does not say about the main reasons patients seek care.
“Most clinicians readily acknowledge that the average number of migraine headache days per month is, at best, a weak predictor of which patients seek care and when,” he said.
Dr. Cowan said that most patients are referred to him by other providers, and when he asks them why they did not seek care for migraine sooner, the answer is usually because the migraine was not severe enough or because over-the-counter medication had previously worked for them. He noted that change in frequency is, in his experience, a primary reason why patients will seek care. “[F]or new (or increasing) headache, it is the concern that the headaches are something more ‘serious,’ and once that is ruled out, the conversation often stops,” he said. “For long-standing migraine sufferers, it is the perception that the headache is a ‘fact of life’ and does not rise to the bar of seeking medical advice.”
The questions a survey or a provider asks matters, Dr. Cowan said. “Often, when we ask a patient how many headache (or migraine) days per month, the answer is in single digits. But if we follow-up with a question about the number of headache-free days [per] month, the answer is ‘never’ or ‘hardly ever,’” he explained. “The point here is that what questions a survey (or a provider) asks introduces a clear bias. The use of machine learning instruments, especially when utilizing supervised learning, only reinforces and amplifies the bias of the designers of the categories.”
Epidemiologic studies are interesting but “often ask the wrong questions,” Dr. Cowan said. “I am less worried about the ... 49% of migraine or possible migraine patients who do not seek care and do [not] progress to more disabling ‘chronic’ migraine than I am with identifying the subpopulations of migraine patients who seek care from providers who do not have adequate tools to match patients to the best treatments.”
The authors reported personal and institutional relationships in the form of advisory board memberships, consultancies, employment, honoraria, research support, speakers bureau positions, stock ownership, and teaching services with AbbVie, Aeon, Alder, Allay Lamp, Allergan, Amgen, Axon, Biohaven Pharmaceuticals, Collegium, CoolTech, Currax, Dr. Reddy’s Laboratories (Promius), electroCore, GlaxoSmithKline, Impel NeuroPharma, Informa, Eli Lilly and Company, Lundbeck, Mainistee, Merck, National Headache Foundation, National Institutes of Health, Novartis, Pfizer, Satsuma, Supernus, Percept, Teva, Theranica, UpsherSmith, the US Food and Drug Administration, Vector, Vedanta Research, and Wolff’s Headache. The study was supported by Eli Lilly. Dr. Cowan reports no relevant conflicts of interest.
FROM HEADACHE
Childhood immunization schedule includes new RSV, mpox, meningococcal, and pneumococcal vaccines
The immunization schedule for children and adolescents, summarized as an American Academy of Pediatrics policy statement in the journal Pediatrics, contains new entries for the monoclonal antibody immunization nirsevimab for respiratory syncytial virus in infants, the maternal RSV vaccine RSVpreF for pregnant people, the mpox vaccine for adolescents, the 2023-2024 COVID-19 vaccine, the 20-valent pneumococcal conjugate vaccine (PCV20), and the pentavalent meningococcal vaccine (MenACWY-TT/MenB-FHbp).
A number of immunizations have been deleted from the 2024 schedule, including the pentavalent meningococcal vaccine MenABCWY because of a discontinuation in its distribution in the United States, the bivalent mRNA COVID-19 vaccines, the diphtheria and tetanus toxoids adsorbed vaccine, the 13-valent pneumococcal conjugate vaccine (PCV13), and the pneumococcal polysaccharide vaccine (PPSV23).
The 2024 childhood and adolescent immunization schedule, also approved by the Centers for Disease Control and Prevention, American Academy of Family Physicians, American College of Obstetricians and Gynecologists, American College of Nurse-Midwives, American Academy of Physician Associates, and National Association of Pediatric Nurse Practitioners, is published each year based on current recommendations that have been approved for use by the Food and Drug Administration.
In a press release, the AAP said the CDC decided to publish the recommendations early to ensure health providers are able to administer immunizations and that they are covered by insurance. They also referenced CDC reports that found vaccination rates for kindergarteners have not bounced back since the beginning of the COVID-19 pandemic, and vaccine exemptions for the 2022-2023 school year were at an “all-time high.”
RSV
New to the schedule are the recently approved RSV monoclonal antibody nirsevimab for infants and the RSV vaccine RSVpreF for pregnant people. According to the CDC’s combined immunization schedule for 2024, the timing of the infant RSV immunization is heavily dependent upon when and whether a RSV vaccine was administered during pregnancy. The RSV vaccine should be routinely given between 32 weeks and 36 weeks of gestation between September and January in most of the United States with the caveat that either the maternal vaccine or the infant immunization is recommended.
Infants born between October and March in most of the United States are eligible for the RSV immunization within 14 days of birth if the pregnant parent did not receive an RSV vaccine during pregnancy, or if the parent received the vaccine in the 14 days prior to birth. For infants born between April and September RSV immunization is recommended prior to the start of RSV season.
The immunization is also recommended for infants who were hospitalized for conditions such as prematurity after birth between October and March, infants aged 8-19 months who are undergoing medical support related to prematurity, infants aged 8-19 months who are severely immunocompromised, and infants aged 9-19 months who are American Indian or Alaska Native, and infants undergoing cardiac surgery with cardiopulmonary bypass.
Mpox
Another new addition to the schedule is mpox, which is recommended for adolescents 18 years or older who are at risk for mpox infection, including gay, bisexual, nonbinary, transgender, or other individuals who have developed a sexually transmitted disease within the last 6 months, had more than one sexual partner, or engaged in sex in a commercial sex venue or public space with confirmed mpox transmission.
Currently, mpox vaccination during pregnancy is not recommended due to a lack of safety data on the vaccine during pregnancy; however, the CDC noted pregnant persons who have been exposed to any of the risk factors above may receive the vaccine.
COVID, influenza, pneumococcal vaccines
The COVID-19 vaccine recommendations were updated to reflect the 2023-2023 formulation of the vaccine. Unvaccinated children between 6 months and 4 years of age will now receive the 2023-2024 formula mRNA vaccines, which includes the two-dose Moderna vaccine and three-dose Pfizer vaccine for use in that age group. Children with a previous history of COVID-19 vaccination are eligible to receive an age-appropriate COVID-19 vaccine from the 2023-2024 formulation, and children between 5-11 years old and 12-18 years old can receive a single dose of an mRNA vaccine regardless of vaccine history; unvaccinated children 12-18 years old are also eligible to receive the two-dose Novavax vaccine.
For influenza, the schedule refers to the Advisory Committee on Immunization Practices recommendations released in August, with a note indicating that individuals with an egg allergy can receive another vaccine recommended for their age group without concerns for safety.
The pneumococcal vaccine recommendations have removed PCV13 completely, with updates on the PCV15, PCV20, and PPSV23 in sections on routine vaccination, catch-up vaccination, and special situations. The poliovirus section has also seen its catch-up section revised with a recommendation to complete a vaccination series in adolescents 18 years old known or suspected to have an incomplete series, and to count trivalent oral poliovirus vaccines and OPV administered before April 2016 toward U.S. vaccination requirements.
‘Timely and necessary’ changes
Michael Pichichero, MD, director of the Rochester (N.Y.) General Hospital Research Institute, said in an interview that the committee that developed the immunization schedule was thorough in its recommendations for children and adolescents.
“The additions are timely and necessary as the landscape of vaccines for children changes,” he said.
Bonnie M. Word, MD, director of the Houston Travel Medicine Clinic, said that the immunization schedule “sets the standard and provides clarification and uniformity for administration of all recommended vaccines for U.S. children.”
The U.S. immunization program “is one of the best success stories in medicine,” Dr. Wood said. She noted it is important for providers to become familiar with these vaccines and their indications “to provide advice and be able to respond to questions of parents and/or patients.
“Often patients spend more time with office staff than the physician. It is helpful to make sure everyone in the office understands the importance of and the rationale for immunizing, so families hear consistent messaging,” she said.
Dr. Pichichero and Dr. Word reported no relevant conflicts of interest.
The immunization schedule for children and adolescents, summarized as an American Academy of Pediatrics policy statement in the journal Pediatrics, contains new entries for the monoclonal antibody immunization nirsevimab for respiratory syncytial virus in infants, the maternal RSV vaccine RSVpreF for pregnant people, the mpox vaccine for adolescents, the 2023-2024 COVID-19 vaccine, the 20-valent pneumococcal conjugate vaccine (PCV20), and the pentavalent meningococcal vaccine (MenACWY-TT/MenB-FHbp).
A number of immunizations have been deleted from the 2024 schedule, including the pentavalent meningococcal vaccine MenABCWY because of a discontinuation in its distribution in the United States, the bivalent mRNA COVID-19 vaccines, the diphtheria and tetanus toxoids adsorbed vaccine, the 13-valent pneumococcal conjugate vaccine (PCV13), and the pneumococcal polysaccharide vaccine (PPSV23).
The 2024 childhood and adolescent immunization schedule, also approved by the Centers for Disease Control and Prevention, American Academy of Family Physicians, American College of Obstetricians and Gynecologists, American College of Nurse-Midwives, American Academy of Physician Associates, and National Association of Pediatric Nurse Practitioners, is published each year based on current recommendations that have been approved for use by the Food and Drug Administration.
In a press release, the AAP said the CDC decided to publish the recommendations early to ensure health providers are able to administer immunizations and that they are covered by insurance. They also referenced CDC reports that found vaccination rates for kindergarteners have not bounced back since the beginning of the COVID-19 pandemic, and vaccine exemptions for the 2022-2023 school year were at an “all-time high.”
RSV
New to the schedule are the recently approved RSV monoclonal antibody nirsevimab for infants and the RSV vaccine RSVpreF for pregnant people. According to the CDC’s combined immunization schedule for 2024, the timing of the infant RSV immunization is heavily dependent upon when and whether a RSV vaccine was administered during pregnancy. The RSV vaccine should be routinely given between 32 weeks and 36 weeks of gestation between September and January in most of the United States with the caveat that either the maternal vaccine or the infant immunization is recommended.
Infants born between October and March in most of the United States are eligible for the RSV immunization within 14 days of birth if the pregnant parent did not receive an RSV vaccine during pregnancy, or if the parent received the vaccine in the 14 days prior to birth. For infants born between April and September RSV immunization is recommended prior to the start of RSV season.
The immunization is also recommended for infants who were hospitalized for conditions such as prematurity after birth between October and March, infants aged 8-19 months who are undergoing medical support related to prematurity, infants aged 8-19 months who are severely immunocompromised, and infants aged 9-19 months who are American Indian or Alaska Native, and infants undergoing cardiac surgery with cardiopulmonary bypass.
Mpox
Another new addition to the schedule is mpox, which is recommended for adolescents 18 years or older who are at risk for mpox infection, including gay, bisexual, nonbinary, transgender, or other individuals who have developed a sexually transmitted disease within the last 6 months, had more than one sexual partner, or engaged in sex in a commercial sex venue or public space with confirmed mpox transmission.
Currently, mpox vaccination during pregnancy is not recommended due to a lack of safety data on the vaccine during pregnancy; however, the CDC noted pregnant persons who have been exposed to any of the risk factors above may receive the vaccine.
COVID, influenza, pneumococcal vaccines
The COVID-19 vaccine recommendations were updated to reflect the 2023-2023 formulation of the vaccine. Unvaccinated children between 6 months and 4 years of age will now receive the 2023-2024 formula mRNA vaccines, which includes the two-dose Moderna vaccine and three-dose Pfizer vaccine for use in that age group. Children with a previous history of COVID-19 vaccination are eligible to receive an age-appropriate COVID-19 vaccine from the 2023-2024 formulation, and children between 5-11 years old and 12-18 years old can receive a single dose of an mRNA vaccine regardless of vaccine history; unvaccinated children 12-18 years old are also eligible to receive the two-dose Novavax vaccine.
For influenza, the schedule refers to the Advisory Committee on Immunization Practices recommendations released in August, with a note indicating that individuals with an egg allergy can receive another vaccine recommended for their age group without concerns for safety.
The pneumococcal vaccine recommendations have removed PCV13 completely, with updates on the PCV15, PCV20, and PPSV23 in sections on routine vaccination, catch-up vaccination, and special situations. The poliovirus section has also seen its catch-up section revised with a recommendation to complete a vaccination series in adolescents 18 years old known or suspected to have an incomplete series, and to count trivalent oral poliovirus vaccines and OPV administered before April 2016 toward U.S. vaccination requirements.
‘Timely and necessary’ changes
Michael Pichichero, MD, director of the Rochester (N.Y.) General Hospital Research Institute, said in an interview that the committee that developed the immunization schedule was thorough in its recommendations for children and adolescents.
“The additions are timely and necessary as the landscape of vaccines for children changes,” he said.
Bonnie M. Word, MD, director of the Houston Travel Medicine Clinic, said that the immunization schedule “sets the standard and provides clarification and uniformity for administration of all recommended vaccines for U.S. children.”
The U.S. immunization program “is one of the best success stories in medicine,” Dr. Wood said. She noted it is important for providers to become familiar with these vaccines and their indications “to provide advice and be able to respond to questions of parents and/or patients.
“Often patients spend more time with office staff than the physician. It is helpful to make sure everyone in the office understands the importance of and the rationale for immunizing, so families hear consistent messaging,” she said.
Dr. Pichichero and Dr. Word reported no relevant conflicts of interest.
The immunization schedule for children and adolescents, summarized as an American Academy of Pediatrics policy statement in the journal Pediatrics, contains new entries for the monoclonal antibody immunization nirsevimab for respiratory syncytial virus in infants, the maternal RSV vaccine RSVpreF for pregnant people, the mpox vaccine for adolescents, the 2023-2024 COVID-19 vaccine, the 20-valent pneumococcal conjugate vaccine (PCV20), and the pentavalent meningococcal vaccine (MenACWY-TT/MenB-FHbp).
A number of immunizations have been deleted from the 2024 schedule, including the pentavalent meningococcal vaccine MenABCWY because of a discontinuation in its distribution in the United States, the bivalent mRNA COVID-19 vaccines, the diphtheria and tetanus toxoids adsorbed vaccine, the 13-valent pneumococcal conjugate vaccine (PCV13), and the pneumococcal polysaccharide vaccine (PPSV23).
The 2024 childhood and adolescent immunization schedule, also approved by the Centers for Disease Control and Prevention, American Academy of Family Physicians, American College of Obstetricians and Gynecologists, American College of Nurse-Midwives, American Academy of Physician Associates, and National Association of Pediatric Nurse Practitioners, is published each year based on current recommendations that have been approved for use by the Food and Drug Administration.
In a press release, the AAP said the CDC decided to publish the recommendations early to ensure health providers are able to administer immunizations and that they are covered by insurance. They also referenced CDC reports that found vaccination rates for kindergarteners have not bounced back since the beginning of the COVID-19 pandemic, and vaccine exemptions for the 2022-2023 school year were at an “all-time high.”
RSV
New to the schedule are the recently approved RSV monoclonal antibody nirsevimab for infants and the RSV vaccine RSVpreF for pregnant people. According to the CDC’s combined immunization schedule for 2024, the timing of the infant RSV immunization is heavily dependent upon when and whether a RSV vaccine was administered during pregnancy. The RSV vaccine should be routinely given between 32 weeks and 36 weeks of gestation between September and January in most of the United States with the caveat that either the maternal vaccine or the infant immunization is recommended.
Infants born between October and March in most of the United States are eligible for the RSV immunization within 14 days of birth if the pregnant parent did not receive an RSV vaccine during pregnancy, or if the parent received the vaccine in the 14 days prior to birth. For infants born between April and September RSV immunization is recommended prior to the start of RSV season.
The immunization is also recommended for infants who were hospitalized for conditions such as prematurity after birth between October and March, infants aged 8-19 months who are undergoing medical support related to prematurity, infants aged 8-19 months who are severely immunocompromised, and infants aged 9-19 months who are American Indian or Alaska Native, and infants undergoing cardiac surgery with cardiopulmonary bypass.
Mpox
Another new addition to the schedule is mpox, which is recommended for adolescents 18 years or older who are at risk for mpox infection, including gay, bisexual, nonbinary, transgender, or other individuals who have developed a sexually transmitted disease within the last 6 months, had more than one sexual partner, or engaged in sex in a commercial sex venue or public space with confirmed mpox transmission.
Currently, mpox vaccination during pregnancy is not recommended due to a lack of safety data on the vaccine during pregnancy; however, the CDC noted pregnant persons who have been exposed to any of the risk factors above may receive the vaccine.
COVID, influenza, pneumococcal vaccines
The COVID-19 vaccine recommendations were updated to reflect the 2023-2023 formulation of the vaccine. Unvaccinated children between 6 months and 4 years of age will now receive the 2023-2024 formula mRNA vaccines, which includes the two-dose Moderna vaccine and three-dose Pfizer vaccine for use in that age group. Children with a previous history of COVID-19 vaccination are eligible to receive an age-appropriate COVID-19 vaccine from the 2023-2024 formulation, and children between 5-11 years old and 12-18 years old can receive a single dose of an mRNA vaccine regardless of vaccine history; unvaccinated children 12-18 years old are also eligible to receive the two-dose Novavax vaccine.
