Neurology Reviews

Immersive virtual reality (VR) distraction therapy may be more effective at controlling pain in hospitalized patients with cancer than a two-dimensional guided imagery experience, suggests a new randomized controlled trial.

While both interventions brought some pain relief, VR therapy yielded greater, longer-lasting comfort, reported lead author Hunter Groninger, MD, of MedStar Health Research Institute, Hyattsville, Maryland, and colleagues.

MedStar Health

“Investigators have explored immersive VR interventions in cancer populations for a variety of indications including anxiety, depression, fatigue, and procedure‐associated pain, particularly among patients with pediatric cancer and adult breast cancer,” the investigators wrote in Cancer. “Nevertheless, despite growing evidence supporting the efficacy of VR‐delivered interventions for analgesia, few data address its role to mitigate cancer‐related pain specifically.”

To address this knowledge gap, Dr. Groninger and colleagues enrolled 128 adult hospitalized patients with cancer of any kind, all of whom had moderate to severe pain (self-reported score at least 4 out of 10) within the past 24 hours.
 

Study Methods and Results

Patients were randomized to receive either 10 minutes of immersive VR distraction therapy or 10 minutes of two-dimensional guided imagery distraction therapy.

“[The VR therapy] provides noncompetitive experiences in which the user can move around and explore natural environments (e.g., beachscape, forest) from standing, seated, or fixed positions, including within a hospital bed or chair,” the investigators wrote. “We provided over‐the‐ear headphones to assure high sound quality for the experience in the virtual natural environment.”

The two-dimensional intervention, delivered via electronic tablet, featured a meditation with images of natural landscapes and instrumental background music.

“We chose this active control because it is readily available and reflects content similar to relaxation‐focused television channels that are increasingly common in hospital settings,” the investigators noted.

Compared with this more common approach, patients who received VR therapy had significantly greater immediate reduction in pain (mean change in pain score, –1.4 vs –0.7; P = .03). Twenty-four hours later, improvements in the VR group generally persisted, while pain level in the two-dimensional group returned almost to baseline (P = .004). In addition, patients in the VR group reported significantly greater improvements in general distress and pain bothersomeness.

“VR therapies may modulate the pain experience by reducing the level of attention paid to noxious stimuli, thereby suppressing transmission of painful sensations via pain processing pathways to the cerebral cortex, particularly with more active VR experiences compared to passive experiences,” the investigators wrote.
 

Downsides to Using VR

Although VR brought more benefit, participants in the VR group more often reported difficulty using the intervention compared with those who interacted with an electronic tablet.

Plus, one VR user described mild dizziness that resolved with pharmacologic intervention. Still, approximately 9 out of 10 participants in each group reported willingness to try the intervention again.
 

Future VR Research

“Virtual reality is a rapidly evolving technology with a wealth of potential patient‐facing applications,” the investigators wrote. “Future studies should explore repeated use, optimal dosing, and impact on VR therapy on opioid analgesic requirements as well as usability testing, VR content preferences and facilitators of analgesia, and barriers and facilitators to use in acute care settings.”

This study was supported by the American Cancer Society. The investigators disclosed no conflicts of interest.

Immersive virtual reality (VR) distraction therapy may be more effective at controlling pain in hospitalized patients with cancer than a two-dimensional guided imagery experience, suggests a new randomized controlled trial.

While both interventions brought some pain relief, VR therapy yielded greater, longer-lasting comfort, reported lead author Hunter Groninger, MD, of MedStar Health Research Institute, Hyattsville, Maryland, and colleagues.

MedStar Health

“Investigators have explored immersive VR interventions in cancer populations for a variety of indications including anxiety, depression, fatigue, and procedure‐associated pain, particularly among patients with pediatric cancer and adult breast cancer,” the investigators wrote in Cancer. “Nevertheless, despite growing evidence supporting the efficacy of VR‐delivered interventions for analgesia, few data address its role to mitigate cancer‐related pain specifically.”

To address this knowledge gap, Dr. Groninger and colleagues enrolled 128 adult hospitalized patients with cancer of any kind, all of whom had moderate to severe pain (self-reported score at least 4 out of 10) within the past 24 hours.
 

Study Methods and Results

Patients were randomized to receive either 10 minutes of immersive VR distraction therapy or 10 minutes of two-dimensional guided imagery distraction therapy.

“[The VR therapy] provides noncompetitive experiences in which the user can move around and explore natural environments (e.g., beachscape, forest) from standing, seated, or fixed positions, including within a hospital bed or chair,” the investigators wrote. “We provided over‐the‐ear headphones to assure high sound quality for the experience in the virtual natural environment.”

The two-dimensional intervention, delivered via electronic tablet, featured a meditation with images of natural landscapes and instrumental background music.

“We chose this active control because it is readily available and reflects content similar to relaxation‐focused television channels that are increasingly common in hospital settings,” the investigators noted.

Compared with this more common approach, patients who received VR therapy had significantly greater immediate reduction in pain (mean change in pain score, –1.4 vs –0.7; P = .03). Twenty-four hours later, improvements in the VR group generally persisted, while pain level in the two-dimensional group returned almost to baseline (P = .004). In addition, patients in the VR group reported significantly greater improvements in general distress and pain bothersomeness.

“VR therapies may modulate the pain experience by reducing the level of attention paid to noxious stimuli, thereby suppressing transmission of painful sensations via pain processing pathways to the cerebral cortex, particularly with more active VR experiences compared to passive experiences,” the investigators wrote.
 

Downsides to Using VR

Although VR brought more benefit, participants in the VR group more often reported difficulty using the intervention compared with those who interacted with an electronic tablet.

Plus, one VR user described mild dizziness that resolved with pharmacologic intervention. Still, approximately 9 out of 10 participants in each group reported willingness to try the intervention again.
 

Future VR Research

“Virtual reality is a rapidly evolving technology with a wealth of potential patient‐facing applications,” the investigators wrote. “Future studies should explore repeated use, optimal dosing, and impact on VR therapy on opioid analgesic requirements as well as usability testing, VR content preferences and facilitators of analgesia, and barriers and facilitators to use in acute care settings.”

This study was supported by the American Cancer Society. The investigators disclosed no conflicts of interest.

Immersive virtual reality (VR) distraction therapy may be more effective at controlling pain in hospitalized patients with cancer than a two-dimensional guided imagery experience, suggests a new randomized controlled trial.

While both interventions brought some pain relief, VR therapy yielded greater, longer-lasting comfort, reported lead author Hunter Groninger, MD, of MedStar Health Research Institute, Hyattsville, Maryland, and colleagues.

MedStar Health

“Investigators have explored immersive VR interventions in cancer populations for a variety of indications including anxiety, depression, fatigue, and procedure‐associated pain, particularly among patients with pediatric cancer and adult breast cancer,” the investigators wrote in Cancer. “Nevertheless, despite growing evidence supporting the efficacy of VR‐delivered interventions for analgesia, few data address its role to mitigate cancer‐related pain specifically.”

To address this knowledge gap, Dr. Groninger and colleagues enrolled 128 adult hospitalized patients with cancer of any kind, all of whom had moderate to severe pain (self-reported score at least 4 out of 10) within the past 24 hours.
 

Study Methods and Results

Patients were randomized to receive either 10 minutes of immersive VR distraction therapy or 10 minutes of two-dimensional guided imagery distraction therapy.

“[The VR therapy] provides noncompetitive experiences in which the user can move around and explore natural environments (e.g., beachscape, forest) from standing, seated, or fixed positions, including within a hospital bed or chair,” the investigators wrote. “We provided over‐the‐ear headphones to assure high sound quality for the experience in the virtual natural environment.”

The two-dimensional intervention, delivered via electronic tablet, featured a meditation with images of natural landscapes and instrumental background music.

“We chose this active control because it is readily available and reflects content similar to relaxation‐focused television channels that are increasingly common in hospital settings,” the investigators noted.

Compared with this more common approach, patients who received VR therapy had significantly greater immediate reduction in pain (mean change in pain score, –1.4 vs –0.7; P = .03). Twenty-four hours later, improvements in the VR group generally persisted, while pain level in the two-dimensional group returned almost to baseline (P = .004). In addition, patients in the VR group reported significantly greater improvements in general distress and pain bothersomeness.

“VR therapies may modulate the pain experience by reducing the level of attention paid to noxious stimuli, thereby suppressing transmission of painful sensations via pain processing pathways to the cerebral cortex, particularly with more active VR experiences compared to passive experiences,” the investigators wrote.
 

Downsides to Using VR

Although VR brought more benefit, participants in the VR group more often reported difficulty using the intervention compared with those who interacted with an electronic tablet.

Plus, one VR user described mild dizziness that resolved with pharmacologic intervention. Still, approximately 9 out of 10 participants in each group reported willingness to try the intervention again.
 

Future VR Research

“Virtual reality is a rapidly evolving technology with a wealth of potential patient‐facing applications,” the investigators wrote. “Future studies should explore repeated use, optimal dosing, and impact on VR therapy on opioid analgesic requirements as well as usability testing, VR content preferences and facilitators of analgesia, and barriers and facilitators to use in acute care settings.”

This study was supported by the American Cancer Society. The investigators disclosed no conflicts of interest.

Three recent publications highlight the ability of telestroke protocols not only to match the quality of in-person care, but in some instances to exceed it. These studies set the stage for larger studies comparing outcomes and efficiency of various telemedicine and transport models and gauging stakeholder satisfaction, authors said.

Surprising Results

In a single-site retrospective comparison of 252 patients with acute stroke assessed under an in-house telestroke protocol and 2437 assessed in person, telestroke provided statistically significant advantages in the following areas:

• Door-to-imaging times (median: 38 minutes vs 44)
• Rates of intravenous (18.2% vs 8.6%) and mechanical (10.4% vs 5.1%) treatment
• Length of stay (median: 6 days vs 8)
• Symptomatic hemorrhagic transformation rate (1.1% vs 5.1%)
• Mortality (6.7% vs 11.1%)

The better metrics observed in the telestroke group were especially surprising, said lead author Rodrigo Meirelles Massaud, MD, because the same team of neurologists conducted both types of evaluations. “This consistency ensures that the quality and expertise of medical care were maintained across both groups,” said Dr. Massaud, a neurologist at the Hospital Israelita Albert Einstein in São Paulo, Brazil. The study appeared online in Frontiers in Neurology.

The findings also counter the preconceived notion that distance medicine could be inferior because of the inability to conduct direct physical examinations and the potential for communication failures, he said. The telestroke group’s younger average age (63.5 years vs 69.5 years) and lower initial National Institutes of Health Stroke Scale (NIHSS) scores — 2 versus 3 — might explain the disparity, Dr. Massaud added, because both factors augur improved outcomes.

Conversely, the authors wrote that the in-person group’s lower median door-to-groin puncture time in ischemic stroke (103.5 minutes vs 151.5 for telemedicine) likely resulted from the need to transport patients from satellite facilities to a hub hospital with neurologists on continuous standby. After adjustment for initial NIHSS score and age, both groups achieved similar percentages of patients with modified Rankin Scale (mRS) scores of 0-2 at discharge: 58.5% for in-person evaluation versus 61.9% for telemedicine (P = .028).
 

Acute Ischemic Stroke

In another study, a systematic review that included 7396 thrombolysed patients with acute ischemic stroke, odds ratios (ORs) revealed no significant differences between telestroke and in-person care for the percentage of mRS scores 0-2 at discharge (1.06; P = .5), 90-day mortality (OR, 1.16; P = .17), and symptomatic intracranial hemorrhage (OR, 0.99; P = .93). The study appeared in the March International Journal of Stroke.

The lack of significant differences between telestroke and in-person care regarding mortality and mRS scores of 0-2 (which defines a good outcome) surprised researchers, said lead author Ahmed Mohamed, who is completing a master of health sciences degree in medical physiology at the University of Toronto Temerty Faculty of Medicine, Toronto, Ontario, Canada.

“When we were starting this project,” he said, “we thought that telemedicine would probably take longer than conventional treatment.” And waiting longer for treatment — especially for patients with acute ischemic stroke — leads to worse outcomes. “However,” Mr. Mohamed said, “that wasn’t the case.” Additional measures that showed no significant differences included rates of intravenous tissue plasminogen activator (ivtPA) use and endovascular mechanical thrombectomy.
 

Telestroke Expansion

Authors of a study that analyzed the impact of expanding telestroke coverage beyond community ERs credited many postexpansion improvements to the addition of advanced practice providers (APPs). ProMedica Stroke Network, Toledo, Ohio, added seven APPs in June 2020 to provide two-way audiovisual inpatient stroke and TIA consultations and follow-ups at 19 spoke facilities supported by vascular neurologists at the hub comprehensive stroke center (CSC).

Revamping the TS workflow resulted in a threefold increase in TS cart utilization, a 31% decrease in transfers to the CSC, and a higher home discharge rate from spoke hospitals than from the CSC (57.38% versus 52.8%, respectively). Diagnostic sensitivity also improved, with overall decreases in stroke and TIA diagnosis of 11.5% and 39.8%, respectively, and a 12.9% increase in identification of stroke mimics. The study was published in the March Annals of Neurology.
 

Future Directions

All three author groups called for larger, more granular follow-up studies. Mr. Mohamed said that the 7396-patient review of 33 studies does not show whether video consultations with neurologists produce better outcomes than phone calls, for example, or whether utilizing different telestroke modalities such as a third-party telemedicine service provides better outcomes than other methods. Additionally, authors wrote, future research should compare telestroke versus non-telestroke patient transport models to optimize treatment plans and outcomes and validate potential advantages and disadvantages of telemedicine for patients with acute ischemic stroke.

“There is also a need to understand the long-term outcomes of patients treated via telestroke versus in-person care,” said Dr. Massaud. Future studies could include randomized, controlled trials comparing telestroke to traditional care in various settings with larger sample sizes, he said. “Additionally, research into the cost-effectiveness of telestroke services, patient satisfaction, and the impact of telestroke on different subtypes of stroke could provide a more comprehensive understanding of its benefits and limitations.”

Dr. Massaud and Mr. Mohamed reported no relevant financial interests. Authors of all three studies reported no funding sources or potential conflicts of interest.

Three recent publications highlight the ability of telestroke protocols not only to match the quality of in-person care, but in some instances to exceed it. These studies set the stage for larger studies comparing outcomes and efficiency of various telemedicine and transport models and gauging stakeholder satisfaction, authors said.

Surprising Results

In a single-site retrospective comparison of 252 patients with acute stroke assessed under an in-house telestroke protocol and 2437 assessed in person, telestroke provided statistically significant advantages in the following areas:

• Door-to-imaging times (median: 38 minutes vs 44)
• Rates of intravenous (18.2% vs 8.6%) and mechanical (10.4% vs 5.1%) treatment
• Length of stay (median: 6 days vs 8)
• Symptomatic hemorrhagic transformation rate (1.1% vs 5.1%)
• Mortality (6.7% vs 11.1%)

The better metrics observed in the telestroke group were especially surprising, said lead author Rodrigo Meirelles Massaud, MD, because the same team of neurologists conducted both types of evaluations. “This consistency ensures that the quality and expertise of medical care were maintained across both groups,” said Dr. Massaud, a neurologist at the Hospital Israelita Albert Einstein in São Paulo, Brazil. The study appeared online in Frontiers in Neurology.

The findings also counter the preconceived notion that distance medicine could be inferior because of the inability to conduct direct physical examinations and the potential for communication failures, he said. The telestroke group’s younger average age (63.5 years vs 69.5 years) and lower initial National Institutes of Health Stroke Scale (NIHSS) scores — 2 versus 3 — might explain the disparity, Dr. Massaud added, because both factors augur improved outcomes.

Conversely, the authors wrote that the in-person group’s lower median door-to-groin puncture time in ischemic stroke (103.5 minutes vs 151.5 for telemedicine) likely resulted from the need to transport patients from satellite facilities to a hub hospital with neurologists on continuous standby. After adjustment for initial NIHSS score and age, both groups achieved similar percentages of patients with modified Rankin Scale (mRS) scores of 0-2 at discharge: 58.5% for in-person evaluation versus 61.9% for telemedicine (P = .028).
 

Acute Ischemic Stroke

In another study, a systematic review that included 7396 thrombolysed patients with acute ischemic stroke, odds ratios (ORs) revealed no significant differences between telestroke and in-person care for the percentage of mRS scores 0-2 at discharge (1.06; P = .5), 90-day mortality (OR, 1.16; P = .17), and symptomatic intracranial hemorrhage (OR, 0.99; P = .93). The study appeared in the March International Journal of Stroke.

The lack of significant differences between telestroke and in-person care regarding mortality and mRS scores of 0-2 (which defines a good outcome) surprised researchers, said lead author Ahmed Mohamed, who is completing a master of health sciences degree in medical physiology at the University of Toronto Temerty Faculty of Medicine, Toronto, Ontario, Canada.

“When we were starting this project,” he said, “we thought that telemedicine would probably take longer than conventional treatment.” And waiting longer for treatment — especially for patients with acute ischemic stroke — leads to worse outcomes. “However,” Mr. Mohamed said, “that wasn’t the case.” Additional measures that showed no significant differences included rates of intravenous tissue plasminogen activator (ivtPA) use and endovascular mechanical thrombectomy.
 

Telestroke Expansion

Authors of a study that analyzed the impact of expanding telestroke coverage beyond community ERs credited many postexpansion improvements to the addition of advanced practice providers (APPs). ProMedica Stroke Network, Toledo, Ohio, added seven APPs in June 2020 to provide two-way audiovisual inpatient stroke and TIA consultations and follow-ups at 19 spoke facilities supported by vascular neurologists at the hub comprehensive stroke center (CSC).

Revamping the TS workflow resulted in a threefold increase in TS cart utilization, a 31% decrease in transfers to the CSC, and a higher home discharge rate from spoke hospitals than from the CSC (57.38% versus 52.8%, respectively). Diagnostic sensitivity also improved, with overall decreases in stroke and TIA diagnosis of 11.5% and 39.8%, respectively, and a 12.9% increase in identification of stroke mimics. The study was published in the March Annals of Neurology.
 

Future Directions

All three author groups called for larger, more granular follow-up studies. Mr. Mohamed said that the 7396-patient review of 33 studies does not show whether video consultations with neurologists produce better outcomes than phone calls, for example, or whether utilizing different telestroke modalities such as a third-party telemedicine service provides better outcomes than other methods. Additionally, authors wrote, future research should compare telestroke versus non-telestroke patient transport models to optimize treatment plans and outcomes and validate potential advantages and disadvantages of telemedicine for patients with acute ischemic stroke.

“There is also a need to understand the long-term outcomes of patients treated via telestroke versus in-person care,” said Dr. Massaud. Future studies could include randomized, controlled trials comparing telestroke to traditional care in various settings with larger sample sizes, he said. “Additionally, research into the cost-effectiveness of telestroke services, patient satisfaction, and the impact of telestroke on different subtypes of stroke could provide a more comprehensive understanding of its benefits and limitations.”

Dr. Massaud and Mr. Mohamed reported no relevant financial interests. Authors of all three studies reported no funding sources or potential conflicts of interest.

Three recent publications highlight the ability of telestroke protocols not only to match the quality of in-person care, but in some instances to exceed it. These studies set the stage for larger studies comparing outcomes and efficiency of various telemedicine and transport models and gauging stakeholder satisfaction, authors said.

Surprising Results

In a single-site retrospective comparison of 252 patients with acute stroke assessed under an in-house telestroke protocol and 2437 assessed in person, telestroke provided statistically significant advantages in the following areas:

• Door-to-imaging times (median: 38 minutes vs 44)
• Rates of intravenous (18.2% vs 8.6%) and mechanical (10.4% vs 5.1%) treatment
• Length of stay (median: 6 days vs 8)
• Symptomatic hemorrhagic transformation rate (1.1% vs 5.1%)
• Mortality (6.7% vs 11.1%)

The better metrics observed in the telestroke group were especially surprising, said lead author Rodrigo Meirelles Massaud, MD, because the same team of neurologists conducted both types of evaluations. “This consistency ensures that the quality and expertise of medical care were maintained across both groups,” said Dr. Massaud, a neurologist at the Hospital Israelita Albert Einstein in São Paulo, Brazil. The study appeared online in Frontiers in Neurology.

