Conference Coverage

To diagnose multiple sclerosis (MS), the central vein sign on brain MRI appears to work as well as oligoclonal bands in cerebrospinal fluid, and combining the two biomarkers yields the highest predictive value for MS, a new study indicates.

The presence of oligoclonal bands is “very specific for MS and is obtained by lumbar puncture, which is invasive and can be unpleasant, so it is not an ideal test,” said study investigator Daniel Ontaneda, MD, PhD, with the Mellen Center for MS Treatment and Research at the Cleveland Clinic.

In a pilot study, the central vein sign was “highly correlated with the presence of oligoclonal bands and in many cases could serve to prove that a person has MS without the need for a spinal tap,” Dr. Ontaneda said.

The study was presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

Reducing the need for lumbar puncture

Oligoclonal bands in cerebrospinal fluid are commonly used as a diagnostic biomarker for MS and can serve to meet the requirement for dissemination in time in the 2017 McDonald criteria. Central vein sign is an emerging neuroimaging biomarker for MS that may improve diagnostic accuracy and reduce the need for lumbar puncture.

For the study, the investigators compared the sensitivity, specificity, and positive predictive value of central vein sign on MRI with that of oligoclonal bands in cerebrospinal fluid for MS diagnosis.

Among the 53 participants, 24 (45%) met 2017 McDonald criteria for dissemination in space and time at baseline, and 27 (51%) met the criteria at 12-month follow-up.

At initial presentation, sensitivity for MS diagnosis was 75% for oligoclonal bands, 83% for central vein sign “Select-3” (3 central vein sign–positive lesions per scan), and 71% for central vein sign “Select-6” (6 central vein sign–positive lesions per scan).

The point estimate of sensitivity of central vein sign was higher than of oligoclonal bands, but there was no significant difference in sensitivities across methods.

Specificity at initial presentation was 76% for oligoclonal bands, 48% for Select-3, and 86% for Select-6.

The presence of oligoclonal bands was more specific than Select-3 for diagnosis of MS at initial presentation (P = .03), as was Select-6 (P = .001). There was no significant difference when comparing cerebrospinal fluid oligoclonal bands with central vein sign Select-6.

At 12-month follow-up, the positive predictive value was 84% for oligoclonal bands and 95% for Select-6; combining oligoclonal bands and Select-6 gave a positive predictive value of 100%.

Dr. Ontaneda said that on the basis of these promising pilot data, the researchers have secured funding from the National Institutes of Health for a prospective study to further investigate the central vein sign as a potential biomarker for MS.

He also said there is “active discussion as to whether central vein sign should be added to the diagnostic criteria for MS.

“We think that it’s probably about time that we have diagnostic biomarkers that are sensitive and specific and can help us do away with complicated criteria to make the diagnosis, in favor of an imaging biomarker,” Dr. Ontaneda said.
 

A green light for further research

Commenting on the study, Shaheen Lakhan, MD, a neurologist and researcher from Boston, said that, “if an imaging finding on an otherwise routinely done MRI for patients with MS is just as good as analyses from the fluid from a spinal tap, of course, neurologists, and for sure patients, would go for the former.

“However, this study doesn’t fully support that argument just yet. It is retrospective with a tiny sample size, and the full way they standardized assessments and reporting hasn’t been fully reported,” said Dr. Lakhan, who was not involved in the study.

The study does, however, offer a “solid signal to green-light further exploration of a noninvasive assessment that may replace the dreaded spinal tap.

“In general, these principles need to be applied to all our invasive diagnostic criteria from biopsies to risky procedures, and also the incorporation of artificial intelligence/machine learning to aid in standardizing and scaling these assessments – and, frankly, reduce human error in readings,” said Dr. Lakhan.

Funding for the study was provided by the Race to Erase MS Foundation and the NIH. Dr. Ontaneda has received research support from the NIH, the National MS Society, the Patient Centered Outcomes Research Institute, the Race to Erase MS Foundation, Genentech, Sanofi, and Novartis and has consulted for Biogen, Genentech, Sanofi, Janssen, Novartis, and Merck. Dr. Lakhan has disclosed no relevant financial relationships.

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

To diagnose multiple sclerosis (MS), the central vein sign on brain MRI appears to work as well as oligoclonal bands in cerebrospinal fluid, and combining the two biomarkers yields the highest predictive value for MS, a new study indicates.

The presence of oligoclonal bands is “very specific for MS and is obtained by lumbar puncture, which is invasive and can be unpleasant, so it is not an ideal test,” said study investigator Daniel Ontaneda, MD, PhD, with the Mellen Center for MS Treatment and Research at the Cleveland Clinic.

In a pilot study, the central vein sign was “highly correlated with the presence of oligoclonal bands and in many cases could serve to prove that a person has MS without the need for a spinal tap,” Dr. Ontaneda said.

The study was presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

Reducing the need for lumbar puncture

Oligoclonal bands in cerebrospinal fluid are commonly used as a diagnostic biomarker for MS and can serve to meet the requirement for dissemination in time in the 2017 McDonald criteria. Central vein sign is an emerging neuroimaging biomarker for MS that may improve diagnostic accuracy and reduce the need for lumbar puncture.

For the study, the investigators compared the sensitivity, specificity, and positive predictive value of central vein sign on MRI with that of oligoclonal bands in cerebrospinal fluid for MS diagnosis.

Among the 53 participants, 24 (45%) met 2017 McDonald criteria for dissemination in space and time at baseline, and 27 (51%) met the criteria at 12-month follow-up.

At initial presentation, sensitivity for MS diagnosis was 75% for oligoclonal bands, 83% for central vein sign “Select-3” (3 central vein sign–positive lesions per scan), and 71% for central vein sign “Select-6” (6 central vein sign–positive lesions per scan).

The point estimate of sensitivity of central vein sign was higher than of oligoclonal bands, but there was no significant difference in sensitivities across methods.

Specificity at initial presentation was 76% for oligoclonal bands, 48% for Select-3, and 86% for Select-6.

The presence of oligoclonal bands was more specific than Select-3 for diagnosis of MS at initial presentation (P = .03), as was Select-6 (P = .001). There was no significant difference when comparing cerebrospinal fluid oligoclonal bands with central vein sign Select-6.

At 12-month follow-up, the positive predictive value was 84% for oligoclonal bands and 95% for Select-6; combining oligoclonal bands and Select-6 gave a positive predictive value of 100%.

Dr. Ontaneda said that on the basis of these promising pilot data, the researchers have secured funding from the National Institutes of Health for a prospective study to further investigate the central vein sign as a potential biomarker for MS.

He also said there is “active discussion as to whether central vein sign should be added to the diagnostic criteria for MS.

“We think that it’s probably about time that we have diagnostic biomarkers that are sensitive and specific and can help us do away with complicated criteria to make the diagnosis, in favor of an imaging biomarker,” Dr. Ontaneda said.
 

A green light for further research

Commenting on the study, Shaheen Lakhan, MD, a neurologist and researcher from Boston, said that, “if an imaging finding on an otherwise routinely done MRI for patients with MS is just as good as analyses from the fluid from a spinal tap, of course, neurologists, and for sure patients, would go for the former.

“However, this study doesn’t fully support that argument just yet. It is retrospective with a tiny sample size, and the full way they standardized assessments and reporting hasn’t been fully reported,” said Dr. Lakhan, who was not involved in the study.

The study does, however, offer a “solid signal to green-light further exploration of a noninvasive assessment that may replace the dreaded spinal tap.

“In general, these principles need to be applied to all our invasive diagnostic criteria from biopsies to risky procedures, and also the incorporation of artificial intelligence/machine learning to aid in standardizing and scaling these assessments – and, frankly, reduce human error in readings,” said Dr. Lakhan.

Funding for the study was provided by the Race to Erase MS Foundation and the NIH. Dr. Ontaneda has received research support from the NIH, the National MS Society, the Patient Centered Outcomes Research Institute, the Race to Erase MS Foundation, Genentech, Sanofi, and Novartis and has consulted for Biogen, Genentech, Sanofi, Janssen, Novartis, and Merck. Dr. Lakhan has disclosed no relevant financial relationships.

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

To diagnose multiple sclerosis (MS), the central vein sign on brain MRI appears to work as well as oligoclonal bands in cerebrospinal fluid, and combining the two biomarkers yields the highest predictive value for MS, a new study indicates.

The presence of oligoclonal bands is “very specific for MS and is obtained by lumbar puncture, which is invasive and can be unpleasant, so it is not an ideal test,” said study investigator Daniel Ontaneda, MD, PhD, with the Mellen Center for MS Treatment and Research at the Cleveland Clinic.

In a pilot study, the central vein sign was “highly correlated with the presence of oligoclonal bands and in many cases could serve to prove that a person has MS without the need for a spinal tap,” Dr. Ontaneda said.

The study was presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

Reducing the need for lumbar puncture

Oligoclonal bands in cerebrospinal fluid are commonly used as a diagnostic biomarker for MS and can serve to meet the requirement for dissemination in time in the 2017 McDonald criteria. Central vein sign is an emerging neuroimaging biomarker for MS that may improve diagnostic accuracy and reduce the need for lumbar puncture.

For the study, the investigators compared the sensitivity, specificity, and positive predictive value of central vein sign on MRI with that of oligoclonal bands in cerebrospinal fluid for MS diagnosis.

Among the 53 participants, 24 (45%) met 2017 McDonald criteria for dissemination in space and time at baseline, and 27 (51%) met the criteria at 12-month follow-up.

At initial presentation, sensitivity for MS diagnosis was 75% for oligoclonal bands, 83% for central vein sign “Select-3” (3 central vein sign–positive lesions per scan), and 71% for central vein sign “Select-6” (6 central vein sign–positive lesions per scan).

The point estimate of sensitivity of central vein sign was higher than of oligoclonal bands, but there was no significant difference in sensitivities across methods.

Specificity at initial presentation was 76% for oligoclonal bands, 48% for Select-3, and 86% for Select-6.

The presence of oligoclonal bands was more specific than Select-3 for diagnosis of MS at initial presentation (P = .03), as was Select-6 (P = .001). There was no significant difference when comparing cerebrospinal fluid oligoclonal bands with central vein sign Select-6.

At 12-month follow-up, the positive predictive value was 84% for oligoclonal bands and 95% for Select-6; combining oligoclonal bands and Select-6 gave a positive predictive value of 100%.

Dr. Ontaneda said that on the basis of these promising pilot data, the researchers have secured funding from the National Institutes of Health for a prospective study to further investigate the central vein sign as a potential biomarker for MS.

He also said there is “active discussion as to whether central vein sign should be added to the diagnostic criteria for MS.

“We think that it’s probably about time that we have diagnostic biomarkers that are sensitive and specific and can help us do away with complicated criteria to make the diagnosis, in favor of an imaging biomarker,” Dr. Ontaneda said.
 

A green light for further research

Commenting on the study, Shaheen Lakhan, MD, a neurologist and researcher from Boston, said that, “if an imaging finding on an otherwise routinely done MRI for patients with MS is just as good as analyses from the fluid from a spinal tap, of course, neurologists, and for sure patients, would go for the former.

“However, this study doesn’t fully support that argument just yet. It is retrospective with a tiny sample size, and the full way they standardized assessments and reporting hasn’t been fully reported,” said Dr. Lakhan, who was not involved in the study.

The study does, however, offer a “solid signal to green-light further exploration of a noninvasive assessment that may replace the dreaded spinal tap.

“In general, these principles need to be applied to all our invasive diagnostic criteria from biopsies to risky procedures, and also the incorporation of artificial intelligence/machine learning to aid in standardizing and scaling these assessments – and, frankly, reduce human error in readings,” said Dr. Lakhan.

Funding for the study was provided by the Race to Erase MS Foundation and the NIH. Dr. Ontaneda has received research support from the NIH, the National MS Society, the Patient Centered Outcomes Research Institute, the Race to Erase MS Foundation, Genentech, Sanofi, and Novartis and has consulted for Biogen, Genentech, Sanofi, Janssen, Novartis, and Merck. Dr. Lakhan has disclosed no relevant financial relationships.

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

Peter A. Lio, MD, is a big user of the “big guns” for his patients with atopic dermatitis – biologics, conventional immunosuppressants, and JAK inhibitors. But he also has a big menu of treatments – from oral hempseed oil and black tea compresses to probiotics and acupressure – that he encourages patients to try as they use the big guns, or as they attempt to wean off of them or avoid their use altogether.

During a presentation at the annual Integrative Dermatology Symposium, Dr. Lio said that he uses “5 pillars” to guide his integrative treatment plans: The skin barrier, the psyche, the microbiome, inflammation, and itch. “I try to flag approaches that predominantly address the categories that I think need the most help,” he said. “And I tell patients [which pillar or pillars] each treatment is addressing.”

PicturePartners/Getty Images

Most commonly, the greatest challenge with AD – and the “single biggest weakness of conventional Western medicine” – lies not with getting patients clear in the first place, but in keeping them clear safely, he said. “I don’t think that using immunosuppressive [medications] is okay for the long-term unless there is no other choice,” said Dr. Lio, who cofounded the Chicago Integrative Eczema Center about 6 years ago and is clinical assistant professor of dermatology and pediatrics at Northwestern University, Chicago. Oftentimes, he said, complementary approaches, including dietary changes, can also serve as supportive adjunctive therapy to biologics and JAK inhibitors.

He has three main criteria, or “filters,” for evaluating these treatments before recommending them to patients: At least some clinical evidence for efficacy (preferably randomized trials but not necessarily), safety, and practicality. The “only way we’re going to move things forward [for AD and other conditions] is to try out less tested treatments ... to open up to them,” Dr. Lio said in an interview after the meeting. And in doing so, he said, dermatologists “can connect with a lot of patients whom naysayers can’t connect with.”
 

An integrative menu

Dr. Lio individualizes plans, suggesting treatments after “listening to patients’ stories” and considering their age, history, symptoms and skin presentation, and other factors. He said he “goes little by little,” telling a patient, for instance, “I’d love for us to try adding a little hemp oil to your diet.”

If patients aren’t pleased with or are tired of treatments, he said in the interview, “we move on and try something else.”

At the meeting, he described some of the treatments on his menu and the supporting evidence for those treatments:

Oral hempseed oil. A randomized crossover study of 20 adult patients with AD found that daily consumption of 2 tablespoons of hempseed oil decreased skin dryness, itchiness, and use of topical medications compared with consumption of olive oil. “It was statistically significant and seemed clinically meaningful,” likely resulting from the high concentration of polyunsaturated fatty acids in the oil, Dr. Lio said.

Topical vitamin B12. In a phase 3 randomized controlled trial of topical B₁₂ applied twice a day for 8 weeks, patients experienced significant improvements in the extent and severity of AD compared with placebo. Another study in children with AD aged 6 months to 18 years found significant improvement in as early as 2 weeks of use. “It really does help, and is very gentle in babies,” Dr. Lio said.

Black tea compresses. “It’s absolutely my favorite kind of compress,” he said. “It was studied on the face and eyelids but I use it all over the body for adults and kids.” A German study of 22 patients with AD or contact facial dermatitis showed significant improvements in facial dermatitis within the first 3 days of treatment with application of black tea dressings plus an emollient cream, with significant reductions in four disease activity scores (the Facial Eczema Area and Severity Index, visual analog scale for pruritus, Investigator’s Global Assessment score, and Patient’s Self-Assessment Score) that continued through day 6.

Oolong tea. In a 2001 study, after 1 month of drinking oolong tea after each meal, 64% of patients with recalcitrant AD who continued with their regular treatment showed marked to moderate improvements in AD, with a beneficial effect first noticed after 1-2 weeks. At 6 months, 54% still had a good response to treatment. “It’s super cheap and accessible,” Dr. Lio said.

Coconut oil. One of the greatest benefits of coconut oil is on the microbiome and the dysbiosis that can result from a disrupted, or “leaky,” skin barrier – especially overgrowth of Staphylococcus aureus, which “drives AD,” Dr. Lio said. In a study of adults with AD from the Philippines, topically applied coconut oil decreased S. aureus colonization by 95% when applied twice daily for 4 weeks, compared with a 50% decrease in an olive oil control group. Other research has shown coconut oil to be superior to mineral oil as a moisturizer, he said at the meeting.

Acupressure. After a pilot study conducted by Dr. Lio and colleagues showed greater decreases in itch (per the visual analogue scale) in adults with AD who applied an acupressure bead at the LI11 point (near the elbow) for 3 minutes three times a week for 4 weeks, than among those who did not use the acupressure tool, Dr. Lio began trying it with some of his patients. “Now I use it broadly,” he added in the interview. “Kids over 10 can figure out how to use it and teenagers love it [to relief itch]. Some don’t use the beads anymore, they just use their fingertips.”
 

Advice on diet, vitamin D, and probiotics

AD severity is “powerfully” correlated with IgE food allergy, but Dr. Lio said at the meeting that he currently takes a cautious approach toward strict elimination diets.

