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Erik Greb joined the staff of Neurology Reviews in January 2012. Since then, he has attended scientific conferences, conducted video interviews, and written about clinical research in multiple sclerosis, epilepsy, Parkinson's disease, Alzheimer's disease, stroke, and other neurologic disorders. In addition to news articles, Erik has written investigative stories about multiple sclerosis, headache, and epilepsy. He previously wrote about pharmaceutical manufacturing, drug formulation and delivery, quality assurance, and regulation for Pharmaceutical Technology.
How do neurologists choose an acute treatment for migraine?
STOWE, VT. – A large and growing number of medications is available for the acute treatment of migraine. Effective acute treatment enables patients to re-engage in their work and other daily activities, as well as reducing the likelihood that their disease will progress from episodic to chronic migraine. efficacy and tolerability according to Barbara L. Nye, MD, assistant professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H.. Dr. Nye discussed the acute treatment of migraine at the annual meeting of the Headache Cooperative of New England.
Choosing an initial treatment
Nonspecific medications are perhaps the first treatments to consider for a patient with acute migraine. This class includes NSAIDs such as naproxen sodium, piroxicam, diclofenac, celecoxib, and indomethacin. Emerging data indicate that some NSAIDs are associated with an increased risk of stroke, which is an important consideration as the population ages, said Dr. Nye. Other nonspecific options are neuroleptics such as prochlorperazine, metoclopramide, promethazine, and chlorpromazine. Many neuroleptics have sedative effects, however, so they do not necessarily help a patient return to function. Nevertheless, these drugs can be good rescue medications, said Dr. Nye.
Triptans are effective in the acute treatment of migraine, and seven drugs in this class are available. Most, such as rizatriptan, almotriptan, eletriptan, naratriptan, and frovatriptan, are available only as tablets. Other routes of delivery are available, however. Sumatriptan, for example, is available in injectable and intranasal formulations, and zolmitriptan is available as an orally dissolving tablet.
Another option to consider is dihydroergotamine (DHE), which has long been used for migraine. The injectable formulation of DHE can be cumbersome because it requires the patients with a headache to open a vial, draw the medication into a filter needle, and inject themselves, said Dr. Nye. “The nasal sprays that are available right now aren’t as effective as we’d like them to be,” she added. But overall, DHE is effective. Associated adverse events include flushing, nausea, and diarrhea.
Lasmiditan received approval from the Food and Drug Administration for the acute treatment of migraine in October 2019. Compared with placebo, the drug increases the likelihood of pain freedom and freedom from the most bothersome symptom at 2 hours. Driving tests indicated that patients were impaired for about 8 hours after treatment, and lasmiditan is a Schedule V drug. It is available in doses of 50 mg/day, 100 mg/day, and 200 mg/day.
The class of drugs known as the “gepants” provides further options. The most recently approved therapy in this class, which targets calcitonin gene–related peptide, is ubrogepant. Because the drug is metabolized through the CYP3A4 system, they are not appropriate for patients who use strong CYP3A4 inhibitors. The most common side effects are nausea, hypersensitivity reaction, and somnolence.
Neuromodulation can provide effective treatment without provoking side effects, said Dr. Nye. Options include transcutaneous supraorbital stimulation, single-pulse transcutaneous magnetic stimulation, noninvasive vagal nerve stimulation, and remote nonpainful stimulation.
If a patient presents during an acute attack, neurologists could consider using a nerve block. The latter may administer occipital nerve blocks, trigger point injections, auriculotemporal nerve blocks, and supraorbital and supratrochlear nerve blocks. This treatment can bring immediate relief, which is gratifying for patients and neurologists. But no consensus about which medications to use or how to administer them has been established. Neurologists most often use a combination of bupivacaine and lidocaine. Another possibility is a sphenopalatine ganglion nerve block, which requires treatment to be inserted through the nose. This treatment can be delivered in the office using the Sphenocath device or the Allevio device. Another device, the Tx360, is intended to enable patient self-administration.
Addressing treatment failure
If a patient returns and reports that the current treatment is ineffective, the neurologist must reevaluate the therapy. A helpful way to conduct this reassessment is to administer the Migraine Treatment Optimization Questionnaire (MTOQ), which was developed by Lipton et al., to the patient. Neurologists ask whether the patient can function normally 2 hours after treatment or whether the medication is, for example, causing a side effect that makes this outcome less likely. Other questions for the patient are whether the headache pain disappears within 2 hours and whether the medication provides consistent relief. Finally, the neurologist can ask whether the patient is comfortable taking the medication. A score lower than 2 on the MTOQ indicates that the acute treatment should be changed, said Dr. Nye.
Gastroparesis is common during migraine attacks. It is inadvisable to give an oral medication to a patient who vomits within 20 minutes of attack onset, said Dr. Nye. “It’s a little less intuitive for those people who are nauseous immediately to think that that oral tablet is probably going to sit in their stomach and not get absorbed in the intestines as intended.” Nasal sprays, injectable medicines, and oral dissolving tablets are appropriate options for patients with gastroparesis.
Treating migraine during pregnancy
Special consideration must be given to treatment when the patient is pregnant. Decreased headache frequency is common in pregnancy, but not universal. Occipital nerve blocks are a good option for prevention and acute management in pregnant patients. They may be administered every 2 weeks. Sphenopalatine ganglion nerve block is another option, and it can be administered several times per week. Data “suggest that stacking the injections 2 or 3 days per week for up to 6 weeks can eliminate headaches for up to 6 months,” said Dr. Nye.
Tylenol is appropriate for acute headache in pregnant patients, “but we do warn about medication overuse headache and limiting its use.” Ondansetron and promethazine are acceptable treatments for nausea. Although ondansetron has less central activity than promethazine, and thus does not reduce the headache, it lessens nausea, said Dr. Nye.
Triptan exposure during the first trimester is not significantly associated with major congenital malformations, which is reassuring, given that many patients take triptans before they realize that they are pregnant. During the second and third trimesters, triptan exposure is significantly associated with atonic uterus and increased blood loss during labor. In a 16-year registry, sumatriptan, naratriptan, and treximet were not associated with teratogenicity.
Nonpharmacological treatments, too, may help pregnant patients. Lifestyle management, including a regular sleep schedule, exercise routine, and diet, can be beneficial. Massage therapy may reduce stress, and cognitive-behavioral therapy and biofeedback are additional options. Behavioral therapy, however, should be initiated before the patient plans the pregnancy, said Dr. Nye. These therapies require training that a patient having an exacerbation of migraine is less likely to have the motivation to begin.
Many medications are transferred to infants through breast milk. The American Pediatric Association considers a relative infant dosing of less than 10% to be safe. A clinician or patient can look up a medication on websites such as LactMed to understand the relative infant dose and possible effects. Another helpful reference is Medications and Mothers’ Milk, said Dr. Nye. Acetaminophen, steroids, ibuprofen, riboflavin, indomethacin, ketorolac, and naproxen are generally safe during lactation. “Eletriptan is the triptan that’s least likely to be in the breast milk,” said Dr. Nye. Aspirin, atenolol, ergotamine, and lithium, however, should be given with caution. The safety of amitriptyline, nortriptyline, and SSRIs during lactation is unknown.
Dr. Nye is on advisory boards for Alder, Allergan, Biohaven, electroCore, Pernix, and Xoc.
STOWE, VT. – A large and growing number of medications is available for the acute treatment of migraine. Effective acute treatment enables patients to re-engage in their work and other daily activities, as well as reducing the likelihood that their disease will progress from episodic to chronic migraine. efficacy and tolerability according to Barbara L. Nye, MD, assistant professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H.. Dr. Nye discussed the acute treatment of migraine at the annual meeting of the Headache Cooperative of New England.
Choosing an initial treatment
Nonspecific medications are perhaps the first treatments to consider for a patient with acute migraine. This class includes NSAIDs such as naproxen sodium, piroxicam, diclofenac, celecoxib, and indomethacin. Emerging data indicate that some NSAIDs are associated with an increased risk of stroke, which is an important consideration as the population ages, said Dr. Nye. Other nonspecific options are neuroleptics such as prochlorperazine, metoclopramide, promethazine, and chlorpromazine. Many neuroleptics have sedative effects, however, so they do not necessarily help a patient return to function. Nevertheless, these drugs can be good rescue medications, said Dr. Nye.
Triptans are effective in the acute treatment of migraine, and seven drugs in this class are available. Most, such as rizatriptan, almotriptan, eletriptan, naratriptan, and frovatriptan, are available only as tablets. Other routes of delivery are available, however. Sumatriptan, for example, is available in injectable and intranasal formulations, and zolmitriptan is available as an orally dissolving tablet.
Another option to consider is dihydroergotamine (DHE), which has long been used for migraine. The injectable formulation of DHE can be cumbersome because it requires the patients with a headache to open a vial, draw the medication into a filter needle, and inject themselves, said Dr. Nye. “The nasal sprays that are available right now aren’t as effective as we’d like them to be,” she added. But overall, DHE is effective. Associated adverse events include flushing, nausea, and diarrhea.
Lasmiditan received approval from the Food and Drug Administration for the acute treatment of migraine in October 2019. Compared with placebo, the drug increases the likelihood of pain freedom and freedom from the most bothersome symptom at 2 hours. Driving tests indicated that patients were impaired for about 8 hours after treatment, and lasmiditan is a Schedule V drug. It is available in doses of 50 mg/day, 100 mg/day, and 200 mg/day.
The class of drugs known as the “gepants” provides further options. The most recently approved therapy in this class, which targets calcitonin gene–related peptide, is ubrogepant. Because the drug is metabolized through the CYP3A4 system, they are not appropriate for patients who use strong CYP3A4 inhibitors. The most common side effects are nausea, hypersensitivity reaction, and somnolence.
Neuromodulation can provide effective treatment without provoking side effects, said Dr. Nye. Options include transcutaneous supraorbital stimulation, single-pulse transcutaneous magnetic stimulation, noninvasive vagal nerve stimulation, and remote nonpainful stimulation.
If a patient presents during an acute attack, neurologists could consider using a nerve block. The latter may administer occipital nerve blocks, trigger point injections, auriculotemporal nerve blocks, and supraorbital and supratrochlear nerve blocks. This treatment can bring immediate relief, which is gratifying for patients and neurologists. But no consensus about which medications to use or how to administer them has been established. Neurologists most often use a combination of bupivacaine and lidocaine. Another possibility is a sphenopalatine ganglion nerve block, which requires treatment to be inserted through the nose. This treatment can be delivered in the office using the Sphenocath device or the Allevio device. Another device, the Tx360, is intended to enable patient self-administration.
Addressing treatment failure
If a patient returns and reports that the current treatment is ineffective, the neurologist must reevaluate the therapy. A helpful way to conduct this reassessment is to administer the Migraine Treatment Optimization Questionnaire (MTOQ), which was developed by Lipton et al., to the patient. Neurologists ask whether the patient can function normally 2 hours after treatment or whether the medication is, for example, causing a side effect that makes this outcome less likely. Other questions for the patient are whether the headache pain disappears within 2 hours and whether the medication provides consistent relief. Finally, the neurologist can ask whether the patient is comfortable taking the medication. A score lower than 2 on the MTOQ indicates that the acute treatment should be changed, said Dr. Nye.
Gastroparesis is common during migraine attacks. It is inadvisable to give an oral medication to a patient who vomits within 20 minutes of attack onset, said Dr. Nye. “It’s a little less intuitive for those people who are nauseous immediately to think that that oral tablet is probably going to sit in their stomach and not get absorbed in the intestines as intended.” Nasal sprays, injectable medicines, and oral dissolving tablets are appropriate options for patients with gastroparesis.
Treating migraine during pregnancy
Special consideration must be given to treatment when the patient is pregnant. Decreased headache frequency is common in pregnancy, but not universal. Occipital nerve blocks are a good option for prevention and acute management in pregnant patients. They may be administered every 2 weeks. Sphenopalatine ganglion nerve block is another option, and it can be administered several times per week. Data “suggest that stacking the injections 2 or 3 days per week for up to 6 weeks can eliminate headaches for up to 6 months,” said Dr. Nye.
Tylenol is appropriate for acute headache in pregnant patients, “but we do warn about medication overuse headache and limiting its use.” Ondansetron and promethazine are acceptable treatments for nausea. Although ondansetron has less central activity than promethazine, and thus does not reduce the headache, it lessens nausea, said Dr. Nye.
Triptan exposure during the first trimester is not significantly associated with major congenital malformations, which is reassuring, given that many patients take triptans before they realize that they are pregnant. During the second and third trimesters, triptan exposure is significantly associated with atonic uterus and increased blood loss during labor. In a 16-year registry, sumatriptan, naratriptan, and treximet were not associated with teratogenicity.
Nonpharmacological treatments, too, may help pregnant patients. Lifestyle management, including a regular sleep schedule, exercise routine, and diet, can be beneficial. Massage therapy may reduce stress, and cognitive-behavioral therapy and biofeedback are additional options. Behavioral therapy, however, should be initiated before the patient plans the pregnancy, said Dr. Nye. These therapies require training that a patient having an exacerbation of migraine is less likely to have the motivation to begin.
Many medications are transferred to infants through breast milk. The American Pediatric Association considers a relative infant dosing of less than 10% to be safe. A clinician or patient can look up a medication on websites such as LactMed to understand the relative infant dose and possible effects. Another helpful reference is Medications and Mothers’ Milk, said Dr. Nye. Acetaminophen, steroids, ibuprofen, riboflavin, indomethacin, ketorolac, and naproxen are generally safe during lactation. “Eletriptan is the triptan that’s least likely to be in the breast milk,” said Dr. Nye. Aspirin, atenolol, ergotamine, and lithium, however, should be given with caution. The safety of amitriptyline, nortriptyline, and SSRIs during lactation is unknown.
Dr. Nye is on advisory boards for Alder, Allergan, Biohaven, electroCore, Pernix, and Xoc.
STOWE, VT. – A large and growing number of medications is available for the acute treatment of migraine. Effective acute treatment enables patients to re-engage in their work and other daily activities, as well as reducing the likelihood that their disease will progress from episodic to chronic migraine. efficacy and tolerability according to Barbara L. Nye, MD, assistant professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H.. Dr. Nye discussed the acute treatment of migraine at the annual meeting of the Headache Cooperative of New England.
Choosing an initial treatment
Nonspecific medications are perhaps the first treatments to consider for a patient with acute migraine. This class includes NSAIDs such as naproxen sodium, piroxicam, diclofenac, celecoxib, and indomethacin. Emerging data indicate that some NSAIDs are associated with an increased risk of stroke, which is an important consideration as the population ages, said Dr. Nye. Other nonspecific options are neuroleptics such as prochlorperazine, metoclopramide, promethazine, and chlorpromazine. Many neuroleptics have sedative effects, however, so they do not necessarily help a patient return to function. Nevertheless, these drugs can be good rescue medications, said Dr. Nye.
Triptans are effective in the acute treatment of migraine, and seven drugs in this class are available. Most, such as rizatriptan, almotriptan, eletriptan, naratriptan, and frovatriptan, are available only as tablets. Other routes of delivery are available, however. Sumatriptan, for example, is available in injectable and intranasal formulations, and zolmitriptan is available as an orally dissolving tablet.
Another option to consider is dihydroergotamine (DHE), which has long been used for migraine. The injectable formulation of DHE can be cumbersome because it requires the patients with a headache to open a vial, draw the medication into a filter needle, and inject themselves, said Dr. Nye. “The nasal sprays that are available right now aren’t as effective as we’d like them to be,” she added. But overall, DHE is effective. Associated adverse events include flushing, nausea, and diarrhea.