The findings also counter the preconceived notion that distance medicine could be inferior because of the inability to conduct direct physical examinations and the potential for communication failures, he said. The telestroke group’s younger average age (63.5 years vs 69.5 years) and lower initial National Institutes of Health Stroke Scale (NIHSS) scores — 2 versus 3 — might explain the disparity, Dr. Massaud added, because both factors augur improved outcomes.

Conversely, the authors wrote that the in-person group’s lower median door-to-groin puncture time in ischemic stroke (103.5 minutes vs 151.5 for telemedicine) likely resulted from the need to transport patients from satellite facilities to a hub hospital with neurologists on continuous standby. After adjustment for initial NIHSS score and age, both groups achieved similar percentages of patients with modified Rankin Scale (mRS) scores of 0-2 at discharge: 58.5% for in-person evaluation versus 61.9% for telemedicine (P = .028).
 

Acute Ischemic Stroke

In another study, a systematic review that included 7396 thrombolysed patients with acute ischemic stroke, odds ratios (ORs) revealed no significant differences between telestroke and in-person care for the percentage of mRS scores 0-2 at discharge (1.06; P = .5), 90-day mortality (OR, 1.16; P = .17), and symptomatic intracranial hemorrhage (OR, 0.99; P = .93). The study appeared in the March International Journal of Stroke.

The lack of significant differences between telestroke and in-person care regarding mortality and mRS scores of 0-2 (which defines a good outcome) surprised researchers, said lead author Ahmed Mohamed, who is completing a master of health sciences degree in medical physiology at the University of Toronto Temerty Faculty of Medicine, Toronto, Ontario, Canada.

“When we were starting this project,” he said, “we thought that telemedicine would probably take longer than conventional treatment.” And waiting longer for treatment — especially for patients with acute ischemic stroke — leads to worse outcomes. “However,” Mr. Mohamed said, “that wasn’t the case.” Additional measures that showed no significant differences included rates of intravenous tissue plasminogen activator (ivtPA) use and endovascular mechanical thrombectomy.
 

Telestroke Expansion

Authors of a study that analyzed the impact of expanding telestroke coverage beyond community ERs credited many postexpansion improvements to the addition of advanced practice providers (APPs). ProMedica Stroke Network, Toledo, Ohio, added seven APPs in June 2020 to provide two-way audiovisual inpatient stroke and TIA consultations and follow-ups at 19 spoke facilities supported by vascular neurologists at the hub comprehensive stroke center (CSC).

Revamping the TS workflow resulted in a threefold increase in TS cart utilization, a 31% decrease in transfers to the CSC, and a higher home discharge rate from spoke hospitals than from the CSC (57.38% versus 52.8%, respectively). Diagnostic sensitivity also improved, with overall decreases in stroke and TIA diagnosis of 11.5% and 39.8%, respectively, and a 12.9% increase in identification of stroke mimics. The study was published in the March Annals of Neurology.
 

Future Directions

All three author groups called for larger, more granular follow-up studies. Mr. Mohamed said that the 7396-patient review of 33 studies does not show whether video consultations with neurologists produce better outcomes than phone calls, for example, or whether utilizing different telestroke modalities such as a third-party telemedicine service provides better outcomes than other methods. Additionally, authors wrote, future research should compare telestroke versus non-telestroke patient transport models to optimize treatment plans and outcomes and validate potential advantages and disadvantages of telemedicine for patients with acute ischemic stroke.

“There is also a need to understand the long-term outcomes of patients treated via telestroke versus in-person care,” said Dr. Massaud. Future studies could include randomized, controlled trials comparing telestroke to traditional care in various settings with larger sample sizes, he said. “Additionally, research into the cost-effectiveness of telestroke services, patient satisfaction, and the impact of telestroke on different subtypes of stroke could provide a more comprehensive understanding of its benefits and limitations.”

Dr. Massaud and Mr. Mohamed reported no relevant financial interests. Authors of all three studies reported no funding sources or potential conflicts of interest.

Cognitive assessments administered via a smartphone app are a reliable and valid way to detect frontotemporal dementia (FTD) in high-risk individuals, new research showed.

Cognitive tests administered remotely on the phone “showed similar findings as our gold standard in-clinic cognitive tests and brain imaging,” said study investigator Adam M. Staffaroni, PhD, with the Memory and Aging Center, University of California San Francisco.

“We also provided evidence that these assessments may be useful for detecting early symptoms of the disease at a level that is on par, or perhaps slightly better, than our gold standard in-person tests,” Dr. Staffaroni said.

The study was published online in JAMA Network Open.
 

Tough to Diagnose

Although relatively rare, FTD is the top cause of dementia in patients younger than 60 years. Patients are usually diagnosed relatively late in the disease because they are young and because their symptoms may be mistaken for psychiatric disorders.

In addition, behavioral and motor symptoms of FTD can make it hard for families to get to an academic center for in-clinic assessments, making remote assessments a huge need.

Dr. Staffaroni and colleagues with the ALLFTD Consortium partnered with software company Datacubed Health to develop the ALLFTD-mApp, which includes cognitive, motor, and speech tasks.

They assessed the reliability and validity of the app, against standard in-clinic assessments, in 350 individuals (mean age, 54 years; 58% women; mean education level, 16.5 years).

Among the 329 individuals with data on disease stage, 195 (59%) were asymptomatic or had preclinical FTD, 66 (20%) had prodromal FTD, and 68 (21%) had symptomatic FTD with a range of clinical syndromes.

The smartphone app showed “moderate to excellent” reliability within a single administration (ie, internally consistent) and across repeated assessments (ie, test-retest reliability), the researchers reported.

Validity was supported by association of smartphones tests with disease severity, criterion-standard neuropsychological tests, and brain volume, they noted.
 

Of Great Interest

They also reported that a composite of brief smartphone tests accurately distinguished dementia from cognitively unimpaired participants, screening out participants without symptoms, and detected prodromal FTD with greater sensitivity than the Montreal Cognitive Assessment.

“This tool is currently being used in several research studies. The remote aspect of this technology is important because it could allow researchers to collect data more frequently, which may give them a more accurate picture of the disease. Furthermore, researchers can be more inclusive in their study designs and include participants who otherwise might have difficulty traveling to academic centers for standard in-person visits,” said Dr. Staffaroni.

“Because the app appears sensitive to early stages of the disease, it could be also used as a screening tool, possibly alongside other remote data collection, to help identify participants that might be appropriate for a clinical trial. At this point, these technologies are not ready for clinical use and require additional research studies to understand their clinical utility,” he cautioned.

Commenting on the study, Walter Kukull, PhD, director of the National Alzheimer’s Coordinating Center at the University of Washington in Seattle, noted that “remote direct and indirect testing/telemetry are of great interest to the field and are being examined carefully in comparison to in-person means both for validity and possibly earlier recognition.”

This research was supported by grants from the National Institutes of Health, the Association for Frontotemporal Degeneration, the Bluefield Project to Cure FTD, the Rainwater Charitable Foundation, and the Larry L. Hillblom Foundation. Dr. Staffaroni reported being a coinventor of four ALLFTD mobile application tasks (not analyzed in the current study); receiving licensing fees from Datacubed Health and research support from the National Institute on Aging of the NIH, Bluefield Project to Cure FTD, the Alzheimer’s Association, the Larry L. Hillblom Foundation, and the Rainwater Charitable Foundation; and consulting for Alector Inc., Eli Lilly and Company Prevail Therapeutics, Passage Bio Inc, and Takeda Pharmaceuticals. Dr. Kukull participated in the ALLFTD Consortium.

A version of this article appeared on Medscape.com.

Cognitive assessments administered via a smartphone app are a reliable and valid way to detect frontotemporal dementia (FTD) in high-risk individuals, new research showed.

Cognitive tests administered remotely on the phone “showed similar findings as our gold standard in-clinic cognitive tests and brain imaging,” said study investigator Adam M. Staffaroni, PhD, with the Memory and Aging Center, University of California San Francisco.

“We also provided evidence that these assessments may be useful for detecting early symptoms of the disease at a level that is on par, or perhaps slightly better, than our gold standard in-person tests,” Dr. Staffaroni said.

The study was published online in JAMA Network Open.
 

Tough to Diagnose

Although relatively rare, FTD is the top cause of dementia in patients younger than 60 years. Patients are usually diagnosed relatively late in the disease because they are young and because their symptoms may be mistaken for psychiatric disorders.

In addition, behavioral and motor symptoms of FTD can make it hard for families to get to an academic center for in-clinic assessments, making remote assessments a huge need.

Dr. Staffaroni and colleagues with the ALLFTD Consortium partnered with software company Datacubed Health to develop the ALLFTD-mApp, which includes cognitive, motor, and speech tasks.

They assessed the reliability and validity of the app, against standard in-clinic assessments, in 350 individuals (mean age, 54 years; 58% women; mean education level, 16.5 years).

Among the 329 individuals with data on disease stage, 195 (59%) were asymptomatic or had preclinical FTD, 66 (20%) had prodromal FTD, and 68 (21%) had symptomatic FTD with a range of clinical syndromes.

The smartphone app showed “moderate to excellent” reliability within a single administration (ie, internally consistent) and across repeated assessments (ie, test-retest reliability), the researchers reported.

Validity was supported by association of smartphones tests with disease severity, criterion-standard neuropsychological tests, and brain volume, they noted.
 

Of Great Interest

They also reported that a composite of brief smartphone tests accurately distinguished dementia from cognitively unimpaired participants, screening out participants without symptoms, and detected prodromal FTD with greater sensitivity than the Montreal Cognitive Assessment.

“This tool is currently being used in several research studies. The remote aspect of this technology is important because it could allow researchers to collect data more frequently, which may give them a more accurate picture of the disease. Furthermore, researchers can be more inclusive in their study designs and include participants who otherwise might have difficulty traveling to academic centers for standard in-person visits,” said Dr. Staffaroni.

“Because the app appears sensitive to early stages of the disease, it could be also used as a screening tool, possibly alongside other remote data collection, to help identify participants that might be appropriate for a clinical trial. At this point, these technologies are not ready for clinical use and require additional research studies to understand their clinical utility,” he cautioned.

Commenting on the study, Walter Kukull, PhD, director of the National Alzheimer’s Coordinating Center at the University of Washington in Seattle, noted that “remote direct and indirect testing/telemetry are of great interest to the field and are being examined carefully in comparison to in-person means both for validity and possibly earlier recognition.”

This research was supported by grants from the National Institutes of Health, the Association for Frontotemporal Degeneration, the Bluefield Project to Cure FTD, the Rainwater Charitable Foundation, and the Larry L. Hillblom Foundation. Dr. Staffaroni reported being a coinventor of four ALLFTD mobile application tasks (not analyzed in the current study); receiving licensing fees from Datacubed Health and research support from the National Institute on Aging of the NIH, Bluefield Project to Cure FTD, the Alzheimer’s Association, the Larry L. Hillblom Foundation, and the Rainwater Charitable Foundation; and consulting for Alector Inc., Eli Lilly and Company Prevail Therapeutics, Passage Bio Inc, and Takeda Pharmaceuticals. Dr. Kukull participated in the ALLFTD Consortium.

A version of this article appeared on Medscape.com.

Cognitive assessments administered via a smartphone app are a reliable and valid way to detect frontotemporal dementia (FTD) in high-risk individuals, new research showed.

Cognitive tests administered remotely on the phone “showed similar findings as our gold standard in-clinic cognitive tests and brain imaging,” said study investigator Adam M. Staffaroni, PhD, with the Memory and Aging Center, University of California San Francisco.

“We also provided evidence that these assessments may be useful for detecting early symptoms of the disease at a level that is on par, or perhaps slightly better, than our gold standard in-person tests,” Dr. Staffaroni said.

The study was published online in JAMA Network Open.
 

Tough to Diagnose

Although relatively rare, FTD is the top cause of dementia in patients younger than 60 years. Patients are usually diagnosed relatively late in the disease because they are young and because their symptoms may be mistaken for psychiatric disorders.

In addition, behavioral and motor symptoms of FTD can make it hard for families to get to an academic center for in-clinic assessments, making remote assessments a huge need.

Dr. Staffaroni and colleagues with the ALLFTD Consortium partnered with software company Datacubed Health to develop the ALLFTD-mApp, which includes cognitive, motor, and speech tasks.

They assessed the reliability and validity of the app, against standard in-clinic assessments, in 350 individuals (mean age, 54 years; 58% women; mean education level, 16.5 years).

Among the 329 individuals with data on disease stage, 195 (59%) were asymptomatic or had preclinical FTD, 66 (20%) had prodromal FTD, and 68 (21%) had symptomatic FTD with a range of clinical syndromes.

The smartphone app showed “moderate to excellent” reliability within a single administration (ie, internally consistent) and across repeated assessments (ie, test-retest reliability), the researchers reported.

Validity was supported by association of smartphones tests with disease severity, criterion-standard neuropsychological tests, and brain volume, they noted.
 

Of Great Interest

They also reported that a composite of brief smartphone tests accurately distinguished dementia from cognitively unimpaired participants, screening out participants without symptoms, and detected prodromal FTD with greater sensitivity than the Montreal Cognitive Assessment.

“This tool is currently being used in several research studies. The remote aspect of this technology is important because it could allow researchers to collect data more frequently, which may give them a more accurate picture of the disease. Furthermore, researchers can be more inclusive in their study designs and include participants who otherwise might have difficulty traveling to academic centers for standard in-person visits,” said Dr. Staffaroni.

“Because the app appears sensitive to early stages of the disease, it could be also used as a screening tool, possibly alongside other remote data collection, to help identify participants that might be appropriate for a clinical trial. At this point, these technologies are not ready for clinical use and require additional research studies to understand their clinical utility,” he cautioned.

Commenting on the study, Walter Kukull, PhD, director of the National Alzheimer’s Coordinating Center at the University of Washington in Seattle, noted that “remote direct and indirect testing/telemetry are of great interest to the field and are being examined carefully in comparison to in-person means both for validity and possibly earlier recognition.”

This research was supported by grants from the National Institutes of Health, the Association for Frontotemporal Degeneration, the Bluefield Project to Cure FTD, the Rainwater Charitable Foundation, and the Larry L. Hillblom Foundation. Dr. Staffaroni reported being a coinventor of four ALLFTD mobile application tasks (not analyzed in the current study); receiving licensing fees from Datacubed Health and research support from the National Institute on Aging of the NIH, Bluefield Project to Cure FTD, the Alzheimer’s Association, the Larry L. Hillblom Foundation, and the Rainwater Charitable Foundation; and consulting for Alector Inc., Eli Lilly and Company Prevail Therapeutics, Passage Bio Inc, and Takeda Pharmaceuticals. Dr. Kukull participated in the ALLFTD Consortium.

A version of this article appeared on Medscape.com.

Nontraditional risk factors such as migraine and autoimmune diseases have a significantly greater effect on stroke risk in young adults than traditional risk factors such as hypertension, high cholesterol, and tobacco use, new research showed.

The findings may offer insight into the increased incidence of stroke in adults under age 45, which has more than doubled in the past 20 years in high-income countries, while incidence in those over 45 has decreased.

Investigators believe the findings are important because most conventional prevention efforts focus on traditional risk factors.

“The younger they are at the time of stroke, the more likely their stroke is due to a nontraditional risk factor,” lead author Michelle Leppert, MD, an assistant professor of neurology at the University of Colorado School of Medicine, Aurora, Colorado, said in a news release.

The findings were published online in Circulation: Cardiovascular Quality and Outcomes.
 

Traditional Versus Nontraditional

The researchers retrospectively analyzed 2618 stroke cases (52% female; 73% ischemic stroke) that resulted in an inpatient admission and 7827 controls, all aged 18-55 years. Data came from the Colorado All Payer Claims Database between January 2012 and April 2019. Controls were matched by age, sex, and insurance type.

Traditional risk factors were defined as being a well-established risk factor for stroke that is routinely noted during stroke prevention screenings in older adults, including hypertension, diabetes, hyperlipidemia, sleep apnea, cardiovascular disease, alcohol, substance use disorder, and obesity.

Nontraditional risk factors were defined as those that are rarely cited as a cause of stroke in older adults, including migraines, malignancy, HIV, hepatitis, thrombophilia, autoimmune disease, vasculitis, sickle cell disease, heart valve disease, renal failure, and hormonal risk factors in women, such as oral contraceptives, pregnancy, or puerperium.

Overall, traditional risk factors were more common in stroke cases, with nontraditional factors playing a smaller role. However, among adults aged 18-34 years, more strokes were associated with nontraditional than traditional risk factors in men (31% vs 25%, respectively) and in women (43% vs 33%, respectively).

Migraine, the most common nontraditional risk factor for stroke in this younger age group, was found in 20% of men (odds ratio [OR], 3.9) and 35% of women (OR, 3.3).

Other notable nontraditional risk factors included heart valve disease in both men and women (OR, 3.1 and OR, 4.2, respectively); renal failure in men (OR, 8.9); and autoimmune diseases in women (OR, 8.8).
 

An Underestimate?

The contribution of nontraditional risk factors declined with age. After the age of 44, they were no longer significant. Hypertension was the most important traditional risk factor and increased in contribution with age.

“There have been many studies demonstrating the association between migraines and strokes, but to our knowledge, this study may be the first to demonstrate just how much stroke risk may be attributable to migraines,” Dr. Leppert said.

Overall, women had significantly more risk factors for stroke than men. Among controls, 52% and 34% of women had at least one traditional and nontraditional risk factors, respectively, compared with 48% and 22% in men.

The total contribution of nontraditional risk factors was likely an underestimate because some such factors, including the autoimmune disorder antiphospholipid syndrome and patent foramen ovale, “lacked reliable administrative algorithms” and could not be assessed in this study, the researchers noted.

Further research on how nontraditional risk factors affect strokes could lead to better prevention.

“We need to better understand the underlying mechanisms of these nontraditional risk factors to develop targeted interventions,” Dr. Leppert said.

The study was funded by the National Institutes of Health/National Center for Advancing Translational Sciences Colorado Clinical and Translational Science Award. Dr. Leppert reports receiving an American Heart Association Career Development Grant. Other disclosures are included in the original article.

A version of this article appeared on Medscape.com.

Nontraditional risk factors such as migraine and autoimmune diseases have a significantly greater effect on stroke risk in young adults than traditional risk factors such as hypertension, high cholesterol, and tobacco use, new research showed.

The findings may offer insight into the increased incidence of stroke in adults under age 45, which has more than doubled in the past 20 years in high-income countries, while incidence in those over 45 has decreased.

Investigators believe the findings are important because most conventional prevention efforts focus on traditional risk factors.

“The younger they are at the time of stroke, the more likely their stroke is due to a nontraditional risk factor,” lead author Michelle Leppert, MD, an assistant professor of neurology at the University of Colorado School of Medicine, Aurora, Colorado, said in a news release.

The findings were published online in Circulation: Cardiovascular Quality and Outcomes.
 

Traditional Versus Nontraditional

The researchers retrospectively analyzed 2618 stroke cases (52% female; 73% ischemic stroke) that resulted in an inpatient admission and 7827 controls, all aged 18-55 years. Data came from the Colorado All Payer Claims Database between January 2012 and April 2019. Controls were matched by age, sex, and insurance type.

Traditional risk factors were defined as being a well-established risk factor for stroke that is routinely noted during stroke prevention screenings in older adults, including hypertension, diabetes, hyperlipidemia, sleep apnea, cardiovascular disease, alcohol, substance use disorder, and obesity.

