Conference Coverage

Atogepant, an oral, small-molecule, calcitonin gene–related peptide receptor antagonist that’s been in development as a preventive treatment for chronic migraine, has been found to have fewer side effects and similar hepatic function profile to standard of care oral treatment after 1 year of use, according to results of a multicenter, open-label trial presented at the 2021 annual meeting of the American Academy of Neurology.

The trial included 739 patients, 543 of whom were randomized to daily oral atogepant with the remainder assigned to the existing standard of care oral migraine prevention medication, said Messoud Ashina, MD, PhD, of the Danish Headache Center at the University of Copenhagen. Initially, 67% (n = 364) of the atogepant patients reported treatment-emergent adverse events (TEAEs). However, he noted, the rate of TEAEs related to treatment was actually 18% (n = 98), and the rate of serious AEs was 4.4% (n = 24); 31 patients (5.7%) discontinued therapy because of TEAEs.

Those rates compared favorably with the standard of care group, Dr. Ashina said. In that group, the rate of TEAEs was 78.6% (154/196), and the rate of treatment-related TEAEs was 36.2% (n = 71).

In the atogepant group, the most common TEAEs were upper respiratory tract infection (10.3%, n = 56), constipation (7.2%, n = 39) and nausea (6.3%, n = 34). “With constipation in particular most cases were mild to moderate,” Dr. Ashina said. “Only one case was considered severe and it resolved before the end of the trial.” One patient discontinued treatment because of constipation.

Most significantly, said Dr. Ashina, “No hepatic safety issues were identified.” In the atogepant group, 2.4% of patients (n = 13) had ALT/AST levels at three times the upper limit of normal versus 3.2% (n = 6) in the standard of care group.

During question-and-answer, Dr. Ashina was pressed on the rate or urinary tract infections in the atogepant patients – 5.2% (n = 28), a measure not reported in the standard of care group – but he said there was no indication the UTIs resulted from atogepant itself. “I assume if there was some problems with urinary tract infections because of the kidneys then you would expect to see the lab data showing that,” he added in an interview. “There were no differences in lab abnormalities between the two groups.”

While Dr. Ashina said “I don’t think it’s something of concern” with regard to the UTI risk, he added: “It doesn’t mean that we don’t have to be careful. As physicians, we have to exhibit pharmacovigilance all the time, especially with the new drugs coming out over the next 5 years. But don’t panic.”

Atogepant, an oral, small-molecule, calcitonin gene–related peptide receptor antagonist that’s been in development as a preventive treatment for chronic migraine, has been found to have fewer side effects and similar hepatic function profile to standard of care oral treatment after 1 year of use, according to results of a multicenter, open-label trial presented at the 2021 annual meeting of the American Academy of Neurology.

The trial included 739 patients, 543 of whom were randomized to daily oral atogepant with the remainder assigned to the existing standard of care oral migraine prevention medication, said Messoud Ashina, MD, PhD, of the Danish Headache Center at the University of Copenhagen. Initially, 67% (n = 364) of the atogepant patients reported treatment-emergent adverse events (TEAEs). However, he noted, the rate of TEAEs related to treatment was actually 18% (n = 98), and the rate of serious AEs was 4.4% (n = 24); 31 patients (5.7%) discontinued therapy because of TEAEs.

Those rates compared favorably with the standard of care group, Dr. Ashina said. In that group, the rate of TEAEs was 78.6% (154/196), and the rate of treatment-related TEAEs was 36.2% (n = 71).

In the atogepant group, the most common TEAEs were upper respiratory tract infection (10.3%, n = 56), constipation (7.2%, n = 39) and nausea (6.3%, n = 34). “With constipation in particular most cases were mild to moderate,” Dr. Ashina said. “Only one case was considered severe and it resolved before the end of the trial.” One patient discontinued treatment because of constipation.

Most significantly, said Dr. Ashina, “No hepatic safety issues were identified.” In the atogepant group, 2.4% of patients (n = 13) had ALT/AST levels at three times the upper limit of normal versus 3.2% (n = 6) in the standard of care group.

During question-and-answer, Dr. Ashina was pressed on the rate or urinary tract infections in the atogepant patients – 5.2% (n = 28), a measure not reported in the standard of care group – but he said there was no indication the UTIs resulted from atogepant itself. “I assume if there was some problems with urinary tract infections because of the kidneys then you would expect to see the lab data showing that,” he added in an interview. “There were no differences in lab abnormalities between the two groups.”

While Dr. Ashina said “I don’t think it’s something of concern” with regard to the UTI risk, he added: “It doesn’t mean that we don’t have to be careful. As physicians, we have to exhibit pharmacovigilance all the time, especially with the new drugs coming out over the next 5 years. But don’t panic.”

Atogepant, an oral, small-molecule, calcitonin gene–related peptide receptor antagonist that’s been in development as a preventive treatment for chronic migraine, has been found to have fewer side effects and similar hepatic function profile to standard of care oral treatment after 1 year of use, according to results of a multicenter, open-label trial presented at the 2021 annual meeting of the American Academy of Neurology.

The trial included 739 patients, 543 of whom were randomized to daily oral atogepant with the remainder assigned to the existing standard of care oral migraine prevention medication, said Messoud Ashina, MD, PhD, of the Danish Headache Center at the University of Copenhagen. Initially, 67% (n = 364) of the atogepant patients reported treatment-emergent adverse events (TEAEs). However, he noted, the rate of TEAEs related to treatment was actually 18% (n = 98), and the rate of serious AEs was 4.4% (n = 24); 31 patients (5.7%) discontinued therapy because of TEAEs.

Those rates compared favorably with the standard of care group, Dr. Ashina said. In that group, the rate of TEAEs was 78.6% (154/196), and the rate of treatment-related TEAEs was 36.2% (n = 71).

In the atogepant group, the most common TEAEs were upper respiratory tract infection (10.3%, n = 56), constipation (7.2%, n = 39) and nausea (6.3%, n = 34). “With constipation in particular most cases were mild to moderate,” Dr. Ashina said. “Only one case was considered severe and it resolved before the end of the trial.” One patient discontinued treatment because of constipation.

Most significantly, said Dr. Ashina, “No hepatic safety issues were identified.” In the atogepant group, 2.4% of patients (n = 13) had ALT/AST levels at three times the upper limit of normal versus 3.2% (n = 6) in the standard of care group.

During question-and-answer, Dr. Ashina was pressed on the rate or urinary tract infections in the atogepant patients – 5.2% (n = 28), a measure not reported in the standard of care group – but he said there was no indication the UTIs resulted from atogepant itself. “I assume if there was some problems with urinary tract infections because of the kidneys then you would expect to see the lab data showing that,” he added in an interview. “There were no differences in lab abnormalities between the two groups.”

While Dr. Ashina said “I don’t think it’s something of concern” with regard to the UTI risk, he added: “It doesn’t mean that we don’t have to be careful. As physicians, we have to exhibit pharmacovigilance all the time, especially with the new drugs coming out over the next 5 years. But don’t panic.”

Long-haul neurologic symptoms of COVID-19 seem to be distinct from neurologic conditions found in acute disease. Among the patient population of long-haulers complaining of brain fog, muscular ache, and other issues, many had mild COVID-19. Much work remains to be done to understand the biological mechanisms behind these problems, but inflammation and autoimmune responses may play a role in some cases.

Those were some of the takeaways from a talk by Serena Spudich, MD, who presented her research at the 2021 annual meeting of the American Academy of Neurology. Dr. Spudich is the division chief of neurologic infections and global neurology and codirector of the Center for Neuroepidemiology and Clinical Neurological Research at Yale University, New Haven, Conn.
 

Examining the nervous system’s involvement in COVID-19

Even early on in the pandemic, it became clear that there were lingering complaints of neuromuscular problems, cognitive dysfunction, and mood and psychiatric issues. Breathing and heart rate problems also can arise. “There seems to be a preponderance of syndromes that reflect involvement of the nervous system,” said Dr. Spudich.

To try to understand the etiology of these persistent problems, Dr. Spudich said it’s important to examine the nervous system’s involvement in acute COVID-19. She has been involved in these efforts since early in the pandemic, when she ran an inpatient consult service at Yale dedicated to neurologic effects of acute COVID-19. She witnessed complications including stroke, encephalopathy, and seizures, among others.

Stroke during acute COVID-19 seemed to be associated with inflammation and endothelial activation or endotheliopathy. SARS-CoV-2 has been undetectable in the cerebrospinal fluid (CSF) of patients with acute COVID-19 and neurologic symptoms, but inflammatory cytokines can be present along with increased frequency of B cells. Anti–SARS-CoV-2 antibodies have also been found in CSF, some of which were auto reactive to brain tissue. The immune response was altered, compared with healthy controls, and in the CNS, compared with in the blood, “raising the question of whether inflammation and autoimmunity may be underlying causes of these syndromes,” said Dr. Spudich.

She also pointed to an MRI study of autopsied brain tissue of patients with COVID-19 and neurologic complications, which showed indications of both hemorrhagic and ischemic microvascular injury. “It’s just a reminder that, during acute COVID-19, there may be inflammation in the brain, there may be autoimmune reactions, and there may be vascular changes that underlie some of the neurologic syndromes that are seen,” said Dr. Spudich.
 

A panoply of different syndromes

In October, Yale set up a post-COVID neurologic clinic that brought together pulmonary, cardiology, and psychiatric specialists, many of whom saw the same patients, about 60% of whom had cognitive impairment, more than 40% had neuromuscular problems, and over 30% headache. “There’s not a single entity of a post-COVID neurologic syndrome. There’s a panoply of different syndromes that may have similar or distinct etiologies,” said Dr. Spudich.

Most patients were in their 30s, 40s, or 50s. That doesn’t necessarily mean this is the most common age range for these issues, though. There could be some bias if these individuals are seeking specialty care because they expected to recover from COVID-19 quickly. But it could be that there is something biologically unique among this age group that predisposes them to complications. Regardless, two out of three patients were never hospitalized, “suggesting that even mild COVID-19 can lead to some long-term sequelae,” said Dr. Spudich.

One potential explanation for long-term neurologic syndromes is that they are an extension of the inflammation, autoimmunity, and immune perturbation occurring during acute disease. One study looked at 18 cancer patients who had neurologic complications with COVID-19. Two months after onset, they had elevated markers of neuroinflammation and neuronal injury in the cerebral spinal fluid compared to cancer patients with no history of COVID-19.
 

Looking for biologic markers

An Italian study looked at patients who were evaluated during acute hospitalization and again 3 months later, and found that some markers of inflation in the blood were associated with later cognitive impairment. The patients were more severely ill, so it’s not clear what the findings mean for patients who present with neurologic symptoms after milder illness.

A PET scan study of 35 patients with persistent neurologic symptoms found patterns of reduced fluorodeoxyglucose uptake in some regions of the brain that are believed to be associated with some symptoms. Lower values were associated with greater severity for symptoms like memory dysfunction, and anosmia. “Why there might be hypometabolism in these regions I think needs to be assessed and used as a biomarker to associate hypometabolism with other kinds of processes in blood and spinal fluid,” said Dr. Spudich.

Along with colleagues at Yale, Dr. Spudich is conducting the MIND study, which is using PET and MRI imaging along with blood and CSF biomarkers to track the progress of patients after COVID-19. There are few results to discuss since only 20 patients have been recruited so far, except that brain imaging and blood values are generally normal despite neurologic complaints. Most were not hospitalized for COVID-19. Dr. Spudich highlighted one man in his 30s who developed new-onset psychosis, despite no previous history. Although clinical tests were all negative, a novel autoantibody detection method revealed a previously unknown autoreactive antibody in his spinal fluid. “This may suggest that there is autoantibody production in some individuals with post–COVID-19 psychosis, and potentially other syndromes,” said Dr. Spudich.
 

The research task ahead

The case illustrates the task ahead for neurology. “There’s a real research mandate to understand the biological substrates of these diverse disorders, not only to address the emergent public health concern and reduce the stigma in our patients, but to develop targeted therapeutic interventions,” said Dr. Spudich.

Anna Cervantes-Arslanian, MD, an associate professor of neurology at Boston University who also treats and studies patients with post-COVID neurologic symptoms, agreed with that assessment. “It’s not like every patient that has muscle aches and fatigue also has brain fog. It’s really hard to parse them out into specific phenotypes that are pretty classic. Some people will have all of those things, some will have very few of them,” said Dr. Cervantes-Arslanian. “We need to be able to identify them sand see if there is clustering of symptoms so we can better look into what the biological underpinnings are. That’s the first step to thinking about a therapeutic target.”

Dr. Spudich and Dr. Cervantes-Arslanian had no relevant financial disclosures.

Long-haul neurologic symptoms of COVID-19 seem to be distinct from neurologic conditions found in acute disease. Among the patient population of long-haulers complaining of brain fog, muscular ache, and other issues, many had mild COVID-19. Much work remains to be done to understand the biological mechanisms behind these problems, but inflammation and autoimmune responses may play a role in some cases.

Those were some of the takeaways from a talk by Serena Spudich, MD, who presented her research at the 2021 annual meeting of the American Academy of Neurology. Dr. Spudich is the division chief of neurologic infections and global neurology and codirector of the Center for Neuroepidemiology and Clinical Neurological Research at Yale University, New Haven, Conn.
 

Examining the nervous system’s involvement in COVID-19

Even early on in the pandemic, it became clear that there were lingering complaints of neuromuscular problems, cognitive dysfunction, and mood and psychiatric issues. Breathing and heart rate problems also can arise. “There seems to be a preponderance of syndromes that reflect involvement of the nervous system,” said Dr. Spudich.

To try to understand the etiology of these persistent problems, Dr. Spudich said it’s important to examine the nervous system’s involvement in acute COVID-19. She has been involved in these efforts since early in the pandemic, when she ran an inpatient consult service at Yale dedicated to neurologic effects of acute COVID-19. She witnessed complications including stroke, encephalopathy, and seizures, among others.

Stroke during acute COVID-19 seemed to be associated with inflammation and endothelial activation or endotheliopathy. SARS-CoV-2 has been undetectable in the cerebrospinal fluid (CSF) of patients with acute COVID-19 and neurologic symptoms, but inflammatory cytokines can be present along with increased frequency of B cells. Anti–SARS-CoV-2 antibodies have also been found in CSF, some of which were auto reactive to brain tissue. The immune response was altered, compared with healthy controls, and in the CNS, compared with in the blood, “raising the question of whether inflammation and autoimmunity may be underlying causes of these syndromes,” said Dr. Spudich.

She also pointed to an MRI study of autopsied brain tissue of patients with COVID-19 and neurologic complications, which showed indications of both hemorrhagic and ischemic microvascular injury. “It’s just a reminder that, during acute COVID-19, there may be inflammation in the brain, there may be autoimmune reactions, and there may be vascular changes that underlie some of the neurologic syndromes that are seen,” said Dr. Spudich.
 

A panoply of different syndromes

In October, Yale set up a post-COVID neurologic clinic that brought together pulmonary, cardiology, and psychiatric specialists, many of whom saw the same patients, about 60% of whom had cognitive impairment, more than 40% had neuromuscular problems, and over 30% headache. “There’s not a single entity of a post-COVID neurologic syndrome. There’s a panoply of different syndromes that may have similar or distinct etiologies,” said Dr. Spudich.

Most patients were in their 30s, 40s, or 50s. That doesn’t necessarily mean this is the most common age range for these issues, though. There could be some bias if these individuals are seeking specialty care because they expected to recover from COVID-19 quickly. But it could be that there is something biologically unique among this age group that predisposes them to complications. Regardless, two out of three patients were never hospitalized, “suggesting that even mild COVID-19 can lead to some long-term sequelae,” said Dr. Spudich.

One potential explanation for long-term neurologic syndromes is that they are an extension of the inflammation, autoimmunity, and immune perturbation occurring during acute disease. One study looked at 18 cancer patients who had neurologic complications with COVID-19. Two months after onset, they had elevated markers of neuroinflammation and neuronal injury in the cerebral spinal fluid compared to cancer patients with no history of COVID-19.
 

Looking for biologic markers

An Italian study looked at patients who were evaluated during acute hospitalization and again 3 months later, and found that some markers of inflation in the blood were associated with later cognitive impairment. The patients were more severely ill, so it’s not clear what the findings mean for patients who present with neurologic symptoms after milder illness.

A PET scan study of 35 patients with persistent neurologic symptoms found patterns of reduced fluorodeoxyglucose uptake in some regions of the brain that are believed to be associated with some symptoms. Lower values were associated with greater severity for symptoms like memory dysfunction, and anosmia. “Why there might be hypometabolism in these regions I think needs to be assessed and used as a biomarker to associate hypometabolism with other kinds of processes in blood and spinal fluid,” said Dr. Spudich.

Along with colleagues at Yale, Dr. Spudich is conducting the MIND study, which is using PET and MRI imaging along with blood and CSF biomarkers to track the progress of patients after COVID-19. There are few results to discuss since only 20 patients have been recruited so far, except that brain imaging and blood values are generally normal despite neurologic complaints. Most were not hospitalized for COVID-19. Dr. Spudich highlighted one man in his 30s who developed new-onset psychosis, despite no previous history. Although clinical tests were all negative, a novel autoantibody detection method revealed a previously unknown autoreactive antibody in his spinal fluid. “This may suggest that there is autoantibody production in some individuals with post–COVID-19 psychosis, and potentially other syndromes,” said Dr. Spudich.
 

The research task ahead

The case illustrates the task ahead for neurology. “There’s a real research mandate to understand the biological substrates of these diverse disorders, not only to address the emergent public health concern and reduce the stigma in our patients, but to develop targeted therapeutic interventions,” said Dr. Spudich.

