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New steroid dosing regimen for myasthenia gravis
. The trial showed that the conventional slow tapering regimen enabled discontinuation of prednisone earlier than previously reported but the new rapid-tapering regimen enabled an even faster discontinuation.
Noting that although both regimens led to a comparable myasthenia gravis status and prednisone dose at 15 months, the authors stated: “We think that the reduction of the cumulative dose over a year (equivalent to 5 mg/day) is a clinically relevant reduction, since the risk of complications is proportional to the daily or cumulative doses of prednisone.
“Our results warrant testing of a more rapid-tapering regimen in a future trial. In the meantime, our trial provides useful information on how prednisone tapering could be managed in patients with generalized myasthenia gravis treated with azathioprine,” they concluded.
The trial was published online Feb. 8 in JAMA Neurology.
Myasthenia gravis is a disorder of neuromuscular transmission, resulting from autoantibodies to components of the neuromuscular junction, most commonly the acetylcholine receptor. The incidence ranges from 0.3 to 2.8 per 100,000, and it is estimated to affect more than 700,000 people worldwide.
The authors of the current paper, led by Tarek Sharshar, MD, PhD, Groupe Hospitalier Universitaire, Paris, explained that many patients whose symptoms are not controlled by cholinesterase inhibitors are treated with corticosteroids and an immunosuppressant, usually azathioprine. No specific dosing protocol for prednisone has been validated, but it is commonly gradually increased to 0.75 mg/kg on alternate days and reduced progressively when minimal manifestation status (MMS; no symptoms or functional limitations) is reached.
They noted that this regimen leads to high and prolonged corticosteroid treatment – often for several years – with the mean daily prednisone dose exceeding 30 mg/day at 15 months and 20 mg/day at 36 months. As long-term use of corticosteroids is often associated with significant complications, reducing or even discontinuing prednisone treatment without destabilizing myasthenia gravis is therefore a therapeutic goal.
Evaluating dosage regimens
To investigate whether different dosage regimens could help wean patients with generalized myasthenia gravis from corticosteroid therapy without compromising efficacy, the researchers conducted this study in which the current recommended regimen was compared with an approach using higher initial corticosteroid doses followed by rapid tapering.
In the conventional slow-tapering group (control group), prednisone was given on alternate days, starting at a dose of 10 mg then increased by increments of 10 mg every 2 days up to 1.5 mg/kg on alternate days without exceeding 100 mg. This dose was maintained until MMS was reached and then reduced by 10 mg every 2 weeks until a dosage of 40 mg was reached, with subsequent slowing of the taper to 5 mg monthly. If MMS was not maintained, the alternate-day prednisone dose was increased by 10 mg every 2 weeks until MMS was restored, and the tapering resumed 4 weeks later.
In the new rapid-tapering group, oral prednisone was immediately started at 0.75 mg/kg per day, and this was followed by an earlier and rapid decrease once improved myasthenia gravis status was attained. Three different tapering schedules were applied dependent on the improvement status of the patient.
First, If the patient reached MMS at 1 month, the dose of prednisone was reduced by 0.1 mg/kg every 10 days up to 0.45 mg/kg per day, then 0.05 mg/kg every 10 days up to 0.25 mg/kg per day, then in decrements of 1 mg by adjusting the duration of the decrements according to the participant’s weight with the aim of achieving complete cessation of corticosteroid therapy within 18-20 weeks for this third stage of tapering.
Second, if the state of MMS was not reached at 1 month but the participant had improved, a slower tapering was conducted, with the dosage reduced in a similar way to the first instance but with each reduction introduced every 20 days. If the participant reached MMS during this tapering process, the tapering of prednisone was similar to the sequence described in the first group.
Third, if MMS was not reached and the participant had not improved, the initial dose was maintained for the first 3 months; beyond that time, a decrease in the prednisone dose was undertaken as in the second group to a minimum dose of 0.25 mg/kg per day, after which the prednisone dose was not reduced further. If the patient improved, the tapering of prednisone followed the sequence described in the second category.
Reductions in prednisone dose could be accelerated in the case of severe prednisone adverse effects, according to the prescriber’s decision.
In the event of a myasthenia gravis exacerbation, the patient was hospitalized and the dose of prednisone was routinely doubled, or for a more moderate aggravation, the dose was increased to the previous dose recommended in the tapering regimen.
Azathioprine, up to a maximum dose of 3 mg/kg per day, was prescribed for all participants. In all, 117 patients were randomly assigned, and 113 completed the study.
The primary outcome was the proportion of participants having reached MMS without prednisone at 12 months and having not relapsed or taken prednisone between months 12 and 15. This was achieved by significantly more patients in the rapid-tapering group (39% vs. 9%; risk ratio, 3.61; P < .001).
Rapid tapering allowed sparing of a mean of 1,898 mg of prednisone over 1 year (5.3 mg/day) per patient.
The rate of myasthenia gravis exacerbation or worsening did not differ significantly between the two groups, nor did the use of plasmapheresis or IVIG or the doses of azathioprine.
The overall number of serious adverse events did not differ significantly between the two groups (slow tapering, 22% vs. rapid-tapering, 36%; P = .15).
The researchers said it is possible that prednisone tapering would differ with another immunosuppressive agent but as azathioprine is the first-line immunosuppressant usually recommended, these results are relevant for a large proportion of patients.
They said the better outcome of the intervention group could have been related to one or more of four differences in prednisone administration: An immediate high dose versus a slow increase of the prednisone dose; daily versus alternate-day dosing; earlier tapering initiation; and faster tapering. However, the structure of the study did not allow identification of which of these factors was responsible.
“Researching the best prednisone-tapering scheme is not only a major issue for patients with myasthenia gravis but also for other autoimmune or inflammatory diseases, because validated prednisone-tapering regimens are scarce,” the authors said.
The rapid tapering of prednisone therapy appears to be feasible, beneficial, and safe in patients with generalized myasthenia gravis and “warrants testing in other autoimmune diseases,” they added.
Particularly relevant to late-onset disease
Commenting on the study, Raffi Topakian, MD, Klinikum Wels-Grieskirchen, Wels, Austria, said the results showed that in patients with moderate to severe generalized myasthenia gravis requiring high-dose prednisone, azathioprine, a widely used immunosuppressant, may have a quicker steroid-sparing effect than previously thought, and that rapid steroid tapering can be achieved safely, resulting in a reduction of the cumulative steroid dose over a year despite higher initial doses.
Dr. Topakian, who was not involved with the research, pointed out that the median age was advanced (around 56 years), and the benefit of a regimen that leads to a reduction of the cumulative steroid dose over a year may be disproportionately larger for older, sicker patients with many comorbidities who are at considerably higher risk for a prednisone-induced increase in cardiovascular complications, osteoporotic fractures, and gastrointestinal bleeding.
“The study findings are particularly relevant for the management of late-onset myasthenia gravis (when first symptoms start after age 45-50 years), which is being encountered more frequently over the past years,” he said.
“But the holy grail of myasthenia gravis treatment has not been found yet,” Dr. Topakian noted. “Disappointingly, rapid tapering of steroids (compared to slow tapering) resulted in a reduction of the cumulative steroid dose only, but was not associated with better myasthenia gravis functional status or lower doses of steroids at 15 months. To my view, this finding points to the limited immunosuppressive efficacy of azathioprine.”
He added that the study findings should not be extrapolated to patients with mild presentations or to those with muscle-specific kinase myasthenia gravis.
Dr. Sharshar disclosed no relevant financial relationships. Disclosures for the study coauthors appear in the original article.
A version of this article first appeared on Medscape.com.
. The trial showed that the conventional slow tapering regimen enabled discontinuation of prednisone earlier than previously reported but the new rapid-tapering regimen enabled an even faster discontinuation.
Noting that although both regimens led to a comparable myasthenia gravis status and prednisone dose at 15 months, the authors stated: “We think that the reduction of the cumulative dose over a year (equivalent to 5 mg/day) is a clinically relevant reduction, since the risk of complications is proportional to the daily or cumulative doses of prednisone.
“Our results warrant testing of a more rapid-tapering regimen in a future trial. In the meantime, our trial provides useful information on how prednisone tapering could be managed in patients with generalized myasthenia gravis treated with azathioprine,” they concluded.
The trial was published online Feb. 8 in JAMA Neurology.
Myasthenia gravis is a disorder of neuromuscular transmission, resulting from autoantibodies to components of the neuromuscular junction, most commonly the acetylcholine receptor. The incidence ranges from 0.3 to 2.8 per 100,000, and it is estimated to affect more than 700,000 people worldwide.
The authors of the current paper, led by Tarek Sharshar, MD, PhD, Groupe Hospitalier Universitaire, Paris, explained that many patients whose symptoms are not controlled by cholinesterase inhibitors are treated with corticosteroids and an immunosuppressant, usually azathioprine. No specific dosing protocol for prednisone has been validated, but it is commonly gradually increased to 0.75 mg/kg on alternate days and reduced progressively when minimal manifestation status (MMS; no symptoms or functional limitations) is reached.
They noted that this regimen leads to high and prolonged corticosteroid treatment – often for several years – with the mean daily prednisone dose exceeding 30 mg/day at 15 months and 20 mg/day at 36 months. As long-term use of corticosteroids is often associated with significant complications, reducing or even discontinuing prednisone treatment without destabilizing myasthenia gravis is therefore a therapeutic goal.
Evaluating dosage regimens
To investigate whether different dosage regimens could help wean patients with generalized myasthenia gravis from corticosteroid therapy without compromising efficacy, the researchers conducted this study in which the current recommended regimen was compared with an approach using higher initial corticosteroid doses followed by rapid tapering.
In the conventional slow-tapering group (control group), prednisone was given on alternate days, starting at a dose of 10 mg then increased by increments of 10 mg every 2 days up to 1.5 mg/kg on alternate days without exceeding 100 mg. This dose was maintained until MMS was reached and then reduced by 10 mg every 2 weeks until a dosage of 40 mg was reached, with subsequent slowing of the taper to 5 mg monthly. If MMS was not maintained, the alternate-day prednisone dose was increased by 10 mg every 2 weeks until MMS was restored, and the tapering resumed 4 weeks later.
In the new rapid-tapering group, oral prednisone was immediately started at 0.75 mg/kg per day, and this was followed by an earlier and rapid decrease once improved myasthenia gravis status was attained. Three different tapering schedules were applied dependent on the improvement status of the patient.
First, If the patient reached MMS at 1 month, the dose of prednisone was reduced by 0.1 mg/kg every 10 days up to 0.45 mg/kg per day, then 0.05 mg/kg every 10 days up to 0.25 mg/kg per day, then in decrements of 1 mg by adjusting the duration of the decrements according to the participant’s weight with the aim of achieving complete cessation of corticosteroid therapy within 18-20 weeks for this third stage of tapering.
Second, if the state of MMS was not reached at 1 month but the participant had improved, a slower tapering was conducted, with the dosage reduced in a similar way to the first instance but with each reduction introduced every 20 days. If the participant reached MMS during this tapering process, the tapering of prednisone was similar to the sequence described in the first group.
Third, if MMS was not reached and the participant had not improved, the initial dose was maintained for the first 3 months; beyond that time, a decrease in the prednisone dose was undertaken as in the second group to a minimum dose of 0.25 mg/kg per day, after which the prednisone dose was not reduced further. If the patient improved, the tapering of prednisone followed the sequence described in the second category.
Reductions in prednisone dose could be accelerated in the case of severe prednisone adverse effects, according to the prescriber’s decision.
In the event of a myasthenia gravis exacerbation, the patient was hospitalized and the dose of prednisone was routinely doubled, or for a more moderate aggravation, the dose was increased to the previous dose recommended in the tapering regimen.
Azathioprine, up to a maximum dose of 3 mg/kg per day, was prescribed for all participants. In all, 117 patients were randomly assigned, and 113 completed the study.
The primary outcome was the proportion of participants having reached MMS without prednisone at 12 months and having not relapsed or taken prednisone between months 12 and 15. This was achieved by significantly more patients in the rapid-tapering group (39% vs. 9%; risk ratio, 3.61; P < .001).
Rapid tapering allowed sparing of a mean of 1,898 mg of prednisone over 1 year (5.3 mg/day) per patient.
The rate of myasthenia gravis exacerbation or worsening did not differ significantly between the two groups, nor did the use of plasmapheresis or IVIG or the doses of azathioprine.
The overall number of serious adverse events did not differ significantly between the two groups (slow tapering, 22% vs. rapid-tapering, 36%; P = .15).
The researchers said it is possible that prednisone tapering would differ with another immunosuppressive agent but as azathioprine is the first-line immunosuppressant usually recommended, these results are relevant for a large proportion of patients.
They said the better outcome of the intervention group could have been related to one or more of four differences in prednisone administration: An immediate high dose versus a slow increase of the prednisone dose; daily versus alternate-day dosing; earlier tapering initiation; and faster tapering. However, the structure of the study did not allow identification of which of these factors was responsible.
“Researching the best prednisone-tapering scheme is not only a major issue for patients with myasthenia gravis but also for other autoimmune or inflammatory diseases, because validated prednisone-tapering regimens are scarce,” the authors said.
The rapid tapering of prednisone therapy appears to be feasible, beneficial, and safe in patients with generalized myasthenia gravis and “warrants testing in other autoimmune diseases,” they added.
Particularly relevant to late-onset disease
Commenting on the study, Raffi Topakian, MD, Klinikum Wels-Grieskirchen, Wels, Austria, said the results showed that in patients with moderate to severe generalized myasthenia gravis requiring high-dose prednisone, azathioprine, a widely used immunosuppressant, may have a quicker steroid-sparing effect than previously thought, and that rapid steroid tapering can be achieved safely, resulting in a reduction of the cumulative steroid dose over a year despite higher initial doses.
Dr. Topakian, who was not involved with the research, pointed out that the median age was advanced (around 56 years), and the benefit of a regimen that leads to a reduction of the cumulative steroid dose over a year may be disproportionately larger for older, sicker patients with many comorbidities who are at considerably higher risk for a prednisone-induced increase in cardiovascular complications, osteoporotic fractures, and gastrointestinal bleeding.
“The study findings are particularly relevant for the management of late-onset myasthenia gravis (when first symptoms start after age 45-50 years), which is being encountered more frequently over the past years,” he said.
“But the holy grail of myasthenia gravis treatment has not been found yet,” Dr. Topakian noted. “Disappointingly, rapid tapering of steroids (compared to slow tapering) resulted in a reduction of the cumulative steroid dose only, but was not associated with better myasthenia gravis functional status or lower doses of steroids at 15 months. To my view, this finding points to the limited immunosuppressive efficacy of azathioprine.”
He added that the study findings should not be extrapolated to patients with mild presentations or to those with muscle-specific kinase myasthenia gravis.
Dr. Sharshar disclosed no relevant financial relationships. Disclosures for the study coauthors appear in the original article.
A version of this article first appeared on Medscape.com.
. The trial showed that the conventional slow tapering regimen enabled discontinuation of prednisone earlier than previously reported but the new rapid-tapering regimen enabled an even faster discontinuation.
Noting that although both regimens led to a comparable myasthenia gravis status and prednisone dose at 15 months, the authors stated: “We think that the reduction of the cumulative dose over a year (equivalent to 5 mg/day) is a clinically relevant reduction, since the risk of complications is proportional to the daily or cumulative doses of prednisone.
“Our results warrant testing of a more rapid-tapering regimen in a future trial. In the meantime, our trial provides useful information on how prednisone tapering could be managed in patients with generalized myasthenia gravis treated with azathioprine,” they concluded.
The trial was published online Feb. 8 in JAMA Neurology.
Myasthenia gravis is a disorder of neuromuscular transmission, resulting from autoantibodies to components of the neuromuscular junction, most commonly the acetylcholine receptor. The incidence ranges from 0.3 to 2.8 per 100,000, and it is estimated to affect more than 700,000 people worldwide.
The authors of the current paper, led by Tarek Sharshar, MD, PhD, Groupe Hospitalier Universitaire, Paris, explained that many patients whose symptoms are not controlled by cholinesterase inhibitors are treated with corticosteroids and an immunosuppressant, usually azathioprine. No specific dosing protocol for prednisone has been validated, but it is commonly gradually increased to 0.75 mg/kg on alternate days and reduced progressively when minimal manifestation status (MMS; no symptoms or functional limitations) is reached.
They noted that this regimen leads to high and prolonged corticosteroid treatment – often for several years – with the mean daily prednisone dose exceeding 30 mg/day at 15 months and 20 mg/day at 36 months. As long-term use of corticosteroids is often associated with significant complications, reducing or even discontinuing prednisone treatment without destabilizing myasthenia gravis is therefore a therapeutic goal.
Evaluating dosage regimens
To investigate whether different dosage regimens could help wean patients with generalized myasthenia gravis from corticosteroid therapy without compromising efficacy, the researchers conducted this study in which the current recommended regimen was compared with an approach using higher initial corticosteroid doses followed by rapid tapering.
In the conventional slow-tapering group (control group), prednisone was given on alternate days, starting at a dose of 10 mg then increased by increments of 10 mg every 2 days up to 1.5 mg/kg on alternate days without exceeding 100 mg. This dose was maintained until MMS was reached and then reduced by 10 mg every 2 weeks until a dosage of 40 mg was reached, with subsequent slowing of the taper to 5 mg monthly. If MMS was not maintained, the alternate-day prednisone dose was increased by 10 mg every 2 weeks until MMS was restored, and the tapering resumed 4 weeks later.
In the new rapid-tapering group, oral prednisone was immediately started at 0.75 mg/kg per day, and this was followed by an earlier and rapid decrease once improved myasthenia gravis status was attained. Three different tapering schedules were applied dependent on the improvement status of the patient.
First, If the patient reached MMS at 1 month, the dose of prednisone was reduced by 0.1 mg/kg every 10 days up to 0.45 mg/kg per day, then 0.05 mg/kg every 10 days up to 0.25 mg/kg per day, then in decrements of 1 mg by adjusting the duration of the decrements according to the participant’s weight with the aim of achieving complete cessation of corticosteroid therapy within 18-20 weeks for this third stage of tapering.
Second, if the state of MMS was not reached at 1 month but the participant had improved, a slower tapering was conducted, with the dosage reduced in a similar way to the first instance but with each reduction introduced every 20 days. If the participant reached MMS during this tapering process, the tapering of prednisone was similar to the sequence described in the first group.
Third, if MMS was not reached and the participant had not improved, the initial dose was maintained for the first 3 months; beyond that time, a decrease in the prednisone dose was undertaken as in the second group to a minimum dose of 0.25 mg/kg per day, after which the prednisone dose was not reduced further. If the patient improved, the tapering of prednisone followed the sequence described in the second category.
Reductions in prednisone dose could be accelerated in the case of severe prednisone adverse effects, according to the prescriber’s decision.
In the event of a myasthenia gravis exacerbation, the patient was hospitalized and the dose of prednisone was routinely doubled, or for a more moderate aggravation, the dose was increased to the previous dose recommended in the tapering regimen.
Azathioprine, up to a maximum dose of 3 mg/kg per day, was prescribed for all participants. In all, 117 patients were randomly assigned, and 113 completed the study.
The primary outcome was the proportion of participants having reached MMS without prednisone at 12 months and having not relapsed or taken prednisone between months 12 and 15. This was achieved by significantly more patients in the rapid-tapering group (39% vs. 9%; risk ratio, 3.61; P < .001).
Rapid tapering allowed sparing of a mean of 1,898 mg of prednisone over 1 year (5.3 mg/day) per patient.
The rate of myasthenia gravis exacerbation or worsening did not differ significantly between the two groups, nor did the use of plasmapheresis or IVIG or the doses of azathioprine.
The overall number of serious adverse events did not differ significantly between the two groups (slow tapering, 22% vs. rapid-tapering, 36%; P = .15).