For influenza, the schedule refers to the Advisory Committee on Immunization Practices recommendations released in August, with a note indicating that individuals with an egg allergy can receive another vaccine recommended for their age group without concerns for safety.
The pneumococcal vaccine recommendations have removed PCV13 completely, with updates on the PCV15, PCV20, and PPSV23 in sections on routine vaccination, catch-up vaccination, and special situations. The poliovirus section has also seen its catch-up section revised with a recommendation to complete a vaccination series in adolescents 18 years old known or suspected to have an incomplete series, and to count trivalent oral poliovirus vaccines and OPV administered before April 2016 toward U.S. vaccination requirements.
‘Timely and necessary’ changes
Michael Pichichero, MD, director of the Rochester (N.Y.) General Hospital Research Institute, said in an interview that the committee that developed the immunization schedule was thorough in its recommendations for children and adolescents.
“The additions are timely and necessary as the landscape of vaccines for children changes,” he said.
Bonnie M. Word, MD, director of the Houston Travel Medicine Clinic, said that the immunization schedule “sets the standard and provides clarification and uniformity for administration of all recommended vaccines for U.S. children.”
The U.S. immunization program “is one of the best success stories in medicine,” Dr. Wood said. She noted it is important for providers to become familiar with these vaccines and their indications “to provide advice and be able to respond to questions of parents and/or patients.
“Often patients spend more time with office staff than the physician. It is helpful to make sure everyone in the office understands the importance of and the rationale for immunizing, so families hear consistent messaging,” she said.
Dr. Pichichero and Dr. Word reported no relevant conflicts of interest.
FROM PEDIATRICS
Are migraine preventives underused in young adults?
, according to recent research published in the journal Headache.
“Approximately two-fifths of young adults with migraine were prescribed preventive medications, and this did not differ between pediatric and adult neurologists,” Hannah F. J. Shapiro MD, of the department of neurology at the University of California, San Francisco, and the UCSF Benioff Children’s Hospitals, and colleagues wrote in their study. “This finding suggests that pediatric neurologists are providing comparable care to adult neurologists for young adults with migraine; however, this may represent the underuse of preventive medications in this patient population.”
Dr. Shapiro and colleagues conducted a retrospective study of 767 patients (mean age 20.3 years) at Mass General Brigham Hospital in Boston between 2017 and 2021 who received care from a pediatric or adult neurologist for episodic migraine. The majority of patients in the study were white (72.2%), non-Hispanic (82.1%) women (80.3%) with episodic migraine (72.8%), some of whom experienced a psychiatric comorbidity (12.7%), and had a 3.88 mean clinic visits for migraine. Researchers assessed prescription of migraine preventive medication as a primary outcome, with a secondary outcome of comparing the rate of migraine preventive prescriptions written by pediatric and adult neurologists.
Overall, 290 patients (37.8%) received care from a pediatric neurologist, and 131 of those 290 patients (45.2%) received preventive medications (95% confidence interval, 39.5%-51.0%). The remaining 477 patients received care from an adult neurologist; of these, 206 patients (43.2%) received preventive medications (95% CI, 39.0%-47.7%; P = .591). The most common preventive medication prescribed was topiramate, which was prescribed in 19.1% of cases by adult neurologists and 15.2% of cases by pediatric neurologists. Other preventive medications included tricyclic antidepressants such as amitriptyline and nortriptyline; pediatric neurologists prescribed amitriptyline more often than adult neurologists (14.5% vs. 5.5%; P < .001), and adult neurologists prescribed nortriptyline more often than pediatric neurologists (12.8% vs. 2.4%; P < .001).
Dr. Shapiro and colleagues performed a mixed effects logistic regression analysis of potential confounders, and found no significant association between clinician specialty and use of preventive medication (adjusted odds ratio, 1.20; 95% CI, 0.62-2.31), while factors such as female sex (aOR, 1.69; 95% CI, 1.07-2.66) and number of visits (aOR, 1.64; 95% CI, 1.49-1.80) carried associations with preventive medication use.
The finding that pediatric and adult neurologists use similar preventive medications is a positive one because “patients who continue care into adulthood with a pediatric neurologist should receive comparable care to the care they would receive with an adult neurologist,” Dr. Shapiro and colleagues said. “It is even more pertinent now for pediatric neurologists to have comfort prescribing preventive medication to young adults, as the newer calcitonin gene-related peptide (CGRP) pathway antagonists are currently only FDA approved for use in patients aged 18 years or older.”
Roadblocks may prevent adoption
M. Cristina Victorio, MD, a pediatric neurologist and director of the headache program at Akron (Ohio) Children’s, said in an interview that the study is well-designed, but the results cannot be generalized as the study is retrospective, was conducted at a single institution, and data about nutraceuticals and drug-free neuromodulation devices were excluded from the analysis.
Another aspect of the study to consider is that episodic migraine, defined as between 0 and 14 migraine days per month, comprised most of the diagnoses in this study, while preventive medication is usually considered in patients with migraines occurring at least 6 days per month. “[I]f migraine is only once every other month or once a month, preventive treatment may not be recommended,” she said.
There is also the element of patient preference, which is “difficult to obtain” in a retrospective study, she noted.
Citing the authors’ comments about pediatric neurologists’ comfortability prescribing preventive medications, including CGRP antagonists, Dr. Victorio said she offers CGRP antagonists to “young adult patients who have failed at least two of the guideline-recommended preventive medications.”
However, pediatric neurologists may encounter roadblocks to prescribing these medications. “A big challenge is access, as it requires prior authorization as well as writing a letter of appeal or medical necessity, which can be a nuisance for clinicians who are already inundated with clinical responsibilities,” she said.
More education is needed
“As a pediatric headache specialist and knowing the results of this study, my colleagues and I have a role in educating all clinicians as well as trainees on headache management to improve and provide optimal care for young adult patients with migraine,” Dr. Victorio said.
In her experience, more clinic visits usually mean a need for preventative medication, and psychiatric morbidities are common. “I differ in the sense that as a headache specialist I am comfortable offering various preventive treatment options when indicated, so I do not believe I am underutilizing,” she said.
Dr. Victorio said she prescribes topiramate, amitriptyline, and propranolol as migraine preventatives for adolescents and young adults, but recommends cyproheptadine for younger children “due to lesser side effects, tolerability, and convenience of formulation (both liquid and tablet forms are available), which can be challenging for younger children who are unable to swallow pills.”
“Cognizant that there are patients who are reluctant to take daily prescription medication and that consideration for preventive treatment includes patient’s preference, I include the use of nutraceuticals and drug-free neuromodulation devices when discussing preventive treatment options,” she added, noting that children and adolescents “[m]ore often than not” prefer nutraceuticals like magnesium and vitamin B2.
“I think the bottom line is that all clinicians managing young adults with migraine should know when to consider starting preventive migraine medication,” Dr. Victorio said. “Not offering preventive treatment to young adults specifically for those who have frequent migraine attacks, or those who have severe migraine despite adequate acute treatment, or those with significant adverse reactions to acute medications will only put these patients at risk to progression to chronic migraine (meaning having migraine more often than not – at least 15 days per month), and increases headache-related disability and reduces quality of life.”
The authors report no relevant financial disclosures. This study was supported by Harvard University and an award from the National Institutes of Health. Dr. Victorio reports being on the advisory board for Theranica Bio-electronics, has received honorarium serving as an author of the Merck Manual, and is involved in industry-sponsored clinical trials through Akron Children’s Hospital.
, according to recent research published in the journal Headache.
“Approximately two-fifths of young adults with migraine were prescribed preventive medications, and this did not differ between pediatric and adult neurologists,” Hannah F. J. Shapiro MD, of the department of neurology at the University of California, San Francisco, and the UCSF Benioff Children’s Hospitals, and colleagues wrote in their study. “This finding suggests that pediatric neurologists are providing comparable care to adult neurologists for young adults with migraine; however, this may represent the underuse of preventive medications in this patient population.”
Dr. Shapiro and colleagues conducted a retrospective study of 767 patients (mean age 20.3 years) at Mass General Brigham Hospital in Boston between 2017 and 2021 who received care from a pediatric or adult neurologist for episodic migraine. The majority of patients in the study were white (72.2%), non-Hispanic (82.1%) women (80.3%) with episodic migraine (72.8%), some of whom experienced a psychiatric comorbidity (12.7%), and had a 3.88 mean clinic visits for migraine. Researchers assessed prescription of migraine preventive medication as a primary outcome, with a secondary outcome of comparing the rate of migraine preventive prescriptions written by pediatric and adult neurologists.
Overall, 290 patients (37.8%) received care from a pediatric neurologist, and 131 of those 290 patients (45.2%) received preventive medications (95% confidence interval, 39.5%-51.0%). The remaining 477 patients received care from an adult neurologist; of these, 206 patients (43.2%) received preventive medications (95% CI, 39.0%-47.7%; P = .591). The most common preventive medication prescribed was topiramate, which was prescribed in 19.1% of cases by adult neurologists and 15.2% of cases by pediatric neurologists. Other preventive medications included tricyclic antidepressants such as amitriptyline and nortriptyline; pediatric neurologists prescribed amitriptyline more often than adult neurologists (14.5% vs. 5.5%; P < .001), and adult neurologists prescribed nortriptyline more often than pediatric neurologists (12.8% vs. 2.4%; P < .001).
Dr. Shapiro and colleagues performed a mixed effects logistic regression analysis of potential confounders, and found no significant association between clinician specialty and use of preventive medication (adjusted odds ratio, 1.20; 95% CI, 0.62-2.31), while factors such as female sex (aOR, 1.69; 95% CI, 1.07-2.66) and number of visits (aOR, 1.64; 95% CI, 1.49-1.80) carried associations with preventive medication use.
The finding that pediatric and adult neurologists use similar preventive medications is a positive one because “patients who continue care into adulthood with a pediatric neurologist should receive comparable care to the care they would receive with an adult neurologist,” Dr. Shapiro and colleagues said. “It is even more pertinent now for pediatric neurologists to have comfort prescribing preventive medication to young adults, as the newer calcitonin gene-related peptide (CGRP) pathway antagonists are currently only FDA approved for use in patients aged 18 years or older.”
Roadblocks may prevent adoption
M. Cristina Victorio, MD, a pediatric neurologist and director of the headache program at Akron (Ohio) Children’s, said in an interview that the study is well-designed, but the results cannot be generalized as the study is retrospective, was conducted at a single institution, and data about nutraceuticals and drug-free neuromodulation devices were excluded from the analysis.
Another aspect of the study to consider is that episodic migraine, defined as between 0 and 14 migraine days per month, comprised most of the diagnoses in this study, while preventive medication is usually considered in patients with migraines occurring at least 6 days per month. “[I]f migraine is only once every other month or once a month, preventive treatment may not be recommended,” she said.
There is also the element of patient preference, which is “difficult to obtain” in a retrospective study, she noted.
Citing the authors’ comments about pediatric neurologists’ comfortability prescribing preventive medications, including CGRP antagonists, Dr. Victorio said she offers CGRP antagonists to “young adult patients who have failed at least two of the guideline-recommended preventive medications.”
However, pediatric neurologists may encounter roadblocks to prescribing these medications. “A big challenge is access, as it requires prior authorization as well as writing a letter of appeal or medical necessity, which can be a nuisance for clinicians who are already inundated with clinical responsibilities,” she said.
More education is needed
“As a pediatric headache specialist and knowing the results of this study, my colleagues and I have a role in educating all clinicians as well as trainees on headache management to improve and provide optimal care for young adult patients with migraine,” Dr. Victorio said.
In her experience, more clinic visits usually mean a need for preventative medication, and psychiatric morbidities are common. “I differ in the sense that as a headache specialist I am comfortable offering various preventive treatment options when indicated, so I do not believe I am underutilizing,” she said.
Dr. Victorio said she prescribes topiramate, amitriptyline, and propranolol as migraine preventatives for adolescents and young adults, but recommends cyproheptadine for younger children “due to lesser side effects, tolerability, and convenience of formulation (both liquid and tablet forms are available), which can be challenging for younger children who are unable to swallow pills.”
“Cognizant that there are patients who are reluctant to take daily prescription medication and that consideration for preventive treatment includes patient’s preference, I include the use of nutraceuticals and drug-free neuromodulation devices when discussing preventive treatment options,” she added, noting that children and adolescents “[m]ore often than not” prefer nutraceuticals like magnesium and vitamin B2.
“I think the bottom line is that all clinicians managing young adults with migraine should know when to consider starting preventive migraine medication,” Dr. Victorio said. “Not offering preventive treatment to young adults specifically for those who have frequent migraine attacks, or those who have severe migraine despite adequate acute treatment, or those with significant adverse reactions to acute medications will only put these patients at risk to progression to chronic migraine (meaning having migraine more often than not – at least 15 days per month), and increases headache-related disability and reduces quality of life.”
The authors report no relevant financial disclosures. This study was supported by Harvard University and an award from the National Institutes of Health. Dr. Victorio reports being on the advisory board for Theranica Bio-electronics, has received honorarium serving as an author of the Merck Manual, and is involved in industry-sponsored clinical trials through Akron Children’s Hospital.
, according to recent research published in the journal Headache.
“Approximately two-fifths of young adults with migraine were prescribed preventive medications, and this did not differ between pediatric and adult neurologists,” Hannah F. J. Shapiro MD, of the department of neurology at the University of California, San Francisco, and the UCSF Benioff Children’s Hospitals, and colleagues wrote in their study. “This finding suggests that pediatric neurologists are providing comparable care to adult neurologists for young adults with migraine; however, this may represent the underuse of preventive medications in this patient population.”
Dr. Shapiro and colleagues conducted a retrospective study of 767 patients (mean age 20.3 years) at Mass General Brigham Hospital in Boston between 2017 and 2021 who received care from a pediatric or adult neurologist for episodic migraine. The majority of patients in the study were white (72.2%), non-Hispanic (82.1%) women (80.3%) with episodic migraine (72.8%), some of whom experienced a psychiatric comorbidity (12.7%), and had a 3.88 mean clinic visits for migraine. Researchers assessed prescription of migraine preventive medication as a primary outcome, with a secondary outcome of comparing the rate of migraine preventive prescriptions written by pediatric and adult neurologists.
Overall, 290 patients (37.8%) received care from a pediatric neurologist, and 131 of those 290 patients (45.2%) received preventive medications (95% confidence interval, 39.5%-51.0%). The remaining 477 patients received care from an adult neurologist; of these, 206 patients (43.2%) received preventive medications (95% CI, 39.0%-47.7%; P = .591). The most common preventive medication prescribed was topiramate, which was prescribed in 19.1% of cases by adult neurologists and 15.2% of cases by pediatric neurologists. Other preventive medications included tricyclic antidepressants such as amitriptyline and nortriptyline; pediatric neurologists prescribed amitriptyline more often than adult neurologists (14.5% vs. 5.5%; P < .001), and adult neurologists prescribed nortriptyline more often than pediatric neurologists (12.8% vs. 2.4%; P < .001).
Dr. Shapiro and colleagues performed a mixed effects logistic regression analysis of potential confounders, and found no significant association between clinician specialty and use of preventive medication (adjusted odds ratio, 1.20; 95% CI, 0.62-2.31), while factors such as female sex (aOR, 1.69; 95% CI, 1.07-2.66) and number of visits (aOR, 1.64; 95% CI, 1.49-1.80) carried associations with preventive medication use.
The finding that pediatric and adult neurologists use similar preventive medications is a positive one because “patients who continue care into adulthood with a pediatric neurologist should receive comparable care to the care they would receive with an adult neurologist,” Dr. Shapiro and colleagues said. “It is even more pertinent now for pediatric neurologists to have comfort prescribing preventive medication to young adults, as the newer calcitonin gene-related peptide (CGRP) pathway antagonists are currently only FDA approved for use in patients aged 18 years or older.”
Roadblocks may prevent adoption
M. Cristina Victorio, MD, a pediatric neurologist and director of the headache program at Akron (Ohio) Children’s, said in an interview that the study is well-designed, but the results cannot be generalized as the study is retrospective, was conducted at a single institution, and data about nutraceuticals and drug-free neuromodulation devices were excluded from the analysis.
Another aspect of the study to consider is that episodic migraine, defined as between 0 and 14 migraine days per month, comprised most of the diagnoses in this study, while preventive medication is usually considered in patients with migraines occurring at least 6 days per month. “[I]f migraine is only once every other month or once a month, preventive treatment may not be recommended,” she said.
There is also the element of patient preference, which is “difficult to obtain” in a retrospective study, she noted.
Citing the authors’ comments about pediatric neurologists’ comfortability prescribing preventive medications, including CGRP antagonists, Dr. Victorio said she offers CGRP antagonists to “young adult patients who have failed at least two of the guideline-recommended preventive medications.”
However, pediatric neurologists may encounter roadblocks to prescribing these medications. “A big challenge is access, as it requires prior authorization as well as writing a letter of appeal or medical necessity, which can be a nuisance for clinicians who are already inundated with clinical responsibilities,” she said.
More education is needed
“As a pediatric headache specialist and knowing the results of this study, my colleagues and I have a role in educating all clinicians as well as trainees on headache management to improve and provide optimal care for young adult patients with migraine,” Dr. Victorio said.