Anna Cervantes-Arslanian, MD, an associate professor of neurology at Boston University who also treats and studies patients with post-COVID neurologic symptoms, agreed with that assessment. “It’s not like every patient that has muscle aches and fatigue also has brain fog. It’s really hard to parse them out into specific phenotypes that are pretty classic. Some people will have all of those things, some will have very few of them,” said Dr. Cervantes-Arslanian. “We need to be able to identify them sand see if there is clustering of symptoms so we can better look into what the biological underpinnings are. That’s the first step to thinking about a therapeutic target.”

Dr. Spudich and Dr. Cervantes-Arslanian had no relevant financial disclosures.

Long-haul neurologic symptoms of COVID-19 seem to be distinct from neurologic conditions found in acute disease. Among the patient population of long-haulers complaining of brain fog, muscular ache, and other issues, many had mild COVID-19. Much work remains to be done to understand the biological mechanisms behind these problems, but inflammation and autoimmune responses may play a role in some cases.

Those were some of the takeaways from a talk by Serena Spudich, MD, who presented her research at the 2021 annual meeting of the American Academy of Neurology. Dr. Spudich is the division chief of neurologic infections and global neurology and codirector of the Center for Neuroepidemiology and Clinical Neurological Research at Yale University, New Haven, Conn.
 

Examining the nervous system’s involvement in COVID-19

Even early on in the pandemic, it became clear that there were lingering complaints of neuromuscular problems, cognitive dysfunction, and mood and psychiatric issues. Breathing and heart rate problems also can arise. “There seems to be a preponderance of syndromes that reflect involvement of the nervous system,” said Dr. Spudich.

To try to understand the etiology of these persistent problems, Dr. Spudich said it’s important to examine the nervous system’s involvement in acute COVID-19. She has been involved in these efforts since early in the pandemic, when she ran an inpatient consult service at Yale dedicated to neurologic effects of acute COVID-19. She witnessed complications including stroke, encephalopathy, and seizures, among others.

Stroke during acute COVID-19 seemed to be associated with inflammation and endothelial activation or endotheliopathy. SARS-CoV-2 has been undetectable in the cerebrospinal fluid (CSF) of patients with acute COVID-19 and neurologic symptoms, but inflammatory cytokines can be present along with increased frequency of B cells. Anti–SARS-CoV-2 antibodies have also been found in CSF, some of which were auto reactive to brain tissue. The immune response was altered, compared with healthy controls, and in the CNS, compared with in the blood, “raising the question of whether inflammation and autoimmunity may be underlying causes of these syndromes,” said Dr. Spudich.

She also pointed to an MRI study of autopsied brain tissue of patients with COVID-19 and neurologic complications, which showed indications of both hemorrhagic and ischemic microvascular injury. “It’s just a reminder that, during acute COVID-19, there may be inflammation in the brain, there may be autoimmune reactions, and there may be vascular changes that underlie some of the neurologic syndromes that are seen,” said Dr. Spudich.
 

A panoply of different syndromes

In October, Yale set up a post-COVID neurologic clinic that brought together pulmonary, cardiology, and psychiatric specialists, many of whom saw the same patients, about 60% of whom had cognitive impairment, more than 40% had neuromuscular problems, and over 30% headache. “There’s not a single entity of a post-COVID neurologic syndrome. There’s a panoply of different syndromes that may have similar or distinct etiologies,” said Dr. Spudich.

Most patients were in their 30s, 40s, or 50s. That doesn’t necessarily mean this is the most common age range for these issues, though. There could be some bias if these individuals are seeking specialty care because they expected to recover from COVID-19 quickly. But it could be that there is something biologically unique among this age group that predisposes them to complications. Regardless, two out of three patients were never hospitalized, “suggesting that even mild COVID-19 can lead to some long-term sequelae,” said Dr. Spudich.

One potential explanation for long-term neurologic syndromes is that they are an extension of the inflammation, autoimmunity, and immune perturbation occurring during acute disease. One study looked at 18 cancer patients who had neurologic complications with COVID-19. Two months after onset, they had elevated markers of neuroinflammation and neuronal injury in the cerebral spinal fluid compared to cancer patients with no history of COVID-19.
 

Looking for biologic markers

An Italian study looked at patients who were evaluated during acute hospitalization and again 3 months later, and found that some markers of inflation in the blood were associated with later cognitive impairment. The patients were more severely ill, so it’s not clear what the findings mean for patients who present with neurologic symptoms after milder illness.

A PET scan study of 35 patients with persistent neurologic symptoms found patterns of reduced fluorodeoxyglucose uptake in some regions of the brain that are believed to be associated with some symptoms. Lower values were associated with greater severity for symptoms like memory dysfunction, and anosmia. “Why there might be hypometabolism in these regions I think needs to be assessed and used as a biomarker to associate hypometabolism with other kinds of processes in blood and spinal fluid,” said Dr. Spudich.

Along with colleagues at Yale, Dr. Spudich is conducting the MIND study, which is using PET and MRI imaging along with blood and CSF biomarkers to track the progress of patients after COVID-19. There are few results to discuss since only 20 patients have been recruited so far, except that brain imaging and blood values are generally normal despite neurologic complaints. Most were not hospitalized for COVID-19. Dr. Spudich highlighted one man in his 30s who developed new-onset psychosis, despite no previous history. Although clinical tests were all negative, a novel autoantibody detection method revealed a previously unknown autoreactive antibody in his spinal fluid. “This may suggest that there is autoantibody production in some individuals with post–COVID-19 psychosis, and potentially other syndromes,” said Dr. Spudich.
 

The research task ahead

The case illustrates the task ahead for neurology. “There’s a real research mandate to understand the biological substrates of these diverse disorders, not only to address the emergent public health concern and reduce the stigma in our patients, but to develop targeted therapeutic interventions,” said Dr. Spudich.

Anna Cervantes-Arslanian, MD, an associate professor of neurology at Boston University who also treats and studies patients with post-COVID neurologic symptoms, agreed with that assessment. “It’s not like every patient that has muscle aches and fatigue also has brain fog. It’s really hard to parse them out into specific phenotypes that are pretty classic. Some people will have all of those things, some will have very few of them,” said Dr. Cervantes-Arslanian. “We need to be able to identify them sand see if there is clustering of symptoms so we can better look into what the biological underpinnings are. That’s the first step to thinking about a therapeutic target.”

Dr. Spudich and Dr. Cervantes-Arslanian had no relevant financial disclosures.

Excess mortality among people with endogenous Cushing’s syndrome (CS) has declined in the past 20 years yet remains three times higher than in the general population, new research finds.

Among more than 90,000 individuals with endogenous CS, the overall proportion of mortality – defined as the ratio of the number of deaths from CS divided by the total number of CS patients – was 0.05, and the standardized mortality rate was an “unacceptable” three times that of the general population, Padiporn Limumpornpetch, MD, reported on March 20 at ENDO 2021: The Endocrine Society Annual Meeting.

Excess deaths were higher among those with adrenal CS, compared with those with Cushing’s disease. The most common causes of death among those with CS were cardiovascular diseases, cerebrovascular accident, infection, and malignancy, noted Dr. Limumpornpetch, of Songkla University, Hat Yai, Thailand, who is also a PhD student at the University of Leeds, United Kingdom.

“While mortality has improved since 2000, it is still significantly compromised compared to the background population ... The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, infection control, and a normalized cortisol level,” she said.

Asked to comment, Maria Fleseriu, MD, told this news organization that the new data show “we are making improvements in the care of patients with CS and thus outcomes, but we are not there yet ... This meta-analysis highlights the whole spectrum of acute and life-threatening complications in CS and their high prevalence, even before disease diagnosis and after successful surgery.”

She noted that although she wasn’t surprised by the overall results, “the improvement over time was indeed lower than I expected. However, interestingly here, the risk of mortality in adrenal Cushing’s was unexpectedly high despite patients with adrenal cancer being excluded.”

Dr. Fleseriu, who is director of the Pituitary Center at Oregon Health and Science University, Portland, advised, “Management of hyperglycemia and diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with standard of clinical care.”

“But we should focus more on optimizing more aggressively this care in addition to the specific Cushing’s treatment,” she stressed.

In addition, she noted, “Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism to decrease complications ... We definitely need a multidisciplinary approach to address complications and etiologic treatment as well as the reduced long-term quality of life in patients with CS.”

Largest study in scale and scope of Cushing’s syndrome mortality

Endogenous Cushing’s syndrome occurs when the body overproduces cortisol. The most common cause of the latter is a tumor of the pituitary gland (Cushing’s disease), but another cause is a usually benign tumor of the adrenal glands (adrenal Cushing’s syndrome). Surgery is the mainstay of initial treatment of Cushing’s syndrome. If an operation to remove the tumor fails to cause remission, medications are available.

Prior to this new meta-analysis, there had been limited data on mortality among patients with endogenous CS. Research has mostly been limited to single-cohort studies. A previous systematic review/meta-analysis comprised only seven articles with 780 patients. All the studies were conducted prior to 2012, and most were limited to Cushing’s disease.

“In 2021, we lacked a detailed understanding of patient outcomes and mortality because of the rarity of Cushing’s syndrome,” Dr. Limumpornpetch noted.

The current meta-analysis included 91 articles that reported mortality among patients with endogenous CS. There was a total of 19,181 patients from 92 study cohorts, including 49 studies on CD (n = 14,971), 24 studies on adrenal CS (n = 2304), and 19 studies that included both (n = 1906).

Among 21 studies that reported standardized mortality rate (SMR) data, including 13 CD studies (n = 2160) and seven on adrenal CS (n = 1531), the overall increase in mortality compared to the background population was a significant 3.00 (range, 1.15-7.84).

This SMR was higher among patients with adrenal Cushing’s syndrome (3.3) versus Cushing’s disease (2.8) (P = .003) and among patients who had active disease (5.7) versus those whose disease was in remission (2.3) (P < .001).

The SMR was also worse among patients with Cushing’s disease with larger tumors (macroadenomas), at 7.4, than among patients with very small tumors (microadenomas), at 1.9 (P = .004).

The proportion of death was 0.05 for CS overall, with 0.04 for CD and 0.02 for adrenal adenomas.

Compared to studies published prior to the year 2000, more recent studies seem to reflect advances in treatment and care. The overall proportion of death for all CS cohorts dropped from 0.10 to 0.03 (P < .001); for all CD cohorts, it dropped from 0.14 to 0.03; and for adrenal CS cohorts, it dropped from 0.09 to 0.03 (P = .04).

Causes of death were cardiovascular diseases (29.5% of cases), cerebrovascular accident (11.5%), infection (10.5%), and malignancy (10.1%). Less common causes of death were gastrointestinal bleeding and acute pancreatitis (3.7%), active CS (3.5%), adrenal insufficiency (2.5%), suicide (2.5%), and surgery (1.6%).

Overall, in the CS groups, the proportion of deaths within 30 days of surgery dropped from 0.04 prior to 2000 to 0.01 since (P = .07). For CD, the proportion dropped from 0.02 to 0.01 (P = .25).

Preventing perioperative mortality: Consider thromboprophylaxis

Dr. Fleseriu told this news organization that she believes hypercoagulability is “the least recognized complication with a big role in mortality.” Because most of the perioperative mortality is due to venous thromboembolism and infections, “thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding.”

Recently, Dr. Fleseriu’s group showed in a single retrospective study that the risk for arterial and venous thromboembolic events among patients with CS was approximately 20%. Many patients experienced more than one event. Risk was higher 30 to 60 days postoperatively.

The odds ratio of venous thromoboembolism among patients with CS was 18 times higher than in the normal population.

“Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in all patients with Cushing’s syndrome and balanced with individual bleeding risk,” Dr. Fleseriu advised.

A recent Pituitary Society workshop discussed the management of complications of CS at length; proceedings will be published soon, she noted.

Dr. Limumpornpetch commented, “We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population.”

Dr. Limumpornpetch has disclosed no relevant financial relationships. Dr. Fleseriu has been a scientific consultant to Recordati, Sparrow, and Strongbridge and has received grants (inst) from Novartis and Strongbridge.

A version of this article first appeared on Medscape.com.

Excess mortality among people with endogenous Cushing’s syndrome (CS) has declined in the past 20 years yet remains three times higher than in the general population, new research finds.

Among more than 90,000 individuals with endogenous CS, the overall proportion of mortality – defined as the ratio of the number of deaths from CS divided by the total number of CS patients – was 0.05, and the standardized mortality rate was an “unacceptable” three times that of the general population, Padiporn Limumpornpetch, MD, reported on March 20 at ENDO 2021: The Endocrine Society Annual Meeting.

Excess deaths were higher among those with adrenal CS, compared with those with Cushing’s disease. The most common causes of death among those with CS were cardiovascular diseases, cerebrovascular accident, infection, and malignancy, noted Dr. Limumpornpetch, of Songkla University, Hat Yai, Thailand, who is also a PhD student at the University of Leeds, United Kingdom.

“While mortality has improved since 2000, it is still significantly compromised compared to the background population ... The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, infection control, and a normalized cortisol level,” she said.

Asked to comment, Maria Fleseriu, MD, told this news organization that the new data show “we are making improvements in the care of patients with CS and thus outcomes, but we are not there yet ... This meta-analysis highlights the whole spectrum of acute and life-threatening complications in CS and their high prevalence, even before disease diagnosis and after successful surgery.”

She noted that although she wasn’t surprised by the overall results, “the improvement over time was indeed lower than I expected. However, interestingly here, the risk of mortality in adrenal Cushing’s was unexpectedly high despite patients with adrenal cancer being excluded.”

Dr. Fleseriu, who is director of the Pituitary Center at Oregon Health and Science University, Portland, advised, “Management of hyperglycemia and diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with standard of clinical care.”

“But we should focus more on optimizing more aggressively this care in addition to the specific Cushing’s treatment,” she stressed.

In addition, she noted, “Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism to decrease complications ... We definitely need a multidisciplinary approach to address complications and etiologic treatment as well as the reduced long-term quality of life in patients with CS.”

Largest study in scale and scope of Cushing’s syndrome mortality

Endogenous Cushing’s syndrome occurs when the body overproduces cortisol. The most common cause of the latter is a tumor of the pituitary gland (Cushing’s disease), but another cause is a usually benign tumor of the adrenal glands (adrenal Cushing’s syndrome). Surgery is the mainstay of initial treatment of Cushing’s syndrome. If an operation to remove the tumor fails to cause remission, medications are available.

Prior to this new meta-analysis, there had been limited data on mortality among patients with endogenous CS. Research has mostly been limited to single-cohort studies. A previous systematic review/meta-analysis comprised only seven articles with 780 patients. All the studies were conducted prior to 2012, and most were limited to Cushing’s disease.

“In 2021, we lacked a detailed understanding of patient outcomes and mortality because of the rarity of Cushing’s syndrome,” Dr. Limumpornpetch noted.

The current meta-analysis included 91 articles that reported mortality among patients with endogenous CS. There was a total of 19,181 patients from 92 study cohorts, including 49 studies on CD (n = 14,971), 24 studies on adrenal CS (n = 2304), and 19 studies that included both (n = 1906).

Among 21 studies that reported standardized mortality rate (SMR) data, including 13 CD studies (n = 2160) and seven on adrenal CS (n = 1531), the overall increase in mortality compared to the background population was a significant 3.00 (range, 1.15-7.84).

This SMR was higher among patients with adrenal Cushing’s syndrome (3.3) versus Cushing’s disease (2.8) (P = .003) and among patients who had active disease (5.7) versus those whose disease was in remission (2.3) (P < .001).

The SMR was also worse among patients with Cushing’s disease with larger tumors (macroadenomas), at 7.4, than among patients with very small tumors (microadenomas), at 1.9 (P = .004).

The proportion of death was 0.05 for CS overall, with 0.04 for CD and 0.02 for adrenal adenomas.

Compared to studies published prior to the year 2000, more recent studies seem to reflect advances in treatment and care. The overall proportion of death for all CS cohorts dropped from 0.10 to 0.03 (P < .001); for all CD cohorts, it dropped from 0.14 to 0.03; and for adrenal CS cohorts, it dropped from 0.09 to 0.03 (P = .04).

Causes of death were cardiovascular diseases (29.5% of cases), cerebrovascular accident (11.5%), infection (10.5%), and malignancy (10.1%). Less common causes of death were gastrointestinal bleeding and acute pancreatitis (3.7%), active CS (3.5%), adrenal insufficiency (2.5%), suicide (2.5%), and surgery (1.6%).

Overall, in the CS groups, the proportion of deaths within 30 days of surgery dropped from 0.04 prior to 2000 to 0.01 since (P = .07). For CD, the proportion dropped from 0.02 to 0.01 (P = .25).

Preventing perioperative mortality: Consider thromboprophylaxis

Dr. Fleseriu told this news organization that she believes hypercoagulability is “the least recognized complication with a big role in mortality.” Because most of the perioperative mortality is due to venous thromboembolism and infections, “thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding.”

Recently, Dr. Fleseriu’s group showed in a single retrospective study that the risk for arterial and venous thromboembolic events among patients with CS was approximately 20%. Many patients experienced more than one event. Risk was higher 30 to 60 days postoperatively.

The odds ratio of venous thromoboembolism among patients with CS was 18 times higher than in the normal population.

“Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in all patients with Cushing’s syndrome and balanced with individual bleeding risk,” Dr. Fleseriu advised.

A recent Pituitary Society workshop discussed the management of complications of CS at length; proceedings will be published soon, she noted.

Dr. Limumpornpetch commented, “We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population.”

Dr. Limumpornpetch has disclosed no relevant financial relationships. Dr. Fleseriu has been a scientific consultant to Recordati, Sparrow, and Strongbridge and has received grants (inst) from Novartis and Strongbridge.

A version of this article first appeared on Medscape.com.