The researchers said it is possible that prednisone tapering would differ with another immunosuppressive agent but as azathioprine is the first-line immunosuppressant usually recommended, these results are relevant for a large proportion of patients.
They said the better outcome of the intervention group could have been related to one or more of four differences in prednisone administration: An immediate high dose versus a slow increase of the prednisone dose; daily versus alternate-day dosing; earlier tapering initiation; and faster tapering. However, the structure of the study did not allow identification of which of these factors was responsible.
“Researching the best prednisone-tapering scheme is not only a major issue for patients with myasthenia gravis but also for other autoimmune or inflammatory diseases, because validated prednisone-tapering regimens are scarce,” the authors said.
The rapid tapering of prednisone therapy appears to be feasible, beneficial, and safe in patients with generalized myasthenia gravis and “warrants testing in other autoimmune diseases,” they added.
Particularly relevant to late-onset disease
Commenting on the study, Raffi Topakian, MD, Klinikum Wels-Grieskirchen, Wels, Austria, said the results showed that in patients with moderate to severe generalized myasthenia gravis requiring high-dose prednisone, azathioprine, a widely used immunosuppressant, may have a quicker steroid-sparing effect than previously thought, and that rapid steroid tapering can be achieved safely, resulting in a reduction of the cumulative steroid dose over a year despite higher initial doses.
Dr. Topakian, who was not involved with the research, pointed out that the median age was advanced (around 56 years), and the benefit of a regimen that leads to a reduction of the cumulative steroid dose over a year may be disproportionately larger for older, sicker patients with many comorbidities who are at considerably higher risk for a prednisone-induced increase in cardiovascular complications, osteoporotic fractures, and gastrointestinal bleeding.
“The study findings are particularly relevant for the management of late-onset myasthenia gravis (when first symptoms start after age 45-50 years), which is being encountered more frequently over the past years,” he said.
“But the holy grail of myasthenia gravis treatment has not been found yet,” Dr. Topakian noted. “Disappointingly, rapid tapering of steroids (compared to slow tapering) resulted in a reduction of the cumulative steroid dose only, but was not associated with better myasthenia gravis functional status or lower doses of steroids at 15 months. To my view, this finding points to the limited immunosuppressive efficacy of azathioprine.”
He added that the study findings should not be extrapolated to patients with mild presentations or to those with muscle-specific kinase myasthenia gravis.
Dr. Sharshar disclosed no relevant financial relationships. Disclosures for the study coauthors appear in the original article.
A version of this article first appeared on Medscape.com.
FROM JAMA NEUROLOGY
CAR T-cell products shine in real-world setting, reveal new insights
Real-world experience with chimeric antigen receptor (CAR) T-cell therapies for large B-cell lymphomas compares favorably with experience in commercial and trial settings and provides new insights for predicting outcomes, according to Paolo Corradini, MD.
The 12-month duration of response (DOR) and progression-free survival (PFS) rates in 152 real-world patients treated with tisagenlecleucel (tisa-cel; Kymriah) for an approved indication were 48.4% and 26.4%, respectively, data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and published in November 2020 in Blood Advances showed.
who relapsed or were refractory to at least two prior lines of therapy, Dr. Corradini said at the third European CAR T-cell Meeting, jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association.
A clinical update of the JULIET trial, as presented by Dr. Corradini and colleagues in a poster at the 2020 annual conference of the American Society of Hematology, showed a relapse-free probability of 60.4% at 24 and 30 months among 61 patients with an initial response.
The 12- and 36-month PFS rates as of February 2020, with median follow-up of 40.3 months, were 33% and 31%, respectively, and no new safety signals were identified, said Dr. Corradini, chair of hematology at the University of Milan.
Similarly, real-world data from the U.S. Lymphoma CAR T Consortium showing median PFS of 8.3 months at median follow-up of 12.9 months in 275 patients treated with axicabtagene ciloleucel (axi-cel; YESCARTA) were comparable with outcomes in the ZUMA-1 registrational trial, he noted.
An ongoing response was seen at 2 years in 39% of patients in ZUMA-1, and 3-year survival was 47%, according to an update reported at ASH 2019.
Of note, 43% of patients in the real-world study, which was published in the Journal of Clinical Oncology in September 2020, would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis.
Predicting outcomes
The real-world data also demonstrated that performance status and lactate dehydrogenase (LDH) levels can predict outcomes: Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 versus less than 2, and elevated LDH had shorter PFS and overall survival (OS) on both univariate and multivariate analysis, Dr. Corradini noted.
A subsequent multicenter study showed similar response rates of 70% and 68% in ZUMA-1-eligible and noneligible patients, but significantly improved DOR, PFS, and OS outcomes among the ZUMA-1-eligible patients.
The authors also looked for “clinical predictive factors or some easy clinical biomarkers to predict the outcomes in our patients receiving CAR T-cells,” and found that C-reactive protein levels of more than 30 mg at infusion were associated with poorer DOR, PFS, and OS, he said.
In 60 patients in another U.S. study of both tisa-cel- and axi-cel-treated patients at Memorial Sloan Kettering Cancer Center, 1-year event-free survival and OS were 40% and 69%, and Dr. Corradini’s experience with 55 patients at the University of Milan similarly showed 1-year PFS and OS of 40% and 70%, respectively.
“So all these studies support the notion that the results of CAR T-cells in real-world practice are durable for our patients, and are very similar to results obtained in the studies,” he said.
Other factors that have been shown to be associated with poor outcomes after CAR T-cell therapy include systemic bridging therapy, high metabolic tumor volume, and extranodal involvement; patients with these characteristics, along with those who have poor ECOG performance status or elevated LDH or CRP levels, do not comprise “a group to exclude from CAR T-cell therapy, but rather ... a group for whom there is an unmet need with our currently available treatments,” he said, adding: “So, it’s a group for which we have to do clinical trials and studies to improve the outcomes of our patient with large B-cell lymphomas.”
“These are all real-world data with commercially available products, he noted.
Product selection
Tisa-cel received Food and Drug Administration approval in 2017 and is used to treat relapsed or refractory acute lymphoblastic leukemia in those aged up to 25 years, and non-Hodgkin lymphoma that has relapsed or is refractory after at least two prior lines of therapy.
Axi-cel was also approved in 2017 for relapsed/refractory non-Hodgkin lymphoma, and in February 2021, after Dr. Corradini’s meeting presentation, the FDA granted a third approval to lisocabtagene maraleucel (liso-cel; Breyanzi) for this indication.
The information to date from both the trial and real-world settings are limited with respect to showing any differences in outcomes between the CAR T-cell products, but provide “an initial suggestion” that outcomes with tisa-cel and axi-cel are comparable, he said, adding that decisions should be strictly based on product registration data given the absence of reliable data for choosing one product over another.
Dr. Corradini reported honoraria and/or payment for travel and accommodations from Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, and a number of other pharmaceutical companies.
Real-world experience with chimeric antigen receptor (CAR) T-cell therapies for large B-cell lymphomas compares favorably with experience in commercial and trial settings and provides new insights for predicting outcomes, according to Paolo Corradini, MD.
The 12-month duration of response (DOR) and progression-free survival (PFS) rates in 152 real-world patients treated with tisagenlecleucel (tisa-cel; Kymriah) for an approved indication were 48.4% and 26.4%, respectively, data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and published in November 2020 in Blood Advances showed.
who relapsed or were refractory to at least two prior lines of therapy, Dr. Corradini said at the third European CAR T-cell Meeting, jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association.
A clinical update of the JULIET trial, as presented by Dr. Corradini and colleagues in a poster at the 2020 annual conference of the American Society of Hematology, showed a relapse-free probability of 60.4% at 24 and 30 months among 61 patients with an initial response.
The 12- and 36-month PFS rates as of February 2020, with median follow-up of 40.3 months, were 33% and 31%, respectively, and no new safety signals were identified, said Dr. Corradini, chair of hematology at the University of Milan.
Similarly, real-world data from the U.S. Lymphoma CAR T Consortium showing median PFS of 8.3 months at median follow-up of 12.9 months in 275 patients treated with axicabtagene ciloleucel (axi-cel; YESCARTA) were comparable with outcomes in the ZUMA-1 registrational trial, he noted.
An ongoing response was seen at 2 years in 39% of patients in ZUMA-1, and 3-year survival was 47%, according to an update reported at ASH 2019.
Of note, 43% of patients in the real-world study, which was published in the Journal of Clinical Oncology in September 2020, would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis.
Predicting outcomes
The real-world data also demonstrated that performance status and lactate dehydrogenase (LDH) levels can predict outcomes: Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 versus less than 2, and elevated LDH had shorter PFS and overall survival (OS) on both univariate and multivariate analysis, Dr. Corradini noted.
A subsequent multicenter study showed similar response rates of 70% and 68% in ZUMA-1-eligible and noneligible patients, but significantly improved DOR, PFS, and OS outcomes among the ZUMA-1-eligible patients.
The authors also looked for “clinical predictive factors or some easy clinical biomarkers to predict the outcomes in our patients receiving CAR T-cells,” and found that C-reactive protein levels of more than 30 mg at infusion were associated with poorer DOR, PFS, and OS, he said.
In 60 patients in another U.S. study of both tisa-cel- and axi-cel-treated patients at Memorial Sloan Kettering Cancer Center, 1-year event-free survival and OS were 40% and 69%, and Dr. Corradini’s experience with 55 patients at the University of Milan similarly showed 1-year PFS and OS of 40% and 70%, respectively.
“So all these studies support the notion that the results of CAR T-cells in real-world practice are durable for our patients, and are very similar to results obtained in the studies,” he said.
Other factors that have been shown to be associated with poor outcomes after CAR T-cell therapy include systemic bridging therapy, high metabolic tumor volume, and extranodal involvement; patients with these characteristics, along with those who have poor ECOG performance status or elevated LDH or CRP levels, do not comprise “a group to exclude from CAR T-cell therapy, but rather ... a group for whom there is an unmet need with our currently available treatments,” he said, adding: “So, it’s a group for which we have to do clinical trials and studies to improve the outcomes of our patient with large B-cell lymphomas.”
“These are all real-world data with commercially available products, he noted.
Product selection
Tisa-cel received Food and Drug Administration approval in 2017 and is used to treat relapsed or refractory acute lymphoblastic leukemia in those aged up to 25 years, and non-Hodgkin lymphoma that has relapsed or is refractory after at least two prior lines of therapy.
Axi-cel was also approved in 2017 for relapsed/refractory non-Hodgkin lymphoma, and in February 2021, after Dr. Corradini’s meeting presentation, the FDA granted a third approval to lisocabtagene maraleucel (liso-cel; Breyanzi) for this indication.
The information to date from both the trial and real-world settings are limited with respect to showing any differences in outcomes between the CAR T-cell products, but provide “an initial suggestion” that outcomes with tisa-cel and axi-cel are comparable, he said, adding that decisions should be strictly based on product registration data given the absence of reliable data for choosing one product over another.
Dr. Corradini reported honoraria and/or payment for travel and accommodations from Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, and a number of other pharmaceutical companies.
Real-world experience with chimeric antigen receptor (CAR) T-cell therapies for large B-cell lymphomas compares favorably with experience in commercial and trial settings and provides new insights for predicting outcomes, according to Paolo Corradini, MD.
The 12-month duration of response (DOR) and progression-free survival (PFS) rates in 152 real-world patients treated with tisagenlecleucel (tisa-cel; Kymriah) for an approved indication were 48.4% and 26.4%, respectively, data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and published in November 2020 in Blood Advances showed.
who relapsed or were refractory to at least two prior lines of therapy, Dr. Corradini said at the third European CAR T-cell Meeting, jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association.
A clinical update of the JULIET trial, as presented by Dr. Corradini and colleagues in a poster at the 2020 annual conference of the American Society of Hematology, showed a relapse-free probability of 60.4% at 24 and 30 months among 61 patients with an initial response.
The 12- and 36-month PFS rates as of February 2020, with median follow-up of 40.3 months, were 33% and 31%, respectively, and no new safety signals were identified, said Dr. Corradini, chair of hematology at the University of Milan.
Similarly, real-world data from the U.S. Lymphoma CAR T Consortium showing median PFS of 8.3 months at median follow-up of 12.9 months in 275 patients treated with axicabtagene ciloleucel (axi-cel; YESCARTA) were comparable with outcomes in the ZUMA-1 registrational trial, he noted.
An ongoing response was seen at 2 years in 39% of patients in ZUMA-1, and 3-year survival was 47%, according to an update reported at ASH 2019.
Of note, 43% of patients in the real-world study, which was published in the Journal of Clinical Oncology in September 2020, would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis.
Predicting outcomes
The real-world data also demonstrated that performance status and lactate dehydrogenase (LDH) levels can predict outcomes: Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 versus less than 2, and elevated LDH had shorter PFS and overall survival (OS) on both univariate and multivariate analysis, Dr. Corradini noted.
A subsequent multicenter study showed similar response rates of 70% and 68% in ZUMA-1-eligible and noneligible patients, but significantly improved DOR, PFS, and OS outcomes among the ZUMA-1-eligible patients.
The authors also looked for “clinical predictive factors or some easy clinical biomarkers to predict the outcomes in our patients receiving CAR T-cells,” and found that C-reactive protein levels of more than 30 mg at infusion were associated with poorer DOR, PFS, and OS, he said.
In 60 patients in another U.S. study of both tisa-cel- and axi-cel-treated patients at Memorial Sloan Kettering Cancer Center, 1-year event-free survival and OS were 40% and 69%, and Dr. Corradini’s experience with 55 patients at the University of Milan similarly showed 1-year PFS and OS of 40% and 70%, respectively.
“So all these studies support the notion that the results of CAR T-cells in real-world practice are durable for our patients, and are very similar to results obtained in the studies,” he said.
Other factors that have been shown to be associated with poor outcomes after CAR T-cell therapy include systemic bridging therapy, high metabolic tumor volume, and extranodal involvement; patients with these characteristics, along with those who have poor ECOG performance status or elevated LDH or CRP levels, do not comprise “a group to exclude from CAR T-cell therapy, but rather ... a group for whom there is an unmet need with our currently available treatments,” he said, adding: “So, it’s a group for which we have to do clinical trials and studies to improve the outcomes of our patient with large B-cell lymphomas.”
“These are all real-world data with commercially available products, he noted.
Product selection
Tisa-cel received Food and Drug Administration approval in 2017 and is used to treat relapsed or refractory acute lymphoblastic leukemia in those aged up to 25 years, and non-Hodgkin lymphoma that has relapsed or is refractory after at least two prior lines of therapy.
Axi-cel was also approved in 2017 for relapsed/refractory non-Hodgkin lymphoma, and in February 2021, after Dr. Corradini’s meeting presentation, the FDA granted a third approval to lisocabtagene maraleucel (liso-cel; Breyanzi) for this indication.
The information to date from both the trial and real-world settings are limited with respect to showing any differences in outcomes between the CAR T-cell products, but provide “an initial suggestion” that outcomes with tisa-cel and axi-cel are comparable, he said, adding that decisions should be strictly based on product registration data given the absence of reliable data for choosing one product over another.
Dr. Corradini reported honoraria and/or payment for travel and accommodations from Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, and a number of other pharmaceutical companies.
FROM CART21
Alien cells may explain COVID-19 brain fog
, a new report suggests.
The authors report five separate post-mortem cases from patients who died with COVID-19 in which large cells resembling megakaryocytes were identified in cortical capillaries. Immunohistochemistry subsequently confirmed their megakaryocyte identity.
They point out that the finding is of interest as – to their knowledge – megakaryocytes have not been found in the brain before.
The observations are described in a research letter published online Feb. 12 in JAMA Neurology.
Bone marrow cells in the brain
Lead author David Nauen, MD, PhD, a neuropathologist from Johns Hopkins University, Baltimore, reported that he identified these cells in the first analysis of post-mortem brain tissue from a patient who had COVID-19.
“Some other viruses cause changes in the brain such as encephalopathy, and as neurologic symptoms are often reported in COVID-19, I was curious to see if similar effects were seen in brain post-mortem samples from patients who had died with the infection,” Dr. Nauen said.
On his first analysis of the brain tissue of a patient who had COVID-19, Dr. Nauen saw no evidence of viral encephalitis, but he observed some “unusually large” cells in the brain capillaries.
“I was taken aback; I couldn’t figure out what they were. Then I realized these cells were megakaryocytes from the bone marrow. I have never seen these cells in the brain before. I asked several colleagues and none of them had either. After extensive literature searches, I could find no evidence of megakaryocytes being in the brain,” Dr. Nauen noted.
Megakaryocytes, he explained, are “very large cells, and the brain capillaries are very small – just large enough to let red blood cells and lymphocytes pass through. To see these very large cells in such vessels is extremely unusual. It looks like they are causing occlusions.”
By occluding flow through individual capillaries, these large cells could cause ischemic alteration in a distinct pattern, potentially resulting in an atypical form of neurologic impairment, the authors suggest.
“This might alter the hemodynamics and put pressure on other vessels, possibly contributing to the increased risk of stroke that has been reported in COVID-19,” Dr. Nauen said. None of the samples he examined came from patients with COVID-19 who had had a stroke, he reported.
Other than the presence of megakaryocytes in the capillaries, the brain looked normal, he said. He has now examined samples from 15 brains of patients who had COVID-19 and megakaryocytes have been found in the brain capillaries in five cases.
New neurologic complication
Classic encephalitis found with other viruses has not been reported in brain post-mortem examinations from patients who had COVID-19, Dr. Nauen noted. “The cognitive issues such as grogginess associated with COVID-19 would indicate problems with the cortex but that hasn’t been documented. This occlusion of a multitude of tiny vessels by megalokaryocytes may offer some explanation of the cognitive issues. This is a new kind of vascular insult seen on pathology, and suggests a new kind of neurologic complication,” he added.
The big question is what these megakaryocytes are doing in the brain.
“Megakaryocytes are bone marrow cells. They are not immune cells. Their job is to produce platelets to help the blood clot. They are not normally found outside the bone marrow, but they have been reported in other organs in COVID-19 patients.
“But the big puzzle associated with finding them in the brain is how they get through the very fine network of blood vessels in the lungs. The geometry just doesn’t work. We don’t know which part of the COVID inflammatory response makes this happen,” said Dr. Nauen.
The authors suggest one possibility is that altered endothelial or other signaling is recruiting megakaryocytes into the circulation and somehow permitting them to pass through the lungs.
“We need to try and understand if there is anything distinctive about these megakaryocytes – which proteins are they expressing that may explain why they are behaving in such an unusual way,” said Dr. Nauen.
Noting that many patients with severe COVID-19 have problems with clotting, and megakaryocytes are part of the clotting system, he speculated that some sort of aberrant message is being sent to these cells.
“It is notable that we found megakaryocytes in cortical capillaries in 33% of cases examined. Because the standard brain autopsy sections taken sampled at random [are] only a minute portion of the cortical volume, finding these cells suggests the total burden could be considerable,” the authors wrote.
Dr. Nauen added that to his knowledge, this is the first report of such observations, and the next step is to look for similar findings in larger sample sizes.
A version of this article first appeared on Medscape.com.
, a new report suggests.
The authors report five separate post-mortem cases from patients who died with COVID-19 in which large cells resembling megakaryocytes were identified in cortical capillaries. Immunohistochemistry subsequently confirmed their megakaryocyte identity.
They point out that the finding is of interest as – to their knowledge – megakaryocytes have not been found in the brain before.
The observations are described in a research letter published online Feb. 12 in JAMA Neurology.
Bone marrow cells in the brain
Lead author David Nauen, MD, PhD, a neuropathologist from Johns Hopkins University, Baltimore, reported that he identified these cells in the first analysis of post-mortem brain tissue from a patient who had COVID-19.
“Some other viruses cause changes in the brain such as encephalopathy, and as neurologic symptoms are often reported in COVID-19, I was curious to see if similar effects were seen in brain post-mortem samples from patients who had died with the infection,” Dr. Nauen said.
