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Long COVID symptoms reported by 6% of pediatric patients
The prevalence of long COVID in children has been unclear, and is complicated by the lack of a consistent definition, said Anna Funk, PhD, an epidemiologist at the University of Calgary (Alba.), during her online presentation of the findings at the 31st European Congress of Clinical Microbiology & Infectious Diseases.
In the several small studies conducted to date, rates range from 0% to 67% 2-4 months after infection, Dr. Funk reported.
To examine prevalence, she and her colleagues, as part of the Pediatric Emergency Research Network (PERN) global research consortium, assessed more than 10,500 children who were screened for SARS-CoV-2 when they presented to the ED at 1 of 41 study sites in 10 countries – Australia, Canada, Indonesia, the United States, plus three countries in Latin America and three in Western Europe – from March 2020 to June 15, 2021.
PERN researchers are following up with the more than 3,100 children who tested positive 14, 30, and 90 days after testing, tracking respiratory, neurologic, and psychobehavioral sequelae.
Dr. Funk presented data on the 1,884 children who tested positive for SARS-CoV-2 before Jan. 20, 2021, and who had completed 90-day follow-up; 447 of those children were hospitalized and 1,437 were not.
Symptoms were reported more often by children admitted to the hospital than not admitted (9.8% vs. 4.6%). Common persistent symptoms were respiratory in 2% of cases, systemic (such as fatigue and fever) in 2%, neurologic (such as headache, seizures, and continued loss of taste or smell) in 1%, and psychological (such as new-onset depression and anxiety) in 1%.
“This study provides the first good epidemiological data on persistent symptoms among SARS-CoV-2–infected children, regardless of severity,” said Kevin Messacar, MD, a pediatric infectious disease clinician and researcher at Children’s Hospital Colorado in Aurora, who was not involved in the study.
And the findings show that, although severe COVID and chronic symptoms are less common in children than in adults, they are “not nonexistent and need to be taken seriously,” he said in an interview.
After adjustment for country of enrollment, children aged 10-17 years were more likely to experience persistent symptoms than children younger than 1 year (odds ratio, 2.4; P = .002).
Hospitalized children were more than twice as likely to experience persistent symptoms as nonhospitalized children (OR, 2.5; P < .001). And children who presented to the ED with at least seven symptoms were four times more likely to have long-term symptoms than those who presented with fewer symptoms (OR, 4.02; P = .01).
‘Some reassurance’
“Given that COVID is new and is known to have acute cardiac and neurologic effects, particularly in children with [multisystem inflammatory syndrome], there were initially concerns about persistent cardiovascular and neurologic effects in any infected child,” Dr. Messacar explained. “These data provide some reassurance that this is uncommon among children with mild or moderate infections who are not hospitalized.”
But “the risk is not zero,” he added. “Getting children vaccinated when it is available to them and taking precautions to prevent unvaccinated children getting COVID is the best way to reduce the risk of severe disease or persistent symptoms.”
The study was limited by its lack of data on variants, reliance on self-reported symptoms, and a population drawn solely from EDs, Dr. Funk acknowledged.
No external funding source was noted. Dr. Messacar and Dr. Funk disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The prevalence of long COVID in children has been unclear, and is complicated by the lack of a consistent definition, said Anna Funk, PhD, an epidemiologist at the University of Calgary (Alba.), during her online presentation of the findings at the 31st European Congress of Clinical Microbiology & Infectious Diseases.
In the several small studies conducted to date, rates range from 0% to 67% 2-4 months after infection, Dr. Funk reported.
To examine prevalence, she and her colleagues, as part of the Pediatric Emergency Research Network (PERN) global research consortium, assessed more than 10,500 children who were screened for SARS-CoV-2 when they presented to the ED at 1 of 41 study sites in 10 countries – Australia, Canada, Indonesia, the United States, plus three countries in Latin America and three in Western Europe – from March 2020 to June 15, 2021.
PERN researchers are following up with the more than 3,100 children who tested positive 14, 30, and 90 days after testing, tracking respiratory, neurologic, and psychobehavioral sequelae.
Dr. Funk presented data on the 1,884 children who tested positive for SARS-CoV-2 before Jan. 20, 2021, and who had completed 90-day follow-up; 447 of those children were hospitalized and 1,437 were not.
Symptoms were reported more often by children admitted to the hospital than not admitted (9.8% vs. 4.6%). Common persistent symptoms were respiratory in 2% of cases, systemic (such as fatigue and fever) in 2%, neurologic (such as headache, seizures, and continued loss of taste or smell) in 1%, and psychological (such as new-onset depression and anxiety) in 1%.
“This study provides the first good epidemiological data on persistent symptoms among SARS-CoV-2–infected children, regardless of severity,” said Kevin Messacar, MD, a pediatric infectious disease clinician and researcher at Children’s Hospital Colorado in Aurora, who was not involved in the study.
And the findings show that, although severe COVID and chronic symptoms are less common in children than in adults, they are “not nonexistent and need to be taken seriously,” he said in an interview.
After adjustment for country of enrollment, children aged 10-17 years were more likely to experience persistent symptoms than children younger than 1 year (odds ratio, 2.4; P = .002).
Hospitalized children were more than twice as likely to experience persistent symptoms as nonhospitalized children (OR, 2.5; P < .001). And children who presented to the ED with at least seven symptoms were four times more likely to have long-term symptoms than those who presented with fewer symptoms (OR, 4.02; P = .01).
‘Some reassurance’
“Given that COVID is new and is known to have acute cardiac and neurologic effects, particularly in children with [multisystem inflammatory syndrome], there were initially concerns about persistent cardiovascular and neurologic effects in any infected child,” Dr. Messacar explained. “These data provide some reassurance that this is uncommon among children with mild or moderate infections who are not hospitalized.”
But “the risk is not zero,” he added. “Getting children vaccinated when it is available to them and taking precautions to prevent unvaccinated children getting COVID is the best way to reduce the risk of severe disease or persistent symptoms.”
The study was limited by its lack of data on variants, reliance on self-reported symptoms, and a population drawn solely from EDs, Dr. Funk acknowledged.
No external funding source was noted. Dr. Messacar and Dr. Funk disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The prevalence of long COVID in children has been unclear, and is complicated by the lack of a consistent definition, said Anna Funk, PhD, an epidemiologist at the University of Calgary (Alba.), during her online presentation of the findings at the 31st European Congress of Clinical Microbiology & Infectious Diseases.
In the several small studies conducted to date, rates range from 0% to 67% 2-4 months after infection, Dr. Funk reported.
To examine prevalence, she and her colleagues, as part of the Pediatric Emergency Research Network (PERN) global research consortium, assessed more than 10,500 children who were screened for SARS-CoV-2 when they presented to the ED at 1 of 41 study sites in 10 countries – Australia, Canada, Indonesia, the United States, plus three countries in Latin America and three in Western Europe – from March 2020 to June 15, 2021.
PERN researchers are following up with the more than 3,100 children who tested positive 14, 30, and 90 days after testing, tracking respiratory, neurologic, and psychobehavioral sequelae.
Dr. Funk presented data on the 1,884 children who tested positive for SARS-CoV-2 before Jan. 20, 2021, and who had completed 90-day follow-up; 447 of those children were hospitalized and 1,437 were not.
Symptoms were reported more often by children admitted to the hospital than not admitted (9.8% vs. 4.6%). Common persistent symptoms were respiratory in 2% of cases, systemic (such as fatigue and fever) in 2%, neurologic (such as headache, seizures, and continued loss of taste or smell) in 1%, and psychological (such as new-onset depression and anxiety) in 1%.
“This study provides the first good epidemiological data on persistent symptoms among SARS-CoV-2–infected children, regardless of severity,” said Kevin Messacar, MD, a pediatric infectious disease clinician and researcher at Children’s Hospital Colorado in Aurora, who was not involved in the study.
And the findings show that, although severe COVID and chronic symptoms are less common in children than in adults, they are “not nonexistent and need to be taken seriously,” he said in an interview.
After adjustment for country of enrollment, children aged 10-17 years were more likely to experience persistent symptoms than children younger than 1 year (odds ratio, 2.4; P = .002).
Hospitalized children were more than twice as likely to experience persistent symptoms as nonhospitalized children (OR, 2.5; P < .001). And children who presented to the ED with at least seven symptoms were four times more likely to have long-term symptoms than those who presented with fewer symptoms (OR, 4.02; P = .01).
‘Some reassurance’
“Given that COVID is new and is known to have acute cardiac and neurologic effects, particularly in children with [multisystem inflammatory syndrome], there were initially concerns about persistent cardiovascular and neurologic effects in any infected child,” Dr. Messacar explained. “These data provide some reassurance that this is uncommon among children with mild or moderate infections who are not hospitalized.”
But “the risk is not zero,” he added. “Getting children vaccinated when it is available to them and taking precautions to prevent unvaccinated children getting COVID is the best way to reduce the risk of severe disease or persistent symptoms.”
The study was limited by its lack of data on variants, reliance on self-reported symptoms, and a population drawn solely from EDs, Dr. Funk acknowledged.
No external funding source was noted. Dr. Messacar and Dr. Funk disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Patients on methotrexate show T-cell response to Pfizer vaccine
People taking methotrexate had low antibody responses after the first dose of the Pfizer-BioNTech mRNA COVID-19 vaccine, but did show evidence of T-cell–mediated immune responses, findings from a small study show.
The common immunosuppressant has previously been linked to poor antibody responses to mRNA COVID-19 vaccines, but this appears to be the first study to look at T-cell responses in people taking methotrexate.
The study findings were presented online July 11 at the 31st European Congress of Clinical Microbiology & Infectious Diseases and published in The Lancet Rheumatology.
“These findings indicate that seroconversion alone might not adequately reflect vaccine immunogenicity in individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression, and caution against routine use of seroconversion data in isolation in clinical practice,” Satveer K. Mahil, MBBChir, PhD, from St. John’s Institute of Dermatology, Guy’s and St. Thomas’ NHS Foundation Trust, London, and colleagues wrote.
“When taking into account functional humoral immunity and T-cell responses, our data suggest that targeted biologics do not impair vaccine responses and provide some reassurance to this vulnerable population,” they wrote. “Notably, although methotrexate attenuated humoral immunity, cellular responses were preserved.”
Dr. Mahil and colleagues assessed 84 consecutive patients from a psoriasis specialist clinic that serves London and southeast England. Median age of the cohort was 43 years, and 85% were White. All had a confirmed psoriasis diagnosis, received the first dose of the Pfizer-BioNTech COVID-19 vaccine, and were taking either methotrexate (17 patients) or a targeted biologic (27 were taking a tumor necrosis factor inhibitor, 15 an interleukin-17 inhibitor, and 25 an IL-23 inhibitor). In addition, 17 healthy patients not receiving immunosuppression therapy who received the Pfizer-BioNTech vaccine served as the control group.
Four weeks after the study participants received their first dose of the vaccine, 78% of the immunosuppressed patients underwent seroconversion – producing measurable antibodies – as did 100% of the control group. Patients taking methotrexate had the lowest seroconversion rate at 47%, compared with 79% with TNF inhibitors, 83% with IL-23 inhibitors, and 100% with IL-17 inhibitors.
Participants taking methotrexate also had lower neutralizing activity against SARS-CoV-2 than control subjects and those taking a targeted biologic, who had similar levels of neutralizing activity.
All participants had low neutralizing titers against the alpha (B.1.1.7) variant.
The researchers also assessed cellular immunity, “defined as the presence of T cells secreting interferon-gamma, IL-2, or IL-21 in response to stimulation with two peptide pools spanning the entire length of the SARS-CoV-2 spike glycoprotein.”
A T-cell response was seen in 84% of participants taking immunosuppressants, including 93% of those in the methotrexate group and 69% of control subjects.
‘Some protection is better than none’
These findings regarding antibodies match what has been seen in other research, said Ignacio Sanz, MD, director of the Lowance Center for Human Immunology at Emory University, Atlanta.
It would be helpful to see antibody responses after the second doses, he added. Those data will be reported later, according to Dr. Mahil and colleagues.
“The authors make the valid point that T-cell immunity should also be measured. The information is meaningful and supports the idea that there could be protection still provided,” Dr. Sanz said in an interview, adding that it would have been helpful to see CD8 T-cell response as well.
“My message to patients, still, is that some protection is better than none, and that, indeed, protection may be afforded in different ways, including T-cell immunity, which, to the extent tested, seems to be induced,” he said. But discussion of B cells independent of their role in producing antibodies is missing.
“When it comes to B-cell responses, antibodies are the easier and more direct measurement. However, it is perfectly possible that the vaccine may fail to induce high antibody titers and still generate good B-cell immunity,” in the same way virus-specific memory B cells do, he explained. “They would not directly produce antibodies, yet they would be available for a good and quick response in the case of subsequent encounter with the virus and, incidentally, in the case of a booster dose. It is possible that the generation of antibody-producing plasma cells might be uncoupled from the generation of memory B cells.”
Temporarily stopping methotrexate
It is well known that methotrexate impairs humoral responses to influenza and pneumococcal vaccines, write Caoilfhionn M. Connolly, MD, and Julie J. Paik, MD, both from the Johns Hopkins University, Baltimore, in an accompanying comment.
Research has also shown that temporarily stopping methotrexate therapy for 2 weeks enhances response to the flu vaccine in patients with rheumatoid arthritis, which prompted the American College of Rheumatology to recommended temporary interruption of methotrexate for 1 week after each dose of the COVID-19 vaccine, the pair notes.
“Although it is encouraging that cellular responses appear to be preserved even in patients with poor humoral responses, these findings are not consistent across study groups,” Dr. Connolly and Dr. Paik explained. “During this period of clinical uncertainty, patients might remain vulnerable, especially after the first dose, and should engage in risk mitigation strategies.”
Mild adverse events after vaccination were reported by 75% of the immunosuppressed patients – most commonly injection-site pain, headache, and fatigue – and by 94% of control subjects. No participants reported moderate or severe adverse effects.
However, 11% of immunosuppressed patients reported a worsening of psoriasis symptoms after vaccination.
This research was funded by the U.K. National Institute for Health Research. Dr. Mahil has received departmental income from AbbVie, Celgene, Eli Lilly, Janssen-Cilag, Novartis, Sano, and UCB unrelated to this study. Seven other authors have relationships with a wide range of pharmaceutical and other companies. Dr. Sanz, Dr. Connolly, and Dr. Paik disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
People taking methotrexate had low antibody responses after the first dose of the Pfizer-BioNTech mRNA COVID-19 vaccine, but did show evidence of T-cell–mediated immune responses, findings from a small study show.
The common immunosuppressant has previously been linked to poor antibody responses to mRNA COVID-19 vaccines, but this appears to be the first study to look at T-cell responses in people taking methotrexate.
The study findings were presented online July 11 at the 31st European Congress of Clinical Microbiology & Infectious Diseases and published in The Lancet Rheumatology.
“These findings indicate that seroconversion alone might not adequately reflect vaccine immunogenicity in individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression, and caution against routine use of seroconversion data in isolation in clinical practice,” Satveer K. Mahil, MBBChir, PhD, from St. John’s Institute of Dermatology, Guy’s and St. Thomas’ NHS Foundation Trust, London, and colleagues wrote.
“When taking into account functional humoral immunity and T-cell responses, our data suggest that targeted biologics do not impair vaccine responses and provide some reassurance to this vulnerable population,” they wrote. “Notably, although methotrexate attenuated humoral immunity, cellular responses were preserved.”
Dr. Mahil and colleagues assessed 84 consecutive patients from a psoriasis specialist clinic that serves London and southeast England. Median age of the cohort was 43 years, and 85% were White. All had a confirmed psoriasis diagnosis, received the first dose of the Pfizer-BioNTech COVID-19 vaccine, and were taking either methotrexate (17 patients) or a targeted biologic (27 were taking a tumor necrosis factor inhibitor, 15 an interleukin-17 inhibitor, and 25 an IL-23 inhibitor). In addition, 17 healthy patients not receiving immunosuppression therapy who received the Pfizer-BioNTech vaccine served as the control group.
Four weeks after the study participants received their first dose of the vaccine, 78% of the immunosuppressed patients underwent seroconversion – producing measurable antibodies – as did 100% of the control group. Patients taking methotrexate had the lowest seroconversion rate at 47%, compared with 79% with TNF inhibitors, 83% with IL-23 inhibitors, and 100% with IL-17 inhibitors.
Participants taking methotrexate also had lower neutralizing activity against SARS-CoV-2 than control subjects and those taking a targeted biologic, who had similar levels of neutralizing activity.
All participants had low neutralizing titers against the alpha (B.1.1.7) variant.
The researchers also assessed cellular immunity, “defined as the presence of T cells secreting interferon-gamma, IL-2, or IL-21 in response to stimulation with two peptide pools spanning the entire length of the SARS-CoV-2 spike glycoprotein.”
A T-cell response was seen in 84% of participants taking immunosuppressants, including 93% of those in the methotrexate group and 69% of control subjects.
‘Some protection is better than none’
These findings regarding antibodies match what has been seen in other research, said Ignacio Sanz, MD, director of the Lowance Center for Human Immunology at Emory University, Atlanta.
It would be helpful to see antibody responses after the second doses, he added. Those data will be reported later, according to Dr. Mahil and colleagues.
“The authors make the valid point that T-cell immunity should also be measured. The information is meaningful and supports the idea that there could be protection still provided,” Dr. Sanz said in an interview, adding that it would have been helpful to see CD8 T-cell response as well.
“My message to patients, still, is that some protection is better than none, and that, indeed, protection may be afforded in different ways, including T-cell immunity, which, to the extent tested, seems to be induced,” he said. But discussion of B cells independent of their role in producing antibodies is missing.
“When it comes to B-cell responses, antibodies are the easier and more direct measurement. However, it is perfectly possible that the vaccine may fail to induce high antibody titers and still generate good B-cell immunity,” in the same way virus-specific memory B cells do, he explained. “They would not directly produce antibodies, yet they would be available for a good and quick response in the case of subsequent encounter with the virus and, incidentally, in the case of a booster dose. It is possible that the generation of antibody-producing plasma cells might be uncoupled from the generation of memory B cells.”
Temporarily stopping methotrexate
It is well known that methotrexate impairs humoral responses to influenza and pneumococcal vaccines, write Caoilfhionn M. Connolly, MD, and Julie J. Paik, MD, both from the Johns Hopkins University, Baltimore, in an accompanying comment.
Research has also shown that temporarily stopping methotrexate therapy for 2 weeks enhances response to the flu vaccine in patients with rheumatoid arthritis, which prompted the American College of Rheumatology to recommended temporary interruption of methotrexate for 1 week after each dose of the COVID-19 vaccine, the pair notes.
“Although it is encouraging that cellular responses appear to be preserved even in patients with poor humoral responses, these findings are not consistent across study groups,” Dr. Connolly and Dr. Paik explained. “During this period of clinical uncertainty, patients might remain vulnerable, especially after the first dose, and should engage in risk mitigation strategies.”
Mild adverse events after vaccination were reported by 75% of the immunosuppressed patients – most commonly injection-site pain, headache, and fatigue – and by 94% of control subjects. No participants reported moderate or severe adverse effects.
However, 11% of immunosuppressed patients reported a worsening of psoriasis symptoms after vaccination.
This research was funded by the U.K. National Institute for Health Research. Dr. Mahil has received departmental income from AbbVie, Celgene, Eli Lilly, Janssen-Cilag, Novartis, Sano, and UCB unrelated to this study. Seven other authors have relationships with a wide range of pharmaceutical and other companies. Dr. Sanz, Dr. Connolly, and Dr. Paik disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
People taking methotrexate had low antibody responses after the first dose of the Pfizer-BioNTech mRNA COVID-19 vaccine, but did show evidence of T-cell–mediated immune responses, findings from a small study show.
The common immunosuppressant has previously been linked to poor antibody responses to mRNA COVID-19 vaccines, but this appears to be the first study to look at T-cell responses in people taking methotrexate.
The study findings were presented online July 11 at the 31st European Congress of Clinical Microbiology & Infectious Diseases and published in The Lancet Rheumatology.
“These findings indicate that seroconversion alone might not adequately reflect vaccine immunogenicity in individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression, and caution against routine use of seroconversion data in isolation in clinical practice,” Satveer K. Mahil, MBBChir, PhD, from St. John’s Institute of Dermatology, Guy’s and St. Thomas’ NHS Foundation Trust, London, and colleagues wrote.
“When taking into account functional humoral immunity and T-cell responses, our data suggest that targeted biologics do not impair vaccine responses and provide some reassurance to this vulnerable population,” they wrote. “Notably, although methotrexate attenuated humoral immunity, cellular responses were preserved.”
Dr. Mahil and colleagues assessed 84 consecutive patients from a psoriasis specialist clinic that serves London and southeast England. Median age of the cohort was 43 years, and 85% were White. All had a confirmed psoriasis diagnosis, received the first dose of the Pfizer-BioNTech COVID-19 vaccine, and were taking either methotrexate (17 patients) or a targeted biologic (27 were taking a tumor necrosis factor inhibitor, 15 an interleukin-17 inhibitor, and 25 an IL-23 inhibitor). In addition, 17 healthy patients not receiving immunosuppression therapy who received the Pfizer-BioNTech vaccine served as the control group.
Four weeks after the study participants received their first dose of the vaccine, 78% of the immunosuppressed patients underwent seroconversion – producing measurable antibodies – as did 100% of the control group. Patients taking methotrexate had the lowest seroconversion rate at 47%, compared with 79% with TNF inhibitors, 83% with IL-23 inhibitors, and 100% with IL-17 inhibitors.
Participants taking methotrexate also had lower neutralizing activity against SARS-CoV-2 than control subjects and those taking a targeted biologic, who had similar levels of neutralizing activity.
All participants had low neutralizing titers against the alpha (B.1.1.7) variant.
The researchers also assessed cellular immunity, “defined as the presence of T cells secreting interferon-gamma, IL-2, or IL-21 in response to stimulation with two peptide pools spanning the entire length of the SARS-CoV-2 spike glycoprotein.”
A T-cell response was seen in 84% of participants taking immunosuppressants, including 93% of those in the methotrexate group and 69% of control subjects.
‘Some protection is better than none’
These findings regarding antibodies match what has been seen in other research, said Ignacio Sanz, MD, director of the Lowance Center for Human Immunology at Emory University, Atlanta.
It would be helpful to see antibody responses after the second doses, he added. Those data will be reported later, according to Dr. Mahil and colleagues.