Lasmiditan received approval from the Food and Drug Administration for the acute treatment of migraine in October 2019. Compared with placebo, the drug increases the likelihood of pain freedom and freedom from the most bothersome symptom at 2 hours. Driving tests indicated that patients were impaired for about 8 hours after treatment, and lasmiditan is a Schedule V drug. It is available in doses of 50 mg/day, 100 mg/day, and 200 mg/day.
The class of drugs known as the “gepants” provides further options. The most recently approved therapy in this class, which targets calcitonin gene–related peptide, is ubrogepant. Because the drug is metabolized through the CYP3A4 system, they are not appropriate for patients who use strong CYP3A4 inhibitors. The most common side effects are nausea, hypersensitivity reaction, and somnolence.
Neuromodulation can provide effective treatment without provoking side effects, said Dr. Nye. Options include transcutaneous supraorbital stimulation, single-pulse transcutaneous magnetic stimulation, noninvasive vagal nerve stimulation, and remote nonpainful stimulation.
If a patient presents during an acute attack, neurologists could consider using a nerve block. The latter may administer occipital nerve blocks, trigger point injections, auriculotemporal nerve blocks, and supraorbital and supratrochlear nerve blocks. This treatment can bring immediate relief, which is gratifying for patients and neurologists. But no consensus about which medications to use or how to administer them has been established. Neurologists most often use a combination of bupivacaine and lidocaine. Another possibility is a sphenopalatine ganglion nerve block, which requires treatment to be inserted through the nose. This treatment can be delivered in the office using the Sphenocath device or the Allevio device. Another device, the Tx360, is intended to enable patient self-administration.
Addressing treatment failure
If a patient returns and reports that the current treatment is ineffective, the neurologist must reevaluate the therapy. A helpful way to conduct this reassessment is to administer the Migraine Treatment Optimization Questionnaire (MTOQ), which was developed by Lipton et al., to the patient. Neurologists ask whether the patient can function normally 2 hours after treatment or whether the medication is, for example, causing a side effect that makes this outcome less likely. Other questions for the patient are whether the headache pain disappears within 2 hours and whether the medication provides consistent relief. Finally, the neurologist can ask whether the patient is comfortable taking the medication. A score lower than 2 on the MTOQ indicates that the acute treatment should be changed, said Dr. Nye.
Gastroparesis is common during migraine attacks. It is inadvisable to give an oral medication to a patient who vomits within 20 minutes of attack onset, said Dr. Nye. “It’s a little less intuitive for those people who are nauseous immediately to think that that oral tablet is probably going to sit in their stomach and not get absorbed in the intestines as intended.” Nasal sprays, injectable medicines, and oral dissolving tablets are appropriate options for patients with gastroparesis.
Treating migraine during pregnancy
Special consideration must be given to treatment when the patient is pregnant. Decreased headache frequency is common in pregnancy, but not universal. Occipital nerve blocks are a good option for prevention and acute management in pregnant patients. They may be administered every 2 weeks. Sphenopalatine ganglion nerve block is another option, and it can be administered several times per week. Data “suggest that stacking the injections 2 or 3 days per week for up to 6 weeks can eliminate headaches for up to 6 months,” said Dr. Nye.
Tylenol is appropriate for acute headache in pregnant patients, “but we do warn about medication overuse headache and limiting its use.” Ondansetron and promethazine are acceptable treatments for nausea. Although ondansetron has less central activity than promethazine, and thus does not reduce the headache, it lessens nausea, said Dr. Nye.
Triptan exposure during the first trimester is not significantly associated with major congenital malformations, which is reassuring, given that many patients take triptans before they realize that they are pregnant. During the second and third trimesters, triptan exposure is significantly associated with atonic uterus and increased blood loss during labor. In a 16-year registry, sumatriptan, naratriptan, and treximet were not associated with teratogenicity.
Nonpharmacological treatments, too, may help pregnant patients. Lifestyle management, including a regular sleep schedule, exercise routine, and diet, can be beneficial. Massage therapy may reduce stress, and cognitive-behavioral therapy and biofeedback are additional options. Behavioral therapy, however, should be initiated before the patient plans the pregnancy, said Dr. Nye. These therapies require training that a patient having an exacerbation of migraine is less likely to have the motivation to begin.
Many medications are transferred to infants through breast milk. The American Pediatric Association considers a relative infant dosing of less than 10% to be safe. A clinician or patient can look up a medication on websites such as LactMed to understand the relative infant dose and possible effects. Another helpful reference is Medications and Mothers’ Milk, said Dr. Nye. Acetaminophen, steroids, ibuprofen, riboflavin, indomethacin, ketorolac, and naproxen are generally safe during lactation. “Eletriptan is the triptan that’s least likely to be in the breast milk,” said Dr. Nye. Aspirin, atenolol, ergotamine, and lithium, however, should be given with caution. The safety of amitriptyline, nortriptyline, and SSRIs during lactation is unknown.
Dr. Nye is on advisory boards for Alder, Allergan, Biohaven, electroCore, Pernix, and Xoc.
REPORTING FROM HCNE 2020
Database will collect data on COVID-19 in patients with MS
The COViMS (COVID-19 Infections in Multiple Sclerosis and Related Diseases) database is gathering information from patients throughout the United States and will soon gain access to Canadian data. Data from patients with CNS demyelinating diseases such as neuromyelitis optica and myelin oligodendrocyte glycoprotein antibody diseases also will be included in COViMS. Amber Salter, PhD, MPH, the director of the North American Research Committee on MS (NARCOMS) is supervising the data collection and analyses.
“COViMS will provide valuable insight on how COVID-19 affects people with MS, including if certain disease-modifying treatments incur special risks,” said June Halper, CEO of CMSC, in a press release.
The project began when CMSC and NMSS established independent registries of epidemiologic data related to MS and COVID-19. The two groups soon began communicating and included other researchers, who also were considering establishing registries, in their discussions. In addition, representatives of the Cleveland Clinic verbally agreed to share data that they have been collecting with the COViMS registry. “The fast-moving, almost parallel, efforts led to this collaboration,” said Gary Cutter, PhD, professor of biostatistics at the University of Alabama at Birmingham. “This in itself is noteworthy because all of this took place within an incredibly short time from inception to the initiation of data collection.”
The effects of SARS-CoV-2 infection on the health of patients with MS is little understood. In North America, no reporting system had been organized to gather information on these patients and track outcomes. Such a system could influence the treatment of people with MS who become infected with the novel coronavirus or other similar future viruses. The COViMS registry is intended to define the impact of COVID-19 on patients with MS and ascertain how factors such as age, comorbidities, and MS treatments affect outcomes of COVID-19. “The estimated median age of MS patients in the U.S. is about 52 years, thus putting many at increased risk just due to age,” said Dr. Cutter.
“People with MS and their health care providers need evidence-based guidance to provide optimal MS care during the COVID-19 pandemic, and the COViMS database will help answer the many pressing questions,” said Bruce Bebo, executive vice president of research for the NMSS, in a press release.
The two organizations encourage neurologists and other health care providers who treat patients with MS and documented COVID-19 infection to complete a Case Report Form on the COViMS website, which includes answers to frequently asked questions, a sample CRF, and other resources. The website will provide real-time data once registry participation is underway.
The COViMS (COVID-19 Infections in Multiple Sclerosis and Related Diseases) database is gathering information from patients throughout the United States and will soon gain access to Canadian data. Data from patients with CNS demyelinating diseases such as neuromyelitis optica and myelin oligodendrocyte glycoprotein antibody diseases also will be included in COViMS. Amber Salter, PhD, MPH, the director of the North American Research Committee on MS (NARCOMS) is supervising the data collection and analyses.
“COViMS will provide valuable insight on how COVID-19 affects people with MS, including if certain disease-modifying treatments incur special risks,” said June Halper, CEO of CMSC, in a press release.
The project began when CMSC and NMSS established independent registries of epidemiologic data related to MS and COVID-19. The two groups soon began communicating and included other researchers, who also were considering establishing registries, in their discussions. In addition, representatives of the Cleveland Clinic verbally agreed to share data that they have been collecting with the COViMS registry. “The fast-moving, almost parallel, efforts led to this collaboration,” said Gary Cutter, PhD, professor of biostatistics at the University of Alabama at Birmingham. “This in itself is noteworthy because all of this took place within an incredibly short time from inception to the initiation of data collection.”
The effects of SARS-CoV-2 infection on the health of patients with MS is little understood. In North America, no reporting system had been organized to gather information on these patients and track outcomes. Such a system could influence the treatment of people with MS who become infected with the novel coronavirus or other similar future viruses. The COViMS registry is intended to define the impact of COVID-19 on patients with MS and ascertain how factors such as age, comorbidities, and MS treatments affect outcomes of COVID-19. “The estimated median age of MS patients in the U.S. is about 52 years, thus putting many at increased risk just due to age,” said Dr. Cutter.
“People with MS and their health care providers need evidence-based guidance to provide optimal MS care during the COVID-19 pandemic, and the COViMS database will help answer the many pressing questions,” said Bruce Bebo, executive vice president of research for the NMSS, in a press release.
The two organizations encourage neurologists and other health care providers who treat patients with MS and documented COVID-19 infection to complete a Case Report Form on the COViMS website, which includes answers to frequently asked questions, a sample CRF, and other resources. The website will provide real-time data once registry participation is underway.
The COViMS (COVID-19 Infections in Multiple Sclerosis and Related Diseases) database is gathering information from patients throughout the United States and will soon gain access to Canadian data. Data from patients with CNS demyelinating diseases such as neuromyelitis optica and myelin oligodendrocyte glycoprotein antibody diseases also will be included in COViMS. Amber Salter, PhD, MPH, the director of the North American Research Committee on MS (NARCOMS) is supervising the data collection and analyses.
“COViMS will provide valuable insight on how COVID-19 affects people with MS, including if certain disease-modifying treatments incur special risks,” said June Halper, CEO of CMSC, in a press release.
The project began when CMSC and NMSS established independent registries of epidemiologic data related to MS and COVID-19. The two groups soon began communicating and included other researchers, who also were considering establishing registries, in their discussions. In addition, representatives of the Cleveland Clinic verbally agreed to share data that they have been collecting with the COViMS registry. “The fast-moving, almost parallel, efforts led to this collaboration,” said Gary Cutter, PhD, professor of biostatistics at the University of Alabama at Birmingham. “This in itself is noteworthy because all of this took place within an incredibly short time from inception to the initiation of data collection.”
The effects of SARS-CoV-2 infection on the health of patients with MS is little understood. In North America, no reporting system had been organized to gather information on these patients and track outcomes. Such a system could influence the treatment of people with MS who become infected with the novel coronavirus or other similar future viruses. The COViMS registry is intended to define the impact of COVID-19 on patients with MS and ascertain how factors such as age, comorbidities, and MS treatments affect outcomes of COVID-19. “The estimated median age of MS patients in the U.S. is about 52 years, thus putting many at increased risk just due to age,” said Dr. Cutter.
“People with MS and their health care providers need evidence-based guidance to provide optimal MS care during the COVID-19 pandemic, and the COViMS database will help answer the many pressing questions,” said Bruce Bebo, executive vice president of research for the NMSS, in a press release.
The two organizations encourage neurologists and other health care providers who treat patients with MS and documented COVID-19 infection to complete a Case Report Form on the COViMS website, which includes answers to frequently asked questions, a sample CRF, and other resources. The website will provide real-time data once registry participation is underway.
American Lung Association announces $25 million initiative to end COVID-19
The goals of the COVID-19 Action Initiative will be to expand the ALA’s respiratory research program, improve public health measures, and create an advanced network to prevent future respiratory virus pandemics. In cooperation with the public and private sectors, the initiative will promote research collaboration and develop new vaccines, diagnostic tests, and therapies. The initiative will take advantage of the ALA’s current research network and will also fund respiratory virus research. It also will fund education and advocacy to support public health measures against current and future respiratory viruses.
The COVID-19 Action Initiative will fund respiratory virus research through three main activities. It will expand COVID-19 research within the current clinical trials of the Airways Clinical Research Center (ACRC) Network. Second, it will fund coronavirus awards and grants for preventive research, vaccines, antivirals, and efforts to promote preparedness for future outbreaks. Third, it will provide ACRC pilot grants to evaluate the effect of COVID-19 on patients with chronic lung disease.
“More than 36 million people in the U.S. suffer from lung disease, which places them at higher risk for experiencing complications of COVID-19, making it even more critical that we urgently work on reducing its impact,” said Harold Wimmer, president and CEO of the ALA, in a press release.
The ALA has $8 million available and earmarked for the initiative. The association plans to raise additional funds during the next 3 years by reaching out to corporate partners, public health entities, and individuals. “With the help of our staff and volunteers, and with the support and donations of generous Americans, we can stand together and face the challenges to lung health of today and tomorrow,” said Mr. Wimmer in a press briefing.
The goals of the COVID-19 Action Initiative will be to expand the ALA’s respiratory research program, improve public health measures, and create an advanced network to prevent future respiratory virus pandemics. In cooperation with the public and private sectors, the initiative will promote research collaboration and develop new vaccines, diagnostic tests, and therapies. The initiative will take advantage of the ALA’s current research network and will also fund respiratory virus research. It also will fund education and advocacy to support public health measures against current and future respiratory viruses.
The COVID-19 Action Initiative will fund respiratory virus research through three main activities. It will expand COVID-19 research within the current clinical trials of the Airways Clinical Research Center (ACRC) Network. Second, it will fund coronavirus awards and grants for preventive research, vaccines, antivirals, and efforts to promote preparedness for future outbreaks. Third, it will provide ACRC pilot grants to evaluate the effect of COVID-19 on patients with chronic lung disease.
“More than 36 million people in the U.S. suffer from lung disease, which places them at higher risk for experiencing complications of COVID-19, making it even more critical that we urgently work on reducing its impact,” said Harold Wimmer, president and CEO of the ALA, in a press release.
The ALA has $8 million available and earmarked for the initiative. The association plans to raise additional funds during the next 3 years by reaching out to corporate partners, public health entities, and individuals. “With the help of our staff and volunteers, and with the support and donations of generous Americans, we can stand together and face the challenges to lung health of today and tomorrow,” said Mr. Wimmer in a press briefing.
The goals of the COVID-19 Action Initiative will be to expand the ALA’s respiratory research program, improve public health measures, and create an advanced network to prevent future respiratory virus pandemics. In cooperation with the public and private sectors, the initiative will promote research collaboration and develop new vaccines, diagnostic tests, and therapies. The initiative will take advantage of the ALA’s current research network and will also fund respiratory virus research. It also will fund education and advocacy to support public health measures against current and future respiratory viruses.
The COVID-19 Action Initiative will fund respiratory virus research through three main activities. It will expand COVID-19 research within the current clinical trials of the Airways Clinical Research Center (ACRC) Network. Second, it will fund coronavirus awards and grants for preventive research, vaccines, antivirals, and efforts to promote preparedness for future outbreaks. Third, it will provide ACRC pilot grants to evaluate the effect of COVID-19 on patients with chronic lung disease.
“More than 36 million people in the U.S. suffer from lung disease, which places them at higher risk for experiencing complications of COVID-19, making it even more critical that we urgently work on reducing its impact,” said Harold Wimmer, president and CEO of the ALA, in a press release.
The ALA has $8 million available and earmarked for the initiative. The association plans to raise additional funds during the next 3 years by reaching out to corporate partners, public health entities, and individuals. “With the help of our staff and volunteers, and with the support and donations of generous Americans, we can stand together and face the challenges to lung health of today and tomorrow,” said Mr. Wimmer in a press briefing.