Nontraditional risk factors were defined as those that are rarely cited as a cause of stroke in older adults, including migraines, malignancy, HIV, hepatitis, thrombophilia, autoimmune disease, vasculitis, sickle cell disease, heart valve disease, renal failure, and hormonal risk factors in women, such as oral contraceptives, pregnancy, or puerperium.

Overall, traditional risk factors were more common in stroke cases, with nontraditional factors playing a smaller role. However, among adults aged 18-34 years, more strokes were associated with nontraditional than traditional risk factors in men (31% vs 25%, respectively) and in women (43% vs 33%, respectively).

Migraine, the most common nontraditional risk factor for stroke in this younger age group, was found in 20% of men (odds ratio [OR], 3.9) and 35% of women (OR, 3.3).

Other notable nontraditional risk factors included heart valve disease in both men and women (OR, 3.1 and OR, 4.2, respectively); renal failure in men (OR, 8.9); and autoimmune diseases in women (OR, 8.8).
 

An Underestimate?

The contribution of nontraditional risk factors declined with age. After the age of 44, they were no longer significant. Hypertension was the most important traditional risk factor and increased in contribution with age.

“There have been many studies demonstrating the association between migraines and strokes, but to our knowledge, this study may be the first to demonstrate just how much stroke risk may be attributable to migraines,” Dr. Leppert said.

Overall, women had significantly more risk factors for stroke than men. Among controls, 52% and 34% of women had at least one traditional and nontraditional risk factors, respectively, compared with 48% and 22% in men.

The total contribution of nontraditional risk factors was likely an underestimate because some such factors, including the autoimmune disorder antiphospholipid syndrome and patent foramen ovale, “lacked reliable administrative algorithms” and could not be assessed in this study, the researchers noted.

Further research on how nontraditional risk factors affect strokes could lead to better prevention.

“We need to better understand the underlying mechanisms of these nontraditional risk factors to develop targeted interventions,” Dr. Leppert said.

The study was funded by the National Institutes of Health/National Center for Advancing Translational Sciences Colorado Clinical and Translational Science Award. Dr. Leppert reports receiving an American Heart Association Career Development Grant. Other disclosures are included in the original article.

A version of this article appeared on Medscape.com.

Nontraditional risk factors such as migraine and autoimmune diseases have a significantly greater effect on stroke risk in young adults than traditional risk factors such as hypertension, high cholesterol, and tobacco use, new research showed.

The findings may offer insight into the increased incidence of stroke in adults under age 45, which has more than doubled in the past 20 years in high-income countries, while incidence in those over 45 has decreased.

Investigators believe the findings are important because most conventional prevention efforts focus on traditional risk factors.

“The younger they are at the time of stroke, the more likely their stroke is due to a nontraditional risk factor,” lead author Michelle Leppert, MD, an assistant professor of neurology at the University of Colorado School of Medicine, Aurora, Colorado, said in a news release.

The findings were published online in Circulation: Cardiovascular Quality and Outcomes.
 

Traditional Versus Nontraditional

The researchers retrospectively analyzed 2618 stroke cases (52% female; 73% ischemic stroke) that resulted in an inpatient admission and 7827 controls, all aged 18-55 years. Data came from the Colorado All Payer Claims Database between January 2012 and April 2019. Controls were matched by age, sex, and insurance type.

Traditional risk factors were defined as being a well-established risk factor for stroke that is routinely noted during stroke prevention screenings in older adults, including hypertension, diabetes, hyperlipidemia, sleep apnea, cardiovascular disease, alcohol, substance use disorder, and obesity.

Nontraditional risk factors were defined as those that are rarely cited as a cause of stroke in older adults, including migraines, malignancy, HIV, hepatitis, thrombophilia, autoimmune disease, vasculitis, sickle cell disease, heart valve disease, renal failure, and hormonal risk factors in women, such as oral contraceptives, pregnancy, or puerperium.

Overall, traditional risk factors were more common in stroke cases, with nontraditional factors playing a smaller role. However, among adults aged 18-34 years, more strokes were associated with nontraditional than traditional risk factors in men (31% vs 25%, respectively) and in women (43% vs 33%, respectively).

Migraine, the most common nontraditional risk factor for stroke in this younger age group, was found in 20% of men (odds ratio [OR], 3.9) and 35% of women (OR, 3.3).

Other notable nontraditional risk factors included heart valve disease in both men and women (OR, 3.1 and OR, 4.2, respectively); renal failure in men (OR, 8.9); and autoimmune diseases in women (OR, 8.8).
 

An Underestimate?

The contribution of nontraditional risk factors declined with age. After the age of 44, they were no longer significant. Hypertension was the most important traditional risk factor and increased in contribution with age.

“There have been many studies demonstrating the association between migraines and strokes, but to our knowledge, this study may be the first to demonstrate just how much stroke risk may be attributable to migraines,” Dr. Leppert said.

Overall, women had significantly more risk factors for stroke than men. Among controls, 52% and 34% of women had at least one traditional and nontraditional risk factors, respectively, compared with 48% and 22% in men.

The total contribution of nontraditional risk factors was likely an underestimate because some such factors, including the autoimmune disorder antiphospholipid syndrome and patent foramen ovale, “lacked reliable administrative algorithms” and could not be assessed in this study, the researchers noted.

Further research on how nontraditional risk factors affect strokes could lead to better prevention.

“We need to better understand the underlying mechanisms of these nontraditional risk factors to develop targeted interventions,” Dr. Leppert said.

The study was funded by the National Institutes of Health/National Center for Advancing Translational Sciences Colorado Clinical and Translational Science Award. Dr. Leppert reports receiving an American Heart Association Career Development Grant. Other disclosures are included in the original article.

A version of this article appeared on Medscape.com.

Healthcare providers hold wide-ranging opinions about prescribing opioids for chronic cancer pain, and many are haunted by the conflicting factors driving their views, from legal concerns to threats of violence, say the authors of new research.

These findings suggest that evidence-based, systematic guidance is needed to steer opioid usage in cancer survivorship, wrote lead author Hailey W. Bulls, PhD, of the University of Pittsburgh, and colleagues.

“Prescription opioids are considered the standard of care to treat moderate to severe cancer pain during active treatment, yet guidance in the posttreatment survivorship phase is much less clear,” the investigators wrote. “Existing clinical resources recognize that opioid prescribing in survivorship is complex and nuanced and that the relative benefits and risks in this population are not fully understood.”
 

Who Should Manage Chronic Cancer Pain?

Despite the knowledge gap, survivors are typically excluded from long-term opioid use studies, leaving providers in a largely data-free zone. Simultaneously, patients who had been receiving focused care during their cancer treatment find themselves with an ill-defined health care team.

“Without a clear transition of care, survivors may seek pain management services from a variety of specialties, including oncologists, palliative care clinicians, primary care clinicians, and pain management specialists,” the investigators wrote. “However, many clinicians may view pain management to be outside of their skill set and may not be well equipped to handle opioid continuation or deprescribing [or] to manage the potential consequences of long‐term opioid use like side effects, misuse, and/or opioid use disorder.”
 

What Factors Guide Opioid Prescribing Practices for Chronic Cancer Pain?

To learn more about prescribing practices in this setting, Dr. Bulls and colleagues conducted qualitative interviews with 20 providers representing four specialties: oncology (n = 5), palliative care (n = 8), primary care (n = 5), and pain management (n = 2). Eighteen of these participants were physicians and two were advanced practice providers. Average time in clinical practice was about 16 years.

These interviews yielded three themes.

First, no “medical home” exists for chronic pain management in cancer survivors.

“Although clinicians generally agreed that minimizing the role of opioids in chronic pain management in cancer survivors was desirable, they described a lack of common treatment protocols to guide pain management in survivorship,” the investigators wrote.

Second, the interviews revealed that prescribing strategies are partly driven by peer pressure, sometimes leading to tension between providers and feelings of self-doubt.

“I feel like there’s been this weird judgment thing that’s happened [to] the prescribers,” one primary care provider said during the interview. “Because, when I trained … pain was a vital sign, and we were supposed to treat pain, and now I feel like we’re all being judged for that.”

The third theme revolved around fear of consequences resulting from prescribing practices, including fears of violent repercussions.

“You may not know, but pain specialists have been shot in this country for [refusing to prescribe opioids],” one pain management specialist said during the interview. “There’s been a number of shootings of pain specialists who would not prescribe opioids. So, I mean, there’s real issues of violence.”

Meanwhile, a palliative care provider described legal pressure from the opposite direction:

“I think there’s a lot of fear of litigiousness … and loss of licenses. That sort of makes them pressure us into not prescribing opioids or sticking with a certain number per day that might not be therapeutic for a patient.”

Reflecting on these themes, the investigators identified “a fundamental uncertainty in survivorship pain management.”
 

What Strategies Might Improve Opioid Prescribing Practices for Chronic Cancer Pain?

After sharing their attitudes about prescribing opioids for chronic cancer pain, the clinicians were asked for suggestions to improve the situation.

They offered four main suggestions: create relevant guidelines, increase education and access to pain management options for clinicians, increase interdisciplinary communication across medical subspecialties, and promote multidisciplinary care in the survivorship setting.

Dr. Bulls and colleagues supported these strategies in their concluding remarks and called for more research.

This study was supported by the National Institute of Drug Abuse, the National Institutes of Health, the National Center for Advancing Translational Sciences, and the National Cancer Institute. The investigators disclosed relationships with Arcadia Health Solutions and Biomotivate.

Healthcare providers hold wide-ranging opinions about prescribing opioids for chronic cancer pain, and many are haunted by the conflicting factors driving their views, from legal concerns to threats of violence, say the authors of new research.

These findings suggest that evidence-based, systematic guidance is needed to steer opioid usage in cancer survivorship, wrote lead author Hailey W. Bulls, PhD, of the University of Pittsburgh, and colleagues.

“Prescription opioids are considered the standard of care to treat moderate to severe cancer pain during active treatment, yet guidance in the posttreatment survivorship phase is much less clear,” the investigators wrote. “Existing clinical resources recognize that opioid prescribing in survivorship is complex and nuanced and that the relative benefits and risks in this population are not fully understood.”
 

Who Should Manage Chronic Cancer Pain?

Despite the knowledge gap, survivors are typically excluded from long-term opioid use studies, leaving providers in a largely data-free zone. Simultaneously, patients who had been receiving focused care during their cancer treatment find themselves with an ill-defined health care team.

“Without a clear transition of care, survivors may seek pain management services from a variety of specialties, including oncologists, palliative care clinicians, primary care clinicians, and pain management specialists,” the investigators wrote. “However, many clinicians may view pain management to be outside of their skill set and may not be well equipped to handle opioid continuation or deprescribing [or] to manage the potential consequences of long‐term opioid use like side effects, misuse, and/or opioid use disorder.”
 

What Factors Guide Opioid Prescribing Practices for Chronic Cancer Pain?

To learn more about prescribing practices in this setting, Dr. Bulls and colleagues conducted qualitative interviews with 20 providers representing four specialties: oncology (n = 5), palliative care (n = 8), primary care (n = 5), and pain management (n = 2). Eighteen of these participants were physicians and two were advanced practice providers. Average time in clinical practice was about 16 years.

These interviews yielded three themes.

First, no “medical home” exists for chronic pain management in cancer survivors.

“Although clinicians generally agreed that minimizing the role of opioids in chronic pain management in cancer survivors was desirable, they described a lack of common treatment protocols to guide pain management in survivorship,” the investigators wrote.

Second, the interviews revealed that prescribing strategies are partly driven by peer pressure, sometimes leading to tension between providers and feelings of self-doubt.

“I feel like there’s been this weird judgment thing that’s happened [to] the prescribers,” one primary care provider said during the interview. “Because, when I trained … pain was a vital sign, and we were supposed to treat pain, and now I feel like we’re all being judged for that.”

The third theme revolved around fear of consequences resulting from prescribing practices, including fears of violent repercussions.

“You may not know, but pain specialists have been shot in this country for [refusing to prescribe opioids],” one pain management specialist said during the interview. “There’s been a number of shootings of pain specialists who would not prescribe opioids. So, I mean, there’s real issues of violence.”

Meanwhile, a palliative care provider described legal pressure from the opposite direction:

“I think there’s a lot of fear of litigiousness … and loss of licenses. That sort of makes them pressure us into not prescribing opioids or sticking with a certain number per day that might not be therapeutic for a patient.”

Reflecting on these themes, the investigators identified “a fundamental uncertainty in survivorship pain management.”
 

What Strategies Might Improve Opioid Prescribing Practices for Chronic Cancer Pain?

After sharing their attitudes about prescribing opioids for chronic cancer pain, the clinicians were asked for suggestions to improve the situation.

They offered four main suggestions: create relevant guidelines, increase education and access to pain management options for clinicians, increase interdisciplinary communication across medical subspecialties, and promote multidisciplinary care in the survivorship setting.

Dr. Bulls and colleagues supported these strategies in their concluding remarks and called for more research.

This study was supported by the National Institute of Drug Abuse, the National Institutes of Health, the National Center for Advancing Translational Sciences, and the National Cancer Institute. The investigators disclosed relationships with Arcadia Health Solutions and Biomotivate.

Healthcare providers hold wide-ranging opinions about prescribing opioids for chronic cancer pain, and many are haunted by the conflicting factors driving their views, from legal concerns to threats of violence, say the authors of new research.

These findings suggest that evidence-based, systematic guidance is needed to steer opioid usage in cancer survivorship, wrote lead author Hailey W. Bulls, PhD, of the University of Pittsburgh, and colleagues.

“Prescription opioids are considered the standard of care to treat moderate to severe cancer pain during active treatment, yet guidance in the posttreatment survivorship phase is much less clear,” the investigators wrote. “Existing clinical resources recognize that opioid prescribing in survivorship is complex and nuanced and that the relative benefits and risks in this population are not fully understood.”
 

Who Should Manage Chronic Cancer Pain?

Despite the knowledge gap, survivors are typically excluded from long-term opioid use studies, leaving providers in a largely data-free zone. Simultaneously, patients who had been receiving focused care during their cancer treatment find themselves with an ill-defined health care team.

“Without a clear transition of care, survivors may seek pain management services from a variety of specialties, including oncologists, palliative care clinicians, primary care clinicians, and pain management specialists,” the investigators wrote. “However, many clinicians may view pain management to be outside of their skill set and may not be well equipped to handle opioid continuation or deprescribing [or] to manage the potential consequences of long‐term opioid use like side effects, misuse, and/or opioid use disorder.”
 

What Factors Guide Opioid Prescribing Practices for Chronic Cancer Pain?

To learn more about prescribing practices in this setting, Dr. Bulls and colleagues conducted qualitative interviews with 20 providers representing four specialties: oncology (n = 5), palliative care (n = 8), primary care (n = 5), and pain management (n = 2). Eighteen of these participants were physicians and two were advanced practice providers. Average time in clinical practice was about 16 years.

These interviews yielded three themes.

First, no “medical home” exists for chronic pain management in cancer survivors.

“Although clinicians generally agreed that minimizing the role of opioids in chronic pain management in cancer survivors was desirable, they described a lack of common treatment protocols to guide pain management in survivorship,” the investigators wrote.

Second, the interviews revealed that prescribing strategies are partly driven by peer pressure, sometimes leading to tension between providers and feelings of self-doubt.

“I feel like there’s been this weird judgment thing that’s happened [to] the prescribers,” one primary care provider said during the interview. “Because, when I trained … pain was a vital sign, and we were supposed to treat pain, and now I feel like we’re all being judged for that.”

The third theme revolved around fear of consequences resulting from prescribing practices, including fears of violent repercussions.

“You may not know, but pain specialists have been shot in this country for [refusing to prescribe opioids],” one pain management specialist said during the interview. “There’s been a number of shootings of pain specialists who would not prescribe opioids. So, I mean, there’s real issues of violence.”

Meanwhile, a palliative care provider described legal pressure from the opposite direction:

“I think there’s a lot of fear of litigiousness … and loss of licenses. That sort of makes them pressure us into not prescribing opioids or sticking with a certain number per day that might not be therapeutic for a patient.”

Reflecting on these themes, the investigators identified “a fundamental uncertainty in survivorship pain management.”
 

What Strategies Might Improve Opioid Prescribing Practices for Chronic Cancer Pain?

After sharing their attitudes about prescribing opioids for chronic cancer pain, the clinicians were asked for suggestions to improve the situation.

They offered four main suggestions: create relevant guidelines, increase education and access to pain management options for clinicians, increase interdisciplinary communication across medical subspecialties, and promote multidisciplinary care in the survivorship setting.

Dr. Bulls and colleagues supported these strategies in their concluding remarks and called for more research.

This study was supported by the National Institute of Drug Abuse, the National Institutes of Health, the National Center for Advancing Translational Sciences, and the National Cancer Institute. The investigators disclosed relationships with Arcadia Health Solutions and Biomotivate.

The second-floor operating rooms at Lehigh Valley Hospital in Allentown, Pennsylvania, are numbered sequentially — except when you get to what should be operation room (OR) 13. It’s OR M. The M doesn’t stand for Maternity or any other specialty. Rather in this high-tech, state-of-the art healthcare center, it’s there to ward off bad juju and evil spirits.

“Just as taller buildings usually don’t have a 13th floor or hotels don’t have a room 13, it revolves around the common superstition of the unlucky nature of number 13,” said a hospital spokesperson.

During the pandemic, the public was told repeatedly that modern medicine is science-based. But when I started talking to surgeons and other physicians for this article, I uncovered something decidedly unscientific.

In ORs and emergency rooms (ERs), small-town doctor’s offices, and mega hospitals, there’s a measure of dread before full moons and Friday the 13th, and no one dares utter the Q word (as in, “It sure is quiet today.”) That would risk bringing the wrath of the medical gods, and you’d earn the reputation of being a jinx or “black cloud.” Likewise, the songs “Stairway to Heaven” or “Another One Bites the Dust” will never be heard in any waiting room, elevator, or OR.

Indeed, when it comes to superstitions and rituals in medicine, it seems everyone has a story or a belief. …
 

A 2-Hour Ritual

Carmen Fong, MD, a colorectal surgeon in New York City, had a presurgical ritual that took her nearly 2 hours to complete. “I’d wake up at the same time every day, pack two hard-boiled eggs and a thermos of coffee in my small leather bag, walk to work via the same route, and swipe into the preop area while waving hi to the front desk,” she recounted. “I’d talk to the patient, sign the consent with the same ballpoint pen, go upstairs to my office, change into my scrubs [same cap and Danskos], then turn on my computer, and take a sip of coffee before heading back down to the OR. I’d always remove my badge and place it near the nurses’ workstation, then put on the patient’s SCDs [sequential compression devices] myself. I’d hold the oxygen mask while telling the patient, ‘See you later.’ Never ‘It will be okay’ or ‘Have a good sleep.’ Always ‘See you later.’ ”

Dr. Fong did this for 5 years prior to more than a thousand surgeries. She did it because it made her feel calm and in control, which translated to more successful operations. “It never failed me.”
 

Wonder Woman Clogs

Anureet Bajaj, MD, a plastic surgeon in Oklahoma City, wore Wonder Woman clogs in the OR for years because “they made me feel stronger, and my surgeries went better.” She’s also very specific about her OR playlist; “it must be ‘80s music.” And for a time, she wore a friendship bracelet that one of her employees made to commemorate getting through a particularly hard day. “If I forgot it, my heart sank, and my anxiety rose,” she said. “Wearing it gave me security and confidence that the day would go well.”

A Moment of Silence

Juliet Emamaullee, MD, PhD, is a liver and kidney transplant surgeon at Keck Hospital and Children’s Hospital Los Angeles. Because of the complexity of her operations, she must know every aspect of her patients’ medical history. This leads to a level of intimacy that most people never have with their doctors. “Transplant surgeons are playing god in many ways,” she said. “During procurement, after we prep and drape the donor and right before I make the incision, everyone in the OR has a moment of silence to acknowledge the donation. If the organ has been transported, then I’ll say a prayer to myself that I do good work with this generous gift of life.”