“The authors make the valid point that T-cell immunity should also be measured. The information is meaningful and supports the idea that there could be protection still provided,” Dr. Sanz said in an interview, adding that it would have been helpful to see CD8 T-cell response as well.
“My message to patients, still, is that some protection is better than none, and that, indeed, protection may be afforded in different ways, including T-cell immunity, which, to the extent tested, seems to be induced,” he said. But discussion of B cells independent of their role in producing antibodies is missing.
“When it comes to B-cell responses, antibodies are the easier and more direct measurement. However, it is perfectly possible that the vaccine may fail to induce high antibody titers and still generate good B-cell immunity,” in the same way virus-specific memory B cells do, he explained. “They would not directly produce antibodies, yet they would be available for a good and quick response in the case of subsequent encounter with the virus and, incidentally, in the case of a booster dose. It is possible that the generation of antibody-producing plasma cells might be uncoupled from the generation of memory B cells.”
Temporarily stopping methotrexate
It is well known that methotrexate impairs humoral responses to influenza and pneumococcal vaccines, write Caoilfhionn M. Connolly, MD, and Julie J. Paik, MD, both from the Johns Hopkins University, Baltimore, in an accompanying comment.
Research has also shown that temporarily stopping methotrexate therapy for 2 weeks enhances response to the flu vaccine in patients with rheumatoid arthritis, which prompted the American College of Rheumatology to recommended temporary interruption of methotrexate for 1 week after each dose of the COVID-19 vaccine, the pair notes.
“Although it is encouraging that cellular responses appear to be preserved even in patients with poor humoral responses, these findings are not consistent across study groups,” Dr. Connolly and Dr. Paik explained. “During this period of clinical uncertainty, patients might remain vulnerable, especially after the first dose, and should engage in risk mitigation strategies.”
Mild adverse events after vaccination were reported by 75% of the immunosuppressed patients – most commonly injection-site pain, headache, and fatigue – and by 94% of control subjects. No participants reported moderate or severe adverse effects.
However, 11% of immunosuppressed patients reported a worsening of psoriasis symptoms after vaccination.
This research was funded by the U.K. National Institute for Health Research. Dr. Mahil has received departmental income from AbbVie, Celgene, Eli Lilly, Janssen-Cilag, Novartis, Sano, and UCB unrelated to this study. Seven other authors have relationships with a wide range of pharmaceutical and other companies. Dr. Sanz, Dr. Connolly, and Dr. Paik disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Standard medical mask can protect wearer from aerosols
A standard medical face mask is more effective at preventing the wearer from inhaling aerosols without causing substantial breathing resistance than various cloth, medical, or respirator masks, new research shows.
“Medical face masks with good filtration efficacies can provide even better protective effects than KN95 respirators,” Christian Sterr, MD, from Philipps University of Marburg (Germany), and colleagues wrote. “FFP2 respirators, on the other hand, could be useful in high-risk situations but require greater breathing effort and therefore physical stress for users.”
Extensive evidence has shown that face masks are an excellent form of source control, preventing infectious people from spreading the SARS-CoV-2 virus into the environment. But evidence has been less clear about how well masks protect the wearer from inhaling particles containing the virus.
The researchers conducted three experiments to test 32 different face masks. The findings were presented at the 31st European Congress of Clinical Microbiology & Infectious Diseases and published online in PLOS One .
First they tested pressure drop, which “relates to how easily air can pass through the material,” said Chris Cappa, PhD, professor of civil and environmental engineering at the University of California, Davis, who was not involved with the study.
“Higher pressure drops mean that there is greater resistance to the air passing through. A higher pressure drop will typically mean breathing through the material will be slightly more challenging, compared to a low pressure drop. There is no relationship between pressure drop and the mask effectiveness,” he said in an interview.
Pressure drop was lowest with type II medical face masks, the typical three-ply surgical masks designed to stop large particles expelled by the wearer from entering the environment, was highest with respirators, including KN95 and FFP2 masks, and varied with the different cloth masks tested.
Next the researchers compared filtration efficacy, which “refers to how well the material removes particles from the air that passes through the mask material,” Dr. Cappa explained. They did this by placing each mask over the opening to an air collector that measured how many particles got through. “A mask that has 100% filtration efficacy will remove all particles from the air that passes through it and 0% means that no particles are removed.”
Cloth masks had the lowest filtration efficacy, at 28%. Certified face masks that met European Standards had a relatively high efficacy, at 70%; for uncertified face masks, filtration efficacy was 63%. As expected, KN95 and FFP2 masks had the highest filtration efficacy, at 94% and 98%, respectively.Finally, the researchers tested as-worn filtration efficacies. They placed each mask on a dummy head with an artificial airway that collected airborne particles. They then pumped a mixture of aerosol particles – ranging in size from 0.3 to 2.0 mcm – and particle-free pressurized air into the air-proof acrylic chamber in which the head was placed.
In this experiment, cloth masks and noncertified face masks were least effective, filtering less than 20% of aerosols. Interestingly, the cloth face mask with the highest filtration on its own (84%) had the lowest filtration efficacy (9%), apparently because of its very high pressure drop (breathing resistance). When more effort is required to breathe through a mask, more air can bypass the filtration system.
Type II medical face masks, however, filtered 47% of aerosols, KN95 masks filtered 41%, and FFP2 masks filtered 65%. Face shields did not prevent the inhalation of any aerosols.
“We know that face shields will only be effective in stopping very large droplets, essentially visible spittle,” Dr. Cappa explained. “Most of the particles that we exhale will travel right around a face shield.”
The “optimal mask effect is a combination of high filter performance and low filter resistance,” which applies to most of the FFP2 and medical type II face masks tested, Dr. Sterr and colleagues wrote. “The type II medical masks in our random sample showed very good as-worn filtration performances with a low additional work of breathing at the same time.”
Although this study showed how well different masks filtered out particles, it could not assess how well different masks prevent actual infection.
“Like any virus, SARS-CoV-2 can only infect people as long as it is viable,” the researchers wrote. “Moreover, a certain number of viable virus particles need to be inhaled to trigger an infection. Thus, the assessed filtration efficacy may differ from the provided protection rate against SARS-CoV-2.”
In addition, particles containing the virus could dry out while going through the mask and become less infectious. “Even a small reduction in inhaled particles might prevent infection or at least lead to a less severe infection,” they noted.
In fact, filtration efficacy does not necessarily indicate how well the mask filters out particles while being worn. “This might be due to the combined effects of mask fit and pressure drop of the mask material and therefore tendency for mask leakage,” the team wrote. “High pressure drop results in higher breathing resistance and therefore supports leakage, especially if combined to a loosely fitting mask.”
These findings are “in line with what we already knew,” Dr. Cappa explained. “Even if the mask material filters out nearly all particles that pass through it, as is the case for high-efficiency masks such as N95 and FFP2, if the mask does not fit well, then it will only provide moderate protection for the wearer.”
Although the findings reaffirm the different levels of filtration provided by various cloth masks, they do not “provide any guidance on which types of cloth masks are better or worse,” he said. But they do show that “medical face masks will generally provide more protection to the wearer.”
It’s not surprising that face shields offer little protection from aerosols, Dr. Cappa said, but they can provide added protection when worn with a mask.
“A face shield could prevent large droplets that might shoot out when a person coughs or sneezes from depositing on a person’s eye,” he pointed out. And it can help “redirect the plume of particles that an infected person exhales, which could be useful in close quarters. However, even then those particles will keep moving around and could be inhaled. A mask can really help to decrease the amount inhaled.”
The study did not use external funding. The authors and Dr. Cappa disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A standard medical face mask is more effective at preventing the wearer from inhaling aerosols without causing substantial breathing resistance than various cloth, medical, or respirator masks, new research shows.
“Medical face masks with good filtration efficacies can provide even better protective effects than KN95 respirators,” Christian Sterr, MD, from Philipps University of Marburg (Germany), and colleagues wrote. “FFP2 respirators, on the other hand, could be useful in high-risk situations but require greater breathing effort and therefore physical stress for users.”
Extensive evidence has shown that face masks are an excellent form of source control, preventing infectious people from spreading the SARS-CoV-2 virus into the environment. But evidence has been less clear about how well masks protect the wearer from inhaling particles containing the virus.
The researchers conducted three experiments to test 32 different face masks. The findings were presented at the 31st European Congress of Clinical Microbiology & Infectious Diseases and published online in PLOS One .
First they tested pressure drop, which “relates to how easily air can pass through the material,” said Chris Cappa, PhD, professor of civil and environmental engineering at the University of California, Davis, who was not involved with the study.
“Higher pressure drops mean that there is greater resistance to the air passing through. A higher pressure drop will typically mean breathing through the material will be slightly more challenging, compared to a low pressure drop. There is no relationship between pressure drop and the mask effectiveness,” he said in an interview.
Pressure drop was lowest with type II medical face masks, the typical three-ply surgical masks designed to stop large particles expelled by the wearer from entering the environment, was highest with respirators, including KN95 and FFP2 masks, and varied with the different cloth masks tested.
Next the researchers compared filtration efficacy, which “refers to how well the material removes particles from the air that passes through the mask material,” Dr. Cappa explained. They did this by placing each mask over the opening to an air collector that measured how many particles got through. “A mask that has 100% filtration efficacy will remove all particles from the air that passes through it and 0% means that no particles are removed.”
Cloth masks had the lowest filtration efficacy, at 28%. Certified face masks that met European Standards had a relatively high efficacy, at 70%; for uncertified face masks, filtration efficacy was 63%. As expected, KN95 and FFP2 masks had the highest filtration efficacy, at 94% and 98%, respectively.Finally, the researchers tested as-worn filtration efficacies. They placed each mask on a dummy head with an artificial airway that collected airborne particles. They then pumped a mixture of aerosol particles – ranging in size from 0.3 to 2.0 mcm – and particle-free pressurized air into the air-proof acrylic chamber in which the head was placed.
In this experiment, cloth masks and noncertified face masks were least effective, filtering less than 20% of aerosols. Interestingly, the cloth face mask with the highest filtration on its own (84%) had the lowest filtration efficacy (9%), apparently because of its very high pressure drop (breathing resistance). When more effort is required to breathe through a mask, more air can bypass the filtration system.
Type II medical face masks, however, filtered 47% of aerosols, KN95 masks filtered 41%, and FFP2 masks filtered 65%. Face shields did not prevent the inhalation of any aerosols.
“We know that face shields will only be effective in stopping very large droplets, essentially visible spittle,” Dr. Cappa explained. “Most of the particles that we exhale will travel right around a face shield.”
The “optimal mask effect is a combination of high filter performance and low filter resistance,” which applies to most of the FFP2 and medical type II face masks tested, Dr. Sterr and colleagues wrote. “The type II medical masks in our random sample showed very good as-worn filtration performances with a low additional work of breathing at the same time.”
Although this study showed how well different masks filtered out particles, it could not assess how well different masks prevent actual infection.
“Like any virus, SARS-CoV-2 can only infect people as long as it is viable,” the researchers wrote. “Moreover, a certain number of viable virus particles need to be inhaled to trigger an infection. Thus, the assessed filtration efficacy may differ from the provided protection rate against SARS-CoV-2.”
In addition, particles containing the virus could dry out while going through the mask and become less infectious. “Even a small reduction in inhaled particles might prevent infection or at least lead to a less severe infection,” they noted.
In fact, filtration efficacy does not necessarily indicate how well the mask filters out particles while being worn. “This might be due to the combined effects of mask fit and pressure drop of the mask material and therefore tendency for mask leakage,” the team wrote. “High pressure drop results in higher breathing resistance and therefore supports leakage, especially if combined to a loosely fitting mask.”
These findings are “in line with what we already knew,” Dr. Cappa explained. “Even if the mask material filters out nearly all particles that pass through it, as is the case for high-efficiency masks such as N95 and FFP2, if the mask does not fit well, then it will only provide moderate protection for the wearer.”
Although the findings reaffirm the different levels of filtration provided by various cloth masks, they do not “provide any guidance on which types of cloth masks are better or worse,” he said. But they do show that “medical face masks will generally provide more protection to the wearer.”
It’s not surprising that face shields offer little protection from aerosols, Dr. Cappa said, but they can provide added protection when worn with a mask.
“A face shield could prevent large droplets that might shoot out when a person coughs or sneezes from depositing on a person’s eye,” he pointed out. And it can help “redirect the plume of particles that an infected person exhales, which could be useful in close quarters. However, even then those particles will keep moving around and could be inhaled. A mask can really help to decrease the amount inhaled.”
The study did not use external funding. The authors and Dr. Cappa disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A standard medical face mask is more effective at preventing the wearer from inhaling aerosols without causing substantial breathing resistance than various cloth, medical, or respirator masks, new research shows.
“Medical face masks with good filtration efficacies can provide even better protective effects than KN95 respirators,” Christian Sterr, MD, from Philipps University of Marburg (Germany), and colleagues wrote. “FFP2 respirators, on the other hand, could be useful in high-risk situations but require greater breathing effort and therefore physical stress for users.”
Extensive evidence has shown that face masks are an excellent form of source control, preventing infectious people from spreading the SARS-CoV-2 virus into the environment. But evidence has been less clear about how well masks protect the wearer from inhaling particles containing the virus.
The researchers conducted three experiments to test 32 different face masks. The findings were presented at the 31st European Congress of Clinical Microbiology & Infectious Diseases and published online in PLOS One .
First they tested pressure drop, which “relates to how easily air can pass through the material,” said Chris Cappa, PhD, professor of civil and environmental engineering at the University of California, Davis, who was not involved with the study.
“Higher pressure drops mean that there is greater resistance to the air passing through. A higher pressure drop will typically mean breathing through the material will be slightly more challenging, compared to a low pressure drop. There is no relationship between pressure drop and the mask effectiveness,” he said in an interview.
Pressure drop was lowest with type II medical face masks, the typical three-ply surgical masks designed to stop large particles expelled by the wearer from entering the environment, was highest with respirators, including KN95 and FFP2 masks, and varied with the different cloth masks tested.
Next the researchers compared filtration efficacy, which “refers to how well the material removes particles from the air that passes through the mask material,” Dr. Cappa explained. They did this by placing each mask over the opening to an air collector that measured how many particles got through. “A mask that has 100% filtration efficacy will remove all particles from the air that passes through it and 0% means that no particles are removed.”
Cloth masks had the lowest filtration efficacy, at 28%. Certified face masks that met European Standards had a relatively high efficacy, at 70%; for uncertified face masks, filtration efficacy was 63%. As expected, KN95 and FFP2 masks had the highest filtration efficacy, at 94% and 98%, respectively.Finally, the researchers tested as-worn filtration efficacies. They placed each mask on a dummy head with an artificial airway that collected airborne particles. They then pumped a mixture of aerosol particles – ranging in size from 0.3 to 2.0 mcm – and particle-free pressurized air into the air-proof acrylic chamber in which the head was placed.
In this experiment, cloth masks and noncertified face masks were least effective, filtering less than 20% of aerosols. Interestingly, the cloth face mask with the highest filtration on its own (84%) had the lowest filtration efficacy (9%), apparently because of its very high pressure drop (breathing resistance). When more effort is required to breathe through a mask, more air can bypass the filtration system.
Type II medical face masks, however, filtered 47% of aerosols, KN95 masks filtered 41%, and FFP2 masks filtered 65%. Face shields did not prevent the inhalation of any aerosols.
“We know that face shields will only be effective in stopping very large droplets, essentially visible spittle,” Dr. Cappa explained. “Most of the particles that we exhale will travel right around a face shield.”
The “optimal mask effect is a combination of high filter performance and low filter resistance,” which applies to most of the FFP2 and medical type II face masks tested, Dr. Sterr and colleagues wrote. “The type II medical masks in our random sample showed very good as-worn filtration performances with a low additional work of breathing at the same time.”
Although this study showed how well different masks filtered out particles, it could not assess how well different masks prevent actual infection.
“Like any virus, SARS-CoV-2 can only infect people as long as it is viable,” the researchers wrote. “Moreover, a certain number of viable virus particles need to be inhaled to trigger an infection. Thus, the assessed filtration efficacy may differ from the provided protection rate against SARS-CoV-2.”
In addition, particles containing the virus could dry out while going through the mask and become less infectious. “Even a small reduction in inhaled particles might prevent infection or at least lead to a less severe infection,” they noted.
In fact, filtration efficacy does not necessarily indicate how well the mask filters out particles while being worn. “This might be due to the combined effects of mask fit and pressure drop of the mask material and therefore tendency for mask leakage,” the team wrote. “High pressure drop results in higher breathing resistance and therefore supports leakage, especially if combined to a loosely fitting mask.”
These findings are “in line with what we already knew,” Dr. Cappa explained. “Even if the mask material filters out nearly all particles that pass through it, as is the case for high-efficiency masks such as N95 and FFP2, if the mask does not fit well, then it will only provide moderate protection for the wearer.”
Although the findings reaffirm the different levels of filtration provided by various cloth masks, they do not “provide any guidance on which types of cloth masks are better or worse,” he said. But they do show that “medical face masks will generally provide more protection to the wearer.”
It’s not surprising that face shields offer little protection from aerosols, Dr. Cappa said, but they can provide added protection when worn with a mask.
“A face shield could prevent large droplets that might shoot out when a person coughs or sneezes from depositing on a person’s eye,” he pointed out. And it can help “redirect the plume of particles that an infected person exhales, which could be useful in close quarters. However, even then those particles will keep moving around and could be inhaled. A mask can really help to decrease the amount inhaled.”
The study did not use external funding. The authors and Dr. Cappa disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
COVID-19 vaccines are safe and effective for patients with migraine
according to a presentation at the American Headache Society’s 2021 annual meeting.
Amy Gelfand, MD, director of pediatric headache at University of California, San Francisco, reviewed common concerns migraine patients or their clinicians might have related any of the three vaccines, starting with a review of how the vaccines work – by targeting the spike protein of the SARS-CoV-2 virus.
“The vaccines induce response to that protein, but only that protein, so there’s no reason to think they’re going to cause the body to produce neutralizing antibodies against any of our migraine therapeutics,” Dr. Gelfand said. She added that the phase 3 clinical trials included participants from a wide range of ages and comorbidities, so there were likely many people in the trials who have migraine, though no subgroup analyses have been performed for this group or are likely to be performed.
Common questions
The two treatments people have the most questions about concerning the COVID-19 vaccine are onabotulinumtoxinA and CGRP pathway monoclonal antibodies (mAbs), likely because both of these are injections, as is the vaccine, Dr. Gelfand said. First, she reminded attendees that onabotulinumtoxinA is not a dermal filler, since some reports following administration of the Moderna vaccine suggested that some people with dermal fillers had swelling in those areas after vaccination.
In addition, “there’s no reason to think the onabotulinumtoxinA would influence our body’s immune response to any vaccine, so there’s no need to retime the onabotulinumtoxinA injections around COVID-19 vaccine administration,” Dr. Gelfand said.
Regarding mAbs, she acknowledged that some white blood cells have CGRP receptors, which may have a pro- or anti-inflammatory role, but clinical trials of mAbs did not show any evidence of being immunosuppressive or myelosuppressive.
“The monoclonal antibodies themselves have undergone engineering so that they are just going after their one target,” Dr. Gelfand said. “They’re not going to be expected to bind to anything else outside of their targets, so I don’t think there’s anything there to make us retime the monoclonal antibody administration relative to the COVID-19 vaccine.”
She did note that patients who choose to get mAbs injections in their arm instead of their thigh or abdomen may want to receive it in the opposite arm than they one they have gotten or will get the vaccine in since the vaccine can cause discomfort.
The other common question patients may have is whether taking any NSAIDs or acetaminophen before getting the COVID-19 vaccine will reduce their immune response to the vaccination. This concern arises because of past evidence showing that some infants tended to have lower immunologic responses when they received acetaminophen after their primary vaccines’ series, but the clinical significance of those reduced responses is not clear since they still had strong responses. Further, this effect was not seen with booster shots, suggesting it’s an age-dependent effect.
During the clinical trials of the AstraZeneca vaccine, several sites gave prophylactic paracetamol without any apparent detrimental effect on antibody response, Dr. Gelfand said. Further, the mRNA and adenovirus-vectored vaccines appear to induce antibodies far above what many believe is needed for protection.
“Even if there were a slight decrease, it’s not clear that that would have any kind of clinical significance for that person in terms of their level of protection against COVID-19,” she said. “Bottom line, it’s fine for patients to use either of these after administration of the COVID-19 vaccine.” The Centers for Disease Control and Prevention doesn’t recommend it prophylactically beforehand, but it’s fine to take it for a fever, aches or headache after getting the vaccine.
Migraine or vaccine reaction?
Dr. Gelfand then addressed whether it should affect physicians’ headache differential if seeing a patient who recently received an adenovirus-vectored vaccine, such as the Johnson & Johnson or AstraZeneca vaccines. The question relates to the discovery of a very rare potential adverse event from these vaccines: cerebral venous sinus thrombosis (CVST) with thrombocytopenia and thromboses in other major vessels, together called thrombosis thrombocytopenia syndrome (TTS). No TTS cases have been reported following mRNA vaccines.
TTS’s mechanism appears similar to autoimmune heparin-induced thrombocytopenia, where the body produces platelet-activating antibodies. TTS currently has three diagnostic criteria: new-onset thrombocytopenia (<150,000/microliter) without evidence of platelet clumping, venous or arterial thrombosis, and absence of prior exposure to heparin.
So far, TTS has been limited only to the vaccines that use an adenovirus vector. One male clinical trial participant experienced CVST with thrombocytopenia in Johnson & Johnson phase 3 trials, and 12 cases out of approximately 8 million Johnson & Johnson doses were reported to the Vaccine Adverse Event Reporting System between March 2 and April 21, 2021. Three TTS more cases followed these, resulting in 15 TTS events per 8 million doses.
In terms of clinical features, all 15 cases were females under age 60, mostly white, and all 11 who were tested were positive for the heparin-platelet factor 4 antibody test. TTS occurred 6-15 days after vaccination for these cases, and all but one had a headache. Their platelet count was 9,000-127,000. None were pregnant or postpartum.
“For us, as headache clinicians, the epidemiology of TTS overlaps with the epidemiology of migraine – they’re happening to the same group of patients,” Dr. Gelfand said. Most of the cases occurred in women aged 30-39 years, while the estimated incidence in women aged 50 or older is 0.9 cases per million doses.