Amid coronavirus concerns, researchers urge mental health interventions for patients with dementia
according to a letter published online ahead of print March 30 in Lancet. Consistent with recommendations from Alzheimer’s Disease International and other dementia experts, teams that include mental health professionals, social workers, nursing home administrators, and volunteers should collaborate to provide mental health care for people with dementia. Experts in dementia should lead each team and support team members from other disciplines, wrote Huali Wang, MD, chair of clinical research at Peking University Institute of Mental Health in Beijing, and colleagues.
Interventions could be administered through telehealth, said the authors. Teams led by mental health professionals could use electronic media to provide self-help guidance for reducing stress, such as relaxation or meditation exercise. These teams also could use telephone hotlines to support behavioral management, and psychological counselors could provide online consultations for caregivers in nursing homes or in the community. “We encourage people who have a parent with dementia to have more frequent contact or spend more time with their parent, or to take on some of the caregiving duties so as to give the carer some respite time,” wrote Dr. Wang and colleagues.
Many local authorities are banning visits to nursing home residents to reduce the latter’s risk of COVID-19 infection. As a consequence, these elderly people are becoming more isolated, and anxiety is increasing among nursing home staffs.
In China, five organizations, including the Chinese Society of Geriatric Psychiatry and Alzheimer’s Disease Chinese, responded to the COVID-19 outbreak by publishing recommendations for providing mental health and psychosocial support. Groups of providers from various disciplines offered free counseling services for people with dementia and their caregivers. “These approaches minimized the complex impact of both COVID-19 outbreak and dementia,” wrote the authors.
“China has contained the epidemic, and business is starting to return to normal,” they continued. “We believe that learning lessons from China would empower the world to tackle the COVID-19 pandemic, with little risk of compromising the quality of life of people living with dementia and their carers.”
Dr. Wang has received lecture fees from Eisai China and Lundbeck China. She owns the copyright for the neuropsychiatric symptoms individualized management system. Her coauthors reported serving as advisory board members and receiving fees from companies such as Biogen, Novartis, and Genentech.
SOURCE: Wang H et al. Lancet. 2020 Mar 30. doi: 10.1016/S0140-6736(20)30755-8.
according to a letter published online ahead of print March 30 in Lancet. Consistent with recommendations from Alzheimer’s Disease International and other dementia experts, teams that include mental health professionals, social workers, nursing home administrators, and volunteers should collaborate to provide mental health care for people with dementia. Experts in dementia should lead each team and support team members from other disciplines, wrote Huali Wang, MD, chair of clinical research at Peking University Institute of Mental Health in Beijing, and colleagues.
Interventions could be administered through telehealth, said the authors. Teams led by mental health professionals could use electronic media to provide self-help guidance for reducing stress, such as relaxation or meditation exercise. These teams also could use telephone hotlines to support behavioral management, and psychological counselors could provide online consultations for caregivers in nursing homes or in the community. “We encourage people who have a parent with dementia to have more frequent contact or spend more time with their parent, or to take on some of the caregiving duties so as to give the carer some respite time,” wrote Dr. Wang and colleagues.
Many local authorities are banning visits to nursing home residents to reduce the latter’s risk of COVID-19 infection. As a consequence, these elderly people are becoming more isolated, and anxiety is increasing among nursing home staffs.
In China, five organizations, including the Chinese Society of Geriatric Psychiatry and Alzheimer’s Disease Chinese, responded to the COVID-19 outbreak by publishing recommendations for providing mental health and psychosocial support. Groups of providers from various disciplines offered free counseling services for people with dementia and their caregivers. “These approaches minimized the complex impact of both COVID-19 outbreak and dementia,” wrote the authors.
“China has contained the epidemic, and business is starting to return to normal,” they continued. “We believe that learning lessons from China would empower the world to tackle the COVID-19 pandemic, with little risk of compromising the quality of life of people living with dementia and their carers.”
Dr. Wang has received lecture fees from Eisai China and Lundbeck China. She owns the copyright for the neuropsychiatric symptoms individualized management system. Her coauthors reported serving as advisory board members and receiving fees from companies such as Biogen, Novartis, and Genentech.
SOURCE: Wang H et al. Lancet. 2020 Mar 30. doi: 10.1016/S0140-6736(20)30755-8.
according to a letter published online ahead of print March 30 in Lancet. Consistent with recommendations from Alzheimer’s Disease International and other dementia experts, teams that include mental health professionals, social workers, nursing home administrators, and volunteers should collaborate to provide mental health care for people with dementia. Experts in dementia should lead each team and support team members from other disciplines, wrote Huali Wang, MD, chair of clinical research at Peking University Institute of Mental Health in Beijing, and colleagues.
Interventions could be administered through telehealth, said the authors. Teams led by mental health professionals could use electronic media to provide self-help guidance for reducing stress, such as relaxation or meditation exercise. These teams also could use telephone hotlines to support behavioral management, and psychological counselors could provide online consultations for caregivers in nursing homes or in the community. “We encourage people who have a parent with dementia to have more frequent contact or spend more time with their parent, or to take on some of the caregiving duties so as to give the carer some respite time,” wrote Dr. Wang and colleagues.
Many local authorities are banning visits to nursing home residents to reduce the latter’s risk of COVID-19 infection. As a consequence, these elderly people are becoming more isolated, and anxiety is increasing among nursing home staffs.
In China, five organizations, including the Chinese Society of Geriatric Psychiatry and Alzheimer’s Disease Chinese, responded to the COVID-19 outbreak by publishing recommendations for providing mental health and psychosocial support. Groups of providers from various disciplines offered free counseling services for people with dementia and their caregivers. “These approaches minimized the complex impact of both COVID-19 outbreak and dementia,” wrote the authors.
“China has contained the epidemic, and business is starting to return to normal,” they continued. “We believe that learning lessons from China would empower the world to tackle the COVID-19 pandemic, with little risk of compromising the quality of life of people living with dementia and their carers.”
Dr. Wang has received lecture fees from Eisai China and Lundbeck China. She owns the copyright for the neuropsychiatric symptoms individualized management system. Her coauthors reported serving as advisory board members and receiving fees from companies such as Biogen, Novartis, and Genentech.
SOURCE: Wang H et al. Lancet. 2020 Mar 30. doi: 10.1016/S0140-6736(20)30755-8.
REPORTING FROM THE LANCET
When is preventive treatment of migraine appropriate?
STOWE, VT – , said Rebecca Burch, MD, staff attending neurologist at Brigham and Women’s Hospital in Boston. Clinical observation suggests that preventive treatment provides benefits for appropriately selected migraineurs, although few data confirm a modifying effect on disease course, she said at the Stowe Headache Symposium sponsored by the Headache Cooperative of New England. In her overview, Dr. Burch discussed when preventive treatment is appropriate, which patients are candidates for preventive therapy, and what the levels of evidence are for the preventive therapies. 
Identifying candidates for preventive treatment
Migraine is the second most disabling condition worldwide and imposes a large social and economic burden, said Dr. Burch. Preventive therapy reduces the disability associated with migraine. It reduces headache frequency and, thus, the risk that episodic migraine will transform into chronic migraine. By reducing the number of headache days, preventive treatment also may reduce the overuse of acute medication, which is a risk factor for migraine chronification.
Neurologists can consider preventive therapy for migraineurs with frequent headaches, but the term “frequent” is not clearly defined. Common definitions include one headache per week and two headaches per month with significant disability. These definitions are based on expert consensus and do not have strong evidential support, said Dr. Burch. Preventive therapy also may be appropriate for migraineurs who overuse acute medication or who have failed acute medications. Special cases, such as patients with exceptional anxiety or disability, may also call for preventive treatment, said Dr. Burch.
Data suggest that preventive treatment for migraine is underused. The American Migraine Prevalence and Prevention study of 2007 found that half of patients who should be offered preventive treatment are currently receiving it. In 2016, the Chronic Migraine Epidemiology and Outcomes study found that 4.5% of chronic migraineurs take both acute and preventive treatment.
Other data published in Cephalalgia in 2015 indicate that adherence to migraine preventive treatment is approximately 20%. About 45% of patients discontinue medication because of side effects, and 45% cite lack of efficacy as their reason for discontinuation. Patients also mentioned cost, interactions with other medications, and the inconvenience of daily medication as other reasons for discontinuation.
Neurologists can take several steps to increase adherence to preventive treatment, said Dr. Burch. First, neurologists should confirm that patients want preventive medication. A clear discussion of the goals of preventive treatment is helpful as well. Furthermore, neurologists should explain that they are offering patients a trial, said Dr. Burch. The medication can be titrated slowly from a low dose to minimize side effects. Patients can be reassured that ineffective medications will be stopped. Neurologists can emphasize that their relationship with the patient is a partnership and that the treatment strategy will be improved over time.
Examining the evidence on treatments’ efficacy
Many drug classes, such as antiepileptics, antidepressants, beta blockers, neurotoxins, and calcitonin gene-related peptide (CGRP) antibodies, include therapies that are used as preventive treatments for migraine. When selecting a medication, a neurologist should start with one that is supported by Level A or Level B evidence, said Dr. Burch. Medications with Level A evidence include divalproex, topiramate, metoprolol, propranolol, erenumab, galcanezumab, fremanezumab, eptinezumab, and onabotulinumtoxinA. Medications with Level B evidence include amitriptyline, venlafaxine, memantine, lisinopril, and candesartan. Neurologists sometimes prescribe gabapentin and verapamil, although the evidence for them is Level U. Duloxetine, nortriptyline, and pregabalin also are used, but the evidence for them has not been evaluated. “We need more evidence in these areas,” said Dr. Burch.
Neurologists should consider access (e.g., cost and insurance coverage), efficacy, side effects, and comorbidities and contraindications when choosing a preventive therapy, she added. Verapamil and memantine are well tolerated and appropriate choices if the goal is to avoid side effects in general. If weight gain or fatigue is a concern, then topiramate and venlafaxine should be considered. Neurologists should avoid prescribing antiepileptic drugs if cognitive symptoms are a concern, said Dr. Burch. Beta blockers and venlafaxine would be better options in this case.
In clinical trials of CGRP therapies, the rates of adverse events were similar between the active and control arms. “But it’s become fairly clear that the clinical trials did not fully capture the side-effect profile that we are seeing in clinical practice,” said Dr. Burch. In a paper currently in review, she and her colleagues retrospectively studied 241 patients that they had treated with CGRP monoclonal antibodies at their headache center. The most common adverse events were constipation (43%), injection-site reaction (24%), muscle or joint pain (17%), and fatigue (15%). Furthermore, CGRP antagonists were associated with maternal hypertension, fetal growth restriction, and fetal mortality in animal studies. The current recommendation is to avoid CGRP monoclonal antibodies during pregnancy or in any patient who is at risk of becoming pregnant, said Dr. Burch.
How should neurologists assess preventive efficacy?
The assessment of a medication’s preventive efficacy “is a moving target in the headache world,” said Dr. Burch. “Historically, we have used headache days per month, and that is still, according to the International Headache Society clinical trials guidelines, how we should be judging whether a medication is working or not. But that doesn’t necessarily tell us what’s going to happen to an individual patient in front of us.”
In 2017, the Institute for Clinical Effectiveness Research compared data for old and new migraine treatments in a network meta-analysis. They all tended to reduce the number of monthly migraine days by one to two, compared with placebo. When one analyzes clinical trials of the drugs using this criterion, “most of these treatments come out about the same,” said Dr. Burch.
More recently, investigators have examined responder rates. They commonly report the proportions of patients who had a reduction in headache days of 50%, 75%, or 100%, for example. To extrapolate responder rates from the trial participants to the general population, a neurologist must know which groups of patients got worse on treatment, said Dr. Burch. Furthermore, the responder rates for older medications are unknown, because they were not examined. This situation makes comparisons of newer and older therapies more complicated.
Phase 3 trials of the CGRP drugs included analyses of the therapies’ 50% responder rates. This rate was about 42% for the 70-mg dose of erenumab and 50% for the 140-mg dose. The 50% responder rates for fremanezumab were 47.7% for the 225-mg dose and 44.4% for the 675-mg dose. In two trials of galcanezumab, the 50% responder rate for the 120-mg dose was approximately 60%, and the rate for the 240-mg dose was about 59%. The 50% responder rates for eptinezumab were 50% for the 100-mg dose and 56% for the 300-mg dose. The 50% responder rate across all trials was around 50%-60% in the active group, which is roughly 25% over the placebo group, said Dr. Burch.
Another measurement of efficacy is the efficacy-to-harm ratio, which is derived from the number needed to treat and the number needed to harm. To calculate this ratio, however, harm needs to be assessed adequately during a clinical trial. Although the ratio can provide a clinically relevant overview of a drug’s effects, patients may differ from each other in the way they evaluate efficacy and harm.
In addition, many questions about preventive treatment of migraine have no clear answers yet. It is uncertain, for example, how long a patient should receive preventive treatment and when treatment should be withdrawn, said Dr. Burch. “Can we expect that a lot of people are going to need to be on it for life, or is there a subpopulation who will get better and [for whom] we can withdraw [treatment]?” she asked. “How do we identify them?” Also, more data are needed before neurologists can understand why a given patient responds to one treatment, but not to another. It is difficult to predict which patients will respond to which treatments. Finally, it remains unclear how much of patients’ improvement can be attributed to regression to the mean, rather than preventive treatment.
STOWE, VT – , said Rebecca Burch, MD, staff attending neurologist at Brigham and Women’s Hospital in Boston. Clinical observation suggests that preventive treatment provides benefits for appropriately selected migraineurs, although few data confirm a modifying effect on disease course, she said at the Stowe Headache Symposium sponsored by the Headache Cooperative of New England. In her overview, Dr. Burch discussed when preventive treatment is appropriate, which patients are candidates for preventive therapy, and what the levels of evidence are for the preventive therapies.
Identifying candidates for preventive treatment
Migraine is the second most disabling condition worldwide and imposes a large social and economic burden, said Dr. Burch. Preventive therapy reduces the disability associated with migraine. It reduces headache frequency and, thus, the risk that episodic migraine will transform into chronic migraine. By reducing the number of headache days, preventive treatment also may reduce the overuse of acute medication, which is a risk factor for migraine chronification.
Neurologists can consider preventive therapy for migraineurs with frequent headaches, but the term “frequent” is not clearly defined. Common definitions include one headache per week and two headaches per month with significant disability. These definitions are based on expert consensus and do not have strong evidential support, said Dr. Burch. Preventive therapy also may be appropriate for migraineurs who overuse acute medication or who have failed acute medications. Special cases, such as patients with exceptional anxiety or disability, may also call for preventive treatment, said Dr. Burch.
Data suggest that preventive treatment for migraine is underused. The American Migraine Prevalence and Prevention study of 2007 found that half of patients who should be offered preventive treatment are currently receiving it. In 2016, the Chronic Migraine Epidemiology and Outcomes study found that 4.5% of chronic migraineurs take both acute and preventive treatment.
Other data published in Cephalalgia in 2015 indicate that adherence to migraine preventive treatment is approximately 20%. About 45% of patients discontinue medication because of side effects, and 45% cite lack of efficacy as their reason for discontinuation. Patients also mentioned cost, interactions with other medications, and the inconvenience of daily medication as other reasons for discontinuation.