Excess mortality among people with endogenous Cushing’s syndrome (CS) has declined in the past 20 years yet remains three times higher than in the general population, new research finds.

Among more than 90,000 individuals with endogenous CS, the overall proportion of mortality – defined as the ratio of the number of deaths from CS divided by the total number of CS patients – was 0.05, and the standardized mortality rate was an “unacceptable” three times that of the general population, Padiporn Limumpornpetch, MD, reported on March 20 at ENDO 2021: The Endocrine Society Annual Meeting.

Excess deaths were higher among those with adrenal CS, compared with those with Cushing’s disease. The most common causes of death among those with CS were cardiovascular diseases, cerebrovascular accident, infection, and malignancy, noted Dr. Limumpornpetch, of Songkla University, Hat Yai, Thailand, who is also a PhD student at the University of Leeds, United Kingdom.

“While mortality has improved since 2000, it is still significantly compromised compared to the background population ... The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, infection control, and a normalized cortisol level,” she said.

Asked to comment, Maria Fleseriu, MD, told this news organization that the new data show “we are making improvements in the care of patients with CS and thus outcomes, but we are not there yet ... This meta-analysis highlights the whole spectrum of acute and life-threatening complications in CS and their high prevalence, even before disease diagnosis and after successful surgery.”

She noted that although she wasn’t surprised by the overall results, “the improvement over time was indeed lower than I expected. However, interestingly here, the risk of mortality in adrenal Cushing’s was unexpectedly high despite patients with adrenal cancer being excluded.”

Dr. Fleseriu, who is director of the Pituitary Center at Oregon Health and Science University, Portland, advised, “Management of hyperglycemia and diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with standard of clinical care.”

“But we should focus more on optimizing more aggressively this care in addition to the specific Cushing’s treatment,” she stressed.

In addition, she noted, “Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism to decrease complications ... We definitely need a multidisciplinary approach to address complications and etiologic treatment as well as the reduced long-term quality of life in patients with CS.”

Largest study in scale and scope of Cushing’s syndrome mortality

Endogenous Cushing’s syndrome occurs when the body overproduces cortisol. The most common cause of the latter is a tumor of the pituitary gland (Cushing’s disease), but another cause is a usually benign tumor of the adrenal glands (adrenal Cushing’s syndrome). Surgery is the mainstay of initial treatment of Cushing’s syndrome. If an operation to remove the tumor fails to cause remission, medications are available.

Prior to this new meta-analysis, there had been limited data on mortality among patients with endogenous CS. Research has mostly been limited to single-cohort studies. A previous systematic review/meta-analysis comprised only seven articles with 780 patients. All the studies were conducted prior to 2012, and most were limited to Cushing’s disease.

“In 2021, we lacked a detailed understanding of patient outcomes and mortality because of the rarity of Cushing’s syndrome,” Dr. Limumpornpetch noted.

The current meta-analysis included 91 articles that reported mortality among patients with endogenous CS. There was a total of 19,181 patients from 92 study cohorts, including 49 studies on CD (n = 14,971), 24 studies on adrenal CS (n = 2304), and 19 studies that included both (n = 1906).

Among 21 studies that reported standardized mortality rate (SMR) data, including 13 CD studies (n = 2160) and seven on adrenal CS (n = 1531), the overall increase in mortality compared to the background population was a significant 3.00 (range, 1.15-7.84).

This SMR was higher among patients with adrenal Cushing’s syndrome (3.3) versus Cushing’s disease (2.8) (P = .003) and among patients who had active disease (5.7) versus those whose disease was in remission (2.3) (P < .001).

The SMR was also worse among patients with Cushing’s disease with larger tumors (macroadenomas), at 7.4, than among patients with very small tumors (microadenomas), at 1.9 (P = .004).

The proportion of death was 0.05 for CS overall, with 0.04 for CD and 0.02 for adrenal adenomas.

Compared to studies published prior to the year 2000, more recent studies seem to reflect advances in treatment and care. The overall proportion of death for all CS cohorts dropped from 0.10 to 0.03 (P < .001); for all CD cohorts, it dropped from 0.14 to 0.03; and for adrenal CS cohorts, it dropped from 0.09 to 0.03 (P = .04).

Causes of death were cardiovascular diseases (29.5% of cases), cerebrovascular accident (11.5%), infection (10.5%), and malignancy (10.1%). Less common causes of death were gastrointestinal bleeding and acute pancreatitis (3.7%), active CS (3.5%), adrenal insufficiency (2.5%), suicide (2.5%), and surgery (1.6%).

Overall, in the CS groups, the proportion of deaths within 30 days of surgery dropped from 0.04 prior to 2000 to 0.01 since (P = .07). For CD, the proportion dropped from 0.02 to 0.01 (P = .25).

Preventing perioperative mortality: Consider thromboprophylaxis

Dr. Fleseriu told this news organization that she believes hypercoagulability is “the least recognized complication with a big role in mortality.” Because most of the perioperative mortality is due to venous thromboembolism and infections, “thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding.”

Recently, Dr. Fleseriu’s group showed in a single retrospective study that the risk for arterial and venous thromboembolic events among patients with CS was approximately 20%. Many patients experienced more than one event. Risk was higher 30 to 60 days postoperatively.

The odds ratio of venous thromoboembolism among patients with CS was 18 times higher than in the normal population.

“Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in all patients with Cushing’s syndrome and balanced with individual bleeding risk,” Dr. Fleseriu advised.

A recent Pituitary Society workshop discussed the management of complications of CS at length; proceedings will be published soon, she noted.

Dr. Limumpornpetch commented, “We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population.”

Dr. Limumpornpetch has disclosed no relevant financial relationships. Dr. Fleseriu has been a scientific consultant to Recordati, Sparrow, and Strongbridge and has received grants (inst) from Novartis and Strongbridge.

A version of this article first appeared on Medscape.com.

The biggest factors that attract medical students to enter pediatric rheumatology are interest in disease pathology, the patient-physician relationship, and clinical exposure in residency, according to preliminary research shared at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance.

A shortage in pediatric rheumatology already exists and is expected to worsen to 61% by 2030, noted the authors. About one-third (32%) of current pediatric rheumatologists will retire in the next decade, and less than two-thirds of fellowship slots have filled in the past 5 years.

Katherine Schultz, MD, a clinical fellow in the division of rheumatology at Cincinnati Children’s Medical Center, led the study and said she was surprised that medical school exposure did not play a bigger role in attracting people to the field, but perhaps that’s because too few people received that early exposure.

“If we had earlier exposure, maybe that wouldn’t be definitive for saying, ‘yes, I want to do this subspecialty of pediatric rheumatology,’ but it would open the door, so when you hit residency, you can explore it further,” Dr. Schultz said in an interview.

Dr. Schultz and her colleagues conducted a survey using the CARRA registry during September-December 2020. Respondents included pediatric rheumatology clinical fellows, early-career pediatric rheumatology faculty with less than 7 years practice experience, and mid- to late-career pediatric rheumatology faculty – those with more than 7 years of practice. They are currently in the process of analyzing additional qualitative data.

Of the 428 clinicians recruited to complete the study, 92 did so, for a response rate of 21%. Most respondents were female and non-Hispanic White. A total of 40% were clinical fellows, 41% were early-career faculty, and 18% were mid- to late-career faculty.

Positive factors for choosing the field

More than 80% of respondents across all three experience levels cited disease pathology as a positive attribute of pediatric rheumatology, something that Dr. Schultz mentioned as well.

“The rewarding part of pediatric rheumatology is we take these complex diseases and we help give kids their life back,” she said.

Nearly all the clinical fellows who responded said the patient-physician relationship was important, which early- and mid- and late-career faculty mentioned as well, although to a slightly lesser extent.

Other factors following closely behind disease pathology, patient-physician relationship, and clinical exposure in residency were having a role model in the field – cited by more than three-quarters of clinical fellows and early-career faculty – and having mentorship during residency.

“One of the strengths of our field and one of the things I love about pediatric rheumatology is our community is so close-knit, so kind, and so welcoming,” Dr. Schultz said. “If students can have that exposure and they can see the kind of people who are in this field, that’s our greatest power to draw people to our field.”

Low compensation is a deterrent

The least frequently mentioned positive factors were research opportunities and income. In fact, income was by far the most commonly cited negative attribute of pediatric rheumatology, reported by nearly half of clinical fellows and more than a quarter of early- and mid- and late-career faculty.

“We are one of the lowest paid specialties in pediatrics. We often make [income] comparable to or less than a general pediatrician,” Dr. Schultz said. One reason for that is the difficulty of doing pediatric rheumatology in private practice. Most positions are at academic institutions, which will nearly always involve lower pay scales, she said. The field is also not a procedure-based one, which makes billing more difficult to quantify.

“If I spend an hour thinking about a patient’s diagnosis and interpreting their labs, how do we quantify that?” she asked. “Our field is so cognitive that it makes it hard to bill in the same manner” as fields who bill more procedures, she said.

The other specialties that respondents considered before choosing pediatric rheumatology varied by generation, but allergy and immunology and endocrinology were among the most cited by early-, mid-, and late-career faculty. Clinical fellows’ responses were more evenly distributed across a range of different subspecialties.

Early exposure is key

A large proportion of all three groups, including almost 90% of early-career faculty and clinical fellows, said they received exposure to pediatric rheumatology during residency. However, only a little more than two-thirds of clinical fellows had exposure to the field in medical school, and fewer than that reported medical school exposure among both faculty groups.

Both Dr. Correll and Dr. Schultz said that early exposure to pediatric rheumatology was key to bringing more people into the workforce.

“I believe that once a medical student or resident has an opportunity to work with a pediatric rheumatologist, they are able to see the many reasons for which this is a great career choice,” Dr. Correll said. “Pediatric rheumatologists are seen as positive role models. We love what we do, we have great patient-physician relationships, and we see interesting disease pathophysiology on a regular basis.”

Although earlier exposure to the field is primarily an institutional issue, clinicians can play a role as well.

“For the individual practitioners, the biggest way they can make an impact is to make themselves visible,” Dr. Schultz said. Although the subspecialty is stretched thin, she encouraged pediatric rheumatologists to do med school and resident lectures, volunteer to do feedback sessions, offer residents opportunities to rotate with them, and generally make themselves more visible. “It’s going to take the community to really make the change we need,” she said.

She and Dr. Correll both cited the American College of Rheumatology and CARRA pediatric residency programs as helpful, but there’s more to do. Other ways to increase exposure to the field include creating medical student rotations in pediatric rheumatology, working on case reports or small research projects with new learners, and requesting that pediatric rheumatology be a mandatory rotation in pediatrics training, Dr. Correll said.

“We absolutely have a responsibility to promote our field because if we don’t, the workforce supply issue will continue to worsen,” Dr. Correll said. “We already have a workforce shortage, and models show this shortage will only worsen if we don’t improve recruitment into the field, especially with many pediatric rheumatologists coming up on retirement. Once we are able to expose medical students and residents to the field, I think they easily see our passion and our love for the field, and it’s easy to recruit them.”

The research was funded by CARRA, which receives funding from the Arthritis Foundation. Dr. Schultz and Dr. Correll had no disclosures. 


The biggest factors that attract medical students to enter pediatric rheumatology are interest in disease pathology, the patient-physician relationship, and clinical exposure in residency, according to preliminary research shared at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance.

A shortage in pediatric rheumatology already exists and is expected to worsen to 61% by 2030, noted the authors. About one-third (32%) of current pediatric rheumatologists will retire in the next decade, and less than two-thirds of fellowship slots have filled in the past 5 years.

Katherine Schultz, MD, a clinical fellow in the division of rheumatology at Cincinnati Children’s Medical Center, led the study and said she was surprised that medical school exposure did not play a bigger role in attracting people to the field, but perhaps that’s because too few people received that early exposure.

“If we had earlier exposure, maybe that wouldn’t be definitive for saying, ‘yes, I want to do this subspecialty of pediatric rheumatology,’ but it would open the door, so when you hit residency, you can explore it further,” Dr. Schultz said in an interview.

Dr. Schultz and her colleagues conducted a survey using the CARRA registry during September-December 2020. Respondents included pediatric rheumatology clinical fellows, early-career pediatric rheumatology faculty with less than 7 years practice experience, and mid- to late-career pediatric rheumatology faculty – those with more than 7 years of practice. They are currently in the process of analyzing additional qualitative data.

Of the 428 clinicians recruited to complete the study, 92 did so, for a response rate of 21%. Most respondents were female and non-Hispanic White. A total of 40% were clinical fellows, 41% were early-career faculty, and 18% were mid- to late-career faculty.

Positive factors for choosing the field

More than 80% of respondents across all three experience levels cited disease pathology as a positive attribute of pediatric rheumatology, something that Dr. Schultz mentioned as well.

“The rewarding part of pediatric rheumatology is we take these complex diseases and we help give kids their life back,” she said.

Nearly all the clinical fellows who responded said the patient-physician relationship was important, which early- and mid- and late-career faculty mentioned as well, although to a slightly lesser extent.

Other factors following closely behind disease pathology, patient-physician relationship, and clinical exposure in residency were having a role model in the field – cited by more than three-quarters of clinical fellows and early-career faculty – and having mentorship during residency.

“One of the strengths of our field and one of the things I love about pediatric rheumatology is our community is so close-knit, so kind, and so welcoming,” Dr. Schultz said. “If students can have that exposure and they can see the kind of people who are in this field, that’s our greatest power to draw people to our field.”

Low compensation is a deterrent

The least frequently mentioned positive factors were research opportunities and income. In fact, income was by far the most commonly cited negative attribute of pediatric rheumatology, reported by nearly half of clinical fellows and more than a quarter of early- and mid- and late-career faculty.

“We are one of the lowest paid specialties in pediatrics. We often make [income] comparable to or less than a general pediatrician,” Dr. Schultz said. One reason for that is the difficulty of doing pediatric rheumatology in private practice. Most positions are at academic institutions, which will nearly always involve lower pay scales, she said. The field is also not a procedure-based one, which makes billing more difficult to quantify.

“If I spend an hour thinking about a patient’s diagnosis and interpreting their labs, how do we quantify that?” she asked. “Our field is so cognitive that it makes it hard to bill in the same manner” as fields who bill more procedures, she said.

The other specialties that respondents considered before choosing pediatric rheumatology varied by generation, but allergy and immunology and endocrinology were among the most cited by early-, mid-, and late-career faculty. Clinical fellows’ responses were more evenly distributed across a range of different subspecialties.

Early exposure is key

A large proportion of all three groups, including almost 90% of early-career faculty and clinical fellows, said they received exposure to pediatric rheumatology during residency. However, only a little more than two-thirds of clinical fellows had exposure to the field in medical school, and fewer than that reported medical school exposure among both faculty groups.

Both Dr. Correll and Dr. Schultz said that early exposure to pediatric rheumatology was key to bringing more people into the workforce.

“I believe that once a medical student or resident has an opportunity to work with a pediatric rheumatologist, they are able to see the many reasons for which this is a great career choice,” Dr. Correll said. “Pediatric rheumatologists are seen as positive role models. We love what we do, we have great patient-physician relationships, and we see interesting disease pathophysiology on a regular basis.”

Although earlier exposure to the field is primarily an institutional issue, clinicians can play a role as well.

“For the individual practitioners, the biggest way they can make an impact is to make themselves visible,” Dr. Schultz said. Although the subspecialty is stretched thin, she encouraged pediatric rheumatologists to do med school and resident lectures, volunteer to do feedback sessions, offer residents opportunities to rotate with them, and generally make themselves more visible. “It’s going to take the community to really make the change we need,” she said.

She and Dr. Correll both cited the American College of Rheumatology and CARRA pediatric residency programs as helpful, but there’s more to do. Other ways to increase exposure to the field include creating medical student rotations in pediatric rheumatology, working on case reports or small research projects with new learners, and requesting that pediatric rheumatology be a mandatory rotation in pediatrics training, Dr. Correll said.

“We absolutely have a responsibility to promote our field because if we don’t, the workforce supply issue will continue to worsen,” Dr. Correll said. “We already have a workforce shortage, and models show this shortage will only worsen if we don’t improve recruitment into the field, especially with many pediatric rheumatologists coming up on retirement. Once we are able to expose medical students and residents to the field, I think they easily see our passion and our love for the field, and it’s easy to recruit them.”

The research was funded by CARRA, which receives funding from the Arthritis Foundation. Dr. Schultz and Dr. Correll had no disclosures. 


The biggest factors that attract medical students to enter pediatric rheumatology are interest in disease pathology, the patient-physician relationship, and clinical exposure in residency, according to preliminary research shared at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance.

A shortage in pediatric rheumatology already exists and is expected to worsen to 61% by 2030, noted the authors. About one-third (32%) of current pediatric rheumatologists will retire in the next decade, and less than two-thirds of fellowship slots have filled in the past 5 years.

Katherine Schultz, MD, a clinical fellow in the division of rheumatology at Cincinnati Children’s Medical Center, led the study and said she was surprised that medical school exposure did not play a bigger role in attracting people to the field, but perhaps that’s because too few people received that early exposure.

“If we had earlier exposure, maybe that wouldn’t be definitive for saying, ‘yes, I want to do this subspecialty of pediatric rheumatology,’ but it would open the door, so when you hit residency, you can explore it further,” Dr. Schultz said in an interview.

Dr. Schultz and her colleagues conducted a survey using the CARRA registry during September-December 2020. Respondents included pediatric rheumatology clinical fellows, early-career pediatric rheumatology faculty with less than 7 years practice experience, and mid- to late-career pediatric rheumatology faculty – those with more than 7 years of practice. They are currently in the process of analyzing additional qualitative data.

Of the 428 clinicians recruited to complete the study, 92 did so, for a response rate of 21%. Most respondents were female and non-Hispanic White. A total of 40% were clinical fellows, 41% were early-career faculty, and 18% were mid- to late-career faculty.