The CDC has proceeded with the Johnson & Johnson vaccine because a risk-benefit analysis revealed that use of the vaccine will result in fewer hospitalization and deaths from COVID-19, compared with adverse events from the vaccine, Dr. Gelfand explained. However, the CDC notes that “women younger than 50 years old should be made aware of a rare risk of blood clots with low platelets following vaccination and the availability of other COVID-19 vaccines where this risk has not been observed.”
For clinicians, the existence of TTS raises a question when patients with a history of migraine call after having received the Johnson & Johnson vaccine, Dr. Gelfand said: “How do we know if this is a spontaneous attack, if it’s a headache provoked by receiving the vaccine, or they have one of these rare cases of [TTS]?”
Three things help with this differential, she said: timing, epidemiology, and headache phenotype. Headache after a vaccine is very common, but it usually happens within the first couple of hours or days after the vaccine. By day 4 after vaccination, few people had headaches in the clinical trials. Since TTS requires production of antibodies, a headache within a few hours of vaccination should not raise concerns about TTS. It should be considered, however, for patients who experience a headache within a week or 2 after vaccination.
Then consider the epidemiology: If it’s a woman between ages 18 and49 calling, the risk is higher than if it’s a male over age 50. Then consider whether there are any unusual headache features, positionality, encephalopathy, or clinical features that could suggest clots in other parts of the body, such as abdominal pain, shortness of breath, or pain in the legs.
“At the end of the day, if it’s a person who’s in this epidemiological window and they’re calling a week or 2 out from the Johnson & Johnson vaccine, we may just need to work it up and see,” Dr. Gelfand said. Work-up involves a CBC, a platelet count to see if they’re thrombocytopenic, and perhaps imaging, preferentially using MRI/MRV over CT since it’s a younger population. Treatment for CVST with thrombocytopenia is a nonheparin anticoagulant, and platelet transfusion should not occur before consulting with hematology.
Continue to vaccinate
“The big take home is that we should continue to vaccinate patients with migraine and that your current therapies do not interfere with the vaccine working and that the vaccine does not interact with our therapies,” Brian D. Loftus, MD, BSChE, immediate past president of the Southern Headache Society and a neurologist at Bellaire (Pa.) Neurology, said of the presentation. He also felt it was helpful to know that NSAIDs likely have no impact on the vaccines’ effectiveness as well.
“The most important new information for me was that the median onset of the CSVT was 8 days post vaccine,” Dr. Loftus said. “Typically, postvaccine headache is seen much sooner, within 1-2 days, so this is a useful clinical feature to separate out who needs to closer follow-up and possible neuroimaging.”
Given the epidemiology of those most likely to have TTS, Dr. Loftus said he would advise his female patients younger than 60 to simply get the Pfizer or Moderna vaccine since they appear safer for this demographic.
Dr. Gelfand is editor of the journal Headache but has no industry disclosures. Her spouse has received clinical trial grant support from Genentech and honoraria for editorial work from Dynamed Plus. Dr. Loftus has received grants or fees from Teva, Amgen, Abbvie, and Biohaven.
according to a presentation at the American Headache Society’s 2021 annual meeting.
Amy Gelfand, MD, director of pediatric headache at University of California, San Francisco, reviewed common concerns migraine patients or their clinicians might have related any of the three vaccines, starting with a review of how the vaccines work – by targeting the spike protein of the SARS-CoV-2 virus.
“The vaccines induce response to that protein, but only that protein, so there’s no reason to think they’re going to cause the body to produce neutralizing antibodies against any of our migraine therapeutics,” Dr. Gelfand said. She added that the phase 3 clinical trials included participants from a wide range of ages and comorbidities, so there were likely many people in the trials who have migraine, though no subgroup analyses have been performed for this group or are likely to be performed.
Common questions
The two treatments people have the most questions about concerning the COVID-19 vaccine are onabotulinumtoxinA and CGRP pathway monoclonal antibodies (mAbs), likely because both of these are injections, as is the vaccine, Dr. Gelfand said. First, she reminded attendees that onabotulinumtoxinA is not a dermal filler, since some reports following administration of the Moderna vaccine suggested that some people with dermal fillers had swelling in those areas after vaccination.
In addition, “there’s no reason to think the onabotulinumtoxinA would influence our body’s immune response to any vaccine, so there’s no need to retime the onabotulinumtoxinA injections around COVID-19 vaccine administration,” Dr. Gelfand said.
Regarding mAbs, she acknowledged that some white blood cells have CGRP receptors, which may have a pro- or anti-inflammatory role, but clinical trials of mAbs did not show any evidence of being immunosuppressive or myelosuppressive.
“The monoclonal antibodies themselves have undergone engineering so that they are just going after their one target,” Dr. Gelfand said. “They’re not going to be expected to bind to anything else outside of their targets, so I don’t think there’s anything there to make us retime the monoclonal antibody administration relative to the COVID-19 vaccine.”
She did note that patients who choose to get mAbs injections in their arm instead of their thigh or abdomen may want to receive it in the opposite arm than they one they have gotten or will get the vaccine in since the vaccine can cause discomfort.
The other common question patients may have is whether taking any NSAIDs or acetaminophen before getting the COVID-19 vaccine will reduce their immune response to the vaccination. This concern arises because of past evidence showing that some infants tended to have lower immunologic responses when they received acetaminophen after their primary vaccines’ series, but the clinical significance of those reduced responses is not clear since they still had strong responses. Further, this effect was not seen with booster shots, suggesting it’s an age-dependent effect.
During the clinical trials of the AstraZeneca vaccine, several sites gave prophylactic paracetamol without any apparent detrimental effect on antibody response, Dr. Gelfand said. Further, the mRNA and adenovirus-vectored vaccines appear to induce antibodies far above what many believe is needed for protection.
“Even if there were a slight decrease, it’s not clear that that would have any kind of clinical significance for that person in terms of their level of protection against COVID-19,” she said. “Bottom line, it’s fine for patients to use either of these after administration of the COVID-19 vaccine.” The Centers for Disease Control and Prevention doesn’t recommend it prophylactically beforehand, but it’s fine to take it for a fever, aches or headache after getting the vaccine.
Migraine or vaccine reaction?
Dr. Gelfand then addressed whether it should affect physicians’ headache differential if seeing a patient who recently received an adenovirus-vectored vaccine, such as the Johnson & Johnson or AstraZeneca vaccines. The question relates to the discovery of a very rare potential adverse event from these vaccines: cerebral venous sinus thrombosis (CVST) with thrombocytopenia and thromboses in other major vessels, together called thrombosis thrombocytopenia syndrome (TTS). No TTS cases have been reported following mRNA vaccines.
TTS’s mechanism appears similar to autoimmune heparin-induced thrombocytopenia, where the body produces platelet-activating antibodies. TTS currently has three diagnostic criteria: new-onset thrombocytopenia (<150,000/microliter) without evidence of platelet clumping, venous or arterial thrombosis, and absence of prior exposure to heparin.
So far, TTS has been limited only to the vaccines that use an adenovirus vector. One male clinical trial participant experienced CVST with thrombocytopenia in Johnson & Johnson phase 3 trials, and 12 cases out of approximately 8 million Johnson & Johnson doses were reported to the Vaccine Adverse Event Reporting System between March 2 and April 21, 2021. Three TTS more cases followed these, resulting in 15 TTS events per 8 million doses.
In terms of clinical features, all 15 cases were females under age 60, mostly white, and all 11 who were tested were positive for the heparin-platelet factor 4 antibody test. TTS occurred 6-15 days after vaccination for these cases, and all but one had a headache. Their platelet count was 9,000-127,000. None were pregnant or postpartum.
“For us, as headache clinicians, the epidemiology of TTS overlaps with the epidemiology of migraine – they’re happening to the same group of patients,” Dr. Gelfand said. Most of the cases occurred in women aged 30-39 years, while the estimated incidence in women aged 50 or older is 0.9 cases per million doses.
The CDC has proceeded with the Johnson & Johnson vaccine because a risk-benefit analysis revealed that use of the vaccine will result in fewer hospitalization and deaths from COVID-19, compared with adverse events from the vaccine, Dr. Gelfand explained. However, the CDC notes that “women younger than 50 years old should be made aware of a rare risk of blood clots with low platelets following vaccination and the availability of other COVID-19 vaccines where this risk has not been observed.”
For clinicians, the existence of TTS raises a question when patients with a history of migraine call after having received the Johnson & Johnson vaccine, Dr. Gelfand said: “How do we know if this is a spontaneous attack, if it’s a headache provoked by receiving the vaccine, or they have one of these rare cases of [TTS]?”
Three things help with this differential, she said: timing, epidemiology, and headache phenotype. Headache after a vaccine is very common, but it usually happens within the first couple of hours or days after the vaccine. By day 4 after vaccination, few people had headaches in the clinical trials. Since TTS requires production of antibodies, a headache within a few hours of vaccination should not raise concerns about TTS. It should be considered, however, for patients who experience a headache within a week or 2 after vaccination.
Then consider the epidemiology: If it’s a woman between ages 18 and49 calling, the risk is higher than if it’s a male over age 50. Then consider whether there are any unusual headache features, positionality, encephalopathy, or clinical features that could suggest clots in other parts of the body, such as abdominal pain, shortness of breath, or pain in the legs.
“At the end of the day, if it’s a person who’s in this epidemiological window and they’re calling a week or 2 out from the Johnson & Johnson vaccine, we may just need to work it up and see,” Dr. Gelfand said. Work-up involves a CBC, a platelet count to see if they’re thrombocytopenic, and perhaps imaging, preferentially using MRI/MRV over CT since it’s a younger population. Treatment for CVST with thrombocytopenia is a nonheparin anticoagulant, and platelet transfusion should not occur before consulting with hematology.
Continue to vaccinate
“The big take home is that we should continue to vaccinate patients with migraine and that your current therapies do not interfere with the vaccine working and that the vaccine does not interact with our therapies,” Brian D. Loftus, MD, BSChE, immediate past president of the Southern Headache Society and a neurologist at Bellaire (Pa.) Neurology, said of the presentation. He also felt it was helpful to know that NSAIDs likely have no impact on the vaccines’ effectiveness as well.
“The most important new information for me was that the median onset of the CSVT was 8 days post vaccine,” Dr. Loftus said. “Typically, postvaccine headache is seen much sooner, within 1-2 days, so this is a useful clinical feature to separate out who needs to closer follow-up and possible neuroimaging.”
Given the epidemiology of those most likely to have TTS, Dr. Loftus said he would advise his female patients younger than 60 to simply get the Pfizer or Moderna vaccine since they appear safer for this demographic.
Dr. Gelfand is editor of the journal Headache but has no industry disclosures. Her spouse has received clinical trial grant support from Genentech and honoraria for editorial work from Dynamed Plus. Dr. Loftus has received grants or fees from Teva, Amgen, Abbvie, and Biohaven.
according to a presentation at the American Headache Society’s 2021 annual meeting.
Amy Gelfand, MD, director of pediatric headache at University of California, San Francisco, reviewed common concerns migraine patients or their clinicians might have related any of the three vaccines, starting with a review of how the vaccines work – by targeting the spike protein of the SARS-CoV-2 virus.
“The vaccines induce response to that protein, but only that protein, so there’s no reason to think they’re going to cause the body to produce neutralizing antibodies against any of our migraine therapeutics,” Dr. Gelfand said. She added that the phase 3 clinical trials included participants from a wide range of ages and comorbidities, so there were likely many people in the trials who have migraine, though no subgroup analyses have been performed for this group or are likely to be performed.
Common questions
The two treatments people have the most questions about concerning the COVID-19 vaccine are onabotulinumtoxinA and CGRP pathway monoclonal antibodies (mAbs), likely because both of these are injections, as is the vaccine, Dr. Gelfand said. First, she reminded attendees that onabotulinumtoxinA is not a dermal filler, since some reports following administration of the Moderna vaccine suggested that some people with dermal fillers had swelling in those areas after vaccination.
In addition, “there’s no reason to think the onabotulinumtoxinA would influence our body’s immune response to any vaccine, so there’s no need to retime the onabotulinumtoxinA injections around COVID-19 vaccine administration,” Dr. Gelfand said.
Regarding mAbs, she acknowledged that some white blood cells have CGRP receptors, which may have a pro- or anti-inflammatory role, but clinical trials of mAbs did not show any evidence of being immunosuppressive or myelosuppressive.
“The monoclonal antibodies themselves have undergone engineering so that they are just going after their one target,” Dr. Gelfand said. “They’re not going to be expected to bind to anything else outside of their targets, so I don’t think there’s anything there to make us retime the monoclonal antibody administration relative to the COVID-19 vaccine.”
She did note that patients who choose to get mAbs injections in their arm instead of their thigh or abdomen may want to receive it in the opposite arm than they one they have gotten or will get the vaccine in since the vaccine can cause discomfort.
The other common question patients may have is whether taking any NSAIDs or acetaminophen before getting the COVID-19 vaccine will reduce their immune response to the vaccination. This concern arises because of past evidence showing that some infants tended to have lower immunologic responses when they received acetaminophen after their primary vaccines’ series, but the clinical significance of those reduced responses is not clear since they still had strong responses. Further, this effect was not seen with booster shots, suggesting it’s an age-dependent effect.
During the clinical trials of the AstraZeneca vaccine, several sites gave prophylactic paracetamol without any apparent detrimental effect on antibody response, Dr. Gelfand said. Further, the mRNA and adenovirus-vectored vaccines appear to induce antibodies far above what many believe is needed for protection.
“Even if there were a slight decrease, it’s not clear that that would have any kind of clinical significance for that person in terms of their level of protection against COVID-19,” she said. “Bottom line, it’s fine for patients to use either of these after administration of the COVID-19 vaccine.” The Centers for Disease Control and Prevention doesn’t recommend it prophylactically beforehand, but it’s fine to take it for a fever, aches or headache after getting the vaccine.
Migraine or vaccine reaction?
Dr. Gelfand then addressed whether it should affect physicians’ headache differential if seeing a patient who recently received an adenovirus-vectored vaccine, such as the Johnson & Johnson or AstraZeneca vaccines. The question relates to the discovery of a very rare potential adverse event from these vaccines: cerebral venous sinus thrombosis (CVST) with thrombocytopenia and thromboses in other major vessels, together called thrombosis thrombocytopenia syndrome (TTS). No TTS cases have been reported following mRNA vaccines.
TTS’s mechanism appears similar to autoimmune heparin-induced thrombocytopenia, where the body produces platelet-activating antibodies. TTS currently has three diagnostic criteria: new-onset thrombocytopenia (<150,000/microliter) without evidence of platelet clumping, venous or arterial thrombosis, and absence of prior exposure to heparin.
So far, TTS has been limited only to the vaccines that use an adenovirus vector. One male clinical trial participant experienced CVST with thrombocytopenia in Johnson & Johnson phase 3 trials, and 12 cases out of approximately 8 million Johnson & Johnson doses were reported to the Vaccine Adverse Event Reporting System between March 2 and April 21, 2021. Three TTS more cases followed these, resulting in 15 TTS events per 8 million doses.
In terms of clinical features, all 15 cases were females under age 60, mostly white, and all 11 who were tested were positive for the heparin-platelet factor 4 antibody test. TTS occurred 6-15 days after vaccination for these cases, and all but one had a headache. Their platelet count was 9,000-127,000. None were pregnant or postpartum.
“For us, as headache clinicians, the epidemiology of TTS overlaps with the epidemiology of migraine – they’re happening to the same group of patients,” Dr. Gelfand said. Most of the cases occurred in women aged 30-39 years, while the estimated incidence in women aged 50 or older is 0.9 cases per million doses.
The CDC has proceeded with the Johnson & Johnson vaccine because a risk-benefit analysis revealed that use of the vaccine will result in fewer hospitalization and deaths from COVID-19, compared with adverse events from the vaccine, Dr. Gelfand explained. However, the CDC notes that “women younger than 50 years old should be made aware of a rare risk of blood clots with low platelets following vaccination and the availability of other COVID-19 vaccines where this risk has not been observed.”
For clinicians, the existence of TTS raises a question when patients with a history of migraine call after having received the Johnson & Johnson vaccine, Dr. Gelfand said: “How do we know if this is a spontaneous attack, if it’s a headache provoked by receiving the vaccine, or they have one of these rare cases of [TTS]?”
Three things help with this differential, she said: timing, epidemiology, and headache phenotype. Headache after a vaccine is very common, but it usually happens within the first couple of hours or days after the vaccine. By day 4 after vaccination, few people had headaches in the clinical trials. Since TTS requires production of antibodies, a headache within a few hours of vaccination should not raise concerns about TTS. It should be considered, however, for patients who experience a headache within a week or 2 after vaccination.
Then consider the epidemiology: If it’s a woman between ages 18 and49 calling, the risk is higher than if it’s a male over age 50. Then consider whether there are any unusual headache features, positionality, encephalopathy, or clinical features that could suggest clots in other parts of the body, such as abdominal pain, shortness of breath, or pain in the legs.
“At the end of the day, if it’s a person who’s in this epidemiological window and they’re calling a week or 2 out from the Johnson & Johnson vaccine, we may just need to work it up and see,” Dr. Gelfand said. Work-up involves a CBC, a platelet count to see if they’re thrombocytopenic, and perhaps imaging, preferentially using MRI/MRV over CT since it’s a younger population. Treatment for CVST with thrombocytopenia is a nonheparin anticoagulant, and platelet transfusion should not occur before consulting with hematology.
Continue to vaccinate
“The big take home is that we should continue to vaccinate patients with migraine and that your current therapies do not interfere with the vaccine working and that the vaccine does not interact with our therapies,” Brian D. Loftus, MD, BSChE, immediate past president of the Southern Headache Society and a neurologist at Bellaire (Pa.) Neurology, said of the presentation. He also felt it was helpful to know that NSAIDs likely have no impact on the vaccines’ effectiveness as well.
“The most important new information for me was that the median onset of the CSVT was 8 days post vaccine,” Dr. Loftus said. “Typically, postvaccine headache is seen much sooner, within 1-2 days, so this is a useful clinical feature to separate out who needs to closer follow-up and possible neuroimaging.”
Given the epidemiology of those most likely to have TTS, Dr. Loftus said he would advise his female patients younger than 60 to simply get the Pfizer or Moderna vaccine since they appear safer for this demographic.
Dr. Gelfand is editor of the journal Headache but has no industry disclosures. Her spouse has received clinical trial grant support from Genentech and honoraria for editorial work from Dynamed Plus. Dr. Loftus has received grants or fees from Teva, Amgen, Abbvie, and Biohaven.
FROM AHS 2021
New biomarkers may predict interstitial lung disease progression in patients with systemic sclerosis
Quantitative assessment of the extent of interstitial lung disease in patients with systemic sclerosis and levels of certain proteins in bronchoalveolar lavage samples have potential for predicting mortality and disease progression, according to two analyses of data from the Scleroderma Lung Study I and II.
The analyses, presented at the annual European Congress of Rheumatology, aim to improve current prognostic abilities in patients with systemic sclerosis–interstitial lung disease (SSc-ILD). Although forced vital capacity is commonly used as a biomarker for survival in many SSc-ILD trials, other factors can affect FVC, such as respiratory muscle weakness and skin fibrosis. Further, FVC correlates poorly with patient-reported outcomes, explained first author Elizabeth Volkmann, MD, director of the scleroderma program at the University of California, Los Angeles, and the founder and codirector of the UCLA connective tissue disease–related interstitial lung disease program.
Dr. Volkmann presented two studies that investigated the potential of radiographic and protein biomarkers for predicting mortality and identifying patients at risk for ILD progression. The biomarkers may also help to identify patients who would benefit most from immunosuppressive therapy.
The first study found that tracking the quantitative extent of ILD (QILD) over time with high-resolution CT (HRCT) predicted poorer outcomes and could therefore act as a surrogate endpoint for mortality among patients with SSc-ILD. The other study identified associations between specific proteins from bronchoalveolar lavage (BAL) and the likelihood of ILD progression, although some associations were treatment dependent.
Jacob M. van Laar, MD, PhD, professor of rheumatology at the University Medical Center Utrecht (the Netherlands), who was not involved in the study, found the results intriguing and noted the importance of further validation in research before these biomarkers are considered for clinical use.
“It would be wonderful if we can tailor therapy based on BAL biomarkers in the future, as clinicians often struggle to decide on selection, timing, and duration of immunosuppressive treatment,” Dr. van Laar told this news organization. “This has become even more relevant with the introduction of new drugs such as nintedanib.”
Extent of ILD progression as a surrogate for mortality
Scleroderma Lung Study I involved 158 patients with SSc-ILD who were randomly assigned to receive either cyclophosphamide or placebo for 12 months. Scleroderma Lung Study II included 142 patients with SSc-ILD who were randomly assigned to receive either mycophenolate for 24 months or cyclophosphamide for 12 months followed by placebo for 12 months.
The researchers calculated QILD in the whole lung at baseline, at 12 months in the first trial, and at 24 months in the second trial. However, only 82 participants from the first trial and 90 participants from the second trial underwent HRCT. Demographic and disease characteristics were similar between the two groups on follow-up scans.
Follow-up continued for 12 years for patients in the first trial and 8 years in the second. The researchers compared survival rates between the 41% of participants from the first study and 31% of participants from the second study who had poorer QILD scores (at least a 2% increase) with the participants who had stable or improved scores (less than 2% increase).
Participants from both trials had significantly poorer long-term survival if their QILD scores had increased by at least 2% at follow-up (P = .01 for I; P = .019 for II). The association was no longer significant after adjustment for baseline FVC, age, and modified Rodnan skin score in the first trial (hazard ratio, 1.98; P = .089), but it remained significant for participants of the second trial (HR, 3.86; P = .014).
“Data from two independent trial cohorts demonstrated that radiographic progression of SSc-ILD at 1 and 2 years is associated with worse long-term survival,” Dr. Volkmann told attendees.
However, FVC did not significantly predict risk of mortality in either trial.
“To me, the most striking finding from the first study was that change in QILD performed better as a predictor of survival than change in FVC,” Dr. van Laar said in an interview. “This indicates QILD is fit for purpose and worth including in future clinical trials.”
Limitations of the study included lack of HRCT for all participants in the trials and the difference in timing (1 year and 2 years) of HRCT assessment between the two trials. The greater hazard ratio for worsened QILD in the second trial may suggest that assessment at 2 years provides more reliable data as a biomarker, Dr. Volkmann said.
“QILD may represent a better proxy for how a patient feels, functions, and survives than FVC,” she said.
Treatment-dependent biomarkers for worsening lung fibrosis
In the second study, the researchers looked for any associations between changes in the radiographic extent of SSc-ILD and 68 proteins from BAL.