Neurologists can take several steps to increase adherence to preventive treatment, said Dr. Burch. First, neurologists should confirm that patients want preventive medication. A clear discussion of the goals of preventive treatment is helpful as well. Furthermore, neurologists should explain that they are offering patients a trial, said Dr. Burch. The medication can be titrated slowly from a low dose to minimize side effects. Patients can be reassured that ineffective medications will be stopped. Neurologists can emphasize that their relationship with the patient is a partnership and that the treatment strategy will be improved over time.
Examining the evidence on treatments’ efficacy
Many drug classes, such as antiepileptics, antidepressants, beta blockers, neurotoxins, and calcitonin gene-related peptide (CGRP) antibodies, include therapies that are used as preventive treatments for migraine. When selecting a medication, a neurologist should start with one that is supported by Level A or Level B evidence, said Dr. Burch. Medications with Level A evidence include divalproex, topiramate, metoprolol, propranolol, erenumab, galcanezumab, fremanezumab, eptinezumab, and onabotulinumtoxinA. Medications with Level B evidence include amitriptyline, venlafaxine, memantine, lisinopril, and candesartan. Neurologists sometimes prescribe gabapentin and verapamil, although the evidence for them is Level U. Duloxetine, nortriptyline, and pregabalin also are used, but the evidence for them has not been evaluated. “We need more evidence in these areas,” said Dr. Burch.
Neurologists should consider access (e.g., cost and insurance coverage), efficacy, side effects, and comorbidities and contraindications when choosing a preventive therapy, she added. Verapamil and memantine are well tolerated and appropriate choices if the goal is to avoid side effects in general. If weight gain or fatigue is a concern, then topiramate and venlafaxine should be considered. Neurologists should avoid prescribing antiepileptic drugs if cognitive symptoms are a concern, said Dr. Burch. Beta blockers and venlafaxine would be better options in this case.
In clinical trials of CGRP therapies, the rates of adverse events were similar between the active and control arms. “But it’s become fairly clear that the clinical trials did not fully capture the side-effect profile that we are seeing in clinical practice,” said Dr. Burch. In a paper currently in review, she and her colleagues retrospectively studied 241 patients that they had treated with CGRP monoclonal antibodies at their headache center. The most common adverse events were constipation (43%), injection-site reaction (24%), muscle or joint pain (17%), and fatigue (15%). Furthermore, CGRP antagonists were associated with maternal hypertension, fetal growth restriction, and fetal mortality in animal studies. The current recommendation is to avoid CGRP monoclonal antibodies during pregnancy or in any patient who is at risk of becoming pregnant, said Dr. Burch.
How should neurologists assess preventive efficacy?
The assessment of a medication’s preventive efficacy “is a moving target in the headache world,” said Dr. Burch. “Historically, we have used headache days per month, and that is still, according to the International Headache Society clinical trials guidelines, how we should be judging whether a medication is working or not. But that doesn’t necessarily tell us what’s going to happen to an individual patient in front of us.”
In 2017, the Institute for Clinical Effectiveness Research compared data for old and new migraine treatments in a network meta-analysis. They all tended to reduce the number of monthly migraine days by one to two, compared with placebo. When one analyzes clinical trials of the drugs using this criterion, “most of these treatments come out about the same,” said Dr. Burch.
More recently, investigators have examined responder rates. They commonly report the proportions of patients who had a reduction in headache days of 50%, 75%, or 100%, for example. To extrapolate responder rates from the trial participants to the general population, a neurologist must know which groups of patients got worse on treatment, said Dr. Burch. Furthermore, the responder rates for older medications are unknown, because they were not examined. This situation makes comparisons of newer and older therapies more complicated.
Phase 3 trials of the CGRP drugs included analyses of the therapies’ 50% responder rates. This rate was about 42% for the 70-mg dose of erenumab and 50% for the 140-mg dose. The 50% responder rates for fremanezumab were 47.7% for the 225-mg dose and 44.4% for the 675-mg dose. In two trials of galcanezumab, the 50% responder rate for the 120-mg dose was approximately 60%, and the rate for the 240-mg dose was about 59%. The 50% responder rates for eptinezumab were 50% for the 100-mg dose and 56% for the 300-mg dose. The 50% responder rate across all trials was around 50%-60% in the active group, which is roughly 25% over the placebo group, said Dr. Burch.
Another measurement of efficacy is the efficacy-to-harm ratio, which is derived from the number needed to treat and the number needed to harm. To calculate this ratio, however, harm needs to be assessed adequately during a clinical trial. Although the ratio can provide a clinically relevant overview of a drug’s effects, patients may differ from each other in the way they evaluate efficacy and harm.
In addition, many questions about preventive treatment of migraine have no clear answers yet. It is uncertain, for example, how long a patient should receive preventive treatment and when treatment should be withdrawn, said Dr. Burch. “Can we expect that a lot of people are going to need to be on it for life, or is there a subpopulation who will get better and [for whom] we can withdraw [treatment]?” she asked. “How do we identify them?” Also, more data are needed before neurologists can understand why a given patient responds to one treatment, but not to another. It is difficult to predict which patients will respond to which treatments. Finally, it remains unclear how much of patients’ improvement can be attributed to regression to the mean, rather than preventive treatment.
STOWE, VT – , said Rebecca Burch, MD, staff attending neurologist at Brigham and Women’s Hospital in Boston. Clinical observation suggests that preventive treatment provides benefits for appropriately selected migraineurs, although few data confirm a modifying effect on disease course, she said at the Stowe Headache Symposium sponsored by the Headache Cooperative of New England. In her overview, Dr. Burch discussed when preventive treatment is appropriate, which patients are candidates for preventive therapy, and what the levels of evidence are for the preventive therapies.
Identifying candidates for preventive treatment
Migraine is the second most disabling condition worldwide and imposes a large social and economic burden, said Dr. Burch. Preventive therapy reduces the disability associated with migraine. It reduces headache frequency and, thus, the risk that episodic migraine will transform into chronic migraine. By reducing the number of headache days, preventive treatment also may reduce the overuse of acute medication, which is a risk factor for migraine chronification.
Neurologists can consider preventive therapy for migraineurs with frequent headaches, but the term “frequent” is not clearly defined. Common definitions include one headache per week and two headaches per month with significant disability. These definitions are based on expert consensus and do not have strong evidential support, said Dr. Burch. Preventive therapy also may be appropriate for migraineurs who overuse acute medication or who have failed acute medications. Special cases, such as patients with exceptional anxiety or disability, may also call for preventive treatment, said Dr. Burch.
Data suggest that preventive treatment for migraine is underused. The American Migraine Prevalence and Prevention study of 2007 found that half of patients who should be offered preventive treatment are currently receiving it. In 2016, the Chronic Migraine Epidemiology and Outcomes study found that 4.5% of chronic migraineurs take both acute and preventive treatment.
Other data published in Cephalalgia in 2015 indicate that adherence to migraine preventive treatment is approximately 20%. About 45% of patients discontinue medication because of side effects, and 45% cite lack of efficacy as their reason for discontinuation. Patients also mentioned cost, interactions with other medications, and the inconvenience of daily medication as other reasons for discontinuation.
Neurologists can take several steps to increase adherence to preventive treatment, said Dr. Burch. First, neurologists should confirm that patients want preventive medication. A clear discussion of the goals of preventive treatment is helpful as well. Furthermore, neurologists should explain that they are offering patients a trial, said Dr. Burch. The medication can be titrated slowly from a low dose to minimize side effects. Patients can be reassured that ineffective medications will be stopped. Neurologists can emphasize that their relationship with the patient is a partnership and that the treatment strategy will be improved over time.
Examining the evidence on treatments’ efficacy
Many drug classes, such as antiepileptics, antidepressants, beta blockers, neurotoxins, and calcitonin gene-related peptide (CGRP) antibodies, include therapies that are used as preventive treatments for migraine. When selecting a medication, a neurologist should start with one that is supported by Level A or Level B evidence, said Dr. Burch. Medications with Level A evidence include divalproex, topiramate, metoprolol, propranolol, erenumab, galcanezumab, fremanezumab, eptinezumab, and onabotulinumtoxinA. Medications with Level B evidence include amitriptyline, venlafaxine, memantine, lisinopril, and candesartan. Neurologists sometimes prescribe gabapentin and verapamil, although the evidence for them is Level U. Duloxetine, nortriptyline, and pregabalin also are used, but the evidence for them has not been evaluated. “We need more evidence in these areas,” said Dr. Burch.
Neurologists should consider access (e.g., cost and insurance coverage), efficacy, side effects, and comorbidities and contraindications when choosing a preventive therapy, she added. Verapamil and memantine are well tolerated and appropriate choices if the goal is to avoid side effects in general. If weight gain or fatigue is a concern, then topiramate and venlafaxine should be considered. Neurologists should avoid prescribing antiepileptic drugs if cognitive symptoms are a concern, said Dr. Burch. Beta blockers and venlafaxine would be better options in this case.
In clinical trials of CGRP therapies, the rates of adverse events were similar between the active and control arms. “But it’s become fairly clear that the clinical trials did not fully capture the side-effect profile that we are seeing in clinical practice,” said Dr. Burch. In a paper currently in review, she and her colleagues retrospectively studied 241 patients that they had treated with CGRP monoclonal antibodies at their headache center. The most common adverse events were constipation (43%), injection-site reaction (24%), muscle or joint pain (17%), and fatigue (15%). Furthermore, CGRP antagonists were associated with maternal hypertension, fetal growth restriction, and fetal mortality in animal studies. The current recommendation is to avoid CGRP monoclonal antibodies during pregnancy or in any patient who is at risk of becoming pregnant, said Dr. Burch.
How should neurologists assess preventive efficacy?
The assessment of a medication’s preventive efficacy “is a moving target in the headache world,” said Dr. Burch. “Historically, we have used headache days per month, and that is still, according to the International Headache Society clinical trials guidelines, how we should be judging whether a medication is working or not. But that doesn’t necessarily tell us what’s going to happen to an individual patient in front of us.”
In 2017, the Institute for Clinical Effectiveness Research compared data for old and new migraine treatments in a network meta-analysis. They all tended to reduce the number of monthly migraine days by one to two, compared with placebo. When one analyzes clinical trials of the drugs using this criterion, “most of these treatments come out about the same,” said Dr. Burch.
More recently, investigators have examined responder rates. They commonly report the proportions of patients who had a reduction in headache days of 50%, 75%, or 100%, for example. To extrapolate responder rates from the trial participants to the general population, a neurologist must know which groups of patients got worse on treatment, said Dr. Burch. Furthermore, the responder rates for older medications are unknown, because they were not examined. This situation makes comparisons of newer and older therapies more complicated.
Phase 3 trials of the CGRP drugs included analyses of the therapies’ 50% responder rates. This rate was about 42% for the 70-mg dose of erenumab and 50% for the 140-mg dose. The 50% responder rates for fremanezumab were 47.7% for the 225-mg dose and 44.4% for the 675-mg dose. In two trials of galcanezumab, the 50% responder rate for the 120-mg dose was approximately 60%, and the rate for the 240-mg dose was about 59%. The 50% responder rates for eptinezumab were 50% for the 100-mg dose and 56% for the 300-mg dose. The 50% responder rate across all trials was around 50%-60% in the active group, which is roughly 25% over the placebo group, said Dr. Burch.
Another measurement of efficacy is the efficacy-to-harm ratio, which is derived from the number needed to treat and the number needed to harm. To calculate this ratio, however, harm needs to be assessed adequately during a clinical trial. Although the ratio can provide a clinically relevant overview of a drug’s effects, patients may differ from each other in the way they evaluate efficacy and harm.
In addition, many questions about preventive treatment of migraine have no clear answers yet. It is uncertain, for example, how long a patient should receive preventive treatment and when treatment should be withdrawn, said Dr. Burch. “Can we expect that a lot of people are going to need to be on it for life, or is there a subpopulation who will get better and [for whom] we can withdraw [treatment]?” she asked. “How do we identify them?” Also, more data are needed before neurologists can understand why a given patient responds to one treatment, but not to another. It is difficult to predict which patients will respond to which treatments. Finally, it remains unclear how much of patients’ improvement can be attributed to regression to the mean, rather than preventive treatment.
REPORTING FROM HCNE STOWE 2020
How can neurologists diagnose and treat menstrual migraine?
STOWE, VT. – , said Susan Hutchinson, MD, director of the Orange County Migraine and Headache Center in Irvine, Calif. Compared with headaches associated with nonmenstrual migraine, headaches resulting from menstrual migraine last longer and are more difficult to treat. They tend to be associated with morning awakening and with nausea and vomiting. But in younger women with regular menses, menstrual migraine is predictable. The disorder offers “an incredible chance to be preemptive and think about short-term preventive strategies,” Dr. Hutchinson said at the annual meeting of the Headache Cooperative of New England.
What is menstrual migraine?
Menstrual migraine occurs during the perimenstrual window, which begins at 2 days before onset of bleeding and ends at 3 days of menses. Migraine that occurs during this window at least two-thirds of the time satisfies the criteria for menstrual migraine. A prospective headache diary is recommended, but not required, for making the diagnosis, said Dr. Hutchinson.
Most women with migraine have perimenstrual exacerbation of their headaches, as well as headaches at other times of the month. This phenotype is called menstrually related migraine. Pure menstrual migraine is migraine associated exclusively with menses. The International Classification of Headache Disorders-3 recognizes that menstrual migraine can be with or without aura. A headache diary can help distinguish between menstrual migraine and menstrually related migraine.
For pure menstrual migraine, it is appropriate to treat during the perimenstrual window. Preventive treatment may not be necessary throughout the month, said Dr. Hutchinson. Furthermore, hormonal treatment is the type of therapy most likely to be effective, she added. Menstrually related migraine requires a broader approach.
Gathering information during the visit
A 1972 study by Somerville and colleagues indicated that a decrease in estrogen is a powerful trigger of migraine. The investigators administered estrogen (i.e., intramuscular estradiol) or progesterone during the late luteal phase to women with menstrual migraine. Among women who received estrogen, migraine onset was postponed until the estrogen level decreased. The administration of progesterone postponed bleeding, but did not affect migraine. Progesterone treatment prevents migraine effectively on occasion, but estrogen treatment is much more likely to be a successful strategy, said Dr. Hutchinson.
Neurologists should ask certain questions of women with migraine, whether the patients are new or not, to gather information needed to make treatment decisions. For example, it is advisable to ask a woman whether she often has a headache with her period. “You may not want to use the word ‘migraine,’ because many women have been taught that headache is part of PMS,” said Dr. Hutchinson. Asking a woman how pregnancy, delivery, and breastfeeding affected her headaches can add further detail to her history and provide insight about the effects of hormonal changes. Asking what type of birth control the woman is taking can influence the choice of treatment, since some therapies are not appropriate during pregnancy.
Available treatments
NSAIDs are among the treatments that neurologists should consider for the short-term prevention of menstrually related migraine, said Dr. Hutchinson. A study of 35 patients by Sances et al. compared placebo with 550 mg of naproxen sodium given twice daily. Treatment began at 7 days before bleeding onset and continued until the 6th day of menses. Patients underwent treatment for three menstrual cycles. Naproxen sodium significantly reduced headache intensity, headache duration, and the number of headache days, compared with baseline. Treatment was superior to placebo at 3 months. Approximately 33% of patients in the active group were headache free, but no controls were.
Magnesium is another potentially effective option. Facchinetti et al. compared placebo with 360 mg/day of magnesium in a study of 20 patients. Treatment, which was given for two cycles, began at 15 days before menses and ended at the start of menses. Compared with placebo, magnesium reduced the number of headache days and the total pain index. Magnesium is inexpensive, but it causes diarrhea in some patients. “Some women choose to take magnesium all month long, other women start at around ovulation,” said Dr. Hutchinson.