On his first analysis of the brain tissue of a patient who had COVID-19, Dr. Nauen saw no evidence of viral encephalitis, but he observed some “unusually large” cells in the brain capillaries.
“I was taken aback; I couldn’t figure out what they were. Then I realized these cells were megakaryocytes from the bone marrow. I have never seen these cells in the brain before. I asked several colleagues and none of them had either. After extensive literature searches, I could find no evidence of megakaryocytes being in the brain,” Dr. Nauen noted.
Megakaryocytes, he explained, are “very large cells, and the brain capillaries are very small – just large enough to let red blood cells and lymphocytes pass through. To see these very large cells in such vessels is extremely unusual. It looks like they are causing occlusions.”
By occluding flow through individual capillaries, these large cells could cause ischemic alteration in a distinct pattern, potentially resulting in an atypical form of neurologic impairment, the authors suggest.
“This might alter the hemodynamics and put pressure on other vessels, possibly contributing to the increased risk of stroke that has been reported in COVID-19,” Dr. Nauen said. None of the samples he examined came from patients with COVID-19 who had had a stroke, he reported.
Other than the presence of megakaryocytes in the capillaries, the brain looked normal, he said. He has now examined samples from 15 brains of patients who had COVID-19 and megakaryocytes have been found in the brain capillaries in five cases.
New neurologic complication
Classic encephalitis found with other viruses has not been reported in brain post-mortem examinations from patients who had COVID-19, Dr. Nauen noted. “The cognitive issues such as grogginess associated with COVID-19 would indicate problems with the cortex but that hasn’t been documented. This occlusion of a multitude of tiny vessels by megalokaryocytes may offer some explanation of the cognitive issues. This is a new kind of vascular insult seen on pathology, and suggests a new kind of neurologic complication,” he added.
The big question is what these megakaryocytes are doing in the brain.
“Megakaryocytes are bone marrow cells. They are not immune cells. Their job is to produce platelets to help the blood clot. They are not normally found outside the bone marrow, but they have been reported in other organs in COVID-19 patients.
“But the big puzzle associated with finding them in the brain is how they get through the very fine network of blood vessels in the lungs. The geometry just doesn’t work. We don’t know which part of the COVID inflammatory response makes this happen,” said Dr. Nauen.
The authors suggest one possibility is that altered endothelial or other signaling is recruiting megakaryocytes into the circulation and somehow permitting them to pass through the lungs.
“We need to try and understand if there is anything distinctive about these megakaryocytes – which proteins are they expressing that may explain why they are behaving in such an unusual way,” said Dr. Nauen.
Noting that many patients with severe COVID-19 have problems with clotting, and megakaryocytes are part of the clotting system, he speculated that some sort of aberrant message is being sent to these cells.
“It is notable that we found megakaryocytes in cortical capillaries in 33% of cases examined. Because the standard brain autopsy sections taken sampled at random [are] only a minute portion of the cortical volume, finding these cells suggests the total burden could be considerable,” the authors wrote.
Dr. Nauen added that to his knowledge, this is the first report of such observations, and the next step is to look for similar findings in larger sample sizes.
A version of this article first appeared on Medscape.com.
, a new report suggests.
The authors report five separate post-mortem cases from patients who died with COVID-19 in which large cells resembling megakaryocytes were identified in cortical capillaries. Immunohistochemistry subsequently confirmed their megakaryocyte identity.
They point out that the finding is of interest as – to their knowledge – megakaryocytes have not been found in the brain before.
The observations are described in a research letter published online Feb. 12 in JAMA Neurology.
Bone marrow cells in the brain
Lead author David Nauen, MD, PhD, a neuropathologist from Johns Hopkins University, Baltimore, reported that he identified these cells in the first analysis of post-mortem brain tissue from a patient who had COVID-19.
“Some other viruses cause changes in the brain such as encephalopathy, and as neurologic symptoms are often reported in COVID-19, I was curious to see if similar effects were seen in brain post-mortem samples from patients who had died with the infection,” Dr. Nauen said.
On his first analysis of the brain tissue of a patient who had COVID-19, Dr. Nauen saw no evidence of viral encephalitis, but he observed some “unusually large” cells in the brain capillaries.
“I was taken aback; I couldn’t figure out what they were. Then I realized these cells were megakaryocytes from the bone marrow. I have never seen these cells in the brain before. I asked several colleagues and none of them had either. After extensive literature searches, I could find no evidence of megakaryocytes being in the brain,” Dr. Nauen noted.
Megakaryocytes, he explained, are “very large cells, and the brain capillaries are very small – just large enough to let red blood cells and lymphocytes pass through. To see these very large cells in such vessels is extremely unusual. It looks like they are causing occlusions.”
By occluding flow through individual capillaries, these large cells could cause ischemic alteration in a distinct pattern, potentially resulting in an atypical form of neurologic impairment, the authors suggest.
“This might alter the hemodynamics and put pressure on other vessels, possibly contributing to the increased risk of stroke that has been reported in COVID-19,” Dr. Nauen said. None of the samples he examined came from patients with COVID-19 who had had a stroke, he reported.
Other than the presence of megakaryocytes in the capillaries, the brain looked normal, he said. He has now examined samples from 15 brains of patients who had COVID-19 and megakaryocytes have been found in the brain capillaries in five cases.
New neurologic complication
Classic encephalitis found with other viruses has not been reported in brain post-mortem examinations from patients who had COVID-19, Dr. Nauen noted. “The cognitive issues such as grogginess associated with COVID-19 would indicate problems with the cortex but that hasn’t been documented. This occlusion of a multitude of tiny vessels by megalokaryocytes may offer some explanation of the cognitive issues. This is a new kind of vascular insult seen on pathology, and suggests a new kind of neurologic complication,” he added.
The big question is what these megakaryocytes are doing in the brain.
“Megakaryocytes are bone marrow cells. They are not immune cells. Their job is to produce platelets to help the blood clot. They are not normally found outside the bone marrow, but they have been reported in other organs in COVID-19 patients.
“But the big puzzle associated with finding them in the brain is how they get through the very fine network of blood vessels in the lungs. The geometry just doesn’t work. We don’t know which part of the COVID inflammatory response makes this happen,” said Dr. Nauen.
The authors suggest one possibility is that altered endothelial or other signaling is recruiting megakaryocytes into the circulation and somehow permitting them to pass through the lungs.
“We need to try and understand if there is anything distinctive about these megakaryocytes – which proteins are they expressing that may explain why they are behaving in such an unusual way,” said Dr. Nauen.
Noting that many patients with severe COVID-19 have problems with clotting, and megakaryocytes are part of the clotting system, he speculated that some sort of aberrant message is being sent to these cells.
“It is notable that we found megakaryocytes in cortical capillaries in 33% of cases examined. Because the standard brain autopsy sections taken sampled at random [are] only a minute portion of the cortical volume, finding these cells suggests the total burden could be considerable,” the authors wrote.
Dr. Nauen added that to his knowledge, this is the first report of such observations, and the next step is to look for similar findings in larger sample sizes.
A version of this article first appeared on Medscape.com.
FROM JAMA NEUROLOGY
Chronic GVHD therapies offer hope for treating refractory disease
Despite improvements in prevention of graft-versus-host disease, chronic GVHD still occurs in 10%-50% of patients who undergo an allogeneic hematopoietic stem cell transplant, and these patients may require prolonged treatment with multiple lines of therapy, said a hematologist and transplant researcher.
“More effective, less toxic therapies for chronic GVHD are needed,” Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle said at the Transplant & Cellular Therapies Meetings.
Dr. Lee reviewed clinical trials for chronic GVHD at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
Although the incidence of chronic GVHD has gradually declined over the last 40 years and both relapse-free and overall survival following a chronic GVHD diagnosis have improved, “for patients who are diagnosed with chronic GVHD, they still will see many lines of therapy and many years of therapy,” she said.
Among 148 patients with chronic GVHD treated at her center, for example, 66% went on to two lines of therapy, 50% went on to three lines, 37% required four lines of therapy, and 20% needed five lines or more.
Salvage therapies for patients with chronic GVHD have evolved away from immunomodulators and immunosuppressants in the early 1990s, toward monoclonal antibodies such as rituximab in the early 2000s, to interleukin-2 and to tyrosine kinase inhibitors such as ruxolitinib (Jakafi) and ibrutinib (Imbruvica).
There are currently 36 agents that are FDA approved for at least one indication and can also be prescribed for the treatment of chronic GVHD, Dr. Lee noted.
Treatment goals
Dr. Lee laid out six goals for treating patients with chronic GVHD. They include:
- Controlling current signs and symptoms, measured by response rates and patient-reported outcomes
- Preventing further tissue and organ damage
- Minimizing toxicity
- Maintaining graft-versus-tumor effect
- Achieving graft tolerance and stopping immunosuppression
- Decreasing nonrelapse mortality and improving survival
Active trials
Dr. Lee identified 33 trials with chronic GVHD as an indication that are currently recruiting, and an additional 13 trials that are active but closed to recruiting. The trials can be generally grouped by mechanism of action, and involve agents targeting T-regulatory cells, B cells and/or B-cell receptor (BCR) signaling, monocytes/macrophages, costimulatory blockage, a proteasome inhibition, Janus kinase (JAK) 1/2 inhibitors, ROCK2 inhibitors, hedgehog pathway inhibition, cellular therapy, and organ-targeted therapy.
Most of the trials have overall response rate as the primary endpoint, and all but five are currently in phase 1 or 2. The currently active phase 3 trials include two with ibrutinib, one with the investigational agent itacitinib, one with ruxolitinib, and one with mesenchymal stem cells.
“I’ll note that, when results are reported, the denominator really matters for the overall response rate, especially if you’re talking about small trials, because if you require the patient to be treated with an agent for a certain period of time, and you take out all the people who didn’t make it to that time point, then your overall response rate looks better,” she said.
BTK inhibitors
The first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first and thus far only agent approved by the Food and Drug Administration for chronic GVHD. The approval was based on a single-arm, multicenter trial with 42 patients.
The ORR in this trial was 69%, consisting of 31% complete responses and 38% partial responses, with a duration of response longer than 10 months in slightly more than half of all patients. In all, 24% of patients had improvement of symptoms in two consecutive visits, and 29% continued on ibrutinib at the time of the primary analysis in 2017.
Based on these promising results, acalabrutinib, which is more potent and selective for BTK than ibrutinib, with no effect on either platelets or natural killer cells, is currently under investigation in a phase 2 trial in 50 patients at a dose of 100 mg orally twice daily.
JAK1/2 inhibition
The JAK1 inhibitor itacitinib failed to meet its primary ORR endpoint in the phase 3 GRAVITAS-301 study, according to a press release, but the manufacturer (Incyte) said that it is continuing its commitment to JAK inhibitors with ruxolitinib, which has shown activity against acute, steroid-refractory GVHD, and is being explored for prevention of chronic GVHD in the randomized, phase 3 REACH3 study.
The trial met its primary endpoint for a higher ORR at week 24 with ruxolitinib versus best available therapy, at 49.7% versus 25.6%, respectively, which translated into an odds ratio for response with the JAK inhibitor of 2.99 (P < .0001).
Selective T-cell expansion
Efavaleukin alfa is an IL-2-mutated protein (mutein), with a mutation in the IL-2RB-binding portion of IL-2 causing increased selectivity for regulatory T-cell expansion. It is bound to an IgG-Fc domain that is itself mutated, with reduced Fc receptor binding and IgG effector function to give it a longer half life. This agent is being studied in a phase 1/2 trial in a subcutaneous formulation delivered every 1 or 2 weeks to 68 patients.
Monocyte/macrophage depletion
Axatilimab is a high-affinity antibody targeting colony stimulating factor–1 receptor (CSF-1R) expressed on monocytes and macrophages. By blocking CSF-1R, it depletes circulation of nonclassical monocytes and prevents the differentiation and survival of M2 macrophages in tissue.
It is currently being investigated 30 patients in a phase 1/2 study in an intravenous formulation delivered over 30 minutes every 2-4 weeks.
Hedgehog pathway inhibition
There is evidence suggesting that hedgehog pathway inhibition can lessen fibrosis. Glasdegib (Daurismo) a potent selective oral inhibitor of the hedgehog signaling pathway, is approved for use with low-dose cytarabine for patients with newly diagnosed acute myeloid leukemia aged older than 75 years or have comorbidities precluding intensive chemotherapy.
This agent is associated with drug intolerance because of muscle spasms, dysgeusia, and alopecia, however.
The drug is currently in phase 1/2 at a dose of 50 mg orally per day in 20 patients.
ROCK2 inhibition
Belumosudil (formerly KD025) “appears to rebalance the immune system,” Dr. Lee said. Investigators think that the drug dampens an autoaggressive inflammatory response by selective inhibition of ROCK2.
This drug has been studied in a dose-escalation study and a phase 2 trial, in which 132 participants were randomized to receive belumosudil 200 mg either once or twice daily.
At a median follow-up of 8 months, the ORR with belumosudil 200 mg once and twice daily was 73% and 74%, respectively. Similar results were seen in patients who had previously received either ruxolitinib or ibrutinib. High response rates were seen in patients with severe chronic GVHD, involvement of four or more organs and a refractory response to their last line of therapy.
Hard-to-manage patients
“We’re very hopeful for many of these agents, but we have to acknowledge that there are still many management dilemmas, patients that we just don’t really know what to do with,” Dr. Lee said. “These include patients who have bad sclerosis and fasciitis, nonhealing skin ulcers, bronchiolitis obliterans, serositis that can be very difficult to manage, severe keratoconjunctivitis that can be eyesight threatening, nonhealing mouth ulcers, esophageal structures, and always patients who have frequent infections.
“We are hopeful that some these agents will be useful for our patients who have severe manifestations, but often the number of patients with these manifestations in the trials is too low to say something specific about them,” she added.
‘Exciting time’
“It’s an exciting time because there are a lot of different drugs that are being studied for chronic GVHD,” commented Betty Hamilton, MD, a hematologist/oncologist at the Cleveland Clinic.
“I think that where the field is going in terms of treatment is recognizing that chronic GVHD is a pretty heterogeneous disease, and we have to learn even more about the underlying biologic pathways to be able to determine which class of drugs to use and when,” she said in an interview.
She agreed with Dr. Lee that the goals of treating patients with chronic GVHD include improving symptoms and quality, preventing progression, ideally tapering patients off immunosuppression, and achieving a balance between preventing negative consequences of GVHD while maintain the benefits of a graft-versus-leukemia effect.
“In our center, drug choice is based on physician preference and comfort with how often they’ve used the drug, patients’ comorbidities, toxicities of the drug, and logistical considerations,” Dr. Hamilton said.
Dr. Lee disclosed consulting activities for Pfizer and Kadmon, travel and lodging from Amgen, and research funding from those companies and others. Dr. Hamilton disclosed consulting for Syndax and Incyte.
Despite improvements in prevention of graft-versus-host disease, chronic GVHD still occurs in 10%-50% of patients who undergo an allogeneic hematopoietic stem cell transplant, and these patients may require prolonged treatment with multiple lines of therapy, said a hematologist and transplant researcher.
“More effective, less toxic therapies for chronic GVHD are needed,” Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle said at the Transplant & Cellular Therapies Meetings.
Dr. Lee reviewed clinical trials for chronic GVHD at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
Although the incidence of chronic GVHD has gradually declined over the last 40 years and both relapse-free and overall survival following a chronic GVHD diagnosis have improved, “for patients who are diagnosed with chronic GVHD, they still will see many lines of therapy and many years of therapy,” she said.
Among 148 patients with chronic GVHD treated at her center, for example, 66% went on to two lines of therapy, 50% went on to three lines, 37% required four lines of therapy, and 20% needed five lines or more.
Salvage therapies for patients with chronic GVHD have evolved away from immunomodulators and immunosuppressants in the early 1990s, toward monoclonal antibodies such as rituximab in the early 2000s, to interleukin-2 and to tyrosine kinase inhibitors such as ruxolitinib (Jakafi) and ibrutinib (Imbruvica).
There are currently 36 agents that are FDA approved for at least one indication and can also be prescribed for the treatment of chronic GVHD, Dr. Lee noted.
Treatment goals
Dr. Lee laid out six goals for treating patients with chronic GVHD. They include:
- Controlling current signs and symptoms, measured by response rates and patient-reported outcomes
- Preventing further tissue and organ damage
- Minimizing toxicity
- Maintaining graft-versus-tumor effect
- Achieving graft tolerance and stopping immunosuppression
- Decreasing nonrelapse mortality and improving survival
Active trials
Dr. Lee identified 33 trials with chronic GVHD as an indication that are currently recruiting, and an additional 13 trials that are active but closed to recruiting. The trials can be generally grouped by mechanism of action, and involve agents targeting T-regulatory cells, B cells and/or B-cell receptor (BCR) signaling, monocytes/macrophages, costimulatory blockage, a proteasome inhibition, Janus kinase (JAK) 1/2 inhibitors, ROCK2 inhibitors, hedgehog pathway inhibition, cellular therapy, and organ-targeted therapy.
Most of the trials have overall response rate as the primary endpoint, and all but five are currently in phase 1 or 2. The currently active phase 3 trials include two with ibrutinib, one with the investigational agent itacitinib, one with ruxolitinib, and one with mesenchymal stem cells.
“I’ll note that, when results are reported, the denominator really matters for the overall response rate, especially if you’re talking about small trials, because if you require the patient to be treated with an agent for a certain period of time, and you take out all the people who didn’t make it to that time point, then your overall response rate looks better,” she said.
BTK inhibitors
The first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first and thus far only agent approved by the Food and Drug Administration for chronic GVHD. The approval was based on a single-arm, multicenter trial with 42 patients.
The ORR in this trial was 69%, consisting of 31% complete responses and 38% partial responses, with a duration of response longer than 10 months in slightly more than half of all patients. In all, 24% of patients had improvement of symptoms in two consecutive visits, and 29% continued on ibrutinib at the time of the primary analysis in 2017.
Based on these promising results, acalabrutinib, which is more potent and selective for BTK than ibrutinib, with no effect on either platelets or natural killer cells, is currently under investigation in a phase 2 trial in 50 patients at a dose of 100 mg orally twice daily.
JAK1/2 inhibition
The JAK1 inhibitor itacitinib failed to meet its primary ORR endpoint in the phase 3 GRAVITAS-301 study, according to a press release, but the manufacturer (Incyte) said that it is continuing its commitment to JAK inhibitors with ruxolitinib, which has shown activity against acute, steroid-refractory GVHD, and is being explored for prevention of chronic GVHD in the randomized, phase 3 REACH3 study.
The trial met its primary endpoint for a higher ORR at week 24 with ruxolitinib versus best available therapy, at 49.7% versus 25.6%, respectively, which translated into an odds ratio for response with the JAK inhibitor of 2.99 (P < .0001).
Selective T-cell expansion
Efavaleukin alfa is an IL-2-mutated protein (mutein), with a mutation in the IL-2RB-binding portion of IL-2 causing increased selectivity for regulatory T-cell expansion. It is bound to an IgG-Fc domain that is itself mutated, with reduced Fc receptor binding and IgG effector function to give it a longer half life. This agent is being studied in a phase 1/2 trial in a subcutaneous formulation delivered every 1 or 2 weeks to 68 patients.
Monocyte/macrophage depletion
Axatilimab is a high-affinity antibody targeting colony stimulating factor–1 receptor (CSF-1R) expressed on monocytes and macrophages. By blocking CSF-1R, it depletes circulation of nonclassical monocytes and prevents the differentiation and survival of M2 macrophages in tissue.
It is currently being investigated 30 patients in a phase 1/2 study in an intravenous formulation delivered over 30 minutes every 2-4 weeks.