“Being able to risk-stratify patients with interstitial lung disease at the time of diagnosis and predict which patients are likely to have a stable versus progressive disease course is critical for making important treatment decisions for these patients,” Dr. Volkmann told attendees.
The second study she presented involved Scleroderma Lung Study I. Of the 158 participants, 144 underwent a bronchoscopy, yielding BAL protein samples from 103 participants. The researchers determined the extent of radiographic fibrosis in the whole lung with quantitative imaging analysis of HRCT of the chest at baseline and 12 months.
Although the researchers identified several statistically significant associations between certain proteins and changes in radiographic fibrosis, “baseline protein levels were differentially associated with the course of ILD based on treatment status,” she told attendees.
For example, increased levels of the following proteins were linked to poor radiographic fibrosis scores for patients who received placebo:
- Granulocyte-macrophage colony-stimulating factor
- Interleukin-1
- Monocyte chemoattractant protein–3
- Chemokine ligand–5
- Transforming growth factor–beta
- Hepatocyte growth factor
- Stem cell factor
- IL-4
- TGF-alpha
Yet increases in these proteins predicted improvement in radiographic fibrosis in patients who had taken cyclophosphamide.
Independently of treatment, the researchers also identified an association between higher levels of fractalkine and poorer radiographic fibrosis scores and between higher IL-7 levels and improved radiographic fibrosis scores.
After adjusting for treatment arm and baseline severity of ILD, significant associations remained between change in radiographic fibrosis score and IL-1, MCP-3, surfactant protein C, IL-7 and CCL-5 levels.
“Biomarker discovery is really central to our ability to risk stratify patients with SSc-ILD,” Dr. Volkmann told attendees. “Understanding how biomarkers predict outcomes in treated and untreated patients may improve personalized medicine to patients with SSc-ILD and could also reveal novel treatment targets.”
Dr. van Laar said in an interview that this study’s biggest strength lay in its large sample size and in the comprehensiveness of the biomarkers studied.
“The findings are interesting from a research perspective and potentially relevant for clinical practice, but the utility of measuring biomarkers in BAL should be further studied for predictive value on clinical endpoints,” Dr. van Laar said. “BAL is an invasive procedure [that] is not routinely done.”
The research was funded by the National Institutes of Health. Dr. Volkmann has consulted for Boehringer Ingelheim and received grant funding from Corbus, Forbius, and Kadmon. Dr. van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.
A version of this article first appeared on Medscape.com.
Quantitative assessment of the extent of interstitial lung disease in patients with systemic sclerosis and levels of certain proteins in bronchoalveolar lavage samples have potential for predicting mortality and disease progression, according to two analyses of data from the Scleroderma Lung Study I and II.
The analyses, presented at the annual European Congress of Rheumatology, aim to improve current prognostic abilities in patients with systemic sclerosis–interstitial lung disease (SSc-ILD). Although forced vital capacity is commonly used as a biomarker for survival in many SSc-ILD trials, other factors can affect FVC, such as respiratory muscle weakness and skin fibrosis. Further, FVC correlates poorly with patient-reported outcomes, explained first author Elizabeth Volkmann, MD, director of the scleroderma program at the University of California, Los Angeles, and the founder and codirector of the UCLA connective tissue disease–related interstitial lung disease program.
Dr. Volkmann presented two studies that investigated the potential of radiographic and protein biomarkers for predicting mortality and identifying patients at risk for ILD progression. The biomarkers may also help to identify patients who would benefit most from immunosuppressive therapy.
The first study found that tracking the quantitative extent of ILD (QILD) over time with high-resolution CT (HRCT) predicted poorer outcomes and could therefore act as a surrogate endpoint for mortality among patients with SSc-ILD. The other study identified associations between specific proteins from bronchoalveolar lavage (BAL) and the likelihood of ILD progression, although some associations were treatment dependent.
Jacob M. van Laar, MD, PhD, professor of rheumatology at the University Medical Center Utrecht (the Netherlands), who was not involved in the study, found the results intriguing and noted the importance of further validation in research before these biomarkers are considered for clinical use.
“It would be wonderful if we can tailor therapy based on BAL biomarkers in the future, as clinicians often struggle to decide on selection, timing, and duration of immunosuppressive treatment,” Dr. van Laar told this news organization. “This has become even more relevant with the introduction of new drugs such as nintedanib.”
Extent of ILD progression as a surrogate for mortality
Scleroderma Lung Study I involved 158 patients with SSc-ILD who were randomly assigned to receive either cyclophosphamide or placebo for 12 months. Scleroderma Lung Study II included 142 patients with SSc-ILD who were randomly assigned to receive either mycophenolate for 24 months or cyclophosphamide for 12 months followed by placebo for 12 months.
The researchers calculated QILD in the whole lung at baseline, at 12 months in the first trial, and at 24 months in the second trial. However, only 82 participants from the first trial and 90 participants from the second trial underwent HRCT. Demographic and disease characteristics were similar between the two groups on follow-up scans.
Follow-up continued for 12 years for patients in the first trial and 8 years in the second. The researchers compared survival rates between the 41% of participants from the first study and 31% of participants from the second study who had poorer QILD scores (at least a 2% increase) with the participants who had stable or improved scores (less than 2% increase).
Participants from both trials had significantly poorer long-term survival if their QILD scores had increased by at least 2% at follow-up (P = .01 for I; P = .019 for II). The association was no longer significant after adjustment for baseline FVC, age, and modified Rodnan skin score in the first trial (hazard ratio, 1.98; P = .089), but it remained significant for participants of the second trial (HR, 3.86; P = .014).
“Data from two independent trial cohorts demonstrated that radiographic progression of SSc-ILD at 1 and 2 years is associated with worse long-term survival,” Dr. Volkmann told attendees.
However, FVC did not significantly predict risk of mortality in either trial.
“To me, the most striking finding from the first study was that change in QILD performed better as a predictor of survival than change in FVC,” Dr. van Laar said in an interview. “This indicates QILD is fit for purpose and worth including in future clinical trials.”
Limitations of the study included lack of HRCT for all participants in the trials and the difference in timing (1 year and 2 years) of HRCT assessment between the two trials. The greater hazard ratio for worsened QILD in the second trial may suggest that assessment at 2 years provides more reliable data as a biomarker, Dr. Volkmann said.
“QILD may represent a better proxy for how a patient feels, functions, and survives than FVC,” she said.
Treatment-dependent biomarkers for worsening lung fibrosis
In the second study, the researchers looked for any associations between changes in the radiographic extent of SSc-ILD and 68 proteins from BAL.
“Being able to risk-stratify patients with interstitial lung disease at the time of diagnosis and predict which patients are likely to have a stable versus progressive disease course is critical for making important treatment decisions for these patients,” Dr. Volkmann told attendees.
The second study she presented involved Scleroderma Lung Study I. Of the 158 participants, 144 underwent a bronchoscopy, yielding BAL protein samples from 103 participants. The researchers determined the extent of radiographic fibrosis in the whole lung with quantitative imaging analysis of HRCT of the chest at baseline and 12 months.
Although the researchers identified several statistically significant associations between certain proteins and changes in radiographic fibrosis, “baseline protein levels were differentially associated with the course of ILD based on treatment status,” she told attendees.
For example, increased levels of the following proteins were linked to poor radiographic fibrosis scores for patients who received placebo:
- Granulocyte-macrophage colony-stimulating factor
- Interleukin-1
- Monocyte chemoattractant protein–3
- Chemokine ligand–5
- Transforming growth factor–beta
- Hepatocyte growth factor
- Stem cell factor
- IL-4
- TGF-alpha
Yet increases in these proteins predicted improvement in radiographic fibrosis in patients who had taken cyclophosphamide.
Independently of treatment, the researchers also identified an association between higher levels of fractalkine and poorer radiographic fibrosis scores and between higher IL-7 levels and improved radiographic fibrosis scores.
After adjusting for treatment arm and baseline severity of ILD, significant associations remained between change in radiographic fibrosis score and IL-1, MCP-3, surfactant protein C, IL-7 and CCL-5 levels.
“Biomarker discovery is really central to our ability to risk stratify patients with SSc-ILD,” Dr. Volkmann told attendees. “Understanding how biomarkers predict outcomes in treated and untreated patients may improve personalized medicine to patients with SSc-ILD and could also reveal novel treatment targets.”
Dr. van Laar said in an interview that this study’s biggest strength lay in its large sample size and in the comprehensiveness of the biomarkers studied.
“The findings are interesting from a research perspective and potentially relevant for clinical practice, but the utility of measuring biomarkers in BAL should be further studied for predictive value on clinical endpoints,” Dr. van Laar said. “BAL is an invasive procedure [that] is not routinely done.”
The research was funded by the National Institutes of Health. Dr. Volkmann has consulted for Boehringer Ingelheim and received grant funding from Corbus, Forbius, and Kadmon. Dr. van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.
A version of this article first appeared on Medscape.com.
Quantitative assessment of the extent of interstitial lung disease in patients with systemic sclerosis and levels of certain proteins in bronchoalveolar lavage samples have potential for predicting mortality and disease progression, according to two analyses of data from the Scleroderma Lung Study I and II.
The analyses, presented at the annual European Congress of Rheumatology, aim to improve current prognostic abilities in patients with systemic sclerosis–interstitial lung disease (SSc-ILD). Although forced vital capacity is commonly used as a biomarker for survival in many SSc-ILD trials, other factors can affect FVC, such as respiratory muscle weakness and skin fibrosis. Further, FVC correlates poorly with patient-reported outcomes, explained first author Elizabeth Volkmann, MD, director of the scleroderma program at the University of California, Los Angeles, and the founder and codirector of the UCLA connective tissue disease–related interstitial lung disease program.
Dr. Volkmann presented two studies that investigated the potential of radiographic and protein biomarkers for predicting mortality and identifying patients at risk for ILD progression. The biomarkers may also help to identify patients who would benefit most from immunosuppressive therapy.
The first study found that tracking the quantitative extent of ILD (QILD) over time with high-resolution CT (HRCT) predicted poorer outcomes and could therefore act as a surrogate endpoint for mortality among patients with SSc-ILD. The other study identified associations between specific proteins from bronchoalveolar lavage (BAL) and the likelihood of ILD progression, although some associations were treatment dependent.
Jacob M. van Laar, MD, PhD, professor of rheumatology at the University Medical Center Utrecht (the Netherlands), who was not involved in the study, found the results intriguing and noted the importance of further validation in research before these biomarkers are considered for clinical use.
“It would be wonderful if we can tailor therapy based on BAL biomarkers in the future, as clinicians often struggle to decide on selection, timing, and duration of immunosuppressive treatment,” Dr. van Laar told this news organization. “This has become even more relevant with the introduction of new drugs such as nintedanib.”
Extent of ILD progression as a surrogate for mortality
Scleroderma Lung Study I involved 158 patients with SSc-ILD who were randomly assigned to receive either cyclophosphamide or placebo for 12 months. Scleroderma Lung Study II included 142 patients with SSc-ILD who were randomly assigned to receive either mycophenolate for 24 months or cyclophosphamide for 12 months followed by placebo for 12 months.
The researchers calculated QILD in the whole lung at baseline, at 12 months in the first trial, and at 24 months in the second trial. However, only 82 participants from the first trial and 90 participants from the second trial underwent HRCT. Demographic and disease characteristics were similar between the two groups on follow-up scans.
Follow-up continued for 12 years for patients in the first trial and 8 years in the second. The researchers compared survival rates between the 41% of participants from the first study and 31% of participants from the second study who had poorer QILD scores (at least a 2% increase) with the participants who had stable or improved scores (less than 2% increase).
Participants from both trials had significantly poorer long-term survival if their QILD scores had increased by at least 2% at follow-up (P = .01 for I; P = .019 for II). The association was no longer significant after adjustment for baseline FVC, age, and modified Rodnan skin score in the first trial (hazard ratio, 1.98; P = .089), but it remained significant for participants of the second trial (HR, 3.86; P = .014).
“Data from two independent trial cohorts demonstrated that radiographic progression of SSc-ILD at 1 and 2 years is associated with worse long-term survival,” Dr. Volkmann told attendees.
However, FVC did not significantly predict risk of mortality in either trial.
“To me, the most striking finding from the first study was that change in QILD performed better as a predictor of survival than change in FVC,” Dr. van Laar said in an interview. “This indicates QILD is fit for purpose and worth including in future clinical trials.”
Limitations of the study included lack of HRCT for all participants in the trials and the difference in timing (1 year and 2 years) of HRCT assessment between the two trials. The greater hazard ratio for worsened QILD in the second trial may suggest that assessment at 2 years provides more reliable data as a biomarker, Dr. Volkmann said.
“QILD may represent a better proxy for how a patient feels, functions, and survives than FVC,” she said.
Treatment-dependent biomarkers for worsening lung fibrosis
In the second study, the researchers looked for any associations between changes in the radiographic extent of SSc-ILD and 68 proteins from BAL.
“Being able to risk-stratify patients with interstitial lung disease at the time of diagnosis and predict which patients are likely to have a stable versus progressive disease course is critical for making important treatment decisions for these patients,” Dr. Volkmann told attendees.
The second study she presented involved Scleroderma Lung Study I. Of the 158 participants, 144 underwent a bronchoscopy, yielding BAL protein samples from 103 participants. The researchers determined the extent of radiographic fibrosis in the whole lung with quantitative imaging analysis of HRCT of the chest at baseline and 12 months.
Although the researchers identified several statistically significant associations between certain proteins and changes in radiographic fibrosis, “baseline protein levels were differentially associated with the course of ILD based on treatment status,” she told attendees.
For example, increased levels of the following proteins were linked to poor radiographic fibrosis scores for patients who received placebo:
- Granulocyte-macrophage colony-stimulating factor
- Interleukin-1
- Monocyte chemoattractant protein–3
- Chemokine ligand–5
- Transforming growth factor–beta
- Hepatocyte growth factor
- Stem cell factor
- IL-4
- TGF-alpha
Yet increases in these proteins predicted improvement in radiographic fibrosis in patients who had taken cyclophosphamide.
Independently of treatment, the researchers also identified an association between higher levels of fractalkine and poorer radiographic fibrosis scores and between higher IL-7 levels and improved radiographic fibrosis scores.
After adjusting for treatment arm and baseline severity of ILD, significant associations remained between change in radiographic fibrosis score and IL-1, MCP-3, surfactant protein C, IL-7 and CCL-5 levels.
“Biomarker discovery is really central to our ability to risk stratify patients with SSc-ILD,” Dr. Volkmann told attendees. “Understanding how biomarkers predict outcomes in treated and untreated patients may improve personalized medicine to patients with SSc-ILD and could also reveal novel treatment targets.”
Dr. van Laar said in an interview that this study’s biggest strength lay in its large sample size and in the comprehensiveness of the biomarkers studied.
“The findings are interesting from a research perspective and potentially relevant for clinical practice, but the utility of measuring biomarkers in BAL should be further studied for predictive value on clinical endpoints,” Dr. van Laar said. “BAL is an invasive procedure [that] is not routinely done.”
The research was funded by the National Institutes of Health. Dr. Volkmann has consulted for Boehringer Ingelheim and received grant funding from Corbus, Forbius, and Kadmon. Dr. van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.
A version of this article first appeared on Medscape.com.
Risankizumab shows efficacy, tolerability in patients with PsA
Risankizumab (Skyrizi) was effective for treating psoriatic arthritis (PsA) in patients who did not respond to or who could not tolerate other biologics or standard disease-modifying antirheumatic drugs (DMARDs), according to a study presented at the annual European Congress of Rheumatology. It was also well tolerated.
“Treatment with risankizumab resulted in significantly greater improvements in signs and symptoms of psoriatic arthritis, including assessments of disease activity in joints and skin and patient-reported outcomes, compared with placebo, in patients who did not respond to or were intolerant to biologics or DMARDs,” reported Andrew Ostor, MD, of Monash University and Cabrini Hospital, both in Melbourne,. The safety profile was “consistent with that established for risankizumab in the treatment moderate to severe psoriasis,” he told attendees.
Risankizumab is approved in the United States for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. It is a humanized immunoglobulin G1 monoclonal antibody that selectively inhibits cytokine interleukin-23 by binding to its p19 subunit. IL-23 has been implicated in the development of PsA.
This was a phase 3 trial with “promising results in line with the ACR 20 response [at least 20% improvement in American College of Rheumatology response criteria] of other biologics in psoriatic arthritis,” according to Gaëlle Varkas, MD, PhD, of the Ghent (the Netherlands) University VIB Center for Inflammation Research and the department of rheumatology, Ghent University Hospital. “Especially in patients with severe and/or refractory skin disease or inadequate response at the level of the joint to other DMARDs or biologics, risankizumab is filling a void,” Dr. Varkas, who was not involved in the research, said in an interview.
There were no major safety problems, although long-term data, especially in regard to cancer and cardiovascular effects, “are always of interest, as they can be missed in randomized, controlled trials,” she said. In addition, “efficacy in concomitant axial disease, uveitis, and inflammatory bowel disease might favor one treatment over the other.” Another clinically significant takeaway was risankizumab’s “better effect on skin psoriasis while maintaining the effect on joint manifestations.”
Details of 24-week trial results
The phase 3, randomized, placebo-controlled, double-blind KEEPSAKE 2 trial involved 444 patients who had active PsA, defined as at least five swollen joints and at least five tender joints. All the patients either had an inadequate response to or were intolerant of one or two biologics or at least one conventional synthetic DMARD.
A total of 224 patients were randomly assigned to receive 150 mg of subcutaneous risankizumab at baseline and at 4 and 16 weeks after baseline; 220 participants received placebo injections. The primary endpoint was the proportion of patients who had at least 20% improvement in American College of Rheumatology response criteria at week 24.
Demographic and clinical characteristics were similar in both groups at baseline. Among the participants, the total mean number of swollen joints was 13.3, and the total mean number of tender joints was 22.6. The participants had PsA for an average of 8.2 years. The proportions of patients previously treated with biologics and DMARDs were similar in both groups, as were the proportions of patients currently taking glucocorticoids, NSAIDs, or methotrexate or another DMARD. At week 24, there remained 199 patients in the placebo group and 215 in the risankizumab group.
Just over half (51.3%) of patients who took risankizumab achieved at least 20% improvement in their ACR 20 score, compared with just over a quarter (26.5%) of those who received placebo (P < .001). All secondary endpoints also showed statistically significant improvements (P < .001 for all except P < .009 for the Fatigue Functional Assessment of Chronic Illness Therapy–Fatigue [FACIT-Fatigue] secondary endpoint).
Scores on the Health Assessment Questionnaire–Disability Index were –0.22 in the risankizumab group and –0.05 in the placebo group (P < .001). In the risankizumab group, 55% of patients achieved at least a 90% reduction in scores on the Psoriasis Area Severity Index, compared with 10.2% of patients who received placebo. Similarly, 25.6% of patients who took risankizumab and 11.4% of patients who received placebo had minimal disease activity 24 weeks after baseline.
In the 36-item Short Form Health Survey Physical Component Summary, the score change among risankizumab patients was 5.9, compared with 2 among the patients who received placebo. The change in FACIT-Fatigue score was 4.9 for patients who took risankizumab and 2.6 for patients who received placebo.
The researchers also assessed how many patients achieved higher levels of response to treatment. At least a 50% improvement in ACR response criteria occurred among 26.3% of patients taking risankizumab and 9.3% of patients taking placebo (P < .001). ACR 70 responses were seen in 12% of patients receiving risankizumab, compared with 5.9% of patients receiving placebo (P < .02). In the risankizumab group, 72.5% of patients had resolution of dactylitis and 42.9% had resolution of enthesitis, compared with 42.1% and 30.4%, respectively, in the placebo group.
Serious adverse events occurred in 4% of patients who received risankizumab and 5.5% of patients who received placebo. Serious infections occurred in 0.9% of those receiving risankizumab and 2.3% of those receiving placebo. Rates of treatment-emergent adverse events were also similar in the risankizumab (55.4%) and placebo (54.8%) groups.
In response to a question about whether it was possible to identify patients who might respond better to IL-23 inhibitors, compared with IL-17 inhibitors, Dr. Ostor acknowledged that rheumatologic practice is not yet proficient at using biomarkers to direct therapy, so the benefit from these drugs lay elsewhere.
“What I think is great is the luxury of choice these days,” Dr. Ostor told attendees. “We have these agents now, including risankizumab, that do work very effectively across the spectrum of the clinical features. It’s just lovely to have these agents available that can truly make a difference to the clinical picture of the individual.”
The trial was sponsored by AbbVie. Dr. Ostor has received research grants or speaking or consulting fees from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Varkas has received research grants or speaker fees from AbbVie and Pfizer.
A version of this article first appeared on Medscape.com.
Risankizumab (Skyrizi) was effective for treating psoriatic arthritis (PsA) in patients who did not respond to or who could not tolerate other biologics or standard disease-modifying antirheumatic drugs (DMARDs), according to a study presented at the annual European Congress of Rheumatology. It was also well tolerated.
“Treatment with risankizumab resulted in significantly greater improvements in signs and symptoms of psoriatic arthritis, including assessments of disease activity in joints and skin and patient-reported outcomes, compared with placebo, in patients who did not respond to or were intolerant to biologics or DMARDs,” reported Andrew Ostor, MD, of Monash University and Cabrini Hospital, both in Melbourne,. The safety profile was “consistent with that established for risankizumab in the treatment moderate to severe psoriasis,” he told attendees.
Risankizumab is approved in the United States for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. It is a humanized immunoglobulin G1 monoclonal antibody that selectively inhibits cytokine interleukin-23 by binding to its p19 subunit. IL-23 has been implicated in the development of PsA.
This was a phase 3 trial with “promising results in line with the ACR 20 response [at least 20% improvement in American College of Rheumatology response criteria] of other biologics in psoriatic arthritis,” according to Gaëlle Varkas, MD, PhD, of the Ghent (the Netherlands) University VIB Center for Inflammation Research and the department of rheumatology, Ghent University Hospital. “Especially in patients with severe and/or refractory skin disease or inadequate response at the level of the joint to other DMARDs or biologics, risankizumab is filling a void,” Dr. Varkas, who was not involved in the research, said in an interview.
There were no major safety problems, although long-term data, especially in regard to cancer and cardiovascular effects, “are always of interest, as they can be missed in randomized, controlled trials,” she said. In addition, “efficacy in concomitant axial disease, uveitis, and inflammatory bowel disease might favor one treatment over the other.” Another clinically significant takeaway was risankizumab’s “better effect on skin psoriasis while maintaining the effect on joint manifestations.”