Hormonal treatments are another possible option for the short-term prevention of menstrually related migraine. For women who do not plan to become pregnant, oral contraceptive pills can keep estrogen levels high enough to prevent menstrually related migraine. Gynecologists may suggest that a woman take the pill continuously, skipping the placebo, for an entire year, but Dr. Hutchinson recommends that a woman stop taking the pill for 4 days approximately every 3 months. This discontinuation allows for withdrawal bleeding, but is not likely to cause a prolonged enough decrease in estrogen to provoke migraine, she said. The continuous contraceptive ring, which is inserted vaginally, is an alternative to the pill.
For women who do not want or need contraception, an estrogen patch or gel may be appropriate. Two studies in the 1980s found that a gel containing 1.5 mg of estradiol per 2.5 g reduced migraine frequency, duration, and severity. These studies did not gather long-term safety data, however. A 2006 study by MacGregor et al. found that percutaneous estradiol was associated with a 22% reduction in the number of migraine days, as well as with decreases in headache severity and associated nausea. But the risk of migraine during the 5 days following treatment cessation was increased by 40%. This finding suggests that the treatment period should be extended, said Dr. Hutchinson.
In addition to the timing, the dose of treatment affects the outcome. Smite et al. found no benefit of a 50-mcg dose of estradiol, compared with placebo. Pradalier and colleagues found that a 100-mcg dose was associated with decreased use of rescue medication, compared with a 25-mcg dose. These studies did not gather long-term safety data.
Oral contraceptives and the risk of stroke
Combined oral contraceptives, however, are associated with increased risk of stroke in women with migraine with aura. The dose of estrogen in the contraceptive affects the level of risk, said Dr. Hutchinson. A systematic review by Sheikh et al. found that high-dose ethinyl estradiol (i.e., greater than 50 mcg) was associated with a higher risk of ischemic and hemorrhagic stroke than low-dose ethinyl estradiol (i.e., less than 50 mcg) was. A 20-mcg dose was associated with an odds ratio of stroke of 1.7. Furthermore, among women using combined hormonal contraception, the risk of stroke was higher in women with aura than in women without aura.
“I like to look at the big picture,” said Dr. Hutchinson. “There’s a big difference between a woman who has one or two auras a year that last for 10 minutes and a woman who has complicated aura. I’m going to approach [the latter] woman differently.”
No consensus guidelines for prescribing combined oral contraceptives to women with migraine and aura have been developed. The International Headache Society says that physicians may prescribe low-dose estrogen to women with simple visual aura. The American College of Obstetricians and Gynecologists recommends progestin-only intrauterine or barrier contraception for this population. The World Health Organization holds that estrogen-containing contraception is contraindicated in all women who have migraine with aura.
“If you have women who have migraine without aura, low–estrogen dose combined hormonal contraceptives can be quite appropriate,” said Dr. Hutchinson. “I would tend to go with a 10- or 20-mcg low dose. It could be an option for women with migraine with aura, but only if the benefits outweigh the risks.” In a study by Calhoun et al., the vaginal ring was associated with reduced aura frequency in women with migraine and aura.
Choosing preventive and rescue medications
Although no triptan has FDA approval for the short-term prevention of menstrual migraine, studies have suggested that they are effective. In a study by Sances and colleagues, a twice-daily 1-mg dose of naratriptan taken 6 days perimenstrually reduced the frequency of menstrual-related migraine. At least 50% of treated patients in the study had no menstrual-related migraine. Silberstein and colleagues found that 59% of women who took 2.5 mg of frovatriptan twice daily had no menstrual-related migraine during the 6-day perimenstrual period, compared with 33% of women who received placebo.
Patients with menstrual migraine sometimes need rescue medication. Sumatriptan, either as an injection or an inhaled therapy, is one option. Another injectable option is a 60-mg intramuscular dose of ketorolac. Finally, occipital or sphenopalatine nerve block may be effective as well.
Dr. Hutchinson reported consulting for or serving on the advisory board of Alder, Allergan, Amgen, Biohaven, electroCore, Lilly, Novartis, Supernus, Teva, Theranica, and Upsher-Smith. She has served on speakers bureaus for Allergan, Amgen, electroCore, Lilly, Novartis, Supernus, and Teva.
STOWE, VT. – , said Susan Hutchinson, MD, director of the Orange County Migraine and Headache Center in Irvine, Calif. Compared with headaches associated with nonmenstrual migraine, headaches resulting from menstrual migraine last longer and are more difficult to treat. They tend to be associated with morning awakening and with nausea and vomiting. But in younger women with regular menses, menstrual migraine is predictable. The disorder offers “an incredible chance to be preemptive and think about short-term preventive strategies,” Dr. Hutchinson said at the annual meeting of the Headache Cooperative of New England.
What is menstrual migraine?
Menstrual migraine occurs during the perimenstrual window, which begins at 2 days before onset of bleeding and ends at 3 days of menses. Migraine that occurs during this window at least two-thirds of the time satisfies the criteria for menstrual migraine. A prospective headache diary is recommended, but not required, for making the diagnosis, said Dr. Hutchinson.
Most women with migraine have perimenstrual exacerbation of their headaches, as well as headaches at other times of the month. This phenotype is called menstrually related migraine. Pure menstrual migraine is migraine associated exclusively with menses. The International Classification of Headache Disorders-3 recognizes that menstrual migraine can be with or without aura. A headache diary can help distinguish between menstrual migraine and menstrually related migraine.
For pure menstrual migraine, it is appropriate to treat during the perimenstrual window. Preventive treatment may not be necessary throughout the month, said Dr. Hutchinson. Furthermore, hormonal treatment is the type of therapy most likely to be effective, she added. Menstrually related migraine requires a broader approach.
Gathering information during the visit
A 1972 study by Somerville and colleagues indicated that a decrease in estrogen is a powerful trigger of migraine. The investigators administered estrogen (i.e., intramuscular estradiol) or progesterone during the late luteal phase to women with menstrual migraine. Among women who received estrogen, migraine onset was postponed until the estrogen level decreased. The administration of progesterone postponed bleeding, but did not affect migraine. Progesterone treatment prevents migraine effectively on occasion, but estrogen treatment is much more likely to be a successful strategy, said Dr. Hutchinson.
Neurologists should ask certain questions of women with migraine, whether the patients are new or not, to gather information needed to make treatment decisions. For example, it is advisable to ask a woman whether she often has a headache with her period. “You may not want to use the word ‘migraine,’ because many women have been taught that headache is part of PMS,” said Dr. Hutchinson. Asking a woman how pregnancy, delivery, and breastfeeding affected her headaches can add further detail to her history and provide insight about the effects of hormonal changes. Asking what type of birth control the woman is taking can influence the choice of treatment, since some therapies are not appropriate during pregnancy.
Available treatments
NSAIDs are among the treatments that neurologists should consider for the short-term prevention of menstrually related migraine, said Dr. Hutchinson. A study of 35 patients by Sances et al. compared placebo with 550 mg of naproxen sodium given twice daily. Treatment began at 7 days before bleeding onset and continued until the 6th day of menses. Patients underwent treatment for three menstrual cycles. Naproxen sodium significantly reduced headache intensity, headache duration, and the number of headache days, compared with baseline. Treatment was superior to placebo at 3 months. Approximately 33% of patients in the active group were headache free, but no controls were.
Magnesium is another potentially effective option. Facchinetti et al. compared placebo with 360 mg/day of magnesium in a study of 20 patients. Treatment, which was given for two cycles, began at 15 days before menses and ended at the start of menses. Compared with placebo, magnesium reduced the number of headache days and the total pain index. Magnesium is inexpensive, but it causes diarrhea in some patients. “Some women choose to take magnesium all month long, other women start at around ovulation,” said Dr. Hutchinson.
Hormonal treatments are another possible option for the short-term prevention of menstrually related migraine. For women who do not plan to become pregnant, oral contraceptive pills can keep estrogen levels high enough to prevent menstrually related migraine. Gynecologists may suggest that a woman take the pill continuously, skipping the placebo, for an entire year, but Dr. Hutchinson recommends that a woman stop taking the pill for 4 days approximately every 3 months. This discontinuation allows for withdrawal bleeding, but is not likely to cause a prolonged enough decrease in estrogen to provoke migraine, she said. The continuous contraceptive ring, which is inserted vaginally, is an alternative to the pill.
For women who do not want or need contraception, an estrogen patch or gel may be appropriate. Two studies in the 1980s found that a gel containing 1.5 mg of estradiol per 2.5 g reduced migraine frequency, duration, and severity. These studies did not gather long-term safety data, however. A 2006 study by MacGregor et al. found that percutaneous estradiol was associated with a 22% reduction in the number of migraine days, as well as with decreases in headache severity and associated nausea. But the risk of migraine during the 5 days following treatment cessation was increased by 40%. This finding suggests that the treatment period should be extended, said Dr. Hutchinson.
In addition to the timing, the dose of treatment affects the outcome. Smite et al. found no benefit of a 50-mcg dose of estradiol, compared with placebo. Pradalier and colleagues found that a 100-mcg dose was associated with decreased use of rescue medication, compared with a 25-mcg dose. These studies did not gather long-term safety data.
Oral contraceptives and the risk of stroke
Combined oral contraceptives, however, are associated with increased risk of stroke in women with migraine with aura. The dose of estrogen in the contraceptive affects the level of risk, said Dr. Hutchinson. A systematic review by Sheikh et al. found that high-dose ethinyl estradiol (i.e., greater than 50 mcg) was associated with a higher risk of ischemic and hemorrhagic stroke than low-dose ethinyl estradiol (i.e., less than 50 mcg) was. A 20-mcg dose was associated with an odds ratio of stroke of 1.7. Furthermore, among women using combined hormonal contraception, the risk of stroke was higher in women with aura than in women without aura.
“I like to look at the big picture,” said Dr. Hutchinson. “There’s a big difference between a woman who has one or two auras a year that last for 10 minutes and a woman who has complicated aura. I’m going to approach [the latter] woman differently.”
No consensus guidelines for prescribing combined oral contraceptives to women with migraine and aura have been developed. The International Headache Society says that physicians may prescribe low-dose estrogen to women with simple visual aura. The American College of Obstetricians and Gynecologists recommends progestin-only intrauterine or barrier contraception for this population. The World Health Organization holds that estrogen-containing contraception is contraindicated in all women who have migraine with aura.
“If you have women who have migraine without aura, low–estrogen dose combined hormonal contraceptives can be quite appropriate,” said Dr. Hutchinson. “I would tend to go with a 10- or 20-mcg low dose. It could be an option for women with migraine with aura, but only if the benefits outweigh the risks.” In a study by Calhoun et al., the vaginal ring was associated with reduced aura frequency in women with migraine and aura.
Choosing preventive and rescue medications
Although no triptan has FDA approval for the short-term prevention of menstrual migraine, studies have suggested that they are effective. In a study by Sances and colleagues, a twice-daily 1-mg dose of naratriptan taken 6 days perimenstrually reduced the frequency of menstrual-related migraine. At least 50% of treated patients in the study had no menstrual-related migraine. Silberstein and colleagues found that 59% of women who took 2.5 mg of frovatriptan twice daily had no menstrual-related migraine during the 6-day perimenstrual period, compared with 33% of women who received placebo.
Patients with menstrual migraine sometimes need rescue medication. Sumatriptan, either as an injection or an inhaled therapy, is one option. Another injectable option is a 60-mg intramuscular dose of ketorolac. Finally, occipital or sphenopalatine nerve block may be effective as well.
Dr. Hutchinson reported consulting for or serving on the advisory board of Alder, Allergan, Amgen, Biohaven, electroCore, Lilly, Novartis, Supernus, Teva, Theranica, and Upsher-Smith. She has served on speakers bureaus for Allergan, Amgen, electroCore, Lilly, Novartis, Supernus, and Teva.
STOWE, VT. – , said Susan Hutchinson, MD, director of the Orange County Migraine and Headache Center in Irvine, Calif. Compared with headaches associated with nonmenstrual migraine, headaches resulting from menstrual migraine last longer and are more difficult to treat. They tend to be associated with morning awakening and with nausea and vomiting. But in younger women with regular menses, menstrual migraine is predictable. The disorder offers “an incredible chance to be preemptive and think about short-term preventive strategies,” Dr. Hutchinson said at the annual meeting of the Headache Cooperative of New England.
What is menstrual migraine?
Menstrual migraine occurs during the perimenstrual window, which begins at 2 days before onset of bleeding and ends at 3 days of menses. Migraine that occurs during this window at least two-thirds of the time satisfies the criteria for menstrual migraine. A prospective headache diary is recommended, but not required, for making the diagnosis, said Dr. Hutchinson.
Most women with migraine have perimenstrual exacerbation of their headaches, as well as headaches at other times of the month. This phenotype is called menstrually related migraine. Pure menstrual migraine is migraine associated exclusively with menses. The International Classification of Headache Disorders-3 recognizes that menstrual migraine can be with or without aura. A headache diary can help distinguish between menstrual migraine and menstrually related migraine.
For pure menstrual migraine, it is appropriate to treat during the perimenstrual window. Preventive treatment may not be necessary throughout the month, said Dr. Hutchinson. Furthermore, hormonal treatment is the type of therapy most likely to be effective, she added. Menstrually related migraine requires a broader approach.
Gathering information during the visit
A 1972 study by Somerville and colleagues indicated that a decrease in estrogen is a powerful trigger of migraine. The investigators administered estrogen (i.e., intramuscular estradiol) or progesterone during the late luteal phase to women with menstrual migraine. Among women who received estrogen, migraine onset was postponed until the estrogen level decreased. The administration of progesterone postponed bleeding, but did not affect migraine. Progesterone treatment prevents migraine effectively on occasion, but estrogen treatment is much more likely to be a successful strategy, said Dr. Hutchinson.
Neurologists should ask certain questions of women with migraine, whether the patients are new or not, to gather information needed to make treatment decisions. For example, it is advisable to ask a woman whether she often has a headache with her period. “You may not want to use the word ‘migraine,’ because many women have been taught that headache is part of PMS,” said Dr. Hutchinson. Asking a woman how pregnancy, delivery, and breastfeeding affected her headaches can add further detail to her history and provide insight about the effects of hormonal changes. Asking what type of birth control the woman is taking can influence the choice of treatment, since some therapies are not appropriate during pregnancy.
Available treatments
NSAIDs are among the treatments that neurologists should consider for the short-term prevention of menstrually related migraine, said Dr. Hutchinson. A study of 35 patients by Sances et al. compared placebo with 550 mg of naproxen sodium given twice daily. Treatment began at 7 days before bleeding onset and continued until the 6th day of menses. Patients underwent treatment for three menstrual cycles. Naproxen sodium significantly reduced headache intensity, headache duration, and the number of headache days, compared with baseline. Treatment was superior to placebo at 3 months. Approximately 33% of patients in the active group were headache free, but no controls were.
Magnesium is another potentially effective option. Facchinetti et al. compared placebo with 360 mg/day of magnesium in a study of 20 patients. Treatment, which was given for two cycles, began at 15 days before menses and ended at the start of menses. Compared with placebo, magnesium reduced the number of headache days and the total pain index. Magnesium is inexpensive, but it causes diarrhea in some patients. “Some women choose to take magnesium all month long, other women start at around ovulation,” said Dr. Hutchinson.