Hedgehog pathway inhibition
There is evidence suggesting that hedgehog pathway inhibition can lessen fibrosis. Glasdegib (Daurismo) a potent selective oral inhibitor of the hedgehog signaling pathway, is approved for use with low-dose cytarabine for patients with newly diagnosed acute myeloid leukemia aged older than 75 years or have comorbidities precluding intensive chemotherapy.
This agent is associated with drug intolerance because of muscle spasms, dysgeusia, and alopecia, however.
The drug is currently in phase 1/2 at a dose of 50 mg orally per day in 20 patients.
ROCK2 inhibition
Belumosudil (formerly KD025) “appears to rebalance the immune system,” Dr. Lee said. Investigators think that the drug dampens an autoaggressive inflammatory response by selective inhibition of ROCK2.
This drug has been studied in a dose-escalation study and a phase 2 trial, in which 132 participants were randomized to receive belumosudil 200 mg either once or twice daily.
At a median follow-up of 8 months, the ORR with belumosudil 200 mg once and twice daily was 73% and 74%, respectively. Similar results were seen in patients who had previously received either ruxolitinib or ibrutinib. High response rates were seen in patients with severe chronic GVHD, involvement of four or more organs and a refractory response to their last line of therapy.
Hard-to-manage patients
“We’re very hopeful for many of these agents, but we have to acknowledge that there are still many management dilemmas, patients that we just don’t really know what to do with,” Dr. Lee said. “These include patients who have bad sclerosis and fasciitis, nonhealing skin ulcers, bronchiolitis obliterans, serositis that can be very difficult to manage, severe keratoconjunctivitis that can be eyesight threatening, nonhealing mouth ulcers, esophageal structures, and always patients who have frequent infections.
“We are hopeful that some these agents will be useful for our patients who have severe manifestations, but often the number of patients with these manifestations in the trials is too low to say something specific about them,” she added.
‘Exciting time’
“It’s an exciting time because there are a lot of different drugs that are being studied for chronic GVHD,” commented Betty Hamilton, MD, a hematologist/oncologist at the Cleveland Clinic.
“I think that where the field is going in terms of treatment is recognizing that chronic GVHD is a pretty heterogeneous disease, and we have to learn even more about the underlying biologic pathways to be able to determine which class of drugs to use and when,” she said in an interview.
She agreed with Dr. Lee that the goals of treating patients with chronic GVHD include improving symptoms and quality, preventing progression, ideally tapering patients off immunosuppression, and achieving a balance between preventing negative consequences of GVHD while maintain the benefits of a graft-versus-leukemia effect.
“In our center, drug choice is based on physician preference and comfort with how often they’ve used the drug, patients’ comorbidities, toxicities of the drug, and logistical considerations,” Dr. Hamilton said.
Dr. Lee disclosed consulting activities for Pfizer and Kadmon, travel and lodging from Amgen, and research funding from those companies and others. Dr. Hamilton disclosed consulting for Syndax and Incyte.
Despite improvements in prevention of graft-versus-host disease, chronic GVHD still occurs in 10%-50% of patients who undergo an allogeneic hematopoietic stem cell transplant, and these patients may require prolonged treatment with multiple lines of therapy, said a hematologist and transplant researcher.
“More effective, less toxic therapies for chronic GVHD are needed,” Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle said at the Transplant & Cellular Therapies Meetings.
Dr. Lee reviewed clinical trials for chronic GVHD at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
Although the incidence of chronic GVHD has gradually declined over the last 40 years and both relapse-free and overall survival following a chronic GVHD diagnosis have improved, “for patients who are diagnosed with chronic GVHD, they still will see many lines of therapy and many years of therapy,” she said.
Among 148 patients with chronic GVHD treated at her center, for example, 66% went on to two lines of therapy, 50% went on to three lines, 37% required four lines of therapy, and 20% needed five lines or more.
Salvage therapies for patients with chronic GVHD have evolved away from immunomodulators and immunosuppressants in the early 1990s, toward monoclonal antibodies such as rituximab in the early 2000s, to interleukin-2 and to tyrosine kinase inhibitors such as ruxolitinib (Jakafi) and ibrutinib (Imbruvica).
There are currently 36 agents that are FDA approved for at least one indication and can also be prescribed for the treatment of chronic GVHD, Dr. Lee noted.
Treatment goals
Dr. Lee laid out six goals for treating patients with chronic GVHD. They include:
- Controlling current signs and symptoms, measured by response rates and patient-reported outcomes
- Preventing further tissue and organ damage
- Minimizing toxicity
- Maintaining graft-versus-tumor effect
- Achieving graft tolerance and stopping immunosuppression
- Decreasing nonrelapse mortality and improving survival
Active trials
Dr. Lee identified 33 trials with chronic GVHD as an indication that are currently recruiting, and an additional 13 trials that are active but closed to recruiting. The trials can be generally grouped by mechanism of action, and involve agents targeting T-regulatory cells, B cells and/or B-cell receptor (BCR) signaling, monocytes/macrophages, costimulatory blockage, a proteasome inhibition, Janus kinase (JAK) 1/2 inhibitors, ROCK2 inhibitors, hedgehog pathway inhibition, cellular therapy, and organ-targeted therapy.
Most of the trials have overall response rate as the primary endpoint, and all but five are currently in phase 1 or 2. The currently active phase 3 trials include two with ibrutinib, one with the investigational agent itacitinib, one with ruxolitinib, and one with mesenchymal stem cells.
“I’ll note that, when results are reported, the denominator really matters for the overall response rate, especially if you’re talking about small trials, because if you require the patient to be treated with an agent for a certain period of time, and you take out all the people who didn’t make it to that time point, then your overall response rate looks better,” she said.
BTK inhibitors
The first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first and thus far only agent approved by the Food and Drug Administration for chronic GVHD. The approval was based on a single-arm, multicenter trial with 42 patients.
The ORR in this trial was 69%, consisting of 31% complete responses and 38% partial responses, with a duration of response longer than 10 months in slightly more than half of all patients. In all, 24% of patients had improvement of symptoms in two consecutive visits, and 29% continued on ibrutinib at the time of the primary analysis in 2017.
Based on these promising results, acalabrutinib, which is more potent and selective for BTK than ibrutinib, with no effect on either platelets or natural killer cells, is currently under investigation in a phase 2 trial in 50 patients at a dose of 100 mg orally twice daily.
JAK1/2 inhibition
The JAK1 inhibitor itacitinib failed to meet its primary ORR endpoint in the phase 3 GRAVITAS-301 study, according to a press release, but the manufacturer (Incyte) said that it is continuing its commitment to JAK inhibitors with ruxolitinib, which has shown activity against acute, steroid-refractory GVHD, and is being explored for prevention of chronic GVHD in the randomized, phase 3 REACH3 study.
The trial met its primary endpoint for a higher ORR at week 24 with ruxolitinib versus best available therapy, at 49.7% versus 25.6%, respectively, which translated into an odds ratio for response with the JAK inhibitor of 2.99 (P < .0001).
Selective T-cell expansion
Efavaleukin alfa is an IL-2-mutated protein (mutein), with a mutation in the IL-2RB-binding portion of IL-2 causing increased selectivity for regulatory T-cell expansion. It is bound to an IgG-Fc domain that is itself mutated, with reduced Fc receptor binding and IgG effector function to give it a longer half life. This agent is being studied in a phase 1/2 trial in a subcutaneous formulation delivered every 1 or 2 weeks to 68 patients.
Monocyte/macrophage depletion
Axatilimab is a high-affinity antibody targeting colony stimulating factor–1 receptor (CSF-1R) expressed on monocytes and macrophages. By blocking CSF-1R, it depletes circulation of nonclassical monocytes and prevents the differentiation and survival of M2 macrophages in tissue.
It is currently being investigated 30 patients in a phase 1/2 study in an intravenous formulation delivered over 30 minutes every 2-4 weeks.
Hedgehog pathway inhibition
There is evidence suggesting that hedgehog pathway inhibition can lessen fibrosis. Glasdegib (Daurismo) a potent selective oral inhibitor of the hedgehog signaling pathway, is approved for use with low-dose cytarabine for patients with newly diagnosed acute myeloid leukemia aged older than 75 years or have comorbidities precluding intensive chemotherapy.
This agent is associated with drug intolerance because of muscle spasms, dysgeusia, and alopecia, however.
The drug is currently in phase 1/2 at a dose of 50 mg orally per day in 20 patients.
ROCK2 inhibition
Belumosudil (formerly KD025) “appears to rebalance the immune system,” Dr. Lee said. Investigators think that the drug dampens an autoaggressive inflammatory response by selective inhibition of ROCK2.
This drug has been studied in a dose-escalation study and a phase 2 trial, in which 132 participants were randomized to receive belumosudil 200 mg either once or twice daily.
At a median follow-up of 8 months, the ORR with belumosudil 200 mg once and twice daily was 73% and 74%, respectively. Similar results were seen in patients who had previously received either ruxolitinib or ibrutinib. High response rates were seen in patients with severe chronic GVHD, involvement of four or more organs and a refractory response to their last line of therapy.
Hard-to-manage patients
“We’re very hopeful for many of these agents, but we have to acknowledge that there are still many management dilemmas, patients that we just don’t really know what to do with,” Dr. Lee said. “These include patients who have bad sclerosis and fasciitis, nonhealing skin ulcers, bronchiolitis obliterans, serositis that can be very difficult to manage, severe keratoconjunctivitis that can be eyesight threatening, nonhealing mouth ulcers, esophageal structures, and always patients who have frequent infections.
“We are hopeful that some these agents will be useful for our patients who have severe manifestations, but often the number of patients with these manifestations in the trials is too low to say something specific about them,” she added.
‘Exciting time’
“It’s an exciting time because there are a lot of different drugs that are being studied for chronic GVHD,” commented Betty Hamilton, MD, a hematologist/oncologist at the Cleveland Clinic.
“I think that where the field is going in terms of treatment is recognizing that chronic GVHD is a pretty heterogeneous disease, and we have to learn even more about the underlying biologic pathways to be able to determine which class of drugs to use and when,” she said in an interview.
She agreed with Dr. Lee that the goals of treating patients with chronic GVHD include improving symptoms and quality, preventing progression, ideally tapering patients off immunosuppression, and achieving a balance between preventing negative consequences of GVHD while maintain the benefits of a graft-versus-leukemia effect.
“In our center, drug choice is based on physician preference and comfort with how often they’ve used the drug, patients’ comorbidities, toxicities of the drug, and logistical considerations,” Dr. Hamilton said.
Dr. Lee disclosed consulting activities for Pfizer and Kadmon, travel and lodging from Amgen, and research funding from those companies and others. Dr. Hamilton disclosed consulting for Syndax and Incyte.
FROM TCT 2021
Headache and COVID-19: Key questions answered
Although coronavirus 19 disease (COVID-19), caused by severe acute respiratory coronavirus 2, is characterized by symptoms that primarily impact the respiratory system, many patients experience neurological manifestations, with headache among leading complaints. Moreover, headache symptoms, including migraine-like headache, can last long after patients recover from COVID-19.
Last November, in an interview with 60 Minutes, Sadie Nagamootoo described her experience. “There are days when I do nothing and cannot get out of bed. The migraines are 10 times worse than a flu headache.”
To help individuals like Nagamootoo and others who experience headache as a result of COVID-19, it is important to understand the data that are emerging and how to incorporate them into practice. Following are answers to important questions that can guide front-line neurologists and other clinicians who are practicing during the pandemic.
Why is headache a symptom of COVID-19? It should come as no surprise that patients with COVID-19 can experience headache. Peng reminds us, in a November 2020 editorial in Cephalalgia, that headache is a common symptom in individuals with acute respiratory disease, representing a physiological response to acute infection. Headache is often the primary reason patients seek treatment.
How is headache associated with COVID-19? It is too early to know with certainty the mechanisms underlying COVID-19 headache, but a possible explanation—according to Uygun and colleagues, writing in the The Journal of Headache and Pain—is that the virus directly invades trigeminal nerve endings in the nasal and oral cavities.
How does headache tend to present in COVID-19? Patricia Pozo-Rosich, MD, PhD, presented on this topic at the American Headache Society’s 2020 Virtual Annual Scientific Meeting in June. In a recent interview with Neurology Reviews, Dr. Pozo-Rosich, head of the Headache & Craniofacial Pain Unit at Vall d’Hebron University Hospital, Barcelona, Spain, noted that “headache seems to have 2 different presentations: 1) migraine-like characteristics that are severe, disabling, and usually start before other COVID symptoms and 2) tension-type headache characteristics, which usually start together with the rest of COVID symptoms.”
Are there symptoms that tend to occur more frequently in patients with COVID-19 and headache? Caronna and colleagues recently published an analysis in Cephalalgia of 130 individuals with COVID-19, showing that loss of smell and/or taste occurred in more than half of patients with headache, compared with fewer than 20% of those without headache. This finding is notable because it has been frequently reported in case reports of patients with COVID-19 and headache.
What does the presence of headache indicate about COVID-19 prognosis? The good news for individuals with COVID-19 who experience headache is that the duration of their COVID-19 illness might very well be shorter. In the Caronna study, COVID-19 duration in individuals with headache was, on average, 1 week shorter (24 days) than in those without headache symptoms (31 days). “We don’t know why,” said Dr. Pozo-Rosich, who is one of the study’s authors. She hypothesizes that it is because of a balance between neuroinflammation and systemic inflammation. “Having an extraordinary initial reaction at the nasal cavity might protect us from having greater systemic inflammation.”
What is the cause of headache from COVID-19? Bolay and colleagues reported in Headache in Spring 2020 that patients developed new-onset, moderate-to-severe, bilateral pulsating or pressing headache toward the frontal area and forehead during the viral phase of disease. The virus activates peripheral trigeminal nerve endings directly or through vasculopathy and/or increased circulating pro-inflammatory cytokines.
What else is important to be aware of regarding headache evolution in individuals with COVID-19? The bad news for many of these individuals is that, although their COVID-19 illness might dissipate more quickly, headaches could linger. Moreover, many will be experiencing chronic headache for the first time in their life. Caronna reported that that one third of follow-up patients who reported headache were experiencing persistent disabling headache daily after 6 weeks, and more than half had no history of recurrent headache.
What is the recommended treatment for headache associated with COVID-19? Dr. Pozo-Rosich recommends starting with a nonsteroidal anti-inflammatory medication. Eventually, steroids might be indicated, “especially if the disease progresses.”
It is important for neurologists to be aware of new-onset headache associated with anosmia early in the disease. Test for the virus in such a patient; hopefully, their course will be shorter, milder, and non-respiratory.
Although coronavirus 19 disease (COVID-19), caused by severe acute respiratory coronavirus 2, is characterized by symptoms that primarily impact the respiratory system, many patients experience neurological manifestations, with headache among leading complaints. Moreover, headache symptoms, including migraine-like headache, can last long after patients recover from COVID-19.
Last November, in an interview with 60 Minutes, Sadie Nagamootoo described her experience. “There are days when I do nothing and cannot get out of bed. The migraines are 10 times worse than a flu headache.”
To help individuals like Nagamootoo and others who experience headache as a result of COVID-19, it is important to understand the data that are emerging and how to incorporate them into practice. Following are answers to important questions that can guide front-line neurologists and other clinicians who are practicing during the pandemic.
Why is headache a symptom of COVID-19? It should come as no surprise that patients with COVID-19 can experience headache. Peng reminds us, in a November 2020 editorial in Cephalalgia, that headache is a common symptom in individuals with acute respiratory disease, representing a physiological response to acute infection. Headache is often the primary reason patients seek treatment.
How is headache associated with COVID-19? It is too early to know with certainty the mechanisms underlying COVID-19 headache, but a possible explanation—according to Uygun and colleagues, writing in the The Journal of Headache and Pain—is that the virus directly invades trigeminal nerve endings in the nasal and oral cavities.
How does headache tend to present in COVID-19? Patricia Pozo-Rosich, MD, PhD, presented on this topic at the American Headache Society’s 2020 Virtual Annual Scientific Meeting in June. In a recent interview with Neurology Reviews, Dr. Pozo-Rosich, head of the Headache & Craniofacial Pain Unit at Vall d’Hebron University Hospital, Barcelona, Spain, noted that “headache seems to have 2 different presentations: 1) migraine-like characteristics that are severe, disabling, and usually start before other COVID symptoms and 2) tension-type headache characteristics, which usually start together with the rest of COVID symptoms.”
Are there symptoms that tend to occur more frequently in patients with COVID-19 and headache? Caronna and colleagues recently published an analysis in Cephalalgia of 130 individuals with COVID-19, showing that loss of smell and/or taste occurred in more than half of patients with headache, compared with fewer than 20% of those without headache. This finding is notable because it has been frequently reported in case reports of patients with COVID-19 and headache.
What does the presence of headache indicate about COVID-19 prognosis? The good news for individuals with COVID-19 who experience headache is that the duration of their COVID-19 illness might very well be shorter. In the Caronna study, COVID-19 duration in individuals with headache was, on average, 1 week shorter (24 days) than in those without headache symptoms (31 days). “We don’t know why,” said Dr. Pozo-Rosich, who is one of the study’s authors. She hypothesizes that it is because of a balance between neuroinflammation and systemic inflammation. “Having an extraordinary initial reaction at the nasal cavity might protect us from having greater systemic inflammation.”
What is the cause of headache from COVID-19? Bolay and colleagues reported in Headache in Spring 2020 that patients developed new-onset, moderate-to-severe, bilateral pulsating or pressing headache toward the frontal area and forehead during the viral phase of disease. The virus activates peripheral trigeminal nerve endings directly or through vasculopathy and/or increased circulating pro-inflammatory cytokines.
What else is important to be aware of regarding headache evolution in individuals with COVID-19? The bad news for many of these individuals is that, although their COVID-19 illness might dissipate more quickly, headaches could linger. Moreover, many will be experiencing chronic headache for the first time in their life. Caronna reported that that one third of follow-up patients who reported headache were experiencing persistent disabling headache daily after 6 weeks, and more than half had no history of recurrent headache.
What is the recommended treatment for headache associated with COVID-19? Dr. Pozo-Rosich recommends starting with a nonsteroidal anti-inflammatory medication. Eventually, steroids might be indicated, “especially if the disease progresses.”
It is important for neurologists to be aware of new-onset headache associated with anosmia early in the disease. Test for the virus in such a patient; hopefully, their course will be shorter, milder, and non-respiratory.
Although coronavirus 19 disease (COVID-19), caused by severe acute respiratory coronavirus 2, is characterized by symptoms that primarily impact the respiratory system, many patients experience neurological manifestations, with headache among leading complaints. Moreover, headache symptoms, including migraine-like headache, can last long after patients recover from COVID-19.
Last November, in an interview with 60 Minutes, Sadie Nagamootoo described her experience. “There are days when I do nothing and cannot get out of bed. The migraines are 10 times worse than a flu headache.”
To help individuals like Nagamootoo and others who experience headache as a result of COVID-19, it is important to understand the data that are emerging and how to incorporate them into practice. Following are answers to important questions that can guide front-line neurologists and other clinicians who are practicing during the pandemic.
Why is headache a symptom of COVID-19? It should come as no surprise that patients with COVID-19 can experience headache. Peng reminds us, in a November 2020 editorial in Cephalalgia, that headache is a common symptom in individuals with acute respiratory disease, representing a physiological response to acute infection. Headache is often the primary reason patients seek treatment.
How is headache associated with COVID-19? It is too early to know with certainty the mechanisms underlying COVID-19 headache, but a possible explanation—according to Uygun and colleagues, writing in the The Journal of Headache and Pain—is that the virus directly invades trigeminal nerve endings in the nasal and oral cavities.