Positive factors for choosing the field

More than 80% of respondents across all three experience levels cited disease pathology as a positive attribute of pediatric rheumatology, something that Dr. Schultz mentioned as well.

“The rewarding part of pediatric rheumatology is we take these complex diseases and we help give kids their life back,” she said.

Nearly all the clinical fellows who responded said the patient-physician relationship was important, which early- and mid- and late-career faculty mentioned as well, although to a slightly lesser extent.

Other factors following closely behind disease pathology, patient-physician relationship, and clinical exposure in residency were having a role model in the field – cited by more than three-quarters of clinical fellows and early-career faculty – and having mentorship during residency.

“One of the strengths of our field and one of the things I love about pediatric rheumatology is our community is so close-knit, so kind, and so welcoming,” Dr. Schultz said. “If students can have that exposure and they can see the kind of people who are in this field, that’s our greatest power to draw people to our field.”

Low compensation is a deterrent

The least frequently mentioned positive factors were research opportunities and income. In fact, income was by far the most commonly cited negative attribute of pediatric rheumatology, reported by nearly half of clinical fellows and more than a quarter of early- and mid- and late-career faculty.

“We are one of the lowest paid specialties in pediatrics. We often make [income] comparable to or less than a general pediatrician,” Dr. Schultz said. One reason for that is the difficulty of doing pediatric rheumatology in private practice. Most positions are at academic institutions, which will nearly always involve lower pay scales, she said. The field is also not a procedure-based one, which makes billing more difficult to quantify.

“If I spend an hour thinking about a patient’s diagnosis and interpreting their labs, how do we quantify that?” she asked. “Our field is so cognitive that it makes it hard to bill in the same manner” as fields who bill more procedures, she said.

The other specialties that respondents considered before choosing pediatric rheumatology varied by generation, but allergy and immunology and endocrinology were among the most cited by early-, mid-, and late-career faculty. Clinical fellows’ responses were more evenly distributed across a range of different subspecialties.

Early exposure is key

A large proportion of all three groups, including almost 90% of early-career faculty and clinical fellows, said they received exposure to pediatric rheumatology during residency. However, only a little more than two-thirds of clinical fellows had exposure to the field in medical school, and fewer than that reported medical school exposure among both faculty groups.

Both Dr. Correll and Dr. Schultz said that early exposure to pediatric rheumatology was key to bringing more people into the workforce.

“I believe that once a medical student or resident has an opportunity to work with a pediatric rheumatologist, they are able to see the many reasons for which this is a great career choice,” Dr. Correll said. “Pediatric rheumatologists are seen as positive role models. We love what we do, we have great patient-physician relationships, and we see interesting disease pathophysiology on a regular basis.”

Although earlier exposure to the field is primarily an institutional issue, clinicians can play a role as well.

“For the individual practitioners, the biggest way they can make an impact is to make themselves visible,” Dr. Schultz said. Although the subspecialty is stretched thin, she encouraged pediatric rheumatologists to do med school and resident lectures, volunteer to do feedback sessions, offer residents opportunities to rotate with them, and generally make themselves more visible. “It’s going to take the community to really make the change we need,” she said.

She and Dr. Correll both cited the American College of Rheumatology and CARRA pediatric residency programs as helpful, but there’s more to do. Other ways to increase exposure to the field include creating medical student rotations in pediatric rheumatology, working on case reports or small research projects with new learners, and requesting that pediatric rheumatology be a mandatory rotation in pediatrics training, Dr. Correll said.

“We absolutely have a responsibility to promote our field because if we don’t, the workforce supply issue will continue to worsen,” Dr. Correll said. “We already have a workforce shortage, and models show this shortage will only worsen if we don’t improve recruitment into the field, especially with many pediatric rheumatologists coming up on retirement. Once we are able to expose medical students and residents to the field, I think they easily see our passion and our love for the field, and it’s easy to recruit them.”

The research was funded by CARRA, which receives funding from the Arthritis Foundation. Dr. Schultz and Dr. Correll had no disclosures. 


Combining plasma cell-free DNA (cfDNA) assessment with MRI improves prediction of pathological complete response to neoadjuvant chemotherapy in locally advanced breast cancer, according to researchers.

When the two techniques were in agreement, the accuracy of response prediction was 92.6% in the study, with a predictive value for complete response of 87.5% and a predictive value for absence of complete response of 94.7%, which was substantially better than either method alone.

“Our work identifies a new parameter that is easily combinable with MRI for a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease,” researcher Francesco Ravera, MD, PhD, of the University of Genoa (Italy), said in a press release.

Dr. Ravera and colleagues presented their research in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB063).

Accurate response prediction is important because it guides subsequent surgical management, Dr. Ravera and colleagues noted. Pathological complete responders – generally about 25% of patients after neoadjuvant therapy – typically undergo a sentinel lymph node biopsy to ensure cancer hasn’t spread, while incomplete responders often have a complete axillary lymph node dissection.

Response is currently assessed by MRI, but accuracy is suboptimal, the researchers noted. A more accurate method might “allow the omission of sentinel lymph node biopsy in complete responders, which could be replaced by longitudinal radiologic monitoring. This would represent substantial progress in the pursuit of an effective, minimally invasive treatment,” Dr. Ravera said.

He and his colleagues turned to plasma cfDNA because it has shown potential for providing useful diagnostic, recurrence, and treatment response information in neoplastic patients.

When healthy cells die, they release similarly sized DNA fragments into the blood, but cancer cells release fragments of varying sizes. The heart of the research was using electrophoresis to assess the degree of fragmentation – called cfDNA integrity – in plasma samples from 38 patients after anthracycline/taxane-based regimens.

The researchers compared how well cfDNA, preoperative MRI, and the combination of the two methods predicted response according to surgical histology.

A total of 11 patients had pathological complete responses to neoadjuvant therapy.

The ratio of large 321-1,000 base pair sized fragments to smaller 150-220 base pair sized fragments, which the team dubbed the “cfDNA integrity index,” best predicted response. At a cutoff above 2.71, the index was 81.6% accurate in predicting pathological complete response, with a sensitivity of 81.8% and specificity of 81.5%.

The predictive power wasn’t much better than MRI, which was 77.1% accurate, with a sensitivity of 72.7% and a specificity of 81.5%.

The two techniques were concordant in their prediction in over two-thirds of patients. When the techniques agreed, accuracy was over 90%.

Prospective studies are needed to evaluate the cfDNA integrity index in combination with MRI, the researchers concluded.

The study was sponsored by the University of Genoa and others. Dr. Ravera disclosed no conflicts of interest.

aotto@mdedge.com

Combining plasma cell-free DNA (cfDNA) assessment with MRI improves prediction of pathological complete response to neoadjuvant chemotherapy in locally advanced breast cancer, according to researchers.

When the two techniques were in agreement, the accuracy of response prediction was 92.6% in the study, with a predictive value for complete response of 87.5% and a predictive value for absence of complete response of 94.7%, which was substantially better than either method alone.

“Our work identifies a new parameter that is easily combinable with MRI for a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease,” researcher Francesco Ravera, MD, PhD, of the University of Genoa (Italy), said in a press release.

Dr. Ravera and colleagues presented their research in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB063).

Accurate response prediction is important because it guides subsequent surgical management, Dr. Ravera and colleagues noted. Pathological complete responders – generally about 25% of patients after neoadjuvant therapy – typically undergo a sentinel lymph node biopsy to ensure cancer hasn’t spread, while incomplete responders often have a complete axillary lymph node dissection.

Response is currently assessed by MRI, but accuracy is suboptimal, the researchers noted. A more accurate method might “allow the omission of sentinel lymph node biopsy in complete responders, which could be replaced by longitudinal radiologic monitoring. This would represent substantial progress in the pursuit of an effective, minimally invasive treatment,” Dr. Ravera said.

He and his colleagues turned to plasma cfDNA because it has shown potential for providing useful diagnostic, recurrence, and treatment response information in neoplastic patients.

When healthy cells die, they release similarly sized DNA fragments into the blood, but cancer cells release fragments of varying sizes. The heart of the research was using electrophoresis to assess the degree of fragmentation – called cfDNA integrity – in plasma samples from 38 patients after anthracycline/taxane-based regimens.

The researchers compared how well cfDNA, preoperative MRI, and the combination of the two methods predicted response according to surgical histology.

A total of 11 patients had pathological complete responses to neoadjuvant therapy.

The ratio of large 321-1,000 base pair sized fragments to smaller 150-220 base pair sized fragments, which the team dubbed the “cfDNA integrity index,” best predicted response. At a cutoff above 2.71, the index was 81.6% accurate in predicting pathological complete response, with a sensitivity of 81.8% and specificity of 81.5%.

The predictive power wasn’t much better than MRI, which was 77.1% accurate, with a sensitivity of 72.7% and a specificity of 81.5%.

The two techniques were concordant in their prediction in over two-thirds of patients. When the techniques agreed, accuracy was over 90%.

Prospective studies are needed to evaluate the cfDNA integrity index in combination with MRI, the researchers concluded.

The study was sponsored by the University of Genoa and others. Dr. Ravera disclosed no conflicts of interest.

aotto@mdedge.com

Combining plasma cell-free DNA (cfDNA) assessment with MRI improves prediction of pathological complete response to neoadjuvant chemotherapy in locally advanced breast cancer, according to researchers.

When the two techniques were in agreement, the accuracy of response prediction was 92.6% in the study, with a predictive value for complete response of 87.5% and a predictive value for absence of complete response of 94.7%, which was substantially better than either method alone.

“Our work identifies a new parameter that is easily combinable with MRI for a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease,” researcher Francesco Ravera, MD, PhD, of the University of Genoa (Italy), said in a press release.

Dr. Ravera and colleagues presented their research in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB063).

Accurate response prediction is important because it guides subsequent surgical management, Dr. Ravera and colleagues noted. Pathological complete responders – generally about 25% of patients after neoadjuvant therapy – typically undergo a sentinel lymph node biopsy to ensure cancer hasn’t spread, while incomplete responders often have a complete axillary lymph node dissection.

Response is currently assessed by MRI, but accuracy is suboptimal, the researchers noted. A more accurate method might “allow the omission of sentinel lymph node biopsy in complete responders, which could be replaced by longitudinal radiologic monitoring. This would represent substantial progress in the pursuit of an effective, minimally invasive treatment,” Dr. Ravera said.

He and his colleagues turned to plasma cfDNA because it has shown potential for providing useful diagnostic, recurrence, and treatment response information in neoplastic patients.

When healthy cells die, they release similarly sized DNA fragments into the blood, but cancer cells release fragments of varying sizes. The heart of the research was using electrophoresis to assess the degree of fragmentation – called cfDNA integrity – in plasma samples from 38 patients after anthracycline/taxane-based regimens.

The researchers compared how well cfDNA, preoperative MRI, and the combination of the two methods predicted response according to surgical histology.

A total of 11 patients had pathological complete responses to neoadjuvant therapy.

The ratio of large 321-1,000 base pair sized fragments to smaller 150-220 base pair sized fragments, which the team dubbed the “cfDNA integrity index,” best predicted response. At a cutoff above 2.71, the index was 81.6% accurate in predicting pathological complete response, with a sensitivity of 81.8% and specificity of 81.5%.

The predictive power wasn’t much better than MRI, which was 77.1% accurate, with a sensitivity of 72.7% and a specificity of 81.5%.

The two techniques were concordant in their prediction in over two-thirds of patients. When the techniques agreed, accuracy was over 90%.

Prospective studies are needed to evaluate the cfDNA integrity index in combination with MRI, the researchers concluded.

The study was sponsored by the University of Genoa and others. Dr. Ravera disclosed no conflicts of interest.

aotto@mdedge.com

As second- or third-line therapy in patients with locally advanced non–small cell lung cancer (NSCLC), tislelizumab was well tolerated and prolonged overall survival (OS), compared with docetaxel in the phase 3 RATIONALE 303 study.

The results were presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT039).

Tislelizumab is an anti–PD-1 antibody engineered to minimize Fc-gamma receptor binding on macrophages, a mechanism of T-cell clearance and potential anti–PD-1 resistance, according to investigator Caicun Zhou, MD, PhD, of Shanghai (China) Pulmonary Hospital.

Tislelizumab is approved for the treatment of relapsed/refractory classical Hodgkin lymphoma, the second-line treatment of locally advanced or metastatic urothelial carcinoma, and first-line treatment of advanced squamous NSCLC in China.

In patients with locally advanced or metastatic NSCLC whose disease has progressed after initial platinum-based chemotherapy, anti–PD-1/PD-L1 therapies have been shown to improve OS by 2-4 months versus docetaxel, Dr. Zhou said. A phase 1/2 study of second-line tislelizumab demonstrated antitumor activity in multiple advanced solid tumors, including NSCLC.

The phase 3 RATIONALE 303 study (NCT3358875) was designed to investigate the efficacy and safety of tislelizumab, compared with docetaxel in patients with locally advanced or metastatic NSCLC whose disease had progressed during or after platinum-containing doublet chemotherapy.
 

Study details

RATIONALE 303 enrolled 805 patients who had received up to two prior lines of systemic therapy and had no known EGFR mutations or ALK fusions.

The patients’ median age was 61 years, about 77% were male, about 80% were Asian, and about 70% were current or former smokers. Roughly 46% of patients had squamous histology, and about 43% had PD-L1 expression of 25% or greater.

Patients were stratified according to histology (squamous vs. nonsquamous), lines of prior therapy (second vs. third), and PD-L1 status (<25% vs. ≥25%).

Patients were randomized 2:1 to receive IV tislelizumab at 200 mg every 3 weeks (n = 535) or IV docetaxel at 75 mg/m² every 3 weeks (n = 270) until unacceptable toxicity or disease progression.

The dual primary endpoints were OS in the intention-to-treat (ITT) population and in patients with PD-L1 expression of 25% or higher.
 

Survival and safety

In the ITT population, the 1-year OS rate was 61.9% in the tislelizumab arm and 49.8% in the docetaxel arm. At 2 years, the OS rates were 39.4% and 25.0%, respectively.

The median OS was 17.2 months in the tislelizumab arm and 11.9 months in the docetaxel arm (hazard ratio, 0.64; 95% CI, 0.53-0.78; P < .0001).

In the PD-L1–high subgroup, the median OS was 19.1 months with tislelizumab and 11.9 months with docetaxel (HR, 0.52; 95% CI, 0.38-0.71; P < .0001). The 1-year OS rates in this group were 67.5% and 49.1%, respectively, and the 2-year OS rates were 44.7% and 24.5%, respectively.

The OS benefit with tislelizumab was observed across nearly all subgroups, Dr. Zhou noted.

In the ITT population, benefits were seen with tislelizumab over docetaxel for progression-free survival (4.1 months vs. 2.6 months, P < .0001), objective response rate (21.9% vs. 7.1%, P < .0001), and median duration of response (13.5 months vs. 6.2 months, P < .0001).

The rate of treatment-related adverse events (TRAEs) was 73.0% in the tislelizumab arm and 93.8% in the docetaxel arm. Rates of grade 3 or higher TRAEs were 14.4% and 66.3%, respectively. Rates of TRAEs leading to permanent discontinuation of treatment were 6.0% and 9.7%, respectively, and rates of TRAEs leading to death were 1.5% and 1.6%, respectively.

The most common treatment-emergent adverse events were anemia in the tislelizumab arm (28.5%) and alopecia in the docetaxel arm (47.3%). The most common grade 3 or higher treatment-emergent adverse event was neutropenia in the docetaxel arm (27.9% vs. 0.6% with tislelizumab).
 

‘Very important trial’

“RATIONALE 303 demonstrated that, as second- or third-line therapy in patients with advanced NSCLC, tislelizumab was tolerable and prolonged overall survival by 5-7 months. It also improved progression-free survival and objective response rate versus docetaxel, regardless of histology or PD-L1 expression,” Dr. Zhou concluded.

Session moderator Marina Chiara Garassino, MD, of the University of Chicago called RATIONALE 303 a “very important trial.”

Citing the range of immunotherapies available for NSCLC, Dr. Garassino said, “We have a very crowded space in the treatment of NSCLC. ... It is difficult to do a direct comparison [of immunotherapy trials] because we know that populations can be different and other factors can play a role. In the near future, we have to understand if they are all the same and interchangeable or if they are different.”

RATIONALE 303 was funded by BeiGene. Dr. Zhou disclosed relationships with Lily China, Sanofi, Roche, and several other companies, not including BeiGene. Dr. Garassino disclosed relationships with AstraZeneca, Novartis, Bristol-Myers Squibb, and several other companies, not including BeiGene.

As second- or third-line therapy in patients with locally advanced non–small cell lung cancer (NSCLC), tislelizumab was well tolerated and prolonged overall survival (OS), compared with docetaxel in the phase 3 RATIONALE 303 study.

The results were presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT039).

Tislelizumab is an anti–PD-1 antibody engineered to minimize Fc-gamma receptor binding on macrophages, a mechanism of T-cell clearance and potential anti–PD-1 resistance, according to investigator Caicun Zhou, MD, PhD, of Shanghai (China) Pulmonary Hospital.

Tislelizumab is approved for the treatment of relapsed/refractory classical Hodgkin lymphoma, the second-line treatment of locally advanced or metastatic urothelial carcinoma, and first-line treatment of advanced squamous NSCLC in China.

In patients with locally advanced or metastatic NSCLC whose disease has progressed after initial platinum-based chemotherapy, anti–PD-1/PD-L1 therapies have been shown to improve OS by 2-4 months versus docetaxel, Dr. Zhou said. A phase 1/2 study of second-line tislelizumab demonstrated antitumor activity in multiple advanced solid tumors, including NSCLC.