Hormonal treatments are another possible option for the short-term prevention of menstrually related migraine. For women who do not plan to become pregnant, oral contraceptive pills can keep estrogen levels high enough to prevent menstrually related migraine. Gynecologists may suggest that a woman take the pill continuously, skipping the placebo, for an entire year, but Dr. Hutchinson recommends that a woman stop taking the pill for 4 days approximately every 3 months. This discontinuation allows for withdrawal bleeding, but is not likely to cause a prolonged enough decrease in estrogen to provoke migraine, she said. The continuous contraceptive ring, which is inserted vaginally, is an alternative to the pill.
For women who do not want or need contraception, an estrogen patch or gel may be appropriate. Two studies in the 1980s found that a gel containing 1.5 mg of estradiol per 2.5 g reduced migraine frequency, duration, and severity. These studies did not gather long-term safety data, however. A 2006 study by MacGregor et al. found that percutaneous estradiol was associated with a 22% reduction in the number of migraine days, as well as with decreases in headache severity and associated nausea. But the risk of migraine during the 5 days following treatment cessation was increased by 40%. This finding suggests that the treatment period should be extended, said Dr. Hutchinson.
In addition to the timing, the dose of treatment affects the outcome. Smite et al. found no benefit of a 50-mcg dose of estradiol, compared with placebo. Pradalier and colleagues found that a 100-mcg dose was associated with decreased use of rescue medication, compared with a 25-mcg dose. These studies did not gather long-term safety data.
Oral contraceptives and the risk of stroke
Combined oral contraceptives, however, are associated with increased risk of stroke in women with migraine with aura. The dose of estrogen in the contraceptive affects the level of risk, said Dr. Hutchinson. A systematic review by Sheikh et al. found that high-dose ethinyl estradiol (i.e., greater than 50 mcg) was associated with a higher risk of ischemic and hemorrhagic stroke than low-dose ethinyl estradiol (i.e., less than 50 mcg) was. A 20-mcg dose was associated with an odds ratio of stroke of 1.7. Furthermore, among women using combined hormonal contraception, the risk of stroke was higher in women with aura than in women without aura.
“I like to look at the big picture,” said Dr. Hutchinson. “There’s a big difference between a woman who has one or two auras a year that last for 10 minutes and a woman who has complicated aura. I’m going to approach [the latter] woman differently.”
No consensus guidelines for prescribing combined oral contraceptives to women with migraine and aura have been developed. The International Headache Society says that physicians may prescribe low-dose estrogen to women with simple visual aura. The American College of Obstetricians and Gynecologists recommends progestin-only intrauterine or barrier contraception for this population. The World Health Organization holds that estrogen-containing contraception is contraindicated in all women who have migraine with aura.
“If you have women who have migraine without aura, low–estrogen dose combined hormonal contraceptives can be quite appropriate,” said Dr. Hutchinson. “I would tend to go with a 10- or 20-mcg low dose. It could be an option for women with migraine with aura, but only if the benefits outweigh the risks.” In a study by Calhoun et al., the vaginal ring was associated with reduced aura frequency in women with migraine and aura.
Choosing preventive and rescue medications
Although no triptan has FDA approval for the short-term prevention of menstrual migraine, studies have suggested that they are effective. In a study by Sances and colleagues, a twice-daily 1-mg dose of naratriptan taken 6 days perimenstrually reduced the frequency of menstrual-related migraine. At least 50% of treated patients in the study had no menstrual-related migraine. Silberstein and colleagues found that 59% of women who took 2.5 mg of frovatriptan twice daily had no menstrual-related migraine during the 6-day perimenstrual period, compared with 33% of women who received placebo.
Patients with menstrual migraine sometimes need rescue medication. Sumatriptan, either as an injection or an inhaled therapy, is one option. Another injectable option is a 60-mg intramuscular dose of ketorolac. Finally, occipital or sphenopalatine nerve block may be effective as well.
Dr. Hutchinson reported consulting for or serving on the advisory board of Alder, Allergan, Amgen, Biohaven, electroCore, Lilly, Novartis, Supernus, Teva, Theranica, and Upsher-Smith. She has served on speakers bureaus for Allergan, Amgen, electroCore, Lilly, Novartis, Supernus, and Teva.
REPORTING FROM HCNE Stowe 2020
Nearly 24 tests for the novel coronavirus are available
according to the Infectious Diseases Society of America (IDSA).
“Based on what we know about influenza, it’s unlikely that all of these tests are going to perform exactly the same way,” said Angela M. Caliendo, MD, executive vice chair of the department of medicine at Brown University in Providence, R.I., at a press briefing. Although these tests are good, no test is perfect, she added.
The development and availability of testing has improved over time, but clinical laboratories still face challenges, said Kimberly E. Hanson, MD, associate professor of internal medicine at University of Utah, Salt Lake City. These challenges include shortages of devices for specimen collection, media, test tubes, and reagents. Although the goal is to test all symptomatic patients, these shortages require laboratories to prioritize health care workers and the sickest patients.
Tests are being approved through an abbreviated process
Two types of test, rapid tests and serology tests, are in use. Rapid tests use polymerase chain reactions to detect the virus in a clinical specimen. This type of testing is used to diagnose infection. Serology tests measure antibodies to the virus and are more appropriate for indicating whether a patient has been exposed to the virus.
The declaration of a national emergency enabled the FDA to activate its EUA policy, which allows for quicker approval of tests. Normally, a test must be assessed in the laboratory (such as with a mock specimen or an inactivated virus) and in a clinical study of patients. Under the EUA, clinical assessment is not required for the approval of a test. Consequently, the clinical performance of a test approved under EUA is unknown.
Collecting a specimen of good quality is critical to the quality of the test result, said Dr. Caliendo, the secretary of IDSA’s board of directors. Clinicians and investigators have used nasopharyngeal swabs, sputum, and specimens collected from deep within the lung. “We’re still collecting data to determine which is the best specimen type.” As coronavirus testing expands, particularly to drive-through testing sites, “we may be using people who are not as experienced, and so you might not get as high a quality specimen in that situation,” Dr. Caliendo added.
The timing of the test influences the quality of the result, as well, because the amount of virus is lower at the onset of symptoms than it is later. Another factor that affects the quality of the results is the test’s sensitivity.
The time to obtain results varies
The value of having several tests available is that it enables many patients to be tested simultaneously, said Dr. Hanson, a member of IDSA’s board of directors. It also helps to reduce potential problems with the supply of test kits. A test manufacturer, however, may supply parts of the test kit but not the whole kit. This requires the hospital or laboratory to obtain the remaining parts from other suppliers. Furthermore, test manufacturers may need to prioritize areas with high rates of infection or transmission when they ship their tests, which limits testing in other areas.
One reason for the lack of a national plan for testing is that the virus has affected different regions at different times, said Dr. Caliendo. Some tests are more difficult to perform than others, and not all laboratories are equally sophisticated, which can limit testing. It is necessary to test not only symptomatic patients who have been hospitalized, but also symptomatic patients in the community, said Dr. Caliendo. “Ideally, we’re going to need to couple acute diagnostics [testing while people are sick] with serologic testing. Serologic testing is going to be important for us to see who has been infected. That will give us an idea of who is left in our community who is at risk for developing infection.”
How quickly test results are available depends on the type of test and where it is administered. Recently established drive-through clinics can provide results in about 30 minutes. Tests performed in hospitals may take between 1 and 6 hours to yield results. “The issue is, do we have reagents that day?” said Dr. Caliendo. “We have to be careful whom we choose to test, and we screen that in the hospital so that we have enough tests to run as we need them.” But many locations have backlogs. “When you have a backlog of testing, you’re going to wait days, unfortunately, to get a result,” said Dr. Caliendo.
Dr. Caliendo and Dr. Hanson did not report disclosures for this briefing.
according to the Infectious Diseases Society of America (IDSA).
“Based on what we know about influenza, it’s unlikely that all of these tests are going to perform exactly the same way,” said Angela M. Caliendo, MD, executive vice chair of the department of medicine at Brown University in Providence, R.I., at a press briefing. Although these tests are good, no test is perfect, she added.
The development and availability of testing has improved over time, but clinical laboratories still face challenges, said Kimberly E. Hanson, MD, associate professor of internal medicine at University of Utah, Salt Lake City. These challenges include shortages of devices for specimen collection, media, test tubes, and reagents. Although the goal is to test all symptomatic patients, these shortages require laboratories to prioritize health care workers and the sickest patients.
Tests are being approved through an abbreviated process
Two types of test, rapid tests and serology tests, are in use. Rapid tests use polymerase chain reactions to detect the virus in a clinical specimen. This type of testing is used to diagnose infection. Serology tests measure antibodies to the virus and are more appropriate for indicating whether a patient has been exposed to the virus.
The declaration of a national emergency enabled the FDA to activate its EUA policy, which allows for quicker approval of tests. Normally, a test must be assessed in the laboratory (such as with a mock specimen or an inactivated virus) and in a clinical study of patients. Under the EUA, clinical assessment is not required for the approval of a test. Consequently, the clinical performance of a test approved under EUA is unknown.
Collecting a specimen of good quality is critical to the quality of the test result, said Dr. Caliendo, the secretary of IDSA’s board of directors. Clinicians and investigators have used nasopharyngeal swabs, sputum, and specimens collected from deep within the lung. “We’re still collecting data to determine which is the best specimen type.” As coronavirus testing expands, particularly to drive-through testing sites, “we may be using people who are not as experienced, and so you might not get as high a quality specimen in that situation,” Dr. Caliendo added.
The timing of the test influences the quality of the result, as well, because the amount of virus is lower at the onset of symptoms than it is later. Another factor that affects the quality of the results is the test’s sensitivity.
The time to obtain results varies
The value of having several tests available is that it enables many patients to be tested simultaneously, said Dr. Hanson, a member of IDSA’s board of directors. It also helps to reduce potential problems with the supply of test kits. A test manufacturer, however, may supply parts of the test kit but not the whole kit. This requires the hospital or laboratory to obtain the remaining parts from other suppliers. Furthermore, test manufacturers may need to prioritize areas with high rates of infection or transmission when they ship their tests, which limits testing in other areas.
One reason for the lack of a national plan for testing is that the virus has affected different regions at different times, said Dr. Caliendo. Some tests are more difficult to perform than others, and not all laboratories are equally sophisticated, which can limit testing. It is necessary to test not only symptomatic patients who have been hospitalized, but also symptomatic patients in the community, said Dr. Caliendo. “Ideally, we’re going to need to couple acute diagnostics [testing while people are sick] with serologic testing. Serologic testing is going to be important for us to see who has been infected. That will give us an idea of who is left in our community who is at risk for developing infection.”
How quickly test results are available depends on the type of test and where it is administered. Recently established drive-through clinics can provide results in about 30 minutes. Tests performed in hospitals may take between 1 and 6 hours to yield results. “The issue is, do we have reagents that day?” said Dr. Caliendo. “We have to be careful whom we choose to test, and we screen that in the hospital so that we have enough tests to run as we need them.” But many locations have backlogs. “When you have a backlog of testing, you’re going to wait days, unfortunately, to get a result,” said Dr. Caliendo.
Dr. Caliendo and Dr. Hanson did not report disclosures for this briefing.
according to the Infectious Diseases Society of America (IDSA).
“Based on what we know about influenza, it’s unlikely that all of these tests are going to perform exactly the same way,” said Angela M. Caliendo, MD, executive vice chair of the department of medicine at Brown University in Providence, R.I., at a press briefing. Although these tests are good, no test is perfect, she added.
The development and availability of testing has improved over time, but clinical laboratories still face challenges, said Kimberly E. Hanson, MD, associate professor of internal medicine at University of Utah, Salt Lake City. These challenges include shortages of devices for specimen collection, media, test tubes, and reagents. Although the goal is to test all symptomatic patients, these shortages require laboratories to prioritize health care workers and the sickest patients.
Tests are being approved through an abbreviated process
Two types of test, rapid tests and serology tests, are in use. Rapid tests use polymerase chain reactions to detect the virus in a clinical specimen. This type of testing is used to diagnose infection. Serology tests measure antibodies to the virus and are more appropriate for indicating whether a patient has been exposed to the virus.
The declaration of a national emergency enabled the FDA to activate its EUA policy, which allows for quicker approval of tests. Normally, a test must be assessed in the laboratory (such as with a mock specimen or an inactivated virus) and in a clinical study of patients. Under the EUA, clinical assessment is not required for the approval of a test. Consequently, the clinical performance of a test approved under EUA is unknown.
Collecting a specimen of good quality is critical to the quality of the test result, said Dr. Caliendo, the secretary of IDSA’s board of directors. Clinicians and investigators have used nasopharyngeal swabs, sputum, and specimens collected from deep within the lung. “We’re still collecting data to determine which is the best specimen type.” As coronavirus testing expands, particularly to drive-through testing sites, “we may be using people who are not as experienced, and so you might not get as high a quality specimen in that situation,” Dr. Caliendo added.
The timing of the test influences the quality of the result, as well, because the amount of virus is lower at the onset of symptoms than it is later. Another factor that affects the quality of the results is the test’s sensitivity.
The time to obtain results varies
The value of having several tests available is that it enables many patients to be tested simultaneously, said Dr. Hanson, a member of IDSA’s board of directors. It also helps to reduce potential problems with the supply of test kits. A test manufacturer, however, may supply parts of the test kit but not the whole kit. This requires the hospital or laboratory to obtain the remaining parts from other suppliers. Furthermore, test manufacturers may need to prioritize areas with high rates of infection or transmission when they ship their tests, which limits testing in other areas.
One reason for the lack of a national plan for testing is that the virus has affected different regions at different times, said Dr. Caliendo. Some tests are more difficult to perform than others, and not all laboratories are equally sophisticated, which can limit testing. It is necessary to test not only symptomatic patients who have been hospitalized, but also symptomatic patients in the community, said Dr. Caliendo. “Ideally, we’re going to need to couple acute diagnostics [testing while people are sick] with serologic testing. Serologic testing is going to be important for us to see who has been infected. That will give us an idea of who is left in our community who is at risk for developing infection.”
How quickly test results are available depends on the type of test and where it is administered. Recently established drive-through clinics can provide results in about 30 minutes. Tests performed in hospitals may take between 1 and 6 hours to yield results. “The issue is, do we have reagents that day?” said Dr. Caliendo. “We have to be careful whom we choose to test, and we screen that in the hospital so that we have enough tests to run as we need them.” But many locations have backlogs. “When you have a backlog of testing, you’re going to wait days, unfortunately, to get a result,” said Dr. Caliendo.
Dr. Caliendo and Dr. Hanson did not report disclosures for this briefing.
Leflunomide-hydroxychloroquine combination for Sjögren’s shows potential
according to results from a phase 2a, randomized clinical trial published in Lancet Rheumatology.
The combination’s statistically significant effect on the European League Against Rheumatism (EULAR) Sjögren’s syndrome disease activity index (ESSDAI) score at 24 weeks, the primary endpoint of the small, double-blind, placebo-controlled trial, suggests that the combination should be studied further in larger trials, according to first author Eefje Hanna Martine van der Heijden, MD, a rheumatologist at University Medical Center Utrecht (the Netherlands), and colleagues.
The investigators decided to study leflunomide and hydroxychloroquine, which target overlapping and distinct immunopathologic pathways, because data support the safety of each drug individually, and a previous in vitro study by the authors indicated that they have complementary effects when administered together.
“To our knowledge, this is the first randomized, placebo-controlled clinical trial in patients with primary Sjögren’s syndrome that shows significant clinical efficacy, as measured by ESSDAI, and is associated with significant improvements in other clinical parameters, including dryness and fatigue,” the investigators wrote.