Magical Thinking

Before we go any further, I should clarify that there’s a difference between rituals and superstitions like the ones just shared and routines and practices such as handwashing or doublechecking that it’s the right hip and not the left. All pilots have a preflight checklist that’s necessary for safety, but some might also make the sign of the cross.

Lester Gottesman, MD, has been a surgeon at the Icahn School of Medicine at Mount Sinai Hospital in New York City for nearly 50 years. He believes rituals and superstitions are more prevalent in medicine than in any other profession, despite there being no definitive research confirming their effectiveness.

In fact, it’s the opposite.

One of the few studies to examine superstitions among physicians was published in the Annals of Surgery in 2021. Researchers analyzed the operational records of 27,914 consecutive patients who underwent general, visceral, or vascular surgery. They found no association of moon phases, zodiac signs, or Friday the 13th with poor outcomes. Having acute coronary syndrome on Friday the 13th also did not influence the 13-year mortality rate compared to other dates in the year. And although 70% of physicians believe that some colleagues are “black clouds,” an analysis of 96 physicians and 6149 admissions found no such pattern.

Granted, this is just one analysis, but the results aren’t surprising. No one really believes in this stuff. So, why does it persist?

Dr. Gottesman cited an episode from the popular medical TV show Grey’s Anatomy, in which chief surgeon Meredith Grey puts it this way: “Superstition lies in the space between what we can control and what we can’t. …We rely on superstitions because we are smart enough to know we don’t have all the answers and that life works in mysterious ways. Don’t diss the juju from wherever it comes.”

“Superstition and science both start at the same place — to explain an unexplainable event,” said Dr. Gottesman, who always checks his suture lines at the end of a surgery in the order in which he did them. “If science provides a coherent answer, so be it. If not, the human’s need for order will assign causality to otherwise inanimate objects, noncausal events, or divine influence.”

In other words, the more unknowns and trepidation, the greater the tendency toward what Dr. Gottesman called “magical thinking.” And when you consider healing’s long history, you realize that ritual and superstition defined medicine for centuries. Gottesman pointed out that it wasn’t until Hippocrates separated religion and superstition from disease around 430 BC that modern medicine was born. But because doctors still don’t know everything, an element of magic endures.

The question is, in this high-tech age, do these stubborn beliefs still have a place? Do they help or hinder doctors, and, most important, do they have any effect on patient outcomes?
 

Five Benefits

To reiterate, there are no studies showing that Wonder Woman clogs convey surgical superpowers or that eating two hard-boiled eggs boosts OR performance. But anecdotally, many doctors admit to experiencing noticeable perks from their quirks. Let’s start with the supposed benefits:

• Less stress: A quarter of US clinicians are considering switching careers, primarily due to burnout, according to a 2022 Bain survey. “The fact that [rituals and superstitions] are so prevalent in such a high-stress field can’t be coincidence,” said Dr. Fong. “Offloading some of the responsibility to whatever gods there may be is a way of taming our anxieties so we can function better.”
• Hyperfocus: Dr. Emamaullee played volleyball in high school and college. She suggested that her presurgical routine isn’t all that different from her warmup before a championship match. It’s habitual behavior that helps induce a state of heightened concentration, confidence, and immersion. Athletes call it being “in the zone” or in a “state of flow,” and Dr. Emamaullee said she experiences the same thing in the OR.
• More control: Remember those horrific images of patients with COVID-19 overwhelming ERs in Brooklyn and Queens during the pandemic? Dr. Fong was in the middle of that. “In crisis situations where there are more unknowns, rituals and superstitions become even more important,” she said. “I may not be able to control what’s happening, but I can control myself. Rituals help restore some normalcy and organization, and they give me a sense of calm.”
• Better performance: A series of general-population experiments published in the journal Psychological Science in 2010 concluded that “good-luck–related superstitions” boosted self-confidence in mastering upcoming tasks and improved motor dexterity, memory, and overall performance.
• Placebo effect: This phenomenon is well-established in medicine. Give someone a special pill or treatment, and a significant portion will claim benefit. “Placebo is magical thinking,” said Dr. Gottesman. “It has identifiable and quantifiable effects on human disease.” And perhaps on medical practitioners, too. If a doctor believes her friendship bracelet has special powers and helps her be a better physician, then it just might.

Four Drawbacks

• Compulsive behavior: When superstitious beliefs or repetitive behaviors begin causing personal distress, interfering with daily duties, or negatively affecting patient outcomes, then there’s a problem. There’s a story on Quora about a neurosurgeon who always ate two Hostess Ho Hos chocolate cakes before operations. When he forgot to do so one day, he supposedly left his patient on the table and ran off to eat them. Even if it’s urban legend, it’s a useful illustration of quirk disrupting work.
• Less flexibility: Every human body and every surgery is different. “When ritualistic behaviors or habits become so rigid that you lose the ability to adapt, then that becomes dangerous for the patient,” said Dr. Fong. “The art of medicine, not unlike jazz, often comes from the improvisation.”
• Self-fulfilling: Just as rituals and superstitions can empower and provide a sense of control, they can quickly turn on physicians who forget a part of their routine or leave their talisman on the bureau. Instead of confidence, they supply doubt. The karma becomes kryptonite.
• Avoiding responsibility: After years of friendship bracelets and Wonder Woman clogs, Dr. Bajaj is making a deliberate effort to excise magical thinking from her practice. “It can hold you back if you’re not careful,” she said. “If you start using it as a crutch when something goes wrong — like ‘Oh, I wasn’t wearing my clogs today and that’s why my flap failed’ — then you’re not doing your due diligence and figuring out what really happened.” Rather than placing the responsibility for her day going well on superstition, she’s trying to own it herself by living with more intent.

The Diagnosis

Most of the medical experts I spoke with didn’t think there was anything wrong with rituals or superstitions as long as they didn’t become compulsive or a convenient repository of blame.

“Rituals and superstitions are an acknowledgment that forces external to ourselves exist,” concluded Dr. Fong. “They’re like tiny offerings to whatever gods are out there to please be on our side. And we keep doing them because there’s a reward — better patient outcomes, which is all we want to achieve in the end. I say embrace them.”

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

The second-floor operating rooms at Lehigh Valley Hospital in Allentown, Pennsylvania, are numbered sequentially — except when you get to what should be operation room (OR) 13. It’s OR M. The M doesn’t stand for Maternity or any other specialty. Rather in this high-tech, state-of-the art healthcare center, it’s there to ward off bad juju and evil spirits.

“Just as taller buildings usually don’t have a 13th floor or hotels don’t have a room 13, it revolves around the common superstition of the unlucky nature of number 13,” said a hospital spokesperson.

During the pandemic, the public was told repeatedly that modern medicine is science-based. But when I started talking to surgeons and other physicians for this article, I uncovered something decidedly unscientific.

In ORs and emergency rooms (ERs), small-town doctor’s offices, and mega hospitals, there’s a measure of dread before full moons and Friday the 13th, and no one dares utter the Q word (as in, “It sure is quiet today.”) That would risk bringing the wrath of the medical gods, and you’d earn the reputation of being a jinx or “black cloud.” Likewise, the songs “Stairway to Heaven” or “Another One Bites the Dust” will never be heard in any waiting room, elevator, or OR.

Indeed, when it comes to superstitions and rituals in medicine, it seems everyone has a story or a belief. …
 

A 2-Hour Ritual

Carmen Fong, MD, a colorectal surgeon in New York City, had a presurgical ritual that took her nearly 2 hours to complete. “I’d wake up at the same time every day, pack two hard-boiled eggs and a thermos of coffee in my small leather bag, walk to work via the same route, and swipe into the preop area while waving hi to the front desk,” she recounted. “I’d talk to the patient, sign the consent with the same ballpoint pen, go upstairs to my office, change into my scrubs [same cap and Danskos], then turn on my computer, and take a sip of coffee before heading back down to the OR. I’d always remove my badge and place it near the nurses’ workstation, then put on the patient’s SCDs [sequential compression devices] myself. I’d hold the oxygen mask while telling the patient, ‘See you later.’ Never ‘It will be okay’ or ‘Have a good sleep.’ Always ‘See you later.’ ”

Dr. Fong did this for 5 years prior to more than a thousand surgeries. She did it because it made her feel calm and in control, which translated to more successful operations. “It never failed me.”
 

Wonder Woman Clogs

Anureet Bajaj, MD, a plastic surgeon in Oklahoma City, wore Wonder Woman clogs in the OR for years because “they made me feel stronger, and my surgeries went better.” She’s also very specific about her OR playlist; “it must be ‘80s music.” And for a time, she wore a friendship bracelet that one of her employees made to commemorate getting through a particularly hard day. “If I forgot it, my heart sank, and my anxiety rose,” she said. “Wearing it gave me security and confidence that the day would go well.”

A Moment of Silence

Juliet Emamaullee, MD, PhD, is a liver and kidney transplant surgeon at Keck Hospital and Children’s Hospital Los Angeles. Because of the complexity of her operations, she must know every aspect of her patients’ medical history. This leads to a level of intimacy that most people never have with their doctors. “Transplant surgeons are playing god in many ways,” she said. “During procurement, after we prep and drape the donor and right before I make the incision, everyone in the OR has a moment of silence to acknowledge the donation. If the organ has been transported, then I’ll say a prayer to myself that I do good work with this generous gift of life.”

Magical Thinking

Before we go any further, I should clarify that there’s a difference between rituals and superstitions like the ones just shared and routines and practices such as handwashing or doublechecking that it’s the right hip and not the left. All pilots have a preflight checklist that’s necessary for safety, but some might also make the sign of the cross.

Lester Gottesman, MD, has been a surgeon at the Icahn School of Medicine at Mount Sinai Hospital in New York City for nearly 50 years. He believes rituals and superstitions are more prevalent in medicine than in any other profession, despite there being no definitive research confirming their effectiveness.

In fact, it’s the opposite.

One of the few studies to examine superstitions among physicians was published in the Annals of Surgery in 2021. Researchers analyzed the operational records of 27,914 consecutive patients who underwent general, visceral, or vascular surgery. They found no association of moon phases, zodiac signs, or Friday the 13th with poor outcomes. Having acute coronary syndrome on Friday the 13th also did not influence the 13-year mortality rate compared to other dates in the year. And although 70% of physicians believe that some colleagues are “black clouds,” an analysis of 96 physicians and 6149 admissions found no such pattern.

Granted, this is just one analysis, but the results aren’t surprising. No one really believes in this stuff. So, why does it persist?

Dr. Gottesman cited an episode from the popular medical TV show Grey’s Anatomy, in which chief surgeon Meredith Grey puts it this way: “Superstition lies in the space between what we can control and what we can’t. …We rely on superstitions because we are smart enough to know we don’t have all the answers and that life works in mysterious ways. Don’t diss the juju from wherever it comes.”

“Superstition and science both start at the same place — to explain an unexplainable event,” said Dr. Gottesman, who always checks his suture lines at the end of a surgery in the order in which he did them. “If science provides a coherent answer, so be it. If not, the human’s need for order will assign causality to otherwise inanimate objects, noncausal events, or divine influence.”

In other words, the more unknowns and trepidation, the greater the tendency toward what Dr. Gottesman called “magical thinking.” And when you consider healing’s long history, you realize that ritual and superstition defined medicine for centuries. Gottesman pointed out that it wasn’t until Hippocrates separated religion and superstition from disease around 430 BC that modern medicine was born. But because doctors still don’t know everything, an element of magic endures.

The question is, in this high-tech age, do these stubborn beliefs still have a place? Do they help or hinder doctors, and, most important, do they have any effect on patient outcomes?
 

Five Benefits

To reiterate, there are no studies showing that Wonder Woman clogs convey surgical superpowers or that eating two hard-boiled eggs boosts OR performance. But anecdotally, many doctors admit to experiencing noticeable perks from their quirks. Let’s start with the supposed benefits:

• Less stress: A quarter of US clinicians are considering switching careers, primarily due to burnout, according to a 2022 Bain survey. “The fact that [rituals and superstitions] are so prevalent in such a high-stress field can’t be coincidence,” said Dr. Fong. “Offloading some of the responsibility to whatever gods there may be is a way of taming our anxieties so we can function better.”
• Hyperfocus: Dr. Emamaullee played volleyball in high school and college. She suggested that her presurgical routine isn’t all that different from her warmup before a championship match. It’s habitual behavior that helps induce a state of heightened concentration, confidence, and immersion. Athletes call it being “in the zone” or in a “state of flow,” and Dr. Emamaullee said she experiences the same thing in the OR.
• More control: Remember those horrific images of patients with COVID-19 overwhelming ERs in Brooklyn and Queens during the pandemic? Dr. Fong was in the middle of that. “In crisis situations where there are more unknowns, rituals and superstitions become even more important,” she said. “I may not be able to control what’s happening, but I can control myself. Rituals help restore some normalcy and organization, and they give me a sense of calm.”
• Better performance: A series of general-population experiments published in the journal Psychological Science in 2010 concluded that “good-luck–related superstitions” boosted self-confidence in mastering upcoming tasks and improved motor dexterity, memory, and overall performance.
• Placebo effect: This phenomenon is well-established in medicine. Give someone a special pill or treatment, and a significant portion will claim benefit. “Placebo is magical thinking,” said Dr. Gottesman. “It has identifiable and quantifiable effects on human disease.” And perhaps on medical practitioners, too. If a doctor believes her friendship bracelet has special powers and helps her be a better physician, then it just might.

Four Drawbacks

• Compulsive behavior: When superstitious beliefs or repetitive behaviors begin causing personal distress, interfering with daily duties, or negatively affecting patient outcomes, then there’s a problem. There’s a story on Quora about a neurosurgeon who always ate two Hostess Ho Hos chocolate cakes before operations. When he forgot to do so one day, he supposedly left his patient on the table and ran off to eat them. Even if it’s urban legend, it’s a useful illustration of quirk disrupting work.
• Less flexibility: Every human body and every surgery is different. “When ritualistic behaviors or habits become so rigid that you lose the ability to adapt, then that becomes dangerous for the patient,” said Dr. Fong. “The art of medicine, not unlike jazz, often comes from the improvisation.”
• Self-fulfilling: Just as rituals and superstitions can empower and provide a sense of control, they can quickly turn on physicians who forget a part of their routine or leave their talisman on the bureau. Instead of confidence, they supply doubt. The karma becomes kryptonite.
• Avoiding responsibility: After years of friendship bracelets and Wonder Woman clogs, Dr. Bajaj is making a deliberate effort to excise magical thinking from her practice. “It can hold you back if you’re not careful,” she said. “If you start using it as a crutch when something goes wrong — like ‘Oh, I wasn’t wearing my clogs today and that’s why my flap failed’ — then you’re not doing your due diligence and figuring out what really happened.” Rather than placing the responsibility for her day going well on superstition, she’s trying to own it herself by living with more intent.

The Diagnosis

Most of the medical experts I spoke with didn’t think there was anything wrong with rituals or superstitions as long as they didn’t become compulsive or a convenient repository of blame.

“Rituals and superstitions are an acknowledgment that forces external to ourselves exist,” concluded Dr. Fong. “They’re like tiny offerings to whatever gods are out there to please be on our side. And we keep doing them because there’s a reward — better patient outcomes, which is all we want to achieve in the end. I say embrace them.”

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

The second-floor operating rooms at Lehigh Valley Hospital in Allentown, Pennsylvania, are numbered sequentially — except when you get to what should be operation room (OR) 13. It’s OR M. The M doesn’t stand for Maternity or any other specialty. Rather in this high-tech, state-of-the art healthcare center, it’s there to ward off bad juju and evil spirits.

“Just as taller buildings usually don’t have a 13th floor or hotels don’t have a room 13, it revolves around the common superstition of the unlucky nature of number 13,” said a hospital spokesperson.

During the pandemic, the public was told repeatedly that modern medicine is science-based. But when I started talking to surgeons and other physicians for this article, I uncovered something decidedly unscientific.

In ORs and emergency rooms (ERs), small-town doctor’s offices, and mega hospitals, there’s a measure of dread before full moons and Friday the 13th, and no one dares utter the Q word (as in, “It sure is quiet today.”) That would risk bringing the wrath of the medical gods, and you’d earn the reputation of being a jinx or “black cloud.” Likewise, the songs “Stairway to Heaven” or “Another One Bites the Dust” will never be heard in any waiting room, elevator, or OR.

Indeed, when it comes to superstitions and rituals in medicine, it seems everyone has a story or a belief. …
 

A 2-Hour Ritual

Carmen Fong, MD, a colorectal surgeon in New York City, had a presurgical ritual that took her nearly 2 hours to complete. “I’d wake up at the same time every day, pack two hard-boiled eggs and a thermos of coffee in my small leather bag, walk to work via the same route, and swipe into the preop area while waving hi to the front desk,” she recounted. “I’d talk to the patient, sign the consent with the same ballpoint pen, go upstairs to my office, change into my scrubs [same cap and Danskos], then turn on my computer, and take a sip of coffee before heading back down to the OR. I’d always remove my badge and place it near the nurses’ workstation, then put on the patient’s SCDs [sequential compression devices] myself. I’d hold the oxygen mask while telling the patient, ‘See you later.’ Never ‘It will be okay’ or ‘Have a good sleep.’ Always ‘See you later.’ ”

Dr. Fong did this for 5 years prior to more than a thousand surgeries. She did it because it made her feel calm and in control, which translated to more successful operations. “It never failed me.”
 

Wonder Woman Clogs

Anureet Bajaj, MD, a plastic surgeon in Oklahoma City, wore Wonder Woman clogs in the OR for years because “they made me feel stronger, and my surgeries went better.” She’s also very specific about her OR playlist; “it must be ‘80s music.” And for a time, she wore a friendship bracelet that one of her employees made to commemorate getting through a particularly hard day. “If I forgot it, my heart sank, and my anxiety rose,” she said. “Wearing it gave me security and confidence that the day would go well.”

A Moment of Silence

Juliet Emamaullee, MD, PhD, is a liver and kidney transplant surgeon at Keck Hospital and Children’s Hospital Los Angeles. Because of the complexity of her operations, she must know every aspect of her patients’ medical history. This leads to a level of intimacy that most people never have with their doctors. “Transplant surgeons are playing god in many ways,” she said. “During procurement, after we prep and drape the donor and right before I make the incision, everyone in the OR has a moment of silence to acknowledge the donation. If the organ has been transported, then I’ll say a prayer to myself that I do good work with this generous gift of life.”

Magical Thinking

Before we go any further, I should clarify that there’s a difference between rituals and superstitions like the ones just shared and routines and practices such as handwashing or doublechecking that it’s the right hip and not the left. All pilots have a preflight checklist that’s necessary for safety, but some might also make the sign of the cross.

Lester Gottesman, MD, has been a surgeon at the Icahn School of Medicine at Mount Sinai Hospital in New York City for nearly 50 years. He believes rituals and superstitions are more prevalent in medicine than in any other profession, despite there being no definitive research confirming their effectiveness.

In fact, it’s the opposite.

One of the few studies to examine superstitions among physicians was published in the Annals of Surgery in 2021. Researchers analyzed the operational records of 27,914 consecutive patients who underwent general, visceral, or vascular surgery. They found no association of moon phases, zodiac signs, or Friday the 13th with poor outcomes. Having acute coronary syndrome on Friday the 13th also did not influence the 13-year mortality rate compared to other dates in the year. And although 70% of physicians believe that some colleagues are “black clouds,” an analysis of 96 physicians and 6149 admissions found no such pattern.

Granted, this is just one analysis, but the results aren’t surprising. No one really believes in this stuff. So, why does it persist?