Details of 24-week trial results
The phase 3, randomized, placebo-controlled, double-blind KEEPSAKE 2 trial involved 444 patients who had active PsA, defined as at least five swollen joints and at least five tender joints. All the patients either had an inadequate response to or were intolerant of one or two biologics or at least one conventional synthetic DMARD.
A total of 224 patients were randomly assigned to receive 150 mg of subcutaneous risankizumab at baseline and at 4 and 16 weeks after baseline; 220 participants received placebo injections. The primary endpoint was the proportion of patients who had at least 20% improvement in American College of Rheumatology response criteria at week 24.
Demographic and clinical characteristics were similar in both groups at baseline. Among the participants, the total mean number of swollen joints was 13.3, and the total mean number of tender joints was 22.6. The participants had PsA for an average of 8.2 years. The proportions of patients previously treated with biologics and DMARDs were similar in both groups, as were the proportions of patients currently taking glucocorticoids, NSAIDs, or methotrexate or another DMARD. At week 24, there remained 199 patients in the placebo group and 215 in the risankizumab group.
Just over half (51.3%) of patients who took risankizumab achieved at least 20% improvement in their ACR 20 score, compared with just over a quarter (26.5%) of those who received placebo (P < .001). All secondary endpoints also showed statistically significant improvements (P < .001 for all except P < .009 for the Fatigue Functional Assessment of Chronic Illness Therapy–Fatigue [FACIT-Fatigue] secondary endpoint).
Scores on the Health Assessment Questionnaire–Disability Index were –0.22 in the risankizumab group and –0.05 in the placebo group (P < .001). In the risankizumab group, 55% of patients achieved at least a 90% reduction in scores on the Psoriasis Area Severity Index, compared with 10.2% of patients who received placebo. Similarly, 25.6% of patients who took risankizumab and 11.4% of patients who received placebo had minimal disease activity 24 weeks after baseline.
In the 36-item Short Form Health Survey Physical Component Summary, the score change among risankizumab patients was 5.9, compared with 2 among the patients who received placebo. The change in FACIT-Fatigue score was 4.9 for patients who took risankizumab and 2.6 for patients who received placebo.
The researchers also assessed how many patients achieved higher levels of response to treatment. At least a 50% improvement in ACR response criteria occurred among 26.3% of patients taking risankizumab and 9.3% of patients taking placebo (P < .001). ACR 70 responses were seen in 12% of patients receiving risankizumab, compared with 5.9% of patients receiving placebo (P < .02). In the risankizumab group, 72.5% of patients had resolution of dactylitis and 42.9% had resolution of enthesitis, compared with 42.1% and 30.4%, respectively, in the placebo group.
Serious adverse events occurred in 4% of patients who received risankizumab and 5.5% of patients who received placebo. Serious infections occurred in 0.9% of those receiving risankizumab and 2.3% of those receiving placebo. Rates of treatment-emergent adverse events were also similar in the risankizumab (55.4%) and placebo (54.8%) groups.
In response to a question about whether it was possible to identify patients who might respond better to IL-23 inhibitors, compared with IL-17 inhibitors, Dr. Ostor acknowledged that rheumatologic practice is not yet proficient at using biomarkers to direct therapy, so the benefit from these drugs lay elsewhere.
“What I think is great is the luxury of choice these days,” Dr. Ostor told attendees. “We have these agents now, including risankizumab, that do work very effectively across the spectrum of the clinical features. It’s just lovely to have these agents available that can truly make a difference to the clinical picture of the individual.”
The trial was sponsored by AbbVie. Dr. Ostor has received research grants or speaking or consulting fees from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Varkas has received research grants or speaker fees from AbbVie and Pfizer.
A version of this article first appeared on Medscape.com.
Risankizumab (Skyrizi) was effective for treating psoriatic arthritis (PsA) in patients who did not respond to or who could not tolerate other biologics or standard disease-modifying antirheumatic drugs (DMARDs), according to a study presented at the annual European Congress of Rheumatology. It was also well tolerated.
“Treatment with risankizumab resulted in significantly greater improvements in signs and symptoms of psoriatic arthritis, including assessments of disease activity in joints and skin and patient-reported outcomes, compared with placebo, in patients who did not respond to or were intolerant to biologics or DMARDs,” reported Andrew Ostor, MD, of Monash University and Cabrini Hospital, both in Melbourne,. The safety profile was “consistent with that established for risankizumab in the treatment moderate to severe psoriasis,” he told attendees.
Risankizumab is approved in the United States for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. It is a humanized immunoglobulin G1 monoclonal antibody that selectively inhibits cytokine interleukin-23 by binding to its p19 subunit. IL-23 has been implicated in the development of PsA.
This was a phase 3 trial with “promising results in line with the ACR 20 response [at least 20% improvement in American College of Rheumatology response criteria] of other biologics in psoriatic arthritis,” according to Gaëlle Varkas, MD, PhD, of the Ghent (the Netherlands) University VIB Center for Inflammation Research and the department of rheumatology, Ghent University Hospital. “Especially in patients with severe and/or refractory skin disease or inadequate response at the level of the joint to other DMARDs or biologics, risankizumab is filling a void,” Dr. Varkas, who was not involved in the research, said in an interview.
There were no major safety problems, although long-term data, especially in regard to cancer and cardiovascular effects, “are always of interest, as they can be missed in randomized, controlled trials,” she said. In addition, “efficacy in concomitant axial disease, uveitis, and inflammatory bowel disease might favor one treatment over the other.” Another clinically significant takeaway was risankizumab’s “better effect on skin psoriasis while maintaining the effect on joint manifestations.”
Details of 24-week trial results
The phase 3, randomized, placebo-controlled, double-blind KEEPSAKE 2 trial involved 444 patients who had active PsA, defined as at least five swollen joints and at least five tender joints. All the patients either had an inadequate response to or were intolerant of one or two biologics or at least one conventional synthetic DMARD.
A total of 224 patients were randomly assigned to receive 150 mg of subcutaneous risankizumab at baseline and at 4 and 16 weeks after baseline; 220 participants received placebo injections. The primary endpoint was the proportion of patients who had at least 20% improvement in American College of Rheumatology response criteria at week 24.
Demographic and clinical characteristics were similar in both groups at baseline. Among the participants, the total mean number of swollen joints was 13.3, and the total mean number of tender joints was 22.6. The participants had PsA for an average of 8.2 years. The proportions of patients previously treated with biologics and DMARDs were similar in both groups, as were the proportions of patients currently taking glucocorticoids, NSAIDs, or methotrexate or another DMARD. At week 24, there remained 199 patients in the placebo group and 215 in the risankizumab group.
Just over half (51.3%) of patients who took risankizumab achieved at least 20% improvement in their ACR 20 score, compared with just over a quarter (26.5%) of those who received placebo (P < .001). All secondary endpoints also showed statistically significant improvements (P < .001 for all except P < .009 for the Fatigue Functional Assessment of Chronic Illness Therapy–Fatigue [FACIT-Fatigue] secondary endpoint).
Scores on the Health Assessment Questionnaire–Disability Index were –0.22 in the risankizumab group and –0.05 in the placebo group (P < .001). In the risankizumab group, 55% of patients achieved at least a 90% reduction in scores on the Psoriasis Area Severity Index, compared with 10.2% of patients who received placebo. Similarly, 25.6% of patients who took risankizumab and 11.4% of patients who received placebo had minimal disease activity 24 weeks after baseline.
In the 36-item Short Form Health Survey Physical Component Summary, the score change among risankizumab patients was 5.9, compared with 2 among the patients who received placebo. The change in FACIT-Fatigue score was 4.9 for patients who took risankizumab and 2.6 for patients who received placebo.
The researchers also assessed how many patients achieved higher levels of response to treatment. At least a 50% improvement in ACR response criteria occurred among 26.3% of patients taking risankizumab and 9.3% of patients taking placebo (P < .001). ACR 70 responses were seen in 12% of patients receiving risankizumab, compared with 5.9% of patients receiving placebo (P < .02). In the risankizumab group, 72.5% of patients had resolution of dactylitis and 42.9% had resolution of enthesitis, compared with 42.1% and 30.4%, respectively, in the placebo group.
Serious adverse events occurred in 4% of patients who received risankizumab and 5.5% of patients who received placebo. Serious infections occurred in 0.9% of those receiving risankizumab and 2.3% of those receiving placebo. Rates of treatment-emergent adverse events were also similar in the risankizumab (55.4%) and placebo (54.8%) groups.
In response to a question about whether it was possible to identify patients who might respond better to IL-23 inhibitors, compared with IL-17 inhibitors, Dr. Ostor acknowledged that rheumatologic practice is not yet proficient at using biomarkers to direct therapy, so the benefit from these drugs lay elsewhere.
“What I think is great is the luxury of choice these days,” Dr. Ostor told attendees. “We have these agents now, including risankizumab, that do work very effectively across the spectrum of the clinical features. It’s just lovely to have these agents available that can truly make a difference to the clinical picture of the individual.”
The trial was sponsored by AbbVie. Dr. Ostor has received research grants or speaking or consulting fees from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Varkas has received research grants or speaker fees from AbbVie and Pfizer.
A version of this article first appeared on Medscape.com.
Moving more, sitting less vital for migraine patients
according to a presentation at the American Headache Society’s 2021 annual meeting.
Though reliable research is sparse overall on how much physical activity people with migraine get, enough exists to reveal the need for clinicians to help patients identify ways to increase their levels of physical activity and make it a habit, said Dale S. Bond, PhD, a professor of psychiatry and human behavior at the Miriam Hospital and Brown University, both in Providence, R.I.
He emphasized the need not only to replace sedentary time with physical activity but also to reduce sedentary time overall.
“It’s important to note that because active and sedentary represent different behavioral domains, people can still be active – that is, achieving recommended levels of moderate to vigorous physical activity [MVPA] – but still be highly sedentary because they sit for long hours throughout the day,” Dr. Bond said. “This is important because MVPA will not necessarily eliminate the health risks of long hours of sitting.”
Dr. Bond reviewed the existing literature on physical activity and sedentary behavior among patients with migraine. His presentation, “Move More, Sit Less,” aimed at finding ways to incorporate more physical activity into the daily lives of those with migraine. Dr. Bond began by briefly reviewing the well-established benefits of physical activity, including healthy sleep; cardiovascular, respiratory, musculoskeletal, mental, and cognitive health; and metabolic functioning.
“Physical activity and exercise in particular enhances the functioning of bodily systems, including those that have direct relevance to migraine in its comorbidities,” Dr. Bond said. “The positive systemic effects of exercise on bodily systems carries potential to reduce migraine severity and related disability and morbidity.”
He also explained the ways in which excessive sedentary time can exacerbate migraine triggers. “Long periods of interrupted sitting elevated levels of glucose and fat in the bloodstream, which in turn triggers the immune system to attack the body via inflammation,” Dr. Bond said. “Low grade chronic inflammation has long been hypothesized to play a role in migraine pathogenesis.”
Recommended levels of exercise
The World Health Organization and the U.S. Department of Health & Human Services recommends at least 150-300 minutes of moderate-intensity aerobic physical activity or 75-150 minutes of vigorous activity each week. An additional recommendation is at least 2 days per week of muscle strengthening activities that involve all major muscle groups.
While neither of those organizations has specific guidelines on how much reduction of sedentary time is recommended, the Canadian Society for Exercise Physiology recommends limiting sedentary time to 8 or fewer hours per day.
Exercise and migraine
“Unfortunately, at present, we have very few studies from which to draw conclusions about the extent to which individuals with migraine adhere to physical activity and sedentary guidelines,” Dr. Bond said. Existing studies vary widely in sample types, study design, physical activity measure and MVPA outcome, including the type or definition of MVPA. “This wide variability in measures and outcomes makes it challenging to draw any conclusions about adherence to guidelines among individuals with migraine,” he said.
Existing evidence suggests anywhere from 32% to 66% of migraine patients are at least moderately active, though it’s not clear what constitutes “moderately active” behavior. It appears that activity levels of patients with migraine are low overall, but it’s less clear the extent to which these levels are lower than in controls given the paucity of evidence.
In one of the few studies using objective measures to assess physical activity in migraine patients, the daily level of MVPA was significantly lower in 25 women with migraine than in 25 age- and body mass index–matched women without migraine (P <. 003). Both groups had obesity. The same study found that virtually no women with migraine adhered to the guidelines recommending less than 8 hours a day of sedentary time, compared with 30% of women without migraine.
“Also, low physical activity and high sedentary levels appear to be consistent across headache and nonheadache days,” Dr. Bond said. “This finding in particular raises an interesting question: If migraine severity is not related to physical activity and sedentary time, what is it about migraine that contributes to an inactive and sedentary lifestyle?”
Dr. Bond noted that future research needs to include reports of frequency, duration, and intensity of activities performed as well as the percentage of participants who meet guidelines for physical activity and sedentary time. Ideally, these studies should include not only self-report but also objective measures of activity as well as assess sleep and identify barriers and facilitators to physical activity in patients.
Exercise avoidance
Dr. Bond described findings from survey of 100 women he conducted to better understand potential barriers and reported that 78% of patients report intentionally avoiding physical activity. These patients typically avoided it an average of 4 days per week, regardless of intensity, and additional survey findings found “that participants who reported any avoidance had stronger beliefs that physical activity would both trigger and worsen a migraine attack, compared with participants who reported no avoidance,” he said.
That finding matches the clinical experience of Jennifer Robblee, MD, MSc, assistant professor of neurology at Barrow Neurological Institute in Phoenix, who viewed the presentation but was not involved with it.
“They often feel that it is a trigger for worsening an attack or, for some people, can actually trigger an attack, and that they feel worse in the midst of an attack when they’re exercising,” Dr. Robblee said in an interview regarding her patients who exercise less frequently. “Since so many of the patients I see have a daily and constant headache, it’s about how they can get themselves to start to exercise when something makes them feel worse, even if it makes them feel better in the long run.”
Yet, experimental research suggests that physical activity is not necessarily a reliable trigger of migraine attacks and only worsens migraine in a minority of attacks, Dr. Bond said, revealing an interesting paradox: “While engaging in regular physical activity is an important migraine management strategy, most individuals in the study reported doing the exact opposite – that is, avoiding physical activity as a management strategy – and this strategy was associated with higher frequency and duration of attacks. Research from our group and others also suggested individuals with migraine could be overestimating the role that physical activity hasn’t triggering or worsening of attacks.”
Encouraging patients to exercise
Since the benefits of physical activity and limiting sedentary time outweigh the potential harms, “some physical activity is better than none,” Dr. Bond said. To help patients begin increasing their physical activity, he recommended advising them to start with small amounts and then gradually increase frequency, intensity, and duration over time.
Dr. Robblee follows a similar approach, taking into account each patient’s particular circumstances and any medications they’re taking, including the side effects of those medications.
“It’s about starting where they are,” Dr. Robblee said. “Some patients, despite having severe migraine, have built themselves up so they’re doing exercise three or four times per week, or every day, and I have other people who never exercise,” she said. “For those patients who are very sedentary, if I can get them to start with 5 minutes per week so they have that sense of accomplishment, then that’s where I start. Then slowly build it up over time. Like most things in the migraine world, I individualize it for the person.”
Dr. Bond offered the following specific tips to clinicians in educating and encouraging patients to increase physical activity:
- Educate patients regarding the short-and long-term benefits of moving more and sitting less, both for their migraines and for overall health.
- Correct misconceptions about the negative effects of physical activity as it relates to migraines.
- Personalize the rationale for physical activity to that patient’s specific values and personal goals.
- Encourage patients to use an activity tracker, both for tracking physical activity and sedentary time, and to monitor migraine attacks, stress, energy levels, and fatigue on days they do and do not exercise.
- Help patients set goals for eventually meeting MVPA recommendations and interrupting prolonged periods of sitting with brief movement breaks.
- Help patients identify rewards for meeting goals that are tied to the activity, such as new exercise clothing.
- Encourage patients to identify a consistent time for physical activity each day to establish a habit, “ideally in the morning before barriers and life get in the way,” he said.
Eventually, physical activity itself should become intrinsically rewarding, Dr. Bond said.
“To limit sitting and encourage more movement throughout the day, we want to make the choice to engage in physical activity easier by adding environmental cues that encourage physical activity,” he said. “Conversely, we want to make the choice to engage in sedentary behavior more difficult by increasing the amount of effort that is required to engage in these behaviors.”
Dr. Robblee found Dr. Bond’s emphasis on sitting less – distinct from moving more – a helpful frame to consider with her patients. “I really like the approach of looking at it from that approach: in addition to how do we get you up and moving, how much time are you sitting, and how often can you break that up into smaller increments so that you’re up more often?” Dr. Robblee said. “That sometimes sounds less scary than ‘let’s get you exercising.’ So ‘let’s get you sitting a little bit less.’ I think that is something I might start to adopt.”
No external funding was noted. Dr. Robblee is a principal investigator for a study sponsored by Eli Lilly and receives stipends for MedLink Neurology and Neurodiem. Dr. Bond reported no disclosures.
according to a presentation at the American Headache Society’s 2021 annual meeting.
Though reliable research is sparse overall on how much physical activity people with migraine get, enough exists to reveal the need for clinicians to help patients identify ways to increase their levels of physical activity and make it a habit, said Dale S. Bond, PhD, a professor of psychiatry and human behavior at the Miriam Hospital and Brown University, both in Providence, R.I.
He emphasized the need not only to replace sedentary time with physical activity but also to reduce sedentary time overall.
“It’s important to note that because active and sedentary represent different behavioral domains, people can still be active – that is, achieving recommended levels of moderate to vigorous physical activity [MVPA] – but still be highly sedentary because they sit for long hours throughout the day,” Dr. Bond said. “This is important because MVPA will not necessarily eliminate the health risks of long hours of sitting.”
Dr. Bond reviewed the existing literature on physical activity and sedentary behavior among patients with migraine. His presentation, “Move More, Sit Less,” aimed at finding ways to incorporate more physical activity into the daily lives of those with migraine. Dr. Bond began by briefly reviewing the well-established benefits of physical activity, including healthy sleep; cardiovascular, respiratory, musculoskeletal, mental, and cognitive health; and metabolic functioning.
“Physical activity and exercise in particular enhances the functioning of bodily systems, including those that have direct relevance to migraine in its comorbidities,” Dr. Bond said. “The positive systemic effects of exercise on bodily systems carries potential to reduce migraine severity and related disability and morbidity.”
He also explained the ways in which excessive sedentary time can exacerbate migraine triggers. “Long periods of interrupted sitting elevated levels of glucose and fat in the bloodstream, which in turn triggers the immune system to attack the body via inflammation,” Dr. Bond said. “Low grade chronic inflammation has long been hypothesized to play a role in migraine pathogenesis.”
Recommended levels of exercise
The World Health Organization and the U.S. Department of Health & Human Services recommends at least 150-300 minutes of moderate-intensity aerobic physical activity or 75-150 minutes of vigorous activity each week. An additional recommendation is at least 2 days per week of muscle strengthening activities that involve all major muscle groups.
While neither of those organizations has specific guidelines on how much reduction of sedentary time is recommended, the Canadian Society for Exercise Physiology recommends limiting sedentary time to 8 or fewer hours per day.
Exercise and migraine
“Unfortunately, at present, we have very few studies from which to draw conclusions about the extent to which individuals with migraine adhere to physical activity and sedentary guidelines,” Dr. Bond said. Existing studies vary widely in sample types, study design, physical activity measure and MVPA outcome, including the type or definition of MVPA. “This wide variability in measures and outcomes makes it challenging to draw any conclusions about adherence to guidelines among individuals with migraine,” he said.
Existing evidence suggests anywhere from 32% to 66% of migraine patients are at least moderately active, though it’s not clear what constitutes “moderately active” behavior. It appears that activity levels of patients with migraine are low overall, but it’s less clear the extent to which these levels are lower than in controls given the paucity of evidence.
In one of the few studies using objective measures to assess physical activity in migraine patients, the daily level of MVPA was significantly lower in 25 women with migraine than in 25 age- and body mass index–matched women without migraine (P <. 003). Both groups had obesity. The same study found that virtually no women with migraine adhered to the guidelines recommending less than 8 hours a day of sedentary time, compared with 30% of women without migraine.
“Also, low physical activity and high sedentary levels appear to be consistent across headache and nonheadache days,” Dr. Bond said. “This finding in particular raises an interesting question: If migraine severity is not related to physical activity and sedentary time, what is it about migraine that contributes to an inactive and sedentary lifestyle?”
Dr. Bond noted that future research needs to include reports of frequency, duration, and intensity of activities performed as well as the percentage of participants who meet guidelines for physical activity and sedentary time. Ideally, these studies should include not only self-report but also objective measures of activity as well as assess sleep and identify barriers and facilitators to physical activity in patients.
Exercise avoidance
Dr. Bond described findings from survey of 100 women he conducted to better understand potential barriers and reported that 78% of patients report intentionally avoiding physical activity. These patients typically avoided it an average of 4 days per week, regardless of intensity, and additional survey findings found “that participants who reported any avoidance had stronger beliefs that physical activity would both trigger and worsen a migraine attack, compared with participants who reported no avoidance,” he said.
That finding matches the clinical experience of Jennifer Robblee, MD, MSc, assistant professor of neurology at Barrow Neurological Institute in Phoenix, who viewed the presentation but was not involved with it.
“They often feel that it is a trigger for worsening an attack or, for some people, can actually trigger an attack, and that they feel worse in the midst of an attack when they’re exercising,” Dr. Robblee said in an interview regarding her patients who exercise less frequently. “Since so many of the patients I see have a daily and constant headache, it’s about how they can get themselves to start to exercise when something makes them feel worse, even if it makes them feel better in the long run.”
Yet, experimental research suggests that physical activity is not necessarily a reliable trigger of migraine attacks and only worsens migraine in a minority of attacks, Dr. Bond said, revealing an interesting paradox: “While engaging in regular physical activity is an important migraine management strategy, most individuals in the study reported doing the exact opposite – that is, avoiding physical activity as a management strategy – and this strategy was associated with higher frequency and duration of attacks. Research from our group and others also suggested individuals with migraine could be overestimating the role that physical activity hasn’t triggering or worsening of attacks.”
Encouraging patients to exercise
Since the benefits of physical activity and limiting sedentary time outweigh the potential harms, “some physical activity is better than none,” Dr. Bond said. To help patients begin increasing their physical activity, he recommended advising them to start with small amounts and then gradually increase frequency, intensity, and duration over time.
Dr. Robblee follows a similar approach, taking into account each patient’s particular circumstances and any medications they’re taking, including the side effects of those medications.