Dr. van der Heijden and colleagues screened 37 patients from the outpatient clinic of their medical center and enrolled 29 (28 women) who met American-European Consensus Criteria into their study. They had moderate to active disease, defined as an ESSDAI score of 5 or higher, and a lymphocytic focus score of 1 or higher in labial salivary gland biopsy specimens that were obtained before inclusion. The population’s average age was approximately 54 years. They had an average disease duration of about 8 years, a mean ESSDAI score of about 9, and mean EULAR Sjögren’s syndrome patient reported index (ESSPRI) score of 6.7. A total of 21 patients were randomized to leflunomide 20 mg and hydroxychloroquine 400 mg daily, and 8 patients were randomized to placebos. Baseline characteristics were similar between groups, but mean serum IgG level was 19.4 g/L in the treatment group and 13.8 g/L in the placebo group. One patient in the placebo group developed polymyalgia rheumatica and required high-dose prednisone treatment. The investigators excluded this patient from the primary analysis.
At 24 weeks, the mean difference in ESSDAI score in the leflunomide-hydroxychloroquine group, compared with the placebo group, was –4.35 points after adjustment for baseline values. This difference was statistically significant.
Secondary endpoints in the study showed inconsistent statistically significant differences between the treatment groups at 8, 16, and 24 weeks. The total ESSPRI score at 16 weeks was 1.66 points lower in the treatment group than in the placebo group. Stimulated whole saliva production was increased in the leflunomide-hydroxychloroquine group at 16 weeks, compared with the placebo group. Unstimulated whole saliva production at 24 weeks was higher in the leflunomide-hydroxychloroquine group than in controls. The investigators found no differences between groups in visual analog scores for ocular or oral dryness.
No patient in the leflunomide-hydroxychloroquine group had a serious adverse event. Two serious adverse events (hospital admission for pancreatitis and hospital admission for nephrolithiasis) occurred in the placebo group. The most common adverse events in the leflunomide-hydroxychloroquine group were GI discomfort (52% vs. 25% in the placebo group), modest transient increases in ALT (48% vs. 13%), and short episodes of general malaise and shivering (43% vs. 13%).
In an accompanying editorial, Astrid Rasmussen, MD, PhD, of the Oklahoma Sjögren’s Syndrome Center of Research Translation at the Oklahoma Medical Research Foundation in Oklahoma City, wrote that the trial by Dr. van der Heijden and colleagues was limited by a small sample size and short duration. In addition, some of the findings were unexplained, such as modest changes in secondary endpoints and a concomitant decrease in ESSDAI scores at 8 weeks for both study groups.
Nevertheless, the study provides reason to think in new ways about old drugs, wrote Dr. Rasmussen. “Combination or sequential use of existing agents that target different aspects of immune dysregulation, while having acceptable safety profiles and cost-benefit ratios, should represent an avenue of further exploration. Just as importantly, subphenotyping patients on the basis of their underlying pathogenic processes and identifying sensitive outcome measures could transform the current enthusiasm for identifying effective treatments for Sjögren’s syndrome into a reality for the patients that need them the most.”
The study was funded by ZonMw. The authors of the study reported no conflicts of interest. Dr. Rasmussen reported having no conflicts of interest.
SOURCE: van der Heijden EHM et al. Lancet Rheumatol. 2020 Mar 26. doi: 10.1016/S2665-9913(20)30057-6.
according to results from a phase 2a, randomized clinical trial published in Lancet Rheumatology.
The combination’s statistically significant effect on the European League Against Rheumatism (EULAR) Sjögren’s syndrome disease activity index (ESSDAI) score at 24 weeks, the primary endpoint of the small, double-blind, placebo-controlled trial, suggests that the combination should be studied further in larger trials, according to first author Eefje Hanna Martine van der Heijden, MD, a rheumatologist at University Medical Center Utrecht (the Netherlands), and colleagues.
The investigators decided to study leflunomide and hydroxychloroquine, which target overlapping and distinct immunopathologic pathways, because data support the safety of each drug individually, and a previous in vitro study by the authors indicated that they have complementary effects when administered together.
“To our knowledge, this is the first randomized, placebo-controlled clinical trial in patients with primary Sjögren’s syndrome that shows significant clinical efficacy, as measured by ESSDAI, and is associated with significant improvements in other clinical parameters, including dryness and fatigue,” the investigators wrote.
Dr. van der Heijden and colleagues screened 37 patients from the outpatient clinic of their medical center and enrolled 29 (28 women) who met American-European Consensus Criteria into their study. They had moderate to active disease, defined as an ESSDAI score of 5 or higher, and a lymphocytic focus score of 1 or higher in labial salivary gland biopsy specimens that were obtained before inclusion. The population’s average age was approximately 54 years. They had an average disease duration of about 8 years, a mean ESSDAI score of about 9, and mean EULAR Sjögren’s syndrome patient reported index (ESSPRI) score of 6.7. A total of 21 patients were randomized to leflunomide 20 mg and hydroxychloroquine 400 mg daily, and 8 patients were randomized to placebos. Baseline characteristics were similar between groups, but mean serum IgG level was 19.4 g/L in the treatment group and 13.8 g/L in the placebo group. One patient in the placebo group developed polymyalgia rheumatica and required high-dose prednisone treatment. The investigators excluded this patient from the primary analysis.
At 24 weeks, the mean difference in ESSDAI score in the leflunomide-hydroxychloroquine group, compared with the placebo group, was –4.35 points after adjustment for baseline values. This difference was statistically significant.
Secondary endpoints in the study showed inconsistent statistically significant differences between the treatment groups at 8, 16, and 24 weeks. The total ESSPRI score at 16 weeks was 1.66 points lower in the treatment group than in the placebo group. Stimulated whole saliva production was increased in the leflunomide-hydroxychloroquine group at 16 weeks, compared with the placebo group. Unstimulated whole saliva production at 24 weeks was higher in the leflunomide-hydroxychloroquine group than in controls. The investigators found no differences between groups in visual analog scores for ocular or oral dryness.
No patient in the leflunomide-hydroxychloroquine group had a serious adverse event. Two serious adverse events (hospital admission for pancreatitis and hospital admission for nephrolithiasis) occurred in the placebo group. The most common adverse events in the leflunomide-hydroxychloroquine group were GI discomfort (52% vs. 25% in the placebo group), modest transient increases in ALT (48% vs. 13%), and short episodes of general malaise and shivering (43% vs. 13%).
In an accompanying editorial, Astrid Rasmussen, MD, PhD, of the Oklahoma Sjögren’s Syndrome Center of Research Translation at the Oklahoma Medical Research Foundation in Oklahoma City, wrote that the trial by Dr. van der Heijden and colleagues was limited by a small sample size and short duration. In addition, some of the findings were unexplained, such as modest changes in secondary endpoints and a concomitant decrease in ESSDAI scores at 8 weeks for both study groups.
Nevertheless, the study provides reason to think in new ways about old drugs, wrote Dr. Rasmussen. “Combination or sequential use of existing agents that target different aspects of immune dysregulation, while having acceptable safety profiles and cost-benefit ratios, should represent an avenue of further exploration. Just as importantly, subphenotyping patients on the basis of their underlying pathogenic processes and identifying sensitive outcome measures could transform the current enthusiasm for identifying effective treatments for Sjögren’s syndrome into a reality for the patients that need them the most.”
The study was funded by ZonMw. The authors of the study reported no conflicts of interest. Dr. Rasmussen reported having no conflicts of interest.
SOURCE: van der Heijden EHM et al. Lancet Rheumatol. 2020 Mar 26. doi: 10.1016/S2665-9913(20)30057-6.
according to results from a phase 2a, randomized clinical trial published in Lancet Rheumatology.
The combination’s statistically significant effect on the European League Against Rheumatism (EULAR) Sjögren’s syndrome disease activity index (ESSDAI) score at 24 weeks, the primary endpoint of the small, double-blind, placebo-controlled trial, suggests that the combination should be studied further in larger trials, according to first author Eefje Hanna Martine van der Heijden, MD, a rheumatologist at University Medical Center Utrecht (the Netherlands), and colleagues.
The investigators decided to study leflunomide and hydroxychloroquine, which target overlapping and distinct immunopathologic pathways, because data support the safety of each drug individually, and a previous in vitro study by the authors indicated that they have complementary effects when administered together.
“To our knowledge, this is the first randomized, placebo-controlled clinical trial in patients with primary Sjögren’s syndrome that shows significant clinical efficacy, as measured by ESSDAI, and is associated with significant improvements in other clinical parameters, including dryness and fatigue,” the investigators wrote.
Dr. van der Heijden and colleagues screened 37 patients from the outpatient clinic of their medical center and enrolled 29 (28 women) who met American-European Consensus Criteria into their study. They had moderate to active disease, defined as an ESSDAI score of 5 or higher, and a lymphocytic focus score of 1 or higher in labial salivary gland biopsy specimens that were obtained before inclusion. The population’s average age was approximately 54 years. They had an average disease duration of about 8 years, a mean ESSDAI score of about 9, and mean EULAR Sjögren’s syndrome patient reported index (ESSPRI) score of 6.7. A total of 21 patients were randomized to leflunomide 20 mg and hydroxychloroquine 400 mg daily, and 8 patients were randomized to placebos. Baseline characteristics were similar between groups, but mean serum IgG level was 19.4 g/L in the treatment group and 13.8 g/L in the placebo group. One patient in the placebo group developed polymyalgia rheumatica and required high-dose prednisone treatment. The investigators excluded this patient from the primary analysis.
At 24 weeks, the mean difference in ESSDAI score in the leflunomide-hydroxychloroquine group, compared with the placebo group, was –4.35 points after adjustment for baseline values. This difference was statistically significant.
Secondary endpoints in the study showed inconsistent statistically significant differences between the treatment groups at 8, 16, and 24 weeks. The total ESSPRI score at 16 weeks was 1.66 points lower in the treatment group than in the placebo group. Stimulated whole saliva production was increased in the leflunomide-hydroxychloroquine group at 16 weeks, compared with the placebo group. Unstimulated whole saliva production at 24 weeks was higher in the leflunomide-hydroxychloroquine group than in controls. The investigators found no differences between groups in visual analog scores for ocular or oral dryness.
No patient in the leflunomide-hydroxychloroquine group had a serious adverse event. Two serious adverse events (hospital admission for pancreatitis and hospital admission for nephrolithiasis) occurred in the placebo group. The most common adverse events in the leflunomide-hydroxychloroquine group were GI discomfort (52% vs. 25% in the placebo group), modest transient increases in ALT (48% vs. 13%), and short episodes of general malaise and shivering (43% vs. 13%).
In an accompanying editorial, Astrid Rasmussen, MD, PhD, of the Oklahoma Sjögren’s Syndrome Center of Research Translation at the Oklahoma Medical Research Foundation in Oklahoma City, wrote that the trial by Dr. van der Heijden and colleagues was limited by a small sample size and short duration. In addition, some of the findings were unexplained, such as modest changes in secondary endpoints and a concomitant decrease in ESSDAI scores at 8 weeks for both study groups.
Nevertheless, the study provides reason to think in new ways about old drugs, wrote Dr. Rasmussen. “Combination or sequential use of existing agents that target different aspects of immune dysregulation, while having acceptable safety profiles and cost-benefit ratios, should represent an avenue of further exploration. Just as importantly, subphenotyping patients on the basis of their underlying pathogenic processes and identifying sensitive outcome measures could transform the current enthusiasm for identifying effective treatments for Sjögren’s syndrome into a reality for the patients that need them the most.”
The study was funded by ZonMw. The authors of the study reported no conflicts of interest. Dr. Rasmussen reported having no conflicts of interest.
SOURCE: van der Heijden EHM et al. Lancet Rheumatol. 2020 Mar 26. doi: 10.1016/S2665-9913(20)30057-6.
FROM LANCET RHEUMATOLOGY
Researchers develop score to predict risk of stroke among migraineurs with aura
LOS ANGELES – The study on which the risk score is based was presented at the International Stroke Conference sponsored by the American Heart Association. Migraine with aura, for which younger women are at higher risk, increases the risk of ischemic stroke. “With our new risk-prediction tool, we could start identifying those at higher risk, treat their risk factors, and lower their risk of stroke,” said Souvik Sen, MD, MPH, professor and chair of neurology at the University of South Carolina in Columbia, in a press release.
Risk groups significantly discriminated stroke risk
To create the score, Dr. Sen and colleagues examined data from the ARIC (Atherosclerosis Risk in Communities) cohort, which includes community-dwelling people in Forsyth County, N.C.; Jackson, Miss.; Washington County, Md.; and the suburbs of Minneapolis. Researchers have been following the participants since 1987. From this population, Dr. Sen and colleagues identified 429 participants with a history of migraine with aura. Most of these participants were women aged 50-59 years at their first visit. The researchers analyzed the association between potential risk factors and ischemic stroke using Cox proportional hazards analysis.
Of the 429 participants, 31 had an ischemic stroke during a follow-up period of 20 years. Dr. Sen’s group created a risk score by identifying five risk factors for stroke and assigning them points in proportion to their influence (i.e., their regression coefficients). They assigned diabetes mellitus – 7 points; age older than 65 years – 5 points; heart rate variability (i.e., the standard deviation of all normal-to-normal RR intervals) – 3 points; hypertension – 3 points – and sex – 1 point. Then the researchers calculated risk scores for each patient and defined a low-risk group (from 0-4 points), a moderate-risk group (5-10 points), and a high-risk group (11-21 points).
After 18 years of follow-up, the incidence of stroke was 3% in the low-risk group, 8% in the moderate-risk group, and 34% in the high-risk group. The hazard ratio for ischemic stroke in the high-risk group, compared with the low-risk group, was 7.35. Kaplan Meier curves indicated that the risk-stratification groups significantly discriminated stroke risk among the sample. The risk score should be validated in an independent population cohort, said the investigators.
Dr. Sen and colleagues did not report any funding for this study. Investigators reported receiving grants from the National Institutes of Health, the American Heart Association, and the American Academy of Neurology.
Score may leave important variables unexamined
One mechanism through which migraine increases the risk of stroke is the constriction of blood vessels, said Louis R. Caplan, MD, professor of neurology at Harvard Medical School in Boston and member of the editorial advisory board of Neurology Reviews. Triptans, which many patients use to treat migraine, also cause vasoconstriction. In addition, migraine increases blood coagulation.
Although the risk score developed by Dr. Sen and colleagues accounts for various comorbidities, it may not apply equally to all patients. “As I understand it, they’re just using migraine with aura as a single factor,” said Dr. Caplan. Variables such as prolonged aura, frequent episodes, and aura-related deficit are associated with increased risk of stroke, but the risk score does not examine these factors.
Patients with severe, long-lasting attacks or attacks that involve weakness or aphasia should receive prophylactic treatment to prevent vasoconstriction, such as verapamil (Verelan), said Dr. Caplan. Antithrombotic agents such as aspirin also may be appropriate prophylaxis. Whether effective treatment of migraine with aura decreases the risk of stroke remains unknown.
SOURCE: Trivedi T et al. ISC 2020. Abstract WMP117.
LOS ANGELES – The study on which the risk score is based was presented at the International Stroke Conference sponsored by the American Heart Association. Migraine with aura, for which younger women are at higher risk, increases the risk of ischemic stroke. “With our new risk-prediction tool, we could start identifying those at higher risk, treat their risk factors, and lower their risk of stroke,” said Souvik Sen, MD, MPH, professor and chair of neurology at the University of South Carolina in Columbia, in a press release.