In her experience, more clinic visits usually mean a need for preventative medication, and psychiatric morbidities are common. “I differ in the sense that as a headache specialist I am comfortable offering various preventive treatment options when indicated, so I do not believe I am underutilizing,” she said.
Dr. Victorio said she prescribes topiramate, amitriptyline, and propranolol as migraine preventatives for adolescents and young adults, but recommends cyproheptadine for younger children “due to lesser side effects, tolerability, and convenience of formulation (both liquid and tablet forms are available), which can be challenging for younger children who are unable to swallow pills.”
“Cognizant that there are patients who are reluctant to take daily prescription medication and that consideration for preventive treatment includes patient’s preference, I include the use of nutraceuticals and drug-free neuromodulation devices when discussing preventive treatment options,” she added, noting that children and adolescents “[m]ore often than not” prefer nutraceuticals like magnesium and vitamin B2.
“I think the bottom line is that all clinicians managing young adults with migraine should know when to consider starting preventive migraine medication,” Dr. Victorio said. “Not offering preventive treatment to young adults specifically for those who have frequent migraine attacks, or those who have severe migraine despite adequate acute treatment, or those with significant adverse reactions to acute medications will only put these patients at risk to progression to chronic migraine (meaning having migraine more often than not – at least 15 days per month), and increases headache-related disability and reduces quality of life.”
The authors report no relevant financial disclosures. This study was supported by Harvard University and an award from the National Institutes of Health. Dr. Victorio reports being on the advisory board for Theranica Bio-electronics, has received honorarium serving as an author of the Merck Manual, and is involved in industry-sponsored clinical trials through Akron Children’s Hospital.
FROM HEADACHE
AAP statement on child pedestrian safety: Educate families, advocate for walkable communities
The policy statement recommends that pediatricians advocate for environmental and urban planning that aims for no pedestrian fatalities or serious injuries, according to authors Sadiqa A. I. Kendi, MD, MPH, CPST; and Brian D. Johnston, MD, MPH, and colleagues.
While pedestrian fatalities have declined over the last 3 decades, child pedestrian fatalities have increased by 11% since 2013, the AAP Council on Injury, Violence, and Poison Prevention noted. Many of these fatalities occur in rural areas, during 6 to 9 p.m., mid-block rather than at intersections, and among adolescents aged 10-19 years, according to statistics from the National Highway Traffic Safety Administration.
“The reminder to ‘Look both ways before you cross the street,’ is good advice, but just part of the equation,” Dr. Kendi stated in a press release. “Research tells us that an even more effective way to consistently improve safety is when communities take intentional steps to create pedestrian-safe environments. We live in a busy, distracted world, and when local leaders create walkable spaces, they also enhance the appeal and vibrance of their communities.”
Advocating for safer communities
The AAP’s policy statement recommends that pediatricians advocate for legislation at the federal, state, and local level that supports a “Complete Streets” policy of including all forms of transportation and people on the roadways as well as incorporates a “Vision Zero” policy of reducing traffic fatalities and injuries. Other recommendations include supporting legislation that reduces speeds in urban areas, and the use of photo speed limit enforcement in areas such as school zones.
The AAP also highlighted the need for the adoption of new safety technology such as pedestrian detection systems, automatic braking in vehicles, and the consideration of child pedestrians with the development of new technologies such as autonomous vehicles.
“Drivers may not see small children when backing up their vehicles in a driveway or lot,” Dr. Kendi said. “Newer and self-driving vehicles are increasingly equipped with safety features and technology to detect pedestrians and avoid crashes, but they’re often more likely to detect adults and may not be able to account for the less predictable movements of a small child.”
In addition, the AAP’s policy statement recommends that pediatricians participate in community advocacy for safer and healthier pedestrian environments, community-level Vision Zero interventions, development of safe routes to school, alternative nonmotorized transportation methods to reduce vehicular traffic, the development of pedestrian infrastructure in communities, 20-mph zones in residential and commercial areas, research into pedestrian education, and surveillance systems that could identify locations where pedestrian injury is a high risk.
Educating families on pedestrian safety
There is also an opportunity to engage in anticipatory guidance with children and their parents, according to the policy statement. The AAP recommends pediatricians counsel families on the complexity of the traffic environment, remind parents that children may not be visible to drivers, and that driveways and unfenced yards are considered unsafe play areas. Adults should be with children aged younger than 10 years and teach young children the importance of pedestrian safety based on the child’s developmental level, the AAP said. When children are older, they can be more independent, but should still use “protected routes with signalized crossings in low-traffic environments,” they noted.
For parents of children with limited mobility or another disability, extra time may be needed to help children safely navigate a pedestrian environment, the AAP explained. “This might include selection of routes with low barriers to mobility, interventions to increase pedestrian visibility, instruction on use of audible pedestrian signals, and white-cane skills for children with visual impairment,” they noted.
All children should be educated on the risk of distracted walking, whether through texting, talking on the phone, or listening to music.
“We know that active transportation, like walking or biking, is good for kids and it’s good for the environment,” Brian D. Johnston, MD, MPH, coauthor of the report, said in a press release. “As children grow older, they will be able to be more independent. Each of us can help keep children safe by paying attention to the people around us and by promoting safer environments that benefit all of us.”
‘Pediatricians always find a way to reach their patients’
In an interview, Christina Johns, MD, MEd, pediatric emergency doctor and senior medical adviser at PM Pediatric Care, said that implementing this policy statement “requires a multilayered approach” that includes funding infrastructure and city planning, policy changes, family education, and other stakeholders and “will require support and buy-in at all levels.”
“While challenging to implement, the return in potential lives saved and additional health benefits of increased mobility for children (decreasing obesity burden, for example) cannot be overstated,” Dr. Johns said. “It will be helpful to create a checklist of the recommended counseling points that can be added to health records to keep this topic top of mind and document that it has been discussed at well visits.”
Emma Sartin, PhD, MPH, a research scientist at the Center for Injury Research and Prevention at Children’s Hospital of Philadelphia, said environmental risks will still be present regardless of whether a child is a safe pedestrian. “Adults and children need to balance practical safe mobility behavior with being present and aware in the current moment; as a pedestrian, without the protection of active and passive safety systems in motor vehicles, staying vigilant is critical to safety,” she said. Many pedestrian injuries and fatalities come from marginalized racial and ethnic groups, and those with neurodivergent statuses, Dr. Sartin explained, who “get licensed later than their peers, which may make being a pedestrian or using other modes of transportation (such as cycling) necessary.”
“These groups also often have higher rates of crash injuries and fatalities when they are inside of vehicles,” she said. “We need to be better at supporting safe mobility across different transportation options – driving, walking, cycling, and public transit – for all children and adults.”
Pediatricians excel at using anticipatory guidance to counsel families, and the refinements in the latest AAP policy statement on child pedestrian safety are something pediatricians can focus on at well visits, Dr. Johns said. Specific age groups will require pediatricians to adjust their conversation based on the child’s development as well as the family’s questions and concerns, she noted.
Dorothy Novick, MD, a pediatrician at Children’s Hospital of Philadelphia, said guidance to families will change as a child grows and develops, starting with teaching young children to hold hands when crossing the street, and not to play near driveways and roads.
“As children grow older, I remind families what I myself was surprised to learn as a new parent – that most children don’t develop the depth perception, judgment, and motor skills they need to cross the street safely by themselves until they’re at least 10 years old,” she explained. “Of course, with teens we place enormous emphasis on avoiding distractions, such as texting and watching videos while walking. One message remains the same for all parents, no matter the child’s age – the importance of modeling safe pedestrian behavior.
“Even during busy annual checkups, pediatricians always find a way to reach their patients and families about topics important to child health and wellness, so I have confidence that my colleagues and I will execute this mission,” Dr. Johns said. “The time required for advocacy and lobbying can be challenging however, and so having advocacy groups like the AAP is key to creating agency for pediatricians to have a voice in their communities and the legislature.
“Children cannot speak or advocate for themselves when it comes to funding, development of social programs or safety policy, or infrastructure planning and building, so it’s up to pediatricians to have a loud and unified voice to make sure that we watch out for their safety and incorporate their unique needs into their surroundings as much as possible,” she added.
The AAP reports that it has not accepted commercial involvement in developing the policy statement, and all authors have resolved potential conflicts of interest through a process approved by the AAP board of directors. Dr. Johns, Dr. Novick, and Dr. Sartin report no relevant financial disclosures.
The policy statement recommends that pediatricians advocate for environmental and urban planning that aims for no pedestrian fatalities or serious injuries, according to authors Sadiqa A. I. Kendi, MD, MPH, CPST; and Brian D. Johnston, MD, MPH, and colleagues.
While pedestrian fatalities have declined over the last 3 decades, child pedestrian fatalities have increased by 11% since 2013, the AAP Council on Injury, Violence, and Poison Prevention noted. Many of these fatalities occur in rural areas, during 6 to 9 p.m., mid-block rather than at intersections, and among adolescents aged 10-19 years, according to statistics from the National Highway Traffic Safety Administration.
“The reminder to ‘Look both ways before you cross the street,’ is good advice, but just part of the equation,” Dr. Kendi stated in a press release. “Research tells us that an even more effective way to consistently improve safety is when communities take intentional steps to create pedestrian-safe environments. We live in a busy, distracted world, and when local leaders create walkable spaces, they also enhance the appeal and vibrance of their communities.”
Advocating for safer communities
The AAP’s policy statement recommends that pediatricians advocate for legislation at the federal, state, and local level that supports a “Complete Streets” policy of including all forms of transportation and people on the roadways as well as incorporates a “Vision Zero” policy of reducing traffic fatalities and injuries. Other recommendations include supporting legislation that reduces speeds in urban areas, and the use of photo speed limit enforcement in areas such as school zones.
The AAP also highlighted the need for the adoption of new safety technology such as pedestrian detection systems, automatic braking in vehicles, and the consideration of child pedestrians with the development of new technologies such as autonomous vehicles.
“Drivers may not see small children when backing up their vehicles in a driveway or lot,” Dr. Kendi said. “Newer and self-driving vehicles are increasingly equipped with safety features and technology to detect pedestrians and avoid crashes, but they’re often more likely to detect adults and may not be able to account for the less predictable movements of a small child.”
In addition, the AAP’s policy statement recommends that pediatricians participate in community advocacy for safer and healthier pedestrian environments, community-level Vision Zero interventions, development of safe routes to school, alternative nonmotorized transportation methods to reduce vehicular traffic, the development of pedestrian infrastructure in communities, 20-mph zones in residential and commercial areas, research into pedestrian education, and surveillance systems that could identify locations where pedestrian injury is a high risk.
Educating families on pedestrian safety
There is also an opportunity to engage in anticipatory guidance with children and their parents, according to the policy statement. The AAP recommends pediatricians counsel families on the complexity of the traffic environment, remind parents that children may not be visible to drivers, and that driveways and unfenced yards are considered unsafe play areas. Adults should be with children aged younger than 10 years and teach young children the importance of pedestrian safety based on the child’s developmental level, the AAP said. When children are older, they can be more independent, but should still use “protected routes with signalized crossings in low-traffic environments,” they noted.
For parents of children with limited mobility or another disability, extra time may be needed to help children safely navigate a pedestrian environment, the AAP explained. “This might include selection of routes with low barriers to mobility, interventions to increase pedestrian visibility, instruction on use of audible pedestrian signals, and white-cane skills for children with visual impairment,” they noted.
All children should be educated on the risk of distracted walking, whether through texting, talking on the phone, or listening to music.
“We know that active transportation, like walking or biking, is good for kids and it’s good for the environment,” Brian D. Johnston, MD, MPH, coauthor of the report, said in a press release. “As children grow older, they will be able to be more independent. Each of us can help keep children safe by paying attention to the people around us and by promoting safer environments that benefit all of us.”
‘Pediatricians always find a way to reach their patients’
In an interview, Christina Johns, MD, MEd, pediatric emergency doctor and senior medical adviser at PM Pediatric Care, said that implementing this policy statement “requires a multilayered approach” that includes funding infrastructure and city planning, policy changes, family education, and other stakeholders and “will require support and buy-in at all levels.”
“While challenging to implement, the return in potential lives saved and additional health benefits of increased mobility for children (decreasing obesity burden, for example) cannot be overstated,” Dr. Johns said. “It will be helpful to create a checklist of the recommended counseling points that can be added to health records to keep this topic top of mind and document that it has been discussed at well visits.”
Emma Sartin, PhD, MPH, a research scientist at the Center for Injury Research and Prevention at Children’s Hospital of Philadelphia, said environmental risks will still be present regardless of whether a child is a safe pedestrian. “Adults and children need to balance practical safe mobility behavior with being present and aware in the current moment; as a pedestrian, without the protection of active and passive safety systems in motor vehicles, staying vigilant is critical to safety,” she said. Many pedestrian injuries and fatalities come from marginalized racial and ethnic groups, and those with neurodivergent statuses, Dr. Sartin explained, who “get licensed later than their peers, which may make being a pedestrian or using other modes of transportation (such as cycling) necessary.”
“These groups also often have higher rates of crash injuries and fatalities when they are inside of vehicles,” she said. “We need to be better at supporting safe mobility across different transportation options – driving, walking, cycling, and public transit – for all children and adults.”
Pediatricians excel at using anticipatory guidance to counsel families, and the refinements in the latest AAP policy statement on child pedestrian safety are something pediatricians can focus on at well visits, Dr. Johns said. Specific age groups will require pediatricians to adjust their conversation based on the child’s development as well as the family’s questions and concerns, she noted.
Dorothy Novick, MD, a pediatrician at Children’s Hospital of Philadelphia, said guidance to families will change as a child grows and develops, starting with teaching young children to hold hands when crossing the street, and not to play near driveways and roads.
“As children grow older, I remind families what I myself was surprised to learn as a new parent – that most children don’t develop the depth perception, judgment, and motor skills they need to cross the street safely by themselves until they’re at least 10 years old,” she explained. “Of course, with teens we place enormous emphasis on avoiding distractions, such as texting and watching videos while walking. One message remains the same for all parents, no matter the child’s age – the importance of modeling safe pedestrian behavior.
“Even during busy annual checkups, pediatricians always find a way to reach their patients and families about topics important to child health and wellness, so I have confidence that my colleagues and I will execute this mission,” Dr. Johns said. “The time required for advocacy and lobbying can be challenging however, and so having advocacy groups like the AAP is key to creating agency for pediatricians to have a voice in their communities and the legislature.
“Children cannot speak or advocate for themselves when it comes to funding, development of social programs or safety policy, or infrastructure planning and building, so it’s up to pediatricians to have a loud and unified voice to make sure that we watch out for their safety and incorporate their unique needs into their surroundings as much as possible,” she added.
The AAP reports that it has not accepted commercial involvement in developing the policy statement, and all authors have resolved potential conflicts of interest through a process approved by the AAP board of directors. Dr. Johns, Dr. Novick, and Dr. Sartin report no relevant financial disclosures.
The policy statement recommends that pediatricians advocate for environmental and urban planning that aims for no pedestrian fatalities or serious injuries, according to authors Sadiqa A. I. Kendi, MD, MPH, CPST; and Brian D. Johnston, MD, MPH, and colleagues.
While pedestrian fatalities have declined over the last 3 decades, child pedestrian fatalities have increased by 11% since 2013, the AAP Council on Injury, Violence, and Poison Prevention noted. Many of these fatalities occur in rural areas, during 6 to 9 p.m., mid-block rather than at intersections, and among adolescents aged 10-19 years, according to statistics from the National Highway Traffic Safety Administration.
“The reminder to ‘Look both ways before you cross the street,’ is good advice, but just part of the equation,” Dr. Kendi stated in a press release. “Research tells us that an even more effective way to consistently improve safety is when communities take intentional steps to create pedestrian-safe environments. We live in a busy, distracted world, and when local leaders create walkable spaces, they also enhance the appeal and vibrance of their communities.”
Advocating for safer communities
The AAP’s policy statement recommends that pediatricians advocate for legislation at the federal, state, and local level that supports a “Complete Streets” policy of including all forms of transportation and people on the roadways as well as incorporates a “Vision Zero” policy of reducing traffic fatalities and injuries. Other recommendations include supporting legislation that reduces speeds in urban areas, and the use of photo speed limit enforcement in areas such as school zones.
The AAP also highlighted the need for the adoption of new safety technology such as pedestrian detection systems, automatic braking in vehicles, and the consideration of child pedestrians with the development of new technologies such as autonomous vehicles.
“Drivers may not see small children when backing up their vehicles in a driveway or lot,” Dr. Kendi said. “Newer and self-driving vehicles are increasingly equipped with safety features and technology to detect pedestrians and avoid crashes, but they’re often more likely to detect adults and may not be able to account for the less predictable movements of a small child.”
In addition, the AAP’s policy statement recommends that pediatricians participate in community advocacy for safer and healthier pedestrian environments, community-level Vision Zero interventions, development of safe routes to school, alternative nonmotorized transportation methods to reduce vehicular traffic, the development of pedestrian infrastructure in communities, 20-mph zones in residential and commercial areas, research into pedestrian education, and surveillance systems that could identify locations where pedestrian injury is a high risk.