The phase 3 RATIONALE 303 study (NCT3358875) was designed to investigate the efficacy and safety of tislelizumab, compared with docetaxel in patients with locally advanced or metastatic NSCLC whose disease had progressed during or after platinum-containing doublet chemotherapy.
 

Study details

RATIONALE 303 enrolled 805 patients who had received up to two prior lines of systemic therapy and had no known EGFR mutations or ALK fusions.

The patients’ median age was 61 years, about 77% were male, about 80% were Asian, and about 70% were current or former smokers. Roughly 46% of patients had squamous histology, and about 43% had PD-L1 expression of 25% or greater.

Patients were stratified according to histology (squamous vs. nonsquamous), lines of prior therapy (second vs. third), and PD-L1 status (<25% vs. ≥25%).

Patients were randomized 2:1 to receive IV tislelizumab at 200 mg every 3 weeks (n = 535) or IV docetaxel at 75 mg/m² every 3 weeks (n = 270) until unacceptable toxicity or disease progression.

The dual primary endpoints were OS in the intention-to-treat (ITT) population and in patients with PD-L1 expression of 25% or higher.
 

Survival and safety

In the ITT population, the 1-year OS rate was 61.9% in the tislelizumab arm and 49.8% in the docetaxel arm. At 2 years, the OS rates were 39.4% and 25.0%, respectively.

The median OS was 17.2 months in the tislelizumab arm and 11.9 months in the docetaxel arm (hazard ratio, 0.64; 95% CI, 0.53-0.78; P < .0001).

In the PD-L1–high subgroup, the median OS was 19.1 months with tislelizumab and 11.9 months with docetaxel (HR, 0.52; 95% CI, 0.38-0.71; P < .0001). The 1-year OS rates in this group were 67.5% and 49.1%, respectively, and the 2-year OS rates were 44.7% and 24.5%, respectively.

The OS benefit with tislelizumab was observed across nearly all subgroups, Dr. Zhou noted.

In the ITT population, benefits were seen with tislelizumab over docetaxel for progression-free survival (4.1 months vs. 2.6 months, P < .0001), objective response rate (21.9% vs. 7.1%, P < .0001), and median duration of response (13.5 months vs. 6.2 months, P < .0001).

The rate of treatment-related adverse events (TRAEs) was 73.0% in the tislelizumab arm and 93.8% in the docetaxel arm. Rates of grade 3 or higher TRAEs were 14.4% and 66.3%, respectively. Rates of TRAEs leading to permanent discontinuation of treatment were 6.0% and 9.7%, respectively, and rates of TRAEs leading to death were 1.5% and 1.6%, respectively.

The most common treatment-emergent adverse events were anemia in the tislelizumab arm (28.5%) and alopecia in the docetaxel arm (47.3%). The most common grade 3 or higher treatment-emergent adverse event was neutropenia in the docetaxel arm (27.9% vs. 0.6% with tislelizumab).
 

‘Very important trial’

“RATIONALE 303 demonstrated that, as second- or third-line therapy in patients with advanced NSCLC, tislelizumab was tolerable and prolonged overall survival by 5-7 months. It also improved progression-free survival and objective response rate versus docetaxel, regardless of histology or PD-L1 expression,” Dr. Zhou concluded.

Session moderator Marina Chiara Garassino, MD, of the University of Chicago called RATIONALE 303 a “very important trial.”

Citing the range of immunotherapies available for NSCLC, Dr. Garassino said, “We have a very crowded space in the treatment of NSCLC. ... It is difficult to do a direct comparison [of immunotherapy trials] because we know that populations can be different and other factors can play a role. In the near future, we have to understand if they are all the same and interchangeable or if they are different.”

RATIONALE 303 was funded by BeiGene. Dr. Zhou disclosed relationships with Lily China, Sanofi, Roche, and several other companies, not including BeiGene. Dr. Garassino disclosed relationships with AstraZeneca, Novartis, Bristol-Myers Squibb, and several other companies, not including BeiGene.

As second- or third-line therapy in patients with locally advanced non–small cell lung cancer (NSCLC), tislelizumab was well tolerated and prolonged overall survival (OS), compared with docetaxel in the phase 3 RATIONALE 303 study.

The results were presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT039).

Tislelizumab is an anti–PD-1 antibody engineered to minimize Fc-gamma receptor binding on macrophages, a mechanism of T-cell clearance and potential anti–PD-1 resistance, according to investigator Caicun Zhou, MD, PhD, of Shanghai (China) Pulmonary Hospital.

Tislelizumab is approved for the treatment of relapsed/refractory classical Hodgkin lymphoma, the second-line treatment of locally advanced or metastatic urothelial carcinoma, and first-line treatment of advanced squamous NSCLC in China.

In patients with locally advanced or metastatic NSCLC whose disease has progressed after initial platinum-based chemotherapy, anti–PD-1/PD-L1 therapies have been shown to improve OS by 2-4 months versus docetaxel, Dr. Zhou said. A phase 1/2 study of second-line tislelizumab demonstrated antitumor activity in multiple advanced solid tumors, including NSCLC.

The phase 3 RATIONALE 303 study (NCT3358875) was designed to investigate the efficacy and safety of tislelizumab, compared with docetaxel in patients with locally advanced or metastatic NSCLC whose disease had progressed during or after platinum-containing doublet chemotherapy.
 

Study details

RATIONALE 303 enrolled 805 patients who had received up to two prior lines of systemic therapy and had no known EGFR mutations or ALK fusions.

The patients’ median age was 61 years, about 77% were male, about 80% were Asian, and about 70% were current or former smokers. Roughly 46% of patients had squamous histology, and about 43% had PD-L1 expression of 25% or greater.

Patients were stratified according to histology (squamous vs. nonsquamous), lines of prior therapy (second vs. third), and PD-L1 status (<25% vs. ≥25%).

Patients were randomized 2:1 to receive IV tislelizumab at 200 mg every 3 weeks (n = 535) or IV docetaxel at 75 mg/m² every 3 weeks (n = 270) until unacceptable toxicity or disease progression.

The dual primary endpoints were OS in the intention-to-treat (ITT) population and in patients with PD-L1 expression of 25% or higher.
 

Survival and safety

In the ITT population, the 1-year OS rate was 61.9% in the tislelizumab arm and 49.8% in the docetaxel arm. At 2 years, the OS rates were 39.4% and 25.0%, respectively.

The median OS was 17.2 months in the tislelizumab arm and 11.9 months in the docetaxel arm (hazard ratio, 0.64; 95% CI, 0.53-0.78; P < .0001).

In the PD-L1–high subgroup, the median OS was 19.1 months with tislelizumab and 11.9 months with docetaxel (HR, 0.52; 95% CI, 0.38-0.71; P < .0001). The 1-year OS rates in this group were 67.5% and 49.1%, respectively, and the 2-year OS rates were 44.7% and 24.5%, respectively.

The OS benefit with tislelizumab was observed across nearly all subgroups, Dr. Zhou noted.

In the ITT population, benefits were seen with tislelizumab over docetaxel for progression-free survival (4.1 months vs. 2.6 months, P < .0001), objective response rate (21.9% vs. 7.1%, P < .0001), and median duration of response (13.5 months vs. 6.2 months, P < .0001).

The rate of treatment-related adverse events (TRAEs) was 73.0% in the tislelizumab arm and 93.8% in the docetaxel arm. Rates of grade 3 or higher TRAEs were 14.4% and 66.3%, respectively. Rates of TRAEs leading to permanent discontinuation of treatment were 6.0% and 9.7%, respectively, and rates of TRAEs leading to death were 1.5% and 1.6%, respectively.

The most common treatment-emergent adverse events were anemia in the tislelizumab arm (28.5%) and alopecia in the docetaxel arm (47.3%). The most common grade 3 or higher treatment-emergent adverse event was neutropenia in the docetaxel arm (27.9% vs. 0.6% with tislelizumab).
 

‘Very important trial’

“RATIONALE 303 demonstrated that, as second- or third-line therapy in patients with advanced NSCLC, tislelizumab was tolerable and prolonged overall survival by 5-7 months. It also improved progression-free survival and objective response rate versus docetaxel, regardless of histology or PD-L1 expression,” Dr. Zhou concluded.

Session moderator Marina Chiara Garassino, MD, of the University of Chicago called RATIONALE 303 a “very important trial.”

Citing the range of immunotherapies available for NSCLC, Dr. Garassino said, “We have a very crowded space in the treatment of NSCLC. ... It is difficult to do a direct comparison [of immunotherapy trials] because we know that populations can be different and other factors can play a role. In the near future, we have to understand if they are all the same and interchangeable or if they are different.”

RATIONALE 303 was funded by BeiGene. Dr. Zhou disclosed relationships with Lily China, Sanofi, Roche, and several other companies, not including BeiGene. Dr. Garassino disclosed relationships with AstraZeneca, Novartis, Bristol-Myers Squibb, and several other companies, not including BeiGene.

Two new large international studies have found relatively low rates of stroke in patients hospitalized with COVID-19. One study showed a stroke rate of 2.2% among patients with COVID-19 admitted to intensive care in 52 different countries. Another found a stroke rate of 1.48% in patients hospitalized with COVID-19 from 70 different countries. These researchers also found a reduction in stroke presentations and stroke care during the pandemic.

Both studies will be presented at the American Academy of Neurology’s 2021 annual meeting.

“Stroke has been a known serious complication of COVID-19, with some studies reporting a higher-than-expected occurrence, especially in young people,” said coauthor of the intensive care study, Jonathon Fanning, MBBS, PhD, University of Queensland, Brisbane, Australia.

“However, among the sickest of COVID patients – those admitted to an ICU – our research found that stroke was not a common complication and that ischemic stroke did not increase the risk of death,” he added.
 

Hemorrhagic stroke more common?

In this study, researchers analyzed a database of 2,699 patients who were admitted to the intensive care unit with COVID-19 in 52 countries and found that 59 of these patients (2.2%) subsequently sustained a stroke. 

Most of the strokes identified in this cohort were hemorrhagic (46%), with 32% being ischemic and 22% unspecified. Hemorrhagic stroke was associated with a fivefold increased risk for death compared with patients who did not have a stroke. Of those with a hemorrhagic stroke, 72% died, but only 15% died of the stroke. Rather, multiorgan failure was the leading cause of death.

There was no association between ischemic stroke and mortality.

“There is scarce research on new-onset stroke complicating ICU admissions, and many of the limitations of assessing stroke in ICU populations confound the true values and result in variability in reported incidence anywhere from a 1%-4% incidence,” Dr. Fanning said. 

He noted that a  large Korean study had shown a 1.2% rate of stroke in patients without COVID admitted to non-neurologic ICUs. “In light of this, I think this 2% is higher than we would expect in a general ICU population, but in the context of earlier reports of COVID-19–associated risk for stroke, this figure is actually somewhat reassuring,” Dr. Fanning said.  

Asked how this study compared with the large American Heart Association study recently reported that showed an overall rate of ischemic stroke of 0.75%, Dr. Fanning said the two studies reported on different populations, which makes them difficult to compare.

“Our study specifically reports on new-onset stroke complicating ICU admission,” he noted. “The AHA study is a large study of all patients admitted to hospital, but both studies identified less than previous estimates of COVID-related stroke.”
 

Largest sample to date  

The other study, which includes 119,967 COVID-19 hospitalizations and represents the largest sample reporting the concomitant diagnoses of stroke and SARS-CoV-2 infection to date, was presented at the AAN meeting by Thanh N. Nguyen, MD, a professor at Boston University.

This study has also been published online in Neurology, with first author Raul G. Nogueira, MD, Emory University, Atlanta.  

In this international observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers, there was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.3% (1,722) of all stroke admissions, which numbered 52,026.

The researchers identified stroke diagnoses by the International Classification of Diseases, 10th revision, codes and/or classifications in stroke center databases, and rates of stroke hospitalizations and numbers of patients receiving thrombolysis were compared between the first 4 months of the pandemic (March to June 2020) compared with two control 4-month periods.
 

Global decline in stroke care during pandemic

Results showed a global decline in the number of stroke patients admitted to the hospital as well as acute stroke treatments, such as thrombolysis, during the first wave of the COVID-19 pandemic. The researchers found that there were 91,373 stroke admissions in the 4 months immediately before the pandemic, compared with 80,894 admissions during the first 4 pandemic months, representing an 11.5% decline.

They also report that 13,334 stroke patients received intravenous thrombolysis in the 4 months preceding the pandemic, compared with 11,570 during the first 4 pandemic months, representing a 13.2% drop.

Interhospital transfers after thrombolysis for a higher level of stroke care decreased from 1,337 before the pandemic to 1,178 during the pandemic, a reduction of 11.9%.  

There were greater declines in primary compared with comprehensive stroke centers for stroke hospitalizations (change, –17.3% vs. –10.3%) and for the number of patients receiving thrombolysis (change, –15.5% vs. –12.6%).

The volume of stroke hospitalizations increased by 9.5% in the two later pandemic months (May, June) versus the two earlier months (March, April), with greater recovery in hospitals with lower COVID-19 hospitalization volume, high-volume stroke centers, and comprehensive stroke centers.

Dr. Nguyen suggested that reasons for the reductions in these stroke numbers at the beginning of the pandemic could include a reduction in stroke risk due to a reduction of exposure to other viral infections or patients not presenting to the hospital for fear of contracting the coronavirus.

The higher recovery of stroke volume in high-volume stroke centers and comprehensive stroke centers may represent patients with higher needs – those having more severe strokes – seeking care more frequently than those with milder symptoms, she noted.

“Preserving access to stroke care and emergency stroke care amidst a pandemic is as important as educating patients on the importance of presenting to the hospital in the event of stroke-like symptoms,” Dr. Nguyen concluded.

“We continue to advocate that if a patient has stroke-like symptoms, such as loss of speech, strength, vision, or balance, it is important for the patient to seek medical care as an emergency, as there are treatments that can improve a patient’s ability to recover from disabling stroke in earlier rather than later time windows,” she added.

In the publication, the authors wrote, “Our results concur with other recent reports on the collateral effects of the COVID-19 pandemic on stroke systems of care,” but added that “this is among the first descriptions of the change at a global level, including primary and comprehensive stroke centers.”

They said that hospital access related to high COVID-19 burden was unlikely a factor because the decline was seen in centers with a few or no patients with COVID-19. They suggested that patient fear of contracting coronavirus may have played a role, along with a decrease in presentation of transient ischemic attacks, mild strokes, or moderate strokes, and physical distancing measures may have prevented the timely witnessing of a stroke.

A version of this article first appeared on Medscape.com.

Two new large international studies have found relatively low rates of stroke in patients hospitalized with COVID-19. One study showed a stroke rate of 2.2% among patients with COVID-19 admitted to intensive care in 52 different countries. Another found a stroke rate of 1.48% in patients hospitalized with COVID-19 from 70 different countries. These researchers also found a reduction in stroke presentations and stroke care during the pandemic.

Both studies will be presented at the American Academy of Neurology’s 2021 annual meeting.

“Stroke has been a known serious complication of COVID-19, with some studies reporting a higher-than-expected occurrence, especially in young people,” said coauthor of the intensive care study, Jonathon Fanning, MBBS, PhD, University of Queensland, Brisbane, Australia.

“However, among the sickest of COVID patients – those admitted to an ICU – our research found that stroke was not a common complication and that ischemic stroke did not increase the risk of death,” he added.
 

Hemorrhagic stroke more common?

In this study, researchers analyzed a database of 2,699 patients who were admitted to the intensive care unit with COVID-19 in 52 countries and found that 59 of these patients (2.2%) subsequently sustained a stroke. 

Most of the strokes identified in this cohort were hemorrhagic (46%), with 32% being ischemic and 22% unspecified. Hemorrhagic stroke was associated with a fivefold increased risk for death compared with patients who did not have a stroke. Of those with a hemorrhagic stroke, 72% died, but only 15% died of the stroke. Rather, multiorgan failure was the leading cause of death.

There was no association between ischemic stroke and mortality.

“There is scarce research on new-onset stroke complicating ICU admissions, and many of the limitations of assessing stroke in ICU populations confound the true values and result in variability in reported incidence anywhere from a 1%-4% incidence,” Dr. Fanning said. 

He noted that a  large Korean study had shown a 1.2% rate of stroke in patients without COVID admitted to non-neurologic ICUs. “In light of this, I think this 2% is higher than we would expect in a general ICU population, but in the context of earlier reports of COVID-19–associated risk for stroke, this figure is actually somewhat reassuring,” Dr. Fanning said.  

Asked how this study compared with the large American Heart Association study recently reported that showed an overall rate of ischemic stroke of 0.75%, Dr. Fanning said the two studies reported on different populations, which makes them difficult to compare.

“Our study specifically reports on new-onset stroke complicating ICU admission,” he noted. “The AHA study is a large study of all patients admitted to hospital, but both studies identified less than previous estimates of COVID-related stroke.”
 

Largest sample to date  

The other study, which includes 119,967 COVID-19 hospitalizations and represents the largest sample reporting the concomitant diagnoses of stroke and SARS-CoV-2 infection to date, was presented at the AAN meeting by Thanh N. Nguyen, MD, a professor at Boston University.

This study has also been published online in Neurology, with first author Raul G. Nogueira, MD, Emory University, Atlanta.  

In this international observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers, there was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.3% (1,722) of all stroke admissions, which numbered 52,026.

The researchers identified stroke diagnoses by the International Classification of Diseases, 10th revision, codes and/or classifications in stroke center databases, and rates of stroke hospitalizations and numbers of patients receiving thrombolysis were compared between the first 4 months of the pandemic (March to June 2020) compared with two control 4-month periods.
 