Dr. Gottesman cited an episode from the popular medical TV show Grey’s Anatomy, in which chief surgeon Meredith Grey puts it this way: “Superstition lies in the space between what we can control and what we can’t. …We rely on superstitions because we are smart enough to know we don’t have all the answers and that life works in mysterious ways. Don’t diss the juju from wherever it comes.”

“Superstition and science both start at the same place — to explain an unexplainable event,” said Dr. Gottesman, who always checks his suture lines at the end of a surgery in the order in which he did them. “If science provides a coherent answer, so be it. If not, the human’s need for order will assign causality to otherwise inanimate objects, noncausal events, or divine influence.”

In other words, the more unknowns and trepidation, the greater the tendency toward what Dr. Gottesman called “magical thinking.” And when you consider healing’s long history, you realize that ritual and superstition defined medicine for centuries. Gottesman pointed out that it wasn’t until Hippocrates separated religion and superstition from disease around 430 BC that modern medicine was born. But because doctors still don’t know everything, an element of magic endures.

The question is, in this high-tech age, do these stubborn beliefs still have a place? Do they help or hinder doctors, and, most important, do they have any effect on patient outcomes?
 

Five Benefits

To reiterate, there are no studies showing that Wonder Woman clogs convey surgical superpowers or that eating two hard-boiled eggs boosts OR performance. But anecdotally, many doctors admit to experiencing noticeable perks from their quirks. Let’s start with the supposed benefits:

• Less stress: A quarter of US clinicians are considering switching careers, primarily due to burnout, according to a 2022 Bain survey. “The fact that [rituals and superstitions] are so prevalent in such a high-stress field can’t be coincidence,” said Dr. Fong. “Offloading some of the responsibility to whatever gods there may be is a way of taming our anxieties so we can function better.”
• Hyperfocus: Dr. Emamaullee played volleyball in high school and college. She suggested that her presurgical routine isn’t all that different from her warmup before a championship match. It’s habitual behavior that helps induce a state of heightened concentration, confidence, and immersion. Athletes call it being “in the zone” or in a “state of flow,” and Dr. Emamaullee said she experiences the same thing in the OR.
• More control: Remember those horrific images of patients with COVID-19 overwhelming ERs in Brooklyn and Queens during the pandemic? Dr. Fong was in the middle of that. “In crisis situations where there are more unknowns, rituals and superstitions become even more important,” she said. “I may not be able to control what’s happening, but I can control myself. Rituals help restore some normalcy and organization, and they give me a sense of calm.”
• Better performance: A series of general-population experiments published in the journal Psychological Science in 2010 concluded that “good-luck–related superstitions” boosted self-confidence in mastering upcoming tasks and improved motor dexterity, memory, and overall performance.
• Placebo effect: This phenomenon is well-established in medicine. Give someone a special pill or treatment, and a significant portion will claim benefit. “Placebo is magical thinking,” said Dr. Gottesman. “It has identifiable and quantifiable effects on human disease.” And perhaps on medical practitioners, too. If a doctor believes her friendship bracelet has special powers and helps her be a better physician, then it just might.

Four Drawbacks

• Compulsive behavior: When superstitious beliefs or repetitive behaviors begin causing personal distress, interfering with daily duties, or negatively affecting patient outcomes, then there’s a problem. There’s a story on Quora about a neurosurgeon who always ate two Hostess Ho Hos chocolate cakes before operations. When he forgot to do so one day, he supposedly left his patient on the table and ran off to eat them. Even if it’s urban legend, it’s a useful illustration of quirk disrupting work.
• Less flexibility: Every human body and every surgery is different. “When ritualistic behaviors or habits become so rigid that you lose the ability to adapt, then that becomes dangerous for the patient,” said Dr. Fong. “The art of medicine, not unlike jazz, often comes from the improvisation.”
• Self-fulfilling: Just as rituals and superstitions can empower and provide a sense of control, they can quickly turn on physicians who forget a part of their routine or leave their talisman on the bureau. Instead of confidence, they supply doubt. The karma becomes kryptonite.
• Avoiding responsibility: After years of friendship bracelets and Wonder Woman clogs, Dr. Bajaj is making a deliberate effort to excise magical thinking from her practice. “It can hold you back if you’re not careful,” she said. “If you start using it as a crutch when something goes wrong — like ‘Oh, I wasn’t wearing my clogs today and that’s why my flap failed’ — then you’re not doing your due diligence and figuring out what really happened.” Rather than placing the responsibility for her day going well on superstition, she’s trying to own it herself by living with more intent.

The Diagnosis

Most of the medical experts I spoke with didn’t think there was anything wrong with rituals or superstitions as long as they didn’t become compulsive or a convenient repository of blame.

“Rituals and superstitions are an acknowledgment that forces external to ourselves exist,” concluded Dr. Fong. “They’re like tiny offerings to whatever gods are out there to please be on our side. And we keep doing them because there’s a reward — better patient outcomes, which is all we want to achieve in the end. I say embrace them.”

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

The Epstein-Barr virus (EBV) is our constant companion, infecting an estimated 90%-95% of adults. Many of us are first infected as children, when the germ may trigger cold and flu symptoms. EBV also causes mononucleosis, or kissing disease, a glandular fever that has afflicted generations of amorous young people.

Post infection, EBV settles in for the long haul and remains in the body until death. It’s thought to be largely innocuous, but EBV is now implicated as a cause of several types of cancer — including lymphoma and nasopharyngeal tumors – and multiple sclerosis (MS). In 2022, a landmark study in Science suggested that previous EBV infection is the primary cause of MS.

While there aren’t many implications for current treatment, greater insight into the origin story of MS may eventually help neurologists better diagnose and treat patients, experts said. The goal is to uncover clues that “can help us understand MS a little bit better and reveal insights that could lead to new disease-modifying therapy,” Bruce Bebo, PhD, executive vice president of research with the National MS Society, said in an interview.
 

EBV Boosts MS Risk 32-Fold

EBV was first linked to MS back in 1981. For the 2022 study, researchers at the Harvard T.H. Chan School of Public Health and Harvard Medical School, Boston, analyzed blood serum from 10 million active-duty members of the US military. They focused on 801 recruits with MS and matched them with more than 1500 controls. All but one of those with MS had been infected with EBV; infection appeared to boost the risk for MS 32-fold (95% CI, 4.3-245.3; P < .001).

Neurologist and associate professor Michael Levy, MD, PhD, of Harvard Medical School and Massachusetts General Hospital, said in an interview that the findings are “groundbreaking” and confirm that EBV is “likely the primary cause of MS.”

According to Dr. Levy, there are two main theories about why EBV causes MS. The first hypothesis, known as the “molecular mimicry” theory, suggests that “EBV is a trigger of MS, possibly when the immune system mistakes a viral protein for a myelin protein and then attacks myelin,” Dr. Levy said. In MS, the immune system attacks the protective myelin sheath and the axons it insulates.

“After that point, the virus is not necessary to maintain the disease state and eradicating the virus likely won’t have much effect since the immune response is already triggered,” he said.

The second theory is that “EBV is a driver of MS where there is an ongoing, lifelong immunological response to EBV that continuously causes damage in the central nervous system [CNS]. In theory, if we could eradicate the virus, the destructive immune response could also resolve. Thus, an EBV antiviral treatment could potentially treat and maybe cure MS,” Dr. Levy explained, noting that “removing the pathogenic antigen may be a more effective strategy than removing the immune response.”

However, “we don’t yet know which hypothesis is correct,” he said. But “there is preliminary evidence in favor of each one.”
 

‘Additional Fuses Must Be Ignited’

It’s also unclear why most people infected with EBV do not develop MS. It appears that “additional fuses must be ignited,” for MS to take hold, according to a commentary accompanying the landmark 2022 study.

“As far as clinical implications, knowing whether a patient has a medical or family history of mononucleosis may be a small clue, a small piece of evidence, to help with diagnosis,” Dr. Bebo said.

He agreed with Dr. Levy that an antiviral could be a promising approach “If the problem in MS is a dysfunctional immune response to EBV.”

Natalia Drosu, MD, PhD, a postdoctoral fellow at Harvard-MIT Biomedical Engineering Center, said that a clinical trial of a non-immunosuppressive antiviral targeting EBV in patients with MS would be a crucial step toward better understanding the MS-EBV connection. “If we learn that antivirals are effective in MS, we should develop non-immunosuppressive therapies for patients with MS as soon as possible,” she said.

Stanford University’s Lawrence Steinman, MD, professor of neurology and neurological sciences, pediatrics, and genetics, who coauthored the commentary on the original Science paper, agreed that it’s worth investigating whether antiviral therapies targeting EBV will benefit patients who already have MS. But he cautioned against clinicians experimenting on their own outside of a research study. “You’d want to use the right antiviral and a properly designed trial,” he said.
 

Antivirals May Place a Crucial Role in MS Control

While there are no approved therapies for EBV, several MS disease-modifying therapies have anti-EBV effects, Dr. Levy said, citing anti-CD20 therapy as a clear example. It depletes B cells from the circulation, and it depletes EBV because the virus lives in the B-cell compartment. “Some MS treatments may be inadvertent EBV antivirals,” he said.

Researchers are also thinking about how they might exploit the MS-EBV link to prevent MS from developing in the first place, but there are uncertainties on that front too.

Conceivably, there may be some way to intervene in patients to treat EBV and prevent MS, such as a unique treatment for infectious mononucleosis (IM), Dr. Levy said.

Researchers are especially intrigued by signs that the timing of infection may play a role, with people infected with EBV via IM after early childhood at especially a high risk of developing MS. A 2022 German study calculated that people who developed IM were almost twice as likely as those who didn’t to develop MS within 10 years, although the risks in both groups were very small. Subgroup analysis revealed the strongest association between IM and MS was in the group infected between age 14 and 20 years (hazard ratio, 3.52; 95% CI, 1.00-12.37). They also saw a stronger association in men than in women.

The authors of a 2023 review in Clinical & Translational Immunology wrote that “further understanding of IM may be critical in solving the mystery” of EBV’s role in MS.

Dr. Levy said this line of questioning is important. “In theory, if we can tell who is prone to develop MS or whose immune system might be reacting to EBV to cause MS, we can intervene early to prevent neurological manifestations.”

However, “remember that while most of the world gets EBV infections, only 1 in 1000 will get MS. So, it might not be feasible to test everyone before neurological manifestations occur,” he said.
 

More Questions to Answer About EBV and MS

Researchers hope to answer several questions moving forward. For one, why is EBV uniquely connected to MS? “You would think that if there were cross-reactivity to myelin, there are many viruses that could cause MS. But the association seems to be very restricted to EBV,” Dr. Levy said. “It is probably due to the fact that EBV is one of the only human viruses that can infect B cells, which play important roles in controlling immune responses.”

The molecular mimicry theory also opens up a potential treatment pathway.

A 2022 study reported “high-affinity molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and the central nervous system protein glial cell adhesion molecule (GlialCAM)”. Antibodies against EBNA1 and GlialCAM are prevalent in patients with MS. In a mouse model of MS, the researchers showed that EBNA1 immunization exacerbates disease. The authors wrote that “Our results provide a mechanistic link for the association between MS and EBV and could guide the development of new MS therapies.”
 

Could an EBV Vaccine Be the Answer?

On the prevention front, perhaps the most obvious question is whether an EBV vaccine could eliminate MS for good?

Dr. Bebo, from the National MS Society, said it will be important to determine which kind of vaccine is best. Is it one that neutralizes infection with EBV? Or is it enough to simply prevent clinical manifestations?

Both types of vaccines are in development, and at least two clinical trials are now in the works. The National Institute of Allergy and Infectious Diseases is sponsoring a phase 1 study of an adjuvanted EBV gp350-Ferritin nanoparticle vaccine. Forty subjects aged 18-29 years will take part: 20 with EBV and 20 who are not infected. The study is expected to end in 2025.

There is also a phase 1 placebo-controlled study in progress testing an EBV vaccine based on mRNA-1189 in 422 subjects aged 12-30 years. This trial is also due to end in 2025.

“This is very exciting, but it may take a decade or two to determine whether a vaccine is effective at preventing MS,” Dr. Levy said.

Dr. Levy, Dr. Steinman, Dr. Drosu, and Dr. Bebo had no disclosures.
 

A version of this article appeared on Medscape.com.

The Epstein-Barr virus (EBV) is our constant companion, infecting an estimated 90%-95% of adults. Many of us are first infected as children, when the germ may trigger cold and flu symptoms. EBV also causes mononucleosis, or kissing disease, a glandular fever that has afflicted generations of amorous young people.

Post infection, EBV settles in for the long haul and remains in the body until death. It’s thought to be largely innocuous, but EBV is now implicated as a cause of several types of cancer — including lymphoma and nasopharyngeal tumors – and multiple sclerosis (MS). In 2022, a landmark study in Science suggested that previous EBV infection is the primary cause of MS.

While there aren’t many implications for current treatment, greater insight into the origin story of MS may eventually help neurologists better diagnose and treat patients, experts said. The goal is to uncover clues that “can help us understand MS a little bit better and reveal insights that could lead to new disease-modifying therapy,” Bruce Bebo, PhD, executive vice president of research with the National MS Society, said in an interview.
 

EBV Boosts MS Risk 32-Fold

EBV was first linked to MS back in 1981. For the 2022 study, researchers at the Harvard T.H. Chan School of Public Health and Harvard Medical School, Boston, analyzed blood serum from 10 million active-duty members of the US military. They focused on 801 recruits with MS and matched them with more than 1500 controls. All but one of those with MS had been infected with EBV; infection appeared to boost the risk for MS 32-fold (95% CI, 4.3-245.3; P < .001).

Neurologist and associate professor Michael Levy, MD, PhD, of Harvard Medical School and Massachusetts General Hospital, said in an interview that the findings are “groundbreaking” and confirm that EBV is “likely the primary cause of MS.”

According to Dr. Levy, there are two main theories about why EBV causes MS. The first hypothesis, known as the “molecular mimicry” theory, suggests that “EBV is a trigger of MS, possibly when the immune system mistakes a viral protein for a myelin protein and then attacks myelin,” Dr. Levy said. In MS, the immune system attacks the protective myelin sheath and the axons it insulates.

“After that point, the virus is not necessary to maintain the disease state and eradicating the virus likely won’t have much effect since the immune response is already triggered,” he said.

The second theory is that “EBV is a driver of MS where there is an ongoing, lifelong immunological response to EBV that continuously causes damage in the central nervous system [CNS]. In theory, if we could eradicate the virus, the destructive immune response could also resolve. Thus, an EBV antiviral treatment could potentially treat and maybe cure MS,” Dr. Levy explained, noting that “removing the pathogenic antigen may be a more effective strategy than removing the immune response.”

However, “we don’t yet know which hypothesis is correct,” he said. But “there is preliminary evidence in favor of each one.”
 

‘Additional Fuses Must Be Ignited’

It’s also unclear why most people infected with EBV do not develop MS. It appears that “additional fuses must be ignited,” for MS to take hold, according to a commentary accompanying the landmark 2022 study.

“As far as clinical implications, knowing whether a patient has a medical or family history of mononucleosis may be a small clue, a small piece of evidence, to help with diagnosis,” Dr. Bebo said.

He agreed with Dr. Levy that an antiviral could be a promising approach “If the problem in MS is a dysfunctional immune response to EBV.”

Natalia Drosu, MD, PhD, a postdoctoral fellow at Harvard-MIT Biomedical Engineering Center, said that a clinical trial of a non-immunosuppressive antiviral targeting EBV in patients with MS would be a crucial step toward better understanding the MS-EBV connection. “If we learn that antivirals are effective in MS, we should develop non-immunosuppressive therapies for patients with MS as soon as possible,” she said.

Stanford University’s Lawrence Steinman, MD, professor of neurology and neurological sciences, pediatrics, and genetics, who coauthored the commentary on the original Science paper, agreed that it’s worth investigating whether antiviral therapies targeting EBV will benefit patients who already have MS. But he cautioned against clinicians experimenting on their own outside of a research study. “You’d want to use the right antiviral and a properly designed trial,” he said.
 

Antivirals May Place a Crucial Role in MS Control

While there are no approved therapies for EBV, several MS disease-modifying therapies have anti-EBV effects, Dr. Levy said, citing anti-CD20 therapy as a clear example. It depletes B cells from the circulation, and it depletes EBV because the virus lives in the B-cell compartment. “Some MS treatments may be inadvertent EBV antivirals,” he said.

Researchers are also thinking about how they might exploit the MS-EBV link to prevent MS from developing in the first place, but there are uncertainties on that front too.

Conceivably, there may be some way to intervene in patients to treat EBV and prevent MS, such as a unique treatment for infectious mononucleosis (IM), Dr. Levy said.

Researchers are especially intrigued by signs that the timing of infection may play a role, with people infected with EBV via IM after early childhood at especially a high risk of developing MS. A 2022 German study calculated that people who developed IM were almost twice as likely as those who didn’t to develop MS within 10 years, although the risks in both groups were very small. Subgroup analysis revealed the strongest association between IM and MS was in the group infected between age 14 and 20 years (hazard ratio, 3.52; 95% CI, 1.00-12.37). They also saw a stronger association in men than in women.

The authors of a 2023 review in Clinical & Translational Immunology wrote that “further understanding of IM may be critical in solving the mystery” of EBV’s role in MS.

Dr. Levy said this line of questioning is important. “In theory, if we can tell who is prone to develop MS or whose immune system might be reacting to EBV to cause MS, we can intervene early to prevent neurological manifestations.”

However, “remember that while most of the world gets EBV infections, only 1 in 1000 will get MS. So, it might not be feasible to test everyone before neurological manifestations occur,” he said.
 

More Questions to Answer About EBV and MS

Researchers hope to answer several questions moving forward. For one, why is EBV uniquely connected to MS? “You would think that if there were cross-reactivity to myelin, there are many viruses that could cause MS. But the association seems to be very restricted to EBV,” Dr. Levy said. “It is probably due to the fact that EBV is one of the only human viruses that can infect B cells, which play important roles in controlling immune responses.”

The molecular mimicry theory also opens up a potential treatment pathway.

A 2022 study reported “high-affinity molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and the central nervous system protein glial cell adhesion molecule (GlialCAM)”. Antibodies against EBNA1 and GlialCAM are prevalent in patients with MS. In a mouse model of MS, the researchers showed that EBNA1 immunization exacerbates disease. The authors wrote that “Our results provide a mechanistic link for the association between MS and EBV and could guide the development of new MS therapies.”
 

Could an EBV Vaccine Be the Answer?

On the prevention front, perhaps the most obvious question is whether an EBV vaccine could eliminate MS for good?

Dr. Bebo, from the National MS Society, said it will be important to determine which kind of vaccine is best. Is it one that neutralizes infection with EBV? Or is it enough to simply prevent clinical manifestations?

Both types of vaccines are in development, and at least two clinical trials are now in the works. The National Institute of Allergy and Infectious Diseases is sponsoring a phase 1 study of an adjuvanted EBV gp350-Ferritin nanoparticle vaccine. Forty subjects aged 18-29 years will take part: 20 with EBV and 20 who are not infected. The study is expected to end in 2025.

There is also a phase 1 placebo-controlled study in progress testing an EBV vaccine based on mRNA-1189 in 422 subjects aged 12-30 years. This trial is also due to end in 2025.

“This is very exciting, but it may take a decade or two to determine whether a vaccine is effective at preventing MS,” Dr. Levy said.

Dr. Levy, Dr. Steinman, Dr. Drosu, and Dr. Bebo had no disclosures.
 

A version of this article appeared on Medscape.com.

The Epstein-Barr virus (EBV) is our constant companion, infecting an estimated 90%-95% of adults. Many of us are first infected as children, when the germ may trigger cold and flu symptoms. EBV also causes mononucleosis, or kissing disease, a glandular fever that has afflicted generations of amorous young people.