How does headache tend to present in COVID-19? Patricia Pozo-Rosich, MD, PhD, presented on this topic at the American Headache Society’s 2020 Virtual Annual Scientific Meeting in June. In a recent interview with Neurology Reviews, Dr. Pozo-Rosich, head of the Headache & Craniofacial Pain Unit at Vall d’Hebron University Hospital, Barcelona, Spain, noted that “headache seems to have 2 different presentations: 1) migraine-like characteristics that are severe, disabling, and usually start before other COVID symptoms and 2) tension-type headache characteristics, which usually start together with the rest of COVID symptoms.”
Are there symptoms that tend to occur more frequently in patients with COVID-19 and headache? Caronna and colleagues recently published an analysis in Cephalalgia of 130 individuals with COVID-19, showing that loss of smell and/or taste occurred in more than half of patients with headache, compared with fewer than 20% of those without headache. This finding is notable because it has been frequently reported in case reports of patients with COVID-19 and headache.
What does the presence of headache indicate about COVID-19 prognosis? The good news for individuals with COVID-19 who experience headache is that the duration of their COVID-19 illness might very well be shorter. In the Caronna study, COVID-19 duration in individuals with headache was, on average, 1 week shorter (24 days) than in those without headache symptoms (31 days). “We don’t know why,” said Dr. Pozo-Rosich, who is one of the study’s authors. She hypothesizes that it is because of a balance between neuroinflammation and systemic inflammation. “Having an extraordinary initial reaction at the nasal cavity might protect us from having greater systemic inflammation.”
What is the cause of headache from COVID-19? Bolay and colleagues reported in Headache in Spring 2020 that patients developed new-onset, moderate-to-severe, bilateral pulsating or pressing headache toward the frontal area and forehead during the viral phase of disease. The virus activates peripheral trigeminal nerve endings directly or through vasculopathy and/or increased circulating pro-inflammatory cytokines.
What else is important to be aware of regarding headache evolution in individuals with COVID-19? The bad news for many of these individuals is that, although their COVID-19 illness might dissipate more quickly, headaches could linger. Moreover, many will be experiencing chronic headache for the first time in their life. Caronna reported that that one third of follow-up patients who reported headache were experiencing persistent disabling headache daily after 6 weeks, and more than half had no history of recurrent headache.
What is the recommended treatment for headache associated with COVID-19? Dr. Pozo-Rosich recommends starting with a nonsteroidal anti-inflammatory medication. Eventually, steroids might be indicated, “especially if the disease progresses.”
It is important for neurologists to be aware of new-onset headache associated with anosmia early in the disease. Test for the virus in such a patient; hopefully, their course will be shorter, milder, and non-respiratory.
Prognostic gene signature identifies high- vs. low-risk DLBCL patients
according to the results of a database analysis.
A total of 33 genes formed the signature that could be transformed into a risk score, according to a study by Santosh Khanal, a senior bioinformatics scientist at Children’s Mercy Kansas City (Mo.), and colleagues published in Cancer Genetics.
Their study used gene expression and clinical parameters from the Lymphoma/Leukemia Molecular Profiling Project from 233 patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy to identify genes whose expression was associated with overall survival (OS). They refined the information to develop prognostic gene signature that could be used to calculate risk scores for each individual and predict OS.
Significant separation
The researchers initially found 61 genes individually associated with OS that had a nonadjusted P ≤ .001 using the univariate Cox regression model. The 61 genes were then assessed using multivariate Cox analysis to identify a minimal set of genes that could predict OS, resulting in a minimal set of 33 genes that were used to develop a survival risk score for each individual.
The OS of the high-risk group was significantly reduced, compared with the low-risk group (hazard ratio, 0.046; P < .0001). Upon stratification of individuals by risk score into quartiles, patients in the lowest quartile risk score had a 100% probability of survival, while individuals in the highest quartile had a 9.2% OS by year 5.
In order to validate their results, the researchers calculated risk scores using their prognostic gene set in three additional published DLBCL studies. For all three studies, individuals with low risk score had significantly better OS, “indicating the robustness of the gene signature for multiple external datasets,” according to the researchers.
The top biological pathways and processes that were significantly overrepresented in the 33-gene set were the thioester biosynthetic process (P = .00005), cellular response to hormone stimulus (P = .002), G protein–coupled receptor ligand binding (P = .003), and myeloid cell activation involved in immune responses (P = 0.006).
“As new therapies for lymphoma become available, including new immunotherapies and personalized medicine approaches such as [chimeric antigen receptor] T cells, it will be important to identify candidate individuals that are at high risk and may benefit from experimental therapeutic approaches compared with individuals who will have lower risk of death with current therapies,” the researchers concluded.
The authors reported that they had no competing interests.
according to the results of a database analysis.
A total of 33 genes formed the signature that could be transformed into a risk score, according to a study by Santosh Khanal, a senior bioinformatics scientist at Children’s Mercy Kansas City (Mo.), and colleagues published in Cancer Genetics.
Their study used gene expression and clinical parameters from the Lymphoma/Leukemia Molecular Profiling Project from 233 patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy to identify genes whose expression was associated with overall survival (OS). They refined the information to develop prognostic gene signature that could be used to calculate risk scores for each individual and predict OS.
Significant separation
The researchers initially found 61 genes individually associated with OS that had a nonadjusted P ≤ .001 using the univariate Cox regression model. The 61 genes were then assessed using multivariate Cox analysis to identify a minimal set of genes that could predict OS, resulting in a minimal set of 33 genes that were used to develop a survival risk score for each individual.
The OS of the high-risk group was significantly reduced, compared with the low-risk group (hazard ratio, 0.046; P < .0001). Upon stratification of individuals by risk score into quartiles, patients in the lowest quartile risk score had a 100% probability of survival, while individuals in the highest quartile had a 9.2% OS by year 5.
In order to validate their results, the researchers calculated risk scores using their prognostic gene set in three additional published DLBCL studies. For all three studies, individuals with low risk score had significantly better OS, “indicating the robustness of the gene signature for multiple external datasets,” according to the researchers.
The top biological pathways and processes that were significantly overrepresented in the 33-gene set were the thioester biosynthetic process (P = .00005), cellular response to hormone stimulus (P = .002), G protein–coupled receptor ligand binding (P = .003), and myeloid cell activation involved in immune responses (P = 0.006).
“As new therapies for lymphoma become available, including new immunotherapies and personalized medicine approaches such as [chimeric antigen receptor] T cells, it will be important to identify candidate individuals that are at high risk and may benefit from experimental therapeutic approaches compared with individuals who will have lower risk of death with current therapies,” the researchers concluded.
The authors reported that they had no competing interests.
according to the results of a database analysis.
A total of 33 genes formed the signature that could be transformed into a risk score, according to a study by Santosh Khanal, a senior bioinformatics scientist at Children’s Mercy Kansas City (Mo.), and colleagues published in Cancer Genetics.
Their study used gene expression and clinical parameters from the Lymphoma/Leukemia Molecular Profiling Project from 233 patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy to identify genes whose expression was associated with overall survival (OS). They refined the information to develop prognostic gene signature that could be used to calculate risk scores for each individual and predict OS.
Significant separation
The researchers initially found 61 genes individually associated with OS that had a nonadjusted P ≤ .001 using the univariate Cox regression model. The 61 genes were then assessed using multivariate Cox analysis to identify a minimal set of genes that could predict OS, resulting in a minimal set of 33 genes that were used to develop a survival risk score for each individual.
The OS of the high-risk group was significantly reduced, compared with the low-risk group (hazard ratio, 0.046; P < .0001). Upon stratification of individuals by risk score into quartiles, patients in the lowest quartile risk score had a 100% probability of survival, while individuals in the highest quartile had a 9.2% OS by year 5.
In order to validate their results, the researchers calculated risk scores using their prognostic gene set in three additional published DLBCL studies. For all three studies, individuals with low risk score had significantly better OS, “indicating the robustness of the gene signature for multiple external datasets,” according to the researchers.
The top biological pathways and processes that were significantly overrepresented in the 33-gene set were the thioester biosynthetic process (P = .00005), cellular response to hormone stimulus (P = .002), G protein–coupled receptor ligand binding (P = .003), and myeloid cell activation involved in immune responses (P = 0.006).
“As new therapies for lymphoma become available, including new immunotherapies and personalized medicine approaches such as [chimeric antigen receptor] T cells, it will be important to identify candidate individuals that are at high risk and may benefit from experimental therapeutic approaches compared with individuals who will have lower risk of death with current therapies,” the researchers concluded.
The authors reported that they had no competing interests.
FROM CANCER GENETICS
The true measure of cluster headache
Patients with cluster headache face a double whammy: Physicians too often fail to recognize it, and their condition is among the most severe and debilitating among headache types. In fact,
The study’s comparison of cluster headaches to other common painful experiences can help nonsufferers relate to the experience, said Larry Schor, PhD, a coauthor of the paper. “Headache is a terrible word. Bee stings sting, burns burn. [A cluster headache] doesn’t ache. It’s a piercing intensity like you just can’t believe,” said Dr. Schor, professor of psychology at the University of West Georgia, Carrollton, and a cluster headache patient since he first experienced an attack at the age of 21.
The study was published in the January 2021 issue of Headache.
Ranking cluster headaches as worse than experiences such as childbirth or kidney stones is “kind of eye opening, and helps to describe the experience in terms that more people can relate to. I think it helps to share the experience of cluster headache more broadly, because we’re in a situation where cluster headache remains underfunded, and we don’t have enough treatments for it. I think one way to overcome that is to spread awareness of what this problem is, and the impact it has on human life,” said Rashmi Halker Singh, MD, associate professor of neurology at the Mayo Clinic in Scottsdale, Ariz., and deputy editor of Headache. She was not involved in the study.
Dr. Schor called for physicians to consider cluster headache an emergency, because of the severity of pain and also the potential for suicidality. Treatments remain comparatively sparse, but high-flow oxygen can help some patients, and intranasal or intravenous triptans can treat acute pain. In 2018, the Food and Drug Administration approved galcanezumab (Eli Lilly) for prevention of episodic cluster headaches.
But cluster headaches are often misdiagnosed. For many patients, it takes more than a year or even as long as 5 years to get an accurate diagnosis, according to Dr. Schor. Women may be particularly vulnerable to misdiagnosis, because migraines are more common in women. It doesn’t help that many neurologists are taught that cluster headache is primarily a male disease. “Because that idea is so ingrained, I think a lot of women who have cluster headache are probably missed and told they have migraine instead. There are a lot of women who have cluster headache, and that gender difference might not be as big a difference as we were initially taught. We need to do a better job of recognizing cluster headache to better understand what the true prevalence is,” said Dr. Halker Singh.
She noted that patients with side-locked headache should be evaluated for cluster headache, and asked how long the pain lasts in the absence of medication. “Also ask about the presence of cranial autonomic symptoms, and if they occur in the context of headache pain, and if they are side-locked to the side of the headache. Those are important questions that can tease out cluster headache from other conditions,” said Dr. Halker Singh.
For the survey, the researchers asked 1,604 patients with cluster headache patients to rate pain on a scale of 1 to 10. Cluster headache ranked highest at 9.7, then labor pain (7.2), pancreatitis (7.0), and nephrolithiasis (6.9). Cluster headache pain was ranked at 10.0 by 72.1% of respondents. Those reporting maximal pain or were more likely to have cranial autonomic features in comparison with patients who reported less pain, including conjunctival injection or lacrimation (91% versus 85%), eyelid edema (77% versus 66%), forehead/facial sweating (60% versus 49%), fullness in the ear (47% versus 35%), and miosis or ptosis (85% versus 75%). They had more frequent attacks (4.0 versus 3.5 per day), higher Hopelessness Depression Symptom Questionnaire scores (24.5 versus 21.1), and reduced effectiveness of calcium channel blockers (2.2 versus 2.5 on a 5-point Likert scale). They were more often female (34% versus 24%). (P < .001 for all).
The study received funding from Autonomic Technologies and Cluster Busters. Dr. Schor and Dr. Halker Singh had no relevant financial disclosures.
Patients with cluster headache face a double whammy: Physicians too often fail to recognize it, and their condition is among the most severe and debilitating among headache types. In fact,
The study’s comparison of cluster headaches to other common painful experiences can help nonsufferers relate to the experience, said Larry Schor, PhD, a coauthor of the paper. “Headache is a terrible word. Bee stings sting, burns burn. [A cluster headache] doesn’t ache. It’s a piercing intensity like you just can’t believe,” said Dr. Schor, professor of psychology at the University of West Georgia, Carrollton, and a cluster headache patient since he first experienced an attack at the age of 21.
The study was published in the January 2021 issue of Headache.
Ranking cluster headaches as worse than experiences such as childbirth or kidney stones is “kind of eye opening, and helps to describe the experience in terms that more people can relate to. I think it helps to share the experience of cluster headache more broadly, because we’re in a situation where cluster headache remains underfunded, and we don’t have enough treatments for it. I think one way to overcome that is to spread awareness of what this problem is, and the impact it has on human life,” said Rashmi Halker Singh, MD, associate professor of neurology at the Mayo Clinic in Scottsdale, Ariz., and deputy editor of Headache. She was not involved in the study.
Dr. Schor called for physicians to consider cluster headache an emergency, because of the severity of pain and also the potential for suicidality. Treatments remain comparatively sparse, but high-flow oxygen can help some patients, and intranasal or intravenous triptans can treat acute pain. In 2018, the Food and Drug Administration approved galcanezumab (Eli Lilly) for prevention of episodic cluster headaches.
But cluster headaches are often misdiagnosed. For many patients, it takes more than a year or even as long as 5 years to get an accurate diagnosis, according to Dr. Schor. Women may be particularly vulnerable to misdiagnosis, because migraines are more common in women. It doesn’t help that many neurologists are taught that cluster headache is primarily a male disease. “Because that idea is so ingrained, I think a lot of women who have cluster headache are probably missed and told they have migraine instead. There are a lot of women who have cluster headache, and that gender difference might not be as big a difference as we were initially taught. We need to do a better job of recognizing cluster headache to better understand what the true prevalence is,” said Dr. Halker Singh.
She noted that patients with side-locked headache should be evaluated for cluster headache, and asked how long the pain lasts in the absence of medication. “Also ask about the presence of cranial autonomic symptoms, and if they occur in the context of headache pain, and if they are side-locked to the side of the headache. Those are important questions that can tease out cluster headache from other conditions,” said Dr. Halker Singh.
For the survey, the researchers asked 1,604 patients with cluster headache patients to rate pain on a scale of 1 to 10. Cluster headache ranked highest at 9.7, then labor pain (7.2), pancreatitis (7.0), and nephrolithiasis (6.9). Cluster headache pain was ranked at 10.0 by 72.1% of respondents. Those reporting maximal pain or were more likely to have cranial autonomic features in comparison with patients who reported less pain, including conjunctival injection or lacrimation (91% versus 85%), eyelid edema (77% versus 66%), forehead/facial sweating (60% versus 49%), fullness in the ear (47% versus 35%), and miosis or ptosis (85% versus 75%). They had more frequent attacks (4.0 versus 3.5 per day), higher Hopelessness Depression Symptom Questionnaire scores (24.5 versus 21.1), and reduced effectiveness of calcium channel blockers (2.2 versus 2.5 on a 5-point Likert scale). They were more often female (34% versus 24%). (P < .001 for all).
The study received funding from Autonomic Technologies and Cluster Busters. Dr. Schor and Dr. Halker Singh had no relevant financial disclosures.
Patients with cluster headache face a double whammy: Physicians too often fail to recognize it, and their condition is among the most severe and debilitating among headache types. In fact,
The study’s comparison of cluster headaches to other common painful experiences can help nonsufferers relate to the experience, said Larry Schor, PhD, a coauthor of the paper. “Headache is a terrible word. Bee stings sting, burns burn. [A cluster headache] doesn’t ache. It’s a piercing intensity like you just can’t believe,” said Dr. Schor, professor of psychology at the University of West Georgia, Carrollton, and a cluster headache patient since he first experienced an attack at the age of 21.
The study was published in the January 2021 issue of Headache.
Ranking cluster headaches as worse than experiences such as childbirth or kidney stones is “kind of eye opening, and helps to describe the experience in terms that more people can relate to. I think it helps to share the experience of cluster headache more broadly, because we’re in a situation where cluster headache remains underfunded, and we don’t have enough treatments for it. I think one way to overcome that is to spread awareness of what this problem is, and the impact it has on human life,” said Rashmi Halker Singh, MD, associate professor of neurology at the Mayo Clinic in Scottsdale, Ariz., and deputy editor of Headache. She was not involved in the study.
Dr. Schor called for physicians to consider cluster headache an emergency, because of the severity of pain and also the potential for suicidality. Treatments remain comparatively sparse, but high-flow oxygen can help some patients, and intranasal or intravenous triptans can treat acute pain. In 2018, the Food and Drug Administration approved galcanezumab (Eli Lilly) for prevention of episodic cluster headaches.
But cluster headaches are often misdiagnosed. For many patients, it takes more than a year or even as long as 5 years to get an accurate diagnosis, according to Dr. Schor. Women may be particularly vulnerable to misdiagnosis, because migraines are more common in women. It doesn’t help that many neurologists are taught that cluster headache is primarily a male disease. “Because that idea is so ingrained, I think a lot of women who have cluster headache are probably missed and told they have migraine instead. There are a lot of women who have cluster headache, and that gender difference might not be as big a difference as we were initially taught. We need to do a better job of recognizing cluster headache to better understand what the true prevalence is,” said Dr. Halker Singh.
She noted that patients with side-locked headache should be evaluated for cluster headache, and asked how long the pain lasts in the absence of medication. “Also ask about the presence of cranial autonomic symptoms, and if they occur in the context of headache pain, and if they are side-locked to the side of the headache. Those are important questions that can tease out cluster headache from other conditions,” said Dr. Halker Singh.
For the survey, the researchers asked 1,604 patients with cluster headache patients to rate pain on a scale of 1 to 10. Cluster headache ranked highest at 9.7, then labor pain (7.2), pancreatitis (7.0), and nephrolithiasis (6.9). Cluster headache pain was ranked at 10.0 by 72.1% of respondents. Those reporting maximal pain or were more likely to have cranial autonomic features in comparison with patients who reported less pain, including conjunctival injection or lacrimation (91% versus 85%), eyelid edema (77% versus 66%), forehead/facial sweating (60% versus 49%), fullness in the ear (47% versus 35%), and miosis or ptosis (85% versus 75%). They had more frequent attacks (4.0 versus 3.5 per day), higher Hopelessness Depression Symptom Questionnaire scores (24.5 versus 21.1), and reduced effectiveness of calcium channel blockers (2.2 versus 2.5 on a 5-point Likert scale). They were more often female (34% versus 24%). (P < .001 for all).
The study received funding from Autonomic Technologies and Cluster Busters. Dr. Schor and Dr. Halker Singh had no relevant financial disclosures.
FROM HEADACHE
Prostate drugs tied to lower risk for Parkinson’s disease
new research suggests. Treatment of BPH with terazosin (Hytrin), doxazosin (Cardura), or alfuzosin (Uroxatral), all of which enhance glycolysis, was associated with a lower risk of developing Parkinson’s disease than patients taking a drug used for the same indication, tamsulosin (Flomax), which does not affect glycolysis.
“If giving someone terazosin or similar medications truly reduces their risk of disease, these results could have significant clinical implications for neurologists,” said lead author Jacob E. Simmering, PhD, assistant professor of internal medicine at the University of Iowa, Iowa City.
There are few reliable neuroprotective treatments for Parkinson’s disease, he said. “We can manage some of the symptoms, but we can’t stop it from progressing. If a randomized trial finds the same result, this will provide a new option to slow progression of Parkinson’s disease.”
The pathogenesis of Parkinson’s disease is heterogeneous, however, and not all patients may benefit from glycolysis-enhancing drugs, the investigators noted. Future research will be needed to identify potential candidates for this treatment, and clarify the effects of these drugs, they wrote.
The findings were published online Feb. 1, 2021, in JAMA Neurology.