There is a growing school of thought among allergists, he said, that positive IgE tests without evidence of acute reactions may not indicate true allergy, but rather sensitivity – and may not warrant food eliminations. And as has been shown with peanuts, there can be a serious downside to elimination, as food avoidance can lead to serious allergy later on, he said.

“More and more people are thinking that if you can tolerate [a food], continue it,” he added in the interview. In the absence of clear reactions, the only way to really know if a food is making eczema worse is to do a double-blind, placebo-controlled food challenge test, he noted.

Patients often come to see him believing that food is the “root cause” of their eczema and feeling frustrated, even anxious, about strict dietary restrictions they’ve implemented. But for many of these patients, the right question “would be to ask, why is my eczema causing my food allergy?” he said at the meeting, referring to the epithelial barrier hypothesis, which posits that skin barrier dysfunction can lead to asthma, allergic rhinitis, and food allergy.

Dr. Lio often recommends the Autoimmune Protocol (AIP) diet, a “close cousin” of the paleo diet for patients with AD, as general guidance to be followed “holistically” and often without the strict eliminations it prescribes. Minimizing processed foods and dairy and grains, which “can be inflammatory in some people,” and focusing on whole, nutrient-rich foods – all in keeping with the AIP principles – should have positive effects on the microbiome, overall health, and likely AD as well, he said.

Across the board, Dr. Lio recommends vitamin D (at nationally recommended dosages) and probiotics. Vitamin D has been shown to significantly help a small percentage of patients with eczema, he said, so he advises patients that it’s worth a trial. “I tell patients that I don’t know how to pick that small group out, so let’s try for a few months and see,” he said. “Inevitably, a percentage of patients come back and say it makes a huge difference.”

Dr. Lio’s understanding and use of probiotics has been “dynamic” over the years. “The “best, most reliable evidence” that probiotics can improve AD symptoms comes with the use of multiple probiotic strains together, he said. Based on limited but growing literature, he ensures that recommended formulations for babies include Lactobacillus rhamnosus, and that formulations for adults include Lactobacillus salivarius.

Dr. Lio works closely with dietitians, hypnotherapists, and psychologists – and will occasionally refer interested patients with AD to a Chinese medicine practitioner who personalizes the use of herbal formulations.

He reported no relevant disclosures.

Peter A. Lio, MD, is a big user of the “big guns” for his patients with atopic dermatitis – biologics, conventional immunosuppressants, and JAK inhibitors. But he also has a big menu of treatments – from oral hempseed oil and black tea compresses to probiotics and acupressure – that he encourages patients to try as they use the big guns, or as they attempt to wean off of them or avoid their use altogether.

During a presentation at the annual Integrative Dermatology Symposium, Dr. Lio said that he uses “5 pillars” to guide his integrative treatment plans: The skin barrier, the psyche, the microbiome, inflammation, and itch. “I try to flag approaches that predominantly address the categories that I think need the most help,” he said. “And I tell patients [which pillar or pillars] each treatment is addressing.”

PicturePartners/Getty Images

Most commonly, the greatest challenge with AD – and the “single biggest weakness of conventional Western medicine” – lies not with getting patients clear in the first place, but in keeping them clear safely, he said. “I don’t think that using immunosuppressive [medications] is okay for the long-term unless there is no other choice,” said Dr. Lio, who cofounded the Chicago Integrative Eczema Center about 6 years ago and is clinical assistant professor of dermatology and pediatrics at Northwestern University, Chicago. Oftentimes, he said, complementary approaches, including dietary changes, can also serve as supportive adjunctive therapy to biologics and JAK inhibitors.

He has three main criteria, or “filters,” for evaluating these treatments before recommending them to patients: At least some clinical evidence for efficacy (preferably randomized trials but not necessarily), safety, and practicality. The “only way we’re going to move things forward [for AD and other conditions] is to try out less tested treatments ... to open up to them,” Dr. Lio said in an interview after the meeting. And in doing so, he said, dermatologists “can connect with a lot of patients whom naysayers can’t connect with.”
 

An integrative menu

Dr. Lio individualizes plans, suggesting treatments after “listening to patients’ stories” and considering their age, history, symptoms and skin presentation, and other factors. He said he “goes little by little,” telling a patient, for instance, “I’d love for us to try adding a little hemp oil to your diet.”

If patients aren’t pleased with or are tired of treatments, he said in the interview, “we move on and try something else.”

At the meeting, he described some of the treatments on his menu and the supporting evidence for those treatments:

Oral hempseed oil. A randomized crossover study of 20 adult patients with AD found that daily consumption of 2 tablespoons of hempseed oil decreased skin dryness, itchiness, and use of topical medications compared with consumption of olive oil. “It was statistically significant and seemed clinically meaningful,” likely resulting from the high concentration of polyunsaturated fatty acids in the oil, Dr. Lio said.

Topical vitamin B12. In a phase 3 randomized controlled trial of topical B₁₂ applied twice a day for 8 weeks, patients experienced significant improvements in the extent and severity of AD compared with placebo. Another study in children with AD aged 6 months to 18 years found significant improvement in as early as 2 weeks of use. “It really does help, and is very gentle in babies,” Dr. Lio said.

Black tea compresses. “It’s absolutely my favorite kind of compress,” he said. “It was studied on the face and eyelids but I use it all over the body for adults and kids.” A German study of 22 patients with AD or contact facial dermatitis showed significant improvements in facial dermatitis within the first 3 days of treatment with application of black tea dressings plus an emollient cream, with significant reductions in four disease activity scores (the Facial Eczema Area and Severity Index, visual analog scale for pruritus, Investigator’s Global Assessment score, and Patient’s Self-Assessment Score) that continued through day 6.

Oolong tea. In a 2001 study, after 1 month of drinking oolong tea after each meal, 64% of patients with recalcitrant AD who continued with their regular treatment showed marked to moderate improvements in AD, with a beneficial effect first noticed after 1-2 weeks. At 6 months, 54% still had a good response to treatment. “It’s super cheap and accessible,” Dr. Lio said.

Coconut oil. One of the greatest benefits of coconut oil is on the microbiome and the dysbiosis that can result from a disrupted, or “leaky,” skin barrier – especially overgrowth of Staphylococcus aureus, which “drives AD,” Dr. Lio said. In a study of adults with AD from the Philippines, topically applied coconut oil decreased S. aureus colonization by 95% when applied twice daily for 4 weeks, compared with a 50% decrease in an olive oil control group. Other research has shown coconut oil to be superior to mineral oil as a moisturizer, he said at the meeting.

Acupressure. After a pilot study conducted by Dr. Lio and colleagues showed greater decreases in itch (per the visual analogue scale) in adults with AD who applied an acupressure bead at the LI11 point (near the elbow) for 3 minutes three times a week for 4 weeks, than among those who did not use the acupressure tool, Dr. Lio began trying it with some of his patients. “Now I use it broadly,” he added in the interview. “Kids over 10 can figure out how to use it and teenagers love it [to relief itch]. Some don’t use the beads anymore, they just use their fingertips.”
 

Advice on diet, vitamin D, and probiotics

AD severity is “powerfully” correlated with IgE food allergy, but Dr. Lio said at the meeting that he currently takes a cautious approach toward strict elimination diets.

There is a growing school of thought among allergists, he said, that positive IgE tests without evidence of acute reactions may not indicate true allergy, but rather sensitivity – and may not warrant food eliminations. And as has been shown with peanuts, there can be a serious downside to elimination, as food avoidance can lead to serious allergy later on, he said.

“More and more people are thinking that if you can tolerate [a food], continue it,” he added in the interview. In the absence of clear reactions, the only way to really know if a food is making eczema worse is to do a double-blind, placebo-controlled food challenge test, he noted.

Patients often come to see him believing that food is the “root cause” of their eczema and feeling frustrated, even anxious, about strict dietary restrictions they’ve implemented. But for many of these patients, the right question “would be to ask, why is my eczema causing my food allergy?” he said at the meeting, referring to the epithelial barrier hypothesis, which posits that skin barrier dysfunction can lead to asthma, allergic rhinitis, and food allergy.

Dr. Lio often recommends the Autoimmune Protocol (AIP) diet, a “close cousin” of the paleo diet for patients with AD, as general guidance to be followed “holistically” and often without the strict eliminations it prescribes. Minimizing processed foods and dairy and grains, which “can be inflammatory in some people,” and focusing on whole, nutrient-rich foods – all in keeping with the AIP principles – should have positive effects on the microbiome, overall health, and likely AD as well, he said.

Across the board, Dr. Lio recommends vitamin D (at nationally recommended dosages) and probiotics. Vitamin D has been shown to significantly help a small percentage of patients with eczema, he said, so he advises patients that it’s worth a trial. “I tell patients that I don’t know how to pick that small group out, so let’s try for a few months and see,” he said. “Inevitably, a percentage of patients come back and say it makes a huge difference.”

Dr. Lio’s understanding and use of probiotics has been “dynamic” over the years. “The “best, most reliable evidence” that probiotics can improve AD symptoms comes with the use of multiple probiotic strains together, he said. Based on limited but growing literature, he ensures that recommended formulations for babies include Lactobacillus rhamnosus, and that formulations for adults include Lactobacillus salivarius.

Dr. Lio works closely with dietitians, hypnotherapists, and psychologists – and will occasionally refer interested patients with AD to a Chinese medicine practitioner who personalizes the use of herbal formulations.

He reported no relevant disclosures.

Peter A. Lio, MD, is a big user of the “big guns” for his patients with atopic dermatitis – biologics, conventional immunosuppressants, and JAK inhibitors. But he also has a big menu of treatments – from oral hempseed oil and black tea compresses to probiotics and acupressure – that he encourages patients to try as they use the big guns, or as they attempt to wean off of them or avoid their use altogether.

During a presentation at the annual Integrative Dermatology Symposium, Dr. Lio said that he uses “5 pillars” to guide his integrative treatment plans: The skin barrier, the psyche, the microbiome, inflammation, and itch. “I try to flag approaches that predominantly address the categories that I think need the most help,” he said. “And I tell patients [which pillar or pillars] each treatment is addressing.”

PicturePartners/Getty Images

Most commonly, the greatest challenge with AD – and the “single biggest weakness of conventional Western medicine” – lies not with getting patients clear in the first place, but in keeping them clear safely, he said. “I don’t think that using immunosuppressive [medications] is okay for the long-term unless there is no other choice,” said Dr. Lio, who cofounded the Chicago Integrative Eczema Center about 6 years ago and is clinical assistant professor of dermatology and pediatrics at Northwestern University, Chicago. Oftentimes, he said, complementary approaches, including dietary changes, can also serve as supportive adjunctive therapy to biologics and JAK inhibitors.

He has three main criteria, or “filters,” for evaluating these treatments before recommending them to patients: At least some clinical evidence for efficacy (preferably randomized trials but not necessarily), safety, and practicality. The “only way we’re going to move things forward [for AD and other conditions] is to try out less tested treatments ... to open up to them,” Dr. Lio said in an interview after the meeting. And in doing so, he said, dermatologists “can connect with a lot of patients whom naysayers can’t connect with.”
 

An integrative menu

Dr. Lio individualizes plans, suggesting treatments after “listening to patients’ stories” and considering their age, history, symptoms and skin presentation, and other factors. He said he “goes little by little,” telling a patient, for instance, “I’d love for us to try adding a little hemp oil to your diet.”

If patients aren’t pleased with or are tired of treatments, he said in the interview, “we move on and try something else.”

At the meeting, he described some of the treatments on his menu and the supporting evidence for those treatments:

Oral hempseed oil. A randomized crossover study of 20 adult patients with AD found that daily consumption of 2 tablespoons of hempseed oil decreased skin dryness, itchiness, and use of topical medications compared with consumption of olive oil. “It was statistically significant and seemed clinically meaningful,” likely resulting from the high concentration of polyunsaturated fatty acids in the oil, Dr. Lio said.

Topical vitamin B12. In a phase 3 randomized controlled trial of topical B₁₂ applied twice a day for 8 weeks, patients experienced significant improvements in the extent and severity of AD compared with placebo. Another study in children with AD aged 6 months to 18 years found significant improvement in as early as 2 weeks of use. “It really does help, and is very gentle in babies,” Dr. Lio said.

Black tea compresses. “It’s absolutely my favorite kind of compress,” he said. “It was studied on the face and eyelids but I use it all over the body for adults and kids.” A German study of 22 patients with AD or contact facial dermatitis showed significant improvements in facial dermatitis within the first 3 days of treatment with application of black tea dressings plus an emollient cream, with significant reductions in four disease activity scores (the Facial Eczema Area and Severity Index, visual analog scale for pruritus, Investigator’s Global Assessment score, and Patient’s Self-Assessment Score) that continued through day 6.

Oolong tea. In a 2001 study, after 1 month of drinking oolong tea after each meal, 64% of patients with recalcitrant AD who continued with their regular treatment showed marked to moderate improvements in AD, with a beneficial effect first noticed after 1-2 weeks. At 6 months, 54% still had a good response to treatment. “It’s super cheap and accessible,” Dr. Lio said.

Coconut oil. One of the greatest benefits of coconut oil is on the microbiome and the dysbiosis that can result from a disrupted, or “leaky,” skin barrier – especially overgrowth of Staphylococcus aureus, which “drives AD,” Dr. Lio said. In a study of adults with AD from the Philippines, topically applied coconut oil decreased S. aureus colonization by 95% when applied twice daily for 4 weeks, compared with a 50% decrease in an olive oil control group. Other research has shown coconut oil to be superior to mineral oil as a moisturizer, he said at the meeting.

Acupressure. After a pilot study conducted by Dr. Lio and colleagues showed greater decreases in itch (per the visual analogue scale) in adults with AD who applied an acupressure bead at the LI11 point (near the elbow) for 3 minutes three times a week for 4 weeks, than among those who did not use the acupressure tool, Dr. Lio began trying it with some of his patients. “Now I use it broadly,” he added in the interview. “Kids over 10 can figure out how to use it and teenagers love it [to relief itch]. Some don’t use the beads anymore, they just use their fingertips.”
 

Advice on diet, vitamin D, and probiotics

AD severity is “powerfully” correlated with IgE food allergy, but Dr. Lio said at the meeting that he currently takes a cautious approach toward strict elimination diets.

There is a growing school of thought among allergists, he said, that positive IgE tests without evidence of acute reactions may not indicate true allergy, but rather sensitivity – and may not warrant food eliminations. And as has been shown with peanuts, there can be a serious downside to elimination, as food avoidance can lead to serious allergy later on, he said.

“More and more people are thinking that if you can tolerate [a food], continue it,” he added in the interview. In the absence of clear reactions, the only way to really know if a food is making eczema worse is to do a double-blind, placebo-controlled food challenge test, he noted.

Patients often come to see him believing that food is the “root cause” of their eczema and feeling frustrated, even anxious, about strict dietary restrictions they’ve implemented. But for many of these patients, the right question “would be to ask, why is my eczema causing my food allergy?” he said at the meeting, referring to the epithelial barrier hypothesis, which posits that skin barrier dysfunction can lead to asthma, allergic rhinitis, and food allergy.

Dr. Lio often recommends the Autoimmune Protocol (AIP) diet, a “close cousin” of the paleo diet for patients with AD, as general guidance to be followed “holistically” and often without the strict eliminations it prescribes. Minimizing processed foods and dairy and grains, which “can be inflammatory in some people,” and focusing on whole, nutrient-rich foods – all in keeping with the AIP principles – should have positive effects on the microbiome, overall health, and likely AD as well, he said.

Across the board, Dr. Lio recommends vitamin D (at nationally recommended dosages) and probiotics. Vitamin D has been shown to significantly help a small percentage of patients with eczema, he said, so he advises patients that it’s worth a trial. “I tell patients that I don’t know how to pick that small group out, so let’s try for a few months and see,” he said. “Inevitably, a percentage of patients come back and say it makes a huge difference.”

Dr. Lio’s understanding and use of probiotics has been “dynamic” over the years. “The “best, most reliable evidence” that probiotics can improve AD symptoms comes with the use of multiple probiotic strains together, he said. Based on limited but growing literature, he ensures that recommended formulations for babies include Lactobacillus rhamnosus, and that formulations for adults include Lactobacillus salivarius.

Dr. Lio works closely with dietitians, hypnotherapists, and psychologists – and will occasionally refer interested patients with AD to a Chinese medicine practitioner who personalizes the use of herbal formulations.

He reported no relevant disclosures.

Among high-risk early breast cancer patients, delivery of a radiation boost to the tumor bed during whole breast irradiation was just as safe and effective as delivering the boost sequentially after whole breast irradiation ended. The findings from the phase 3 clinical trial are a boon to patient convenience.

“These findings are indeed practice changing. This was a well-designed trial that looked at shortening treatment from six to three weeks. They showed equivalent local control and importantly, a good cosmetic outcome over time,” said Kathleen Horst, MD, who served as a discussant during a presentation given by Frank Vicini, MD, FASTRO, GenesisCare, during the annual meeting of the American Society for Radiation Oncology.