Global decline in stroke care during pandemic

Results showed a global decline in the number of stroke patients admitted to the hospital as well as acute stroke treatments, such as thrombolysis, during the first wave of the COVID-19 pandemic. The researchers found that there were 91,373 stroke admissions in the 4 months immediately before the pandemic, compared with 80,894 admissions during the first 4 pandemic months, representing an 11.5% decline.

They also report that 13,334 stroke patients received intravenous thrombolysis in the 4 months preceding the pandemic, compared with 11,570 during the first 4 pandemic months, representing a 13.2% drop.

Interhospital transfers after thrombolysis for a higher level of stroke care decreased from 1,337 before the pandemic to 1,178 during the pandemic, a reduction of 11.9%.  

There were greater declines in primary compared with comprehensive stroke centers for stroke hospitalizations (change, –17.3% vs. –10.3%) and for the number of patients receiving thrombolysis (change, –15.5% vs. –12.6%).

The volume of stroke hospitalizations increased by 9.5% in the two later pandemic months (May, June) versus the two earlier months (March, April), with greater recovery in hospitals with lower COVID-19 hospitalization volume, high-volume stroke centers, and comprehensive stroke centers.

Dr. Nguyen suggested that reasons for the reductions in these stroke numbers at the beginning of the pandemic could include a reduction in stroke risk due to a reduction of exposure to other viral infections or patients not presenting to the hospital for fear of contracting the coronavirus.

The higher recovery of stroke volume in high-volume stroke centers and comprehensive stroke centers may represent patients with higher needs – those having more severe strokes – seeking care more frequently than those with milder symptoms, she noted.

“Preserving access to stroke care and emergency stroke care amidst a pandemic is as important as educating patients on the importance of presenting to the hospital in the event of stroke-like symptoms,” Dr. Nguyen concluded.

“We continue to advocate that if a patient has stroke-like symptoms, such as loss of speech, strength, vision, or balance, it is important for the patient to seek medical care as an emergency, as there are treatments that can improve a patient’s ability to recover from disabling stroke in earlier rather than later time windows,” she added.

In the publication, the authors wrote, “Our results concur with other recent reports on the collateral effects of the COVID-19 pandemic on stroke systems of care,” but added that “this is among the first descriptions of the change at a global level, including primary and comprehensive stroke centers.”

They said that hospital access related to high COVID-19 burden was unlikely a factor because the decline was seen in centers with a few or no patients with COVID-19. They suggested that patient fear of contracting coronavirus may have played a role, along with a decrease in presentation of transient ischemic attacks, mild strokes, or moderate strokes, and physical distancing measures may have prevented the timely witnessing of a stroke.

A version of this article first appeared on Medscape.com.

Two new large international studies have found relatively low rates of stroke in patients hospitalized with COVID-19. One study showed a stroke rate of 2.2% among patients with COVID-19 admitted to intensive care in 52 different countries. Another found a stroke rate of 1.48% in patients hospitalized with COVID-19 from 70 different countries. These researchers also found a reduction in stroke presentations and stroke care during the pandemic.

Both studies will be presented at the American Academy of Neurology’s 2021 annual meeting.

“Stroke has been a known serious complication of COVID-19, with some studies reporting a higher-than-expected occurrence, especially in young people,” said coauthor of the intensive care study, Jonathon Fanning, MBBS, PhD, University of Queensland, Brisbane, Australia.

“However, among the sickest of COVID patients – those admitted to an ICU – our research found that stroke was not a common complication and that ischemic stroke did not increase the risk of death,” he added.
 

Hemorrhagic stroke more common?

In this study, researchers analyzed a database of 2,699 patients who were admitted to the intensive care unit with COVID-19 in 52 countries and found that 59 of these patients (2.2%) subsequently sustained a stroke. 

Most of the strokes identified in this cohort were hemorrhagic (46%), with 32% being ischemic and 22% unspecified. Hemorrhagic stroke was associated with a fivefold increased risk for death compared with patients who did not have a stroke. Of those with a hemorrhagic stroke, 72% died, but only 15% died of the stroke. Rather, multiorgan failure was the leading cause of death.

There was no association between ischemic stroke and mortality.

“There is scarce research on new-onset stroke complicating ICU admissions, and many of the limitations of assessing stroke in ICU populations confound the true values and result in variability in reported incidence anywhere from a 1%-4% incidence,” Dr. Fanning said. 

He noted that a  large Korean study had shown a 1.2% rate of stroke in patients without COVID admitted to non-neurologic ICUs. “In light of this, I think this 2% is higher than we would expect in a general ICU population, but in the context of earlier reports of COVID-19–associated risk for stroke, this figure is actually somewhat reassuring,” Dr. Fanning said.  

Asked how this study compared with the large American Heart Association study recently reported that showed an overall rate of ischemic stroke of 0.75%, Dr. Fanning said the two studies reported on different populations, which makes them difficult to compare.

“Our study specifically reports on new-onset stroke complicating ICU admission,” he noted. “The AHA study is a large study of all patients admitted to hospital, but both studies identified less than previous estimates of COVID-related stroke.”
 

Largest sample to date  

The other study, which includes 119,967 COVID-19 hospitalizations and represents the largest sample reporting the concomitant diagnoses of stroke and SARS-CoV-2 infection to date, was presented at the AAN meeting by Thanh N. Nguyen, MD, a professor at Boston University.

This study has also been published online in Neurology, with first author Raul G. Nogueira, MD, Emory University, Atlanta.  

In this international observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers, there was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.3% (1,722) of all stroke admissions, which numbered 52,026.

The researchers identified stroke diagnoses by the International Classification of Diseases, 10th revision, codes and/or classifications in stroke center databases, and rates of stroke hospitalizations and numbers of patients receiving thrombolysis were compared between the first 4 months of the pandemic (March to June 2020) compared with two control 4-month periods.
 

Global decline in stroke care during pandemic

Results showed a global decline in the number of stroke patients admitted to the hospital as well as acute stroke treatments, such as thrombolysis, during the first wave of the COVID-19 pandemic. The researchers found that there were 91,373 stroke admissions in the 4 months immediately before the pandemic, compared with 80,894 admissions during the first 4 pandemic months, representing an 11.5% decline.

They also report that 13,334 stroke patients received intravenous thrombolysis in the 4 months preceding the pandemic, compared with 11,570 during the first 4 pandemic months, representing a 13.2% drop.

Interhospital transfers after thrombolysis for a higher level of stroke care decreased from 1,337 before the pandemic to 1,178 during the pandemic, a reduction of 11.9%.  

There were greater declines in primary compared with comprehensive stroke centers for stroke hospitalizations (change, –17.3% vs. –10.3%) and for the number of patients receiving thrombolysis (change, –15.5% vs. –12.6%).

The volume of stroke hospitalizations increased by 9.5% in the two later pandemic months (May, June) versus the two earlier months (March, April), with greater recovery in hospitals with lower COVID-19 hospitalization volume, high-volume stroke centers, and comprehensive stroke centers.

Dr. Nguyen suggested that reasons for the reductions in these stroke numbers at the beginning of the pandemic could include a reduction in stroke risk due to a reduction of exposure to other viral infections or patients not presenting to the hospital for fear of contracting the coronavirus.

The higher recovery of stroke volume in high-volume stroke centers and comprehensive stroke centers may represent patients with higher needs – those having more severe strokes – seeking care more frequently than those with milder symptoms, she noted.

“Preserving access to stroke care and emergency stroke care amidst a pandemic is as important as educating patients on the importance of presenting to the hospital in the event of stroke-like symptoms,” Dr. Nguyen concluded.

“We continue to advocate that if a patient has stroke-like symptoms, such as loss of speech, strength, vision, or balance, it is important for the patient to seek medical care as an emergency, as there are treatments that can improve a patient’s ability to recover from disabling stroke in earlier rather than later time windows,” she added.

In the publication, the authors wrote, “Our results concur with other recent reports on the collateral effects of the COVID-19 pandemic on stroke systems of care,” but added that “this is among the first descriptions of the change at a global level, including primary and comprehensive stroke centers.”

They said that hospital access related to high COVID-19 burden was unlikely a factor because the decline was seen in centers with a few or no patients with COVID-19. They suggested that patient fear of contracting coronavirus may have played a role, along with a decrease in presentation of transient ischemic attacks, mild strokes, or moderate strokes, and physical distancing measures may have prevented the timely witnessing of a stroke.

A version of this article first appeared on Medscape.com.

A remote model using telehealth for genetic testing and counseling for people with Parkinson’s disease results in levels of patient satisfaction close to those who undergo in-patient testing and counseling and shows the potential for gathering genetic data on a broad scale for further research, according to a pilot study sponsored by the Parkinson’s Foundation.

“Overall we found high levels of participant satisfaction with Parkinson’s testing and genetic counseling and no significant difference in outcomes concerning satisfaction, knowledge, and impact of genetic testing between disclosure of results and genetic counseling in-person by either a neurologist or a genetic counselor or via telephone by a remove genetic counselor at a centralized center,” said Jennifer L. Verbrugge, MS, a genetic counselor at Indiana University, Indianapolis, in reporting results of the PD GENEration pilot study, presented at the 2021 annual meeting of the American Academy of Neurology.
 

COVID complication

The study launched in the summer of 2019 with the goal of enrolling 600 participants. However, because of the COVID-19 pandemic, enrollment was truncated. The pilot study eventually enrolled 289 patients, 205 of whom returned their postgenetic counseling surveys, Ms. Verbrugge said. The pilot study goal was to evaluate the feasibility and impact of in-person versus remote genetic testing and counseling for people with Parkinson’s disease.

“The study hopes to reach its ultimate goal, which is to deliver Parkinson’s disease–related genetic testing and counseling to upward of 15,000 people with Parkinson’s,” Ms. Verbrugge said. The program is also planning to expand to include Spanish speakers.

In the pilot study, genetic results were positive in 17% of patients, with 15% (n = 42) having positive heterozygous variants and 8% having variants of uncertain significance. “We did not see significant differences in these outcomes when we compared the mode and genetic counselors involved,” Ms. Verbrugge said.

The study did find that in-person testing and counseling “was associated with increased participant feelings that they were partners in care,” Ms. Verbrugge added. “This is something we are going to continue to evaluate as time goes on.”

However, as the COVID-19 pandemic pushed clinicians to develop virtual platforms, it resulted in a function through which participants can complete all genetic study activities remotely, she said. The study organizers anticipate that as pandemic restrictions ease, they will be able to reach their original goal of 600 participants along with those recruited in an expansion phase.

“As restrictions related to the pandemic ease, we anticipate that more Parkinson’s disease gene-targeted clinical trials will emerge, with aims to recruit people who carry certain gene variants,” Ms. Verbrugge said in an interview. “Many people with Parkinson’s disease may therefore benefit from genetic testing and learning if they carry a Parkinson’s disease related gene variant from participation in the PD GENEration study.”
 

Increasing patient access

To scale up to the 15,000-population goal for the program, PD GENEration has launched a new protocol designed to increase patient access at new study sites, Ms. Verbrugge said. “This protocol includes an abbreviate version of the clinical data collected, while it maintains the critical component of genetic counseling in the testing process.”

Going forward, the PD GENEration study will focus on improving access to genetic testing and counseling in underrepresented and rural populations, Ms. Verbrugge said. “These efforts will also generate valuable genomic data, allowing researchers to learn more about the causes of Parkinson’s disease in diverse and underrepresented populations. The study will be expanding research efforts concerning the genomic data to gain insights about the seven key genes studied as well as new genes linked to Parkinson’s disease.”

The work of the PD GENEration study is timely, said David K. Simon, MD, PhD, of Harvard Medical School and director of the Parkinson’s Disease & Movement Disorders Center at Beth Israel Deaconess Medical Center, both in Boston. “This is very important to identify such patients now, as clinical trials targeting people with specific genetic mutations or variants are coming soon, and in some cases already are underway. The feasibility and speed of enrollment for those trials will be greatly facilitate if we know in advance who are the people with Parkinson’s disease who have mutations that would make them eligible for the particular trials.”

The fact that the study provides free genetic testing to people with Parkinson’s disease isn’t to be overlooked. “This was an important study to address the question of whether or not remote genetic counseling was feasible and effective, and the results are meaningful given the randomized prospective design,” Dr. Simon said.

Ms. Verbrugge has no relevant relationships to disclose. Dr. Simon reports receiving research funding from the Parkinson’s Foundation.

A remote model using telehealth for genetic testing and counseling for people with Parkinson’s disease results in levels of patient satisfaction close to those who undergo in-patient testing and counseling and shows the potential for gathering genetic data on a broad scale for further research, according to a pilot study sponsored by the Parkinson’s Foundation.

“Overall we found high levels of participant satisfaction with Parkinson’s testing and genetic counseling and no significant difference in outcomes concerning satisfaction, knowledge, and impact of genetic testing between disclosure of results and genetic counseling in-person by either a neurologist or a genetic counselor or via telephone by a remove genetic counselor at a centralized center,” said Jennifer L. Verbrugge, MS, a genetic counselor at Indiana University, Indianapolis, in reporting results of the PD GENEration pilot study, presented at the 2021 annual meeting of the American Academy of Neurology.
 

COVID complication

The study launched in the summer of 2019 with the goal of enrolling 600 participants. However, because of the COVID-19 pandemic, enrollment was truncated. The pilot study eventually enrolled 289 patients, 205 of whom returned their postgenetic counseling surveys, Ms. Verbrugge said. The pilot study goal was to evaluate the feasibility and impact of in-person versus remote genetic testing and counseling for people with Parkinson’s disease.

“The study hopes to reach its ultimate goal, which is to deliver Parkinson’s disease–related genetic testing and counseling to upward of 15,000 people with Parkinson’s,” Ms. Verbrugge said. The program is also planning to expand to include Spanish speakers.

In the pilot study, genetic results were positive in 17% of patients, with 15% (n = 42) having positive heterozygous variants and 8% having variants of uncertain significance. “We did not see significant differences in these outcomes when we compared the mode and genetic counselors involved,” Ms. Verbrugge said.

The study did find that in-person testing and counseling “was associated with increased participant feelings that they were partners in care,” Ms. Verbrugge added. “This is something we are going to continue to evaluate as time goes on.”

However, as the COVID-19 pandemic pushed clinicians to develop virtual platforms, it resulted in a function through which participants can complete all genetic study activities remotely, she said. The study organizers anticipate that as pandemic restrictions ease, they will be able to reach their original goal of 600 participants along with those recruited in an expansion phase.

“As restrictions related to the pandemic ease, we anticipate that more Parkinson’s disease gene-targeted clinical trials will emerge, with aims to recruit people who carry certain gene variants,” Ms. Verbrugge said in an interview. “Many people with Parkinson’s disease may therefore benefit from genetic testing and learning if they carry a Parkinson’s disease related gene variant from participation in the PD GENEration study.”
 

Increasing patient access

To scale up to the 15,000-population goal for the program, PD GENEration has launched a new protocol designed to increase patient access at new study sites, Ms. Verbrugge said. “This protocol includes an abbreviate version of the clinical data collected, while it maintains the critical component of genetic counseling in the testing process.”

Going forward, the PD GENEration study will focus on improving access to genetic testing and counseling in underrepresented and rural populations, Ms. Verbrugge said. “These efforts will also generate valuable genomic data, allowing researchers to learn more about the causes of Parkinson’s disease in diverse and underrepresented populations. The study will be expanding research efforts concerning the genomic data to gain insights about the seven key genes studied as well as new genes linked to Parkinson’s disease.”

The work of the PD GENEration study is timely, said David K. Simon, MD, PhD, of Harvard Medical School and director of the Parkinson’s Disease & Movement Disorders Center at Beth Israel Deaconess Medical Center, both in Boston. “This is very important to identify such patients now, as clinical trials targeting people with specific genetic mutations or variants are coming soon, and in some cases already are underway. The feasibility and speed of enrollment for those trials will be greatly facilitate if we know in advance who are the people with Parkinson’s disease who have mutations that would make them eligible for the particular trials.”

The fact that the study provides free genetic testing to people with Parkinson’s disease isn’t to be overlooked. “This was an important study to address the question of whether or not remote genetic counseling was feasible and effective, and the results are meaningful given the randomized prospective design,” Dr. Simon said.

Ms. Verbrugge has no relevant relationships to disclose. Dr. Simon reports receiving research funding from the Parkinson’s Foundation.

A remote model using telehealth for genetic testing and counseling for people with Parkinson’s disease results in levels of patient satisfaction close to those who undergo in-patient testing and counseling and shows the potential for gathering genetic data on a broad scale for further research, according to a pilot study sponsored by the Parkinson’s Foundation.

“Overall we found high levels of participant satisfaction with Parkinson’s testing and genetic counseling and no significant difference in outcomes concerning satisfaction, knowledge, and impact of genetic testing between disclosure of results and genetic counseling in-person by either a neurologist or a genetic counselor or via telephone by a remove genetic counselor at a centralized center,” said Jennifer L. Verbrugge, MS, a genetic counselor at Indiana University, Indianapolis, in reporting results of the PD GENEration pilot study, presented at the 2021 annual meeting of the American Academy of Neurology.
 

COVID complication

The study launched in the summer of 2019 with the goal of enrolling 600 participants. However, because of the COVID-19 pandemic, enrollment was truncated. The pilot study eventually enrolled 289 patients, 205 of whom returned their postgenetic counseling surveys, Ms. Verbrugge said. The pilot study goal was to evaluate the feasibility and impact of in-person versus remote genetic testing and counseling for people with Parkinson’s disease.

“The study hopes to reach its ultimate goal, which is to deliver Parkinson’s disease–related genetic testing and counseling to upward of 15,000 people with Parkinson’s,” Ms. Verbrugge said. The program is also planning to expand to include Spanish speakers.