Educating families on pedestrian safety
There is also an opportunity to engage in anticipatory guidance with children and their parents, according to the policy statement. The AAP recommends pediatricians counsel families on the complexity of the traffic environment, remind parents that children may not be visible to drivers, and that driveways and unfenced yards are considered unsafe play areas. Adults should be with children aged younger than 10 years and teach young children the importance of pedestrian safety based on the child’s developmental level, the AAP said. When children are older, they can be more independent, but should still use “protected routes with signalized crossings in low-traffic environments,” they noted.
For parents of children with limited mobility or another disability, extra time may be needed to help children safely navigate a pedestrian environment, the AAP explained. “This might include selection of routes with low barriers to mobility, interventions to increase pedestrian visibility, instruction on use of audible pedestrian signals, and white-cane skills for children with visual impairment,” they noted.
All children should be educated on the risk of distracted walking, whether through texting, talking on the phone, or listening to music.
“We know that active transportation, like walking or biking, is good for kids and it’s good for the environment,” Brian D. Johnston, MD, MPH, coauthor of the report, said in a press release. “As children grow older, they will be able to be more independent. Each of us can help keep children safe by paying attention to the people around us and by promoting safer environments that benefit all of us.”
‘Pediatricians always find a way to reach their patients’
In an interview, Christina Johns, MD, MEd, pediatric emergency doctor and senior medical adviser at PM Pediatric Care, said that implementing this policy statement “requires a multilayered approach” that includes funding infrastructure and city planning, policy changes, family education, and other stakeholders and “will require support and buy-in at all levels.”
“While challenging to implement, the return in potential lives saved and additional health benefits of increased mobility for children (decreasing obesity burden, for example) cannot be overstated,” Dr. Johns said. “It will be helpful to create a checklist of the recommended counseling points that can be added to health records to keep this topic top of mind and document that it has been discussed at well visits.”
Emma Sartin, PhD, MPH, a research scientist at the Center for Injury Research and Prevention at Children’s Hospital of Philadelphia, said environmental risks will still be present regardless of whether a child is a safe pedestrian. “Adults and children need to balance practical safe mobility behavior with being present and aware in the current moment; as a pedestrian, without the protection of active and passive safety systems in motor vehicles, staying vigilant is critical to safety,” she said. Many pedestrian injuries and fatalities come from marginalized racial and ethnic groups, and those with neurodivergent statuses, Dr. Sartin explained, who “get licensed later than their peers, which may make being a pedestrian or using other modes of transportation (such as cycling) necessary.”
“These groups also often have higher rates of crash injuries and fatalities when they are inside of vehicles,” she said. “We need to be better at supporting safe mobility across different transportation options – driving, walking, cycling, and public transit – for all children and adults.”
Pediatricians excel at using anticipatory guidance to counsel families, and the refinements in the latest AAP policy statement on child pedestrian safety are something pediatricians can focus on at well visits, Dr. Johns said. Specific age groups will require pediatricians to adjust their conversation based on the child’s development as well as the family’s questions and concerns, she noted.
Dorothy Novick, MD, a pediatrician at Children’s Hospital of Philadelphia, said guidance to families will change as a child grows and develops, starting with teaching young children to hold hands when crossing the street, and not to play near driveways and roads.
“As children grow older, I remind families what I myself was surprised to learn as a new parent – that most children don’t develop the depth perception, judgment, and motor skills they need to cross the street safely by themselves until they’re at least 10 years old,” she explained. “Of course, with teens we place enormous emphasis on avoiding distractions, such as texting and watching videos while walking. One message remains the same for all parents, no matter the child’s age – the importance of modeling safe pedestrian behavior.
“Even during busy annual checkups, pediatricians always find a way to reach their patients and families about topics important to child health and wellness, so I have confidence that my colleagues and I will execute this mission,” Dr. Johns said. “The time required for advocacy and lobbying can be challenging however, and so having advocacy groups like the AAP is key to creating agency for pediatricians to have a voice in their communities and the legislature.
“Children cannot speak or advocate for themselves when it comes to funding, development of social programs or safety policy, or infrastructure planning and building, so it’s up to pediatricians to have a loud and unified voice to make sure that we watch out for their safety and incorporate their unique needs into their surroundings as much as possible,” she added.
The AAP reports that it has not accepted commercial involvement in developing the policy statement, and all authors have resolved potential conflicts of interest through a process approved by the AAP board of directors. Dr. Johns, Dr. Novick, and Dr. Sartin report no relevant financial disclosures.
FROM PEDIATRICS
Father’s influence impacts whether their infant is breastfed, follows safe sleeping practices
Infants of fathers who want their child to breastfeed are more likely to be part of a family unit that starts and continues breastfeeding, and fathers informed of safe sleep practices are more likely to follow those sleeping recommendations for their infant, according to the results of a recent survey published in Pediatrics.
The results suggest that the researchers said.
“Our findings underscore that new fathers are a critical audience to promote breastfeeding and safe infant sleep,” John James Parker, MD, instructor of pediatrics at Northwestern University, Chicago, stated in a press release. “Many families do not gain the health benefits from breastfeeding because they are not provided the support to breastfeed successfully. Fathers need to be directly engaged in breastfeeding discussions, and providers need to describe the important role fathers play in breastfeeding success.”
Population-based survey results
Dr. Parker and colleagues used the Pregnancy Risk Assessment Monitoring System (PRAMS) for Dads population-based survey to evaluate the rate of adherence to breastfeeding and infant sleep practices recommended by the American Academy of Pediatrics. In total, 250 fathers in Georgia were surveyed between October 2018 and July 2019 about whether their infants were breastfeeding and if they were breastfeeding at 8 weeks. The fathers were also asked how often the infant slept in a back sleeping position, on an approved sleep surface, and sleeping with no soft objects or soft bedding.
In addition to surveying fathers on their attitudes on breastfeeding and whether they followed safe infant sleep practices, the researchers collected information on paternal sociodemographic characteristics such as age, race and ethnicity, education, health insurance status, and marital status. Overall, a majority fathers who responded to the survey were between 25 years and 34 years old (56.5%), non-Hispanic White (44.7%), had a high school diploma or less (43.7%) or completed college (37.1%), and were married (65.2%).
Dr. Parker and colleagues found fathers surveyed said 86.1% of infants were ever breastfed, which decreased to 63.4% at 8 weeks. Compared with fathers who did not want their infant to breastfeed or expressed no opinion, fathers who wanted to have the infant’s mother breastfeed had a higher likelihood of reporting breastfeeding initiation (adjusted prevalence ratio, 1.39; 95% confidence interval, 1.15-1.68) and breastfeeding at 8 weeks (aPR, 2.33; 95% CI, 1.59-3.42). Having a college degree was also associated with the infant breastfeeding (93.6% vs. 75.1%; aPR, 1.25; 95% CI, 1.06-1.46) and breastfeeding at 8 weeks (74.7% vs. 52.0%; aPR, 1.44; 95% CI, 1.08-1.91), compared with fathers who graduated from high school or less.
Regarding safe infant sleeping practices, 81.18% of fathers said they placed their infants on their back to sleep, but 44.1% said they did not use soft bedding, and 31.9% said they used an approved sleep surface. In total, 99.4% of fathers put their infant to sleep, and 68.4% said they received information on all three infant safe sleeping practices, while 15.7% said they followed all three sleeping recommendations. A health care provider was the most common person giving advice to the father on placing the infant to sleep on their back (84.7%); to use a safe sleep surface such as a crib, bassinet, or pack-and-play (78.7%); and receiving information about what not to place in the infant’s bed (79.1%).
The survey found non-Hispanic Black fathers reported they were less likely to put the infant to sleep on their back (62.5% vs. 89.5%; aPR, 0.70; 95% CI, 0.54-0.90) and not use soft bedding (28.1% vs. 54.1%; aPR, 0.52; 95% CI, 0.30-0.89), compared with non-Hispanic White fathers. College graduates were more likely to not use soft bedding (61.4% vs. 31.9%; aPR, 1.92; 95% CI, 1.25-2.95), more likely to get advice on placing the infant on their back for sleep (94.3% vs. 73.6%; aPR, 1.28; 95% CI, 1.09-1.51), and more likely to receive advice on what not to place in the infant’s bed (88.1% vs. 68.5%; aPR, 1.29; 95% CI, 1.06-1.57), compared with fathers with a high school diploma or less.
“Fathers need to receive counseling on all the safe sleep practices for their infants,” Dr. Parker said. “To reduce racial disparities in sudden unexpected infant death, we need tailored strategies to increase safe infant sleep practices in the Black community, including public campaigns to increase awareness and home visiting programs. These interventions must involve both parents to be most effective.”
Educational efforts should recognize father’s contributions
In an interview, Deborah E. Campbell, MD, chief of neonatology at the Children’s Hospital at Montefiore, New York, said the survey “adds further important information on the role of fathers both in the care of their infants and young children, but also in terms of supporting the birth parent and a number of the parenting decisions, whether it’s breastfeeding as well as safe sleep practices for the infant.”
The benefits of breastfeeding are important for the infant but also for the health of the family and the community, Dr. Campbell explained, noting that breastfeeding can aid in preventing chronic disease and cancer. Promoting safe sleep practices for infants, on the other hand, helps reduce factors such as infant mortality and sudden unexpected infant death.
While PRAMS has existed for decades, PRAMS for Dads is relatively new and localized as a pilot program in Georgia, Dr. Campbell noted. The pilot program “really shows that you can get helpful information, and it would be wonderful to see that model expanded to begin to look at the father’s role in other states as well.”
To improve adherence to breastfeeding and infant safe sleeping practices, creating broadly educational efforts that include and recognize the contributions of the father are important, especially as fathers today are generally more involved and engaged than in past generations, Dr. Campbell said. For instance, pediatric or family practice offices could be structured in a way that welcomes fathers and appreciates them, rather than focusing solely on the birth mother or the baby.
“I think certainly as we have greater diversity among our families, greater diversity within our communities, just more varied family constellations, recognizing and valuing each member of the family becomes important and then providing them with the information and the tools,” she said.
While health literacy is important, structural inequalities in care provision in health care settings mean that “it’s honestly much more likely that an educated parent is going to have an opportunity to hear more of those messages,” Dr. Campbell said. “They are much more likely to be able to go to childbirth classes, go to the pediatrician visits, take off from work, have leaves so that they can spend time in the hospital during the infant’s stay and the birth parent’s initial recoveries so that they have greater opportunity to get those messages.”
Fathers with lower educational attainment may have good health literacy, but may be unable to be around for these conversations. “Education is really a proxy for a lot of other structural issues,” she said.
Educational messages around safe sleeping practices for the infant should acknowledge that many families might not have the space to have a dedicated room with a crib for an infant, and offer assurances that other safe sleeping options exist, such as a pack-and-play or Moses basket. The most important message to get across to parents is that the baby is “sleeping alone” in a firm, noninclined surface and does not have bedding or other objects around them.
It is not just the infant’s bed that should follow the AAP recommendations: the family bed should also be a firm surface free of soft objects and bedding for breastfeeding, Dr. Campbell noted. If a parent falls asleep while breastfeeding in bed, the AAP’s most recent guidance notes the parent should move the infant to a separate sleep space as soon as they wake up, but the Academy also acknowledges how that can be challenging in early months with sleep deprivation.
“I think it’s dealing with the realities of having a new baby and trying to create the safest environment for that baby, one that supports and promotes breastfeeding as well as safe sleep,” she said.
In families where there are “strong cultural beliefs and traditions” about the baby sleeping with the parents, it is important to “convey the messages in a way that, that honors and values, family traditions and customs, but also assures the safety of the infant,” Dr. Campbell said.
This study was supported by the Centers for Disease Control and Prevention and CDC Innovation Fund. The authors reported no relevant conflicts of interest. Dr. Campbell reported no relevant conflicts of interest.
Infants of fathers who want their child to breastfeed are more likely to be part of a family unit that starts and continues breastfeeding, and fathers informed of safe sleep practices are more likely to follow those sleeping recommendations for their infant, according to the results of a recent survey published in Pediatrics.
The results suggest that the researchers said.
“Our findings underscore that new fathers are a critical audience to promote breastfeeding and safe infant sleep,” John James Parker, MD, instructor of pediatrics at Northwestern University, Chicago, stated in a press release. “Many families do not gain the health benefits from breastfeeding because they are not provided the support to breastfeed successfully. Fathers need to be directly engaged in breastfeeding discussions, and providers need to describe the important role fathers play in breastfeeding success.”
Population-based survey results
Dr. Parker and colleagues used the Pregnancy Risk Assessment Monitoring System (PRAMS) for Dads population-based survey to evaluate the rate of adherence to breastfeeding and infant sleep practices recommended by the American Academy of Pediatrics. In total, 250 fathers in Georgia were surveyed between October 2018 and July 2019 about whether their infants were breastfeeding and if they were breastfeeding at 8 weeks. The fathers were also asked how often the infant slept in a back sleeping position, on an approved sleep surface, and sleeping with no soft objects or soft bedding.
In addition to surveying fathers on their attitudes on breastfeeding and whether they followed safe infant sleep practices, the researchers collected information on paternal sociodemographic characteristics such as age, race and ethnicity, education, health insurance status, and marital status. Overall, a majority fathers who responded to the survey were between 25 years and 34 years old (56.5%), non-Hispanic White (44.7%), had a high school diploma or less (43.7%) or completed college (37.1%), and were married (65.2%).
Dr. Parker and colleagues found fathers surveyed said 86.1% of infants were ever breastfed, which decreased to 63.4% at 8 weeks. Compared with fathers who did not want their infant to breastfeed or expressed no opinion, fathers who wanted to have the infant’s mother breastfeed had a higher likelihood of reporting breastfeeding initiation (adjusted prevalence ratio, 1.39; 95% confidence interval, 1.15-1.68) and breastfeeding at 8 weeks (aPR, 2.33; 95% CI, 1.59-3.42). Having a college degree was also associated with the infant breastfeeding (93.6% vs. 75.1%; aPR, 1.25; 95% CI, 1.06-1.46) and breastfeeding at 8 weeks (74.7% vs. 52.0%; aPR, 1.44; 95% CI, 1.08-1.91), compared with fathers who graduated from high school or less.
Regarding safe infant sleeping practices, 81.18% of fathers said they placed their infants on their back to sleep, but 44.1% said they did not use soft bedding, and 31.9% said they used an approved sleep surface. In total, 99.4% of fathers put their infant to sleep, and 68.4% said they received information on all three infant safe sleeping practices, while 15.7% said they followed all three sleeping recommendations. A health care provider was the most common person giving advice to the father on placing the infant to sleep on their back (84.7%); to use a safe sleep surface such as a crib, bassinet, or pack-and-play (78.7%); and receiving information about what not to place in the infant’s bed (79.1%).
The survey found non-Hispanic Black fathers reported they were less likely to put the infant to sleep on their back (62.5% vs. 89.5%; aPR, 0.70; 95% CI, 0.54-0.90) and not use soft bedding (28.1% vs. 54.1%; aPR, 0.52; 95% CI, 0.30-0.89), compared with non-Hispanic White fathers. College graduates were more likely to not use soft bedding (61.4% vs. 31.9%; aPR, 1.92; 95% CI, 1.25-2.95), more likely to get advice on placing the infant on their back for sleep (94.3% vs. 73.6%; aPR, 1.28; 95% CI, 1.09-1.51), and more likely to receive advice on what not to place in the infant’s bed (88.1% vs. 68.5%; aPR, 1.29; 95% CI, 1.06-1.57), compared with fathers with a high school diploma or less.
“Fathers need to receive counseling on all the safe sleep practices for their infants,” Dr. Parker said. “To reduce racial disparities in sudden unexpected infant death, we need tailored strategies to increase safe infant sleep practices in the Black community, including public campaigns to increase awareness and home visiting programs. These interventions must involve both parents to be most effective.”
Educational efforts should recognize father’s contributions
In an interview, Deborah E. Campbell, MD, chief of neonatology at the Children’s Hospital at Montefiore, New York, said the survey “adds further important information on the role of fathers both in the care of their infants and young children, but also in terms of supporting the birth parent and a number of the parenting decisions, whether it’s breastfeeding as well as safe sleep practices for the infant.”
The benefits of breastfeeding are important for the infant but also for the health of the family and the community, Dr. Campbell explained, noting that breastfeeding can aid in preventing chronic disease and cancer. Promoting safe sleep practices for infants, on the other hand, helps reduce factors such as infant mortality and sudden unexpected infant death.
While PRAMS has existed for decades, PRAMS for Dads is relatively new and localized as a pilot program in Georgia, Dr. Campbell noted. The pilot program “really shows that you can get helpful information, and it would be wonderful to see that model expanded to begin to look at the father’s role in other states as well.”
To improve adherence to breastfeeding and infant safe sleeping practices, creating broadly educational efforts that include and recognize the contributions of the father are important, especially as fathers today are generally more involved and engaged than in past generations, Dr. Campbell said. For instance, pediatric or family practice offices could be structured in a way that welcomes fathers and appreciates them, rather than focusing solely on the birth mother or the baby.
“I think certainly as we have greater diversity among our families, greater diversity within our communities, just more varied family constellations, recognizing and valuing each member of the family becomes important and then providing them with the information and the tools,” she said.