“This is substantially more convenient. It’s cost effective both for the health care system and individual patients. Importantly, our patients come in for treatment every day and they’re taking time from work which means they have to arrange for childcare and transportation. So, this makes a big difference for these patients,” said Dr. Horst, who is a professor of radiation oncology at Stanford (Calif.) Medicine and director of well-being in the radiation department at Stanford Medicine.

“One of the things that was surprising is that I think all of us were thinking this might be a more toxic regimen, but as Dr. Vicini showed, it was equally effective over time with minimal toxicity and cosmesis was stable over time, which is important. Importantly, it included patient-reported outcomes, not just the physician-reported outcomes. Broadly, I think these findings are applicable for many patients, including all patients who are receiving whole breast radiotherapy with an added boost. I think over time this is going to improve the quality of life of our patients. It represents an innovative change that everyone is going to be excited to embrace,” Dr. Horst said.

Previous randomized controlled trials showed that an additional radiation dose to the tumor bed following lumpectomy and whole breast irradiation reduces the relative risk of local recurrence by about 35%. However, this increases treatment time for patients who have already endured an extensive regimen. For whole breast irradiation, hypofractionated radiation in 15-16 fractions over 3 weeks has comparable recurrence rates as a 5-week regimen, but the relevant trials did not examine the effect hypofractionation may have on a radiation boost to the tumor bed of high-risk patients. Because of this lack of evidence, current practice calls for the boost to remain sequential in five to eight fractions after completion of whole breast irradiation, which adds 1 week to a 1.5 week–long treatment.

The study included 2,262 patients who were randomized to receive a sequential boost or a concomitant boost. After a median follow-up of 7.4 years, there were 54 ipsilateral breast recurrence (IBR) events. The estimated 7-year risk of IBR was 2.2% in the sequential boost and 2.6% in the concurrent risk group (hazard ratio, 1.32; noninferiority test P = .039). Approximately 60% of patients received adjuvant chemotherapy.

Grade 3 or higher adverse events were similar with a frequency of 3.3% in the sequential group and 3.5% in the concurrent group (P = .79). The researchers used the Global Cosmetic Score (GCS) to assess outcomes from the perspective of both physicians and patients. 86% of physicians rated the outcome as excellent/good in the sequential group versus 82% in the concurrent group (P = .33).

“For high-risk early-stage breast cancer patients undergoing breast conservation, a concurrent boost with hypofractionated whole breast irradiation – compared to a sequential boost – results in noninferior local recurrence rates with no significant difference in toxicity, noninferior patient rated cosmesis, and no significant difference in physician rated cosmesis. The entire treatment was delivered in three weeks, even for high-risk patients. Just as critical, the use of target volume based radiation planning for [three-dimensional conformal or IMRT whole breast irradiation assessed by dose volume analysis is feasible, and resulted in very low toxicity in the treatment arms, regardless of the fractionation schedule, or the boost delivery,” Dr. Vincini said.

No conflicts of interest were disclosed for Dr. Horst or Dr. Vicini.

Among high-risk early breast cancer patients, delivery of a radiation boost to the tumor bed during whole breast irradiation was just as safe and effective as delivering the boost sequentially after whole breast irradiation ended. The findings from the phase 3 clinical trial are a boon to patient convenience.

“These findings are indeed practice changing. This was a well-designed trial that looked at shortening treatment from six to three weeks. They showed equivalent local control and importantly, a good cosmetic outcome over time,” said Kathleen Horst, MD, who served as a discussant during a presentation given by Frank Vicini, MD, FASTRO, GenesisCare, during the annual meeting of the American Society for Radiation Oncology.

“This is substantially more convenient. It’s cost effective both for the health care system and individual patients. Importantly, our patients come in for treatment every day and they’re taking time from work which means they have to arrange for childcare and transportation. So, this makes a big difference for these patients,” said Dr. Horst, who is a professor of radiation oncology at Stanford (Calif.) Medicine and director of well-being in the radiation department at Stanford Medicine.

“One of the things that was surprising is that I think all of us were thinking this might be a more toxic regimen, but as Dr. Vicini showed, it was equally effective over time with minimal toxicity and cosmesis was stable over time, which is important. Importantly, it included patient-reported outcomes, not just the physician-reported outcomes. Broadly, I think these findings are applicable for many patients, including all patients who are receiving whole breast radiotherapy with an added boost. I think over time this is going to improve the quality of life of our patients. It represents an innovative change that everyone is going to be excited to embrace,” Dr. Horst said.

Previous randomized controlled trials showed that an additional radiation dose to the tumor bed following lumpectomy and whole breast irradiation reduces the relative risk of local recurrence by about 35%. However, this increases treatment time for patients who have already endured an extensive regimen. For whole breast irradiation, hypofractionated radiation in 15-16 fractions over 3 weeks has comparable recurrence rates as a 5-week regimen, but the relevant trials did not examine the effect hypofractionation may have on a radiation boost to the tumor bed of high-risk patients. Because of this lack of evidence, current practice calls for the boost to remain sequential in five to eight fractions after completion of whole breast irradiation, which adds 1 week to a 1.5 week–long treatment.

The study included 2,262 patients who were randomized to receive a sequential boost or a concomitant boost. After a median follow-up of 7.4 years, there were 54 ipsilateral breast recurrence (IBR) events. The estimated 7-year risk of IBR was 2.2% in the sequential boost and 2.6% in the concurrent risk group (hazard ratio, 1.32; noninferiority test P = .039). Approximately 60% of patients received adjuvant chemotherapy.

Grade 3 or higher adverse events were similar with a frequency of 3.3% in the sequential group and 3.5% in the concurrent group (P = .79). The researchers used the Global Cosmetic Score (GCS) to assess outcomes from the perspective of both physicians and patients. 86% of physicians rated the outcome as excellent/good in the sequential group versus 82% in the concurrent group (P = .33).

“For high-risk early-stage breast cancer patients undergoing breast conservation, a concurrent boost with hypofractionated whole breast irradiation – compared to a sequential boost – results in noninferior local recurrence rates with no significant difference in toxicity, noninferior patient rated cosmesis, and no significant difference in physician rated cosmesis. The entire treatment was delivered in three weeks, even for high-risk patients. Just as critical, the use of target volume based radiation planning for [three-dimensional conformal or IMRT whole breast irradiation assessed by dose volume analysis is feasible, and resulted in very low toxicity in the treatment arms, regardless of the fractionation schedule, or the boost delivery,” Dr. Vincini said.

No conflicts of interest were disclosed for Dr. Horst or Dr. Vicini.

Among high-risk early breast cancer patients, delivery of a radiation boost to the tumor bed during whole breast irradiation was just as safe and effective as delivering the boost sequentially after whole breast irradiation ended. The findings from the phase 3 clinical trial are a boon to patient convenience.

“These findings are indeed practice changing. This was a well-designed trial that looked at shortening treatment from six to three weeks. They showed equivalent local control and importantly, a good cosmetic outcome over time,” said Kathleen Horst, MD, who served as a discussant during a presentation given by Frank Vicini, MD, FASTRO, GenesisCare, during the annual meeting of the American Society for Radiation Oncology.

“This is substantially more convenient. It’s cost effective both for the health care system and individual patients. Importantly, our patients come in for treatment every day and they’re taking time from work which means they have to arrange for childcare and transportation. So, this makes a big difference for these patients,” said Dr. Horst, who is a professor of radiation oncology at Stanford (Calif.) Medicine and director of well-being in the radiation department at Stanford Medicine.

“One of the things that was surprising is that I think all of us were thinking this might be a more toxic regimen, but as Dr. Vicini showed, it was equally effective over time with minimal toxicity and cosmesis was stable over time, which is important. Importantly, it included patient-reported outcomes, not just the physician-reported outcomes. Broadly, I think these findings are applicable for many patients, including all patients who are receiving whole breast radiotherapy with an added boost. I think over time this is going to improve the quality of life of our patients. It represents an innovative change that everyone is going to be excited to embrace,” Dr. Horst said.

Previous randomized controlled trials showed that an additional radiation dose to the tumor bed following lumpectomy and whole breast irradiation reduces the relative risk of local recurrence by about 35%. However, this increases treatment time for patients who have already endured an extensive regimen. For whole breast irradiation, hypofractionated radiation in 15-16 fractions over 3 weeks has comparable recurrence rates as a 5-week regimen, but the relevant trials did not examine the effect hypofractionation may have on a radiation boost to the tumor bed of high-risk patients. Because of this lack of evidence, current practice calls for the boost to remain sequential in five to eight fractions after completion of whole breast irradiation, which adds 1 week to a 1.5 week–long treatment.

The study included 2,262 patients who were randomized to receive a sequential boost or a concomitant boost. After a median follow-up of 7.4 years, there were 54 ipsilateral breast recurrence (IBR) events. The estimated 7-year risk of IBR was 2.2% in the sequential boost and 2.6% in the concurrent risk group (hazard ratio, 1.32; noninferiority test P = .039). Approximately 60% of patients received adjuvant chemotherapy.

Grade 3 or higher adverse events were similar with a frequency of 3.3% in the sequential group and 3.5% in the concurrent group (P = .79). The researchers used the Global Cosmetic Score (GCS) to assess outcomes from the perspective of both physicians and patients. 86% of physicians rated the outcome as excellent/good in the sequential group versus 82% in the concurrent group (P = .33).

“For high-risk early-stage breast cancer patients undergoing breast conservation, a concurrent boost with hypofractionated whole breast irradiation – compared to a sequential boost – results in noninferior local recurrence rates with no significant difference in toxicity, noninferior patient rated cosmesis, and no significant difference in physician rated cosmesis. The entire treatment was delivered in three weeks, even for high-risk patients. Just as critical, the use of target volume based radiation planning for [three-dimensional conformal or IMRT whole breast irradiation assessed by dose volume analysis is feasible, and resulted in very low toxicity in the treatment arms, regardless of the fractionation schedule, or the boost delivery,” Dr. Vincini said.

No conflicts of interest were disclosed for Dr. Horst or Dr. Vicini.

Neurofilament light chain (NfL) is a well-known and useful biomarker for multiple sclerosis (MS) disease activity, but its association with disease progression is not well understood. A new analysis of MS patients in California’s EPIC cohort suggests that NfL spikes occur about 1 year before clinical sign of MS disease worsening.

“We see evidence for accelerated neuroaxonal damage in the year preceding the first diagnosis of the progression events, [but] only if they were associated with evidence of focal inflammatory activity – that can be either clinical or imaging evidence,” said Ahmed Abdelhak, MD, during a presentation of the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

“By the time we diagnose the EDSS progression, it’s already too late. Every damage or any accelerated neuroaxonal damage that has happened in association with this event already took place around a year ago. I think [this has] huge implications for the designing of clinical trials,” said Dr. Abdelhak, who is a postdoctoral researcher at the University of California, San Francisco.

In the study, researchers analyzed data from 609 MS cases, with a total of 3,906 office visits. The median age was 42 years, and 69.6% were female. Median disease duration was 6 years.

They examined the association between NfL scores and confirmed disease worsening, as recorded by an increase in EDSS score. There was an increase in NfL age-adjusted z score about 12 months in advance among patients with a progression association with a relapse in the past year, compared with individuals who did not experience disease progression. There was also a more modest increase among individuals who had disease progression without a recent relapse, but this was not statistically significant.

“Our findings suggest that the association between NfL levels and EDSS worsening is most prominent in the setting of relapse-associated events,” said Dr. Abdelhak.
 

Clinical implications and audience skepticism

During the Q&A following the talk, session moderator Charlotte Teunissen, PhD, professor of neurochemistry at Amsterdam University Medical Center, asked about the clinical implication of the finding. “It seems that you concluded that axonal damage has been done before the progression starts. Is that your conclusion? So it means that there is no option to interfere anymore, consequently.”

Dr. Abdelhak responded: “I think that’s a very important interpretation of the data, which I’m sure is a relatively new way of thinking about it. That means, indeed, that when we see these patients, measuring NfL wouldn’t deliver any additional value because they don’t differ between the groups at the time of EDSS worsening. And there is probably nothing more we can do about this event. But it’s still very important to know that any therapeutic intervention has also the need to prevent future disability progression, future neuroaxonal damage, but regarding what has happened already, I’m a little bit skeptical if we will be able to change anything.”

Dr. Teunissen expressed skepticism that there was no further neurodegeneration following the spike in NfL, and pointed out an important caveat, which was the study’s reliance on NfL. “You base your conclusions on what you observe for NfL, and it’s a far-fetched conclusion that there is no further axonal damage ongoing. Maybe NfL is just one marker, and it’s not the best biomarker to measure progression,” she said.

Dr. Abdelhak conceded that it will be necessary to confirm the findings with other biomarkers of neurological injury. Even different subunits of the NfL protein have been shown to have different dynamics in other neurological conditions. “So the data we have give definitely an incomplete picture because we [know] nothing about the other biomarkers of neuroaxonal injury, including the other subunits of NfL,” he said.

Later in the Q&A, Alasdair Coles, MD, professor of neurology at University of Cambridge (England), spoke from the audience. He suggested that the findings could be seen as dispiriting for clinicians. “Would the panel agree that actually for a clinician this is all rather disappointing, because none of these markers are telling us anything that we don’t otherwise know by examining the patient and doing scans?”

“I can attempt to tackle that provocative question,” replied Elias Sotirchos, MD, who also presented on an association between NfL and brain atrophy research during the session. He pointed out that all clinical tests are imperfect, and suggested that NfL isn’t something to be used in isolation. It could be useful when patients are experiencing new symptoms, or worsening symptoms, and in combination with MRI results. “My interpretation of NfL is that it does have incremental value, telling us which patients have lesions that are more destructive, potentially, given all of these consistent associations with brain atrophy and disability progression over time,” said Dr. Sotirchos, who is an assistant professor of neurology at Johns Hopkins Medicine, Baltimore.

Dr. Abdelhak and Dr. Teunissen have no relevant financial disclosures. Dr. Sotirchos has financial relationships with Alexion, Viela Bio, Horizon Therapeutics, Genentech, and Ad Scientiam.

Neurofilament light chain (NfL) is a well-known and useful biomarker for multiple sclerosis (MS) disease activity, but its association with disease progression is not well understood. A new analysis of MS patients in California’s EPIC cohort suggests that NfL spikes occur about 1 year before clinical sign of MS disease worsening.

“We see evidence for accelerated neuroaxonal damage in the year preceding the first diagnosis of the progression events, [but] only if they were associated with evidence of focal inflammatory activity – that can be either clinical or imaging evidence,” said Ahmed Abdelhak, MD, during a presentation of the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

“By the time we diagnose the EDSS progression, it’s already too late. Every damage or any accelerated neuroaxonal damage that has happened in association with this event already took place around a year ago. I think [this has] huge implications for the designing of clinical trials,” said Dr. Abdelhak, who is a postdoctoral researcher at the University of California, San Francisco.

In the study, researchers analyzed data from 609 MS cases, with a total of 3,906 office visits. The median age was 42 years, and 69.6% were female. Median disease duration was 6 years.

They examined the association between NfL scores and confirmed disease worsening, as recorded by an increase in EDSS score. There was an increase in NfL age-adjusted z score about 12 months in advance among patients with a progression association with a relapse in the past year, compared with individuals who did not experience disease progression. There was also a more modest increase among individuals who had disease progression without a recent relapse, but this was not statistically significant.

“Our findings suggest that the association between NfL levels and EDSS worsening is most prominent in the setting of relapse-associated events,” said Dr. Abdelhak.
 

Clinical implications and audience skepticism

During the Q&A following the talk, session moderator Charlotte Teunissen, PhD, professor of neurochemistry at Amsterdam University Medical Center, asked about the clinical implication of the finding. “It seems that you concluded that axonal damage has been done before the progression starts. Is that your conclusion? So it means that there is no option to interfere anymore, consequently.”

Dr. Abdelhak responded: “I think that’s a very important interpretation of the data, which I’m sure is a relatively new way of thinking about it. That means, indeed, that when we see these patients, measuring NfL wouldn’t deliver any additional value because they don’t differ between the groups at the time of EDSS worsening. And there is probably nothing more we can do about this event. But it’s still very important to know that any therapeutic intervention has also the need to prevent future disability progression, future neuroaxonal damage, but regarding what has happened already, I’m a little bit skeptical if we will be able to change anything.”

Dr. Teunissen expressed skepticism that there was no further neurodegeneration following the spike in NfL, and pointed out an important caveat, which was the study’s reliance on NfL. “You base your conclusions on what you observe for NfL, and it’s a far-fetched conclusion that there is no further axonal damage ongoing. Maybe NfL is just one marker, and it’s not the best biomarker to measure progression,” she said.

Dr. Abdelhak conceded that it will be necessary to confirm the findings with other biomarkers of neurological injury. Even different subunits of the NfL protein have been shown to have different dynamics in other neurological conditions. “So the data we have give definitely an incomplete picture because we [know] nothing about the other biomarkers of neuroaxonal injury, including the other subunits of NfL,” he said.