Risk groups significantly discriminated stroke risk
To create the score, Dr. Sen and colleagues examined data from the ARIC (Atherosclerosis Risk in Communities) cohort, which includes community-dwelling people in Forsyth County, N.C.; Jackson, Miss.; Washington County, Md.; and the suburbs of Minneapolis. Researchers have been following the participants since 1987. From this population, Dr. Sen and colleagues identified 429 participants with a history of migraine with aura. Most of these participants were women aged 50-59 years at their first visit. The researchers analyzed the association between potential risk factors and ischemic stroke using Cox proportional hazards analysis.
Of the 429 participants, 31 had an ischemic stroke during a follow-up period of 20 years. Dr. Sen’s group created a risk score by identifying five risk factors for stroke and assigning them points in proportion to their influence (i.e., their regression coefficients). They assigned diabetes mellitus – 7 points; age older than 65 years – 5 points; heart rate variability (i.e., the standard deviation of all normal-to-normal RR intervals) – 3 points; hypertension – 3 points – and sex – 1 point. Then the researchers calculated risk scores for each patient and defined a low-risk group (from 0-4 points), a moderate-risk group (5-10 points), and a high-risk group (11-21 points).
After 18 years of follow-up, the incidence of stroke was 3% in the low-risk group, 8% in the moderate-risk group, and 34% in the high-risk group. The hazard ratio for ischemic stroke in the high-risk group, compared with the low-risk group, was 7.35. Kaplan Meier curves indicated that the risk-stratification groups significantly discriminated stroke risk among the sample. The risk score should be validated in an independent population cohort, said the investigators.
Dr. Sen and colleagues did not report any funding for this study. Investigators reported receiving grants from the National Institutes of Health, the American Heart Association, and the American Academy of Neurology.
Score may leave important variables unexamined
One mechanism through which migraine increases the risk of stroke is the constriction of blood vessels, said Louis R. Caplan, MD, professor of neurology at Harvard Medical School in Boston and member of the editorial advisory board of Neurology Reviews. Triptans, which many patients use to treat migraine, also cause vasoconstriction. In addition, migraine increases blood coagulation.
Although the risk score developed by Dr. Sen and colleagues accounts for various comorbidities, it may not apply equally to all patients. “As I understand it, they’re just using migraine with aura as a single factor,” said Dr. Caplan. Variables such as prolonged aura, frequent episodes, and aura-related deficit are associated with increased risk of stroke, but the risk score does not examine these factors.
Patients with severe, long-lasting attacks or attacks that involve weakness or aphasia should receive prophylactic treatment to prevent vasoconstriction, such as verapamil (Verelan), said Dr. Caplan. Antithrombotic agents such as aspirin also may be appropriate prophylaxis. Whether effective treatment of migraine with aura decreases the risk of stroke remains unknown.
SOURCE: Trivedi T et al. ISC 2020. Abstract WMP117.
LOS ANGELES – The study on which the risk score is based was presented at the International Stroke Conference sponsored by the American Heart Association. Migraine with aura, for which younger women are at higher risk, increases the risk of ischemic stroke. “With our new risk-prediction tool, we could start identifying those at higher risk, treat their risk factors, and lower their risk of stroke,” said Souvik Sen, MD, MPH, professor and chair of neurology at the University of South Carolina in Columbia, in a press release.
Risk groups significantly discriminated stroke risk
To create the score, Dr. Sen and colleagues examined data from the ARIC (Atherosclerosis Risk in Communities) cohort, which includes community-dwelling people in Forsyth County, N.C.; Jackson, Miss.; Washington County, Md.; and the suburbs of Minneapolis. Researchers have been following the participants since 1987. From this population, Dr. Sen and colleagues identified 429 participants with a history of migraine with aura. Most of these participants were women aged 50-59 years at their first visit. The researchers analyzed the association between potential risk factors and ischemic stroke using Cox proportional hazards analysis.
Of the 429 participants, 31 had an ischemic stroke during a follow-up period of 20 years. Dr. Sen’s group created a risk score by identifying five risk factors for stroke and assigning them points in proportion to their influence (i.e., their regression coefficients). They assigned diabetes mellitus – 7 points; age older than 65 years – 5 points; heart rate variability (i.e., the standard deviation of all normal-to-normal RR intervals) – 3 points; hypertension – 3 points – and sex – 1 point. Then the researchers calculated risk scores for each patient and defined a low-risk group (from 0-4 points), a moderate-risk group (5-10 points), and a high-risk group (11-21 points).
After 18 years of follow-up, the incidence of stroke was 3% in the low-risk group, 8% in the moderate-risk group, and 34% in the high-risk group. The hazard ratio for ischemic stroke in the high-risk group, compared with the low-risk group, was 7.35. Kaplan Meier curves indicated that the risk-stratification groups significantly discriminated stroke risk among the sample. The risk score should be validated in an independent population cohort, said the investigators.
Dr. Sen and colleagues did not report any funding for this study. Investigators reported receiving grants from the National Institutes of Health, the American Heart Association, and the American Academy of Neurology.
Score may leave important variables unexamined
One mechanism through which migraine increases the risk of stroke is the constriction of blood vessels, said Louis R. Caplan, MD, professor of neurology at Harvard Medical School in Boston and member of the editorial advisory board of Neurology Reviews. Triptans, which many patients use to treat migraine, also cause vasoconstriction. In addition, migraine increases blood coagulation.
Although the risk score developed by Dr. Sen and colleagues accounts for various comorbidities, it may not apply equally to all patients. “As I understand it, they’re just using migraine with aura as a single factor,” said Dr. Caplan. Variables such as prolonged aura, frequent episodes, and aura-related deficit are associated with increased risk of stroke, but the risk score does not examine these factors.
Patients with severe, long-lasting attacks or attacks that involve weakness or aphasia should receive prophylactic treatment to prevent vasoconstriction, such as verapamil (Verelan), said Dr. Caplan. Antithrombotic agents such as aspirin also may be appropriate prophylaxis. Whether effective treatment of migraine with aura decreases the risk of stroke remains unknown.
SOURCE: Trivedi T et al. ISC 2020. Abstract WMP117.
REPORTING FROM ISC 2020
Teriflunomide increases the likelihood of achieving NEDA in relapsing-remitting MS
WEST PALM BEACH, FLA. – , according to an analysis presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. Teriflunomide reduces the risks of relapse, relapse resulting in hospital admission, and relapse resulting in prolonged hospitalization, compared with placebo.
Teriflunomide modulates the immune system and is an approved treatment for relapsing-remitting MS and clinically isolated syndrome. The phase 3 TEMSO study provided evidence that established the treatment’s safety and efficacy. In that study, significantly more patients who received a 14-mg dose of teriflunomide achieved NEDA, compared with patients who received placebo. Researchers generally weight all components of NEDA (i.e., confirmed disability worsening [CDW], relapse, and unique active MRI lesions) equally, but this approach could limit the interpretation of how each endpoint contributes to the effectiveness of a disease-modifying therapy.
A new analysis of TEMSO data
Keith R. Edwards, MD, director of the MS Center of Northeastern New York in Latham and colleagues conducted a win ratio matched-pairs analysis of TEMSO data to evaluate the efficacy of teriflunomide in enabling patients to achieve NEDA. In this analysis, the components of NEDA were assessed in order of priority, rather than as factors of equal weight.
In TEMSO, patients with relapsing-remitting MS received placebo or 14 mg of teriflunomide for 108 weeks. Dr. Edwards and colleagues matched active and control patients according to baseline characteristics. They compared the occurrence of disease activity events between the members of each pair. If a patient receiving teriflunomide had an event later than a control did, or did not have the event at all, teriflunomide was considered to “win.” If neither patient in a pair had a given event, the researchers omitted the pair from their analysis. Dr. Edwards and colleagues counted wins and summarized them as ratios. They conducted a second win ratio analysis of all relapses and relapses resulting in deaths, life-threatening events, prolonged hospitalizations, and hospital admissions.
NEDA components were ranked and assessed in the following order of decreasing priority: CDW, relapse, unique active MRI lesions. In a sensitivity analysis, the investigators ranked and assessed these components in the reverse order.
Sensitivity analysis supported primary analysis
Dr. Edwards and colleagues included 363 participants who received placebo and 358 who received teriflunomide in their analysis. Baseline characteristics did not differ significantly between the two groups. The population’s mean age was approximately 38 years, and about 73% of participants were female. The population’s mean baseline Expanded Disability Status Scale score was 2.7. Overall, about 72% of participants completed the study.
The researchers created 321 risk-matched pairs of participants. The win ratio analysis indicated that patients who received teriflunomide were significantly more likely to achieve NEDA, compared with controls (win ratio, 1.33). When the investigators analyzed the data by prioritizing the NEDA components in the reverse order, they found similar results (win ratio, 1.41).
When Dr. Edwards and colleagues analyzed relapse severity, they found that no relapses resulting in death or life-threatening events occurred in the active or control groups. Compared with placebo, teriflunomide significantly reduced the risk of relapse, relapses resulting in hospital admissions, and relapses resulting in prolonged hospitalizations (win ratio, 1.37).
The TEMSO study was funded by Sanofi. Dr. Edwards received grant or research support from Biogen, Genentech, Genzyme, and Novartis. Several authors received funding from Sanofi.
SOURCE: Edwards KR et al. ACTRIMS 2020, Abstract P036.
WEST PALM BEACH, FLA. – , according to an analysis presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. Teriflunomide reduces the risks of relapse, relapse resulting in hospital admission, and relapse resulting in prolonged hospitalization, compared with placebo.
Teriflunomide modulates the immune system and is an approved treatment for relapsing-remitting MS and clinically isolated syndrome. The phase 3 TEMSO study provided evidence that established the treatment’s safety and efficacy. In that study, significantly more patients who received a 14-mg dose of teriflunomide achieved NEDA, compared with patients who received placebo. Researchers generally weight all components of NEDA (i.e., confirmed disability worsening [CDW], relapse, and unique active MRI lesions) equally, but this approach could limit the interpretation of how each endpoint contributes to the effectiveness of a disease-modifying therapy.
A new analysis of TEMSO data
Keith R. Edwards, MD, director of the MS Center of Northeastern New York in Latham and colleagues conducted a win ratio matched-pairs analysis of TEMSO data to evaluate the efficacy of teriflunomide in enabling patients to achieve NEDA. In this analysis, the components of NEDA were assessed in order of priority, rather than as factors of equal weight.
In TEMSO, patients with relapsing-remitting MS received placebo or 14 mg of teriflunomide for 108 weeks. Dr. Edwards and colleagues matched active and control patients according to baseline characteristics. They compared the occurrence of disease activity events between the members of each pair. If a patient receiving teriflunomide had an event later than a control did, or did not have the event at all, teriflunomide was considered to “win.” If neither patient in a pair had a given event, the researchers omitted the pair from their analysis. Dr. Edwards and colleagues counted wins and summarized them as ratios. They conducted a second win ratio analysis of all relapses and relapses resulting in deaths, life-threatening events, prolonged hospitalizations, and hospital admissions.
NEDA components were ranked and assessed in the following order of decreasing priority: CDW, relapse, unique active MRI lesions. In a sensitivity analysis, the investigators ranked and assessed these components in the reverse order.
Sensitivity analysis supported primary analysis
Dr. Edwards and colleagues included 363 participants who received placebo and 358 who received teriflunomide in their analysis. Baseline characteristics did not differ significantly between the two groups. The population’s mean age was approximately 38 years, and about 73% of participants were female. The population’s mean baseline Expanded Disability Status Scale score was 2.7. Overall, about 72% of participants completed the study.
The researchers created 321 risk-matched pairs of participants. The win ratio analysis indicated that patients who received teriflunomide were significantly more likely to achieve NEDA, compared with controls (win ratio, 1.33). When the investigators analyzed the data by prioritizing the NEDA components in the reverse order, they found similar results (win ratio, 1.41).
When Dr. Edwards and colleagues analyzed relapse severity, they found that no relapses resulting in death or life-threatening events occurred in the active or control groups. Compared with placebo, teriflunomide significantly reduced the risk of relapse, relapses resulting in hospital admissions, and relapses resulting in prolonged hospitalizations (win ratio, 1.37).
The TEMSO study was funded by Sanofi. Dr. Edwards received grant or research support from Biogen, Genentech, Genzyme, and Novartis. Several authors received funding from Sanofi.
SOURCE: Edwards KR et al. ACTRIMS 2020, Abstract P036.
WEST PALM BEACH, FLA. – , according to an analysis presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. Teriflunomide reduces the risks of relapse, relapse resulting in hospital admission, and relapse resulting in prolonged hospitalization, compared with placebo.
Teriflunomide modulates the immune system and is an approved treatment for relapsing-remitting MS and clinically isolated syndrome. The phase 3 TEMSO study provided evidence that established the treatment’s safety and efficacy. In that study, significantly more patients who received a 14-mg dose of teriflunomide achieved NEDA, compared with patients who received placebo. Researchers generally weight all components of NEDA (i.e., confirmed disability worsening [CDW], relapse, and unique active MRI lesions) equally, but this approach could limit the interpretation of how each endpoint contributes to the effectiveness of a disease-modifying therapy.
A new analysis of TEMSO data
Keith R. Edwards, MD, director of the MS Center of Northeastern New York in Latham and colleagues conducted a win ratio matched-pairs analysis of TEMSO data to evaluate the efficacy of teriflunomide in enabling patients to achieve NEDA. In this analysis, the components of NEDA were assessed in order of priority, rather than as factors of equal weight.
In TEMSO, patients with relapsing-remitting MS received placebo or 14 mg of teriflunomide for 108 weeks. Dr. Edwards and colleagues matched active and control patients according to baseline characteristics. They compared the occurrence of disease activity events between the members of each pair. If a patient receiving teriflunomide had an event later than a control did, or did not have the event at all, teriflunomide was considered to “win.” If neither patient in a pair had a given event, the researchers omitted the pair from their analysis. Dr. Edwards and colleagues counted wins and summarized them as ratios. They conducted a second win ratio analysis of all relapses and relapses resulting in deaths, life-threatening events, prolonged hospitalizations, and hospital admissions.
NEDA components were ranked and assessed in the following order of decreasing priority: CDW, relapse, unique active MRI lesions. In a sensitivity analysis, the investigators ranked and assessed these components in the reverse order.
Sensitivity analysis supported primary analysis
Dr. Edwards and colleagues included 363 participants who received placebo and 358 who received teriflunomide in their analysis. Baseline characteristics did not differ significantly between the two groups. The population’s mean age was approximately 38 years, and about 73% of participants were female. The population’s mean baseline Expanded Disability Status Scale score was 2.7. Overall, about 72% of participants completed the study.
The researchers created 321 risk-matched pairs of participants. The win ratio analysis indicated that patients who received teriflunomide were significantly more likely to achieve NEDA, compared with controls (win ratio, 1.33). When the investigators analyzed the data by prioritizing the NEDA components in the reverse order, they found similar results (win ratio, 1.41).
When Dr. Edwards and colleagues analyzed relapse severity, they found that no relapses resulting in death or life-threatening events occurred in the active or control groups. Compared with placebo, teriflunomide significantly reduced the risk of relapse, relapses resulting in hospital admissions, and relapses resulting in prolonged hospitalizations (win ratio, 1.37).
The TEMSO study was funded by Sanofi. Dr. Edwards received grant or research support from Biogen, Genentech, Genzyme, and Novartis. Several authors received funding from Sanofi.
SOURCE: Edwards KR et al. ACTRIMS 2020, Abstract P036.
REPORTING FROM ACTRIMS Forum 2020