Post infection, EBV settles in for the long haul and remains in the body until death. It’s thought to be largely innocuous, but EBV is now implicated as a cause of several types of cancer — including lymphoma and nasopharyngeal tumors – and multiple sclerosis (MS). In 2022, a landmark study in Science suggested that previous EBV infection is the primary cause of MS.

While there aren’t many implications for current treatment, greater insight into the origin story of MS may eventually help neurologists better diagnose and treat patients, experts said. The goal is to uncover clues that “can help us understand MS a little bit better and reveal insights that could lead to new disease-modifying therapy,” Bruce Bebo, PhD, executive vice president of research with the National MS Society, said in an interview.
 

EBV Boosts MS Risk 32-Fold

EBV was first linked to MS back in 1981. For the 2022 study, researchers at the Harvard T.H. Chan School of Public Health and Harvard Medical School, Boston, analyzed blood serum from 10 million active-duty members of the US military. They focused on 801 recruits with MS and matched them with more than 1500 controls. All but one of those with MS had been infected with EBV; infection appeared to boost the risk for MS 32-fold (95% CI, 4.3-245.3; P < .001).

Neurologist and associate professor Michael Levy, MD, PhD, of Harvard Medical School and Massachusetts General Hospital, said in an interview that the findings are “groundbreaking” and confirm that EBV is “likely the primary cause of MS.”

According to Dr. Levy, there are two main theories about why EBV causes MS. The first hypothesis, known as the “molecular mimicry” theory, suggests that “EBV is a trigger of MS, possibly when the immune system mistakes a viral protein for a myelin protein and then attacks myelin,” Dr. Levy said. In MS, the immune system attacks the protective myelin sheath and the axons it insulates.

“After that point, the virus is not necessary to maintain the disease state and eradicating the virus likely won’t have much effect since the immune response is already triggered,” he said.

The second theory is that “EBV is a driver of MS where there is an ongoing, lifelong immunological response to EBV that continuously causes damage in the central nervous system [CNS]. In theory, if we could eradicate the virus, the destructive immune response could also resolve. Thus, an EBV antiviral treatment could potentially treat and maybe cure MS,” Dr. Levy explained, noting that “removing the pathogenic antigen may be a more effective strategy than removing the immune response.”

However, “we don’t yet know which hypothesis is correct,” he said. But “there is preliminary evidence in favor of each one.”
 

‘Additional Fuses Must Be Ignited’

It’s also unclear why most people infected with EBV do not develop MS. It appears that “additional fuses must be ignited,” for MS to take hold, according to a commentary accompanying the landmark 2022 study.

“As far as clinical implications, knowing whether a patient has a medical or family history of mononucleosis may be a small clue, a small piece of evidence, to help with diagnosis,” Dr. Bebo said.

He agreed with Dr. Levy that an antiviral could be a promising approach “If the problem in MS is a dysfunctional immune response to EBV.”

Natalia Drosu, MD, PhD, a postdoctoral fellow at Harvard-MIT Biomedical Engineering Center, said that a clinical trial of a non-immunosuppressive antiviral targeting EBV in patients with MS would be a crucial step toward better understanding the MS-EBV connection. “If we learn that antivirals are effective in MS, we should develop non-immunosuppressive therapies for patients with MS as soon as possible,” she said.

Stanford University’s Lawrence Steinman, MD, professor of neurology and neurological sciences, pediatrics, and genetics, who coauthored the commentary on the original Science paper, agreed that it’s worth investigating whether antiviral therapies targeting EBV will benefit patients who already have MS. But he cautioned against clinicians experimenting on their own outside of a research study. “You’d want to use the right antiviral and a properly designed trial,” he said.
 

Antivirals May Place a Crucial Role in MS Control

While there are no approved therapies for EBV, several MS disease-modifying therapies have anti-EBV effects, Dr. Levy said, citing anti-CD20 therapy as a clear example. It depletes B cells from the circulation, and it depletes EBV because the virus lives in the B-cell compartment. “Some MS treatments may be inadvertent EBV antivirals,” he said.

Researchers are also thinking about how they might exploit the MS-EBV link to prevent MS from developing in the first place, but there are uncertainties on that front too.

Conceivably, there may be some way to intervene in patients to treat EBV and prevent MS, such as a unique treatment for infectious mononucleosis (IM), Dr. Levy said.

Researchers are especially intrigued by signs that the timing of infection may play a role, with people infected with EBV via IM after early childhood at especially a high risk of developing MS. A 2022 German study calculated that people who developed IM were almost twice as likely as those who didn’t to develop MS within 10 years, although the risks in both groups were very small. Subgroup analysis revealed the strongest association between IM and MS was in the group infected between age 14 and 20 years (hazard ratio, 3.52; 95% CI, 1.00-12.37). They also saw a stronger association in men than in women.

The authors of a 2023 review in Clinical & Translational Immunology wrote that “further understanding of IM may be critical in solving the mystery” of EBV’s role in MS.

Dr. Levy said this line of questioning is important. “In theory, if we can tell who is prone to develop MS or whose immune system might be reacting to EBV to cause MS, we can intervene early to prevent neurological manifestations.”

However, “remember that while most of the world gets EBV infections, only 1 in 1000 will get MS. So, it might not be feasible to test everyone before neurological manifestations occur,” he said.
 

More Questions to Answer About EBV and MS

Researchers hope to answer several questions moving forward. For one, why is EBV uniquely connected to MS? “You would think that if there were cross-reactivity to myelin, there are many viruses that could cause MS. But the association seems to be very restricted to EBV,” Dr. Levy said. “It is probably due to the fact that EBV is one of the only human viruses that can infect B cells, which play important roles in controlling immune responses.”

The molecular mimicry theory also opens up a potential treatment pathway.

A 2022 study reported “high-affinity molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and the central nervous system protein glial cell adhesion molecule (GlialCAM)”. Antibodies against EBNA1 and GlialCAM are prevalent in patients with MS. In a mouse model of MS, the researchers showed that EBNA1 immunization exacerbates disease. The authors wrote that “Our results provide a mechanistic link for the association between MS and EBV and could guide the development of new MS therapies.”
 

Could an EBV Vaccine Be the Answer?

On the prevention front, perhaps the most obvious question is whether an EBV vaccine could eliminate MS for good?

Dr. Bebo, from the National MS Society, said it will be important to determine which kind of vaccine is best. Is it one that neutralizes infection with EBV? Or is it enough to simply prevent clinical manifestations?

Both types of vaccines are in development, and at least two clinical trials are now in the works. The National Institute of Allergy and Infectious Diseases is sponsoring a phase 1 study of an adjuvanted EBV gp350-Ferritin nanoparticle vaccine. Forty subjects aged 18-29 years will take part: 20 with EBV and 20 who are not infected. The study is expected to end in 2025.

There is also a phase 1 placebo-controlled study in progress testing an EBV vaccine based on mRNA-1189 in 422 subjects aged 12-30 years. This trial is also due to end in 2025.

“This is very exciting, but it may take a decade or two to determine whether a vaccine is effective at preventing MS,” Dr. Levy said.

Dr. Levy, Dr. Steinman, Dr. Drosu, and Dr. Bebo had no disclosures.
 

A version of this article appeared on Medscape.com.

A review of the federal Open Payments database found that the pharmaceutical and medical device industry paid physicians $12.1 billion over nearly a decade.

Almost two thirds of eligible physicians — 826,313 doctors — received a payment from a drug or device maker from 2013 to 2022, according to a study published online in JAMA on March 28. Overall, the median payment was $48 per physician.

Orthopedists received the largest amount of payments in aggregate, $1.3 billion, followed by neurologists and psychiatrists at $1.2 billion and cardiologists at $1.29 billion.

Geriatric and nuclear medicine specialists and trauma and pediatric surgeons received the least amount of money in aggregate, and the mean amount paid to a pediatric surgeon in the top 0.1% was just $338,183 over the 9-year study period.

Excluding 2013 (the database was established in August that year), the total value of payments was highest in 2019 at $1.6 billion, up from $1.34 billion in 2014. It was lowest in 2020, the peak year of the COVID-19 pandemic, but dipped to $864 billion that year and rebounded to $1.28 billion in 2022, wrote the authors.

The Open Payments database, administered by the Centers for Medicare & Medicaid Services, requires drug and device makers and group purchasing organizations to report payments made to physicians, including for consulting services, speaking fees, food and beverages, travel and lodging, education, gifts, grants, and honoraria.

The database was created to shed light on these payments, which have been linked in multiple studies to more prescribing of a particular drug or more use of a particular device.

The JAMA review appeared to show that with the exception of the pandemic year, the relationships have more or less stayed the same since Open Payments began.

“There’s been no sea change, no massive shift in how these interactions are happening,” said Deborah C. Marshall, MD, assistant professor in the Department of Radiation Oncology at the Icahn School of Medicine at Mount Sinai in New York City, who has studied industry payments.

“There’s no suggestion that anything is really changing other than that’s there is transparency,” said Robert Steinbrook, MD, director of the Health Research Group at Public Citizen.

Still, Dr. Steinbrook told this news organization, “it’s better to know this than to not know this.”

The unchanging nature of industry-physician relationships “suggests that to reduce the volume and magnitude of payments, more would need to be done,” he said.

“Really, this should be banned. Doctors should not be allowed to get gifts from pharmaceutical companies,” said Adriane Fugh-Berman, MD, professor of pharmacology and physiology at Georgetown University, and director of PharmedOut, a Georgetown-based project that advances evidence-based prescribing and educates healthcare professionals about pharmaceutical marketing practices.

“The interactions wouldn’t be happening unless there was a purpose for them,” said Dr. Marshall. The relationships are “built with intention,” Dr. Marshall told this news organization.
 

Top Earners Range From $195,000 to $4.8 Million

Payments to the median physician over the study period ranged from $0 to $2339, but the mean payment to top earners — those in the top 0.1% — ranged from $194,933 for hospitalists to $4.8 million for orthopedic specialists.

Overall, the median payment was $48 per physician.

But small dollar amounts should not be discounted — even if it’s just a $25-catered lunch — said Aaron Mitchell, MD, a medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center in New York City who has studied industry-physician relationships. “The influence is not just in the dollar value,” Dr. Mitchell told this news organization. “It’s about the time listening to and the time in personal contact with industry representatives that these dollars are a marker for,” he said.

“There’s no such thing as a free lunch,” agreed Dr. Marshall. It’s “pretty well established” that lower-value payments do have influence, which is why academic institutions have established policies that limit gifts and meals and other payments from industry, she said.

Dr. Fugh-Berman said, “the size of the gift doesn’t really matter,” adding that research she conducted had shown that “accepting a meal increased not only the expense of the prescriptions that Medicare physicians wrote but also the number of prescriptions.”
 

Payments Mostly for High-Dollar Products

The top 25 drugs and devices that were related to industry payments tended to be high-cost brand-name products.

The top drug was Janssen’s Xarelto, an anticoagulant first approved in 2011 that costs about $600 a month, according to GoodRx. The drug has had annual sales of $4-$6 billion.

Xarelto was followed by Eliquis, another anticoagulant; Humira, used for a variety of autoimmune conditions including plaque psoriasis, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis; Invokana, Jardiance, and Farxiga, all for type 2 diabetes.

The top medical devices included the da Vinci Surgical System, Mako SmartRobotics, CoreValve Evolut, Natrelle Implants, and Impella, a heart pump that received a US Food and Drug Administration (FDA) warning that it was associated with a heightened risk for death.
 

Industry Influence May Lead to Higher Cost, Poor Quality Care

Multiple studies have shown that payments to physicians tend to lead to increased prescribing and, often, higher costs for Medicare, a health system, or patients.

“I’m sure there are still a lot of physicians out there who think they’re getting away with something, that they can take meals, or they can take consulting fees and not be influenced, but there’s overwhelming data showing that it always influences you,” said Dr. Fugh-Berman.

One study in 2020 that used the Open Payments database found that physicians increase prescribing of the drugs for which they receive payment in the months just after the payment. The authors also showed that physicians who are paid prescribe lower-quality drugs following the payment, “although the magnitude is small and unlikely to be clinically significant.”

Dr. Marshall said that more studies are needed to determine whether quality of care is being affected when a physician prescribes a drug after an industry payment.

For now, there seems to be little appetite among physicians to give up the payments, said Dr. Marshall and others.

Physicians in some specialties see the payments as “an implicit statement about their value,” said Dr. Marshall.

In oncology, having received a lot of payments “gets worn more as a badge of honor,” said Dr. Mitchell.

The clinicians believe that “by collaborating with industry we are providing scientific expertise to help develop the next generation of technology and cures,” Dr. Mitchell said, adding that they see the payments “as a mark of their impact.”

Among the JAMA study authors, Joseph S. Ross, MD, reported that he is a deputy editor of JAMA but was not involved in decisions regarding acceptance of the manuscript or its review. Dr. Ross also reported receiving grants from the FDA, Johnson and Johnson, the Medical Devices Innovation Consortium, the Agency for Healthcare Research and Quality, and the National Heart, Lung, and Blood Institute. He was an expert witness in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled in 2022. Dr. Steinbrook, Dr. Marshall, and Dr. Mitchell reported no relevant financial relationships. Dr. Fugh-Berman reported being an expert witness for plaintiffs in complaints about drug and device marketing practices.

A version of this article appeared on Medscape.com.

A review of the federal Open Payments database found that the pharmaceutical and medical device industry paid physicians $12.1 billion over nearly a decade.

Almost two thirds of eligible physicians — 826,313 doctors — received a payment from a drug or device maker from 2013 to 2022, according to a study published online in JAMA on March 28. Overall, the median payment was $48 per physician.

Orthopedists received the largest amount of payments in aggregate, $1.3 billion, followed by neurologists and psychiatrists at $1.2 billion and cardiologists at $1.29 billion.

Geriatric and nuclear medicine specialists and trauma and pediatric surgeons received the least amount of money in aggregate, and the mean amount paid to a pediatric surgeon in the top 0.1% was just $338,183 over the 9-year study period.

Excluding 2013 (the database was established in August that year), the total value of payments was highest in 2019 at $1.6 billion, up from $1.34 billion in 2014. It was lowest in 2020, the peak year of the COVID-19 pandemic, but dipped to $864 billion that year and rebounded to $1.28 billion in 2022, wrote the authors.

The Open Payments database, administered by the Centers for Medicare & Medicaid Services, requires drug and device makers and group purchasing organizations to report payments made to physicians, including for consulting services, speaking fees, food and beverages, travel and lodging, education, gifts, grants, and honoraria.

The database was created to shed light on these payments, which have been linked in multiple studies to more prescribing of a particular drug or more use of a particular device.

The JAMA review appeared to show that with the exception of the pandemic year, the relationships have more or less stayed the same since Open Payments began.

“There’s been no sea change, no massive shift in how these interactions are happening,” said Deborah C. Marshall, MD, assistant professor in the Department of Radiation Oncology at the Icahn School of Medicine at Mount Sinai in New York City, who has studied industry payments.

“There’s no suggestion that anything is really changing other than that’s there is transparency,” said Robert Steinbrook, MD, director of the Health Research Group at Public Citizen.

Still, Dr. Steinbrook told this news organization, “it’s better to know this than to not know this.”

The unchanging nature of industry-physician relationships “suggests that to reduce the volume and magnitude of payments, more would need to be done,” he said.

“Really, this should be banned. Doctors should not be allowed to get gifts from pharmaceutical companies,” said Adriane Fugh-Berman, MD, professor of pharmacology and physiology at Georgetown University, and director of PharmedOut, a Georgetown-based project that advances evidence-based prescribing and educates healthcare professionals about pharmaceutical marketing practices.

“The interactions wouldn’t be happening unless there was a purpose for them,” said Dr. Marshall. The relationships are “built with intention,” Dr. Marshall told this news organization.
 

Top Earners Range From $195,000 to $4.8 Million

Payments to the median physician over the study period ranged from $0 to $2339, but the mean payment to top earners — those in the top 0.1% — ranged from $194,933 for hospitalists to $4.8 million for orthopedic specialists.

Overall, the median payment was $48 per physician.

But small dollar amounts should not be discounted — even if it’s just a $25-catered lunch — said Aaron Mitchell, MD, a medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center in New York City who has studied industry-physician relationships. “The influence is not just in the dollar value,” Dr. Mitchell told this news organization. “It’s about the time listening to and the time in personal contact with industry representatives that these dollars are a marker for,” he said.

“There’s no such thing as a free lunch,” agreed Dr. Marshall. It’s “pretty well established” that lower-value payments do have influence, which is why academic institutions have established policies that limit gifts and meals and other payments from industry, she said.

Dr. Fugh-Berman said, “the size of the gift doesn’t really matter,” adding that research she conducted had shown that “accepting a meal increased not only the expense of the prescriptions that Medicare physicians wrote but also the number of prescriptions.”
 

Payments Mostly for High-Dollar Products

The top 25 drugs and devices that were related to industry payments tended to be high-cost brand-name products.

The top drug was Janssen’s Xarelto, an anticoagulant first approved in 2011 that costs about $600 a month, according to GoodRx. The drug has had annual sales of $4-$6 billion.

Xarelto was followed by Eliquis, another anticoagulant; Humira, used for a variety of autoimmune conditions including plaque psoriasis, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis; Invokana, Jardiance, and Farxiga, all for type 2 diabetes.

The top medical devices included the da Vinci Surgical System, Mako SmartRobotics, CoreValve Evolut, Natrelle Implants, and Impella, a heart pump that received a US Food and Drug Administration (FDA) warning that it was associated with a heightened risk for death.
 

Industry Influence May Lead to Higher Cost, Poor Quality Care

Multiple studies have shown that payments to physicians tend to lead to increased prescribing and, often, higher costs for Medicare, a health system, or patients.

“I’m sure there are still a lot of physicians out there who think they’re getting away with something, that they can take meals, or they can take consulting fees and not be influenced, but there’s overwhelming data showing that it always influences you,” said Dr. Fugh-Berman.

One study in 2020 that used the Open Payments database found that physicians increase prescribing of the drugs for which they receive payment in the months just after the payment. The authors also showed that physicians who are paid prescribe lower-quality drugs following the payment, “although the magnitude is small and unlikely to be clinically significant.”

Dr. Marshall said that more studies are needed to determine whether quality of care is being affected when a physician prescribes a drug after an industry payment.

For now, there seems to be little appetite among physicians to give up the payments, said Dr. Marshall and others.

Physicians in some specialties see the payments as “an implicit statement about their value,” said Dr. Marshall.

In oncology, having received a lot of payments “gets worn more as a badge of honor,” said Dr. Mitchell.

The clinicians believe that “by collaborating with industry we are providing scientific expertise to help develop the next generation of technology and cures,” Dr. Mitchell said, adding that they see the payments “as a mark of their impact.”

Among the JAMA study authors, Joseph S. Ross, MD, reported that he is a deputy editor of JAMA but was not involved in decisions regarding acceptance of the manuscript or its review. Dr. Ross also reported receiving grants from the FDA, Johnson and Johnson, the Medical Devices Innovation Consortium, the Agency for Healthcare Research and Quality, and the National Heart, Lung, and Blood Institute. He was an expert witness in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled in 2022. Dr. Steinbrook, Dr. Marshall, and Dr. Mitchell reported no relevant financial relationships. Dr. Fugh-Berman reported being an expert witness for plaintiffs in complaints about drug and device marketing practices.

A version of this article appeared on Medscape.com.

A review of the federal Open Payments database found that the pharmaceutical and medical device industry paid physicians $12.1 billion over nearly a decade.

Almost two thirds of eligible physicians — 826,313 doctors — received a payment from a drug or device maker from 2013 to 2022, according to a study published online in JAMA on March 28. Overall, the median payment was $48 per physician.

Orthopedists received the largest amount of payments in aggregate, $1.3 billion, followed by neurologists and psychiatrists at $1.2 billion and cardiologists at $1.29 billion.