Later in the Q&A, Alasdair Coles, MD, professor of neurology at University of Cambridge (England), spoke from the audience. He suggested that the findings could be seen as dispiriting for clinicians. “Would the panel agree that actually for a clinician this is all rather disappointing, because none of these markers are telling us anything that we don’t otherwise know by examining the patient and doing scans?”

“I can attempt to tackle that provocative question,” replied Elias Sotirchos, MD, who also presented on an association between NfL and brain atrophy research during the session. He pointed out that all clinical tests are imperfect, and suggested that NfL isn’t something to be used in isolation. It could be useful when patients are experiencing new symptoms, or worsening symptoms, and in combination with MRI results. “My interpretation of NfL is that it does have incremental value, telling us which patients have lesions that are more destructive, potentially, given all of these consistent associations with brain atrophy and disability progression over time,” said Dr. Sotirchos, who is an assistant professor of neurology at Johns Hopkins Medicine, Baltimore.

Dr. Abdelhak and Dr. Teunissen have no relevant financial disclosures. Dr. Sotirchos has financial relationships with Alexion, Viela Bio, Horizon Therapeutics, Genentech, and Ad Scientiam.

Neurofilament light chain (NfL) is a well-known and useful biomarker for multiple sclerosis (MS) disease activity, but its association with disease progression is not well understood. A new analysis of MS patients in California’s EPIC cohort suggests that NfL spikes occur about 1 year before clinical sign of MS disease worsening.

“We see evidence for accelerated neuroaxonal damage in the year preceding the first diagnosis of the progression events, [but] only if they were associated with evidence of focal inflammatory activity – that can be either clinical or imaging evidence,” said Ahmed Abdelhak, MD, during a presentation of the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

“By the time we diagnose the EDSS progression, it’s already too late. Every damage or any accelerated neuroaxonal damage that has happened in association with this event already took place around a year ago. I think [this has] huge implications for the designing of clinical trials,” said Dr. Abdelhak, who is a postdoctoral researcher at the University of California, San Francisco.

In the study, researchers analyzed data from 609 MS cases, with a total of 3,906 office visits. The median age was 42 years, and 69.6% were female. Median disease duration was 6 years.

They examined the association between NfL scores and confirmed disease worsening, as recorded by an increase in EDSS score. There was an increase in NfL age-adjusted z score about 12 months in advance among patients with a progression association with a relapse in the past year, compared with individuals who did not experience disease progression. There was also a more modest increase among individuals who had disease progression without a recent relapse, but this was not statistically significant.

“Our findings suggest that the association between NfL levels and EDSS worsening is most prominent in the setting of relapse-associated events,” said Dr. Abdelhak.
 

Clinical implications and audience skepticism

During the Q&A following the talk, session moderator Charlotte Teunissen, PhD, professor of neurochemistry at Amsterdam University Medical Center, asked about the clinical implication of the finding. “It seems that you concluded that axonal damage has been done before the progression starts. Is that your conclusion? So it means that there is no option to interfere anymore, consequently.”

Dr. Abdelhak responded: “I think that’s a very important interpretation of the data, which I’m sure is a relatively new way of thinking about it. That means, indeed, that when we see these patients, measuring NfL wouldn’t deliver any additional value because they don’t differ between the groups at the time of EDSS worsening. And there is probably nothing more we can do about this event. But it’s still very important to know that any therapeutic intervention has also the need to prevent future disability progression, future neuroaxonal damage, but regarding what has happened already, I’m a little bit skeptical if we will be able to change anything.”

Dr. Teunissen expressed skepticism that there was no further neurodegeneration following the spike in NfL, and pointed out an important caveat, which was the study’s reliance on NfL. “You base your conclusions on what you observe for NfL, and it’s a far-fetched conclusion that there is no further axonal damage ongoing. Maybe NfL is just one marker, and it’s not the best biomarker to measure progression,” she said.

Dr. Abdelhak conceded that it will be necessary to confirm the findings with other biomarkers of neurological injury. Even different subunits of the NfL protein have been shown to have different dynamics in other neurological conditions. “So the data we have give definitely an incomplete picture because we [know] nothing about the other biomarkers of neuroaxonal injury, including the other subunits of NfL,” he said.

Later in the Q&A, Alasdair Coles, MD, professor of neurology at University of Cambridge (England), spoke from the audience. He suggested that the findings could be seen as dispiriting for clinicians. “Would the panel agree that actually for a clinician this is all rather disappointing, because none of these markers are telling us anything that we don’t otherwise know by examining the patient and doing scans?”

“I can attempt to tackle that provocative question,” replied Elias Sotirchos, MD, who also presented on an association between NfL and brain atrophy research during the session. He pointed out that all clinical tests are imperfect, and suggested that NfL isn’t something to be used in isolation. It could be useful when patients are experiencing new symptoms, or worsening symptoms, and in combination with MRI results. “My interpretation of NfL is that it does have incremental value, telling us which patients have lesions that are more destructive, potentially, given all of these consistent associations with brain atrophy and disability progression over time,” said Dr. Sotirchos, who is an assistant professor of neurology at Johns Hopkins Medicine, Baltimore.

Dr. Abdelhak and Dr. Teunissen have no relevant financial disclosures. Dr. Sotirchos has financial relationships with Alexion, Viela Bio, Horizon Therapeutics, Genentech, and Ad Scientiam.

Circulating tumor DNA (ctDNA) has garnered attention in recent years as a potential noninvasive biomarker that could help determine prognosis and treatment responses in solid tumors. They could also provide a more complete picture of tumor genetics than the limited samples often available from a biopsy.

ctDNA studies have been conducted in a range of solid tumors, but esophageal cancer has received less attention than other cancers. It is currently diagnosed by endoscopy, but this method is not suitable for population-wide surveillance because of its cost and invasiveness.

Esophageal squamous cell carcinoma (ESCC) is the predominant histologic type of esophageal cancer in China, and it is difficult to diagnose using normal radiological techniques because of the hollow nature of the esophagus.

In a virtual poster session at the annual meeting of the American Society for Radiation Oncology, Xin Wang, MD, discussed the results of a small study looking at ctDNA and ESCC. “We aimed to investigate if ctDNA could detect disease progression before radiological imaging and try identifying patients with inferior prognosis based on ctDNA positivity and dynamics,” said Dr. Wang, who is a researcher at the Chinese Academy of Medical Sciences, Beijing.

85% of enrolled patients were male, and the median age at diagnosis was 64 years. The gross tumor volume was larger in patients with ctDNA-positive tumors at baseline 40.1 cm³ versus 28.7 cm³ (P = .001) and 14% underwent esophagectomy following radiotherapy, compared with 58% of the ctDNA-negative group (P = .008). Other baseline factors were similar between the two groups.

The researchers used a 474-gene panel to analyze plasma samples. 106 of the genes are known to be associated with radiosensitivity. Prior to radiotherapy (T0), 28 of 40 patients (70%) had a positive ctDNA sample. At week 4 of radiotherapy (T1), 42% of 36 patients were ctDNA positive. One to 3 months after radiotherapy/chemoradiotherapy (T2), among 27 patients, 30% were ctDNA positive. 27 patients ultimately underwent esophagectomy, while 9 did not have surgery. Three to 6 months after radiotherapy/chemoradiotherapy (T3), among 23 patients, 22% were ctDNA positive. Of 14 patients alive after 1 year, 43% were ctDNA positive.

Over a median follow-up of 20.6 months, 17 patients were diagnosed with progression through radiological imaging. Of these, 13 patients (77%) were ctDNA positive before or after progression (Cohen’s kappa, 0.512; P < .01). The mean lead time was 5.5 months (95% confidence interval, 1.5-9.4 months).

The researchers also observed links between ctDNA and survival. “We observed a strong association between inferior progression-free survival [PFS] and ctDNA positivity at T1, T2, and T3 time points. Similar associations were detected in OS [overall survival] as well,” Dr. Wang said.

In a multivariate analysis, ctDNA positivity at T1 was associated worse PFS (hazard ratio, 3.35; 95% CI, 1.10-10.22), and there was a trend toward worse overall survival (HR, 2.48; 95% CI, 0.83-7.37). There were no statistically significant associations between ctDNA positivity and PFS or OS at T2.

Twenty-one patients experienced a decrease in ctDNA concentration between T0 and T1. Of these, eight patients achieved a clearance of ctDNA by T1, and they had a trend toward better PFS than patients who did not achieve clearance (HR, 0.31; P = .06).

“The relatively poor locoregional recurrence-free survival remains related to ctDNA positivity at T1. Interestingly, for ctDNA-negative patients who received surgery, none of them were diagnosed with radiological progression. To summarize, ctDNA is a promising biomarker for detecting disease progression. Positive ctDNA status indicates for PFS and OS, but patients achieving ctDNA clearance after radiation are likely to have a better PFS. There is also a potential association between ctDNA positivity at the fourth week during radiation therapy and higher risk of local recurrence, but further studies with a larger sample size are required,” Dr. Wang said.

Ann Raldow, MD, who served as a discussant following the poster presentation, pointed out that ctDNA has been found to be a useful prognostic and predictive tool in colon cancer. The new work suggests “that detectable ctDNA may help guide recommendations for postchemoradiation treatment. Of course, the ctDNA and esophageal cancer space is still in its infancy, and I would really encourage future studies to incorporate ctDNA as part of what they’re studying so that we can get more information about both the prognostic and predictive value of ctDNA in esophageal cancer,” said Dr. Raldow, who is an assistant professor of radiation oncology, University of California, Los Angeles.

Dr. Wang has no relevant financial disclosures. Dr. Raldow had received research funding from Intelligent Automation, Clarity, and Viewray.

Circulating tumor DNA (ctDNA) has garnered attention in recent years as a potential noninvasive biomarker that could help determine prognosis and treatment responses in solid tumors. They could also provide a more complete picture of tumor genetics than the limited samples often available from a biopsy.

ctDNA studies have been conducted in a range of solid tumors, but esophageal cancer has received less attention than other cancers. It is currently diagnosed by endoscopy, but this method is not suitable for population-wide surveillance because of its cost and invasiveness.

Esophageal squamous cell carcinoma (ESCC) is the predominant histologic type of esophageal cancer in China, and it is difficult to diagnose using normal radiological techniques because of the hollow nature of the esophagus.

In a virtual poster session at the annual meeting of the American Society for Radiation Oncology, Xin Wang, MD, discussed the results of a small study looking at ctDNA and ESCC. “We aimed to investigate if ctDNA could detect disease progression before radiological imaging and try identifying patients with inferior prognosis based on ctDNA positivity and dynamics,” said Dr. Wang, who is a researcher at the Chinese Academy of Medical Sciences, Beijing.

85% of enrolled patients were male, and the median age at diagnosis was 64 years. The gross tumor volume was larger in patients with ctDNA-positive tumors at baseline 40.1 cm³ versus 28.7 cm³ (P = .001) and 14% underwent esophagectomy following radiotherapy, compared with 58% of the ctDNA-negative group (P = .008). Other baseline factors were similar between the two groups.

The researchers used a 474-gene panel to analyze plasma samples. 106 of the genes are known to be associated with radiosensitivity. Prior to radiotherapy (T0), 28 of 40 patients (70%) had a positive ctDNA sample. At week 4 of radiotherapy (T1), 42% of 36 patients were ctDNA positive. One to 3 months after radiotherapy/chemoradiotherapy (T2), among 27 patients, 30% were ctDNA positive. 27 patients ultimately underwent esophagectomy, while 9 did not have surgery. Three to 6 months after radiotherapy/chemoradiotherapy (T3), among 23 patients, 22% were ctDNA positive. Of 14 patients alive after 1 year, 43% were ctDNA positive.

Over a median follow-up of 20.6 months, 17 patients were diagnosed with progression through radiological imaging. Of these, 13 patients (77%) were ctDNA positive before or after progression (Cohen’s kappa, 0.512; P < .01). The mean lead time was 5.5 months (95% confidence interval, 1.5-9.4 months).

The researchers also observed links between ctDNA and survival. “We observed a strong association between inferior progression-free survival [PFS] and ctDNA positivity at T1, T2, and T3 time points. Similar associations were detected in OS [overall survival] as well,” Dr. Wang said.

In a multivariate analysis, ctDNA positivity at T1 was associated worse PFS (hazard ratio, 3.35; 95% CI, 1.10-10.22), and there was a trend toward worse overall survival (HR, 2.48; 95% CI, 0.83-7.37). There were no statistically significant associations between ctDNA positivity and PFS or OS at T2.

Twenty-one patients experienced a decrease in ctDNA concentration between T0 and T1. Of these, eight patients achieved a clearance of ctDNA by T1, and they had a trend toward better PFS than patients who did not achieve clearance (HR, 0.31; P = .06).

“The relatively poor locoregional recurrence-free survival remains related to ctDNA positivity at T1. Interestingly, for ctDNA-negative patients who received surgery, none of them were diagnosed with radiological progression. To summarize, ctDNA is a promising biomarker for detecting disease progression. Positive ctDNA status indicates for PFS and OS, but patients achieving ctDNA clearance after radiation are likely to have a better PFS. There is also a potential association between ctDNA positivity at the fourth week during radiation therapy and higher risk of local recurrence, but further studies with a larger sample size are required,” Dr. Wang said.

Ann Raldow, MD, who served as a discussant following the poster presentation, pointed out that ctDNA has been found to be a useful prognostic and predictive tool in colon cancer. The new work suggests “that detectable ctDNA may help guide recommendations for postchemoradiation treatment. Of course, the ctDNA and esophageal cancer space is still in its infancy, and I would really encourage future studies to incorporate ctDNA as part of what they’re studying so that we can get more information about both the prognostic and predictive value of ctDNA in esophageal cancer,” said Dr. Raldow, who is an assistant professor of radiation oncology, University of California, Los Angeles.

Dr. Wang has no relevant financial disclosures. Dr. Raldow had received research funding from Intelligent Automation, Clarity, and Viewray.

Circulating tumor DNA (ctDNA) has garnered attention in recent years as a potential noninvasive biomarker that could help determine prognosis and treatment responses in solid tumors. They could also provide a more complete picture of tumor genetics than the limited samples often available from a biopsy.

ctDNA studies have been conducted in a range of solid tumors, but esophageal cancer has received less attention than other cancers. It is currently diagnosed by endoscopy, but this method is not suitable for population-wide surveillance because of its cost and invasiveness.

Esophageal squamous cell carcinoma (ESCC) is the predominant histologic type of esophageal cancer in China, and it is difficult to diagnose using normal radiological techniques because of the hollow nature of the esophagus.

In a virtual poster session at the annual meeting of the American Society for Radiation Oncology, Xin Wang, MD, discussed the results of a small study looking at ctDNA and ESCC. “We aimed to investigate if ctDNA could detect disease progression before radiological imaging and try identifying patients with inferior prognosis based on ctDNA positivity and dynamics,” said Dr. Wang, who is a researcher at the Chinese Academy of Medical Sciences, Beijing.

85% of enrolled patients were male, and the median age at diagnosis was 64 years. The gross tumor volume was larger in patients with ctDNA-positive tumors at baseline 40.1 cm³ versus 28.7 cm³ (P = .001) and 14% underwent esophagectomy following radiotherapy, compared with 58% of the ctDNA-negative group (P = .008). Other baseline factors were similar between the two groups.

The researchers used a 474-gene panel to analyze plasma samples. 106 of the genes are known to be associated with radiosensitivity. Prior to radiotherapy (T0), 28 of 40 patients (70%) had a positive ctDNA sample. At week 4 of radiotherapy (T1), 42% of 36 patients were ctDNA positive. One to 3 months after radiotherapy/chemoradiotherapy (T2), among 27 patients, 30% were ctDNA positive. 27 patients ultimately underwent esophagectomy, while 9 did not have surgery. Three to 6 months after radiotherapy/chemoradiotherapy (T3), among 23 patients, 22% were ctDNA positive. Of 14 patients alive after 1 year, 43% were ctDNA positive.

Over a median follow-up of 20.6 months, 17 patients were diagnosed with progression through radiological imaging. Of these, 13 patients (77%) were ctDNA positive before or after progression (Cohen’s kappa, 0.512; P < .01). The mean lead time was 5.5 months (95% confidence interval, 1.5-9.4 months).

The researchers also observed links between ctDNA and survival. “We observed a strong association between inferior progression-free survival [PFS] and ctDNA positivity at T1, T2, and T3 time points. Similar associations were detected in OS [overall survival] as well,” Dr. Wang said.

In a multivariate analysis, ctDNA positivity at T1 was associated worse PFS (hazard ratio, 3.35; 95% CI, 1.10-10.22), and there was a trend toward worse overall survival (HR, 2.48; 95% CI, 0.83-7.37). There were no statistically significant associations between ctDNA positivity and PFS or OS at T2.