While health literacy is important, structural inequalities in care provision in health care settings mean that “it’s honestly much more likely that an educated parent is going to have an opportunity to hear more of those messages,” Dr. Campbell said. “They are much more likely to be able to go to childbirth classes, go to the pediatrician visits, take off from work, have leaves so that they can spend time in the hospital during the infant’s stay and the birth parent’s initial recoveries so that they have greater opportunity to get those messages.”
Fathers with lower educational attainment may have good health literacy, but may be unable to be around for these conversations. “Education is really a proxy for a lot of other structural issues,” she said.
Educational messages around safe sleeping practices for the infant should acknowledge that many families might not have the space to have a dedicated room with a crib for an infant, and offer assurances that other safe sleeping options exist, such as a pack-and-play or Moses basket. The most important message to get across to parents is that the baby is “sleeping alone” in a firm, noninclined surface and does not have bedding or other objects around them.
It is not just the infant’s bed that should follow the AAP recommendations: the family bed should also be a firm surface free of soft objects and bedding for breastfeeding, Dr. Campbell noted. If a parent falls asleep while breastfeeding in bed, the AAP’s most recent guidance notes the parent should move the infant to a separate sleep space as soon as they wake up, but the Academy also acknowledges how that can be challenging in early months with sleep deprivation.
“I think it’s dealing with the realities of having a new baby and trying to create the safest environment for that baby, one that supports and promotes breastfeeding as well as safe sleep,” she said.
In families where there are “strong cultural beliefs and traditions” about the baby sleeping with the parents, it is important to “convey the messages in a way that, that honors and values, family traditions and customs, but also assures the safety of the infant,” Dr. Campbell said.
This study was supported by the Centers for Disease Control and Prevention and CDC Innovation Fund. The authors reported no relevant conflicts of interest. Dr. Campbell reported no relevant conflicts of interest.
Infants of fathers who want their child to breastfeed are more likely to be part of a family unit that starts and continues breastfeeding, and fathers informed of safe sleep practices are more likely to follow those sleeping recommendations for their infant, according to the results of a recent survey published in Pediatrics.
The results suggest that the researchers said.
“Our findings underscore that new fathers are a critical audience to promote breastfeeding and safe infant sleep,” John James Parker, MD, instructor of pediatrics at Northwestern University, Chicago, stated in a press release. “Many families do not gain the health benefits from breastfeeding because they are not provided the support to breastfeed successfully. Fathers need to be directly engaged in breastfeeding discussions, and providers need to describe the important role fathers play in breastfeeding success.”
Population-based survey results
Dr. Parker and colleagues used the Pregnancy Risk Assessment Monitoring System (PRAMS) for Dads population-based survey to evaluate the rate of adherence to breastfeeding and infant sleep practices recommended by the American Academy of Pediatrics. In total, 250 fathers in Georgia were surveyed between October 2018 and July 2019 about whether their infants were breastfeeding and if they were breastfeeding at 8 weeks. The fathers were also asked how often the infant slept in a back sleeping position, on an approved sleep surface, and sleeping with no soft objects or soft bedding.
In addition to surveying fathers on their attitudes on breastfeeding and whether they followed safe infant sleep practices, the researchers collected information on paternal sociodemographic characteristics such as age, race and ethnicity, education, health insurance status, and marital status. Overall, a majority fathers who responded to the survey were between 25 years and 34 years old (56.5%), non-Hispanic White (44.7%), had a high school diploma or less (43.7%) or completed college (37.1%), and were married (65.2%).
Dr. Parker and colleagues found fathers surveyed said 86.1% of infants were ever breastfed, which decreased to 63.4% at 8 weeks. Compared with fathers who did not want their infant to breastfeed or expressed no opinion, fathers who wanted to have the infant’s mother breastfeed had a higher likelihood of reporting breastfeeding initiation (adjusted prevalence ratio, 1.39; 95% confidence interval, 1.15-1.68) and breastfeeding at 8 weeks (aPR, 2.33; 95% CI, 1.59-3.42). Having a college degree was also associated with the infant breastfeeding (93.6% vs. 75.1%; aPR, 1.25; 95% CI, 1.06-1.46) and breastfeeding at 8 weeks (74.7% vs. 52.0%; aPR, 1.44; 95% CI, 1.08-1.91), compared with fathers who graduated from high school or less.
Regarding safe infant sleeping practices, 81.18% of fathers said they placed their infants on their back to sleep, but 44.1% said they did not use soft bedding, and 31.9% said they used an approved sleep surface. In total, 99.4% of fathers put their infant to sleep, and 68.4% said they received information on all three infant safe sleeping practices, while 15.7% said they followed all three sleeping recommendations. A health care provider was the most common person giving advice to the father on placing the infant to sleep on their back (84.7%); to use a safe sleep surface such as a crib, bassinet, or pack-and-play (78.7%); and receiving information about what not to place in the infant’s bed (79.1%).
The survey found non-Hispanic Black fathers reported they were less likely to put the infant to sleep on their back (62.5% vs. 89.5%; aPR, 0.70; 95% CI, 0.54-0.90) and not use soft bedding (28.1% vs. 54.1%; aPR, 0.52; 95% CI, 0.30-0.89), compared with non-Hispanic White fathers. College graduates were more likely to not use soft bedding (61.4% vs. 31.9%; aPR, 1.92; 95% CI, 1.25-2.95), more likely to get advice on placing the infant on their back for sleep (94.3% vs. 73.6%; aPR, 1.28; 95% CI, 1.09-1.51), and more likely to receive advice on what not to place in the infant’s bed (88.1% vs. 68.5%; aPR, 1.29; 95% CI, 1.06-1.57), compared with fathers with a high school diploma or less.
“Fathers need to receive counseling on all the safe sleep practices for their infants,” Dr. Parker said. “To reduce racial disparities in sudden unexpected infant death, we need tailored strategies to increase safe infant sleep practices in the Black community, including public campaigns to increase awareness and home visiting programs. These interventions must involve both parents to be most effective.”
Educational efforts should recognize father’s contributions
In an interview, Deborah E. Campbell, MD, chief of neonatology at the Children’s Hospital at Montefiore, New York, said the survey “adds further important information on the role of fathers both in the care of their infants and young children, but also in terms of supporting the birth parent and a number of the parenting decisions, whether it’s breastfeeding as well as safe sleep practices for the infant.”
The benefits of breastfeeding are important for the infant but also for the health of the family and the community, Dr. Campbell explained, noting that breastfeeding can aid in preventing chronic disease and cancer. Promoting safe sleep practices for infants, on the other hand, helps reduce factors such as infant mortality and sudden unexpected infant death.
While PRAMS has existed for decades, PRAMS for Dads is relatively new and localized as a pilot program in Georgia, Dr. Campbell noted. The pilot program “really shows that you can get helpful information, and it would be wonderful to see that model expanded to begin to look at the father’s role in other states as well.”
To improve adherence to breastfeeding and infant safe sleeping practices, creating broadly educational efforts that include and recognize the contributions of the father are important, especially as fathers today are generally more involved and engaged than in past generations, Dr. Campbell said. For instance, pediatric or family practice offices could be structured in a way that welcomes fathers and appreciates them, rather than focusing solely on the birth mother or the baby.
“I think certainly as we have greater diversity among our families, greater diversity within our communities, just more varied family constellations, recognizing and valuing each member of the family becomes important and then providing them with the information and the tools,” she said.
While health literacy is important, structural inequalities in care provision in health care settings mean that “it’s honestly much more likely that an educated parent is going to have an opportunity to hear more of those messages,” Dr. Campbell said. “They are much more likely to be able to go to childbirth classes, go to the pediatrician visits, take off from work, have leaves so that they can spend time in the hospital during the infant’s stay and the birth parent’s initial recoveries so that they have greater opportunity to get those messages.”
Fathers with lower educational attainment may have good health literacy, but may be unable to be around for these conversations. “Education is really a proxy for a lot of other structural issues,” she said.
Educational messages around safe sleeping practices for the infant should acknowledge that many families might not have the space to have a dedicated room with a crib for an infant, and offer assurances that other safe sleeping options exist, such as a pack-and-play or Moses basket. The most important message to get across to parents is that the baby is “sleeping alone” in a firm, noninclined surface and does not have bedding or other objects around them.
It is not just the infant’s bed that should follow the AAP recommendations: the family bed should also be a firm surface free of soft objects and bedding for breastfeeding, Dr. Campbell noted. If a parent falls asleep while breastfeeding in bed, the AAP’s most recent guidance notes the parent should move the infant to a separate sleep space as soon as they wake up, but the Academy also acknowledges how that can be challenging in early months with sleep deprivation.
“I think it’s dealing with the realities of having a new baby and trying to create the safest environment for that baby, one that supports and promotes breastfeeding as well as safe sleep,” she said.
In families where there are “strong cultural beliefs and traditions” about the baby sleeping with the parents, it is important to “convey the messages in a way that, that honors and values, family traditions and customs, but also assures the safety of the infant,” Dr. Campbell said.
This study was supported by the Centers for Disease Control and Prevention and CDC Innovation Fund. The authors reported no relevant conflicts of interest. Dr. Campbell reported no relevant conflicts of interest.
FROM PEDIATRICS
Atogepant prevents episodic migraine in some difficult-to-treat cases
BOSTON – , according to findings from a study presented at the 2023 annual meeting of the American Academy of Neurology.
Initial results from the double-blind ELEVATE trial showed the oral atogepant group had significantly fewer mean monthly migraine days (MMD) compared with a placebo group. There was also a significant difference in the number of participants who achieved 50% or greater reduction in the number of mean MMDs and a significant reduction in acute medication use days compared with the placebo group, according to Patricia Pozo-Rosich, MD, PhD, a headache specialist in the neurology department and director of the headache and craniofacial pain clinical unit and the Migraine Adaptive Brain Center at the Vall d’Hebron University Hospital in Barcelona, and colleagues.
The oral calcitonin gene-related peptide (CGRP) receptor antagonist is currently approved in the United States by the Food and Drug Administration as a preventative for both episodic and chronic migraine.
Results from ELEVATE
Overall, ELEVATE’s initial efficacy analysis population consisted of 309 adults aged between 18 and 80 years from North America and Europe with episodic migraine who had 4-14 MMDs and had treatment failure with at least two classes of conventional oral medication. After a 28-day screening period, participants received either 60 mg of oral atogepant once per day (154 participants) or a placebo (155 participants). In the efficacy analysis population, 56.0% of participants had failed two oral migraine preventative medication classes, while 44.0% failed three or more classes of medication. Dr. Pozo-Rosich noted that participants were taking a number of different oral preventatives across different medication classes, including flunarizine, beta blockers, topiramate, and amitriptyline, but data are not yet available on which participants had received certain combinations of oral medications.
“[T]hese people have already taken some type of prevention, so they’re not naive patients,” she said. “They’re usually more or less well treated in the sense of having had a contact with specialists or a general neurologist, someone that actually tries to do some prevention.”
The researchers examined change from MMDs at baseline and at 12 weeks as a primary outcome, with 50% or greater MMD reduction, change in mean monthly headache days, and change in acute medication use days as secondary outcomes. Regarding the different acute medications used, Dr. Pozo-Rosich said the main three types were analgesics, nonsteroid anti-inflammatory drugs, and triptans, with participants excluded from the trial if they were taking opioids.
The results showed participants in the atogepant group had significantly fewer mean MMDs compared with the placebo group at 12 weeks compared with baseline (–4.20 vs. –1.85 days; P < .0001). Researchers also found statistically significant improvement in the atogepant group for 50% or greater reduction in MMD, change in mean monthly headache days, and change in acute medication use days across 12 weeks of treatment compared with the placebo group. While the specific data analyses for secondary outcomes were not conducted in the initial analysis, Dr. Pozo-Rosich said the numbers “correlate with the primary outcome” as seen in other migraine trials.
Compared with the placebo group, participants in the atogepant group had higher rates of constipation (10.3% vs. 2.5%), COVID-19 (9.6% vs. 8.3%), and nausea (7.1% vs. 3.2%), while the placebo group had a higher rate of nasopharyngitis (5.1% vs. 7.6%).*
Migraine is a prevalent and undertreated disease, and patients around the world with migraine are in need of treatment options that are both safe and effective, Dr. Pozo-Rosich said in an interview. “[E]ven in these hard-to-treat or difficult-to-treat migraine patients, you have a drug that works, and is safe, and well tolerated and effective,” she said.
That’s “kind of good news for all of us,” she said. Patients “need this type of good news and solution,” she explained, because they may not tolerate or have access to injectable medications. Atogepant would also give clinicians have another option to offer patients with difficult-to-treat migraine cases, she noted. “It makes life easier for many physicians and many patients for many different reasons,” she said.
Dr. Pozo-Rosich said the likely next step in the research is to conduct the main analysis as well as post hoc analyses with accumulated data from pathology trials “to understand patterns of response, understand the sustainability of the response, [and] adherence to the treatment in the long term.”
‘Exciting that it works well’ in difficult-to-treat patients
Commenting on the study, Alan M. Rapoport, MD, clinical professor of neurology at University of California, Los Angeles, and past president of the International Headache Society, agreed that better options in migraine treatment and prevention are needed.
“We needed something that was going to be better than what we had before,” he said.
Dr. Rapoport noted the study was well designed with strongly positive results. “It looks like it’s an effective drug, and it looks really good in that it’s effective for people that have failed all these preventives that have very little hope for the future,” he said.
He specifically praised the inclusion of older participants in the population. “You never see a study on 80-year-olds,” he said, “but I like that, because they felt it would be safe. There are 80-year-old patients – fewer of them than 40-year-old patients – but there are 80-year-old patients who still have migraine, so I’m really glad they put older patients in it,” he said.
For atogepant, he noted that “some patients won’t get the side effects, and some patients will tolerate the side effects because it’s working really well.” While the study was not a head-to-head comparison against other oral migraine preventatives, he pointed out the high rate of constipation among participants in the trial setting may be a warning sign of future issues, as seen with other CGRP receptor agonists.
“I can tell you that with erenumab, the monoclonal antibody that was injected in the double-blind studies, they didn’t find any significant increase in constipation,” he explained. However, some clinicians using erenumab in the real world have reported up to 20% of their patients are constipated. “It’s not good that they’re reporting 10% are constipated” in the study, he said.
Overall, “all you can really say is it does work well,” Dr. Rapoport said. “It’s exciting that it works well in such difficult-to-treat patients, and it does come with some side effects.”
Dr. Pozo-Rosich reports serving as a consultant and developing education materials for AbbVie, Eli Lilly, Novartis, Teva Pharmaceuticals, and Pfizer. Dr. Rapoport is the editor-in-chief of Neurology Reviews; he reports being a consultant for AbbVie, the developer of atogepant. The ELEVATE trial is supported by AbbVie.
*Correction, 5/4/23: An earlier version of this article misstated the percentage of COVID-positive patients in the study population.
BOSTON – , according to findings from a study presented at the 2023 annual meeting of the American Academy of Neurology.
Initial results from the double-blind ELEVATE trial showed the oral atogepant group had significantly fewer mean monthly migraine days (MMD) compared with a placebo group. There was also a significant difference in the number of participants who achieved 50% or greater reduction in the number of mean MMDs and a significant reduction in acute medication use days compared with the placebo group, according to Patricia Pozo-Rosich, MD, PhD, a headache specialist in the neurology department and director of the headache and craniofacial pain clinical unit and the Migraine Adaptive Brain Center at the Vall d’Hebron University Hospital in Barcelona, and colleagues.
The oral calcitonin gene-related peptide (CGRP) receptor antagonist is currently approved in the United States by the Food and Drug Administration as a preventative for both episodic and chronic migraine.
Results from ELEVATE
Overall, ELEVATE’s initial efficacy analysis population consisted of 309 adults aged between 18 and 80 years from North America and Europe with episodic migraine who had 4-14 MMDs and had treatment failure with at least two classes of conventional oral medication. After a 28-day screening period, participants received either 60 mg of oral atogepant once per day (154 participants) or a placebo (155 participants). In the efficacy analysis population, 56.0% of participants had failed two oral migraine preventative medication classes, while 44.0% failed three or more classes of medication. Dr. Pozo-Rosich noted that participants were taking a number of different oral preventatives across different medication classes, including flunarizine, beta blockers, topiramate, and amitriptyline, but data are not yet available on which participants had received certain combinations of oral medications.
“[T]hese people have already taken some type of prevention, so they’re not naive patients,” she said. “They’re usually more or less well treated in the sense of having had a contact with specialists or a general neurologist, someone that actually tries to do some prevention.”
The researchers examined change from MMDs at baseline and at 12 weeks as a primary outcome, with 50% or greater MMD reduction, change in mean monthly headache days, and change in acute medication use days as secondary outcomes. Regarding the different acute medications used, Dr. Pozo-Rosich said the main three types were analgesics, nonsteroid anti-inflammatory drugs, and triptans, with participants excluded from the trial if they were taking opioids.