Time-dependent effects
The major risk factor for Parkinson’s disease is age, which is associated with impaired energy metabolism. Glycolysis is decreased among patients with Parkinson’s disease, yet impaired energy metabolism has not been investigated widely as a pathogenic factor in the disease, the authors wrote.
Studies have indicated that terazosin increases the activity of an enzyme important in glycolysis. Doxazosin and alfuzosin have a similar mechanism of action and enhance energy metabolism. Tamsulosin, a structurally unrelated drug, has the same mechanism of action as the other three drugs, but does not enhance energy metabolism.
In this report, the researchers investigated the hypothesis that patients who received therapy with terazosin, doxazosin, or alfuzosin would have a lower risk of developing Parkinson’s disease than patients receiving tamsulosin. To do that, they used health care utilization data from Denmark and the United States, including the Danish National Prescription Registry, the Danish National Patient Registry, the Danish Civil Registration System, and the Truven Health Analytics MarketScan database.
The investigators searched the records for patients who filled prescriptions for any of the four drugs of interest. They excluded any patients who developed Parkinson’s disease within 1 year of starting medication. Because use of these drugs is rare among women, they included only men in their analysis.
They looked at patient outcomes beginning at 1 year after the initiation of treatment. They also required patients to fill at least two prescriptions before the beginning of follow-up. Patients who switched from tamsulosin to any of the other drugs, or vice versa, were excluded from analysis.
The investigators used propensity-score matching to ensure that patients in the tamsulosin and terazosin/doxazosin/alfuzosin groups were similar in terms of their other potential risk factors. The primary outcome was the development of Parkinson’s disease.
They identified 52,365 propensity score–matched pairs in the Danish registries and 94,883 pairs in the Truven database. The mean age was 67.9 years in the Danish registries and 63.8 years in the Truven database, and follow-up was approximately 5 years and 3 years respectively. Baseline covariates were well balanced between cohorts.
Among Danish patients, those who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease versus those who took tamsulosin (hazard ratio, 0.88). Similarly, patients in the Truven database who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease than those who took tamsulosin (HR, 0.63).
In both cohorts, the risk for Parkinson’s disease among patients receiving terazosin, doxazosin, or alfuzosin, compared with those receiving tamsulosin, decreased with increasing numbers of prescriptions filled. Long-term treatment with any of the three glycolysis-enhancing drugs was associated with greater risk reduction in the Danish (HR, 0.79) and Truven (HR, 0.46) cohorts versus tamsulosin.
Differences in case definitions, which may reflect how Parkinson’s disease was managed, complicate comparisons between the Danish and Truven cohorts, said Dr. Simmering. Another challenge is the source of the data. “The Truven data set was derived from insurance claims from people with private insurance or Medicare supplemental plans,” he said. “This group is quite large but may not be representative of everyone in the United States. We would also only be able to follow people while they were on one insurance plan. If they switched coverage to a company that doesn’t contribute data, we would lose them.”
The Danish database, however, includes all residents of Denmark. Only people who left the country were lost to follow-up.
The results support the hypothesis that increasing energy in cells slows disease progression, Dr. Simmering added. “There are a few conditions, mostly REM sleep disorders, that are associated with future diagnosis of Parkinson’s disease. Right now, we don’t have anything to offer people at elevated risk of Parkinson’s disease that might prevent the disease. If a controlled trial finds that terazosin slows or prevents Parkinson’s disease, we would have something truly protective to offer these patients.”
Biomarker needed
Commenting on the results, Alberto J. Espay, MD, MSc, professor of neurology at the University of Cincinnati Academic Health Center, was cautious. “These findings are of unclear applicability to any particular patient without a biomarker for a deficit of glycolysis that these drugs are presumed to affect,” Dr. Espay said. “Hence, there is no feasible or warranted change in practice as a result of this study.”
Pathogenic mechanisms are heterogeneous among patients with Parkinson’s disease, Dr. Espay added. “We will need to understand who among the large biological universe of Parkinson’s patients may have impaired energy metabolism as a pathogenic mechanism to be selected for a future clinical trial evaluating terazosin, doxazosin, or alfuzosin as a potential disease-modifying intervention.”
Parkinson’s disease is not one disease, but a group of disorders with unique biological abnormalities, said Dr. Espay. “We know so much about ‘Parkinson’s disease’ and next to nothing about the biology of individuals with Parkinson’s disease.”
This situation has enabled the development of symptomatic treatments, such as dopaminergic therapies, but failed to yield disease-modifying treatments, he said.
The University of Iowa contributed funds for this study. Dr. Simmering has received pilot funding from the University of Iowa Institute for Clinical and Translational Science. He had no conflicts of interest to disclose. Dr. Espay disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests. Treatment of BPH with terazosin (Hytrin), doxazosin (Cardura), or alfuzosin (Uroxatral), all of which enhance glycolysis, was associated with a lower risk of developing Parkinson’s disease than patients taking a drug used for the same indication, tamsulosin (Flomax), which does not affect glycolysis.
“If giving someone terazosin or similar medications truly reduces their risk of disease, these results could have significant clinical implications for neurologists,” said lead author Jacob E. Simmering, PhD, assistant professor of internal medicine at the University of Iowa, Iowa City.
There are few reliable neuroprotective treatments for Parkinson’s disease, he said. “We can manage some of the symptoms, but we can’t stop it from progressing. If a randomized trial finds the same result, this will provide a new option to slow progression of Parkinson’s disease.”
The pathogenesis of Parkinson’s disease is heterogeneous, however, and not all patients may benefit from glycolysis-enhancing drugs, the investigators noted. Future research will be needed to identify potential candidates for this treatment, and clarify the effects of these drugs, they wrote.
The findings were published online Feb. 1, 2021, in JAMA Neurology.
Time-dependent effects
The major risk factor for Parkinson’s disease is age, which is associated with impaired energy metabolism. Glycolysis is decreased among patients with Parkinson’s disease, yet impaired energy metabolism has not been investigated widely as a pathogenic factor in the disease, the authors wrote.
Studies have indicated that terazosin increases the activity of an enzyme important in glycolysis. Doxazosin and alfuzosin have a similar mechanism of action and enhance energy metabolism. Tamsulosin, a structurally unrelated drug, has the same mechanism of action as the other three drugs, but does not enhance energy metabolism.
In this report, the researchers investigated the hypothesis that patients who received therapy with terazosin, doxazosin, or alfuzosin would have a lower risk of developing Parkinson’s disease than patients receiving tamsulosin. To do that, they used health care utilization data from Denmark and the United States, including the Danish National Prescription Registry, the Danish National Patient Registry, the Danish Civil Registration System, and the Truven Health Analytics MarketScan database.
The investigators searched the records for patients who filled prescriptions for any of the four drugs of interest. They excluded any patients who developed Parkinson’s disease within 1 year of starting medication. Because use of these drugs is rare among women, they included only men in their analysis.
They looked at patient outcomes beginning at 1 year after the initiation of treatment. They also required patients to fill at least two prescriptions before the beginning of follow-up. Patients who switched from tamsulosin to any of the other drugs, or vice versa, were excluded from analysis.
The investigators used propensity-score matching to ensure that patients in the tamsulosin and terazosin/doxazosin/alfuzosin groups were similar in terms of their other potential risk factors. The primary outcome was the development of Parkinson’s disease.
They identified 52,365 propensity score–matched pairs in the Danish registries and 94,883 pairs in the Truven database. The mean age was 67.9 years in the Danish registries and 63.8 years in the Truven database, and follow-up was approximately 5 years and 3 years respectively. Baseline covariates were well balanced between cohorts.
Among Danish patients, those who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease versus those who took tamsulosin (hazard ratio, 0.88). Similarly, patients in the Truven database who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease than those who took tamsulosin (HR, 0.63).
In both cohorts, the risk for Parkinson’s disease among patients receiving terazosin, doxazosin, or alfuzosin, compared with those receiving tamsulosin, decreased with increasing numbers of prescriptions filled. Long-term treatment with any of the three glycolysis-enhancing drugs was associated with greater risk reduction in the Danish (HR, 0.79) and Truven (HR, 0.46) cohorts versus tamsulosin.
Differences in case definitions, which may reflect how Parkinson’s disease was managed, complicate comparisons between the Danish and Truven cohorts, said Dr. Simmering. Another challenge is the source of the data. “The Truven data set was derived from insurance claims from people with private insurance or Medicare supplemental plans,” he said. “This group is quite large but may not be representative of everyone in the United States. We would also only be able to follow people while they were on one insurance plan. If they switched coverage to a company that doesn’t contribute data, we would lose them.”
The Danish database, however, includes all residents of Denmark. Only people who left the country were lost to follow-up.
The results support the hypothesis that increasing energy in cells slows disease progression, Dr. Simmering added. “There are a few conditions, mostly REM sleep disorders, that are associated with future diagnosis of Parkinson’s disease. Right now, we don’t have anything to offer people at elevated risk of Parkinson’s disease that might prevent the disease. If a controlled trial finds that terazosin slows or prevents Parkinson’s disease, we would have something truly protective to offer these patients.”
Biomarker needed
Commenting on the results, Alberto J. Espay, MD, MSc, professor of neurology at the University of Cincinnati Academic Health Center, was cautious. “These findings are of unclear applicability to any particular patient without a biomarker for a deficit of glycolysis that these drugs are presumed to affect,” Dr. Espay said. “Hence, there is no feasible or warranted change in practice as a result of this study.”
Pathogenic mechanisms are heterogeneous among patients with Parkinson’s disease, Dr. Espay added. “We will need to understand who among the large biological universe of Parkinson’s patients may have impaired energy metabolism as a pathogenic mechanism to be selected for a future clinical trial evaluating terazosin, doxazosin, or alfuzosin as a potential disease-modifying intervention.”
Parkinson’s disease is not one disease, but a group of disorders with unique biological abnormalities, said Dr. Espay. “We know so much about ‘Parkinson’s disease’ and next to nothing about the biology of individuals with Parkinson’s disease.”
This situation has enabled the development of symptomatic treatments, such as dopaminergic therapies, but failed to yield disease-modifying treatments, he said.
The University of Iowa contributed funds for this study. Dr. Simmering has received pilot funding from the University of Iowa Institute for Clinical and Translational Science. He had no conflicts of interest to disclose. Dr. Espay disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests. Treatment of BPH with terazosin (Hytrin), doxazosin (Cardura), or alfuzosin (Uroxatral), all of which enhance glycolysis, was associated with a lower risk of developing Parkinson’s disease than patients taking a drug used for the same indication, tamsulosin (Flomax), which does not affect glycolysis.
“If giving someone terazosin or similar medications truly reduces their risk of disease, these results could have significant clinical implications for neurologists,” said lead author Jacob E. Simmering, PhD, assistant professor of internal medicine at the University of Iowa, Iowa City.
There are few reliable neuroprotective treatments for Parkinson’s disease, he said. “We can manage some of the symptoms, but we can’t stop it from progressing. If a randomized trial finds the same result, this will provide a new option to slow progression of Parkinson’s disease.”
The pathogenesis of Parkinson’s disease is heterogeneous, however, and not all patients may benefit from glycolysis-enhancing drugs, the investigators noted. Future research will be needed to identify potential candidates for this treatment, and clarify the effects of these drugs, they wrote.
The findings were published online Feb. 1, 2021, in JAMA Neurology.
Time-dependent effects
The major risk factor for Parkinson’s disease is age, which is associated with impaired energy metabolism. Glycolysis is decreased among patients with Parkinson’s disease, yet impaired energy metabolism has not been investigated widely as a pathogenic factor in the disease, the authors wrote.
Studies have indicated that terazosin increases the activity of an enzyme important in glycolysis. Doxazosin and alfuzosin have a similar mechanism of action and enhance energy metabolism. Tamsulosin, a structurally unrelated drug, has the same mechanism of action as the other three drugs, but does not enhance energy metabolism.
In this report, the researchers investigated the hypothesis that patients who received therapy with terazosin, doxazosin, or alfuzosin would have a lower risk of developing Parkinson’s disease than patients receiving tamsulosin. To do that, they used health care utilization data from Denmark and the United States, including the Danish National Prescription Registry, the Danish National Patient Registry, the Danish Civil Registration System, and the Truven Health Analytics MarketScan database.
The investigators searched the records for patients who filled prescriptions for any of the four drugs of interest. They excluded any patients who developed Parkinson’s disease within 1 year of starting medication. Because use of these drugs is rare among women, they included only men in their analysis.
They looked at patient outcomes beginning at 1 year after the initiation of treatment. They also required patients to fill at least two prescriptions before the beginning of follow-up. Patients who switched from tamsulosin to any of the other drugs, or vice versa, were excluded from analysis.
The investigators used propensity-score matching to ensure that patients in the tamsulosin and terazosin/doxazosin/alfuzosin groups were similar in terms of their other potential risk factors. The primary outcome was the development of Parkinson’s disease.
They identified 52,365 propensity score–matched pairs in the Danish registries and 94,883 pairs in the Truven database. The mean age was 67.9 years in the Danish registries and 63.8 years in the Truven database, and follow-up was approximately 5 years and 3 years respectively. Baseline covariates were well balanced between cohorts.
Among Danish patients, those who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease versus those who took tamsulosin (hazard ratio, 0.88). Similarly, patients in the Truven database who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease than those who took tamsulosin (HR, 0.63).
In both cohorts, the risk for Parkinson’s disease among patients receiving terazosin, doxazosin, or alfuzosin, compared with those receiving tamsulosin, decreased with increasing numbers of prescriptions filled. Long-term treatment with any of the three glycolysis-enhancing drugs was associated with greater risk reduction in the Danish (HR, 0.79) and Truven (HR, 0.46) cohorts versus tamsulosin.
Differences in case definitions, which may reflect how Parkinson’s disease was managed, complicate comparisons between the Danish and Truven cohorts, said Dr. Simmering. Another challenge is the source of the data. “The Truven data set was derived from insurance claims from people with private insurance or Medicare supplemental plans,” he said. “This group is quite large but may not be representative of everyone in the United States. We would also only be able to follow people while they were on one insurance plan. If they switched coverage to a company that doesn’t contribute data, we would lose them.”
The Danish database, however, includes all residents of Denmark. Only people who left the country were lost to follow-up.
The results support the hypothesis that increasing energy in cells slows disease progression, Dr. Simmering added. “There are a few conditions, mostly REM sleep disorders, that are associated with future diagnosis of Parkinson’s disease. Right now, we don’t have anything to offer people at elevated risk of Parkinson’s disease that might prevent the disease. If a controlled trial finds that terazosin slows or prevents Parkinson’s disease, we would have something truly protective to offer these patients.”
Biomarker needed
Commenting on the results, Alberto J. Espay, MD, MSc, professor of neurology at the University of Cincinnati Academic Health Center, was cautious. “These findings are of unclear applicability to any particular patient without a biomarker for a deficit of glycolysis that these drugs are presumed to affect,” Dr. Espay said. “Hence, there is no feasible or warranted change in practice as a result of this study.”
Pathogenic mechanisms are heterogeneous among patients with Parkinson’s disease, Dr. Espay added. “We will need to understand who among the large biological universe of Parkinson’s patients may have impaired energy metabolism as a pathogenic mechanism to be selected for a future clinical trial evaluating terazosin, doxazosin, or alfuzosin as a potential disease-modifying intervention.”
Parkinson’s disease is not one disease, but a group of disorders with unique biological abnormalities, said Dr. Espay. “We know so much about ‘Parkinson’s disease’ and next to nothing about the biology of individuals with Parkinson’s disease.”
This situation has enabled the development of symptomatic treatments, such as dopaminergic therapies, but failed to yield disease-modifying treatments, he said.
The University of Iowa contributed funds for this study. Dr. Simmering has received pilot funding from the University of Iowa Institute for Clinical and Translational Science. He had no conflicts of interest to disclose. Dr. Espay disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY
Researchers examine factors associated with opioid use among migraineurs
Among patients with migraine who use prescription medications, the increasing use of prescription opioids is associated with chronic migraine, more severe disability, and anxiety and depression, according to an analysis published in the January issue of Headache . The use of prescription opioids also is associated with treatment-related variables such as poor acute treatment optimization and treatment in a pain clinic. The results indicate the continued need to educate patients and clinicians about the potential risks of opioids for migraineurs, according to the researchers.
In the Migraine in America Symptoms and Treatment (MAST) study, which the researchers analyzed for their investigation, one-third of migraineurs who use acute prescriptions reported using opioids. Among opioid users, 42% took opioids on 4 or more days per month. “These findings are like [those of] a previous report from the American Migraine Prevalence and Prevention study and more recent findings from the Observational Survey of the Epidemiology, Treatment, and Care of Migraine (OVERCOME) study,” said Richard Lipton, MD, Edwin S. Lowe professor and vice chair of neurology at Albert Einstein College of Medicine in the Bronx, New York. “High rates of opioid use are problematic because opioid use is associated with worsening of migraine over time.”
Opioids remain in widespread use for migraine, even though guidelines recommend against this treatment. Among migraineurs, opioid use is associated with more severe headache-related disability and greater use of health care resources. Opioid use also increases the risk of progressing from episodic migraine to chronic migraine.
A review of MAST data
Dr. Lipton and colleagues set out to identify the variables associated with the frequency of opioid use in people with migraine. Among the variables that they sought to examine were demographic characteristics, comorbidities, headache characteristics, medication use, and patterns of health care use. Dr. Lipton’s group hypothesized that migraine-related severity and burden would increase with increasing frequency of opioid use.
To conduct their research, the investigators examined data from the MAST study, a nationwide sample of American adults with migraine. They focused specifically on participants who reported receiving prescription acute medications. Participants eligible for this analysis reported 3 or more headache days in the previous 3 months and at least 1 monthly headache day in the previous month. In all, 15,133 participants met these criteria.
Dr. Lipton and colleagues categorized participants into four groups based on their frequency of opioid use. The groups had no opioid use, 3 or fewer monthly days of opioid use, 4 to 9 monthly days of opioid use, and 10 or more days of monthly opioid use. The last category is consistent with the International Classification of Headache Disorders-3 criteria for overuse of opioids in migraine.
At baseline, MAST participants provided information about variables such as gender, age, marital status, smoking status, education, and income. Participants also reported how many times in the previous 6 months they had visited a primary care doctor, a neurologist, a headache specialist, or a pain specialist. Dr. Lipton’s group calculated monthly headache days using the number of days during the previous 3 months affected by headache. The Migraine Disability Assessment (MIDAS) questionnaire was used to measure headache-related disability. The four-item Patient Health Questionnaire (PHQ-4) was used to screen for anxiety and depression, and the Migraine Treatment Optimization Questionnaire (mTOQ-4) evaluated participants’ treatment optimization.
Men predominated among opioid users
The investigators included 4,701 MAST participants in their analysis. The population’s mean age was 45 years, and 71.6% of participants were women. Of the entire sample, 67.5% reported no opioid use, and 32.5% reported opioid use. Of the total study population, 18.7% of patients took opioids 3 or fewer days per month, 6.5% took opioids 4 to 9 days per month, and 7.3% took opioids on 10 or more days per month.
Opioid users did not differ from nonusers on race or marital status. Men were overrepresented among all groups of opioid users, however. In addition, opioid use was more prevalent among participants with fewer than 4 years of college education (34.9%) than among participants with 4 or more years of college (30.8%). The proportion of participants with fewer than 4 years of college increased with increasing monthly opioid use. Furthermore, opioid use increased with decreasing household income. As opioid use increased, rates of employment decreased. Approximately 33% of the entire sample were obese, and the proportion of obese participants increased with increasing days per month of opioid use.