“It’s about starting where they are,” Dr. Robblee said. “Some patients, despite having severe migraine, have built themselves up so they’re doing exercise three or four times per week, or every day, and I have other people who never exercise,” she said. “For those patients who are very sedentary, if I can get them to start with 5 minutes per week so they have that sense of accomplishment, then that’s where I start. Then slowly build it up over time. Like most things in the migraine world, I individualize it for the person.”
Dr. Bond offered the following specific tips to clinicians in educating and encouraging patients to increase physical activity:
- Educate patients regarding the short-and long-term benefits of moving more and sitting less, both for their migraines and for overall health.
- Correct misconceptions about the negative effects of physical activity as it relates to migraines.
- Personalize the rationale for physical activity to that patient’s specific values and personal goals.
- Encourage patients to use an activity tracker, both for tracking physical activity and sedentary time, and to monitor migraine attacks, stress, energy levels, and fatigue on days they do and do not exercise.
- Help patients set goals for eventually meeting MVPA recommendations and interrupting prolonged periods of sitting with brief movement breaks.
- Help patients identify rewards for meeting goals that are tied to the activity, such as new exercise clothing.
- Encourage patients to identify a consistent time for physical activity each day to establish a habit, “ideally in the morning before barriers and life get in the way,” he said.
Eventually, physical activity itself should become intrinsically rewarding, Dr. Bond said.
“To limit sitting and encourage more movement throughout the day, we want to make the choice to engage in physical activity easier by adding environmental cues that encourage physical activity,” he said. “Conversely, we want to make the choice to engage in sedentary behavior more difficult by increasing the amount of effort that is required to engage in these behaviors.”
Dr. Robblee found Dr. Bond’s emphasis on sitting less – distinct from moving more – a helpful frame to consider with her patients. “I really like the approach of looking at it from that approach: in addition to how do we get you up and moving, how much time are you sitting, and how often can you break that up into smaller increments so that you’re up more often?” Dr. Robblee said. “That sometimes sounds less scary than ‘let’s get you exercising.’ So ‘let’s get you sitting a little bit less.’ I think that is something I might start to adopt.”
No external funding was noted. Dr. Robblee is a principal investigator for a study sponsored by Eli Lilly and receives stipends for MedLink Neurology and Neurodiem. Dr. Bond reported no disclosures.
according to a presentation at the American Headache Society’s 2021 annual meeting.
Though reliable research is sparse overall on how much physical activity people with migraine get, enough exists to reveal the need for clinicians to help patients identify ways to increase their levels of physical activity and make it a habit, said Dale S. Bond, PhD, a professor of psychiatry and human behavior at the Miriam Hospital and Brown University, both in Providence, R.I.
He emphasized the need not only to replace sedentary time with physical activity but also to reduce sedentary time overall.
“It’s important to note that because active and sedentary represent different behavioral domains, people can still be active – that is, achieving recommended levels of moderate to vigorous physical activity [MVPA] – but still be highly sedentary because they sit for long hours throughout the day,” Dr. Bond said. “This is important because MVPA will not necessarily eliminate the health risks of long hours of sitting.”
Dr. Bond reviewed the existing literature on physical activity and sedentary behavior among patients with migraine. His presentation, “Move More, Sit Less,” aimed at finding ways to incorporate more physical activity into the daily lives of those with migraine. Dr. Bond began by briefly reviewing the well-established benefits of physical activity, including healthy sleep; cardiovascular, respiratory, musculoskeletal, mental, and cognitive health; and metabolic functioning.
“Physical activity and exercise in particular enhances the functioning of bodily systems, including those that have direct relevance to migraine in its comorbidities,” Dr. Bond said. “The positive systemic effects of exercise on bodily systems carries potential to reduce migraine severity and related disability and morbidity.”
He also explained the ways in which excessive sedentary time can exacerbate migraine triggers. “Long periods of interrupted sitting elevated levels of glucose and fat in the bloodstream, which in turn triggers the immune system to attack the body via inflammation,” Dr. Bond said. “Low grade chronic inflammation has long been hypothesized to play a role in migraine pathogenesis.”
Recommended levels of exercise
The World Health Organization and the U.S. Department of Health & Human Services recommends at least 150-300 minutes of moderate-intensity aerobic physical activity or 75-150 minutes of vigorous activity each week. An additional recommendation is at least 2 days per week of muscle strengthening activities that involve all major muscle groups.
While neither of those organizations has specific guidelines on how much reduction of sedentary time is recommended, the Canadian Society for Exercise Physiology recommends limiting sedentary time to 8 or fewer hours per day.
Exercise and migraine
“Unfortunately, at present, we have very few studies from which to draw conclusions about the extent to which individuals with migraine adhere to physical activity and sedentary guidelines,” Dr. Bond said. Existing studies vary widely in sample types, study design, physical activity measure and MVPA outcome, including the type or definition of MVPA. “This wide variability in measures and outcomes makes it challenging to draw any conclusions about adherence to guidelines among individuals with migraine,” he said.
Existing evidence suggests anywhere from 32% to 66% of migraine patients are at least moderately active, though it’s not clear what constitutes “moderately active” behavior. It appears that activity levels of patients with migraine are low overall, but it’s less clear the extent to which these levels are lower than in controls given the paucity of evidence.
In one of the few studies using objective measures to assess physical activity in migraine patients, the daily level of MVPA was significantly lower in 25 women with migraine than in 25 age- and body mass index–matched women without migraine (P <. 003). Both groups had obesity. The same study found that virtually no women with migraine adhered to the guidelines recommending less than 8 hours a day of sedentary time, compared with 30% of women without migraine.
“Also, low physical activity and high sedentary levels appear to be consistent across headache and nonheadache days,” Dr. Bond said. “This finding in particular raises an interesting question: If migraine severity is not related to physical activity and sedentary time, what is it about migraine that contributes to an inactive and sedentary lifestyle?”
Dr. Bond noted that future research needs to include reports of frequency, duration, and intensity of activities performed as well as the percentage of participants who meet guidelines for physical activity and sedentary time. Ideally, these studies should include not only self-report but also objective measures of activity as well as assess sleep and identify barriers and facilitators to physical activity in patients.
Exercise avoidance
Dr. Bond described findings from survey of 100 women he conducted to better understand potential barriers and reported that 78% of patients report intentionally avoiding physical activity. These patients typically avoided it an average of 4 days per week, regardless of intensity, and additional survey findings found “that participants who reported any avoidance had stronger beliefs that physical activity would both trigger and worsen a migraine attack, compared with participants who reported no avoidance,” he said.
That finding matches the clinical experience of Jennifer Robblee, MD, MSc, assistant professor of neurology at Barrow Neurological Institute in Phoenix, who viewed the presentation but was not involved with it.
“They often feel that it is a trigger for worsening an attack or, for some people, can actually trigger an attack, and that they feel worse in the midst of an attack when they’re exercising,” Dr. Robblee said in an interview regarding her patients who exercise less frequently. “Since so many of the patients I see have a daily and constant headache, it’s about how they can get themselves to start to exercise when something makes them feel worse, even if it makes them feel better in the long run.”
Yet, experimental research suggests that physical activity is not necessarily a reliable trigger of migraine attacks and only worsens migraine in a minority of attacks, Dr. Bond said, revealing an interesting paradox: “While engaging in regular physical activity is an important migraine management strategy, most individuals in the study reported doing the exact opposite – that is, avoiding physical activity as a management strategy – and this strategy was associated with higher frequency and duration of attacks. Research from our group and others also suggested individuals with migraine could be overestimating the role that physical activity hasn’t triggering or worsening of attacks.”
Encouraging patients to exercise
Since the benefits of physical activity and limiting sedentary time outweigh the potential harms, “some physical activity is better than none,” Dr. Bond said. To help patients begin increasing their physical activity, he recommended advising them to start with small amounts and then gradually increase frequency, intensity, and duration over time.
Dr. Robblee follows a similar approach, taking into account each patient’s particular circumstances and any medications they’re taking, including the side effects of those medications.
“It’s about starting where they are,” Dr. Robblee said. “Some patients, despite having severe migraine, have built themselves up so they’re doing exercise three or four times per week, or every day, and I have other people who never exercise,” she said. “For those patients who are very sedentary, if I can get them to start with 5 minutes per week so they have that sense of accomplishment, then that’s where I start. Then slowly build it up over time. Like most things in the migraine world, I individualize it for the person.”
Dr. Bond offered the following specific tips to clinicians in educating and encouraging patients to increase physical activity:
- Educate patients regarding the short-and long-term benefits of moving more and sitting less, both for their migraines and for overall health.
- Correct misconceptions about the negative effects of physical activity as it relates to migraines.
- Personalize the rationale for physical activity to that patient’s specific values and personal goals.
- Encourage patients to use an activity tracker, both for tracking physical activity and sedentary time, and to monitor migraine attacks, stress, energy levels, and fatigue on days they do and do not exercise.
- Help patients set goals for eventually meeting MVPA recommendations and interrupting prolonged periods of sitting with brief movement breaks.
- Help patients identify rewards for meeting goals that are tied to the activity, such as new exercise clothing.
- Encourage patients to identify a consistent time for physical activity each day to establish a habit, “ideally in the morning before barriers and life get in the way,” he said.
Eventually, physical activity itself should become intrinsically rewarding, Dr. Bond said.
“To limit sitting and encourage more movement throughout the day, we want to make the choice to engage in physical activity easier by adding environmental cues that encourage physical activity,” he said. “Conversely, we want to make the choice to engage in sedentary behavior more difficult by increasing the amount of effort that is required to engage in these behaviors.”
Dr. Robblee found Dr. Bond’s emphasis on sitting less – distinct from moving more – a helpful frame to consider with her patients. “I really like the approach of looking at it from that approach: in addition to how do we get you up and moving, how much time are you sitting, and how often can you break that up into smaller increments so that you’re up more often?” Dr. Robblee said. “That sometimes sounds less scary than ‘let’s get you exercising.’ So ‘let’s get you sitting a little bit less.’ I think that is something I might start to adopt.”
No external funding was noted. Dr. Robblee is a principal investigator for a study sponsored by Eli Lilly and receives stipends for MedLink Neurology and Neurodiem. Dr. Bond reported no disclosures.
FROM AHS 2021
Ubrogepant effective for acute migraine even with preventive monoclonal antibody therapy
according to preliminary findings presented at the American Headache Society’s 2021 annual meeting.
“Because prevention [with mAbs] is rarely 100% effective, virtually everyone on preventive treatment needs to also take acute treatment,” presenter Richard B. Lipton, MD, a professor of neurology and director of the Montefiore Headache Center at Albert Einstein College of Medicine, New York, said in an interview after his presentation. He explained that ubrogepant, a small-molecule CGRP receptor blocker, is approved for acute treatment of migraine, while mAbs, which block the CGRP receptor or CGRP itself, are approved for prevention. “Many people predicted that gepants would not work in people on CGRP-targeted mAbs because of overlapping mechanisms.”
Dr. Lipton himself was not surprised by the findings, however. “For me, the surprise was that ubrogepant worked so well,” he said.
Novel data collection
Uniquely, his study used an entirely remote design with mobile applications to safely evaluate the drug’s real-world effectiveness in the midst of the COVID-19 pandemic. The prospective, observational study used the mobile app Migraine Buddy to collect data and assess outcomes from the use of 50 mg or 100 mg of ubrogepant along with a mAb, onabotA, or both.
In most migraine trials, researchers ask patients to track their symptoms in electronic diaries they learn how to use in the clinic.
“One disadvantage of this approach is that people usually need to carry two devices, the study device and their smartphone,” Dr. Lipton said in an interview. “In this study, people download an app at home to their smartphone and only need to carry one device. Though remote studies are particularly valuable in the time of pandemic, I believe that apps like Migraine Buddy are and will remain a valuable tool for addressing many research questions.”
Jennifer Robblee, MD, MSc, an assistant professor of neurology at Barrow Neurological Institute in Phoenix, viewed the presentation and was also impressed with the novel use of a smartphone app to conduct the study. “I think that was a unique and cool demonstration of what can be done with the apps out there now,” Dr. Robblee said in an interview. “If you want to have really good tracking and more through tracking, apps like this are fabulous and are very patient forward and patient friendly.”
Combination therapy
The researchers invited 4,541 adults to participate in the study if they had previously reported at least three migraine attacks in the past 30 days and if they had treated at least three prior attacks with ubrogepant. The 483 participants who enrolled after consent and screening included 272 taking ubrogepant with mAb, 132 participants taking ubrogepant with onabotA, and 79 taking ubrogepant with both onabotA and mAb.
For 30 days, participants reported in the app’s diary their pain relief and the time elapsed since taking ubrogepant until they returned to normal functioning. Endpoints included meaningful pain relief – defined as “a level of pain relief that is meaningful to you” – and return to normal function at 2 and 4 hours.
During the study, 352 participants reported treating a migraine attack with a single dose of ubrogepant, and 78 participants treated migraine with two doses. The former group included 193 patients in the ubrogepant plus mAb group, 102 patients in the ubrogepant plus onabotA group, and 57 patients in the ubrogepant plus both group. Because of the limited enrollment in the second two arms, the data Dr. Lipton presented data only on the ubrogepant with mAb arm.
Most of this group (89.1%) was female, with an average age of 40 years and an average Migraine Disability Assessment score of 72.2. Most of the patients were taking erenumab (44.6%) or galcanezumab (34.2%) with the remaining patients taking fremanezumab (17.6%), eptinezumab (3.1%) or multiple mAbs (0.5%). Most participants (59.6%) were prescribed 100-mg ubrogepant dose while the remaining participants took 50 mg.
The analysis of the ubrogepant plus mAb group revealed that 64.2% of patients reported meaningful pain relief at 2 hours, and 84.5% had meaningful pain relief 4 hours after taking ubrogepant. The odds of achieving meaningful pain relief were statistically significant at both time points and remained significant after adjustment for participants’ age, Migraine Disability Assessment score and self-reported prescribed ubrogepant dose (P < .001).
“This study shows that in patients with migraine on CGRP-targeted monoclonal antibodies, ubrogepant is an acute treatment to consider for breakthrough headaches,” Dr. Lipton said. He added that they have now completed the study with more participants and begun analyzing all three groups.
“Full analyses will include data from multiple attacks, attacks treated with a second dose of ubrogepant, additional daily and 30-day effectiveness measures for use of ubrogepant with onabotA and use of ubrogepant with both onabotA and CGRP mAbs,” Dr. Lipton said.
While the findings did not surprise Dr. Robblee, she was happy to see a study that explicitly testing the combination of these treatments, especially given access challenges. “Right now, because treatments are new, we get a lot of insurance denials,” Dr. Robblee said in an interview. “It’s great to have a study out there that we can turn to and say, ‘hey, look, they had all these patients safely using these together.’ It’s going to help us improve access for patients.”
Though Dr. Robblee typically uses old-school pen-and-calendar diaries with her patients, she also sees potential for the use of apps going forward, just as she sees for virtual health care.
“I’ve found telemedicine in general to be a really great addition to the migraine world, and this plays into our ability to use telemedicine paired with tracking,” Dr. Robblee said. “In so many studies, we’re doing a diary anyway, so if there are standard diaries and programs we’re all using, that would be a nice way to do these.”
She notes that most symptom tracking for pain is subjective already, and these apps often include the options to print out the data or to export or transfer it electronically to physicians. “It’s giving us meaningful data,” she said.
The research was funded by AbbVie. Dr. Lipton has received honoraria or research support from AbbVie, Amgen, Biohaven, Dr. Reddy’s Laboratories, electroCore, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, Novartis, Teva, Vector and Vedanta Research. He holds stock options in Biohaven and Ctrl M. Dr. Robblee is a principal investigator for a study sponsored by Eli Lilly and receives stipends for MedLink Neurology and Neurodiem.
according to preliminary findings presented at the American Headache Society’s 2021 annual meeting.
“Because prevention [with mAbs] is rarely 100% effective, virtually everyone on preventive treatment needs to also take acute treatment,” presenter Richard B. Lipton, MD, a professor of neurology and director of the Montefiore Headache Center at Albert Einstein College of Medicine, New York, said in an interview after his presentation. He explained that ubrogepant, a small-molecule CGRP receptor blocker, is approved for acute treatment of migraine, while mAbs, which block the CGRP receptor or CGRP itself, are approved for prevention. “Many people predicted that gepants would not work in people on CGRP-targeted mAbs because of overlapping mechanisms.”
Dr. Lipton himself was not surprised by the findings, however. “For me, the surprise was that ubrogepant worked so well,” he said.
Novel data collection
Uniquely, his study used an entirely remote design with mobile applications to safely evaluate the drug’s real-world effectiveness in the midst of the COVID-19 pandemic. The prospective, observational study used the mobile app Migraine Buddy to collect data and assess outcomes from the use of 50 mg or 100 mg of ubrogepant along with a mAb, onabotA, or both.
In most migraine trials, researchers ask patients to track their symptoms in electronic diaries they learn how to use in the clinic.
“One disadvantage of this approach is that people usually need to carry two devices, the study device and their smartphone,” Dr. Lipton said in an interview. “In this study, people download an app at home to their smartphone and only need to carry one device. Though remote studies are particularly valuable in the time of pandemic, I believe that apps like Migraine Buddy are and will remain a valuable tool for addressing many research questions.”
Jennifer Robblee, MD, MSc, an assistant professor of neurology at Barrow Neurological Institute in Phoenix, viewed the presentation and was also impressed with the novel use of a smartphone app to conduct the study. “I think that was a unique and cool demonstration of what can be done with the apps out there now,” Dr. Robblee said in an interview. “If you want to have really good tracking and more through tracking, apps like this are fabulous and are very patient forward and patient friendly.”
Combination therapy
The researchers invited 4,541 adults to participate in the study if they had previously reported at least three migraine attacks in the past 30 days and if they had treated at least three prior attacks with ubrogepant. The 483 participants who enrolled after consent and screening included 272 taking ubrogepant with mAb, 132 participants taking ubrogepant with onabotA, and 79 taking ubrogepant with both onabotA and mAb.
For 30 days, participants reported in the app’s diary their pain relief and the time elapsed since taking ubrogepant until they returned to normal functioning. Endpoints included meaningful pain relief – defined as “a level of pain relief that is meaningful to you” – and return to normal function at 2 and 4 hours.
During the study, 352 participants reported treating a migraine attack with a single dose of ubrogepant, and 78 participants treated migraine with two doses. The former group included 193 patients in the ubrogepant plus mAb group, 102 patients in the ubrogepant plus onabotA group, and 57 patients in the ubrogepant plus both group. Because of the limited enrollment in the second two arms, the data Dr. Lipton presented data only on the ubrogepant with mAb arm.
Most of this group (89.1%) was female, with an average age of 40 years and an average Migraine Disability Assessment score of 72.2. Most of the patients were taking erenumab (44.6%) or galcanezumab (34.2%) with the remaining patients taking fremanezumab (17.6%), eptinezumab (3.1%) or multiple mAbs (0.5%). Most participants (59.6%) were prescribed 100-mg ubrogepant dose while the remaining participants took 50 mg.
The analysis of the ubrogepant plus mAb group revealed that 64.2% of patients reported meaningful pain relief at 2 hours, and 84.5% had meaningful pain relief 4 hours after taking ubrogepant. The odds of achieving meaningful pain relief were statistically significant at both time points and remained significant after adjustment for participants’ age, Migraine Disability Assessment score and self-reported prescribed ubrogepant dose (P < .001).
“This study shows that in patients with migraine on CGRP-targeted monoclonal antibodies, ubrogepant is an acute treatment to consider for breakthrough headaches,” Dr. Lipton said. He added that they have now completed the study with more participants and begun analyzing all three groups.
“Full analyses will include data from multiple attacks, attacks treated with a second dose of ubrogepant, additional daily and 30-day effectiveness measures for use of ubrogepant with onabotA and use of ubrogepant with both onabotA and CGRP mAbs,” Dr. Lipton said.
While the findings did not surprise Dr. Robblee, she was happy to see a study that explicitly testing the combination of these treatments, especially given access challenges. “Right now, because treatments are new, we get a lot of insurance denials,” Dr. Robblee said in an interview. “It’s great to have a study out there that we can turn to and say, ‘hey, look, they had all these patients safely using these together.’ It’s going to help us improve access for patients.”
Though Dr. Robblee typically uses old-school pen-and-calendar diaries with her patients, she also sees potential for the use of apps going forward, just as she sees for virtual health care.
“I’ve found telemedicine in general to be a really great addition to the migraine world, and this plays into our ability to use telemedicine paired with tracking,” Dr. Robblee said. “In so many studies, we’re doing a diary anyway, so if there are standard diaries and programs we’re all using, that would be a nice way to do these.”
She notes that most symptom tracking for pain is subjective already, and these apps often include the options to print out the data or to export or transfer it electronically to physicians. “It’s giving us meaningful data,” she said.
The research was funded by AbbVie. Dr. Lipton has received honoraria or research support from AbbVie, Amgen, Biohaven, Dr. Reddy’s Laboratories, electroCore, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, Novartis, Teva, Vector and Vedanta Research. He holds stock options in Biohaven and Ctrl M. Dr. Robblee is a principal investigator for a study sponsored by Eli Lilly and receives stipends for MedLink Neurology and Neurodiem.
according to preliminary findings presented at the American Headache Society’s 2021 annual meeting.
“Because prevention [with mAbs] is rarely 100% effective, virtually everyone on preventive treatment needs to also take acute treatment,” presenter Richard B. Lipton, MD, a professor of neurology and director of the Montefiore Headache Center at Albert Einstein College of Medicine, New York, said in an interview after his presentation. He explained that ubrogepant, a small-molecule CGRP receptor blocker, is approved for acute treatment of migraine, while mAbs, which block the CGRP receptor or CGRP itself, are approved for prevention. “Many people predicted that gepants would not work in people on CGRP-targeted mAbs because of overlapping mechanisms.”
Dr. Lipton himself was not surprised by the findings, however. “For me, the surprise was that ubrogepant worked so well,” he said.
Novel data collection
Uniquely, his study used an entirely remote design with mobile applications to safely evaluate the drug’s real-world effectiveness in the midst of the COVID-19 pandemic. The prospective, observational study used the mobile app Migraine Buddy to collect data and assess outcomes from the use of 50 mg or 100 mg of ubrogepant along with a mAb, onabotA, or both.
In most migraine trials, researchers ask patients to track their symptoms in electronic diaries they learn how to use in the clinic.