Twenty-one patients experienced a decrease in ctDNA concentration between T0 and T1. Of these, eight patients achieved a clearance of ctDNA by T1, and they had a trend toward better PFS than patients who did not achieve clearance (HR, 0.31; P = .06).

“The relatively poor locoregional recurrence-free survival remains related to ctDNA positivity at T1. Interestingly, for ctDNA-negative patients who received surgery, none of them were diagnosed with radiological progression. To summarize, ctDNA is a promising biomarker for detecting disease progression. Positive ctDNA status indicates for PFS and OS, but patients achieving ctDNA clearance after radiation are likely to have a better PFS. There is also a potential association between ctDNA positivity at the fourth week during radiation therapy and higher risk of local recurrence, but further studies with a larger sample size are required,” Dr. Wang said.

Ann Raldow, MD, who served as a discussant following the poster presentation, pointed out that ctDNA has been found to be a useful prognostic and predictive tool in colon cancer. The new work suggests “that detectable ctDNA may help guide recommendations for postchemoradiation treatment. Of course, the ctDNA and esophageal cancer space is still in its infancy, and I would really encourage future studies to incorporate ctDNA as part of what they’re studying so that we can get more information about both the prognostic and predictive value of ctDNA in esophageal cancer,” said Dr. Raldow, who is an assistant professor of radiation oncology, University of California, Los Angeles.

Dr. Wang has no relevant financial disclosures. Dr. Raldow had received research funding from Intelligent Automation, Clarity, and Viewray.

Among patients with advanced hepatocellular carcinoma (HCC), and especially those with macrovascular invasion, stereotactic body radiation therapy (SBRT) appears to grant a survival benefit when added to systemic therapy. That was the finding from a phase 3 clinical trial presented at the annual meeting of the American Society for Radiation Oncology.

For unresectable HCC or cases that cannot be treated with thermal ablation or regional therapy, the current standard of care is systemic therapy. When the study was conducted, the recommended therapy was the sorafenib, a tyrosine kinase inhibitor. But with the publication of the IMbrave 150 study in 2021, atezolizumab plus bevacizumab is now increasingly preferred by some oncologists.

In 2008, the SHARP study found that sorafenib improved median survival, but it provided less benefit for patients with macrovascular invasion. Various studies have addressed the question of whether radiation could improve survival among this patient population, but results have not been encouraging. Direct comparisons between sorafenib and radiotherapy in the SARAH and SIRveNIB studies showed no significant differences in outcomes.

To determine the efficacy of combined SBRT and sorafenib, researchers randomized 177 patients with locally advanced HCC to receive 400 mg sorafenib every 12 hours or SBRT of 27.5-50 Gy in five fractions, followed by 200 mg sorafenib every 12 hours for 4 weeks, then 400 mg sorafenib every 12 hours thereafter. The median age was 66 years, 85% of patients were male, 74% had macrovascular invasion. The study included patients with locally advanced tumors up to a 20-cm sum of diameters or up to a 20-cm conglomerate tumor, as well as those with metastases of 3 cm size or smaller.

After a median follow-up of 13.2 months, median overall survival was 15.8 months in the combination group, versus 12.3 months in sorafenib group (hazard ratio, 0.77; 1-sided P = .055). After a multivariable analysis, the combined treatment was associated with better overall survival (HR, 0.72; P = .042).

“This overall survival is greater than expected and impressive even in the era now of immunotherapy trials,” said Laura Dawson, MD, who presented the results of the study during a press conference at the meeting. Dr. Dawson is a professor of radiation oncology at University of Toronto and a radiation oncologist at Princess Margaret Hospital in Toronto.

Median progression-free survival was 9.2 months in the combined group versus 5.5 months in the sorafenib-only group (HR, 0.55; P = .0001). At 24 months, 17% of the combination group had 7% of the sorafenib group remained had not progressed. The median time to progression was 18.5 months in the combination group and 9.5 months in the sorafenib group (HR, 0.69; P = .034). The frequency of adverse events was similar in both groups. The study admitted patients with any level of vascular invasion, which contrasted with many earlier trials that excluded those with involvement of the main portal vein.

“I think this is really one of the most important studies that’s come out in many years in terms of practice changing outcomes. We’ve seen that with patients who have very high-risk HCC, especially patients who have portal vein or macrovascular vascular invasion, there’s been a significant improvement in overall survival for these patients, and this is a very difficult patient population. Adding SBRT in this group improved both the progression free survival and overall survival, so I think we’re really at a point where we can call this a standard of care for patients,” Karyn A. Goodman, MD, professor and vice chair of clinical research and radiation oncology at the Icahn School of Medicine at Mount Sinai, New York, said at the press conference.

A limitation of the study is that it closed early to accrual because of a change in the standard of care.

Dr. Goodman has served on advisory boards for Novartis, Philips Healthcare, and Genentech, and has consulted for RenovoRx and Syntactx. Dr. Dawson has received research grants from Merck and received patent/license fees or copyright compensation from RaySearch.

Among patients with advanced hepatocellular carcinoma (HCC), and especially those with macrovascular invasion, stereotactic body radiation therapy (SBRT) appears to grant a survival benefit when added to systemic therapy. That was the finding from a phase 3 clinical trial presented at the annual meeting of the American Society for Radiation Oncology.

For unresectable HCC or cases that cannot be treated with thermal ablation or regional therapy, the current standard of care is systemic therapy. When the study was conducted, the recommended therapy was the sorafenib, a tyrosine kinase inhibitor. But with the publication of the IMbrave 150 study in 2021, atezolizumab plus bevacizumab is now increasingly preferred by some oncologists.

In 2008, the SHARP study found that sorafenib improved median survival, but it provided less benefit for patients with macrovascular invasion. Various studies have addressed the question of whether radiation could improve survival among this patient population, but results have not been encouraging. Direct comparisons between sorafenib and radiotherapy in the SARAH and SIRveNIB studies showed no significant differences in outcomes.

To determine the efficacy of combined SBRT and sorafenib, researchers randomized 177 patients with locally advanced HCC to receive 400 mg sorafenib every 12 hours or SBRT of 27.5-50 Gy in five fractions, followed by 200 mg sorafenib every 12 hours for 4 weeks, then 400 mg sorafenib every 12 hours thereafter. The median age was 66 years, 85% of patients were male, 74% had macrovascular invasion. The study included patients with locally advanced tumors up to a 20-cm sum of diameters or up to a 20-cm conglomerate tumor, as well as those with metastases of 3 cm size or smaller.

After a median follow-up of 13.2 months, median overall survival was 15.8 months in the combination group, versus 12.3 months in sorafenib group (hazard ratio, 0.77; 1-sided P = .055). After a multivariable analysis, the combined treatment was associated with better overall survival (HR, 0.72; P = .042).

“This overall survival is greater than expected and impressive even in the era now of immunotherapy trials,” said Laura Dawson, MD, who presented the results of the study during a press conference at the meeting. Dr. Dawson is a professor of radiation oncology at University of Toronto and a radiation oncologist at Princess Margaret Hospital in Toronto.

Median progression-free survival was 9.2 months in the combined group versus 5.5 months in the sorafenib-only group (HR, 0.55; P = .0001). At 24 months, 17% of the combination group had 7% of the sorafenib group remained had not progressed. The median time to progression was 18.5 months in the combination group and 9.5 months in the sorafenib group (HR, 0.69; P = .034). The frequency of adverse events was similar in both groups. The study admitted patients with any level of vascular invasion, which contrasted with many earlier trials that excluded those with involvement of the main portal vein.

“I think this is really one of the most important studies that’s come out in many years in terms of practice changing outcomes. We’ve seen that with patients who have very high-risk HCC, especially patients who have portal vein or macrovascular vascular invasion, there’s been a significant improvement in overall survival for these patients, and this is a very difficult patient population. Adding SBRT in this group improved both the progression free survival and overall survival, so I think we’re really at a point where we can call this a standard of care for patients,” Karyn A. Goodman, MD, professor and vice chair of clinical research and radiation oncology at the Icahn School of Medicine at Mount Sinai, New York, said at the press conference.

A limitation of the study is that it closed early to accrual because of a change in the standard of care.

Dr. Goodman has served on advisory boards for Novartis, Philips Healthcare, and Genentech, and has consulted for RenovoRx and Syntactx. Dr. Dawson has received research grants from Merck and received patent/license fees or copyright compensation from RaySearch.

Among patients with advanced hepatocellular carcinoma (HCC), and especially those with macrovascular invasion, stereotactic body radiation therapy (SBRT) appears to grant a survival benefit when added to systemic therapy. That was the finding from a phase 3 clinical trial presented at the annual meeting of the American Society for Radiation Oncology.

For unresectable HCC or cases that cannot be treated with thermal ablation or regional therapy, the current standard of care is systemic therapy. When the study was conducted, the recommended therapy was the sorafenib, a tyrosine kinase inhibitor. But with the publication of the IMbrave 150 study in 2021, atezolizumab plus bevacizumab is now increasingly preferred by some oncologists.

In 2008, the SHARP study found that sorafenib improved median survival, but it provided less benefit for patients with macrovascular invasion. Various studies have addressed the question of whether radiation could improve survival among this patient population, but results have not been encouraging. Direct comparisons between sorafenib and radiotherapy in the SARAH and SIRveNIB studies showed no significant differences in outcomes.

To determine the efficacy of combined SBRT and sorafenib, researchers randomized 177 patients with locally advanced HCC to receive 400 mg sorafenib every 12 hours or SBRT of 27.5-50 Gy in five fractions, followed by 200 mg sorafenib every 12 hours for 4 weeks, then 400 mg sorafenib every 12 hours thereafter. The median age was 66 years, 85% of patients were male, 74% had macrovascular invasion. The study included patients with locally advanced tumors up to a 20-cm sum of diameters or up to a 20-cm conglomerate tumor, as well as those with metastases of 3 cm size or smaller.

After a median follow-up of 13.2 months, median overall survival was 15.8 months in the combination group, versus 12.3 months in sorafenib group (hazard ratio, 0.77; 1-sided P = .055). After a multivariable analysis, the combined treatment was associated with better overall survival (HR, 0.72; P = .042).

“This overall survival is greater than expected and impressive even in the era now of immunotherapy trials,” said Laura Dawson, MD, who presented the results of the study during a press conference at the meeting. Dr. Dawson is a professor of radiation oncology at University of Toronto and a radiation oncologist at Princess Margaret Hospital in Toronto.

Median progression-free survival was 9.2 months in the combined group versus 5.5 months in the sorafenib-only group (HR, 0.55; P = .0001). At 24 months, 17% of the combination group had 7% of the sorafenib group remained had not progressed. The median time to progression was 18.5 months in the combination group and 9.5 months in the sorafenib group (HR, 0.69; P = .034). The frequency of adverse events was similar in both groups. The study admitted patients with any level of vascular invasion, which contrasted with many earlier trials that excluded those with involvement of the main portal vein.

“I think this is really one of the most important studies that’s come out in many years in terms of practice changing outcomes. We’ve seen that with patients who have very high-risk HCC, especially patients who have portal vein or macrovascular vascular invasion, there’s been a significant improvement in overall survival for these patients, and this is a very difficult patient population. Adding SBRT in this group improved both the progression free survival and overall survival, so I think we’re really at a point where we can call this a standard of care for patients,” Karyn A. Goodman, MD, professor and vice chair of clinical research and radiation oncology at the Icahn School of Medicine at Mount Sinai, New York, said at the press conference.

A limitation of the study is that it closed early to accrual because of a change in the standard of care.

Dr. Goodman has served on advisory boards for Novartis, Philips Healthcare, and Genentech, and has consulted for RenovoRx and Syntactx. Dr. Dawson has received research grants from Merck and received patent/license fees or copyright compensation from RaySearch.

Falls are common in patients with multiple sclerosis (MS) and a new study suggests impairment in a specific aspect of neuromuscular function can identify those at highest risk. Compared with patients with MS who didn’t fall, those who did fall had worse neuromuscular function as evidenced by a reduced rate of force development.

“Our study suggests that instead of looking at reduced maximum muscle strength, perhaps we should start looking at reduced rate of force development when trying to identify potential fallers,” said Laurits Taul-Madsen, PhD student, Aarhus University, Denmark.

The study was presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

Explosive strength

In contrast to maximal muscle strength, the rate of force development is a measure of explosive strength, or simply the amount of force that an individual can produce over a given time period. When a patient is about to fall, what’s most important is not how strong the person is, but how quickly they can produce enough force to counteract the balance perturbation, thus avoid falling, said Dr. Taul-Madsen.

“If a person is very slow to produce this force, [that person] will have fallen before he or she has produced enough force to counteract the balance perturbation that the person is experiencing,” he added.

Research has shown a reduced rate of force development (RFD) in patients with MS, compared with healthy controls. However, little is known about the impact of RFD on falls in those with MS.

To investigate, researchers studied 53 adults with MS: Twenty-four had no fall history in the prior year, 16 had one to two prior falls, and 13 had three or more falls. The two groups of fallers were both slightly older and had a slightly higher Expanded Disability Status Scale (EDSS) scores, “which may not be so surprising,” Dr. Taul-Madsen said.

Knee extensor neuromuscular function, including maximum muscle strength and RFD at 50 and 200 milliseconds, was assessed via isokinetic dynamometry.

A high RFD is “good and the non-fallers had the highest RFD at 50 ms.” On this measure, “we saw quite a big difference between the non-fallers and the two groups of fallers,” Dr. Taul-Madsen reported.

At 200 ms, the RFD was again highest in the group of non-fallers but the difference was somewhat smaller. Non-fallers also had greater maximum muscle strength than that of the fallers.

There was “good” correlation between these neuromuscular measurements and falls, Dr. Taul-Madsen said.

He noted that RFD, which can be improved with resistance training, “seems like a specialized and difficult measurement, but it doesn’t have to be. It can be measured with just a linear encoder and a chair to perform the sit-to-stand test, so in clinical practice, it’s quite easily measured.”
 

‘Highly promising’ approach

“There are some data on predictors of falls in persons with MS, but not yet on neuromuscular function, as has been done in other populations,” said Brian Sandroff, PhD, senior research scientist, Kessler Foundation, West Orange, N.J.

This study is “interesting in that recurrent fallers were distinguished based on having worse neuromuscular function,” said Dr. Sandroff, who was not part of the research team.

“Although this relationship is somewhat intuitive,” RFD provides a “potentially sensitive measure that can be addressed via specific resistance exercise programs as a highly promising approach for reducing fall risk and falls themselves in persons with MS,” Dr. Sandroff said.

More generally, he said this study provides “more evidence on the multisystemic benefits of exercise training and having better physical fitness in persons with MS.

“The evidence seems to be converging more and more on this, as research groups across countries and continents are reporting on similar themes,” said Dr. Sandroff.

The study had no specific funding. Dr. Taul-Madsen and Dr. Sandroff report no relevant financial relationships.

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

Falls are common in patients with multiple sclerosis (MS) and a new study suggests impairment in a specific aspect of neuromuscular function can identify those at highest risk. Compared with patients with MS who didn’t fall, those who did fall had worse neuromuscular function as evidenced by a reduced rate of force development.

“Our study suggests that instead of looking at reduced maximum muscle strength, perhaps we should start looking at reduced rate of force development when trying to identify potential fallers,” said Laurits Taul-Madsen, PhD student, Aarhus University, Denmark.

The study was presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

Explosive strength

In contrast to maximal muscle strength, the rate of force development is a measure of explosive strength, or simply the amount of force that an individual can produce over a given time period. When a patient is about to fall, what’s most important is not how strong the person is, but how quickly they can produce enough force to counteract the balance perturbation, thus avoid falling, said Dr. Taul-Madsen.

“If a person is very slow to produce this force, [that person] will have fallen before he or she has produced enough force to counteract the balance perturbation that the person is experiencing,” he added.

Research has shown a reduced rate of force development (RFD) in patients with MS, compared with healthy controls. However, little is known about the impact of RFD on falls in those with MS.

To investigate, researchers studied 53 adults with MS: Twenty-four had no fall history in the prior year, 16 had one to two prior falls, and 13 had three or more falls. The two groups of fallers were both slightly older and had a slightly higher Expanded Disability Status Scale (EDSS) scores, “which may not be so surprising,” Dr. Taul-Madsen said.

Knee extensor neuromuscular function, including maximum muscle strength and RFD at 50 and 200 milliseconds, was assessed via isokinetic dynamometry.

A high RFD is “good and the non-fallers had the highest RFD at 50 ms.” On this measure, “we saw quite a big difference between the non-fallers and the two groups of fallers,” Dr. Taul-Madsen reported.

At 200 ms, the RFD was again highest in the group of non-fallers but the difference was somewhat smaller. Non-fallers also had greater maximum muscle strength than that of the fallers.

There was “good” correlation between these neuromuscular measurements and falls, Dr. Taul-Madsen said.

He noted that RFD, which can be improved with resistance training, “seems like a specialized and difficult measurement, but it doesn’t have to be. It can be measured with just a linear encoder and a chair to perform the sit-to-stand test, so in clinical practice, it’s quite easily measured.”
 