Geriatric and nuclear medicine specialists and trauma and pediatric surgeons received the least amount of money in aggregate, and the mean amount paid to a pediatric surgeon in the top 0.1% was just $338,183 over the 9-year study period.

Excluding 2013 (the database was established in August that year), the total value of payments was highest in 2019 at $1.6 billion, up from $1.34 billion in 2014. It was lowest in 2020, the peak year of the COVID-19 pandemic, but dipped to $864 billion that year and rebounded to $1.28 billion in 2022, wrote the authors.

The Open Payments database, administered by the Centers for Medicare & Medicaid Services, requires drug and device makers and group purchasing organizations to report payments made to physicians, including for consulting services, speaking fees, food and beverages, travel and lodging, education, gifts, grants, and honoraria.

The database was created to shed light on these payments, which have been linked in multiple studies to more prescribing of a particular drug or more use of a particular device.

The JAMA review appeared to show that with the exception of the pandemic year, the relationships have more or less stayed the same since Open Payments began.

“There’s been no sea change, no massive shift in how these interactions are happening,” said Deborah C. Marshall, MD, assistant professor in the Department of Radiation Oncology at the Icahn School of Medicine at Mount Sinai in New York City, who has studied industry payments.

“There’s no suggestion that anything is really changing other than that’s there is transparency,” said Robert Steinbrook, MD, director of the Health Research Group at Public Citizen.

Still, Dr. Steinbrook told this news organization, “it’s better to know this than to not know this.”

The unchanging nature of industry-physician relationships “suggests that to reduce the volume and magnitude of payments, more would need to be done,” he said.

“Really, this should be banned. Doctors should not be allowed to get gifts from pharmaceutical companies,” said Adriane Fugh-Berman, MD, professor of pharmacology and physiology at Georgetown University, and director of PharmedOut, a Georgetown-based project that advances evidence-based prescribing and educates healthcare professionals about pharmaceutical marketing practices.

“The interactions wouldn’t be happening unless there was a purpose for them,” said Dr. Marshall. The relationships are “built with intention,” Dr. Marshall told this news organization.
 

Top Earners Range From $195,000 to $4.8 Million

Payments to the median physician over the study period ranged from $0 to $2339, but the mean payment to top earners — those in the top 0.1% — ranged from $194,933 for hospitalists to $4.8 million for orthopedic specialists.

Overall, the median payment was $48 per physician.

But small dollar amounts should not be discounted — even if it’s just a $25-catered lunch — said Aaron Mitchell, MD, a medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center in New York City who has studied industry-physician relationships. “The influence is not just in the dollar value,” Dr. Mitchell told this news organization. “It’s about the time listening to and the time in personal contact with industry representatives that these dollars are a marker for,” he said.

“There’s no such thing as a free lunch,” agreed Dr. Marshall. It’s “pretty well established” that lower-value payments do have influence, which is why academic institutions have established policies that limit gifts and meals and other payments from industry, she said.

Dr. Fugh-Berman said, “the size of the gift doesn’t really matter,” adding that research she conducted had shown that “accepting a meal increased not only the expense of the prescriptions that Medicare physicians wrote but also the number of prescriptions.”
 

Payments Mostly for High-Dollar Products

The top 25 drugs and devices that were related to industry payments tended to be high-cost brand-name products.

The top drug was Janssen’s Xarelto, an anticoagulant first approved in 2011 that costs about $600 a month, according to GoodRx. The drug has had annual sales of $4-$6 billion.

Xarelto was followed by Eliquis, another anticoagulant; Humira, used for a variety of autoimmune conditions including plaque psoriasis, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis; Invokana, Jardiance, and Farxiga, all for type 2 diabetes.

The top medical devices included the da Vinci Surgical System, Mako SmartRobotics, CoreValve Evolut, Natrelle Implants, and Impella, a heart pump that received a US Food and Drug Administration (FDA) warning that it was associated with a heightened risk for death.
 

Industry Influence May Lead to Higher Cost, Poor Quality Care

Multiple studies have shown that payments to physicians tend to lead to increased prescribing and, often, higher costs for Medicare, a health system, or patients.

“I’m sure there are still a lot of physicians out there who think they’re getting away with something, that they can take meals, or they can take consulting fees and not be influenced, but there’s overwhelming data showing that it always influences you,” said Dr. Fugh-Berman.

One study in 2020 that used the Open Payments database found that physicians increase prescribing of the drugs for which they receive payment in the months just after the payment. The authors also showed that physicians who are paid prescribe lower-quality drugs following the payment, “although the magnitude is small and unlikely to be clinically significant.”

Dr. Marshall said that more studies are needed to determine whether quality of care is being affected when a physician prescribes a drug after an industry payment.

For now, there seems to be little appetite among physicians to give up the payments, said Dr. Marshall and others.

Physicians in some specialties see the payments as “an implicit statement about their value,” said Dr. Marshall.

In oncology, having received a lot of payments “gets worn more as a badge of honor,” said Dr. Mitchell.

The clinicians believe that “by collaborating with industry we are providing scientific expertise to help develop the next generation of technology and cures,” Dr. Mitchell said, adding that they see the payments “as a mark of their impact.”

Among the JAMA study authors, Joseph S. Ross, MD, reported that he is a deputy editor of JAMA but was not involved in decisions regarding acceptance of the manuscript or its review. Dr. Ross also reported receiving grants from the FDA, Johnson and Johnson, the Medical Devices Innovation Consortium, the Agency for Healthcare Research and Quality, and the National Heart, Lung, and Blood Institute. He was an expert witness in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled in 2022. Dr. Steinbrook, Dr. Marshall, and Dr. Mitchell reported no relevant financial relationships. Dr. Fugh-Berman reported being an expert witness for plaintiffs in complaints about drug and device marketing practices.

A version of this article appeared on Medscape.com.

Once upon a time, treating multiple sclerosis (MS) was easy — steroids.

Then, in the 1990s, came Betaseron, then Avonex, then Copaxone. Suddenly we had three options to choose from, though overall roughly similar in efficacy (yeah, I’m leaving Novantrone out; it’s a niche drug). Treatment required some decision making, though not a huge amount. I usually laid out the different schedules and side effect to patients and let them decide.

MS treatment was uncomplicated enough that I knew family doctors who treated MS patients on their own, and I can’t say I could have done any better. If you’ve got a clear MRI, then prescribe Betaseron and hope.

Then came Rebif, then Tysabri, and then pretty much an explosion of new drugs which hasn’t slowed down. Next up are the BTK agents. An embarrassment of riches, though for patients, their families, and neurologists, a very welcome one.

But as more drugs come out, with different mechanisms of action and monitoring requirements, the treatment of MS becomes more complicated, slowly moving from the realm of a general neurologist to an MS subspecialist.

At some point it raises the question of when does a disease become its own specialty? Perhaps this is a bit of hyperbole — I’m pretty sure I’ll be seeing MS patients for a long time to come — but it’s a valid point. Especially as further research may subdivide MS treatment by genetics and other breakdowns.

Alzheimer’s disease may follow a similar (albeit very welcome) trajectory. While nothing really game-changing has come out in the 20 years, the number of new drugs and different mechanisms of action in development is large. Granted, not all of them will work, but hopefully some will. At some point it may come down to treating patients with a cocktail of drugs with separate ways of managing the disease, with guidance based on genetic or clinical profiles.

And that’s a good thing, but it may, again, move the disease from the province of general neurologists to subspecialists. Maybe that would be a good, maybe not. Probably will depend on the patient, their families, and other factors.

Of course, I may be overthinking this. The number of drugs we have for MS is nothing compared with the available treatments we have for hypertension, yet it’s certainly well within the capabilities of most internists to treat without referring to a cardiologist or nephrologist.

Perhaps the new drugs won’t make a difference except in a handful of cases. As new drugs come out we also move on from the old ones, dropping them from our mental armamentarium except in rare cases. When was the last time you prescribed Betaseron?

These drugs are very welcome, and very needed. I will be happy if we can beat back some of the diseases neurologist see, regardless of whom the patients and up seeing.
 

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Once upon a time, treating multiple sclerosis (MS) was easy — steroids.

Then, in the 1990s, came Betaseron, then Avonex, then Copaxone. Suddenly we had three options to choose from, though overall roughly similar in efficacy (yeah, I’m leaving Novantrone out; it’s a niche drug). Treatment required some decision making, though not a huge amount. I usually laid out the different schedules and side effect to patients and let them decide.

MS treatment was uncomplicated enough that I knew family doctors who treated MS patients on their own, and I can’t say I could have done any better. If you’ve got a clear MRI, then prescribe Betaseron and hope.

Then came Rebif, then Tysabri, and then pretty much an explosion of new drugs which hasn’t slowed down. Next up are the BTK agents. An embarrassment of riches, though for patients, their families, and neurologists, a very welcome one.

But as more drugs come out, with different mechanisms of action and monitoring requirements, the treatment of MS becomes more complicated, slowly moving from the realm of a general neurologist to an MS subspecialist.

At some point it raises the question of when does a disease become its own specialty? Perhaps this is a bit of hyperbole — I’m pretty sure I’ll be seeing MS patients for a long time to come — but it’s a valid point. Especially as further research may subdivide MS treatment by genetics and other breakdowns.

Alzheimer’s disease may follow a similar (albeit very welcome) trajectory. While nothing really game-changing has come out in the 20 years, the number of new drugs and different mechanisms of action in development is large. Granted, not all of them will work, but hopefully some will. At some point it may come down to treating patients with a cocktail of drugs with separate ways of managing the disease, with guidance based on genetic or clinical profiles.

And that’s a good thing, but it may, again, move the disease from the province of general neurologists to subspecialists. Maybe that would be a good, maybe not. Probably will depend on the patient, their families, and other factors.

Of course, I may be overthinking this. The number of drugs we have for MS is nothing compared with the available treatments we have for hypertension, yet it’s certainly well within the capabilities of most internists to treat without referring to a cardiologist or nephrologist.

Perhaps the new drugs won’t make a difference except in a handful of cases. As new drugs come out we also move on from the old ones, dropping them from our mental armamentarium except in rare cases. When was the last time you prescribed Betaseron?

These drugs are very welcome, and very needed. I will be happy if we can beat back some of the diseases neurologist see, regardless of whom the patients and up seeing.
 

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Once upon a time, treating multiple sclerosis (MS) was easy — steroids.

Then, in the 1990s, came Betaseron, then Avonex, then Copaxone. Suddenly we had three options to choose from, though overall roughly similar in efficacy (yeah, I’m leaving Novantrone out; it’s a niche drug). Treatment required some decision making, though not a huge amount. I usually laid out the different schedules and side effect to patients and let them decide.

MS treatment was uncomplicated enough that I knew family doctors who treated MS patients on their own, and I can’t say I could have done any better. If you’ve got a clear MRI, then prescribe Betaseron and hope.

Then came Rebif, then Tysabri, and then pretty much an explosion of new drugs which hasn’t slowed down. Next up are the BTK agents. An embarrassment of riches, though for patients, their families, and neurologists, a very welcome one.

But as more drugs come out, with different mechanisms of action and monitoring requirements, the treatment of MS becomes more complicated, slowly moving from the realm of a general neurologist to an MS subspecialist.

At some point it raises the question of when does a disease become its own specialty? Perhaps this is a bit of hyperbole — I’m pretty sure I’ll be seeing MS patients for a long time to come — but it’s a valid point. Especially as further research may subdivide MS treatment by genetics and other breakdowns.

Alzheimer’s disease may follow a similar (albeit very welcome) trajectory. While nothing really game-changing has come out in the 20 years, the number of new drugs and different mechanisms of action in development is large. Granted, not all of them will work, but hopefully some will. At some point it may come down to treating patients with a cocktail of drugs with separate ways of managing the disease, with guidance based on genetic or clinical profiles.

And that’s a good thing, but it may, again, move the disease from the province of general neurologists to subspecialists. Maybe that would be a good, maybe not. Probably will depend on the patient, their families, and other factors.

Of course, I may be overthinking this. The number of drugs we have for MS is nothing compared with the available treatments we have for hypertension, yet it’s certainly well within the capabilities of most internists to treat without referring to a cardiologist or nephrologist.

Perhaps the new drugs won’t make a difference except in a handful of cases. As new drugs come out we also move on from the old ones, dropping them from our mental armamentarium except in rare cases. When was the last time you prescribed Betaseron?

These drugs are very welcome, and very needed. I will be happy if we can beat back some of the diseases neurologist see, regardless of whom the patients and up seeing.
 

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Female bias in autoimmune disease can be profound, with nine females developing lupus for every male affected, and nearly twice that ratio seen in Sjögren disease.

For years, researchers have worked to determine the reasons for sex-linked differences in immune response and autoimmunity, with environmental factors, sex hormones, and X-chromosome inactivation — the process by which a second X chromosome is silenced — all seen as having roles.

More recently, different groups of researchers have homed in on a long noncoding RNA fragment called X-inactive specific transcript, or Xist, as a potential driver of sex bias in autoimmune disease. Xist, which occurs in female mammals, has been known since the 1990s as the master regulator of X-chromosome inactivation, the process by which the second X chromosome is silenced, averting a fatal double dose of X-linked genes.

The inactivation process, which scientists liken to wrapping the extra X with a fluffy cloud of proteins, occurs early in embryonic development. After its initial work silencing the X, Xist is produced throughout the female’s life, allowing X inactivation to be maintained.

But is it possible that Xist, and the many dozens of proteins it recruits to keep that extra X chromosome silent, can also provoke autoimmunity? This is the question that several teams of researchers have been grappling with, resulting in provocative findings and opening exciting new avenues of discovery.
 

Xist Protein Complexes Make Male Mice Vulnerable to Lupus

In February, researchers Howard Chang, MD, PhD, and Diana Dou, PhD, of Stanford University in Stanford, California, made worldwide news when they published results from an experiment using male mice genetically engineered to carry a non-silencing form of Xist on one of their chromosomes.

Xist acts like a scaffold, recruiting multiple protein complexes to help it do its job. Dr. Dou explained in an interview that her team has been eyeing suspiciously for years the dozens of proteins Xist recruits in the process of X-chromosome inactivation, many of which are known autoantigens.

When the mice were injected with pristane, a chemical that induces lupus-like autoimmunity in mice, the Xist-producing males developed symptoms at a rate similar to that of females, while wild-type male mice did not.

By using a male model, the scientists could determine whether Xist could cause an increased vulnerability for autoimmunity absent the influence of female hormones and development. “Everything else about the animal is male,” Dr. Dou commented. “You just add the formation of the Xist ribonucleoprotein particles — Xist RNA plus the associating proteins — to male cells that would not ordinarily have these particles. Is just having the particles present in these animals sufficient to increase their autoimmunity? This is what our paper showed: That just having expression of Xist, the presence of these Xist [ribonucleoproteins], is enough in permissive genetic backgrounds to invoke higher incidence and severity of autoimmune disease development in our pristane-induced lupus model.”

The Stanford group sees the Xist protein complex, which they have studied extensively, as a key to understanding how Xist might provoke autoimmunity. Nonetheless, Dr. Dou said, “It’s important to note that there are other contributing factors, which is why not all females develop autoimmunity, and we had very different results in our autoimmune-resistant mouse strain compared to the more autoimmune-prone strain. Xist is a factor, but many factors are required to subvert the checkpoints in immune balance and allow the progression to full-blown autoimmunity.”
 

Faulty X Inactivation and Gene Escape

The understanding that Xist might be implicated in autoimmune disease — and explain some of its female bias — is not new.

About a decade ago, Montserrat Anguera, PhD, a biologist at the University of Pennsylvania, Philadelphia, began looking at the relationship of X-chromosome inactivation, which by definition involves Xist, and lupus.

University of Pennsylvania

Dr. Anguera hypothesized that imperfect X inactivation allowed for greater escape of genes associated with immunity and autoimmunity. Studying patients with lupus, Dr. Anguera found that the silencing process was abnormal, allowing more of these genes to escape the silenced X — including toll-like receptor 7 (TLR-7) and other genes implicated in the pathogenesis of lupus.

“If you get increased expression of certain genes from the [silenced] X, like TLR-7, it can result in autoimmune disease,” Dr. Anguera said. “So what we think is that in the lupus patients, because the silencing is impacted, you’re going to have more expression happening from the inactive X. And then in conjunction with the active X, that’s going to throw off the dosage [of autoimmunity-linked genes]. You’re changing the dosage of genes, and that’s what’s critical.”

Even among patients with lupus whose symptoms are well controlled with medication, “if you look at their T cells and B cells, they still have messed up X inactivation,” Dr. Anguera said. “The Xist RNA that’s supposed to be tethered to the inactive X in a fluffy cloud is not localized, and instead is dispersed all over the nucleus.”

Dr. Anguera pointed out that autoimmune diseases are complex and can result from a combination of factors. “You also have a host of hormonal and environmental contributors, such as previous viral infections,” she said. And of course men can also develop lupus, meaning that the X chromosome cannot explain everything.

Dr. Anguera said that, while the findings by the Stanford scientists do not explain the full pathogenesis of lupus and related diseases, they still support a strong role for Xist in sex-biased autoimmune diseases. “It’s sort of another take on it,” she said.
 

Is It the Proteins, the RNA, or Both?

The Stanford team points to the proteins recruited by Xist in the process of X-chromosome inactivation as the likely trigger of autoimmunity. However, a group of researchers at Johns Hopkins University in Baltimore, Maryland, made the case in a 2022 paper that Xist RNA itself was dangerous. They found that numerous short RNA sequences within the Xist molecule serve as ligands for TLR-7. And TLR-7 ligation causes plasmacytoid dendritic cells to overproduce type 1 interferon, a classic hallmark of lupus.

Alexander Girgis

“Within rheumatology, the diseases that tend to be most female biased are the ones that are antibody positive and have this presence of upregulated interferon,” explained Brendan Antiochos, MD. “Lupus is an example of that. Sjögren’s syndrome is another. So there’s always been this quest to want to understand the mechanisms that explain why women would have more autoimmunity. And are there specific pathways which could contribute? One of the key pathways that’s been shown in humans and in mice to be important in lupus is toll-like receptor signaling.” Most convincingly, one recent study showed that people who have a gain-of-function mutation in their TLR-7 gene get a spontaneous form of lupus.

Wes Linda

These findings led Erika Darrah, PhD, and her colleague Dr. Antiochos to begin looking more deeply into which RNAs could be triggering this signaling pathway. “We started to think: Well, there is this sex bias. Could it be that women have unique RNAs that could potentially act as triggers for TLR-7 signaling?” Dr. Darrah said.

Dr. Darrah and Dr. Antiochos looked at publicly available genetic data to identify sex-biased sources of self-RNA containing TLR-7 ligands. Xist, they found, was chock full of them. “Every time we analyzed that data, no matter what filter we applied, Xist kept popping out over and over again as the most highly female skewed RNA, the RNA most likely to contain these TLR-7 binding motifs,” Dr. Darrah said. “We started to formulate the hypothesis that Xist was actually promoting responses that were dangerous and pathogenic in lupus.”

That finding led the team to conduct in-vitro experiments that showed different fragments of Xist can activate TLR-7, resulting in higher interferon production. Finally, they looked at blood and kidney cells from women with lupus and found that higher Xist expression correlated with more interferon production, and higher disease activity. “The more Xist, the sicker people were,” Dr. Darrah said.
 

Xist’s Other Functions

Xist was first studied in the 1990s, and most research has centered on its primary role in X-chromosome inactivation. A research group led by Kathrin Plath, PhD, at the University of California, Los Angeles, has been occupied for years with untangling exactly how Xist does what it does. “It’s a very clever RNA, right? It can silence the whole chromosome,” Dr. Plath said in an interview.