“One disadvantage of this approach is that people usually need to carry two devices, the study device and their smartphone,” Dr. Lipton said in an interview. “In this study, people download an app at home to their smartphone and only need to carry one device. Though remote studies are particularly valuable in the time of pandemic, I believe that apps like Migraine Buddy are and will remain a valuable tool for addressing many research questions.”
Jennifer Robblee, MD, MSc, an assistant professor of neurology at Barrow Neurological Institute in Phoenix, viewed the presentation and was also impressed with the novel use of a smartphone app to conduct the study. “I think that was a unique and cool demonstration of what can be done with the apps out there now,” Dr. Robblee said in an interview. “If you want to have really good tracking and more through tracking, apps like this are fabulous and are very patient forward and patient friendly.”
Combination therapy
The researchers invited 4,541 adults to participate in the study if they had previously reported at least three migraine attacks in the past 30 days and if they had treated at least three prior attacks with ubrogepant. The 483 participants who enrolled after consent and screening included 272 taking ubrogepant with mAb, 132 participants taking ubrogepant with onabotA, and 79 taking ubrogepant with both onabotA and mAb.
For 30 days, participants reported in the app’s diary their pain relief and the time elapsed since taking ubrogepant until they returned to normal functioning. Endpoints included meaningful pain relief – defined as “a level of pain relief that is meaningful to you” – and return to normal function at 2 and 4 hours.
During the study, 352 participants reported treating a migraine attack with a single dose of ubrogepant, and 78 participants treated migraine with two doses. The former group included 193 patients in the ubrogepant plus mAb group, 102 patients in the ubrogepant plus onabotA group, and 57 patients in the ubrogepant plus both group. Because of the limited enrollment in the second two arms, the data Dr. Lipton presented data only on the ubrogepant with mAb arm.
Most of this group (89.1%) was female, with an average age of 40 years and an average Migraine Disability Assessment score of 72.2. Most of the patients were taking erenumab (44.6%) or galcanezumab (34.2%) with the remaining patients taking fremanezumab (17.6%), eptinezumab (3.1%) or multiple mAbs (0.5%). Most participants (59.6%) were prescribed 100-mg ubrogepant dose while the remaining participants took 50 mg.
The analysis of the ubrogepant plus mAb group revealed that 64.2% of patients reported meaningful pain relief at 2 hours, and 84.5% had meaningful pain relief 4 hours after taking ubrogepant. The odds of achieving meaningful pain relief were statistically significant at both time points and remained significant after adjustment for participants’ age, Migraine Disability Assessment score and self-reported prescribed ubrogepant dose (P < .001).
“This study shows that in patients with migraine on CGRP-targeted monoclonal antibodies, ubrogepant is an acute treatment to consider for breakthrough headaches,” Dr. Lipton said. He added that they have now completed the study with more participants and begun analyzing all three groups.
“Full analyses will include data from multiple attacks, attacks treated with a second dose of ubrogepant, additional daily and 30-day effectiveness measures for use of ubrogepant with onabotA and use of ubrogepant with both onabotA and CGRP mAbs,” Dr. Lipton said.
While the findings did not surprise Dr. Robblee, she was happy to see a study that explicitly testing the combination of these treatments, especially given access challenges. “Right now, because treatments are new, we get a lot of insurance denials,” Dr. Robblee said in an interview. “It’s great to have a study out there that we can turn to and say, ‘hey, look, they had all these patients safely using these together.’ It’s going to help us improve access for patients.”
Though Dr. Robblee typically uses old-school pen-and-calendar diaries with her patients, she also sees potential for the use of apps going forward, just as she sees for virtual health care.
“I’ve found telemedicine in general to be a really great addition to the migraine world, and this plays into our ability to use telemedicine paired with tracking,” Dr. Robblee said. “In so many studies, we’re doing a diary anyway, so if there are standard diaries and programs we’re all using, that would be a nice way to do these.”
She notes that most symptom tracking for pain is subjective already, and these apps often include the options to print out the data or to export or transfer it electronically to physicians. “It’s giving us meaningful data,” she said.
The research was funded by AbbVie. Dr. Lipton has received honoraria or research support from AbbVie, Amgen, Biohaven, Dr. Reddy’s Laboratories, electroCore, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, Novartis, Teva, Vector and Vedanta Research. He holds stock options in Biohaven and Ctrl M. Dr. Robblee is a principal investigator for a study sponsored by Eli Lilly and receives stipends for MedLink Neurology and Neurodiem.
FROM AHS 2021
Lenabasum missed mark for systemic sclerosis but may show promise for adjunctive therapy
Although a phase 3 trial of lenabasum did not meet its primary endpoint for treatment of diffuse cutaneous systemic sclerosis (dcSSc), the drug led to more improvement in participants who were not receiving background immunosuppressant therapy during the trial than that seen in participants who received the placebo. Lenabasum also had a favorable safety profile, according to findings presented at the annual European Congress of Rheumatology.
The double-blind, randomized, placebo-controlled trial involved 363 adults who had had dcSSc for up to 6 years. One third of the participants received 5 mg of oral lenabasum, one third received 20 mg, and one third received a placebo. Patients already receiving immunosuppressant therapy could continue to receive it during the trial if the dose had been stable for at least 8 weeks before screening and corticosteroid therapy did not exceed 10 mg prednisone per day or the equivalent.
“The decision to allow background immunosuppressant therapies was made to reflect real-world clinical practice,” coprincipal investigator Robert Dr. Spiera, MD, director of the Vasculitis and Scleroderma Program at the Hospital for Special Surgery, New York, told attendees.
“It is surprising that we do not see any added efficacy of lenabasum in this trial, given the fact that the previous phase 2 trial in 42 patients did show a clear benefit of lenabasum over placebo in the same population,” Jeska K. de Vries-Bouwstra, MD, PhD, a rheumatologist at Leiden (the Netherlands) University Medical Center told this news organization. “Even more, the clinical response in the phase 2 study was supported by a greater change in gene expression in skin tissue of pathways involved in inflammation and fibrosis with lenabasum as compared to placebo.”
Background immunosuppressants contribute to unprecedented placebo responses
The researchers compared the ACR CRISS (Combined Response Index in Diffuse Cutaneous Systemic Sclerosis) score and several secondary endpoints at 52 weeks between the 123 participants who received the placebo and the 120 participants who received 20 mg of lenabasum. A total of 60% of the lenabasum group and 66% of the placebo group had a disease duration of 3 or fewer years, and the modified Rodnan skin score (mRSS) was 22 in the lenabasum group and 23.3 in the placebo group at baseline.
A large majority of participants in both groups – 89% in the lenabasum group and 84% in the placebo group – were receiving background immunosuppressant therapy during the trial. Specifically, 53% of each group was taking mycophenolate, and 23% of the lenabasum group and 32% of the placebo group were taking corticosteroids. In addition, 22% of the lenabasum group and 12% of the placebo group were on methotrexate, and 27% of the lenabasum group and 22% of the placebo group were on another immunosuppressant therapy.
Half of the placebo group and 58% of the lenabasum group were taking only one immunosuppressive therapy. About one-third of the lenabasum (32%) and placebo (34%) groups were taking two or more immunosuppressive therapies.
The primary endpoint at 52 weeks was not significantly different between the two groups: a CRISS score of 0.888 in the lenabasum group and 0.887 in the placebo group. A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Patients with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.
“We had very high CRISS scores in all three groups, and they were comparable in all three groups,” Dr. Spiera reported. Because improvement in placebo group far exceeded expectations, the researchers were unable to discern the treatment effect of lenabasum on top of the placebo effect.
The placebo group had better outcomes than expected because of the background immunosuppressant therapy, particularly the use of mycophenolate. When the researchers looked only at placebo participants, the CRISS score was 0.936 in the 97 patients receiving background immunosuppressant therapy of any kind and 0.935 in the 29 patients taking only mycophenolate with no other immunosuppressant therapy, compared with 0.417 in the 16 patients not receiving any background therapy.
In a prespecified analysis, the researchers investigated background immunosuppressive therapy as a mediator. The CRISS score for the 10 lenabasum participants not receiving background therapy was 0.811, compared with 0.417 seen in the placebo group patients not on background therapy.
Among the 173 participants taking mycophenolate in particular, the mycophenolate “had a statistically significant improvement on CRISS score that increased with each visit,” Dr. Spiera reported. The duration of mycophenolate therapy also affected efficacy results.
Patients who had been taking mycophenolate longer saw less improvement in their CRISS score over time. Those taking it more than 2 years at baseline had a CRISS score of 0.86, compared with 0.96 for those taking it for 1-2 years at baseline and 0.98 for those taking it from 6 months to 1 year at baseline. Those who had only been taking mycophenolate for up to 6 months at baseline had a CRISS score of 0.99. Meanwhile, patients not taking any background immunosuppressant therapies only had a CRISS score of about 0.35.
Changes in secondary endpoints followed same pattern as CRISS
The secondary endpoints similarly showed no statistically significant difference when comparing the lenabasum and placebo groups overall. These endpoints included change in mRSS score, change in forced vital capacity (FVC) percentage and volume, and change in the Health Assessment Questionnaire Disability Index (HAQ-DI) score.
However, the researchers again found that duration of background therapy affected FVC.
“You were more likely to have declined [in FVC] if you were on placebo and more likely to have improved or stayed stable if you were on lenabasum if you were a patient on more than 2 years of immunomodulatory therapy at baseline,” Dr. Spiera reported. “There was evidence for an effect of lenabasum on FVC suggested by post-hoc analyses that considered the effect of background immunosuppressive therapies on outcomes, but those results would require confirmation in additional studies to determine the potential of lenabasum for treating patients with diffuse cutaneous systemic sclerosis,” Dr. Spiera noted in his conclusions.
Serious adverse events occurred in 9.2% of the lenabasum group and 5.8% of the placebo group. Rates of severe adverse events were similar between the lenabasum (14.6%) and placebo (13%) groups.
Is there a subgroup for whom lenabasum would be efficacious?
Although De Vries-Bouwstra of Leiden University Medical Center acknowledged the role of mycophenolate in the trial, she does not think background therapy can totally explain the observation and speculated on other possibilities.
“For example, there were fewer males in the placebo group as compared to the phase 2 study. From previous cohort studies we know that males have higher risk of worsening of skin disease,” she said. “In addition, it could be worthwhile to evaluate antibody profiles of the population under study; some subpopulations defined by autoantibody have higher risk for skin progression, while others can show spontaneous improvement.”
Dr. De Vries-Bouwstra said that, although it’s not currently appropriate to advocate for lenabasum to treat dcSSc, it may eventually become an additional treatment in those who still show active skin or lung disease after 2 years of mycophenolate treatment if future research identifies a benefit from that application. She would also like to see an evaluation of lenabasum’s possible benefits in patients with very early and active inflammatory disease. “Ideally, one could stratify patients based on biomarkers reflecting activation in relevant pathways, for example by using gene expression analysis from skin tissue to stratify,” she said.
Jacob M. van Laar, MD, PhD, professor of rheumatology at University Medical Center Utrecht (the Netherlands), also commented on the potential differences in using the drug in early versus later disease.
“Based on ex vivo analyses of skin samples from systemic sclerosis patients, one would expect such a mechanism of action to be particularly relevant in very early disease, so the observation that it might also be effective at a later disease stage is interesting,” Dr. van Laar told this news organization. “We still have a lot to learn about this complex disease.”
Given that safety does not appear to be a major concern and that there may be a benefit in a subgroup of patients, Dr. van Laar also said he hoped “the company is not deterred by the seemingly negative result of the primary endpoint.”
Dr. Spiera expressed optimism about what this trial’s findings have revealed about management of dcSSc.
“Independent of what lenabasum did or didn’t do in this trial, I think there’s going to be a lot that we’re going to learn from this trial and that we’re already learning and analyzing right now about treating scleroderma,” he said in an interview.
He reiterated the value of allowing background therapy in the trial to ensure it better replicated real-world clinical practice.
“You’re not withholding therapies that we think are probably active from patients with active disease that, once you incur organ damage, is probably not going to be reversible,” Dr. Spiera said. “The downside is that it makes it harder to see an effect of a drug on top of the background therapy if that background therapy is effective. So what we saw in terms of this absence of benefit from lenabasum really may have been a ceiling effect.”
Nevertheless, Dr. Spiera said the findings still strongly suggest that lenabasum is an active compound.
“It’s not an enormously powerful effect, but it probably has a role as an adjunctive therapy in people on stable background therapy who have either plateaued or are getting worse,” he said. “The thing we have to keep in mind also is this was an incredibly safe therapy. It’s not immunosuppressive.”
The trial was funded by Corbus. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Inflarx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen. Dr. De Vries-Bouwstra has received consulting fees from AbbVie and Boehringer Ingelheim and research grants from Galapagos and Janssen. Dr. Van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.
A version of this article first appeared on Medscape.com.
Although a phase 3 trial of lenabasum did not meet its primary endpoint for treatment of diffuse cutaneous systemic sclerosis (dcSSc), the drug led to more improvement in participants who were not receiving background immunosuppressant therapy during the trial than that seen in participants who received the placebo. Lenabasum also had a favorable safety profile, according to findings presented at the annual European Congress of Rheumatology.
The double-blind, randomized, placebo-controlled trial involved 363 adults who had had dcSSc for up to 6 years. One third of the participants received 5 mg of oral lenabasum, one third received 20 mg, and one third received a placebo. Patients already receiving immunosuppressant therapy could continue to receive it during the trial if the dose had been stable for at least 8 weeks before screening and corticosteroid therapy did not exceed 10 mg prednisone per day or the equivalent.
“The decision to allow background immunosuppressant therapies was made to reflect real-world clinical practice,” coprincipal investigator Robert Dr. Spiera, MD, director of the Vasculitis and Scleroderma Program at the Hospital for Special Surgery, New York, told attendees.
“It is surprising that we do not see any added efficacy of lenabasum in this trial, given the fact that the previous phase 2 trial in 42 patients did show a clear benefit of lenabasum over placebo in the same population,” Jeska K. de Vries-Bouwstra, MD, PhD, a rheumatologist at Leiden (the Netherlands) University Medical Center told this news organization. “Even more, the clinical response in the phase 2 study was supported by a greater change in gene expression in skin tissue of pathways involved in inflammation and fibrosis with lenabasum as compared to placebo.”
Background immunosuppressants contribute to unprecedented placebo responses
The researchers compared the ACR CRISS (Combined Response Index in Diffuse Cutaneous Systemic Sclerosis) score and several secondary endpoints at 52 weeks between the 123 participants who received the placebo and the 120 participants who received 20 mg of lenabasum. A total of 60% of the lenabasum group and 66% of the placebo group had a disease duration of 3 or fewer years, and the modified Rodnan skin score (mRSS) was 22 in the lenabasum group and 23.3 in the placebo group at baseline.
A large majority of participants in both groups – 89% in the lenabasum group and 84% in the placebo group – were receiving background immunosuppressant therapy during the trial. Specifically, 53% of each group was taking mycophenolate, and 23% of the lenabasum group and 32% of the placebo group were taking corticosteroids. In addition, 22% of the lenabasum group and 12% of the placebo group were on methotrexate, and 27% of the lenabasum group and 22% of the placebo group were on another immunosuppressant therapy.
Half of the placebo group and 58% of the lenabasum group were taking only one immunosuppressive therapy. About one-third of the lenabasum (32%) and placebo (34%) groups were taking two or more immunosuppressive therapies.
The primary endpoint at 52 weeks was not significantly different between the two groups: a CRISS score of 0.888 in the lenabasum group and 0.887 in the placebo group. A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Patients with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.
“We had very high CRISS scores in all three groups, and they were comparable in all three groups,” Dr. Spiera reported. Because improvement in placebo group far exceeded expectations, the researchers were unable to discern the treatment effect of lenabasum on top of the placebo effect.
The placebo group had better outcomes than expected because of the background immunosuppressant therapy, particularly the use of mycophenolate. When the researchers looked only at placebo participants, the CRISS score was 0.936 in the 97 patients receiving background immunosuppressant therapy of any kind and 0.935 in the 29 patients taking only mycophenolate with no other immunosuppressant therapy, compared with 0.417 in the 16 patients not receiving any background therapy.
In a prespecified analysis, the researchers investigated background immunosuppressive therapy as a mediator. The CRISS score for the 10 lenabasum participants not receiving background therapy was 0.811, compared with 0.417 seen in the placebo group patients not on background therapy.
Among the 173 participants taking mycophenolate in particular, the mycophenolate “had a statistically significant improvement on CRISS score that increased with each visit,” Dr. Spiera reported. The duration of mycophenolate therapy also affected efficacy results.
Patients who had been taking mycophenolate longer saw less improvement in their CRISS score over time. Those taking it more than 2 years at baseline had a CRISS score of 0.86, compared with 0.96 for those taking it for 1-2 years at baseline and 0.98 for those taking it from 6 months to 1 year at baseline. Those who had only been taking mycophenolate for up to 6 months at baseline had a CRISS score of 0.99. Meanwhile, patients not taking any background immunosuppressant therapies only had a CRISS score of about 0.35.
Changes in secondary endpoints followed same pattern as CRISS
The secondary endpoints similarly showed no statistically significant difference when comparing the lenabasum and placebo groups overall. These endpoints included change in mRSS score, change in forced vital capacity (FVC) percentage and volume, and change in the Health Assessment Questionnaire Disability Index (HAQ-DI) score.
However, the researchers again found that duration of background therapy affected FVC.
“You were more likely to have declined [in FVC] if you were on placebo and more likely to have improved or stayed stable if you were on lenabasum if you were a patient on more than 2 years of immunomodulatory therapy at baseline,” Dr. Spiera reported. “There was evidence for an effect of lenabasum on FVC suggested by post-hoc analyses that considered the effect of background immunosuppressive therapies on outcomes, but those results would require confirmation in additional studies to determine the potential of lenabasum for treating patients with diffuse cutaneous systemic sclerosis,” Dr. Spiera noted in his conclusions.
Serious adverse events occurred in 9.2% of the lenabasum group and 5.8% of the placebo group. Rates of severe adverse events were similar between the lenabasum (14.6%) and placebo (13%) groups.
Is there a subgroup for whom lenabasum would be efficacious?
Although De Vries-Bouwstra of Leiden University Medical Center acknowledged the role of mycophenolate in the trial, she does not think background therapy can totally explain the observation and speculated on other possibilities.
“For example, there were fewer males in the placebo group as compared to the phase 2 study. From previous cohort studies we know that males have higher risk of worsening of skin disease,” she said. “In addition, it could be worthwhile to evaluate antibody profiles of the population under study; some subpopulations defined by autoantibody have higher risk for skin progression, while others can show spontaneous improvement.”
Dr. De Vries-Bouwstra said that, although it’s not currently appropriate to advocate for lenabasum to treat dcSSc, it may eventually become an additional treatment in those who still show active skin or lung disease after 2 years of mycophenolate treatment if future research identifies a benefit from that application. She would also like to see an evaluation of lenabasum’s possible benefits in patients with very early and active inflammatory disease. “Ideally, one could stratify patients based on biomarkers reflecting activation in relevant pathways, for example by using gene expression analysis from skin tissue to stratify,” she said.
Jacob M. van Laar, MD, PhD, professor of rheumatology at University Medical Center Utrecht (the Netherlands), also commented on the potential differences in using the drug in early versus later disease.
“Based on ex vivo analyses of skin samples from systemic sclerosis patients, one would expect such a mechanism of action to be particularly relevant in very early disease, so the observation that it might also be effective at a later disease stage is interesting,” Dr. van Laar told this news organization. “We still have a lot to learn about this complex disease.”
Given that safety does not appear to be a major concern and that there may be a benefit in a subgroup of patients, Dr. van Laar also said he hoped “the company is not deterred by the seemingly negative result of the primary endpoint.”
Dr. Spiera expressed optimism about what this trial’s findings have revealed about management of dcSSc.
“Independent of what lenabasum did or didn’t do in this trial, I think there’s going to be a lot that we’re going to learn from this trial and that we’re already learning and analyzing right now about treating scleroderma,” he said in an interview.
He reiterated the value of allowing background therapy in the trial to ensure it better replicated real-world clinical practice.
“You’re not withholding therapies that we think are probably active from patients with active disease that, once you incur organ damage, is probably not going to be reversible,” Dr. Spiera said. “The downside is that it makes it harder to see an effect of a drug on top of the background therapy if that background therapy is effective. So what we saw in terms of this absence of benefit from lenabasum really may have been a ceiling effect.”
Nevertheless, Dr. Spiera said the findings still strongly suggest that lenabasum is an active compound.
“It’s not an enormously powerful effect, but it probably has a role as an adjunctive therapy in people on stable background therapy who have either plateaued or are getting worse,” he said. “The thing we have to keep in mind also is this was an incredibly safe therapy. It’s not immunosuppressive.”
The trial was funded by Corbus. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Inflarx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen. Dr. De Vries-Bouwstra has received consulting fees from AbbVie and Boehringer Ingelheim and research grants from Galapagos and Janssen. Dr. Van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.
A version of this article first appeared on Medscape.com.
Although a phase 3 trial of lenabasum did not meet its primary endpoint for treatment of diffuse cutaneous systemic sclerosis (dcSSc), the drug led to more improvement in participants who were not receiving background immunosuppressant therapy during the trial than that seen in participants who received the placebo. Lenabasum also had a favorable safety profile, according to findings presented at the annual European Congress of Rheumatology.
The double-blind, randomized, placebo-controlled trial involved 363 adults who had had dcSSc for up to 6 years. One third of the participants received 5 mg of oral lenabasum, one third received 20 mg, and one third received a placebo. Patients already receiving immunosuppressant therapy could continue to receive it during the trial if the dose had been stable for at least 8 weeks before screening and corticosteroid therapy did not exceed 10 mg prednisone per day or the equivalent.
“The decision to allow background immunosuppressant therapies was made to reflect real-world clinical practice,” coprincipal investigator Robert Dr. Spiera, MD, director of the Vasculitis and Scleroderma Program at the Hospital for Special Surgery, New York, told attendees.
“It is surprising that we do not see any added efficacy of lenabasum in this trial, given the fact that the previous phase 2 trial in 42 patients did show a clear benefit of lenabasum over placebo in the same population,” Jeska K. de Vries-Bouwstra, MD, PhD, a rheumatologist at Leiden (the Netherlands) University Medical Center told this news organization. “Even more, the clinical response in the phase 2 study was supported by a greater change in gene expression in skin tissue of pathways involved in inflammation and fibrosis with lenabasum as compared to placebo.”