‘Highly promising’ approach

“There are some data on predictors of falls in persons with MS, but not yet on neuromuscular function, as has been done in other populations,” said Brian Sandroff, PhD, senior research scientist, Kessler Foundation, West Orange, N.J.

This study is “interesting in that recurrent fallers were distinguished based on having worse neuromuscular function,” said Dr. Sandroff, who was not part of the research team.

“Although this relationship is somewhat intuitive,” RFD provides a “potentially sensitive measure that can be addressed via specific resistance exercise programs as a highly promising approach for reducing fall risk and falls themselves in persons with MS,” Dr. Sandroff said.

More generally, he said this study provides “more evidence on the multisystemic benefits of exercise training and having better physical fitness in persons with MS.

“The evidence seems to be converging more and more on this, as research groups across countries and continents are reporting on similar themes,” said Dr. Sandroff.

The study had no specific funding. Dr. Taul-Madsen and Dr. Sandroff report no relevant financial relationships.

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

Falls are common in patients with multiple sclerosis (MS) and a new study suggests impairment in a specific aspect of neuromuscular function can identify those at highest risk. Compared with patients with MS who didn’t fall, those who did fall had worse neuromuscular function as evidenced by a reduced rate of force development.

“Our study suggests that instead of looking at reduced maximum muscle strength, perhaps we should start looking at reduced rate of force development when trying to identify potential fallers,” said Laurits Taul-Madsen, PhD student, Aarhus University, Denmark.

The study was presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

Explosive strength

In contrast to maximal muscle strength, the rate of force development is a measure of explosive strength, or simply the amount of force that an individual can produce over a given time period. When a patient is about to fall, what’s most important is not how strong the person is, but how quickly they can produce enough force to counteract the balance perturbation, thus avoid falling, said Dr. Taul-Madsen.

“If a person is very slow to produce this force, [that person] will have fallen before he or she has produced enough force to counteract the balance perturbation that the person is experiencing,” he added.

Research has shown a reduced rate of force development (RFD) in patients with MS, compared with healthy controls. However, little is known about the impact of RFD on falls in those with MS.

To investigate, researchers studied 53 adults with MS: Twenty-four had no fall history in the prior year, 16 had one to two prior falls, and 13 had three or more falls. The two groups of fallers were both slightly older and had a slightly higher Expanded Disability Status Scale (EDSS) scores, “which may not be so surprising,” Dr. Taul-Madsen said.

Knee extensor neuromuscular function, including maximum muscle strength and RFD at 50 and 200 milliseconds, was assessed via isokinetic dynamometry.

A high RFD is “good and the non-fallers had the highest RFD at 50 ms.” On this measure, “we saw quite a big difference between the non-fallers and the two groups of fallers,” Dr. Taul-Madsen reported.

At 200 ms, the RFD was again highest in the group of non-fallers but the difference was somewhat smaller. Non-fallers also had greater maximum muscle strength than that of the fallers.

There was “good” correlation between these neuromuscular measurements and falls, Dr. Taul-Madsen said.

He noted that RFD, which can be improved with resistance training, “seems like a specialized and difficult measurement, but it doesn’t have to be. It can be measured with just a linear encoder and a chair to perform the sit-to-stand test, so in clinical practice, it’s quite easily measured.”
 

‘Highly promising’ approach

“There are some data on predictors of falls in persons with MS, but not yet on neuromuscular function, as has been done in other populations,” said Brian Sandroff, PhD, senior research scientist, Kessler Foundation, West Orange, N.J.

This study is “interesting in that recurrent fallers were distinguished based on having worse neuromuscular function,” said Dr. Sandroff, who was not part of the research team.

“Although this relationship is somewhat intuitive,” RFD provides a “potentially sensitive measure that can be addressed via specific resistance exercise programs as a highly promising approach for reducing fall risk and falls themselves in persons with MS,” Dr. Sandroff said.

More generally, he said this study provides “more evidence on the multisystemic benefits of exercise training and having better physical fitness in persons with MS.

“The evidence seems to be converging more and more on this, as research groups across countries and continents are reporting on similar themes,” said Dr. Sandroff.

The study had no specific funding. Dr. Taul-Madsen and Dr. Sandroff report no relevant financial relationships.

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

Continuing treatment with two common multiple sclerosis (MS) medications during pregnancy is associated with significantly lower relapse rates and few pregnancy-related complications, new research shows. Results of two studies show that preterm birth, spontaneous abortions, and major congenital anomalies were rare with anti-CD20 drugs ocrelizumab or natalizumab, even when continued well into the third trimester. However, hematologic abnormalities were common in newborns who were exposed to MS therapies during pregnancy.

The research comes at a time when the incidence of MS is on the rise worldwide and pregnancy in MS patients is becoming more common (Neurology. 2018 Oct 23;91[17]:e1559-69). “The results of our study should lead to a distinct risk-benefit discussion between neurologists and pregnant natalizumab-treated women to maintain treatment up to the 30th or even the 34th week of gestation, in combination with an early restart during the first 4 weeks after delivery,” Sandra Thiel, PhD, an investigator in one of the studies, told delegates attending the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Dr. Thiel is in the department of neurology at St. Josef Hospital and Ruhr University Bochum (Germany).
 

Rising number of pregnancies

In a second study, researchers from Spain presented results from the largest dataset of pregnancy outcomes for an anti-CD20 therapy in MS. The trial included 2,020 pregnancies, most of which were followed prospectively. The study included data on pregnancies since 2008. The largest single-year increase among participants was in the past year, in which there was a 65% rise in the number of pregnancies.

“The number of women with MS exposed to ocrelizumab before, during, and after the pregnancy is increasing and increasing,” Celia Oreja-Guevara, MD, PhD, vice-chair of neurology and head of the Multiple Sclerosis Center of the University Hospital San Carlos, Madrid, told conference attendees. “We have more evidence, we have more knowledge, patients and physicians trust ocrelizumab more. They know that it’s a safe treatment, and more patients are becoming pregnant.”

Dr. Oreja-Guevara highlighted a decrease in the number of elective abortions, which dropped from 50% in 2021 to 11% in the past year. The number was higher for patients with known exposure to ocrelizumab (11.5% vs. 3.7%).

Among the prospective cases, ectopic pregnancies occurred in 1.8% of those who were not exposed to ocrelizumab versus 1.4% of those exposed to the medication. The overall rate of spontaneous abortion was 11.8%, which, Dr. Oreja-Guevara said, is lower than the rate among the general population in Spain.

In the total cohort, 79.0% of pregnancies resulted in live births. Rates were similar regardless of ocrelizumab exposure. About 57% of births were full term, and 10.0% were preterm. Gestational age was unknown in 32.9% of the cases.

Overall, 0.9% of infants had a major congenital anomaly, which Dr. Oreja-Guevara said is lower than the rate of 2%-3% in all children born in Europe.
 

A look at natalizumab

To examine outcomes following use of natalizumab during pregnancy, researchers examined data from the German Multiple Sclerosis and Pregnancy Registry, which was created in 2006 and follows people during pregnancy and up to 6 years post partum. Of the 350 pregnant people included in the study, 171 continued natalizumab therapy beyond the first trimester. Discontinuation occurred at a median of 30.9 gestational weeks.

Most patients did not experience MS relapse during pregnancy, but the number was higher for patients who continued taking natalizumab later into pregnancy compared with those who stopped taking the drug in the first trimester (94.8% vs. 67.6%).

In the group analysis, women who continued treatment after the first trimester had significantly fewer relapses during pregnancy (5.9% vs. 32.4%; P < .001) and in the postpartum period (22.8% vs. 49.7%, P < .001). Resuming treatment with natalizumab within 4 weeks after birth significantly reduced relapse risk post partum (odds ratio, 0.32; P < .001).

The researchers also examined relapse risk with respect to treatment duration after the first trimester. Significantly more women who discontinued natalizumab before the 30th gestational week experienced postpartum relapses, compared with those whose treatment extended beyond that point (38.5% vs. 16.0%; P = .008), especially during the first postpartum trimester (26.9% vs. 8.00%; P = .009).

There were no significant differences in preterm births or major congenital abnormalities between groups. However, about half of the infants exposed to natalizumab beyond the first trimester were born with anemia or other hematologic abnormalities.

Another unexpected finding was the number of infants who were small for their gestational age (SGA). About 19% of infants born to women who continued treatment later in pregnancy were SGA. Among those in the group that discontinued therapy in the first trimester, the figure was just under 17%.

“Pregnancy outcomes were within the expected range, but a potential increased risk for small for gestational age newborns justified further investigation,” Dr. Thiel said.
 

Reassuring data

Angie Child Jelin, MD, director of the first trimester screening program and associate professor of gynecology and obstetrics at Johns Hopkins University, Baltimore, said that the increase in the number of pregnant patients with MS seen in their clinic could be caused in part by the growing body of work on MS treatment during pregnancy.

“It’s very reassuring that these data have come out and showed how safe they are generally in pregnancy,” Dr. Jalin said.

Although hematologic abnormalities in newborns are thought to be acute, Dr. Jalin said long-term study is needed to better understand any potential lasting effects from those abnormalities, as well as any effects in SGA newborns.

“Long-term outcomes are very hard to acquire, but ideally you’d want long-term outcomes on all of these measures,” Dr. Jalin said.

Funding for the natalizumab study was not disclosed. The ocrelizumab study was funded by F. Hoffmann–La Roche. Dr. Oreja-Guevara received honoraria for consulting and serving on advisory boards from Biogen Idec, F. Hoffmann–La Roche, Genzyme, Merck, Novartis, and Teva. Dr. Thiel has received speaker honoraria from Bayer Healthcare. Dr. Jalin reported no relevant financial relationships.

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

Continuing treatment with two common multiple sclerosis (MS) medications during pregnancy is associated with significantly lower relapse rates and few pregnancy-related complications, new research shows. Results of two studies show that preterm birth, spontaneous abortions, and major congenital anomalies were rare with anti-CD20 drugs ocrelizumab or natalizumab, even when continued well into the third trimester. However, hematologic abnormalities were common in newborns who were exposed to MS therapies during pregnancy.

The research comes at a time when the incidence of MS is on the rise worldwide and pregnancy in MS patients is becoming more common (Neurology. 2018 Oct 23;91[17]:e1559-69). “The results of our study should lead to a distinct risk-benefit discussion between neurologists and pregnant natalizumab-treated women to maintain treatment up to the 30th or even the 34th week of gestation, in combination with an early restart during the first 4 weeks after delivery,” Sandra Thiel, PhD, an investigator in one of the studies, told delegates attending the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Dr. Thiel is in the department of neurology at St. Josef Hospital and Ruhr University Bochum (Germany).
 

Rising number of pregnancies

In a second study, researchers from Spain presented results from the largest dataset of pregnancy outcomes for an anti-CD20 therapy in MS. The trial included 2,020 pregnancies, most of which were followed prospectively. The study included data on pregnancies since 2008. The largest single-year increase among participants was in the past year, in which there was a 65% rise in the number of pregnancies.

“The number of women with MS exposed to ocrelizumab before, during, and after the pregnancy is increasing and increasing,” Celia Oreja-Guevara, MD, PhD, vice-chair of neurology and head of the Multiple Sclerosis Center of the University Hospital San Carlos, Madrid, told conference attendees. “We have more evidence, we have more knowledge, patients and physicians trust ocrelizumab more. They know that it’s a safe treatment, and more patients are becoming pregnant.”

Dr. Oreja-Guevara highlighted a decrease in the number of elective abortions, which dropped from 50% in 2021 to 11% in the past year. The number was higher for patients with known exposure to ocrelizumab (11.5% vs. 3.7%).

Among the prospective cases, ectopic pregnancies occurred in 1.8% of those who were not exposed to ocrelizumab versus 1.4% of those exposed to the medication. The overall rate of spontaneous abortion was 11.8%, which, Dr. Oreja-Guevara said, is lower than the rate among the general population in Spain.

In the total cohort, 79.0% of pregnancies resulted in live births. Rates were similar regardless of ocrelizumab exposure. About 57% of births were full term, and 10.0% were preterm. Gestational age was unknown in 32.9% of the cases.

Overall, 0.9% of infants had a major congenital anomaly, which Dr. Oreja-Guevara said is lower than the rate of 2%-3% in all children born in Europe.
 

A look at natalizumab

To examine outcomes following use of natalizumab during pregnancy, researchers examined data from the German Multiple Sclerosis and Pregnancy Registry, which was created in 2006 and follows people during pregnancy and up to 6 years post partum. Of the 350 pregnant people included in the study, 171 continued natalizumab therapy beyond the first trimester. Discontinuation occurred at a median of 30.9 gestational weeks.

Most patients did not experience MS relapse during pregnancy, but the number was higher for patients who continued taking natalizumab later into pregnancy compared with those who stopped taking the drug in the first trimester (94.8% vs. 67.6%).

In the group analysis, women who continued treatment after the first trimester had significantly fewer relapses during pregnancy (5.9% vs. 32.4%; P < .001) and in the postpartum period (22.8% vs. 49.7%, P < .001). Resuming treatment with natalizumab within 4 weeks after birth significantly reduced relapse risk post partum (odds ratio, 0.32; P < .001).

The researchers also examined relapse risk with respect to treatment duration after the first trimester. Significantly more women who discontinued natalizumab before the 30th gestational week experienced postpartum relapses, compared with those whose treatment extended beyond that point (38.5% vs. 16.0%; P = .008), especially during the first postpartum trimester (26.9% vs. 8.00%; P = .009).

There were no significant differences in preterm births or major congenital abnormalities between groups. However, about half of the infants exposed to natalizumab beyond the first trimester were born with anemia or other hematologic abnormalities.

Another unexpected finding was the number of infants who were small for their gestational age (SGA). About 19% of infants born to women who continued treatment later in pregnancy were SGA. Among those in the group that discontinued therapy in the first trimester, the figure was just under 17%.

“Pregnancy outcomes were within the expected range, but a potential increased risk for small for gestational age newborns justified further investigation,” Dr. Thiel said.
 

Reassuring data

Angie Child Jelin, MD, director of the first trimester screening program and associate professor of gynecology and obstetrics at Johns Hopkins University, Baltimore, said that the increase in the number of pregnant patients with MS seen in their clinic could be caused in part by the growing body of work on MS treatment during pregnancy.

“It’s very reassuring that these data have come out and showed how safe they are generally in pregnancy,” Dr. Jalin said.

Although hematologic abnormalities in newborns are thought to be acute, Dr. Jalin said long-term study is needed to better understand any potential lasting effects from those abnormalities, as well as any effects in SGA newborns.

“Long-term outcomes are very hard to acquire, but ideally you’d want long-term outcomes on all of these measures,” Dr. Jalin said.

Funding for the natalizumab study was not disclosed. The ocrelizumab study was funded by F. Hoffmann–La Roche. Dr. Oreja-Guevara received honoraria for consulting and serving on advisory boards from Biogen Idec, F. Hoffmann–La Roche, Genzyme, Merck, Novartis, and Teva. Dr. Thiel has received speaker honoraria from Bayer Healthcare. Dr. Jalin reported no relevant financial relationships.

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

Continuing treatment with two common multiple sclerosis (MS) medications during pregnancy is associated with significantly lower relapse rates and few pregnancy-related complications, new research shows. Results of two studies show that preterm birth, spontaneous abortions, and major congenital anomalies were rare with anti-CD20 drugs ocrelizumab or natalizumab, even when continued well into the third trimester. However, hematologic abnormalities were common in newborns who were exposed to MS therapies during pregnancy.

The research comes at a time when the incidence of MS is on the rise worldwide and pregnancy in MS patients is becoming more common (Neurology. 2018 Oct 23;91[17]:e1559-69). “The results of our study should lead to a distinct risk-benefit discussion between neurologists and pregnant natalizumab-treated women to maintain treatment up to the 30th or even the 34th week of gestation, in combination with an early restart during the first 4 weeks after delivery,” Sandra Thiel, PhD, an investigator in one of the studies, told delegates attending the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Dr. Thiel is in the department of neurology at St. Josef Hospital and Ruhr University Bochum (Germany).
 

Rising number of pregnancies

In a second study, researchers from Spain presented results from the largest dataset of pregnancy outcomes for an anti-CD20 therapy in MS. The trial included 2,020 pregnancies, most of which were followed prospectively. The study included data on pregnancies since 2008. The largest single-year increase among participants was in the past year, in which there was a 65% rise in the number of pregnancies.

“The number of women with MS exposed to ocrelizumab before, during, and after the pregnancy is increasing and increasing,” Celia Oreja-Guevara, MD, PhD, vice-chair of neurology and head of the Multiple Sclerosis Center of the University Hospital San Carlos, Madrid, told conference attendees. “We have more evidence, we have more knowledge, patients and physicians trust ocrelizumab more. They know that it’s a safe treatment, and more patients are becoming pregnant.”