In 2021, Dr. Plath and her colleagues established in detail how Xist executes silencing, setting down pairs of molecules in specific spots along the chromosome and building huge protein clouds around them. “We worked on learning where Xist binds and what proteins it binds, drilling down to understand how these proteins and the RNA are coming together.”

Dr. Plath has long suspected that Xist has other functions besides X inactivation, and she and her colleagues are starting to identify them. Early this year they published the surprising finding that Xist can regulate gene expression in autosomes, or non–sex-linked chromosomes, “which it might well also do in cancer cells and lymphocytes,” Dr. Plath said. “And now there is this new evidence of an autoimmune function,” she said. “It’s a super exciting time.”

The different hypotheses surrounding Xist’s role in sex-biased autoimmunity aren’t mutually exclusive, Dr. Plath said. “There’s a tremendous enrichment of proteins occurring” during X inactivation, she said, supporting the Stanford team’s hypothesis that proteins are triggering autoimmunity. As for the Johns Hopkins researchers’ understanding that Xist RNA itself is the trigger, “I’m totally open to that,” she said. “Why can’t it be an autoantigen?”

The other model in the field, Dr. Plath noted, is the one proposed by Dr. Anguera — “that there’s [gene] escape from X-inactivation — that females have more escape expression, and that Xist is more dispersed in the lymphocytes [of patients with lupus]. In fact, Xist becoming a little dispersed might make it a better antigen. So I do think everything is possible.”

The plethora of new findings related to autoimmunity has caused Dr. Plath to consider redirecting her lab’s focus toward more translational work, “because we are obviously good at studying Xist.” Among the mysteries Dr. Plath would like to solve is how some genes manage to escape the Xist cloud.

What is needed, she said, is collaboration. “Everyone will come up with different ideas. So I think it’s good to have more people look at things together. Then the field will achieve a breakthrough treatment.”

Female bias in autoimmune disease can be profound, with nine females developing lupus for every male affected, and nearly twice that ratio seen in Sjögren disease.

For years, researchers have worked to determine the reasons for sex-linked differences in immune response and autoimmunity, with environmental factors, sex hormones, and X-chromosome inactivation — the process by which a second X chromosome is silenced — all seen as having roles.

More recently, different groups of researchers have homed in on a long noncoding RNA fragment called X-inactive specific transcript, or Xist, as a potential driver of sex bias in autoimmune disease. Xist, which occurs in female mammals, has been known since the 1990s as the master regulator of X-chromosome inactivation, the process by which the second X chromosome is silenced, averting a fatal double dose of X-linked genes.

The inactivation process, which scientists liken to wrapping the extra X with a fluffy cloud of proteins, occurs early in embryonic development. After its initial work silencing the X, Xist is produced throughout the female’s life, allowing X inactivation to be maintained.

But is it possible that Xist, and the many dozens of proteins it recruits to keep that extra X chromosome silent, can also provoke autoimmunity? This is the question that several teams of researchers have been grappling with, resulting in provocative findings and opening exciting new avenues of discovery.
 

Xist Protein Complexes Make Male Mice Vulnerable to Lupus

In February, researchers Howard Chang, MD, PhD, and Diana Dou, PhD, of Stanford University in Stanford, California, made worldwide news when they published results from an experiment using male mice genetically engineered to carry a non-silencing form of Xist on one of their chromosomes.

Xist acts like a scaffold, recruiting multiple protein complexes to help it do its job. Dr. Dou explained in an interview that her team has been eyeing suspiciously for years the dozens of proteins Xist recruits in the process of X-chromosome inactivation, many of which are known autoantigens.

When the mice were injected with pristane, a chemical that induces lupus-like autoimmunity in mice, the Xist-producing males developed symptoms at a rate similar to that of females, while wild-type male mice did not.

By using a male model, the scientists could determine whether Xist could cause an increased vulnerability for autoimmunity absent the influence of female hormones and development. “Everything else about the animal is male,” Dr. Dou commented. “You just add the formation of the Xist ribonucleoprotein particles — Xist RNA plus the associating proteins — to male cells that would not ordinarily have these particles. Is just having the particles present in these animals sufficient to increase their autoimmunity? This is what our paper showed: That just having expression of Xist, the presence of these Xist [ribonucleoproteins], is enough in permissive genetic backgrounds to invoke higher incidence and severity of autoimmune disease development in our pristane-induced lupus model.”

The Stanford group sees the Xist protein complex, which they have studied extensively, as a key to understanding how Xist might provoke autoimmunity. Nonetheless, Dr. Dou said, “It’s important to note that there are other contributing factors, which is why not all females develop autoimmunity, and we had very different results in our autoimmune-resistant mouse strain compared to the more autoimmune-prone strain. Xist is a factor, but many factors are required to subvert the checkpoints in immune balance and allow the progression to full-blown autoimmunity.”
 

Faulty X Inactivation and Gene Escape

The understanding that Xist might be implicated in autoimmune disease — and explain some of its female bias — is not new.

About a decade ago, Montserrat Anguera, PhD, a biologist at the University of Pennsylvania, Philadelphia, began looking at the relationship of X-chromosome inactivation, which by definition involves Xist, and lupus.

University of Pennsylvania

Dr. Anguera hypothesized that imperfect X inactivation allowed for greater escape of genes associated with immunity and autoimmunity. Studying patients with lupus, Dr. Anguera found that the silencing process was abnormal, allowing more of these genes to escape the silenced X — including toll-like receptor 7 (TLR-7) and other genes implicated in the pathogenesis of lupus.

“If you get increased expression of certain genes from the [silenced] X, like TLR-7, it can result in autoimmune disease,” Dr. Anguera said. “So what we think is that in the lupus patients, because the silencing is impacted, you’re going to have more expression happening from the inactive X. And then in conjunction with the active X, that’s going to throw off the dosage [of autoimmunity-linked genes]. You’re changing the dosage of genes, and that’s what’s critical.”

Even among patients with lupus whose symptoms are well controlled with medication, “if you look at their T cells and B cells, they still have messed up X inactivation,” Dr. Anguera said. “The Xist RNA that’s supposed to be tethered to the inactive X in a fluffy cloud is not localized, and instead is dispersed all over the nucleus.”

Dr. Anguera pointed out that autoimmune diseases are complex and can result from a combination of factors. “You also have a host of hormonal and environmental contributors, such as previous viral infections,” she said. And of course men can also develop lupus, meaning that the X chromosome cannot explain everything.

Dr. Anguera said that, while the findings by the Stanford scientists do not explain the full pathogenesis of lupus and related diseases, they still support a strong role for Xist in sex-biased autoimmune diseases. “It’s sort of another take on it,” she said.
 

Is It the Proteins, the RNA, or Both?

The Stanford team points to the proteins recruited by Xist in the process of X-chromosome inactivation as the likely trigger of autoimmunity. However, a group of researchers at Johns Hopkins University in Baltimore, Maryland, made the case in a 2022 paper that Xist RNA itself was dangerous. They found that numerous short RNA sequences within the Xist molecule serve as ligands for TLR-7. And TLR-7 ligation causes plasmacytoid dendritic cells to overproduce type 1 interferon, a classic hallmark of lupus.

Alexander Girgis

“Within rheumatology, the diseases that tend to be most female biased are the ones that are antibody positive and have this presence of upregulated interferon,” explained Brendan Antiochos, MD. “Lupus is an example of that. Sjögren’s syndrome is another. So there’s always been this quest to want to understand the mechanisms that explain why women would have more autoimmunity. And are there specific pathways which could contribute? One of the key pathways that’s been shown in humans and in mice to be important in lupus is toll-like receptor signaling.” Most convincingly, one recent study showed that people who have a gain-of-function mutation in their TLR-7 gene get a spontaneous form of lupus.

Wes Linda

These findings led Erika Darrah, PhD, and her colleague Dr. Antiochos to begin looking more deeply into which RNAs could be triggering this signaling pathway. “We started to think: Well, there is this sex bias. Could it be that women have unique RNAs that could potentially act as triggers for TLR-7 signaling?” Dr. Darrah said.

Dr. Darrah and Dr. Antiochos looked at publicly available genetic data to identify sex-biased sources of self-RNA containing TLR-7 ligands. Xist, they found, was chock full of them. “Every time we analyzed that data, no matter what filter we applied, Xist kept popping out over and over again as the most highly female skewed RNA, the RNA most likely to contain these TLR-7 binding motifs,” Dr. Darrah said. “We started to formulate the hypothesis that Xist was actually promoting responses that were dangerous and pathogenic in lupus.”

That finding led the team to conduct in-vitro experiments that showed different fragments of Xist can activate TLR-7, resulting in higher interferon production. Finally, they looked at blood and kidney cells from women with lupus and found that higher Xist expression correlated with more interferon production, and higher disease activity. “The more Xist, the sicker people were,” Dr. Darrah said.
 

Xist’s Other Functions

Xist was first studied in the 1990s, and most research has centered on its primary role in X-chromosome inactivation. A research group led by Kathrin Plath, PhD, at the University of California, Los Angeles, has been occupied for years with untangling exactly how Xist does what it does. “It’s a very clever RNA, right? It can silence the whole chromosome,” Dr. Plath said in an interview.

In 2021, Dr. Plath and her colleagues established in detail how Xist executes silencing, setting down pairs of molecules in specific spots along the chromosome and building huge protein clouds around them. “We worked on learning where Xist binds and what proteins it binds, drilling down to understand how these proteins and the RNA are coming together.”

Dr. Plath has long suspected that Xist has other functions besides X inactivation, and she and her colleagues are starting to identify them. Early this year they published the surprising finding that Xist can regulate gene expression in autosomes, or non–sex-linked chromosomes, “which it might well also do in cancer cells and lymphocytes,” Dr. Plath said. “And now there is this new evidence of an autoimmune function,” she said. “It’s a super exciting time.”

The different hypotheses surrounding Xist’s role in sex-biased autoimmunity aren’t mutually exclusive, Dr. Plath said. “There’s a tremendous enrichment of proteins occurring” during X inactivation, she said, supporting the Stanford team’s hypothesis that proteins are triggering autoimmunity. As for the Johns Hopkins researchers’ understanding that Xist RNA itself is the trigger, “I’m totally open to that,” she said. “Why can’t it be an autoantigen?”

The other model in the field, Dr. Plath noted, is the one proposed by Dr. Anguera — “that there’s [gene] escape from X-inactivation — that females have more escape expression, and that Xist is more dispersed in the lymphocytes [of patients with lupus]. In fact, Xist becoming a little dispersed might make it a better antigen. So I do think everything is possible.”

The plethora of new findings related to autoimmunity has caused Dr. Plath to consider redirecting her lab’s focus toward more translational work, “because we are obviously good at studying Xist.” Among the mysteries Dr. Plath would like to solve is how some genes manage to escape the Xist cloud.

What is needed, she said, is collaboration. “Everyone will come up with different ideas. So I think it’s good to have more people look at things together. Then the field will achieve a breakthrough treatment.”

Female bias in autoimmune disease can be profound, with nine females developing lupus for every male affected, and nearly twice that ratio seen in Sjögren disease.

For years, researchers have worked to determine the reasons for sex-linked differences in immune response and autoimmunity, with environmental factors, sex hormones, and X-chromosome inactivation — the process by which a second X chromosome is silenced — all seen as having roles.

More recently, different groups of researchers have homed in on a long noncoding RNA fragment called X-inactive specific transcript, or Xist, as a potential driver of sex bias in autoimmune disease. Xist, which occurs in female mammals, has been known since the 1990s as the master regulator of X-chromosome inactivation, the process by which the second X chromosome is silenced, averting a fatal double dose of X-linked genes.

The inactivation process, which scientists liken to wrapping the extra X with a fluffy cloud of proteins, occurs early in embryonic development. After its initial work silencing the X, Xist is produced throughout the female’s life, allowing X inactivation to be maintained.

But is it possible that Xist, and the many dozens of proteins it recruits to keep that extra X chromosome silent, can also provoke autoimmunity? This is the question that several teams of researchers have been grappling with, resulting in provocative findings and opening exciting new avenues of discovery.
 

Xist Protein Complexes Make Male Mice Vulnerable to Lupus

In February, researchers Howard Chang, MD, PhD, and Diana Dou, PhD, of Stanford University in Stanford, California, made worldwide news when they published results from an experiment using male mice genetically engineered to carry a non-silencing form of Xist on one of their chromosomes.

Xist acts like a scaffold, recruiting multiple protein complexes to help it do its job. Dr. Dou explained in an interview that her team has been eyeing suspiciously for years the dozens of proteins Xist recruits in the process of X-chromosome inactivation, many of which are known autoantigens.

When the mice were injected with pristane, a chemical that induces lupus-like autoimmunity in mice, the Xist-producing males developed symptoms at a rate similar to that of females, while wild-type male mice did not.

By using a male model, the scientists could determine whether Xist could cause an increased vulnerability for autoimmunity absent the influence of female hormones and development. “Everything else about the animal is male,” Dr. Dou commented. “You just add the formation of the Xist ribonucleoprotein particles — Xist RNA plus the associating proteins — to male cells that would not ordinarily have these particles. Is just having the particles present in these animals sufficient to increase their autoimmunity? This is what our paper showed: That just having expression of Xist, the presence of these Xist [ribonucleoproteins], is enough in permissive genetic backgrounds to invoke higher incidence and severity of autoimmune disease development in our pristane-induced lupus model.”

The Stanford group sees the Xist protein complex, which they have studied extensively, as a key to understanding how Xist might provoke autoimmunity. Nonetheless, Dr. Dou said, “It’s important to note that there are other contributing factors, which is why not all females develop autoimmunity, and we had very different results in our autoimmune-resistant mouse strain compared to the more autoimmune-prone strain. Xist is a factor, but many factors are required to subvert the checkpoints in immune balance and allow the progression to full-blown autoimmunity.”
 

Faulty X Inactivation and Gene Escape

The understanding that Xist might be implicated in autoimmune disease — and explain some of its female bias — is not new.

About a decade ago, Montserrat Anguera, PhD, a biologist at the University of Pennsylvania, Philadelphia, began looking at the relationship of X-chromosome inactivation, which by definition involves Xist, and lupus.

University of Pennsylvania

Dr. Anguera hypothesized that imperfect X inactivation allowed for greater escape of genes associated with immunity and autoimmunity. Studying patients with lupus, Dr. Anguera found that the silencing process was abnormal, allowing more of these genes to escape the silenced X — including toll-like receptor 7 (TLR-7) and other genes implicated in the pathogenesis of lupus.

“If you get increased expression of certain genes from the [silenced] X, like TLR-7, it can result in autoimmune disease,” Dr. Anguera said. “So what we think is that in the lupus patients, because the silencing is impacted, you’re going to have more expression happening from the inactive X. And then in conjunction with the active X, that’s going to throw off the dosage [of autoimmunity-linked genes]. You’re changing the dosage of genes, and that’s what’s critical.”

Even among patients with lupus whose symptoms are well controlled with medication, “if you look at their T cells and B cells, they still have messed up X inactivation,” Dr. Anguera said. “The Xist RNA that’s supposed to be tethered to the inactive X in a fluffy cloud is not localized, and instead is dispersed all over the nucleus.”

Dr. Anguera pointed out that autoimmune diseases are complex and can result from a combination of factors. “You also have a host of hormonal and environmental contributors, such as previous viral infections,” she said. And of course men can also develop lupus, meaning that the X chromosome cannot explain everything.

Dr. Anguera said that, while the findings by the Stanford scientists do not explain the full pathogenesis of lupus and related diseases, they still support a strong role for Xist in sex-biased autoimmune diseases. “It’s sort of another take on it,” she said.
 

Is It the Proteins, the RNA, or Both?

The Stanford team points to the proteins recruited by Xist in the process of X-chromosome inactivation as the likely trigger of autoimmunity. However, a group of researchers at Johns Hopkins University in Baltimore, Maryland, made the case in a 2022 paper that Xist RNA itself was dangerous. They found that numerous short RNA sequences within the Xist molecule serve as ligands for TLR-7. And TLR-7 ligation causes plasmacytoid dendritic cells to overproduce type 1 interferon, a classic hallmark of lupus.

Alexander Girgis

“Within rheumatology, the diseases that tend to be most female biased are the ones that are antibody positive and have this presence of upregulated interferon,” explained Brendan Antiochos, MD. “Lupus is an example of that. Sjögren’s syndrome is another. So there’s always been this quest to want to understand the mechanisms that explain why women would have more autoimmunity. And are there specific pathways which could contribute? One of the key pathways that’s been shown in humans and in mice to be important in lupus is toll-like receptor signaling.” Most convincingly, one recent study showed that people who have a gain-of-function mutation in their TLR-7 gene get a spontaneous form of lupus.

Wes Linda

These findings led Erika Darrah, PhD, and her colleague Dr. Antiochos to begin looking more deeply into which RNAs could be triggering this signaling pathway. “We started to think: Well, there is this sex bias. Could it be that women have unique RNAs that could potentially act as triggers for TLR-7 signaling?” Dr. Darrah said.

Dr. Darrah and Dr. Antiochos looked at publicly available genetic data to identify sex-biased sources of self-RNA containing TLR-7 ligands. Xist, they found, was chock full of them. “Every time we analyzed that data, no matter what filter we applied, Xist kept popping out over and over again as the most highly female skewed RNA, the RNA most likely to contain these TLR-7 binding motifs,” Dr. Darrah said. “We started to formulate the hypothesis that Xist was actually promoting responses that were dangerous and pathogenic in lupus.”

That finding led the team to conduct in-vitro experiments that showed different fragments of Xist can activate TLR-7, resulting in higher interferon production. Finally, they looked at blood and kidney cells from women with lupus and found that higher Xist expression correlated with more interferon production, and higher disease activity. “The more Xist, the sicker people were,” Dr. Darrah said.
 

Xist’s Other Functions

Xist was first studied in the 1990s, and most research has centered on its primary role in X-chromosome inactivation. A research group led by Kathrin Plath, PhD, at the University of California, Los Angeles, has been occupied for years with untangling exactly how Xist does what it does. “It’s a very clever RNA, right? It can silence the whole chromosome,” Dr. Plath said in an interview.

In 2021, Dr. Plath and her colleagues established in detail how Xist executes silencing, setting down pairs of molecules in specific spots along the chromosome and building huge protein clouds around them. “We worked on learning where Xist binds and what proteins it binds, drilling down to understand how these proteins and the RNA are coming together.”

Dr. Plath has long suspected that Xist has other functions besides X inactivation, and she and her colleagues are starting to identify them. Early this year they published the surprising finding that Xist can regulate gene expression in autosomes, or non–sex-linked chromosomes, “which it might well also do in cancer cells and lymphocytes,” Dr. Plath said. “And now there is this new evidence of an autoimmune function,” she said. “It’s a super exciting time.”

The different hypotheses surrounding Xist’s role in sex-biased autoimmunity aren’t mutually exclusive, Dr. Plath said. “There’s a tremendous enrichment of proteins occurring” during X inactivation, she said, supporting the Stanford team’s hypothesis that proteins are triggering autoimmunity. As for the Johns Hopkins researchers’ understanding that Xist RNA itself is the trigger, “I’m totally open to that,” she said. “Why can’t it be an autoantigen?”

The other model in the field, Dr. Plath noted, is the one proposed by Dr. Anguera — “that there’s [gene] escape from X-inactivation — that females have more escape expression, and that Xist is more dispersed in the lymphocytes [of patients with lupus]. In fact, Xist becoming a little dispersed might make it a better antigen. So I do think everything is possible.”

The plethora of new findings related to autoimmunity has caused Dr. Plath to consider redirecting her lab’s focus toward more translational work, “because we are obviously good at studying Xist.” Among the mysteries Dr. Plath would like to solve is how some genes manage to escape the Xist cloud.

What is needed, she said, is collaboration. “Everyone will come up with different ideas. So I think it’s good to have more people look at things together. Then the field will achieve a breakthrough treatment.”