Background immunosuppressants contribute to unprecedented placebo responses
The researchers compared the ACR CRISS (Combined Response Index in Diffuse Cutaneous Systemic Sclerosis) score and several secondary endpoints at 52 weeks between the 123 participants who received the placebo and the 120 participants who received 20 mg of lenabasum. A total of 60% of the lenabasum group and 66% of the placebo group had a disease duration of 3 or fewer years, and the modified Rodnan skin score (mRSS) was 22 in the lenabasum group and 23.3 in the placebo group at baseline.
A large majority of participants in both groups – 89% in the lenabasum group and 84% in the placebo group – were receiving background immunosuppressant therapy during the trial. Specifically, 53% of each group was taking mycophenolate, and 23% of the lenabasum group and 32% of the placebo group were taking corticosteroids. In addition, 22% of the lenabasum group and 12% of the placebo group were on methotrexate, and 27% of the lenabasum group and 22% of the placebo group were on another immunosuppressant therapy.
Half of the placebo group and 58% of the lenabasum group were taking only one immunosuppressive therapy. About one-third of the lenabasum (32%) and placebo (34%) groups were taking two or more immunosuppressive therapies.
The primary endpoint at 52 weeks was not significantly different between the two groups: a CRISS score of 0.888 in the lenabasum group and 0.887 in the placebo group. A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Patients with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.
“We had very high CRISS scores in all three groups, and they were comparable in all three groups,” Dr. Spiera reported. Because improvement in placebo group far exceeded expectations, the researchers were unable to discern the treatment effect of lenabasum on top of the placebo effect.
The placebo group had better outcomes than expected because of the background immunosuppressant therapy, particularly the use of mycophenolate. When the researchers looked only at placebo participants, the CRISS score was 0.936 in the 97 patients receiving background immunosuppressant therapy of any kind and 0.935 in the 29 patients taking only mycophenolate with no other immunosuppressant therapy, compared with 0.417 in the 16 patients not receiving any background therapy.
In a prespecified analysis, the researchers investigated background immunosuppressive therapy as a mediator. The CRISS score for the 10 lenabasum participants not receiving background therapy was 0.811, compared with 0.417 seen in the placebo group patients not on background therapy.
Among the 173 participants taking mycophenolate in particular, the mycophenolate “had a statistically significant improvement on CRISS score that increased with each visit,” Dr. Spiera reported. The duration of mycophenolate therapy also affected efficacy results.
Patients who had been taking mycophenolate longer saw less improvement in their CRISS score over time. Those taking it more than 2 years at baseline had a CRISS score of 0.86, compared with 0.96 for those taking it for 1-2 years at baseline and 0.98 for those taking it from 6 months to 1 year at baseline. Those who had only been taking mycophenolate for up to 6 months at baseline had a CRISS score of 0.99. Meanwhile, patients not taking any background immunosuppressant therapies only had a CRISS score of about 0.35.
Changes in secondary endpoints followed same pattern as CRISS
The secondary endpoints similarly showed no statistically significant difference when comparing the lenabasum and placebo groups overall. These endpoints included change in mRSS score, change in forced vital capacity (FVC) percentage and volume, and change in the Health Assessment Questionnaire Disability Index (HAQ-DI) score.
However, the researchers again found that duration of background therapy affected FVC.
“You were more likely to have declined [in FVC] if you were on placebo and more likely to have improved or stayed stable if you were on lenabasum if you were a patient on more than 2 years of immunomodulatory therapy at baseline,” Dr. Spiera reported. “There was evidence for an effect of lenabasum on FVC suggested by post-hoc analyses that considered the effect of background immunosuppressive therapies on outcomes, but those results would require confirmation in additional studies to determine the potential of lenabasum for treating patients with diffuse cutaneous systemic sclerosis,” Dr. Spiera noted in his conclusions.
Serious adverse events occurred in 9.2% of the lenabasum group and 5.8% of the placebo group. Rates of severe adverse events were similar between the lenabasum (14.6%) and placebo (13%) groups.
Is there a subgroup for whom lenabasum would be efficacious?
Although De Vries-Bouwstra of Leiden University Medical Center acknowledged the role of mycophenolate in the trial, she does not think background therapy can totally explain the observation and speculated on other possibilities.
“For example, there were fewer males in the placebo group as compared to the phase 2 study. From previous cohort studies we know that males have higher risk of worsening of skin disease,” she said. “In addition, it could be worthwhile to evaluate antibody profiles of the population under study; some subpopulations defined by autoantibody have higher risk for skin progression, while others can show spontaneous improvement.”
Dr. De Vries-Bouwstra said that, although it’s not currently appropriate to advocate for lenabasum to treat dcSSc, it may eventually become an additional treatment in those who still show active skin or lung disease after 2 years of mycophenolate treatment if future research identifies a benefit from that application. She would also like to see an evaluation of lenabasum’s possible benefits in patients with very early and active inflammatory disease. “Ideally, one could stratify patients based on biomarkers reflecting activation in relevant pathways, for example by using gene expression analysis from skin tissue to stratify,” she said.
Jacob M. van Laar, MD, PhD, professor of rheumatology at University Medical Center Utrecht (the Netherlands), also commented on the potential differences in using the drug in early versus later disease.
“Based on ex vivo analyses of skin samples from systemic sclerosis patients, one would expect such a mechanism of action to be particularly relevant in very early disease, so the observation that it might also be effective at a later disease stage is interesting,” Dr. van Laar told this news organization. “We still have a lot to learn about this complex disease.”
Given that safety does not appear to be a major concern and that there may be a benefit in a subgroup of patients, Dr. van Laar also said he hoped “the company is not deterred by the seemingly negative result of the primary endpoint.”
Dr. Spiera expressed optimism about what this trial’s findings have revealed about management of dcSSc.
“Independent of what lenabasum did or didn’t do in this trial, I think there’s going to be a lot that we’re going to learn from this trial and that we’re already learning and analyzing right now about treating scleroderma,” he said in an interview.
He reiterated the value of allowing background therapy in the trial to ensure it better replicated real-world clinical practice.
“You’re not withholding therapies that we think are probably active from patients with active disease that, once you incur organ damage, is probably not going to be reversible,” Dr. Spiera said. “The downside is that it makes it harder to see an effect of a drug on top of the background therapy if that background therapy is effective. So what we saw in terms of this absence of benefit from lenabasum really may have been a ceiling effect.”
Nevertheless, Dr. Spiera said the findings still strongly suggest that lenabasum is an active compound.
“It’s not an enormously powerful effect, but it probably has a role as an adjunctive therapy in people on stable background therapy who have either plateaued or are getting worse,” he said. “The thing we have to keep in mind also is this was an incredibly safe therapy. It’s not immunosuppressive.”
The trial was funded by Corbus. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Inflarx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen. Dr. De Vries-Bouwstra has received consulting fees from AbbVie and Boehringer Ingelheim and research grants from Galapagos and Janssen. Dr. Van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.
A version of this article first appeared on Medscape.com.
Migraine linked to more COVID-19 infections, symptoms but less health care utilization
, according to a study presented at the American Headache Society’s 2021 annual meeting.
“These data suggest that people with migraine are either more susceptible to contracting COVID-19, or that they may be more sensitive to the development of symptoms once COVID-19 has been contracted, or both,” Robert Shapiro, MD, PhD, professor of neurological science at the University of Vermont, Burlington. “Further, once COVID-19 has been contracted, people with migraine may be less likely to develop serious COVID-19 outcomes, or they may be less likely to seek health care for COVID-19, or both.”
In providing background information, Dr. Shapiro noted previous research showing that headache is associated with a positive prognosis in COVID-19 inpatients, including lower IL-6 levels throughout the disease course, a 1-week shorter disease course, and a 2.2 times greater relative risk of survival.
Yet in a study across 171 countries, a higher population prevalence of migraine is associated with higher COVID-19 mortality rates. It’s unclear what conclusions can be drawn from that association, however, said Deborah I. Friedman, MD, MPH, professor of neurology and ophthalmology at University of Texas, Dallas, who was not involved in the research.
Dr. Shapiro suggested a theoretical possibility, noting that two genes linked to migraine susceptibility – SCN1A and IFNAR2 – are among 15 host loci also associated with COVID-19 outcomes. Further, Dr. Shapiro noted in his background information, COVID-19 is linked to lower serum calcitonin gene-related peptide levels.
For the study, Dr. Shapiro and colleagues analyzed data from U.S. adults who responded to the National Health and Wellness Survey from April to July 2020. The researchers limited their analysis to the 41,155 participants who had not received the flu vaccine in 2020 since previous research has suggested reduced morbidity among those with COVID-19 who had been vaccinated against the flu. In this group, 4,550 participants had ever been diagnosed by a doctor with migraine (11%) and 36,605 participants had not (89%).
The majority of those with a history of migraine were female (78%), compared with the overall sample (50% female), and tended to be younger, with an average age of 39 compared with 45 for those without migraine (P < .001).
Among those with a previous migraine diagnosis, 3.8% self-reported having had a COVID-19 infection, compared with infection in 2.4% of those without a history of migraine (P < .001). That translated to a 58% increased risk of COVID-19 infection in those with migraine history, with a similar rate of test positivity in both groups (33.7% with migraine history vs. 34.5% without). Test negativity was also similar in both groups (15.9% vs. 17.8%).
Of 360 respondents who had tested positive for COVID-19, the 60 with a history of migraine reported more frequent symptoms than those without migraine. The increased frequency was statistically significant (P < .001 unless otherwise indicated) for the following symptoms:
- Difficulty breathing or shortness of breath (P = .005).
- Fever.
- Headache, sore throat, and/or congestion.
- Fatigue.
- Loss of smell and taste.
- Chills and body aches.
- Persistent pain or pressure in the chest.
- Confusion or inability to arouse.
- Digestive issues (P = .005).
- Bluish lips or face.
For several of these symptoms – such as headache/sore throat/congestion, persistent pain or pressure in the chest, confusion/inability to arouse, and digestive issues – more than twice as many respondents with migraine reported the symptom, vs. those without migraine.
Changes in health care utilization
“I think that people with migraine are aware of their bodies and aware of their symptoms more than the average person,” Dr. Friedman said. Yet those with migraine were less likely to use health care while diagnosed with COVID-19 than were those without migraine. Migraine sufferers with a COVID-19 infection were 1.2 times more likely to visit a health care provider than were those without an infection, but the similar relative risk was 1.35 greater for those with COVID-19 infections and no migraines.
Similarly, those with a migraine history were more than twice as likely to visit the emergency department when they had a COVID-19 vaccine infection than were those without an infection (RR = 2.6), but among those without a history of migraine, respondents were nearly five times more likely to visit the emergency department when they had a COVID-19 infection than when they didn’t (RR = 4.9).
Dr. Friedman suggested that the lower utilization rate may have to do with the nature of migraine itself. “There are people with migraine who go to the emergency room all the time, but then there’s most of the people with migraine, who would rather die than go to the emergency room because with the light and the noise, it’s just a horrible place to be if you have migraine,” Dr. Friedman said. “I think the majority of people would prefer not to go to the emergency room if given the choice.”
Increased likelihood of hospitalization among those with migraine and a COVID-19 infection was 4.6 compared with those with a migraine and no infection; the corresponding hospitalization risk for COVID-19 among those without migraine was 7.6 times greater than for those with no infection. All these risk ratios were statistically significant.
Dr. Shapiro then speculated on what it might mean that headache is a positive prognostic indicator for COVID-19 inpatients and that migraine population prevalence is linked to higher COVID-19 mortality.
“A hypothesis emerges that headache as a symptom, and migraine as a disease, may reflect adaptive processes associated with host defenses against viruses,” Dr. Shapiro said. “For example, migraine-driven behaviors, such as social distancing due to photophobia, in the setting of viral illness may play adaptive roles in reducing viral spread.”
The researchers did not receive external funding. Dr. Shapiro has consulted for Eli Lilly and Lundbeck. Dr. Friedman reports grant support and/or advisory board participation for Allergan, Biohaven Pharmaceuticals, Eli Lilly, Impel NeuroPharma, Invex, Lundbeck, Merck, Revance Therapeutics, Satsuma Pharmaceuticals, Teva Pharmaceuticals, Theranica, and Zosano Pharma.
, according to a study presented at the American Headache Society’s 2021 annual meeting.
“These data suggest that people with migraine are either more susceptible to contracting COVID-19, or that they may be more sensitive to the development of symptoms once COVID-19 has been contracted, or both,” Robert Shapiro, MD, PhD, professor of neurological science at the University of Vermont, Burlington. “Further, once COVID-19 has been contracted, people with migraine may be less likely to develop serious COVID-19 outcomes, or they may be less likely to seek health care for COVID-19, or both.”
In providing background information, Dr. Shapiro noted previous research showing that headache is associated with a positive prognosis in COVID-19 inpatients, including lower IL-6 levels throughout the disease course, a 1-week shorter disease course, and a 2.2 times greater relative risk of survival.
Yet in a study across 171 countries, a higher population prevalence of migraine is associated with higher COVID-19 mortality rates. It’s unclear what conclusions can be drawn from that association, however, said Deborah I. Friedman, MD, MPH, professor of neurology and ophthalmology at University of Texas, Dallas, who was not involved in the research.
Dr. Shapiro suggested a theoretical possibility, noting that two genes linked to migraine susceptibility – SCN1A and IFNAR2 – are among 15 host loci also associated with COVID-19 outcomes. Further, Dr. Shapiro noted in his background information, COVID-19 is linked to lower serum calcitonin gene-related peptide levels.
For the study, Dr. Shapiro and colleagues analyzed data from U.S. adults who responded to the National Health and Wellness Survey from April to July 2020. The researchers limited their analysis to the 41,155 participants who had not received the flu vaccine in 2020 since previous research has suggested reduced morbidity among those with COVID-19 who had been vaccinated against the flu. In this group, 4,550 participants had ever been diagnosed by a doctor with migraine (11%) and 36,605 participants had not (89%).
The majority of those with a history of migraine were female (78%), compared with the overall sample (50% female), and tended to be younger, with an average age of 39 compared with 45 for those without migraine (P < .001).
Among those with a previous migraine diagnosis, 3.8% self-reported having had a COVID-19 infection, compared with infection in 2.4% of those without a history of migraine (P < .001). That translated to a 58% increased risk of COVID-19 infection in those with migraine history, with a similar rate of test positivity in both groups (33.7% with migraine history vs. 34.5% without). Test negativity was also similar in both groups (15.9% vs. 17.8%).
Of 360 respondents who had tested positive for COVID-19, the 60 with a history of migraine reported more frequent symptoms than those without migraine. The increased frequency was statistically significant (P < .001 unless otherwise indicated) for the following symptoms:
- Difficulty breathing or shortness of breath (P = .005).
- Fever.
- Headache, sore throat, and/or congestion.
- Fatigue.
- Loss of smell and taste.
- Chills and body aches.
- Persistent pain or pressure in the chest.
- Confusion or inability to arouse.
- Digestive issues (P = .005).
- Bluish lips or face.
For several of these symptoms – such as headache/sore throat/congestion, persistent pain or pressure in the chest, confusion/inability to arouse, and digestive issues – more than twice as many respondents with migraine reported the symptom, vs. those without migraine.
Changes in health care utilization
“I think that people with migraine are aware of their bodies and aware of their symptoms more than the average person,” Dr. Friedman said. Yet those with migraine were less likely to use health care while diagnosed with COVID-19 than were those without migraine. Migraine sufferers with a COVID-19 infection were 1.2 times more likely to visit a health care provider than were those without an infection, but the similar relative risk was 1.35 greater for those with COVID-19 infections and no migraines.
Similarly, those with a migraine history were more than twice as likely to visit the emergency department when they had a COVID-19 vaccine infection than were those without an infection (RR = 2.6), but among those without a history of migraine, respondents were nearly five times more likely to visit the emergency department when they had a COVID-19 infection than when they didn’t (RR = 4.9).
Dr. Friedman suggested that the lower utilization rate may have to do with the nature of migraine itself. “There are people with migraine who go to the emergency room all the time, but then there’s most of the people with migraine, who would rather die than go to the emergency room because with the light and the noise, it’s just a horrible place to be if you have migraine,” Dr. Friedman said. “I think the majority of people would prefer not to go to the emergency room if given the choice.”
Increased likelihood of hospitalization among those with migraine and a COVID-19 infection was 4.6 compared with those with a migraine and no infection; the corresponding hospitalization risk for COVID-19 among those without migraine was 7.6 times greater than for those with no infection. All these risk ratios were statistically significant.
Dr. Shapiro then speculated on what it might mean that headache is a positive prognostic indicator for COVID-19 inpatients and that migraine population prevalence is linked to higher COVID-19 mortality.
“A hypothesis emerges that headache as a symptom, and migraine as a disease, may reflect adaptive processes associated with host defenses against viruses,” Dr. Shapiro said. “For example, migraine-driven behaviors, such as social distancing due to photophobia, in the setting of viral illness may play adaptive roles in reducing viral spread.”
The researchers did not receive external funding. Dr. Shapiro has consulted for Eli Lilly and Lundbeck. Dr. Friedman reports grant support and/or advisory board participation for Allergan, Biohaven Pharmaceuticals, Eli Lilly, Impel NeuroPharma, Invex, Lundbeck, Merck, Revance Therapeutics, Satsuma Pharmaceuticals, Teva Pharmaceuticals, Theranica, and Zosano Pharma.
, according to a study presented at the American Headache Society’s 2021 annual meeting.
“These data suggest that people with migraine are either more susceptible to contracting COVID-19, or that they may be more sensitive to the development of symptoms once COVID-19 has been contracted, or both,” Robert Shapiro, MD, PhD, professor of neurological science at the University of Vermont, Burlington. “Further, once COVID-19 has been contracted, people with migraine may be less likely to develop serious COVID-19 outcomes, or they may be less likely to seek health care for COVID-19, or both.”
In providing background information, Dr. Shapiro noted previous research showing that headache is associated with a positive prognosis in COVID-19 inpatients, including lower IL-6 levels throughout the disease course, a 1-week shorter disease course, and a 2.2 times greater relative risk of survival.
Yet in a study across 171 countries, a higher population prevalence of migraine is associated with higher COVID-19 mortality rates. It’s unclear what conclusions can be drawn from that association, however, said Deborah I. Friedman, MD, MPH, professor of neurology and ophthalmology at University of Texas, Dallas, who was not involved in the research.
Dr. Shapiro suggested a theoretical possibility, noting that two genes linked to migraine susceptibility – SCN1A and IFNAR2 – are among 15 host loci also associated with COVID-19 outcomes. Further, Dr. Shapiro noted in his background information, COVID-19 is linked to lower serum calcitonin gene-related peptide levels.
For the study, Dr. Shapiro and colleagues analyzed data from U.S. adults who responded to the National Health and Wellness Survey from April to July 2020. The researchers limited their analysis to the 41,155 participants who had not received the flu vaccine in 2020 since previous research has suggested reduced morbidity among those with COVID-19 who had been vaccinated against the flu. In this group, 4,550 participants had ever been diagnosed by a doctor with migraine (11%) and 36,605 participants had not (89%).
The majority of those with a history of migraine were female (78%), compared with the overall sample (50% female), and tended to be younger, with an average age of 39 compared with 45 for those without migraine (P < .001).
Among those with a previous migraine diagnosis, 3.8% self-reported having had a COVID-19 infection, compared with infection in 2.4% of those without a history of migraine (P < .001). That translated to a 58% increased risk of COVID-19 infection in those with migraine history, with a similar rate of test positivity in both groups (33.7% with migraine history vs. 34.5% without). Test negativity was also similar in both groups (15.9% vs. 17.8%).
Of 360 respondents who had tested positive for COVID-19, the 60 with a history of migraine reported more frequent symptoms than those without migraine. The increased frequency was statistically significant (P < .001 unless otherwise indicated) for the following symptoms:
- Difficulty breathing or shortness of breath (P = .005).
- Fever.
- Headache, sore throat, and/or congestion.
- Fatigue.
- Loss of smell and taste.
- Chills and body aches.
- Persistent pain or pressure in the chest.
- Confusion or inability to arouse.
- Digestive issues (P = .005).
- Bluish lips or face.
For several of these symptoms – such as headache/sore throat/congestion, persistent pain or pressure in the chest, confusion/inability to arouse, and digestive issues – more than twice as many respondents with migraine reported the symptom, vs. those without migraine.
Changes in health care utilization
“I think that people with migraine are aware of their bodies and aware of their symptoms more than the average person,” Dr. Friedman said. Yet those with migraine were less likely to use health care while diagnosed with COVID-19 than were those without migraine. Migraine sufferers with a COVID-19 infection were 1.2 times more likely to visit a health care provider than were those without an infection, but the similar relative risk was 1.35 greater for those with COVID-19 infections and no migraines.
Similarly, those with a migraine history were more than twice as likely to visit the emergency department when they had a COVID-19 vaccine infection than were those without an infection (RR = 2.6), but among those without a history of migraine, respondents were nearly five times more likely to visit the emergency department when they had a COVID-19 infection than when they didn’t (RR = 4.9).
Dr. Friedman suggested that the lower utilization rate may have to do with the nature of migraine itself. “There are people with migraine who go to the emergency room all the time, but then there’s most of the people with migraine, who would rather die than go to the emergency room because with the light and the noise, it’s just a horrible place to be if you have migraine,” Dr. Friedman said. “I think the majority of people would prefer not to go to the emergency room if given the choice.”
Increased likelihood of hospitalization among those with migraine and a COVID-19 infection was 4.6 compared with those with a migraine and no infection; the corresponding hospitalization risk for COVID-19 among those without migraine was 7.6 times greater than for those with no infection. All these risk ratios were statistically significant.
Dr. Shapiro then speculated on what it might mean that headache is a positive prognostic indicator for COVID-19 inpatients and that migraine population prevalence is linked to higher COVID-19 mortality.
“A hypothesis emerges that headache as a symptom, and migraine as a disease, may reflect adaptive processes associated with host defenses against viruses,” Dr. Shapiro said. “For example, migraine-driven behaviors, such as social distancing due to photophobia, in the setting of viral illness may play adaptive roles in reducing viral spread.”
The researchers did not receive external funding. Dr. Shapiro has consulted for Eli Lilly and Lundbeck. Dr. Friedman reports grant support and/or advisory board participation for Allergan, Biohaven Pharmaceuticals, Eli Lilly, Impel NeuroPharma, Invex, Lundbeck, Merck, Revance Therapeutics, Satsuma Pharmaceuticals, Teva Pharmaceuticals, Theranica, and Zosano Pharma.
FROM AHS 2021