The results showed participants in the atogepant group had significantly fewer mean MMDs compared with the placebo group at 12 weeks compared with baseline (–4.20 vs. –1.85 days; P < .0001). Researchers also found statistically significant improvement in the atogepant group for 50% or greater reduction in MMD, change in mean monthly headache days, and change in acute medication use days across 12 weeks of treatment compared with the placebo group. While the specific data analyses for secondary outcomes were not conducted in the initial analysis, Dr. Pozo-Rosich said the numbers “correlate with the primary outcome” as seen in other migraine trials.
Compared with the placebo group, participants in the atogepant group had higher rates of constipation (10.3% vs. 2.5%), COVID-19 (9.6% vs. 8.3%), and nausea (7.1% vs. 3.2%), while the placebo group had a higher rate of nasopharyngitis (5.1% vs. 7.6%).*
Migraine is a prevalent and undertreated disease, and patients around the world with migraine are in need of treatment options that are both safe and effective, Dr. Pozo-Rosich said in an interview. “[E]ven in these hard-to-treat or difficult-to-treat migraine patients, you have a drug that works, and is safe, and well tolerated and effective,” she said.
That’s “kind of good news for all of us,” she said. Patients “need this type of good news and solution,” she explained, because they may not tolerate or have access to injectable medications. Atogepant would also give clinicians have another option to offer patients with difficult-to-treat migraine cases, she noted. “It makes life easier for many physicians and many patients for many different reasons,” she said.
Dr. Pozo-Rosich said the likely next step in the research is to conduct the main analysis as well as post hoc analyses with accumulated data from pathology trials “to understand patterns of response, understand the sustainability of the response, [and] adherence to the treatment in the long term.”
‘Exciting that it works well’ in difficult-to-treat patients
Commenting on the study, Alan M. Rapoport, MD, clinical professor of neurology at University of California, Los Angeles, and past president of the International Headache Society, agreed that better options in migraine treatment and prevention are needed.
“We needed something that was going to be better than what we had before,” he said.
Dr. Rapoport noted the study was well designed with strongly positive results. “It looks like it’s an effective drug, and it looks really good in that it’s effective for people that have failed all these preventives that have very little hope for the future,” he said.
He specifically praised the inclusion of older participants in the population. “You never see a study on 80-year-olds,” he said, “but I like that, because they felt it would be safe. There are 80-year-old patients – fewer of them than 40-year-old patients – but there are 80-year-old patients who still have migraine, so I’m really glad they put older patients in it,” he said.
For atogepant, he noted that “some patients won’t get the side effects, and some patients will tolerate the side effects because it’s working really well.” While the study was not a head-to-head comparison against other oral migraine preventatives, he pointed out the high rate of constipation among participants in the trial setting may be a warning sign of future issues, as seen with other CGRP receptor agonists.
“I can tell you that with erenumab, the monoclonal antibody that was injected in the double-blind studies, they didn’t find any significant increase in constipation,” he explained. However, some clinicians using erenumab in the real world have reported up to 20% of their patients are constipated. “It’s not good that they’re reporting 10% are constipated” in the study, he said.
Overall, “all you can really say is it does work well,” Dr. Rapoport said. “It’s exciting that it works well in such difficult-to-treat patients, and it does come with some side effects.”
Dr. Pozo-Rosich reports serving as a consultant and developing education materials for AbbVie, Eli Lilly, Novartis, Teva Pharmaceuticals, and Pfizer. Dr. Rapoport is the editor-in-chief of Neurology Reviews; he reports being a consultant for AbbVie, the developer of atogepant. The ELEVATE trial is supported by AbbVie.
*Correction, 5/4/23: An earlier version of this article misstated the percentage of COVID-positive patients in the study population.
BOSTON – , according to findings from a study presented at the 2023 annual meeting of the American Academy of Neurology.
Initial results from the double-blind ELEVATE trial showed the oral atogepant group had significantly fewer mean monthly migraine days (MMD) compared with a placebo group. There was also a significant difference in the number of participants who achieved 50% or greater reduction in the number of mean MMDs and a significant reduction in acute medication use days compared with the placebo group, according to Patricia Pozo-Rosich, MD, PhD, a headache specialist in the neurology department and director of the headache and craniofacial pain clinical unit and the Migraine Adaptive Brain Center at the Vall d’Hebron University Hospital in Barcelona, and colleagues.
The oral calcitonin gene-related peptide (CGRP) receptor antagonist is currently approved in the United States by the Food and Drug Administration as a preventative for both episodic and chronic migraine.
Results from ELEVATE
Overall, ELEVATE’s initial efficacy analysis population consisted of 309 adults aged between 18 and 80 years from North America and Europe with episodic migraine who had 4-14 MMDs and had treatment failure with at least two classes of conventional oral medication. After a 28-day screening period, participants received either 60 mg of oral atogepant once per day (154 participants) or a placebo (155 participants). In the efficacy analysis population, 56.0% of participants had failed two oral migraine preventative medication classes, while 44.0% failed three or more classes of medication. Dr. Pozo-Rosich noted that participants were taking a number of different oral preventatives across different medication classes, including flunarizine, beta blockers, topiramate, and amitriptyline, but data are not yet available on which participants had received certain combinations of oral medications.
“[T]hese people have already taken some type of prevention, so they’re not naive patients,” she said. “They’re usually more or less well treated in the sense of having had a contact with specialists or a general neurologist, someone that actually tries to do some prevention.”
The researchers examined change from MMDs at baseline and at 12 weeks as a primary outcome, with 50% or greater MMD reduction, change in mean monthly headache days, and change in acute medication use days as secondary outcomes. Regarding the different acute medications used, Dr. Pozo-Rosich said the main three types were analgesics, nonsteroid anti-inflammatory drugs, and triptans, with participants excluded from the trial if they were taking opioids.
The results showed participants in the atogepant group had significantly fewer mean MMDs compared with the placebo group at 12 weeks compared with baseline (–4.20 vs. –1.85 days; P < .0001). Researchers also found statistically significant improvement in the atogepant group for 50% or greater reduction in MMD, change in mean monthly headache days, and change in acute medication use days across 12 weeks of treatment compared with the placebo group. While the specific data analyses for secondary outcomes were not conducted in the initial analysis, Dr. Pozo-Rosich said the numbers “correlate with the primary outcome” as seen in other migraine trials.
Compared with the placebo group, participants in the atogepant group had higher rates of constipation (10.3% vs. 2.5%), COVID-19 (9.6% vs. 8.3%), and nausea (7.1% vs. 3.2%), while the placebo group had a higher rate of nasopharyngitis (5.1% vs. 7.6%).*
Migraine is a prevalent and undertreated disease, and patients around the world with migraine are in need of treatment options that are both safe and effective, Dr. Pozo-Rosich said in an interview. “[E]ven in these hard-to-treat or difficult-to-treat migraine patients, you have a drug that works, and is safe, and well tolerated and effective,” she said.
That’s “kind of good news for all of us,” she said. Patients “need this type of good news and solution,” she explained, because they may not tolerate or have access to injectable medications. Atogepant would also give clinicians have another option to offer patients with difficult-to-treat migraine cases, she noted. “It makes life easier for many physicians and many patients for many different reasons,” she said.
Dr. Pozo-Rosich said the likely next step in the research is to conduct the main analysis as well as post hoc analyses with accumulated data from pathology trials “to understand patterns of response, understand the sustainability of the response, [and] adherence to the treatment in the long term.”
‘Exciting that it works well’ in difficult-to-treat patients
Commenting on the study, Alan M. Rapoport, MD, clinical professor of neurology at University of California, Los Angeles, and past president of the International Headache Society, agreed that better options in migraine treatment and prevention are needed.
“We needed something that was going to be better than what we had before,” he said.
Dr. Rapoport noted the study was well designed with strongly positive results. “It looks like it’s an effective drug, and it looks really good in that it’s effective for people that have failed all these preventives that have very little hope for the future,” he said.
He specifically praised the inclusion of older participants in the population. “You never see a study on 80-year-olds,” he said, “but I like that, because they felt it would be safe. There are 80-year-old patients – fewer of them than 40-year-old patients – but there are 80-year-old patients who still have migraine, so I’m really glad they put older patients in it,” he said.
For atogepant, he noted that “some patients won’t get the side effects, and some patients will tolerate the side effects because it’s working really well.” While the study was not a head-to-head comparison against other oral migraine preventatives, he pointed out the high rate of constipation among participants in the trial setting may be a warning sign of future issues, as seen with other CGRP receptor agonists.
“I can tell you that with erenumab, the monoclonal antibody that was injected in the double-blind studies, they didn’t find any significant increase in constipation,” he explained. However, some clinicians using erenumab in the real world have reported up to 20% of their patients are constipated. “It’s not good that they’re reporting 10% are constipated” in the study, he said.
Overall, “all you can really say is it does work well,” Dr. Rapoport said. “It’s exciting that it works well in such difficult-to-treat patients, and it does come with some side effects.”
Dr. Pozo-Rosich reports serving as a consultant and developing education materials for AbbVie, Eli Lilly, Novartis, Teva Pharmaceuticals, and Pfizer. Dr. Rapoport is the editor-in-chief of Neurology Reviews; he reports being a consultant for AbbVie, the developer of atogepant. The ELEVATE trial is supported by AbbVie.
*Correction, 5/4/23: An earlier version of this article misstated the percentage of COVID-positive patients in the study population.
FROM AAN 2023
Mississippi–Ohio River valley linked to higher risk of Parkinson’s disease
according to findings from a study that was released ahead of its scheduled presentation at the annual meeting of the American Academy of Neurology.
The association was attributed to concentrations of particulate matter (PM) 2.5 in the Mississippi–Ohio River valley, which was on average higher than in other areas, but that didn’t entirely explain the increase in Parkinson’s disease in that region, Brittany Krzyzanowski, PhD, a postdoctoral research fellow in the neuroepidemiology research program of the department of neurology at Barrow Neurological Institute, Dignity Health St. Joseph’s Hospital and Medical Center, Phoenix, said in an interview.
“This study revealed Parkinson’s disease hot spots in the Mississippi–Ohio River valley, a region that has some of the highest levels of air pollution in the nation,” she said, “but we also still find a relationship between air pollution and Parkinson’s risk in the regions in the western half of the United States where Parkinson’s disease and air pollution levels are relatively low.”
Dr. Krzyzanowski and colleagues evaluated 22,546,965 Medicare beneficiaries in 2009, using a multimethod approach that included geospatial analytical techniques to categorize their exposure to PM2.5 based on age, sex, race, smoking status, and health care usage. The researchers also performed individual-level case-control analysis to assess PM2.5 results at the county level. The Medicare beneficiaries were grouped according to average exposure, with the lowest group having an average annual exposure of 5 mcg/m3 and the group with the highest exposure having an average annual exposure of 19 mcg/m3.
In total, researchers identified 83,674 Medicare beneficiaries with incident Parkinson’s disease, with 434 new cases per 100,000 people in the highest exposure group, compared with 359 new cases per 100,000 people in the lowest-exposure group. The relative risk for Parkinson’s disease increased in the highest quartile of PM2.5 by 25%, compared with the lowest quartile after adjusting for factors such as age, smoking status, and health care usage (95% confidence interval, 20%–29%).
The results showed the nationwide average annual PM2.5 was associated with incident Parkinson’s disease, and the Rocky Mountain region carried a strong association between PM2.5 and Parkson’s disease with a 16% increase in risk per level of exposure to PM2.5. While the Mississippi-Ohio River valley was also associated with Parkinson’s disease, there was a weaker association between PM2.5 and Parkinson’s disease, which the researchers attributed to a “ceiling effect” of PM2.5 between approximately 12-19 mcg/m3.
Dr. Krzyzanowski said that use of a large-population-based dataset and high-resolution location data were major strengths of the study. “Having this level of information leaves less room for uncertainty in our measures and analyses,” she said. “Our study also leveraged innovative geographic information systems which allowed us to refine local patterns of disease by using population behavior and demographic information (such as smoking and age) to ensure that we could provide the most accurate map representation available to date.”
A focus on air pollution
Existing research in examining the etiology of Parkinson’s mainly focused on exposure to pesticides,* Dr. Krzyzanowski explained, and “consists of studies using relatively small populations and low-resolution air pollution data.” Genetics is another possible cause, she noted, but only explains some Parkinson’s disease cases.
“Our work suggests that we should also be looking at air pollution as a contributor in the development of Parkinson’s disease,” she said.
Ray Dorsey, MD, professor of neurology at the University of Rochester (N.Y.), who was not involved with the study, said that evidence is mounting that “air pollution may be an important causal factor in Parkinson’s and especially Alzheimer’s disease.”
“This study by a well-regarded group of researchers adds epidemiological evidence for that association,” he said. Another strength is that the study was conducted in the United States, as many epidemiological studies evaluating air pollution and Parkinson’s disease have been performed outside the country because of “a dearth of reliable data sources.”
“This study, along with others, suggest that some of the important environmental toxicants tied to brain disease may be inhaled,” Dr. Dorsey said. “The nose may be the front door to the brain.”
Dr. Krzyzanowski said the next step in their research is further examination of different types of air pollution. “Air pollution contains a variety of toxic components which vary from region to region. Understanding the different components in air pollution and how they interact with climate, temperature, and topography could help explain the regional differences we observed.”
One potential limitation in the study is a lag between air pollution exposure and development of Parkinson’s disease, Dr. Dorsey noted.
“Here, it looks like (but I am not certain) that the investigators looked at current air pollution levels and new cases of Parkinson’s. Ideally, for incident cases of Parkinson’s disease, we would want to know historical data on exposure to air pollution,” he said.
Future studies should include prospective evaluation of adults as well as babies and children who have been exposed to both high and low levels of air pollution. That kind of study “would be incredibly valuable for determining the role of an important environmental toxicant in many brain diseases, including stroke, Alzheimer’s, and Parkinson’s,” he said.
Dr. Krzyzanowski and Dr. Dorsey reported no relevant financial disclosures. This study was supported by grants from the Department of Defense, the National Institute of Environmental Health Sciences, and The Michael J. Fox Foundation for Parkinson’s Research.
*Correction, 4/14/23: An earlier version of this article mischaracterized the disease that was the subject of this research.
according to findings from a study that was released ahead of its scheduled presentation at the annual meeting of the American Academy of Neurology.
The association was attributed to concentrations of particulate matter (PM) 2.5 in the Mississippi–Ohio River valley, which was on average higher than in other areas, but that didn’t entirely explain the increase in Parkinson’s disease in that region, Brittany Krzyzanowski, PhD, a postdoctoral research fellow in the neuroepidemiology research program of the department of neurology at Barrow Neurological Institute, Dignity Health St. Joseph’s Hospital and Medical Center, Phoenix, said in an interview.
“This study revealed Parkinson’s disease hot spots in the Mississippi–Ohio River valley, a region that has some of the highest levels of air pollution in the nation,” she said, “but we also still find a relationship between air pollution and Parkinson’s risk in the regions in the western half of the United States where Parkinson’s disease and air pollution levels are relatively low.”
Dr. Krzyzanowski and colleagues evaluated 22,546,965 Medicare beneficiaries in 2009, using a multimethod approach that included geospatial analytical techniques to categorize their exposure to PM2.5 based on age, sex, race, smoking status, and health care usage. The researchers also performed individual-level case-control analysis to assess PM2.5 results at the county level. The Medicare beneficiaries were grouped according to average exposure, with the lowest group having an average annual exposure of 5 mcg/m3 and the group with the highest exposure having an average annual exposure of 19 mcg/m3.
In total, researchers identified 83,674 Medicare beneficiaries with incident Parkinson’s disease, with 434 new cases per 100,000 people in the highest exposure group, compared with 359 new cases per 100,000 people in the lowest-exposure group. The relative risk for Parkinson’s disease increased in the highest quartile of PM2.5 by 25%, compared with the lowest quartile after adjusting for factors such as age, smoking status, and health care usage (95% confidence interval, 20%–29%).
The results showed the nationwide average annual PM2.5 was associated with incident Parkinson’s disease, and the Rocky Mountain region carried a strong association between PM2.5 and Parkson’s disease with a 16% increase in risk per level of exposure to PM2.5. While the Mississippi-Ohio River valley was also associated with Parkinson’s disease, there was a weaker association between PM2.5 and Parkinson’s disease, which the researchers attributed to a “ceiling effect” of PM2.5 between approximately 12-19 mcg/m3.
Dr. Krzyzanowski said that use of a large-population-based dataset and high-resolution location data were major strengths of the study. “Having this level of information leaves less room for uncertainty in our measures and analyses,” she said. “Our study also leveraged innovative geographic information systems which allowed us to refine local patterns of disease by using population behavior and demographic information (such as smoking and age) to ensure that we could provide the most accurate map representation available to date.”
A focus on air pollution
Existing research in examining the etiology of Parkinson’s mainly focused on exposure to pesticides,* Dr. Krzyzanowski explained, and “consists of studies using relatively small populations and low-resolution air pollution data.” Genetics is another possible cause, she noted, but only explains some Parkinson’s disease cases.
“Our work suggests that we should also be looking at air pollution as a contributor in the development of Parkinson’s disease,” she said.
Ray Dorsey, MD, professor of neurology at the University of Rochester (N.Y.), who was not involved with the study, said that evidence is mounting that “air pollution may be an important causal factor in Parkinson’s and especially Alzheimer’s disease.”