Dr. Oreja-Guevara highlighted a decrease in the number of elective abortions, which dropped from 50% in 2021 to 11% in the past year. The number was higher for patients with known exposure to ocrelizumab (11.5% vs. 3.7%).

Among the prospective cases, ectopic pregnancies occurred in 1.8% of those who were not exposed to ocrelizumab versus 1.4% of those exposed to the medication. The overall rate of spontaneous abortion was 11.8%, which, Dr. Oreja-Guevara said, is lower than the rate among the general population in Spain.

In the total cohort, 79.0% of pregnancies resulted in live births. Rates were similar regardless of ocrelizumab exposure. About 57% of births were full term, and 10.0% were preterm. Gestational age was unknown in 32.9% of the cases.

Overall, 0.9% of infants had a major congenital anomaly, which Dr. Oreja-Guevara said is lower than the rate of 2%-3% in all children born in Europe.
 

A look at natalizumab

To examine outcomes following use of natalizumab during pregnancy, researchers examined data from the German Multiple Sclerosis and Pregnancy Registry, which was created in 2006 and follows people during pregnancy and up to 6 years post partum. Of the 350 pregnant people included in the study, 171 continued natalizumab therapy beyond the first trimester. Discontinuation occurred at a median of 30.9 gestational weeks.

Most patients did not experience MS relapse during pregnancy, but the number was higher for patients who continued taking natalizumab later into pregnancy compared with those who stopped taking the drug in the first trimester (94.8% vs. 67.6%).

In the group analysis, women who continued treatment after the first trimester had significantly fewer relapses during pregnancy (5.9% vs. 32.4%; P < .001) and in the postpartum period (22.8% vs. 49.7%, P < .001). Resuming treatment with natalizumab within 4 weeks after birth significantly reduced relapse risk post partum (odds ratio, 0.32; P < .001).

The researchers also examined relapse risk with respect to treatment duration after the first trimester. Significantly more women who discontinued natalizumab before the 30th gestational week experienced postpartum relapses, compared with those whose treatment extended beyond that point (38.5% vs. 16.0%; P = .008), especially during the first postpartum trimester (26.9% vs. 8.00%; P = .009).

There were no significant differences in preterm births or major congenital abnormalities between groups. However, about half of the infants exposed to natalizumab beyond the first trimester were born with anemia or other hematologic abnormalities.

Another unexpected finding was the number of infants who were small for their gestational age (SGA). About 19% of infants born to women who continued treatment later in pregnancy were SGA. Among those in the group that discontinued therapy in the first trimester, the figure was just under 17%.

“Pregnancy outcomes were within the expected range, but a potential increased risk for small for gestational age newborns justified further investigation,” Dr. Thiel said.
 

Reassuring data

Angie Child Jelin, MD, director of the first trimester screening program and associate professor of gynecology and obstetrics at Johns Hopkins University, Baltimore, said that the increase in the number of pregnant patients with MS seen in their clinic could be caused in part by the growing body of work on MS treatment during pregnancy.

“It’s very reassuring that these data have come out and showed how safe they are generally in pregnancy,” Dr. Jalin said.

Although hematologic abnormalities in newborns are thought to be acute, Dr. Jalin said long-term study is needed to better understand any potential lasting effects from those abnormalities, as well as any effects in SGA newborns.

“Long-term outcomes are very hard to acquire, but ideally you’d want long-term outcomes on all of these measures,” Dr. Jalin said.

Funding for the natalizumab study was not disclosed. The ocrelizumab study was funded by F. Hoffmann–La Roche. Dr. Oreja-Guevara received honoraria for consulting and serving on advisory boards from Biogen Idec, F. Hoffmann–La Roche, Genzyme, Merck, Novartis, and Teva. Dr. Thiel has received speaker honoraria from Bayer Healthcare. Dr. Jalin reported no relevant financial relationships.

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

INDIANAPOLIS – The way Maria C. Garzon, MD, sees it, capillary malformations are often misunderstood. She views them not as a single diagnosis but rather as a variety of conditions that fall under the term capillary malformation.

“The challenge is, we also use that term to describe a diagnosis,” Dr. Garzon, professor of dermatology and pediatrics at Columbia University, New York, said at the annual meeting of the Society for Pediatric Dermatology. “We have imperfect terminology. We use many different terms like capillary nevi and vascular stain. Instead of port wine stain, we now use the term port wine birthmark, and old terms like nevus flammeus are still used. This leads to diagnostic confusion, and it’s a barrier to developing care guidelines.”

Some capillary malformations, she noted, are benign and fade away while others can cause disfigurement or herald significant medical issues.

Histologically, she continued, not all capillary malformations are composed of capillaries. “Some are composed of postcapillary venules,” she said. “There are also mixed type capillary malformations that include lymphatic tissue, and the capillary malformation of capillary malformation-arteriovenous malformation (CM-AVM) syndrome shares histologic features of evolving AVMs as opposed to classic port wine birthmarks.”

The most recent International Society for the Study of Vascular Anomalies Classification of Vascular Anomalies was published in 2018 and is currently being updated. Other proposed clinical classifications have been published, including one that is diagnosis-specific and includes 20 different types of capillary malformations (J Eur Acad Dermatol Venereol. 2015 29[12]:2295-305, Pediatr Dermatol. 2016;33[6]:570-84).

“There are also syndromic classifications. Another question relates to the role of genomics: Are we ready for a classification that’s based purely on genetic variants, or do we need to incorporate it into existing classifications?” Dr. Garzon said. “Novel testing technologies using cell-free DNA and digital droplet PCR may be used in the future to establish diagnoses.” Genetic variants are found within capillary malformations, and they tend to be associated with three major pathways: the RAS-MAPK/ERK pathway, the PI3K/Akt/mTOR pathway, and the G protein pathway.

The type of capillary malformation that dermatologists and pediatricians most commonly see is nevus simplex, which occurs in 20%-82% of neonates. Other terms used include angel’s kiss, stork bite, salmon patch, nevus flammeus simplex, fading vascular stain, medial telangiectatic nevus, and butterfly mark. “It’s important to differentiate this from a port wine birthmark,” Dr. Garzon said. “This can be challenging when the birthmark is a darker red color. I have cared for patients who were initially thought to have nevus simplex and later found to have Sturge-Weber syndrome.”

Typical locations of nevus simplex include the central forehead/glabella, eyelids, the nape of the neck, scalp (parietal and occipital), nose, lip area (including philtrum), and the back (lumbosacral area and upper back). Most lesions fade/disappear without treatment (J Am Acad Dermatol. 2020;63[5]:805-14). Rare genetic syndromes associated with exaggerated nevus simplex complex include macrocephaly-capillary malformation syndrome and Beckwith-Wiedemann syndrome, “which tells us that this is a heterogeneous group of patients,” she said.

Dr. Garzon added that it’s “incredibly common” to see an eczema flare occurring within a nevus simplex on the nape of the neck. These patients will have a patch of atopic dermatitis that doesn’t get better. “Beneath it is their nevus simplex,” she said. “Remind parents that even after treating the eczema, the pink patch is not going to go away” (Pediatr Rep. 2021;13[1]:131-4).

Meanwhile, the classic port wine birthmark is usually congenital, uniform, and darker red in color. It darkens with maturity and the pattern will correlate with embryonic vasculature. “I am very wary of acquired port wine lesions,” she added. “It’s been described with trauma-related lesions, but early morphea can also mimic a port wine birthmark. You will see this if you’re practicing pediatric dermatology.”

Nearly a decade ago researchers established a link between port wine birthmarks and genetic variants in the GNAQ gene. “We see this in GNA11 as well,” Dr. Garzon said. “These changes are found in isolated port wine stains, and in Sturge-Weber syndrome. We now know that GNAQ drives the formation of large blood vessels through angiopoietin-2,” she noted (Arterioscler Throm Vasc Biol. 2022;42[1]:e27-43).

In general, studies that have examined genotype-phenotype correlations have demonstrated that the classic port wine birthmark is associated with GNAQ while GNA11 variants can be associated with a more reticulated pattern. “But this is not as clearcut as it seems,” she said. Investigators of a recent study showed an association between hypertension and renal anomalies in patients with skin capillary malformations and mosaic GNAQ or GNA11 variants. “This is a new finding,” she said. “Investigators are working to understand this association.”

Port wine birthmarks with the highest risk of Sturge-Weber syndrome include those that involve the forehead, upper eyelid, the midline frontonasal area, the hemifacial area, and median sites. “Patients who have this should be evaluated at birth,” Dr. Garzon said. “You should not delay for 2 months. They should be evaluated by ophthalmology and neurology early.”

The other morphologies commonly seen are “geographic” well-demarcated capillary malformations, which are dark in color. These lesions can be seen in conditions that are associated with genetic variants in PIK3CA (PROS) and include classic Klippel-Trenaunay syndrome, CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal) syndrome, and CLAPO (capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry of the face and limbs, and partial or generalized overgrowth) syndrome.

“Reticulated stains are much more heterogeneous,” Dr. Garzon said. “They can be localized or widespread. When you see a patient with a widespread reticulated capillary malformation, think about diffuse capillary malformation with overgrowth (DCMO). This condition is clinically and genetically heterogenous with the affected tissue of some patients showing variants in GNA11 while others have variants in PIK3CA. Therefore, a thorough examination at presentation and long-term follow-up is very important.”

Dr. Garzon disclosed that she is a member of the executive board for the International Society for the Study of Vascular Anomalies.

INDIANAPOLIS – The way Maria C. Garzon, MD, sees it, capillary malformations are often misunderstood. She views them not as a single diagnosis but rather as a variety of conditions that fall under the term capillary malformation.

“The challenge is, we also use that term to describe a diagnosis,” Dr. Garzon, professor of dermatology and pediatrics at Columbia University, New York, said at the annual meeting of the Society for Pediatric Dermatology. “We have imperfect terminology. We use many different terms like capillary nevi and vascular stain. Instead of port wine stain, we now use the term port wine birthmark, and old terms like nevus flammeus are still used. This leads to diagnostic confusion, and it’s a barrier to developing care guidelines.”

Some capillary malformations, she noted, are benign and fade away while others can cause disfigurement or herald significant medical issues.

Histologically, she continued, not all capillary malformations are composed of capillaries. “Some are composed of postcapillary venules,” she said. “There are also mixed type capillary malformations that include lymphatic tissue, and the capillary malformation of capillary malformation-arteriovenous malformation (CM-AVM) syndrome shares histologic features of evolving AVMs as opposed to classic port wine birthmarks.”

The most recent International Society for the Study of Vascular Anomalies Classification of Vascular Anomalies was published in 2018 and is currently being updated. Other proposed clinical classifications have been published, including one that is diagnosis-specific and includes 20 different types of capillary malformations (J Eur Acad Dermatol Venereol. 2015 29[12]:2295-305, Pediatr Dermatol. 2016;33[6]:570-84).

“There are also syndromic classifications. Another question relates to the role of genomics: Are we ready for a classification that’s based purely on genetic variants, or do we need to incorporate it into existing classifications?” Dr. Garzon said. “Novel testing technologies using cell-free DNA and digital droplet PCR may be used in the future to establish diagnoses.” Genetic variants are found within capillary malformations, and they tend to be associated with three major pathways: the RAS-MAPK/ERK pathway, the PI3K/Akt/mTOR pathway, and the G protein pathway.

The type of capillary malformation that dermatologists and pediatricians most commonly see is nevus simplex, which occurs in 20%-82% of neonates. Other terms used include angel’s kiss, stork bite, salmon patch, nevus flammeus simplex, fading vascular stain, medial telangiectatic nevus, and butterfly mark. “It’s important to differentiate this from a port wine birthmark,” Dr. Garzon said. “This can be challenging when the birthmark is a darker red color. I have cared for patients who were initially thought to have nevus simplex and later found to have Sturge-Weber syndrome.”

Typical locations of nevus simplex include the central forehead/glabella, eyelids, the nape of the neck, scalp (parietal and occipital), nose, lip area (including philtrum), and the back (lumbosacral area and upper back). Most lesions fade/disappear without treatment (J Am Acad Dermatol. 2020;63[5]:805-14). Rare genetic syndromes associated with exaggerated nevus simplex complex include macrocephaly-capillary malformation syndrome and Beckwith-Wiedemann syndrome, “which tells us that this is a heterogeneous group of patients,” she said.

Dr. Garzon added that it’s “incredibly common” to see an eczema flare occurring within a nevus simplex on the nape of the neck. These patients will have a patch of atopic dermatitis that doesn’t get better. “Beneath it is their nevus simplex,” she said. “Remind parents that even after treating the eczema, the pink patch is not going to go away” (Pediatr Rep. 2021;13[1]:131-4).

Meanwhile, the classic port wine birthmark is usually congenital, uniform, and darker red in color. It darkens with maturity and the pattern will correlate with embryonic vasculature. “I am very wary of acquired port wine lesions,” she added. “It’s been described with trauma-related lesions, but early morphea can also mimic a port wine birthmark. You will see this if you’re practicing pediatric dermatology.”

Nearly a decade ago researchers established a link between port wine birthmarks and genetic variants in the GNAQ gene. “We see this in GNA11 as well,” Dr. Garzon said. “These changes are found in isolated port wine stains, and in Sturge-Weber syndrome. We now know that GNAQ drives the formation of large blood vessels through angiopoietin-2,” she noted (Arterioscler Throm Vasc Biol. 2022;42[1]:e27-43).

In general, studies that have examined genotype-phenotype correlations have demonstrated that the classic port wine birthmark is associated with GNAQ while GNA11 variants can be associated with a more reticulated pattern. “But this is not as clearcut as it seems,” she said. Investigators of a recent study showed an association between hypertension and renal anomalies in patients with skin capillary malformations and mosaic GNAQ or GNA11 variants. “This is a new finding,” she said. “Investigators are working to understand this association.”

Port wine birthmarks with the highest risk of Sturge-Weber syndrome include those that involve the forehead, upper eyelid, the midline frontonasal area, the hemifacial area, and median sites. “Patients who have this should be evaluated at birth,” Dr. Garzon said. “You should not delay for 2 months. They should be evaluated by ophthalmology and neurology early.”

The other morphologies commonly seen are “geographic” well-demarcated capillary malformations, which are dark in color. These lesions can be seen in conditions that are associated with genetic variants in PIK3CA (PROS) and include classic Klippel-Trenaunay syndrome, CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal) syndrome, and CLAPO (capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry of the face and limbs, and partial or generalized overgrowth) syndrome.

“Reticulated stains are much more heterogeneous,” Dr. Garzon said. “They can be localized or widespread. When you see a patient with a widespread reticulated capillary malformation, think about diffuse capillary malformation with overgrowth (DCMO). This condition is clinically and genetically heterogenous with the affected tissue of some patients showing variants in GNA11 while others have variants in PIK3CA. Therefore, a thorough examination at presentation and long-term follow-up is very important.”

Dr. Garzon disclosed that she is a member of the executive board for the International Society for the Study of Vascular Anomalies.

INDIANAPOLIS – The way Maria C. Garzon, MD, sees it, capillary malformations are often misunderstood. She views them not as a single diagnosis but rather as a variety of conditions that fall under the term capillary malformation.

“The challenge is, we also use that term to describe a diagnosis,” Dr. Garzon, professor of dermatology and pediatrics at Columbia University, New York, said at the annual meeting of the Society for Pediatric Dermatology. “We have imperfect terminology. We use many different terms like capillary nevi and vascular stain. Instead of port wine stain, we now use the term port wine birthmark, and old terms like nevus flammeus are still used. This leads to diagnostic confusion, and it’s a barrier to developing care guidelines.”

Some capillary malformations, she noted, are benign and fade away while others can cause disfigurement or herald significant medical issues.

Histologically, she continued, not all capillary malformations are composed of capillaries. “Some are composed of postcapillary venules,” she said. “There are also mixed type capillary malformations that include lymphatic tissue, and the capillary malformation of capillary malformation-arteriovenous malformation (CM-AVM) syndrome shares histologic features of evolving AVMs as opposed to classic port wine birthmarks.”

The most recent International Society for the Study of Vascular Anomalies Classification of Vascular Anomalies was published in 2018 and is currently being updated. Other proposed clinical classifications have been published, including one that is diagnosis-specific and includes 20 different types of capillary malformations (J Eur Acad Dermatol Venereol. 2015 29[12]:2295-305, Pediatr Dermatol. 2016;33[6]:570-84).

“There are also syndromic classifications. Another question relates to the role of genomics: Are we ready for a classification that’s based purely on genetic variants, or do we need to incorporate it into existing classifications?” Dr. Garzon said. “Novel testing technologies using cell-free DNA and digital droplet PCR may be used in the future to establish diagnoses.” Genetic variants are found within capillary malformations, and they tend to be associated with three major pathways: the RAS-MAPK/ERK pathway, the PI3K/Akt/mTOR pathway, and the G protein pathway.