The most frequent setting during the previous 6 months for participants seeking care was primary care (49.7%). The next most frequent setting was neurology units (20.9%), pain clinics (8.3%), and headache clinics (7.7%). The prevalence of opioid use was 37.5% among participants with primary care visits, 37.3% among participants with neurologist visits, 43.0% among participants with headache clinic visits, and 53.5% with pain clinic visits.
About 15% of the population had chronic migraine. The prevalence of chronic migraine increased with increasing frequency of opioid use. About 49% of the sample had allodynia, and the prevalence of allodynia increased with increasing frequency of opioid use. Overall, disability was moderate to severe in 57.3% of participants. Participants who used opioids on 3 or fewer days per month had the lowest prevalence of moderate to severe disability (50.2%), and participants who used opioids on 10 or more days per month had the highest prevalence of moderate to severe disability (83.8%).
Approximately 21% of participants had anxiety or depression. The lowest prevalence of anxiety or depression was among participants who took opioids on 3 or fewer days per month (17.4%), and the highest prevalence was among participants who took opioids on 10 or more days per month (43.2%). About 39% of the population had very poor to poor treatment optimization. Among opioid nonusers, 35.6% had very poor to poor treatment optimization, and 59.4% of participants who used opioids on 10 or more days per month had very poor to poor treatment optimization.
Dr. Lipton and colleagues also examined the study population’s use of triptans. Overall, 51.5% of participants reported taking triptans. The prevalence of triptan use was highest among participants who did not use opioids (64.1%) and lowest among participants who used opioids on 3 or fewer days per month (20.5%). Triptan use increased as monthly days of opioid use increased.
Pain clinics and opioid prescription
“In the general population, women are more likely to receive opioids than men,” said Dr. Lipton. “This [finding] could reflect, in part, that women have more pain disorders than men and are more likely to seek medical care for pain than men.” In the current study, however, men with migraine were more likely to receive opioid prescriptions than were women with migraine. One potential explanation for this finding is that men with migraine are less likely to receive a migraine diagnosis, which might attenuate opioid prescribing, than women with migraine. “It may be that opioids are perceived to be serious drugs for serious pain, and that some physicians may be more likely to prescribe opioids to men because the disorder is taken more seriously in men than women,” said Dr. Lipton.
The observation that opioids were more likely to be prescribed for people treated in pain clinics “is consistent with my understanding of practice patterns,” he added. “Generally, neurologists strive to find effective acute treatment alternatives to opioids. The emergence of [drug classes known as] gepants and ditans provides a helpful set of alternatives to tritpans.”
Dr. Lipton and his colleagues plan further research into the treatment of migraineurs. “In a claims analysis, we showed that when people with migraine fail a triptan, they are most likely to get an opioid as their next drug,” he said. “Reasonable [clinicians] might disagree on the next step. The next step, in the absence of contraindications, could be a different oral triptan, a nonoral triptan, or a gepant or ditan. We are planning a randomized trial to probe this question.”
Why are opioids still being used?
The study’s reliance on patients’ self-report and its retrospective design are two of its weaknesses, said Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews. One strength, however, is that the stratified sampling methodology produced a study population that accurately reflects the demographic characteristics of the U.S. adult population, he added. Another strength is the investigators’ examination of opioid use by patient characteristics such as marital status, education, income, obesity, and smoking.
Given the harmful effects of opioids in migraine, it is hard to understand why as much as one-third of study participants using acute care medication for migraine were using opioids, said Dr. Rapoport. Using opioids for the acute treatment of migraine attacks often indicates inadequate treatment optimization, which leads to ongoing headache. As a consequence, patients may take more medication, which can increase headache frequency and lead to diagnoses of chronic migraine and medication overuse headache. Although the study found an association between the increased use of opioids and decreased household income and increased unemployment, smoking, and obesity, “it is not possible to assign causality to any of these associations, even though some would argue that decreased socioeconomic status was somehow related to more headache, disability, obesity, smoking, and unemployment,” he added.
“The paper suggests that future research should look at the risk factors for use of opioids and should determine if depression is a risk factor for or a consequence of opioid use,” said Dr. Rapoport. “Interventional studies designed to improve the acute care of migraine attacks might be able to reduce the use of opioids. I have not used opioids or butalbital-containing medication in my office for many years.”
This study was funded and sponsored by Dr. Reddy’s Laboratories group of companies, Princeton, N.J. Dr. Lipton has received grant support from the National Institutes of Health, the National Headache Foundation, and the Migraine Research Fund. He serves as a consultant, serves as an advisory board member, or has received honoraria from Alder, Allergan, American Headache Society, Autonomic Technologies, Biohaven, Dr. Reddy’s Laboratories, Eli Lilly, eNeura Therapeutics, Merck, Novartis, Pfizer, and Teva, Inc. He receives royalties from Wolff’s Headache, 8th Edition (New York: Oxford University Press, 2009) and holds stock options in eNeura Therapeutics and Biohaven.
SOURCE: Lipton RB, et al. Headache. https://doi.org/10.1111/head.14018. 2020;61(1):103-16.
Among patients with migraine who use prescription medications, the increasing use of prescription opioids is associated with chronic migraine, more severe disability, and anxiety and depression, according to an analysis published in the January issue of Headache . The use of prescription opioids also is associated with treatment-related variables such as poor acute treatment optimization and treatment in a pain clinic. The results indicate the continued need to educate patients and clinicians about the potential risks of opioids for migraineurs, according to the researchers.
In the Migraine in America Symptoms and Treatment (MAST) study, which the researchers analyzed for their investigation, one-third of migraineurs who use acute prescriptions reported using opioids. Among opioid users, 42% took opioids on 4 or more days per month. “These findings are like [those of] a previous report from the American Migraine Prevalence and Prevention study and more recent findings from the Observational Survey of the Epidemiology, Treatment, and Care of Migraine (OVERCOME) study,” said Richard Lipton, MD, Edwin S. Lowe professor and vice chair of neurology at Albert Einstein College of Medicine in the Bronx, New York. “High rates of opioid use are problematic because opioid use is associated with worsening of migraine over time.”
Opioids remain in widespread use for migraine, even though guidelines recommend against this treatment. Among migraineurs, opioid use is associated with more severe headache-related disability and greater use of health care resources. Opioid use also increases the risk of progressing from episodic migraine to chronic migraine.
A review of MAST data
Dr. Lipton and colleagues set out to identify the variables associated with the frequency of opioid use in people with migraine. Among the variables that they sought to examine were demographic characteristics, comorbidities, headache characteristics, medication use, and patterns of health care use. Dr. Lipton’s group hypothesized that migraine-related severity and burden would increase with increasing frequency of opioid use.
To conduct their research, the investigators examined data from the MAST study, a nationwide sample of American adults with migraine. They focused specifically on participants who reported receiving prescription acute medications. Participants eligible for this analysis reported 3 or more headache days in the previous 3 months and at least 1 monthly headache day in the previous month. In all, 15,133 participants met these criteria.
Dr. Lipton and colleagues categorized participants into four groups based on their frequency of opioid use. The groups had no opioid use, 3 or fewer monthly days of opioid use, 4 to 9 monthly days of opioid use, and 10 or more days of monthly opioid use. The last category is consistent with the International Classification of Headache Disorders-3 criteria for overuse of opioids in migraine.
At baseline, MAST participants provided information about variables such as gender, age, marital status, smoking status, education, and income. Participants also reported how many times in the previous 6 months they had visited a primary care doctor, a neurologist, a headache specialist, or a pain specialist. Dr. Lipton’s group calculated monthly headache days using the number of days during the previous 3 months affected by headache. The Migraine Disability Assessment (MIDAS) questionnaire was used to measure headache-related disability. The four-item Patient Health Questionnaire (PHQ-4) was used to screen for anxiety and depression, and the Migraine Treatment Optimization Questionnaire (mTOQ-4) evaluated participants’ treatment optimization.
Men predominated among opioid users
The investigators included 4,701 MAST participants in their analysis. The population’s mean age was 45 years, and 71.6% of participants were women. Of the entire sample, 67.5% reported no opioid use, and 32.5% reported opioid use. Of the total study population, 18.7% of patients took opioids 3 or fewer days per month, 6.5% took opioids 4 to 9 days per month, and 7.3% took opioids on 10 or more days per month.
Opioid users did not differ from nonusers on race or marital status. Men were overrepresented among all groups of opioid users, however. In addition, opioid use was more prevalent among participants with fewer than 4 years of college education (34.9%) than among participants with 4 or more years of college (30.8%). The proportion of participants with fewer than 4 years of college increased with increasing monthly opioid use. Furthermore, opioid use increased with decreasing household income. As opioid use increased, rates of employment decreased. Approximately 33% of the entire sample were obese, and the proportion of obese participants increased with increasing days per month of opioid use.
The most frequent setting during the previous 6 months for participants seeking care was primary care (49.7%). The next most frequent setting was neurology units (20.9%), pain clinics (8.3%), and headache clinics (7.7%). The prevalence of opioid use was 37.5% among participants with primary care visits, 37.3% among participants with neurologist visits, 43.0% among participants with headache clinic visits, and 53.5% with pain clinic visits.
About 15% of the population had chronic migraine. The prevalence of chronic migraine increased with increasing frequency of opioid use. About 49% of the sample had allodynia, and the prevalence of allodynia increased with increasing frequency of opioid use. Overall, disability was moderate to severe in 57.3% of participants. Participants who used opioids on 3 or fewer days per month had the lowest prevalence of moderate to severe disability (50.2%), and participants who used opioids on 10 or more days per month had the highest prevalence of moderate to severe disability (83.8%).
Approximately 21% of participants had anxiety or depression. The lowest prevalence of anxiety or depression was among participants who took opioids on 3 or fewer days per month (17.4%), and the highest prevalence was among participants who took opioids on 10 or more days per month (43.2%). About 39% of the population had very poor to poor treatment optimization. Among opioid nonusers, 35.6% had very poor to poor treatment optimization, and 59.4% of participants who used opioids on 10 or more days per month had very poor to poor treatment optimization.
Dr. Lipton and colleagues also examined the study population’s use of triptans. Overall, 51.5% of participants reported taking triptans. The prevalence of triptan use was highest among participants who did not use opioids (64.1%) and lowest among participants who used opioids on 3 or fewer days per month (20.5%). Triptan use increased as monthly days of opioid use increased.
Pain clinics and opioid prescription
“In the general population, women are more likely to receive opioids than men,” said Dr. Lipton. “This [finding] could reflect, in part, that women have more pain disorders than men and are more likely to seek medical care for pain than men.” In the current study, however, men with migraine were more likely to receive opioid prescriptions than were women with migraine. One potential explanation for this finding is that men with migraine are less likely to receive a migraine diagnosis, which might attenuate opioid prescribing, than women with migraine. “It may be that opioids are perceived to be serious drugs for serious pain, and that some physicians may be more likely to prescribe opioids to men because the disorder is taken more seriously in men than women,” said Dr. Lipton.
The observation that opioids were more likely to be prescribed for people treated in pain clinics “is consistent with my understanding of practice patterns,” he added. “Generally, neurologists strive to find effective acute treatment alternatives to opioids. The emergence of [drug classes known as] gepants and ditans provides a helpful set of alternatives to tritpans.”
Dr. Lipton and his colleagues plan further research into the treatment of migraineurs. “In a claims analysis, we showed that when people with migraine fail a triptan, they are most likely to get an opioid as their next drug,” he said. “Reasonable [clinicians] might disagree on the next step. The next step, in the absence of contraindications, could be a different oral triptan, a nonoral triptan, or a gepant or ditan. We are planning a randomized trial to probe this question.”
Why are opioids still being used?
The study’s reliance on patients’ self-report and its retrospective design are two of its weaknesses, said Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews. One strength, however, is that the stratified sampling methodology produced a study population that accurately reflects the demographic characteristics of the U.S. adult population, he added. Another strength is the investigators’ examination of opioid use by patient characteristics such as marital status, education, income, obesity, and smoking.
Given the harmful effects of opioids in migraine, it is hard to understand why as much as one-third of study participants using acute care medication for migraine were using opioids, said Dr. Rapoport. Using opioids for the acute treatment of migraine attacks often indicates inadequate treatment optimization, which leads to ongoing headache. As a consequence, patients may take more medication, which can increase headache frequency and lead to diagnoses of chronic migraine and medication overuse headache. Although the study found an association between the increased use of opioids and decreased household income and increased unemployment, smoking, and obesity, “it is not possible to assign causality to any of these associations, even though some would argue that decreased socioeconomic status was somehow related to more headache, disability, obesity, smoking, and unemployment,” he added.
“The paper suggests that future research should look at the risk factors for use of opioids and should determine if depression is a risk factor for or a consequence of opioid use,” said Dr. Rapoport. “Interventional studies designed to improve the acute care of migraine attacks might be able to reduce the use of opioids. I have not used opioids or butalbital-containing medication in my office for many years.”
This study was funded and sponsored by Dr. Reddy’s Laboratories group of companies, Princeton, N.J. Dr. Lipton has received grant support from the National Institutes of Health, the National Headache Foundation, and the Migraine Research Fund. He serves as a consultant, serves as an advisory board member, or has received honoraria from Alder, Allergan, American Headache Society, Autonomic Technologies, Biohaven, Dr. Reddy’s Laboratories, Eli Lilly, eNeura Therapeutics, Merck, Novartis, Pfizer, and Teva, Inc. He receives royalties from Wolff’s Headache, 8th Edition (New York: Oxford University Press, 2009) and holds stock options in eNeura Therapeutics and Biohaven.
SOURCE: Lipton RB, et al. Headache. https://doi.org/10.1111/head.14018. 2020;61(1):103-16.
Among patients with migraine who use prescription medications, the increasing use of prescription opioids is associated with chronic migraine, more severe disability, and anxiety and depression, according to an analysis published in the January issue of Headache . The use of prescription opioids also is associated with treatment-related variables such as poor acute treatment optimization and treatment in a pain clinic. The results indicate the continued need to educate patients and clinicians about the potential risks of opioids for migraineurs, according to the researchers.
In the Migraine in America Symptoms and Treatment (MAST) study, which the researchers analyzed for their investigation, one-third of migraineurs who use acute prescriptions reported using opioids. Among opioid users, 42% took opioids on 4 or more days per month. “These findings are like [those of] a previous report from the American Migraine Prevalence and Prevention study and more recent findings from the Observational Survey of the Epidemiology, Treatment, and Care of Migraine (OVERCOME) study,” said Richard Lipton, MD, Edwin S. Lowe professor and vice chair of neurology at Albert Einstein College of Medicine in the Bronx, New York. “High rates of opioid use are problematic because opioid use is associated with worsening of migraine over time.”
Opioids remain in widespread use for migraine, even though guidelines recommend against this treatment. Among migraineurs, opioid use is associated with more severe headache-related disability and greater use of health care resources. Opioid use also increases the risk of progressing from episodic migraine to chronic migraine.
A review of MAST data
Dr. Lipton and colleagues set out to identify the variables associated with the frequency of opioid use in people with migraine. Among the variables that they sought to examine were demographic characteristics, comorbidities, headache characteristics, medication use, and patterns of health care use. Dr. Lipton’s group hypothesized that migraine-related severity and burden would increase with increasing frequency of opioid use.
To conduct their research, the investigators examined data from the MAST study, a nationwide sample of American adults with migraine. They focused specifically on participants who reported receiving prescription acute medications. Participants eligible for this analysis reported 3 or more headache days in the previous 3 months and at least 1 monthly headache day in the previous month. In all, 15,133 participants met these criteria.
Dr. Lipton and colleagues categorized participants into four groups based on their frequency of opioid use. The groups had no opioid use, 3 or fewer monthly days of opioid use, 4 to 9 monthly days of opioid use, and 10 or more days of monthly opioid use. The last category is consistent with the International Classification of Headache Disorders-3 criteria for overuse of opioids in migraine.
At baseline, MAST participants provided information about variables such as gender, age, marital status, smoking status, education, and income. Participants also reported how many times in the previous 6 months they had visited a primary care doctor, a neurologist, a headache specialist, or a pain specialist. Dr. Lipton’s group calculated monthly headache days using the number of days during the previous 3 months affected by headache. The Migraine Disability Assessment (MIDAS) questionnaire was used to measure headache-related disability. The four-item Patient Health Questionnaire (PHQ-4) was used to screen for anxiety and depression, and the Migraine Treatment Optimization Questionnaire (mTOQ-4) evaluated participants’ treatment optimization.
Men predominated among opioid users
The investigators included 4,701 MAST participants in their analysis. The population’s mean age was 45 years, and 71.6% of participants were women. Of the entire sample, 67.5% reported no opioid use, and 32.5% reported opioid use. Of the total study population, 18.7% of patients took opioids 3 or fewer days per month, 6.5% took opioids 4 to 9 days per month, and 7.3% took opioids on 10 or more days per month.
Opioid users did not differ from nonusers on race or marital status. Men were overrepresented among all groups of opioid users, however. In addition, opioid use was more prevalent among participants with fewer than 4 years of college education (34.9%) than among participants with 4 or more years of college (30.8%). The proportion of participants with fewer than 4 years of college increased with increasing monthly opioid use. Furthermore, opioid use increased with decreasing household income. As opioid use increased, rates of employment decreased. Approximately 33% of the entire sample were obese, and the proportion of obese participants increased with increasing days per month of opioid use.
The most frequent setting during the previous 6 months for participants seeking care was primary care (49.7%). The next most frequent setting was neurology units (20.9%), pain clinics (8.3%), and headache clinics (7.7%). The prevalence of opioid use was 37.5% among participants with primary care visits, 37.3% among participants with neurologist visits, 43.0% among participants with headache clinic visits, and 53.5% with pain clinic visits.
About 15% of the population had chronic migraine. The prevalence of chronic migraine increased with increasing frequency of opioid use. About 49% of the sample had allodynia, and the prevalence of allodynia increased with increasing frequency of opioid use. Overall, disability was moderate to severe in 57.3% of participants. Participants who used opioids on 3 or fewer days per month had the lowest prevalence of moderate to severe disability (50.2%), and participants who used opioids on 10 or more days per month had the highest prevalence of moderate to severe disability (83.8%).
Approximately 21% of participants had anxiety or depression. The lowest prevalence of anxiety or depression was among participants who took opioids on 3 or fewer days per month (17.4%), and the highest prevalence was among participants who took opioids on 10 or more days per month (43.2%). About 39% of the population had very poor to poor treatment optimization. Among opioid nonusers, 35.6% had very poor to poor treatment optimization, and 59.4% of participants who used opioids on 10 or more days per month had very poor to poor treatment optimization.
Dr. Lipton and colleagues also examined the study population’s use of triptans. Overall, 51.5% of participants reported taking triptans. The prevalence of triptan use was highest among participants who did not use opioids (64.1%) and lowest among participants who used opioids on 3 or fewer days per month (20.5%). Triptan use increased as monthly days of opioid use increased.
Pain clinics and opioid prescription
“In the general population, women are more likely to receive opioids than men,” said Dr. Lipton. “This [finding] could reflect, in part, that women have more pain disorders than men and are more likely to seek medical care for pain than men.” In the current study, however, men with migraine were more likely to receive opioid prescriptions than were women with migraine. One potential explanation for this finding is that men with migraine are less likely to receive a migraine diagnosis, which might attenuate opioid prescribing, than women with migraine. “It may be that opioids are perceived to be serious drugs for serious pain, and that some physicians may be more likely to prescribe opioids to men because the disorder is taken more seriously in men than women,” said Dr. Lipton.
The observation that opioids were more likely to be prescribed for people treated in pain clinics “is consistent with my understanding of practice patterns,” he added. “Generally, neurologists strive to find effective acute treatment alternatives to opioids. The emergence of [drug classes known as] gepants and ditans provides a helpful set of alternatives to tritpans.”