“This study by a well-regarded group of researchers adds epidemiological evidence for that association,” he said. Another strength is that the study was conducted in the United States, as many epidemiological studies evaluating air pollution and Parkinson’s disease have been performed outside the country because of “a dearth of reliable data sources.”
“This study, along with others, suggest that some of the important environmental toxicants tied to brain disease may be inhaled,” Dr. Dorsey said. “The nose may be the front door to the brain.”
Dr. Krzyzanowski said the next step in their research is further examination of different types of air pollution. “Air pollution contains a variety of toxic components which vary from region to region. Understanding the different components in air pollution and how they interact with climate, temperature, and topography could help explain the regional differences we observed.”
One potential limitation in the study is a lag between air pollution exposure and development of Parkinson’s disease, Dr. Dorsey noted.
“Here, it looks like (but I am not certain) that the investigators looked at current air pollution levels and new cases of Parkinson’s. Ideally, for incident cases of Parkinson’s disease, we would want to know historical data on exposure to air pollution,” he said.
Future studies should include prospective evaluation of adults as well as babies and children who have been exposed to both high and low levels of air pollution. That kind of study “would be incredibly valuable for determining the role of an important environmental toxicant in many brain diseases, including stroke, Alzheimer’s, and Parkinson’s,” he said.
Dr. Krzyzanowski and Dr. Dorsey reported no relevant financial disclosures. This study was supported by grants from the Department of Defense, the National Institute of Environmental Health Sciences, and The Michael J. Fox Foundation for Parkinson’s Research.
*Correction, 4/14/23: An earlier version of this article mischaracterized the disease that was the subject of this research.
according to findings from a study that was released ahead of its scheduled presentation at the annual meeting of the American Academy of Neurology.
The association was attributed to concentrations of particulate matter (PM) 2.5 in the Mississippi–Ohio River valley, which was on average higher than in other areas, but that didn’t entirely explain the increase in Parkinson’s disease in that region, Brittany Krzyzanowski, PhD, a postdoctoral research fellow in the neuroepidemiology research program of the department of neurology at Barrow Neurological Institute, Dignity Health St. Joseph’s Hospital and Medical Center, Phoenix, said in an interview.
“This study revealed Parkinson’s disease hot spots in the Mississippi–Ohio River valley, a region that has some of the highest levels of air pollution in the nation,” she said, “but we also still find a relationship between air pollution and Parkinson’s risk in the regions in the western half of the United States where Parkinson’s disease and air pollution levels are relatively low.”
Dr. Krzyzanowski and colleagues evaluated 22,546,965 Medicare beneficiaries in 2009, using a multimethod approach that included geospatial analytical techniques to categorize their exposure to PM2.5 based on age, sex, race, smoking status, and health care usage. The researchers also performed individual-level case-control analysis to assess PM2.5 results at the county level. The Medicare beneficiaries were grouped according to average exposure, with the lowest group having an average annual exposure of 5 mcg/m3 and the group with the highest exposure having an average annual exposure of 19 mcg/m3.
In total, researchers identified 83,674 Medicare beneficiaries with incident Parkinson’s disease, with 434 new cases per 100,000 people in the highest exposure group, compared with 359 new cases per 100,000 people in the lowest-exposure group. The relative risk for Parkinson’s disease increased in the highest quartile of PM2.5 by 25%, compared with the lowest quartile after adjusting for factors such as age, smoking status, and health care usage (95% confidence interval, 20%–29%).
The results showed the nationwide average annual PM2.5 was associated with incident Parkinson’s disease, and the Rocky Mountain region carried a strong association between PM2.5 and Parkson’s disease with a 16% increase in risk per level of exposure to PM2.5. While the Mississippi-Ohio River valley was also associated with Parkinson’s disease, there was a weaker association between PM2.5 and Parkinson’s disease, which the researchers attributed to a “ceiling effect” of PM2.5 between approximately 12-19 mcg/m3.
Dr. Krzyzanowski said that use of a large-population-based dataset and high-resolution location data were major strengths of the study. “Having this level of information leaves less room for uncertainty in our measures and analyses,” she said. “Our study also leveraged innovative geographic information systems which allowed us to refine local patterns of disease by using population behavior and demographic information (such as smoking and age) to ensure that we could provide the most accurate map representation available to date.”
A focus on air pollution
Existing research in examining the etiology of Parkinson’s mainly focused on exposure to pesticides,* Dr. Krzyzanowski explained, and “consists of studies using relatively small populations and low-resolution air pollution data.” Genetics is another possible cause, she noted, but only explains some Parkinson’s disease cases.
“Our work suggests that we should also be looking at air pollution as a contributor in the development of Parkinson’s disease,” she said.
Ray Dorsey, MD, professor of neurology at the University of Rochester (N.Y.), who was not involved with the study, said that evidence is mounting that “air pollution may be an important causal factor in Parkinson’s and especially Alzheimer’s disease.”
“This study by a well-regarded group of researchers adds epidemiological evidence for that association,” he said. Another strength is that the study was conducted in the United States, as many epidemiological studies evaluating air pollution and Parkinson’s disease have been performed outside the country because of “a dearth of reliable data sources.”
“This study, along with others, suggest that some of the important environmental toxicants tied to brain disease may be inhaled,” Dr. Dorsey said. “The nose may be the front door to the brain.”
Dr. Krzyzanowski said the next step in their research is further examination of different types of air pollution. “Air pollution contains a variety of toxic components which vary from region to region. Understanding the different components in air pollution and how they interact with climate, temperature, and topography could help explain the regional differences we observed.”
One potential limitation in the study is a lag between air pollution exposure and development of Parkinson’s disease, Dr. Dorsey noted.
“Here, it looks like (but I am not certain) that the investigators looked at current air pollution levels and new cases of Parkinson’s. Ideally, for incident cases of Parkinson’s disease, we would want to know historical data on exposure to air pollution,” he said.
Future studies should include prospective evaluation of adults as well as babies and children who have been exposed to both high and low levels of air pollution. That kind of study “would be incredibly valuable for determining the role of an important environmental toxicant in many brain diseases, including stroke, Alzheimer’s, and Parkinson’s,” he said.
Dr. Krzyzanowski and Dr. Dorsey reported no relevant financial disclosures. This study was supported by grants from the Department of Defense, the National Institute of Environmental Health Sciences, and The Michael J. Fox Foundation for Parkinson’s Research.
*Correction, 4/14/23: An earlier version of this article mischaracterized the disease that was the subject of this research.
FROM AAN 2023
Experts share early details prescribing avacopan for ANCA-associated vasculitis
When the Food and Drug Administration approved avacopan (Tavneos) as an adjunctive treatment for severe, active antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV) in October 2021, the oral complement C5a receptor inhibitor was hailed by its developer, ChemoCentryx, as a “new hope” for patients with the disease.
But avacopan’s novelty as a new drug for the rare diseases granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), coupled with its approval as an adjunctive to standard therapy, including glucocorticoids, rather than strictly as a glucocorticoid-sparing agent as it was tested, has so far led to little reported real-world experience with the drug.
In the phase 3 ADVOCATE trial, the pivotal trial that served as the basis for avacopan’s approval, 331 patients with active newly diagnosed or relapsing GPA or MPA received either avacopan or an oral prednisone taper over 20 weeks on a background of cyclophosphamide followed by azathioprine or rituximab. The results of the trial showed avacopan was noninferior to the group that received prednisone taper for remission at 26 weeks and superior to prednisone taper for sustained remission at 52 weeks, but the FDA was concerned that its complex design made it difficult to define the clinically meaningful benefit of avacopan and its role in the management of AAV.
The FDA noted that, in the avacopan arm of the trial, 86% of patients received glucocorticoids outside of the study protocol. Despite this, avacopan reduced the cumulative glucocorticoid dose over the trial’s 52 weeks by nearly two-thirds, compared with the prednisone group (1,349 mg vs. 3,655 mg).
The data also indicate a higher sustained remission rate at 52 weeks in patients who received induction with rituximab, compared with cyclophosphamide. But trial did not include a maintenance therapy dose of rituximab and is thereby not a good comparison against the standard of care, the FDA said. (ADVOCATE began enrolling patients prior to the FDA's 2018 approval of an expanded indication for patients with GPA or MPA who have achieved disease control after induction treatment.)
At the FDA’s Arthritis Advisory Committee meeting in May 2021, committee members were split on whether to recommend avacopan for approval. The committee voted 9-9 on whether the ADVOCATE trial showed efficacy supporting approval of avacopan, 10-8 in favor of whether the drug’s safety profile supported approval, and 10-8 in favor of the overall benefit-risk profile of avacopan for approval. But rather than give an indication to avacopan to reduce the use of glucocorticoids in adults with GPA or MPA, the agency approved avacopan as an adjunctive treatment for severe, active disease, noting in particular that avacopan “does not eliminate glucocorticoid use.”
The European Union’s marketing authorization for avacopan states its indication for use in combination with a rituximab or cyclophosphamide regimen for the treatment of adult patients with severe, active GPA or MPA and does not mention a role for reducing glucocorticoids. Avacopan will appear in forthcoming guidelines on management of AAV released by the European Alliance of Associations for Rheumatology.
In North America, the Canadian Vasculitis Research Network recently released an addendum to their guidelines on AAV specifically for avacopan, which includes recommendations to consider adding oral avacopan (30 mg twice daily) for induction of remission in patients with new or relapsing GPA or MPA who are also receiving cyclophosphamide or rituximab. The guidelines also recommend clinicians consider a glucocorticoid tapering schedule that aims for discontinuation at 4 weeks, and continuing avacopan for at least 1 year after induction therapy. The American College of Rheumatology guideline for AAV management, updated in 2021, acknowledges avacopan but did not consider its inclusion prior to FDA approval.
There have been few real-world studies of how patients with AAV are responding to avacopan, but recent studies from researchers in the Netherlands and in France have evaluated prednisone tapering and clinical outcomes.
Anisha B. Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago, said those real-world studies “seemed to re-enforce the findings from the ADVOCATE study demonstrating the efficacy of avacopan in severe disease with steroid-sparing effects.”
However, Carol Langford, MD, MHS, director of the Center for Vasculitis Care and Research at the Cleveland Clinic, emphasized caution is needed when drawing conclusions about avacopan use outside formal studies.
“We are all interested in what other settings this might be used. I think those are things that really require formal investigation to really try and understand better as far as through a study process,” she said.
Prescribing experience with avacopan
A spokesperson from Amgen, which recently acquired ChemoCentryx, said in an interview that over 800 physicians in the United States have prescribed avacopan to patients with new or relapsing ANCA-associated vasculitis as induction or maintenance treatment, and physicians have reported outcomes consistent with the ADVOCATE trial.
Many rheumatologists are likely familiar with avacopan but are not used to prescribing it, said Lindsay S. Lally, MD, a rheumatologist with Hospital for Special Surgery in New York.
“Rituximab was approved for GPA and MPA a decade ago at this point. It was a drug that we as rheumatologists were used to using. We used it for other indications. Avacopan is a totally new drug, a new mechanism of action, so there’s not a lot of extractable data that we have in terms of comfort with the drug, and so I think that’s one of the biggest hurdles,” she said.
Mehrnaz Hojjati, MD, a rheumatologist with Loma Linda (Calif.) University Health, said that, when the FDA approved avacopan, it was an “exciting time” in her practice. “I have used avacopan now in a handful of my patients with severe ANCA-associated vasculitis, and the results are similar to what [was] reported in the ADVOCATE trial.”
Amgen offers help for clinicians in obtaining avacopan for patients, financial assistance for patients, and support in navigating insurance, which several rheumatologists noted was important for patients. Dr. Langford said the process of working with the manufacturer to get avacopan while insurance information is being processed has been “fairly smooth.”
“Certainly, the ability to get a very rapid 30-day supply with the goal of trying to initiate this as early as possible in the disease process has been helpful,” she said.
In Dr. Dua’s experience, while there were “some glitches or difficulty for providers early on” in how to access and prescribe avacopan, since then “it has been much easier to obtain the medication with the first month being provided to patients free while the authorization process is managed.”
Prescribing avacopan from inpatient pharmacies has been more challenging, she said. “The inpatient side is trickier because each hospital system has their own pharmacy system and regulations that have to be navigated. For outpatients, all the provider needs to do is fill out the start form available on their website, have the patients sign it, and then have it sent in.”
Concerns about affordability, insurance approval
Another consideration is cost, with avacopan having an estimated price of $150,000-$200,000 per patient per year.
Dr. Hojjati noted that, while it is easy to prescribe, avacopan is hard to get approved through insurance. “We face the same challenge every time a new medication comes to the market on how to convince the payers to pay for it given higher prices,” she said.
Rheumatologist Michael Putman, MD, MSCI, assistant professor of medicine at the Medical College of Wisconsin, Milwaukee, also acknowledged some difficulties in prescribing the medication. “The insurance companies have no interest in spending $150,000 on a drug that they know nothing about, and patients are a little hesitant to take it because it’s just so new,” he said.
While Dr. Lally said avacopan has not been difficult to get for patients with commercial insurance, reimbursement through Medicare has been problematic. “In many of the Medicare patients it has not really been a feasible option for them to be on the drug for the year of therapy.”
Patient response
Dr. Dua said almost all her patients with new or relapsing AAV who require induction are being prescribed avacopan, and that the medication is well tolerated. “The remission and ability to wean prednisone has really paralleled the findings from the clinical trial.”
In her practice, Dr. Hojjati starts patients on avacopan immediately after discharge from the hospital after a major vasculitis flare requiring high-dose glucocorticoids. “Avacopan does not eliminate/replace GC [glucocorticoid] use but has a notable GC-sparing effect and assists in rapid tapering of the GC while treating our severe ANCA-associated vasculitis patients,” she said.
Dr. Lally said her patients are tolerating avacopan well and hasn’t seen any of the safety signals seen in the trial, including liver function abnormalities. She has treated about 20-25 patients with avacopan.
Dr. Putman noted that he has treated about five patients with avacopan but hasn’t seen dramatic efficacy or side effects in his practice, compared with standard therapy.
Unanswered questions about avacopan
A key unanswered question with avacopan is the timeline for tapering glucocorticoids once patients start treatment. “I would like to see much more data on how prednisone is being tapered in clinical practice as well as outcomes in patients who are treated with the standard of care second dose of rituximab at 6 months,” Dr. Dua said.
Dr. Lally noted she has tried to expedite the steroid taper in her patients. “That’s really where I feel this drug is going to have most relevance, is getting it started early in active disease and getting patients off of the reliance on high doses of oral steroids. I have been able to see that in practice, and I do think ultimately that’s going to lead to better outcomes and quality of life for these patients.”
Of the rheumatologists Dr. Lally has spoken to about avacopan, there is “some confusion about what type of patients are appropriate, [and] how sick or not sick the patient needs to be.”
Dr. Putman noted he is unsure which of his patients should be receiving avacopan. “I don’t totally have a sense for where avacopan stands and how often we should be using it” outside of patients with severe disease. He added that the drug is still trying to find a niche because most patients with AAV who take rituximab and steroids get better without additional treatments.
“I think we do a pretty good job treating these diseases even in the preavacopan era. But it’s really a matter of how to really optimize these outcomes, reduce damage, reduce steroid-related and treatment-related toxicity for our patients,” Dr. Lally said.
Dr. Dua reported being a consultant and serving on advisory boards for ChemoCentryx; she was also a site principal investigator for the ADVOCATE trial. Dr. Hojjati reported being on the speaker’s bureau for Amgen. Dr. Langford reported being an investigator in the ADVOCATE trial, and her institution received funding to conduct the trial. Dr. Lally reported being a consultant for Amgen on avacopan. Dr. Putman reported no relevant financial disclosures.
*This story was updated 3/15/2023.
When the Food and Drug Administration approved avacopan (Tavneos) as an adjunctive treatment for severe, active antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV) in October 2021, the oral complement C5a receptor inhibitor was hailed by its developer, ChemoCentryx, as a “new hope” for patients with the disease.
But avacopan’s novelty as a new drug for the rare diseases granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), coupled with its approval as an adjunctive to standard therapy, including glucocorticoids, rather than strictly as a glucocorticoid-sparing agent as it was tested, has so far led to little reported real-world experience with the drug.
In the phase 3 ADVOCATE trial, the pivotal trial that served as the basis for avacopan’s approval, 331 patients with active newly diagnosed or relapsing GPA or MPA received either avacopan or an oral prednisone taper over 20 weeks on a background of cyclophosphamide followed by azathioprine or rituximab. The results of the trial showed avacopan was noninferior to the group that received prednisone taper for remission at 26 weeks and superior to prednisone taper for sustained remission at 52 weeks, but the FDA was concerned that its complex design made it difficult to define the clinically meaningful benefit of avacopan and its role in the management of AAV.
The FDA noted that, in the avacopan arm of the trial, 86% of patients received glucocorticoids outside of the study protocol. Despite this, avacopan reduced the cumulative glucocorticoid dose over the trial’s 52 weeks by nearly two-thirds, compared with the prednisone group (1,349 mg vs. 3,655 mg).