In the pilot study, genetic results were positive in 17% of patients, with 15% (n = 42) having positive heterozygous variants and 8% having variants of uncertain significance. “We did not see significant differences in these outcomes when we compared the mode and genetic counselors involved,” Ms. Verbrugge said.

The study did find that in-person testing and counseling “was associated with increased participant feelings that they were partners in care,” Ms. Verbrugge added. “This is something we are going to continue to evaluate as time goes on.”

However, as the COVID-19 pandemic pushed clinicians to develop virtual platforms, it resulted in a function through which participants can complete all genetic study activities remotely, she said. The study organizers anticipate that as pandemic restrictions ease, they will be able to reach their original goal of 600 participants along with those recruited in an expansion phase.

“As restrictions related to the pandemic ease, we anticipate that more Parkinson’s disease gene-targeted clinical trials will emerge, with aims to recruit people who carry certain gene variants,” Ms. Verbrugge said in an interview. “Many people with Parkinson’s disease may therefore benefit from genetic testing and learning if they carry a Parkinson’s disease related gene variant from participation in the PD GENEration study.”
 

Increasing patient access

To scale up to the 15,000-population goal for the program, PD GENEration has launched a new protocol designed to increase patient access at new study sites, Ms. Verbrugge said. “This protocol includes an abbreviate version of the clinical data collected, while it maintains the critical component of genetic counseling in the testing process.”

Going forward, the PD GENEration study will focus on improving access to genetic testing and counseling in underrepresented and rural populations, Ms. Verbrugge said. “These efforts will also generate valuable genomic data, allowing researchers to learn more about the causes of Parkinson’s disease in diverse and underrepresented populations. The study will be expanding research efforts concerning the genomic data to gain insights about the seven key genes studied as well as new genes linked to Parkinson’s disease.”

The work of the PD GENEration study is timely, said David K. Simon, MD, PhD, of Harvard Medical School and director of the Parkinson’s Disease & Movement Disorders Center at Beth Israel Deaconess Medical Center, both in Boston. “This is very important to identify such patients now, as clinical trials targeting people with specific genetic mutations or variants are coming soon, and in some cases already are underway. The feasibility and speed of enrollment for those trials will be greatly facilitate if we know in advance who are the people with Parkinson’s disease who have mutations that would make them eligible for the particular trials.”

The fact that the study provides free genetic testing to people with Parkinson’s disease isn’t to be overlooked. “This was an important study to address the question of whether or not remote genetic counseling was feasible and effective, and the results are meaningful given the randomized prospective design,” Dr. Simon said.

Ms. Verbrugge has no relevant relationships to disclose. Dr. Simon reports receiving research funding from the Parkinson’s Foundation.

Results from a 1-year, open-label safety study suggest that the oral migraine prevention drug rimegepant is safe and effective in patients with cardiovascular risk factors. Patients who fall into this category may be ineligible for treatment with triptans.

There are mechanistic concerns with rimegepant and related CGRP receptor antagonists. They block CGRP’s effect in the central nervous system, but CGRP is also active in blood vessels and the heart, leading to the possibility that countering its vasodilating effect could expose organs to risk of ischemia.

The Food and Drug Administration approved rimegepant in 2020 for treatment of acute migraine attacks. Sponsor Biohaven is also seeking approval for migraine prevention after a successful phase 3 study published January 2021 in The Lancet.

Susan Hutchinson, MD, who is a headache specialist at Orange County Migraine & Headache Center in Irvine, Calif., presented the results at the American Academy of Neurology’s 2021 annual meeting. The open-label study suggested that rimegepant is generally safe. “The proportion of subjects reporting at least one adverse event was similar among subjects whether they had zero, one, or two or more cardiovascular disease risk factors, and also among those with low and moderate to high 10-year cardiovascular risk, as determined by the Framingham Risk Score,” said Dr. Hutchinson during her presentation.

Still, there was one concerning case: A 53-year-old man experienced an attack of angina. But he already had angina prior to the study, was being treated for hypercholesterolemia, and had current or former exposure to statins. “This adverse event was deemed by the investigator to not be related to rimegepant,” said Dr. Hutchinson.

During the following question-and-answer session, an attendee pressed Dr. Hutchinson about the case, and she admitted to some initial doubts. “That was my concern when I saw those slides. I’m like, ‘oh, my goodness.’ ” She clarified that the man’s angina history dated to 2016, which was several years before the trial, and the episode of angina occurred 7 months after the first dose of rimegepant. “He was treated with nitroglycerin and taken out of the trial,” said Dr. Hutchinson.
 

Proper patient selection is key

The research adds to the literature on rimegepant by providing data on multiple uses, as opposed to the phase 3 study, which only looked at single use, according to Olivia Begasse de Dhaem, MD, who is a neurology attending physician at Stamford (Conn.) Health and was the session moderator. Rimegepant and other oral CGRP receptor antagonists, including the FDA-approved ubrogepant and the investigative drug atogepant, will help fill the gap of patients who don’t tolerate or are ineligible for triptans, she said.

Dr. Begasse de Dhaem pointed out that patient selection remains important. “I think the main thing for patient care is to look at whether the patient we are treating would fit within the inclusion criteria, or would have been excluded from this study,” said Dr. Begasse de Dhaem. Specifically, according to its clinicaltrials.gov page, the trial excluded patients with hemiplegic and basilar migraine, as well as patients with uncontrolled, unstable, or recently diagnosed cardiovascular disease, those with a body mass index of 30 kg/m² or higher, and hemoglobin A1c levels of 6.5% or higher. “This also looked at people with less than 15 migraine days per month, so it’s limited in how much we can extrapolate to people with chronic migraine who may take more than 7.7 rimegepant [doses, the mean value taken by trial participants] per month,” Dr. Begasse de Dhaem added.

She also applauded the inclusion of older patients in the study, noting that most migraine studies have an upper age limit.

The study included subjects who experienced 2-14 moderate or severe migraine attacks per month, and they were allowed to take other migraine medications. Cardiovascular risk factors did not prevent entry to the trial and, like the previous pivotal trial, the long-term safety study admitted subjects older than 65. Among the study cohort, 1,514 participants were told to treat migraine pain of any intensity with 75 mg rimegepant up to once per day on an as-needed basis (PRN), and a second group of 286 were told to take 75 mg rimegepant every other day for 12 weeks, along with PRN dosing on nonscheduled treatment days.

Nearly 90% of subjects were female, the mean age was 43.1 years, and 3.7% were age 65 or older. Among the study participants, 40.8% had cardiovascular risk factors, including 28.8% with one risk factor, and 12.1% with two or more. About 7% had a moderate to high (≥10%) 10-year cardiovascular risk by Framingham Risk Score, 23.6% had a family history of coronary artery disease, 11.7% were being treated for hypertension, 10.4% smoked, 8.3% were being treated with a statin, and 3.0% had a history of diabetes.

In total, subjects were exposed to 112,014 doses of rimegepant, a mean of 7.7 doses per 4-week period. The exposure was similar across all risk groups, which included zero risk factors, one risk factor, and two or more risk factors; FRS of less than 10%; and FRS of 10% or greater. The most common adverse events were upper respiratory tract infection (8.8%), nasopharyngitis (6.8%), and sinusitis (5.1%). The frequency of one or more adverse events was similar among those with zero cardiovascular risk factors (59.6%), one risk factor (61.4%), two or more risk factors (62.2%), FRS less than 10% (59.9%), and FRS of 10% or greater (59.9%).

The study was funded by Biohaven Pharmaceuticals. Dr. Hutchinson has been a consultant or advisory board member for Biohaven, Alder, Allergan, Amgen, Avanir, electroCore, Lilly, Novartis, Promius, Supernus, and Teva. She has been on the speaker’s bureau for Allergan, Amgen, Avanir, electroCore, Lilly, Novartis, Promius, Supernus, and Teva. Dr. Begasse de Dhaem has no relevant financial disclosures.

Results from a 1-year, open-label safety study suggest that the oral migraine prevention drug rimegepant is safe and effective in patients with cardiovascular risk factors. Patients who fall into this category may be ineligible for treatment with triptans.

There are mechanistic concerns with rimegepant and related CGRP receptor antagonists. They block CGRP’s effect in the central nervous system, but CGRP is also active in blood vessels and the heart, leading to the possibility that countering its vasodilating effect could expose organs to risk of ischemia.

The Food and Drug Administration approved rimegepant in 2020 for treatment of acute migraine attacks. Sponsor Biohaven is also seeking approval for migraine prevention after a successful phase 3 study published January 2021 in The Lancet.

Susan Hutchinson, MD, who is a headache specialist at Orange County Migraine & Headache Center in Irvine, Calif., presented the results at the American Academy of Neurology’s 2021 annual meeting. The open-label study suggested that rimegepant is generally safe. “The proportion of subjects reporting at least one adverse event was similar among subjects whether they had zero, one, or two or more cardiovascular disease risk factors, and also among those with low and moderate to high 10-year cardiovascular risk, as determined by the Framingham Risk Score,” said Dr. Hutchinson during her presentation.

Still, there was one concerning case: A 53-year-old man experienced an attack of angina. But he already had angina prior to the study, was being treated for hypercholesterolemia, and had current or former exposure to statins. “This adverse event was deemed by the investigator to not be related to rimegepant,” said Dr. Hutchinson.

During the following question-and-answer session, an attendee pressed Dr. Hutchinson about the case, and she admitted to some initial doubts. “That was my concern when I saw those slides. I’m like, ‘oh, my goodness.’ ” She clarified that the man’s angina history dated to 2016, which was several years before the trial, and the episode of angina occurred 7 months after the first dose of rimegepant. “He was treated with nitroglycerin and taken out of the trial,” said Dr. Hutchinson.
 

Proper patient selection is key

The research adds to the literature on rimegepant by providing data on multiple uses, as opposed to the phase 3 study, which only looked at single use, according to Olivia Begasse de Dhaem, MD, who is a neurology attending physician at Stamford (Conn.) Health and was the session moderator. Rimegepant and other oral CGRP receptor antagonists, including the FDA-approved ubrogepant and the investigative drug atogepant, will help fill the gap of patients who don’t tolerate or are ineligible for triptans, she said.

Dr. Begasse de Dhaem pointed out that patient selection remains important. “I think the main thing for patient care is to look at whether the patient we are treating would fit within the inclusion criteria, or would have been excluded from this study,” said Dr. Begasse de Dhaem. Specifically, according to its clinicaltrials.gov page, the trial excluded patients with hemiplegic and basilar migraine, as well as patients with uncontrolled, unstable, or recently diagnosed cardiovascular disease, those with a body mass index of 30 kg/m² or higher, and hemoglobin A1c levels of 6.5% or higher. “This also looked at people with less than 15 migraine days per month, so it’s limited in how much we can extrapolate to people with chronic migraine who may take more than 7.7 rimegepant [doses, the mean value taken by trial participants] per month,” Dr. Begasse de Dhaem added.

She also applauded the inclusion of older patients in the study, noting that most migraine studies have an upper age limit.

The study included subjects who experienced 2-14 moderate or severe migraine attacks per month, and they were allowed to take other migraine medications. Cardiovascular risk factors did not prevent entry to the trial and, like the previous pivotal trial, the long-term safety study admitted subjects older than 65. Among the study cohort, 1,514 participants were told to treat migraine pain of any intensity with 75 mg rimegepant up to once per day on an as-needed basis (PRN), and a second group of 286 were told to take 75 mg rimegepant every other day for 12 weeks, along with PRN dosing on nonscheduled treatment days.

Nearly 90% of subjects were female, the mean age was 43.1 years, and 3.7% were age 65 or older. Among the study participants, 40.8% had cardiovascular risk factors, including 28.8% with one risk factor, and 12.1% with two or more. About 7% had a moderate to high (≥10%) 10-year cardiovascular risk by Framingham Risk Score, 23.6% had a family history of coronary artery disease, 11.7% were being treated for hypertension, 10.4% smoked, 8.3% were being treated with a statin, and 3.0% had a history of diabetes.

In total, subjects were exposed to 112,014 doses of rimegepant, a mean of 7.7 doses per 4-week period. The exposure was similar across all risk groups, which included zero risk factors, one risk factor, and two or more risk factors; FRS of less than 10%; and FRS of 10% or greater. The most common adverse events were upper respiratory tract infection (8.8%), nasopharyngitis (6.8%), and sinusitis (5.1%). The frequency of one or more adverse events was similar among those with zero cardiovascular risk factors (59.6%), one risk factor (61.4%), two or more risk factors (62.2%), FRS less than 10% (59.9%), and FRS of 10% or greater (59.9%).

The study was funded by Biohaven Pharmaceuticals. Dr. Hutchinson has been a consultant or advisory board member for Biohaven, Alder, Allergan, Amgen, Avanir, electroCore, Lilly, Novartis, Promius, Supernus, and Teva. She has been on the speaker’s bureau for Allergan, Amgen, Avanir, electroCore, Lilly, Novartis, Promius, Supernus, and Teva. Dr. Begasse de Dhaem has no relevant financial disclosures.

Results from a 1-year, open-label safety study suggest that the oral migraine prevention drug rimegepant is safe and effective in patients with cardiovascular risk factors. Patients who fall into this category may be ineligible for treatment with triptans.

There are mechanistic concerns with rimegepant and related CGRP receptor antagonists. They block CGRP’s effect in the central nervous system, but CGRP is also active in blood vessels and the heart, leading to the possibility that countering its vasodilating effect could expose organs to risk of ischemia.

The Food and Drug Administration approved rimegepant in 2020 for treatment of acute migraine attacks. Sponsor Biohaven is also seeking approval for migraine prevention after a successful phase 3 study published January 2021 in The Lancet.

Susan Hutchinson, MD, who is a headache specialist at Orange County Migraine & Headache Center in Irvine, Calif., presented the results at the American Academy of Neurology’s 2021 annual meeting. The open-label study suggested that rimegepant is generally safe. “The proportion of subjects reporting at least one adverse event was similar among subjects whether they had zero, one, or two or more cardiovascular disease risk factors, and also among those with low and moderate to high 10-year cardiovascular risk, as determined by the Framingham Risk Score,” said Dr. Hutchinson during her presentation.

Still, there was one concerning case: A 53-year-old man experienced an attack of angina. But he already had angina prior to the study, was being treated for hypercholesterolemia, and had current or former exposure to statins. “This adverse event was deemed by the investigator to not be related to rimegepant,” said Dr. Hutchinson.

During the following question-and-answer session, an attendee pressed Dr. Hutchinson about the case, and she admitted to some initial doubts. “That was my concern when I saw those slides. I’m like, ‘oh, my goodness.’ ” She clarified that the man’s angina history dated to 2016, which was several years before the trial, and the episode of angina occurred 7 months after the first dose of rimegepant. “He was treated with nitroglycerin and taken out of the trial,” said Dr. Hutchinson.
 

Proper patient selection is key

The research adds to the literature on rimegepant by providing data on multiple uses, as opposed to the phase 3 study, which only looked at single use, according to Olivia Begasse de Dhaem, MD, who is a neurology attending physician at Stamford (Conn.) Health and was the session moderator. Rimegepant and other oral CGRP receptor antagonists, including the FDA-approved ubrogepant and the investigative drug atogepant, will help fill the gap of patients who don’t tolerate or are ineligible for triptans, she said.

Dr. Begasse de Dhaem pointed out that patient selection remains important. “I think the main thing for patient care is to look at whether the patient we are treating would fit within the inclusion criteria, or would have been excluded from this study,” said Dr. Begasse de Dhaem. Specifically, according to its clinicaltrials.gov page, the trial excluded patients with hemiplegic and basilar migraine, as well as patients with uncontrolled, unstable, or recently diagnosed cardiovascular disease, those with a body mass index of 30 kg/m² or higher, and hemoglobin A1c levels of 6.5% or higher. “This also looked at people with less than 15 migraine days per month, so it’s limited in how much we can extrapolate to people with chronic migraine who may take more than 7.7 rimegepant [doses, the mean value taken by trial participants] per month,” Dr. Begasse de Dhaem added.

She also applauded the inclusion of older patients in the study, noting that most migraine studies have an upper age limit.

The study included subjects who experienced 2-14 moderate or severe migraine attacks per month, and they were allowed to take other migraine medications. Cardiovascular risk factors did not prevent entry to the trial and, like the previous pivotal trial, the long-term safety study admitted subjects older than 65. Among the study cohort, 1,514 participants were told to treat migraine pain of any intensity with 75 mg rimegepant up to once per day on an as-needed basis (PRN), and a second group of 286 were told to take 75 mg rimegepant every other day for 12 weeks, along with PRN dosing on nonscheduled treatment days.

Nearly 90% of subjects were female, the mean age was 43.1 years, and 3.7% were age 65 or older. Among the study participants, 40.8% had cardiovascular risk factors, including 28.8% with one risk factor, and 12.1% with two or more. About 7% had a moderate to high (≥10%) 10-year cardiovascular risk by Framingham Risk Score, 23.6% had a family history of coronary artery disease, 11.7% were being treated for hypertension, 10.4% smoked, 8.3% were being treated with a statin, and 3.0% had a history of diabetes.

In total, subjects were exposed to 112,014 doses of rimegepant, a mean of 7.7 doses per 4-week period. The exposure was similar across all risk groups, which included zero risk factors, one risk factor, and two or more risk factors; FRS of less than 10%; and FRS of 10% or greater. The most common adverse events were upper respiratory tract infection (8.8%), nasopharyngitis (6.8%), and sinusitis (5.1%). The frequency of one or more adverse events was similar among those with zero cardiovascular risk factors (59.6%), one risk factor (61.4%), two or more risk factors (62.2%), FRS less than 10% (59.9%), and FRS of 10% or greater (59.9%).