Dr. Lipton and his colleagues plan further research into the treatment of migraineurs. “In a claims analysis, we showed that when people with migraine fail a triptan, they are most likely to get an opioid as their next drug,” he said. “Reasonable [clinicians] might disagree on the next step. The next step, in the absence of contraindications, could be a different oral triptan, a nonoral triptan, or a gepant or ditan. We are planning a randomized trial to probe this question.”
Why are opioids still being used?
The study’s reliance on patients’ self-report and its retrospective design are two of its weaknesses, said Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews. One strength, however, is that the stratified sampling methodology produced a study population that accurately reflects the demographic characteristics of the U.S. adult population, he added. Another strength is the investigators’ examination of opioid use by patient characteristics such as marital status, education, income, obesity, and smoking.
Given the harmful effects of opioids in migraine, it is hard to understand why as much as one-third of study participants using acute care medication for migraine were using opioids, said Dr. Rapoport. Using opioids for the acute treatment of migraine attacks often indicates inadequate treatment optimization, which leads to ongoing headache. As a consequence, patients may take more medication, which can increase headache frequency and lead to diagnoses of chronic migraine and medication overuse headache. Although the study found an association between the increased use of opioids and decreased household income and increased unemployment, smoking, and obesity, “it is not possible to assign causality to any of these associations, even though some would argue that decreased socioeconomic status was somehow related to more headache, disability, obesity, smoking, and unemployment,” he added.
“The paper suggests that future research should look at the risk factors for use of opioids and should determine if depression is a risk factor for or a consequence of opioid use,” said Dr. Rapoport. “Interventional studies designed to improve the acute care of migraine attacks might be able to reduce the use of opioids. I have not used opioids or butalbital-containing medication in my office for many years.”
This study was funded and sponsored by Dr. Reddy’s Laboratories group of companies, Princeton, N.J. Dr. Lipton has received grant support from the National Institutes of Health, the National Headache Foundation, and the Migraine Research Fund. He serves as a consultant, serves as an advisory board member, or has received honoraria from Alder, Allergan, American Headache Society, Autonomic Technologies, Biohaven, Dr. Reddy’s Laboratories, Eli Lilly, eNeura Therapeutics, Merck, Novartis, Pfizer, and Teva, Inc. He receives royalties from Wolff’s Headache, 8th Edition (New York: Oxford University Press, 2009) and holds stock options in eNeura Therapeutics and Biohaven.
SOURCE: Lipton RB, et al. Headache. https://doi.org/10.1111/head.14018. 2020;61(1):103-16.
FROM HEADACHE
PFO closure reduces migraine: New meta-analysis
A meta-analysis of two randomized studies evaluating patent foramen ovale (PFO) closure as a treatment strategy for migraine has shown significant benefits in several key endpoints, prompting the authors to conclude the approach warrants reevaluation.
The pooled analysis of patient-level data from the PRIMA and PREMIUM studies, both of which evaluated the Amplatzer PFO Occluder device (Abbott Vascular), showed that
The study, led by Mohammad K. Mojadidi, MD, Virginia Commonwealth University, Richmond, was published online in the Journal of the American College of Cardiology on Feb. 8, 2021.
Commenting on the article, the coauthor of an accompanying editorial, Zubair Ahmed, MD, of the Cleveland Clinic said the meta-analysis gave some useful new information but is not enough to recommend PFO closure routinely for patients with migraine.
“This meta-analysis looked at different endpoints that are more relevant to current clinical practice than those in the two original studies, and the results show that we shouldn’t rule out PFO closure as a treatment strategy for some migraine patients,” Dr. Ahmed stated. “But we’re still not sure exactly which patients are most likely to benefit from this approach, and we need additional studies to gain more understanding on that.”
The study authors noted that there is an established link between the presence of PFO and migraine, especially migraine with aura. In observational studies of PFO closure for cryptogenic stroke, the vast majority of patients who also had migraine reported a more than 50% reduction in migraine days per month after PFO closure.
However, two recent randomized clinical trials evaluating the Amplatzer PFO Occluder device for reducing the frequency and duration of episodic migraine headaches did not meet their respective primary endpoints, although they did show significant benefit of PFO closure in most of their secondary endpoints.
The current meta-analysis pooled individual participant data from the two trials to increase the power to detect the effect of percutaneous PFO closure for treating patients with episodic migraine compared with medical therapy alone.
In the two studies including a total of 337 patients, 176 were randomized to PFO closure and 161 to medical treatment only. At 12 months, three of the four efficacy endpoints evaluated in the meta-analysis were significantly reduced in the PFO-closure group. These were mean reduction of monthly migraine days (–3.1 days vs. –1.9 days; P = .02), mean reduction of monthly migraine attacks (–2.0 vs. –1.4; P = .01), and number of patients who experienced complete cessation of migraine (9% vs. 0.7%; P < .001).
The responder rate, defined as more than a 50% reduction in migraine attacks, showed a trend towards an increase in the PFO-closure group but did not achieve statistical significance (38% vs. 29%; P = .13).
For the safety analysis, nine procedure-related and four device-related adverse events occurred in 245 patients who eventually received devices. All events were transient and resolved.
Better effect in patients with aura
Patients with migraine with aura, in particular frequent aura, had a significantly greater reduction in migraine days and a higher incidence of complete migraine cessation following PFO closure versus no closure, the authors reported.
In those without aura, PFO closure did not significantly reduce migraine days or improve complete headache cessation. However, some patients without aura did respond to PFO closure, which was statistically significant for reduction of migraine attacks (–2.0 vs. –1.0; P = .03).
“The interaction between the brain that is susceptible to migraine and the plethora of potential triggers is complex. A PFO may be the potential pathway for a variety of chemical triggers, such as serotonin from platelets, and although less frequent, some people with migraine without aura may trigger their migraine through this mechanism,” the researchers suggested. This hypothesis will be tested in the RELIEF trial, which is now being planned.
In the accompanying editorial, Dr. Ahmed and coauthor Robert J. Sommer, MD, Columbia University Medical Center, New York, pointed out that the meta-analysis demonstrates benefit of PFO closure in the migraine population for the first time.
“Moreover, the investigators defined a population of patients who may benefit most from PFO closure, those with migraine with frequent aura, suggesting that these may be different physiologically than other migraine subtypes. The analysis also places the PRIMA and PREMIUM outcomes in the context of endpoints that are more practical and are more commonly assessed in current clinical trials,” the editorialists noted.
Many unanswered questions
But the editorialists highlighted several significant limitations of the analysis, including “pooling of patient cohorts, methods, and outcome measures that might not be entirely comparable,” which they say could have introduced bias.
They also pointed out that the underlying pathophysiological mechanism linking migraine symptoms to PFO remains unknown. They explain that the mechanism is thought to involve the right-to-left passage of systemic venous blood, with some component – which would normally be eliminated or reduced on passage through the pulmonary vasculature – reaching the cerebral circulation via the PFO in supranormal concentrations and acting as a trigger for migraine activity in patients with susceptible brains.
But not all patients with migraine who have PFO benefit from PFO closure, they noted, and therefore presumably have PFO-unrelated migraines. There is no verified way to distinguish between these two groups at present.
“Once we learn to identify the subset of migraine patients in whom PFOs are actually causal of headache symptoms, screening and treatment of PFO for migraine can become a reality,” they wrote.
Although the meta-analysis is a step in the right direction, “it is not a home run,” Dr. Ahmed elaborated. “This was a post hoc analysis of two studies, neither of which showed significant benefits on their primary endpoints. That weakens the findings somewhat.”
He added: “At present, PFO closure is not routinely recommended as a migraine treatment strategy as we haven’t been sure which patients are most likely to benefit. And while this meta-analysis suggests patients with aura may be more likely to benefit, one quarter of patients without aura in the PREMIUM trial responded to PFO closure, so it’s not just about aura.
“There are still many unanswered questions.
“I don’t think the new information from this meta-analysis is enough to persuade me to change my practice, but it is a small building block in the overall picture and suggests this may be a suitable strategy for some patients in future,” he concluded.
The study had no outside funding. Participant-level data were provided by Abbott. Several coauthors were on the steering committee for the PREMIUM or PRIMA trials. Dr. Ahmed reported receiving consulting fees from, Amgen, AbbVie, electroCore, and Eli Lilly; serving on advisory boards for Amgen and Supernus; serving as a speaker for AbbVie; and receiving funding for an investigator-initiated trial from Teva and Eli Lilly.
A version of this article first appeared on Medscape.com.
A meta-analysis of two randomized studies evaluating patent foramen ovale (PFO) closure as a treatment strategy for migraine has shown significant benefits in several key endpoints, prompting the authors to conclude the approach warrants reevaluation.
The pooled analysis of patient-level data from the PRIMA and PREMIUM studies, both of which evaluated the Amplatzer PFO Occluder device (Abbott Vascular), showed that
The study, led by Mohammad K. Mojadidi, MD, Virginia Commonwealth University, Richmond, was published online in the Journal of the American College of Cardiology on Feb. 8, 2021.
Commenting on the article, the coauthor of an accompanying editorial, Zubair Ahmed, MD, of the Cleveland Clinic said the meta-analysis gave some useful new information but is not enough to recommend PFO closure routinely for patients with migraine.
“This meta-analysis looked at different endpoints that are more relevant to current clinical practice than those in the two original studies, and the results show that we shouldn’t rule out PFO closure as a treatment strategy for some migraine patients,” Dr. Ahmed stated. “But we’re still not sure exactly which patients are most likely to benefit from this approach, and we need additional studies to gain more understanding on that.”
The study authors noted that there is an established link between the presence of PFO and migraine, especially migraine with aura. In observational studies of PFO closure for cryptogenic stroke, the vast majority of patients who also had migraine reported a more than 50% reduction in migraine days per month after PFO closure.
However, two recent randomized clinical trials evaluating the Amplatzer PFO Occluder device for reducing the frequency and duration of episodic migraine headaches did not meet their respective primary endpoints, although they did show significant benefit of PFO closure in most of their secondary endpoints.
The current meta-analysis pooled individual participant data from the two trials to increase the power to detect the effect of percutaneous PFO closure for treating patients with episodic migraine compared with medical therapy alone.
In the two studies including a total of 337 patients, 176 were randomized to PFO closure and 161 to medical treatment only. At 12 months, three of the four efficacy endpoints evaluated in the meta-analysis were significantly reduced in the PFO-closure group. These were mean reduction of monthly migraine days (–3.1 days vs. –1.9 days; P = .02), mean reduction of monthly migraine attacks (–2.0 vs. –1.4; P = .01), and number of patients who experienced complete cessation of migraine (9% vs. 0.7%; P < .001).
The responder rate, defined as more than a 50% reduction in migraine attacks, showed a trend towards an increase in the PFO-closure group but did not achieve statistical significance (38% vs. 29%; P = .13).
For the safety analysis, nine procedure-related and four device-related adverse events occurred in 245 patients who eventually received devices. All events were transient and resolved.
Better effect in patients with aura
Patients with migraine with aura, in particular frequent aura, had a significantly greater reduction in migraine days and a higher incidence of complete migraine cessation following PFO closure versus no closure, the authors reported.
In those without aura, PFO closure did not significantly reduce migraine days or improve complete headache cessation. However, some patients without aura did respond to PFO closure, which was statistically significant for reduction of migraine attacks (–2.0 vs. –1.0; P = .03).
“The interaction between the brain that is susceptible to migraine and the plethora of potential triggers is complex. A PFO may be the potential pathway for a variety of chemical triggers, such as serotonin from platelets, and although less frequent, some people with migraine without aura may trigger their migraine through this mechanism,” the researchers suggested. This hypothesis will be tested in the RELIEF trial, which is now being planned.
In the accompanying editorial, Dr. Ahmed and coauthor Robert J. Sommer, MD, Columbia University Medical Center, New York, pointed out that the meta-analysis demonstrates benefit of PFO closure in the migraine population for the first time.
“Moreover, the investigators defined a population of patients who may benefit most from PFO closure, those with migraine with frequent aura, suggesting that these may be different physiologically than other migraine subtypes. The analysis also places the PRIMA and PREMIUM outcomes in the context of endpoints that are more practical and are more commonly assessed in current clinical trials,” the editorialists noted.
Many unanswered questions
But the editorialists highlighted several significant limitations of the analysis, including “pooling of patient cohorts, methods, and outcome measures that might not be entirely comparable,” which they say could have introduced bias.
They also pointed out that the underlying pathophysiological mechanism linking migraine symptoms to PFO remains unknown. They explain that the mechanism is thought to involve the right-to-left passage of systemic venous blood, with some component – which would normally be eliminated or reduced on passage through the pulmonary vasculature – reaching the cerebral circulation via the PFO in supranormal concentrations and acting as a trigger for migraine activity in patients with susceptible brains.
But not all patients with migraine who have PFO benefit from PFO closure, they noted, and therefore presumably have PFO-unrelated migraines. There is no verified way to distinguish between these two groups at present.
“Once we learn to identify the subset of migraine patients in whom PFOs are actually causal of headache symptoms, screening and treatment of PFO for migraine can become a reality,” they wrote.
Although the meta-analysis is a step in the right direction, “it is not a home run,” Dr. Ahmed elaborated. “This was a post hoc analysis of two studies, neither of which showed significant benefits on their primary endpoints. That weakens the findings somewhat.”
He added: “At present, PFO closure is not routinely recommended as a migraine treatment strategy as we haven’t been sure which patients are most likely to benefit. And while this meta-analysis suggests patients with aura may be more likely to benefit, one quarter of patients without aura in the PREMIUM trial responded to PFO closure, so it’s not just about aura.
“There are still many unanswered questions.
“I don’t think the new information from this meta-analysis is enough to persuade me to change my practice, but it is a small building block in the overall picture and suggests this may be a suitable strategy for some patients in future,” he concluded.
The study had no outside funding. Participant-level data were provided by Abbott. Several coauthors were on the steering committee for the PREMIUM or PRIMA trials. Dr. Ahmed reported receiving consulting fees from, Amgen, AbbVie, electroCore, and Eli Lilly; serving on advisory boards for Amgen and Supernus; serving as a speaker for AbbVie; and receiving funding for an investigator-initiated trial from Teva and Eli Lilly.
A version of this article first appeared on Medscape.com.
A meta-analysis of two randomized studies evaluating patent foramen ovale (PFO) closure as a treatment strategy for migraine has shown significant benefits in several key endpoints, prompting the authors to conclude the approach warrants reevaluation.
The pooled analysis of patient-level data from the PRIMA and PREMIUM studies, both of which evaluated the Amplatzer PFO Occluder device (Abbott Vascular), showed that
The study, led by Mohammad K. Mojadidi, MD, Virginia Commonwealth University, Richmond, was published online in the Journal of the American College of Cardiology on Feb. 8, 2021.
Commenting on the article, the coauthor of an accompanying editorial, Zubair Ahmed, MD, of the Cleveland Clinic said the meta-analysis gave some useful new information but is not enough to recommend PFO closure routinely for patients with migraine.
“This meta-analysis looked at different endpoints that are more relevant to current clinical practice than those in the two original studies, and the results show that we shouldn’t rule out PFO closure as a treatment strategy for some migraine patients,” Dr. Ahmed stated. “But we’re still not sure exactly which patients are most likely to benefit from this approach, and we need additional studies to gain more understanding on that.”
The study authors noted that there is an established link between the presence of PFO and migraine, especially migraine with aura. In observational studies of PFO closure for cryptogenic stroke, the vast majority of patients who also had migraine reported a more than 50% reduction in migraine days per month after PFO closure.
However, two recent randomized clinical trials evaluating the Amplatzer PFO Occluder device for reducing the frequency and duration of episodic migraine headaches did not meet their respective primary endpoints, although they did show significant benefit of PFO closure in most of their secondary endpoints.
The current meta-analysis pooled individual participant data from the two trials to increase the power to detect the effect of percutaneous PFO closure for treating patients with episodic migraine compared with medical therapy alone.
In the two studies including a total of 337 patients, 176 were randomized to PFO closure and 161 to medical treatment only. At 12 months, three of the four efficacy endpoints evaluated in the meta-analysis were significantly reduced in the PFO-closure group. These were mean reduction of monthly migraine days (–3.1 days vs. –1.9 days; P = .02), mean reduction of monthly migraine attacks (–2.0 vs. –1.4; P = .01), and number of patients who experienced complete cessation of migraine (9% vs. 0.7%; P < .001).
The responder rate, defined as more than a 50% reduction in migraine attacks, showed a trend towards an increase in the PFO-closure group but did not achieve statistical significance (38% vs. 29%; P = .13).
For the safety analysis, nine procedure-related and four device-related adverse events occurred in 245 patients who eventually received devices. All events were transient and resolved.
Better effect in patients with aura
Patients with migraine with aura, in particular frequent aura, had a significantly greater reduction in migraine days and a higher incidence of complete migraine cessation following PFO closure versus no closure, the authors reported.
In those without aura, PFO closure did not significantly reduce migraine days or improve complete headache cessation. However, some patients without aura did respond to PFO closure, which was statistically significant for reduction of migraine attacks (–2.0 vs. –1.0; P = .03).
“The interaction between the brain that is susceptible to migraine and the plethora of potential triggers is complex. A PFO may be the potential pathway for a variety of chemical triggers, such as serotonin from platelets, and although less frequent, some people with migraine without aura may trigger their migraine through this mechanism,” the researchers suggested. This hypothesis will be tested in the RELIEF trial, which is now being planned.
In the accompanying editorial, Dr. Ahmed and coauthor Robert J. Sommer, MD, Columbia University Medical Center, New York, pointed out that the meta-analysis demonstrates benefit of PFO closure in the migraine population for the first time.
“Moreover, the investigators defined a population of patients who may benefit most from PFO closure, those with migraine with frequent aura, suggesting that these may be different physiologically than other migraine subtypes. The analysis also places the PRIMA and PREMIUM outcomes in the context of endpoints that are more practical and are more commonly assessed in current clinical trials,” the editorialists noted.
Many unanswered questions
But the editorialists highlighted several significant limitations of the analysis, including “pooling of patient cohorts, methods, and outcome measures that might not be entirely comparable,” which they say could have introduced bias.
They also pointed out that the underlying pathophysiological mechanism linking migraine symptoms to PFO remains unknown. They explain that the mechanism is thought to involve the right-to-left passage of systemic venous blood, with some component – which would normally be eliminated or reduced on passage through the pulmonary vasculature – reaching the cerebral circulation via the PFO in supranormal concentrations and acting as a trigger for migraine activity in patients with susceptible brains.
But not all patients with migraine who have PFO benefit from PFO closure, they noted, and therefore presumably have PFO-unrelated migraines. There is no verified way to distinguish between these two groups at present.
“Once we learn to identify the subset of migraine patients in whom PFOs are actually causal of headache symptoms, screening and treatment of PFO for migraine can become a reality,” they wrote.
Although the meta-analysis is a step in the right direction, “it is not a home run,” Dr. Ahmed elaborated. “This was a post hoc analysis of two studies, neither of which showed significant benefits on their primary endpoints. That weakens the findings somewhat.”
He added: “At present, PFO closure is not routinely recommended as a migraine treatment strategy as we haven’t been sure which patients are most likely to benefit. And while this meta-analysis suggests patients with aura may be more likely to benefit, one quarter of patients without aura in the PREMIUM trial responded to PFO closure, so it’s not just about aura.
“There are still many unanswered questions.
“I don’t think the new information from this meta-analysis is enough to persuade me to change my practice, but it is a small building block in the overall picture and suggests this may be a suitable strategy for some patients in future,” he concluded.
The study had no outside funding. Participant-level data were provided by Abbott. Several coauthors were on the steering committee for the PREMIUM or PRIMA trials. Dr. Ahmed reported receiving consulting fees from, Amgen, AbbVie, electroCore, and Eli Lilly; serving on advisory boards for Amgen and Supernus; serving as a speaker for AbbVie; and receiving funding for an investigator-initiated trial from Teva and Eli Lilly.
A version of this article first appeared on Medscape.com.