The data also indicate a higher sustained remission rate at 52 weeks in patients who received induction with rituximab, compared with cyclophosphamide. But trial did not include a maintenance therapy dose of rituximab and is thereby not a good comparison against the standard of care, the FDA said. (ADVOCATE began enrolling patients prior to the FDA's 2018 approval of an expanded indication for patients with GPA or MPA who have achieved disease control after induction treatment.)
At the FDA’s Arthritis Advisory Committee meeting in May 2021, committee members were split on whether to recommend avacopan for approval. The committee voted 9-9 on whether the ADVOCATE trial showed efficacy supporting approval of avacopan, 10-8 in favor of whether the drug’s safety profile supported approval, and 10-8 in favor of the overall benefit-risk profile of avacopan for approval. But rather than give an indication to avacopan to reduce the use of glucocorticoids in adults with GPA or MPA, the agency approved avacopan as an adjunctive treatment for severe, active disease, noting in particular that avacopan “does not eliminate glucocorticoid use.”
The European Union’s marketing authorization for avacopan states its indication for use in combination with a rituximab or cyclophosphamide regimen for the treatment of adult patients with severe, active GPA or MPA and does not mention a role for reducing glucocorticoids. Avacopan will appear in forthcoming guidelines on management of AAV released by the European Alliance of Associations for Rheumatology.
In North America, the Canadian Vasculitis Research Network recently released an addendum to their guidelines on AAV specifically for avacopan, which includes recommendations to consider adding oral avacopan (30 mg twice daily) for induction of remission in patients with new or relapsing GPA or MPA who are also receiving cyclophosphamide or rituximab. The guidelines also recommend clinicians consider a glucocorticoid tapering schedule that aims for discontinuation at 4 weeks, and continuing avacopan for at least 1 year after induction therapy. The American College of Rheumatology guideline for AAV management, updated in 2021, acknowledges avacopan but did not consider its inclusion prior to FDA approval.
There have been few real-world studies of how patients with AAV are responding to avacopan, but recent studies from researchers in the Netherlands and in France have evaluated prednisone tapering and clinical outcomes.
Anisha B. Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago, said those real-world studies “seemed to re-enforce the findings from the ADVOCATE study demonstrating the efficacy of avacopan in severe disease with steroid-sparing effects.”
However, Carol Langford, MD, MHS, director of the Center for Vasculitis Care and Research at the Cleveland Clinic, emphasized caution is needed when drawing conclusions about avacopan use outside formal studies.
“We are all interested in what other settings this might be used. I think those are things that really require formal investigation to really try and understand better as far as through a study process,” she said.
Prescribing experience with avacopan
A spokesperson from Amgen, which recently acquired ChemoCentryx, said in an interview that over 800 physicians in the United States have prescribed avacopan to patients with new or relapsing ANCA-associated vasculitis as induction or maintenance treatment, and physicians have reported outcomes consistent with the ADVOCATE trial.
Many rheumatologists are likely familiar with avacopan but are not used to prescribing it, said Lindsay S. Lally, MD, a rheumatologist with Hospital for Special Surgery in New York.
“Rituximab was approved for GPA and MPA a decade ago at this point. It was a drug that we as rheumatologists were used to using. We used it for other indications. Avacopan is a totally new drug, a new mechanism of action, so there’s not a lot of extractable data that we have in terms of comfort with the drug, and so I think that’s one of the biggest hurdles,” she said.
Mehrnaz Hojjati, MD, a rheumatologist with Loma Linda (Calif.) University Health, said that, when the FDA approved avacopan, it was an “exciting time” in her practice. “I have used avacopan now in a handful of my patients with severe ANCA-associated vasculitis, and the results are similar to what [was] reported in the ADVOCATE trial.”
Amgen offers help for clinicians in obtaining avacopan for patients, financial assistance for patients, and support in navigating insurance, which several rheumatologists noted was important for patients. Dr. Langford said the process of working with the manufacturer to get avacopan while insurance information is being processed has been “fairly smooth.”
“Certainly, the ability to get a very rapid 30-day supply with the goal of trying to initiate this as early as possible in the disease process has been helpful,” she said.
In Dr. Dua’s experience, while there were “some glitches or difficulty for providers early on” in how to access and prescribe avacopan, since then “it has been much easier to obtain the medication with the first month being provided to patients free while the authorization process is managed.”
Prescribing avacopan from inpatient pharmacies has been more challenging, she said. “The inpatient side is trickier because each hospital system has their own pharmacy system and regulations that have to be navigated. For outpatients, all the provider needs to do is fill out the start form available on their website, have the patients sign it, and then have it sent in.”
Concerns about affordability, insurance approval
Another consideration is cost, with avacopan having an estimated price of $150,000-$200,000 per patient per year.
Dr. Hojjati noted that, while it is easy to prescribe, avacopan is hard to get approved through insurance. “We face the same challenge every time a new medication comes to the market on how to convince the payers to pay for it given higher prices,” she said.
Rheumatologist Michael Putman, MD, MSCI, assistant professor of medicine at the Medical College of Wisconsin, Milwaukee, also acknowledged some difficulties in prescribing the medication. “The insurance companies have no interest in spending $150,000 on a drug that they know nothing about, and patients are a little hesitant to take it because it’s just so new,” he said.
While Dr. Lally said avacopan has not been difficult to get for patients with commercial insurance, reimbursement through Medicare has been problematic. “In many of the Medicare patients it has not really been a feasible option for them to be on the drug for the year of therapy.”
Patient response
Dr. Dua said almost all her patients with new or relapsing AAV who require induction are being prescribed avacopan, and that the medication is well tolerated. “The remission and ability to wean prednisone has really paralleled the findings from the clinical trial.”
In her practice, Dr. Hojjati starts patients on avacopan immediately after discharge from the hospital after a major vasculitis flare requiring high-dose glucocorticoids. “Avacopan does not eliminate/replace GC [glucocorticoid] use but has a notable GC-sparing effect and assists in rapid tapering of the GC while treating our severe ANCA-associated vasculitis patients,” she said.
Dr. Lally said her patients are tolerating avacopan well and hasn’t seen any of the safety signals seen in the trial, including liver function abnormalities. She has treated about 20-25 patients with avacopan.
Dr. Putman noted that he has treated about five patients with avacopan but hasn’t seen dramatic efficacy or side effects in his practice, compared with standard therapy.
Unanswered questions about avacopan
A key unanswered question with avacopan is the timeline for tapering glucocorticoids once patients start treatment. “I would like to see much more data on how prednisone is being tapered in clinical practice as well as outcomes in patients who are treated with the standard of care second dose of rituximab at 6 months,” Dr. Dua said.
Dr. Lally noted she has tried to expedite the steroid taper in her patients. “That’s really where I feel this drug is going to have most relevance, is getting it started early in active disease and getting patients off of the reliance on high doses of oral steroids. I have been able to see that in practice, and I do think ultimately that’s going to lead to better outcomes and quality of life for these patients.”
Of the rheumatologists Dr. Lally has spoken to about avacopan, there is “some confusion about what type of patients are appropriate, [and] how sick or not sick the patient needs to be.”
Dr. Putman noted he is unsure which of his patients should be receiving avacopan. “I don’t totally have a sense for where avacopan stands and how often we should be using it” outside of patients with severe disease. He added that the drug is still trying to find a niche because most patients with AAV who take rituximab and steroids get better without additional treatments.
“I think we do a pretty good job treating these diseases even in the preavacopan era. But it’s really a matter of how to really optimize these outcomes, reduce damage, reduce steroid-related and treatment-related toxicity for our patients,” Dr. Lally said.
Dr. Dua reported being a consultant and serving on advisory boards for ChemoCentryx; she was also a site principal investigator for the ADVOCATE trial. Dr. Hojjati reported being on the speaker’s bureau for Amgen. Dr. Langford reported being an investigator in the ADVOCATE trial, and her institution received funding to conduct the trial. Dr. Lally reported being a consultant for Amgen on avacopan. Dr. Putman reported no relevant financial disclosures.
*This story was updated 3/15/2023.
When the Food and Drug Administration approved avacopan (Tavneos) as an adjunctive treatment for severe, active antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV) in October 2021, the oral complement C5a receptor inhibitor was hailed by its developer, ChemoCentryx, as a “new hope” for patients with the disease.
But avacopan’s novelty as a new drug for the rare diseases granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), coupled with its approval as an adjunctive to standard therapy, including glucocorticoids, rather than strictly as a glucocorticoid-sparing agent as it was tested, has so far led to little reported real-world experience with the drug.
In the phase 3 ADVOCATE trial, the pivotal trial that served as the basis for avacopan’s approval, 331 patients with active newly diagnosed or relapsing GPA or MPA received either avacopan or an oral prednisone taper over 20 weeks on a background of cyclophosphamide followed by azathioprine or rituximab. The results of the trial showed avacopan was noninferior to the group that received prednisone taper for remission at 26 weeks and superior to prednisone taper for sustained remission at 52 weeks, but the FDA was concerned that its complex design made it difficult to define the clinically meaningful benefit of avacopan and its role in the management of AAV.
The FDA noted that, in the avacopan arm of the trial, 86% of patients received glucocorticoids outside of the study protocol. Despite this, avacopan reduced the cumulative glucocorticoid dose over the trial’s 52 weeks by nearly two-thirds, compared with the prednisone group (1,349 mg vs. 3,655 mg).
The data also indicate a higher sustained remission rate at 52 weeks in patients who received induction with rituximab, compared with cyclophosphamide. But trial did not include a maintenance therapy dose of rituximab and is thereby not a good comparison against the standard of care, the FDA said. (ADVOCATE began enrolling patients prior to the FDA's 2018 approval of an expanded indication for patients with GPA or MPA who have achieved disease control after induction treatment.)
At the FDA’s Arthritis Advisory Committee meeting in May 2021, committee members were split on whether to recommend avacopan for approval. The committee voted 9-9 on whether the ADVOCATE trial showed efficacy supporting approval of avacopan, 10-8 in favor of whether the drug’s safety profile supported approval, and 10-8 in favor of the overall benefit-risk profile of avacopan for approval. But rather than give an indication to avacopan to reduce the use of glucocorticoids in adults with GPA or MPA, the agency approved avacopan as an adjunctive treatment for severe, active disease, noting in particular that avacopan “does not eliminate glucocorticoid use.”
The European Union’s marketing authorization for avacopan states its indication for use in combination with a rituximab or cyclophosphamide regimen for the treatment of adult patients with severe, active GPA or MPA and does not mention a role for reducing glucocorticoids. Avacopan will appear in forthcoming guidelines on management of AAV released by the European Alliance of Associations for Rheumatology.
In North America, the Canadian Vasculitis Research Network recently released an addendum to their guidelines on AAV specifically for avacopan, which includes recommendations to consider adding oral avacopan (30 mg twice daily) for induction of remission in patients with new or relapsing GPA or MPA who are also receiving cyclophosphamide or rituximab. The guidelines also recommend clinicians consider a glucocorticoid tapering schedule that aims for discontinuation at 4 weeks, and continuing avacopan for at least 1 year after induction therapy. The American College of Rheumatology guideline for AAV management, updated in 2021, acknowledges avacopan but did not consider its inclusion prior to FDA approval.
There have been few real-world studies of how patients with AAV are responding to avacopan, but recent studies from researchers in the Netherlands and in France have evaluated prednisone tapering and clinical outcomes.
Anisha B. Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago, said those real-world studies “seemed to re-enforce the findings from the ADVOCATE study demonstrating the efficacy of avacopan in severe disease with steroid-sparing effects.”
However, Carol Langford, MD, MHS, director of the Center for Vasculitis Care and Research at the Cleveland Clinic, emphasized caution is needed when drawing conclusions about avacopan use outside formal studies.
“We are all interested in what other settings this might be used. I think those are things that really require formal investigation to really try and understand better as far as through a study process,” she said.
Prescribing experience with avacopan
A spokesperson from Amgen, which recently acquired ChemoCentryx, said in an interview that over 800 physicians in the United States have prescribed avacopan to patients with new or relapsing ANCA-associated vasculitis as induction or maintenance treatment, and physicians have reported outcomes consistent with the ADVOCATE trial.
Many rheumatologists are likely familiar with avacopan but are not used to prescribing it, said Lindsay S. Lally, MD, a rheumatologist with Hospital for Special Surgery in New York.
“Rituximab was approved for GPA and MPA a decade ago at this point. It was a drug that we as rheumatologists were used to using. We used it for other indications. Avacopan is a totally new drug, a new mechanism of action, so there’s not a lot of extractable data that we have in terms of comfort with the drug, and so I think that’s one of the biggest hurdles,” she said.
Mehrnaz Hojjati, MD, a rheumatologist with Loma Linda (Calif.) University Health, said that, when the FDA approved avacopan, it was an “exciting time” in her practice. “I have used avacopan now in a handful of my patients with severe ANCA-associated vasculitis, and the results are similar to what [was] reported in the ADVOCATE trial.”
Amgen offers help for clinicians in obtaining avacopan for patients, financial assistance for patients, and support in navigating insurance, which several rheumatologists noted was important for patients. Dr. Langford said the process of working with the manufacturer to get avacopan while insurance information is being processed has been “fairly smooth.”
“Certainly, the ability to get a very rapid 30-day supply with the goal of trying to initiate this as early as possible in the disease process has been helpful,” she said.
In Dr. Dua’s experience, while there were “some glitches or difficulty for providers early on” in how to access and prescribe avacopan, since then “it has been much easier to obtain the medication with the first month being provided to patients free while the authorization process is managed.”
Prescribing avacopan from inpatient pharmacies has been more challenging, she said. “The inpatient side is trickier because each hospital system has their own pharmacy system and regulations that have to be navigated. For outpatients, all the provider needs to do is fill out the start form available on their website, have the patients sign it, and then have it sent in.”
Concerns about affordability, insurance approval
Another consideration is cost, with avacopan having an estimated price of $150,000-$200,000 per patient per year.
Dr. Hojjati noted that, while it is easy to prescribe, avacopan is hard to get approved through insurance. “We face the same challenge every time a new medication comes to the market on how to convince the payers to pay for it given higher prices,” she said.
Rheumatologist Michael Putman, MD, MSCI, assistant professor of medicine at the Medical College of Wisconsin, Milwaukee, also acknowledged some difficulties in prescribing the medication. “The insurance companies have no interest in spending $150,000 on a drug that they know nothing about, and patients are a little hesitant to take it because it’s just so new,” he said.
While Dr. Lally said avacopan has not been difficult to get for patients with commercial insurance, reimbursement through Medicare has been problematic. “In many of the Medicare patients it has not really been a feasible option for them to be on the drug for the year of therapy.”
Patient response
Dr. Dua said almost all her patients with new or relapsing AAV who require induction are being prescribed avacopan, and that the medication is well tolerated. “The remission and ability to wean prednisone has really paralleled the findings from the clinical trial.”
In her practice, Dr. Hojjati starts patients on avacopan immediately after discharge from the hospital after a major vasculitis flare requiring high-dose glucocorticoids. “Avacopan does not eliminate/replace GC [glucocorticoid] use but has a notable GC-sparing effect and assists in rapid tapering of the GC while treating our severe ANCA-associated vasculitis patients,” she said.
Dr. Lally said her patients are tolerating avacopan well and hasn’t seen any of the safety signals seen in the trial, including liver function abnormalities. She has treated about 20-25 patients with avacopan.
Dr. Putman noted that he has treated about five patients with avacopan but hasn’t seen dramatic efficacy or side effects in his practice, compared with standard therapy.
Unanswered questions about avacopan
A key unanswered question with avacopan is the timeline for tapering glucocorticoids once patients start treatment. “I would like to see much more data on how prednisone is being tapered in clinical practice as well as outcomes in patients who are treated with the standard of care second dose of rituximab at 6 months,” Dr. Dua said.
Dr. Lally noted she has tried to expedite the steroid taper in her patients. “That’s really where I feel this drug is going to have most relevance, is getting it started early in active disease and getting patients off of the reliance on high doses of oral steroids. I have been able to see that in practice, and I do think ultimately that’s going to lead to better outcomes and quality of life for these patients.”
Of the rheumatologists Dr. Lally has spoken to about avacopan, there is “some confusion about what type of patients are appropriate, [and] how sick or not sick the patient needs to be.”
Dr. Putman noted he is unsure which of his patients should be receiving avacopan. “I don’t totally have a sense for where avacopan stands and how often we should be using it” outside of patients with severe disease. He added that the drug is still trying to find a niche because most patients with AAV who take rituximab and steroids get better without additional treatments.
“I think we do a pretty good job treating these diseases even in the preavacopan era. But it’s really a matter of how to really optimize these outcomes, reduce damage, reduce steroid-related and treatment-related toxicity for our patients,” Dr. Lally said.
Dr. Dua reported being a consultant and serving on advisory boards for ChemoCentryx; she was also a site principal investigator for the ADVOCATE trial. Dr. Hojjati reported being on the speaker’s bureau for Amgen. Dr. Langford reported being an investigator in the ADVOCATE trial, and her institution received funding to conduct the trial. Dr. Lally reported being a consultant for Amgen on avacopan. Dr. Putman reported no relevant financial disclosures.
*This story was updated 3/15/2023.