The study was funded by Biohaven Pharmaceuticals. Dr. Hutchinson has been a consultant or advisory board member for Biohaven, Alder, Allergan, Amgen, Avanir, electroCore, Lilly, Novartis, Promius, Supernus, and Teva. She has been on the speaker’s bureau for Allergan, Amgen, Avanir, electroCore, Lilly, Novartis, Promius, Supernus, and Teva. Dr. Begasse de Dhaem has no relevant financial disclosures.

Black patients with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) may respond differently to common MS treatment compared to their White peers, new research suggests. In a study of almost 200 patients, Black participants with MS or NMOSD showed significantly more rapid B-cell repopulation 6-12 months after receiving anti-CD20 infusion therapy with rituximab or ocrelizumab (Rituxan, Ocrevus, Genentech) than did White participants.

“The results showed that this B-cell targeted therapy wore off more quickly in African Americans,” said study coinvestigator Gregg J. Silverman, MD, a professor at New York University.

He said that, although the study was more observational in design, “over time when people come back to the clinic, it gives you an idea of whether the agent is still working in their bodies.”

Overall, “our findings raise the question of whether the same therapy dose may be equally effective for all people,” coinvestigator Ilya Kister, MD, also from NYU, added in a press release.

Dr. Kister noted that this could have implications for the way Black patients with autoimmune diseases are treated in the future.

The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
 

More severe disease in Black patients

Anti-CD20 infusion therapy, or B-cell depletion therapy, is commonly used to treat autoimmune diseases, including MS and NMOSD. “While previous research has shown that this type of infusion therapy is effective for people with these diseases, we also know that Black people tend to have more severe courses of MS,” Dr. Kister said.

“We wanted to compare how quickly the B cells came back in Black people and White people after treatment,” he added.

Dr. Silverman noted that he has been “studying this agent in autoimmune disease for many years. And from all the different studies, I don’t think we had the right population to ask this question. Demographics were just reviewed as they were.”

The current study included 168 participants (mean age, 44 years; 71% women) who had a diagnosis of MS (n = 134) or NMOSD (n = 32) or who were considered to have MS or NMOSD (n = 2). In addition, 36% of the participants self-identified as Black or African American, 36% self-identified as White, and 28% self-identified as another race.

Flow cytometry results were available for all patients after undergoing anti-CD20 infusions at the NYU MS Care Center. Cluster analyses were conducted on the following B-cell subsets: CD19, CD20, IgD, and CD27. “B-cell repopulation was defined as any detectable number of CD19+ cells on flow cytometry,” the investigators reported.
 

Clinical implications?

Results showed that 29.8% of the full study group showed B-cell repopulation a mean of 6.8 months after infusion. In those with B-cell repopulation, 80.3% had IgD+/CD27– subsets, 11.6% had IgD–/CD27+, 6.2% had IgD–/CD27–, and 1.8% had IgD+/CD27+. These B-cell subset ratios did not differ significantly between the Black and White participants.

Interestingly, no patients showed B-cell repopulation before 4 months after infusion. From 4 to 6 months after infusion, there were no significant differences between the Black and White participants in terms of frequency of B-cell repopulation (20.8% vs. 17.9%, respectively; P = .79).

However, repopulation was significantly more frequent in the Black patients 6-12 months after infusion (76.2% vs. 33.3%; P = .02).

Overall, the findings “may have implications for clinical management of MS/NMOSD” in Black individuals, the investigators wrote.

“I was impressed by the differences we saw in responses of patients that were self-declaring as African Americans versus those who were Whites,” Dr. Silverman said. However, “as we say in science: it gives us an answer but it raises even more questions, which may well be important for helping us understand how the agent works and how the disease affects different people.”

Still, Dr. Silverman noted that the findings give clinicians using the agent “a signal that they should be very vigilant. It was an observation at one center, but we’re asking our colleagues [at other clinics] to think about being more careful as they review data with their patients.”

He added that future multicenter studies will allow these issues to be assessed more comprehensively. “This was a discovery study; it now needs validation; and maybe the next step would be looking into the mechanism.”

Dr. Silverman pointed out that the Food and Drug Administration–approved label for this type of therapy “allows for somewhat more frequent dosing. So that might be indicated if it’s found that it’s wearing off in an individual. Perhaps they should be treated more frequently?”

“At a minimum, this has raised our vigilance – and we’re interested to see what the feedback will be at the [AAN] meeting,” he added.
 

Real-world data

Commenting on the findings, Eric Klawiter, MD, associate professor of neurology at Harvard Medical School and director of the Multiple Sclerosis and NMO unit at Massachusetts General Hospital, both in Boston, noted that an important study factor was the focus on repopulation to identify specific groups “who may be early repopulators” as it relates to disease activity and disability progression in MS.

“I thought this was a nicely designed study that made good use of real-world data in MS and NMOSD,” added Dr. Klawiter, who was not involved with the research. He pointed out that timing was another interesting aspect of the study. “As we typically use these cell-depleting agents on an ‘every-6-month’ basis, the most pertinent time frame surrounds those that repopulate prior to 6 months.”

If the current study would have shown differences between the Black and White participants at that time point, “I think that would have been most pertinent from a clinical standpoint and a greater opportunity for intervention,” Dr. Klawiter said. “But we saw that, before 4 and 6 months, [the difference] wasn’t significant.”

Still, “after 6 months, the study demonstrates that Black people with MS and NMOSD may repopulate faster,” he added.

“The only real change a clinician could make would be to modify the frequency of the dosing. So if we can identify certain characteristics that would lead you to want to evaluate for the need of redosing sooner, I think that would be useful,” he said.

Specific characteristics identified in previous research include body mass index. “If there are also ethnicity factors, that would be an additional demographic factor that a clinician should pay close attention to,” said Dr. Klawiter.

He noted that his current practice is to check flow cytometry and B-cell counts at the time of a patient’s next infusion. “And if I’m seeing that B-cell levels are repleting at that time point, I am already then making adjustments with their next infusion as to the dosing frequency,” he added.

“This [study] may elucidate some of the potential reasons why we see some people replete their B cells faster than others, but I think additional studies are necessary to make that determination,” Dr. Klawiter concluded.

Genentech provided funding for the study. Dr. Silverman reported no relevant financial relationships. Dr. Klawiter reported having received research funds and consulting fees from Genentech.

A version of this article first appeared on Medscape.com.

Black patients with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) may respond differently to common MS treatment compared to their White peers, new research suggests. In a study of almost 200 patients, Black participants with MS or NMOSD showed significantly more rapid B-cell repopulation 6-12 months after receiving anti-CD20 infusion therapy with rituximab or ocrelizumab (Rituxan, Ocrevus, Genentech) than did White participants.

“The results showed that this B-cell targeted therapy wore off more quickly in African Americans,” said study coinvestigator Gregg J. Silverman, MD, a professor at New York University.

He said that, although the study was more observational in design, “over time when people come back to the clinic, it gives you an idea of whether the agent is still working in their bodies.”

Overall, “our findings raise the question of whether the same therapy dose may be equally effective for all people,” coinvestigator Ilya Kister, MD, also from NYU, added in a press release.

Dr. Kister noted that this could have implications for the way Black patients with autoimmune diseases are treated in the future.

The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
 

More severe disease in Black patients

Anti-CD20 infusion therapy, or B-cell depletion therapy, is commonly used to treat autoimmune diseases, including MS and NMOSD. “While previous research has shown that this type of infusion therapy is effective for people with these diseases, we also know that Black people tend to have more severe courses of MS,” Dr. Kister said.

“We wanted to compare how quickly the B cells came back in Black people and White people after treatment,” he added.

Dr. Silverman noted that he has been “studying this agent in autoimmune disease for many years. And from all the different studies, I don’t think we had the right population to ask this question. Demographics were just reviewed as they were.”

The current study included 168 participants (mean age, 44 years; 71% women) who had a diagnosis of MS (n = 134) or NMOSD (n = 32) or who were considered to have MS or NMOSD (n = 2). In addition, 36% of the participants self-identified as Black or African American, 36% self-identified as White, and 28% self-identified as another race.

Flow cytometry results were available for all patients after undergoing anti-CD20 infusions at the NYU MS Care Center. Cluster analyses were conducted on the following B-cell subsets: CD19, CD20, IgD, and CD27. “B-cell repopulation was defined as any detectable number of CD19+ cells on flow cytometry,” the investigators reported.
 

Clinical implications?

Results showed that 29.8% of the full study group showed B-cell repopulation a mean of 6.8 months after infusion. In those with B-cell repopulation, 80.3% had IgD+/CD27– subsets, 11.6% had IgD–/CD27+, 6.2% had IgD–/CD27–, and 1.8% had IgD+/CD27+. These B-cell subset ratios did not differ significantly between the Black and White participants.

Interestingly, no patients showed B-cell repopulation before 4 months after infusion. From 4 to 6 months after infusion, there were no significant differences between the Black and White participants in terms of frequency of B-cell repopulation (20.8% vs. 17.9%, respectively; P = .79).

However, repopulation was significantly more frequent in the Black patients 6-12 months after infusion (76.2% vs. 33.3%; P = .02).

Overall, the findings “may have implications for clinical management of MS/NMOSD” in Black individuals, the investigators wrote.

“I was impressed by the differences we saw in responses of patients that were self-declaring as African Americans versus those who were Whites,” Dr. Silverman said. However, “as we say in science: it gives us an answer but it raises even more questions, which may well be important for helping us understand how the agent works and how the disease affects different people.”

Still, Dr. Silverman noted that the findings give clinicians using the agent “a signal that they should be very vigilant. It was an observation at one center, but we’re asking our colleagues [at other clinics] to think about being more careful as they review data with their patients.”

He added that future multicenter studies will allow these issues to be assessed more comprehensively. “This was a discovery study; it now needs validation; and maybe the next step would be looking into the mechanism.”

Dr. Silverman pointed out that the Food and Drug Administration–approved label for this type of therapy “allows for somewhat more frequent dosing. So that might be indicated if it’s found that it’s wearing off in an individual. Perhaps they should be treated more frequently?”

“At a minimum, this has raised our vigilance – and we’re interested to see what the feedback will be at the [AAN] meeting,” he added.
 

Real-world data

Commenting on the findings, Eric Klawiter, MD, associate professor of neurology at Harvard Medical School and director of the Multiple Sclerosis and NMO unit at Massachusetts General Hospital, both in Boston, noted that an important study factor was the focus on repopulation to identify specific groups “who may be early repopulators” as it relates to disease activity and disability progression in MS.

“I thought this was a nicely designed study that made good use of real-world data in MS and NMOSD,” added Dr. Klawiter, who was not involved with the research. He pointed out that timing was another interesting aspect of the study. “As we typically use these cell-depleting agents on an ‘every-6-month’ basis, the most pertinent time frame surrounds those that repopulate prior to 6 months.”

If the current study would have shown differences between the Black and White participants at that time point, “I think that would have been most pertinent from a clinical standpoint and a greater opportunity for intervention,” Dr. Klawiter said. “But we saw that, before 4 and 6 months, [the difference] wasn’t significant.”

Still, “after 6 months, the study demonstrates that Black people with MS and NMOSD may repopulate faster,” he added.

“The only real change a clinician could make would be to modify the frequency of the dosing. So if we can identify certain characteristics that would lead you to want to evaluate for the need of redosing sooner, I think that would be useful,” he said.

Specific characteristics identified in previous research include body mass index. “If there are also ethnicity factors, that would be an additional demographic factor that a clinician should pay close attention to,” said Dr. Klawiter.

He noted that his current practice is to check flow cytometry and B-cell counts at the time of a patient’s next infusion. “And if I’m seeing that B-cell levels are repleting at that time point, I am already then making adjustments with their next infusion as to the dosing frequency,” he added.

“This [study] may elucidate some of the potential reasons why we see some people replete their B cells faster than others, but I think additional studies are necessary to make that determination,” Dr. Klawiter concluded.

Genentech provided funding for the study. Dr. Silverman reported no relevant financial relationships. Dr. Klawiter reported having received research funds and consulting fees from Genentech.

A version of this article first appeared on Medscape.com.

Black patients with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) may respond differently to common MS treatment compared to their White peers, new research suggests. In a study of almost 200 patients, Black participants with MS or NMOSD showed significantly more rapid B-cell repopulation 6-12 months after receiving anti-CD20 infusion therapy with rituximab or ocrelizumab (Rituxan, Ocrevus, Genentech) than did White participants.

“The results showed that this B-cell targeted therapy wore off more quickly in African Americans,” said study coinvestigator Gregg J. Silverman, MD, a professor at New York University.

He said that, although the study was more observational in design, “over time when people come back to the clinic, it gives you an idea of whether the agent is still working in their bodies.”

Overall, “our findings raise the question of whether the same therapy dose may be equally effective for all people,” coinvestigator Ilya Kister, MD, also from NYU, added in a press release.

Dr. Kister noted that this could have implications for the way Black patients with autoimmune diseases are treated in the future.

The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
 

More severe disease in Black patients

Anti-CD20 infusion therapy, or B-cell depletion therapy, is commonly used to treat autoimmune diseases, including MS and NMOSD. “While previous research has shown that this type of infusion therapy is effective for people with these diseases, we also know that Black people tend to have more severe courses of MS,” Dr. Kister said.

“We wanted to compare how quickly the B cells came back in Black people and White people after treatment,” he added.

Dr. Silverman noted that he has been “studying this agent in autoimmune disease for many years. And from all the different studies, I don’t think we had the right population to ask this question. Demographics were just reviewed as they were.”

The current study included 168 participants (mean age, 44 years; 71% women) who had a diagnosis of MS (n = 134) or NMOSD (n = 32) or who were considered to have MS or NMOSD (n = 2). In addition, 36% of the participants self-identified as Black or African American, 36% self-identified as White, and 28% self-identified as another race.

Flow cytometry results were available for all patients after undergoing anti-CD20 infusions at the NYU MS Care Center. Cluster analyses were conducted on the following B-cell subsets: CD19, CD20, IgD, and CD27. “B-cell repopulation was defined as any detectable number of CD19+ cells on flow cytometry,” the investigators reported.
 

Clinical implications?

Results showed that 29.8% of the full study group showed B-cell repopulation a mean of 6.8 months after infusion. In those with B-cell repopulation, 80.3% had IgD+/CD27– subsets, 11.6% had IgD–/CD27+, 6.2% had IgD–/CD27–, and 1.8% had IgD+/CD27+. These B-cell subset ratios did not differ significantly between the Black and White participants.

Interestingly, no patients showed B-cell repopulation before 4 months after infusion. From 4 to 6 months after infusion, there were no significant differences between the Black and White participants in terms of frequency of B-cell repopulation (20.8% vs. 17.9%, respectively; P = .79).

However, repopulation was significantly more frequent in the Black patients 6-12 months after infusion (76.2% vs. 33.3%; P = .02).

Overall, the findings “may have implications for clinical management of MS/NMOSD” in Black individuals, the investigators wrote.

“I was impressed by the differences we saw in responses of patients that were self-declaring as African Americans versus those who were Whites,” Dr. Silverman said. However, “as we say in science: it gives us an answer but it raises even more questions, which may well be important for helping us understand how the agent works and how the disease affects different people.”

Still, Dr. Silverman noted that the findings give clinicians using the agent “a signal that they should be very vigilant. It was an observation at one center, but we’re asking our colleagues [at other clinics] to think about being more careful as they review data with their patients.”

He added that future multicenter studies will allow these issues to be assessed more comprehensively. “This was a discovery study; it now needs validation; and maybe the next step would be looking into the mechanism.”

Dr. Silverman pointed out that the Food and Drug Administration–approved label for this type of therapy “allows for somewhat more frequent dosing. So that might be indicated if it’s found that it’s wearing off in an individual. Perhaps they should be treated more frequently?”

“At a minimum, this has raised our vigilance – and we’re interested to see what the feedback will be at the [AAN] meeting,” he added.
 

Real-world data

Commenting on the findings, Eric Klawiter, MD, associate professor of neurology at Harvard Medical School and director of the Multiple Sclerosis and NMO unit at Massachusetts General Hospital, both in Boston, noted that an important study factor was the focus on repopulation to identify specific groups “who may be early repopulators” as it relates to disease activity and disability progression in MS.

“I thought this was a nicely designed study that made good use of real-world data in MS and NMOSD,” added Dr. Klawiter, who was not involved with the research. He pointed out that timing was another interesting aspect of the study. “As we typically use these cell-depleting agents on an ‘every-6-month’ basis, the most pertinent time frame surrounds those that repopulate prior to 6 months.”

If the current study would have shown differences between the Black and White participants at that time point, “I think that would have been most pertinent from a clinical standpoint and a greater opportunity for intervention,” Dr. Klawiter said. “But we saw that, before 4 and 6 months, [the difference] wasn’t significant.”

Still, “after 6 months, the study demonstrates that Black people with MS and NMOSD may repopulate faster,” he added.

“The only real change a clinician could make would be to modify the frequency of the dosing. So if we can identify certain characteristics that would lead you to want to evaluate for the need of redosing sooner, I think that would be useful,” he said.

Specific characteristics identified in previous research include body mass index. “If there are also ethnicity factors, that would be an additional demographic factor that a clinician should pay close attention to,” said Dr. Klawiter.

He noted that his current practice is to check flow cytometry and B-cell counts at the time of a patient’s next infusion. “And if I’m seeing that B-cell levels are repleting at that time point, I am already then making adjustments with their next infusion as to the dosing frequency,” he added.

“This [study] may elucidate some of the potential reasons why we see some people replete their B cells faster than others, but I think additional studies are necessary to make that determination,” Dr. Klawiter concluded.

Genentech provided funding for the study. Dr. Silverman reported no relevant financial relationships. Dr. Klawiter reported having received research funds and consulting fees from Genentech.

A version of this article first appeared on Medscape.com.