The type of capillary malformation that dermatologists and pediatricians most commonly see is nevus simplex, which occurs in 20%-82% of neonates. Other terms used include angel’s kiss, stork bite, salmon patch, nevus flammeus simplex, fading vascular stain, medial telangiectatic nevus, and butterfly mark. “It’s important to differentiate this from a port wine birthmark,” Dr. Garzon said. “This can be challenging when the birthmark is a darker red color. I have cared for patients who were initially thought to have nevus simplex and later found to have Sturge-Weber syndrome.”

Typical locations of nevus simplex include the central forehead/glabella, eyelids, the nape of the neck, scalp (parietal and occipital), nose, lip area (including philtrum), and the back (lumbosacral area and upper back). Most lesions fade/disappear without treatment (J Am Acad Dermatol. 2020;63[5]:805-14). Rare genetic syndromes associated with exaggerated nevus simplex complex include macrocephaly-capillary malformation syndrome and Beckwith-Wiedemann syndrome, “which tells us that this is a heterogeneous group of patients,” she said.

Dr. Garzon added that it’s “incredibly common” to see an eczema flare occurring within a nevus simplex on the nape of the neck. These patients will have a patch of atopic dermatitis that doesn’t get better. “Beneath it is their nevus simplex,” she said. “Remind parents that even after treating the eczema, the pink patch is not going to go away” (Pediatr Rep. 2021;13[1]:131-4).

Meanwhile, the classic port wine birthmark is usually congenital, uniform, and darker red in color. It darkens with maturity and the pattern will correlate with embryonic vasculature. “I am very wary of acquired port wine lesions,” she added. “It’s been described with trauma-related lesions, but early morphea can also mimic a port wine birthmark. You will see this if you’re practicing pediatric dermatology.”

Nearly a decade ago researchers established a link between port wine birthmarks and genetic variants in the GNAQ gene. “We see this in GNA11 as well,” Dr. Garzon said. “These changes are found in isolated port wine stains, and in Sturge-Weber syndrome. We now know that GNAQ drives the formation of large blood vessels through angiopoietin-2,” she noted (Arterioscler Throm Vasc Biol. 2022;42[1]:e27-43).

In general, studies that have examined genotype-phenotype correlations have demonstrated that the classic port wine birthmark is associated with GNAQ while GNA11 variants can be associated with a more reticulated pattern. “But this is not as clearcut as it seems,” she said. Investigators of a recent study showed an association between hypertension and renal anomalies in patients with skin capillary malformations and mosaic GNAQ or GNA11 variants. “This is a new finding,” she said. “Investigators are working to understand this association.”

Port wine birthmarks with the highest risk of Sturge-Weber syndrome include those that involve the forehead, upper eyelid, the midline frontonasal area, the hemifacial area, and median sites. “Patients who have this should be evaluated at birth,” Dr. Garzon said. “You should not delay for 2 months. They should be evaluated by ophthalmology and neurology early.”

The other morphologies commonly seen are “geographic” well-demarcated capillary malformations, which are dark in color. These lesions can be seen in conditions that are associated with genetic variants in PIK3CA (PROS) and include classic Klippel-Trenaunay syndrome, CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal) syndrome, and CLAPO (capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry of the face and limbs, and partial or generalized overgrowth) syndrome.

“Reticulated stains are much more heterogeneous,” Dr. Garzon said. “They can be localized or widespread. When you see a patient with a widespread reticulated capillary malformation, think about diffuse capillary malformation with overgrowth (DCMO). This condition is clinically and genetically heterogenous with the affected tissue of some patients showing variants in GNA11 while others have variants in PIK3CA. Therefore, a thorough examination at presentation and long-term follow-up is very important.”

Dr. Garzon disclosed that she is a member of the executive board for the International Society for the Study of Vascular Anomalies.

The McDonald criteria for diagnosing multiple sclerosis (MS) has been around since 2001, with revisions in 2005, 2010, and 2017. They focus on lesions disseminated in space (DIS) and disseminated in time (DIT). As with any diagnostic, new science and methods inform changes. Although optic nerve lesions (ONL) have been considered in past revisions, they have yet to be adopted as a key diagnostic measure of MS.

At the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), several speakers made the case for the addition of ONL to the next McDonald revision. Arguments ranged from the inherent injustice that patients with a diagnosis of optic lesions should have to meet three symptoms of MS to get a diagnosis, while other patients require only two, to the possibility that early presentation with ocular symptoms could be an indicator of a more severe prognosis.

Still, many conditions can mimic the symptoms of ONL, so it is critical to be sure of the diagnosis before considering it a symptom of MS. For example, central serious maculopathy in young to middle-aged patients is often painless and could lead to an inadvertent MS diagnosis if it were added to the criteria. However, treatment with steroids can make it worse, according to Laura Balcer, MD, who spoke at the session. Dr. Balcer is a neuro-ophthalmologist at NYU Langone Health.
 

Adding ONL to McDonald

In the first talk of the session, Frederik Barkhof, MD, PhD, discussed some of the history of the McDonald criteria and laid a groundwork for why it should be updated. He began by pointing out that the latest criteria require either symptomatic or asymptomatic MRI lesions to determine DIS or DIT.

Dr. Barkhof has led the Magnetic Imaging in Multiple Sclerosis (MAGNIMS) group, which had some doubts about the 2017 revision to the McDonald criteria. “We discussed this and said, ‘Well, that is interesting. So you can have a brainstem lesion, which can be the symptomatic lesion and then you need one further region, so you have two regions, and then you have MS. But now if you have an optic nerve presentation, and you can find the optic nerve, it doesn’t count, and then you need two more regions. So there’s a bit of an imbalance. Why would you need three regions if you have an optic nerve, and only two if you have a spinal cord or a brainstem presentation?” recalled Dr. Barkhof, professor of radiology and neuroscience at Vrije Universiteit Amsterdam.

Identifying optic nerve lesions requires a good MRI that should use fat-saturation techniques.

Dr. Barkhof pointed out that the ONLs are a common presentation among MS patients. “We’re now preparing for the next revisions of the McDonnell criteria, and I’m confident and hopeful that we’ll make it this time,” said Dr. Barkhof.
 

Confirm the MS diagnosis

In the second talk, Angela Vidal-Jordana, MD, PhD, discussed ways to implement ONLs in the clinic. She emphasized the importance of ruling out other causes. “Even when a patient comes to us with a diagnosis of optic neuritis, we should question that. Different studies have shown that the optic neuritis overdiagnosis rate at referral might be as high as 60% of the cases,” said Dr. Vidal-Jordana, a neurologist at Centre d’Esclerosi Multiple de Catalunya in Barcelona. Studies show that about half of those are due to misinterpretation of the clinical history and examination, she said.

“So when presenting new visual symptoms, we should ask whether this is suggestive of an inflammatory etiology or not, and whether they are typical for MS or not. If both answers to these questions are yes, then we should apply the diagnostic criteria,” said Dr. Vidal-Jordana.

She presented results from a longitudinal, prospective study conducted within the MAGNIMS network supporting the inclusion of ONL into DIS criteria for MS. It included use of optic nerve MRI, OCT, and VEP [visual evoked potential]. “All of the modified DIS criteria, that is including one of the tests at each time, or a combination of them, led to a higher sensitivity of the diagnostic criteria (when optic nerve involvement was included), albeit with a small decrease in specificity which mainly was due to the fact that we only had 3 years of follow-up. The same held true when analyzing the secondary outcome of new T2 lesions or second relapse during the follow up,” said Dr. Vidal-Jordana.

“As a summary, I would say for sure we will need first of all an MRI, and we need to know if we can evaluate the optic nerve by MRI or not. If not, and we still do not have a diagnosis of a MS, maybe we can order VEP or OCT and then the test selection should be based on the time elapsed since first CIS [clinically isolated syndrome]. If it’s less than 3 months, I would go for a VEP. If it’s more than 3 months, then I probably want to go for OCT,” said Dr. Vidal-Jordana.
 

An aid to earlier diagnosis

In the last talk, Dr. Balcer discussed non-MRI methods for assessing ONLs. She noted that in about 25% of MS patients, ONLs are the first clinical demyelinating event. “Adding the optic nerve to the MS diagnostic criteria will allow us to diagnose our patients even earlier, (it) may help their vision, and could also help us to reduce the overall burden of MS disability over a lifetime. Importantly, entry into MS diagnosis can be delayed among patients for whom optic neuritis or even asymptomatic optic nerve lesions are noted at presentation, and there has been an enormous amount of data that have emerged over the past 5 years demonstrating the importance of the optic nerve in the MS diagnosis with implications for early therapy,” said Dr. Balcer.

She discussed optical coherence tomography (OCT), which is a key technique for diagnosing optic neuropathy. It measures the thickness of the retinal nerve fiber and ganglion cell layers, which have been associated with vision impairment and can reveal asymptomatic involvement of optic nerves in MS.
 

Beware of misdiagnosis

In the Q&A period following the talks, much of the discussion turned to reliability of ONL diagnoses.

“Misdiagnosis is a huge problem. That’s my experience: People who are referred to me with optic neuritis often don’t have optic neuritis,” said comoderator Wallace Brownlee, MBChB, PhD, a consultant neurologist at Cleveland Clinic London. Misha Pless, MD, spoke up from the audience to second that. “I’m delighted that the optic nerve will finally get a place at the table. I’ve been practicing neuro-ophthalmology and I have also [been] an MS doctor for about 25 years. What I see here in this fantastic discussion is that a lot of neurologists are going to be – I hate to use the word ‘misled’ – into relying on technology like OCT, VEP, and MRI to make the diagnosis. I will submit to this panel that that will lead to a number of MS misdiagnoses because I have been doing this for 25 years and the number of patients that I’ve received with rule-out optic neuritis that had macular disease, optical changes, or corneal abrasions are too numerous to count. If you’re going to add optic neuritis in the list of criteria [for MS], you definitely have to have a little asterisk in my opinion and say, ‘with prior blessing from an ophthalmologist to rule out ocular disease,’ because I don’t know any neurologist that knows how to look in the back of the eye, and I don’t know any neurologist that has an OCT in their office,” said Dr. Pless, professor of ophthalmology and a neurologist at Mayo Clinic in Jacksonville, Fla.

The panelists generally agreed with his point, although the hot mic picked up when one panelist whispered to another, ‘I have one,’ referring to an office OCT. “Using OCT in that regard, but also collaborating with your neuro-ophthalmologist and ophthalmologist is critical,” said Dr. Balcer.

Dr. Barkhof has financial relationships with Biogen, Merck, Roche, EISAI, Prothena, IXICO, Jansen, Combinostics, Novartis, GE, Queen Square, and Analytics. Dr. Vidal-Jordana has financial relationships with Roche, Novartis, Merck, and Sanofi. Dr. Balcer has no relevant financial disclosures. Dr. Brownlee has financial relationships with Biogen, Celgene, Merck, Mylan, Novartis, Roche, and Sanofi.

The McDonald criteria for diagnosing multiple sclerosis (MS) has been around since 2001, with revisions in 2005, 2010, and 2017. They focus on lesions disseminated in space (DIS) and disseminated in time (DIT). As with any diagnostic, new science and methods inform changes. Although optic nerve lesions (ONL) have been considered in past revisions, they have yet to be adopted as a key diagnostic measure of MS.

At the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), several speakers made the case for the addition of ONL to the next McDonald revision. Arguments ranged from the inherent injustice that patients with a diagnosis of optic lesions should have to meet three symptoms of MS to get a diagnosis, while other patients require only two, to the possibility that early presentation with ocular symptoms could be an indicator of a more severe prognosis.

Still, many conditions can mimic the symptoms of ONL, so it is critical to be sure of the diagnosis before considering it a symptom of MS. For example, central serious maculopathy in young to middle-aged patients is often painless and could lead to an inadvertent MS diagnosis if it were added to the criteria. However, treatment with steroids can make it worse, according to Laura Balcer, MD, who spoke at the session. Dr. Balcer is a neuro-ophthalmologist at NYU Langone Health.
 

Adding ONL to McDonald

In the first talk of the session, Frederik Barkhof, MD, PhD, discussed some of the history of the McDonald criteria and laid a groundwork for why it should be updated. He began by pointing out that the latest criteria require either symptomatic or asymptomatic MRI lesions to determine DIS or DIT.

Dr. Barkhof has led the Magnetic Imaging in Multiple Sclerosis (MAGNIMS) group, which had some doubts about the 2017 revision to the McDonald criteria. “We discussed this and said, ‘Well, that is interesting. So you can have a brainstem lesion, which can be the symptomatic lesion and then you need one further region, so you have two regions, and then you have MS. But now if you have an optic nerve presentation, and you can find the optic nerve, it doesn’t count, and then you need two more regions. So there’s a bit of an imbalance. Why would you need three regions if you have an optic nerve, and only two if you have a spinal cord or a brainstem presentation?” recalled Dr. Barkhof, professor of radiology and neuroscience at Vrije Universiteit Amsterdam.

Identifying optic nerve lesions requires a good MRI that should use fat-saturation techniques.

Dr. Barkhof pointed out that the ONLs are a common presentation among MS patients. “We’re now preparing for the next revisions of the McDonnell criteria, and I’m confident and hopeful that we’ll make it this time,” said Dr. Barkhof.
 

Confirm the MS diagnosis

In the second talk, Angela Vidal-Jordana, MD, PhD, discussed ways to implement ONLs in the clinic. She emphasized the importance of ruling out other causes. “Even when a patient comes to us with a diagnosis of optic neuritis, we should question that. Different studies have shown that the optic neuritis overdiagnosis rate at referral might be as high as 60% of the cases,” said Dr. Vidal-Jordana, a neurologist at Centre d’Esclerosi Multiple de Catalunya in Barcelona. Studies show that about half of those are due to misinterpretation of the clinical history and examination, she said.

“So when presenting new visual symptoms, we should ask whether this is suggestive of an inflammatory etiology or not, and whether they are typical for MS or not. If both answers to these questions are yes, then we should apply the diagnostic criteria,” said Dr. Vidal-Jordana.

She presented results from a longitudinal, prospective study conducted within the MAGNIMS network supporting the inclusion of ONL into DIS criteria for MS. It included use of optic nerve MRI, OCT, and VEP [visual evoked potential]. “All of the modified DIS criteria, that is including one of the tests at each time, or a combination of them, led to a higher sensitivity of the diagnostic criteria (when optic nerve involvement was included), albeit with a small decrease in specificity which mainly was due to the fact that we only had 3 years of follow-up. The same held true when analyzing the secondary outcome of new T2 lesions or second relapse during the follow up,” said Dr. Vidal-Jordana.

“As a summary, I would say for sure we will need first of all an MRI, and we need to know if we can evaluate the optic nerve by MRI or not. If not, and we still do not have a diagnosis of a MS, maybe we can order VEP or OCT and then the test selection should be based on the time elapsed since first CIS [clinically isolated syndrome]. If it’s less than 3 months, I would go for a VEP. If it’s more than 3 months, then I probably want to go for OCT,” said Dr. Vidal-Jordana.
 

An aid to earlier diagnosis

In the last talk, Dr. Balcer discussed non-MRI methods for assessing ONLs. She noted that in about 25% of MS patients, ONLs are the first clinical demyelinating event. “Adding the optic nerve to the MS diagnostic criteria will allow us to diagnose our patients even earlier, (it) may help their vision, and could also help us to reduce the overall burden of MS disability over a lifetime. Importantly, entry into MS diagnosis can be delayed among patients for whom optic neuritis or even asymptomatic optic nerve lesions are noted at presentation, and there has been an enormous amount of data that have emerged over the past 5 years demonstrating the importance of the optic nerve in the MS diagnosis with implications for early therapy,” said Dr. Balcer.

She discussed optical coherence tomography (OCT), which is a key technique for diagnosing optic neuropathy. It measures the thickness of the retinal nerve fiber and ganglion cell layers, which have been associated with vision impairment and can reveal asymptomatic involvement of optic nerves in MS.
 

Beware of misdiagnosis

In the Q&A period following the talks, much of the discussion turned to reliability of ONL diagnoses.

“Misdiagnosis is a huge problem. That’s my experience: People who are referred to me with optic neuritis often don’t have optic neuritis,” said comoderator Wallace Brownlee, MBChB, PhD, a consultant neurologist at Cleveland Clinic London. Misha Pless, MD, spoke up from the audience to second that. “I’m delighted that the optic nerve will finally get a place at the table. I’ve been practicing neuro-ophthalmology and I have also [been] an MS doctor for about 25 years. What I see here in this fantastic discussion is that a lot of neurologists are going to be – I hate to use the word ‘misled’ – into relying on technology like OCT, VEP, and MRI to make the diagnosis. I will submit to this panel that that will lead to a number of MS misdiagnoses because I have been doing this for 25 years and the number of patients that I’ve received with rule-out optic neuritis that had macular disease, optical changes, or corneal abrasions are too numerous to count. If you’re going to add optic neuritis in the list of criteria [for MS], you definitely have to have a little asterisk in my opinion and say, ‘with prior blessing from an ophthalmologist to rule out ocular disease,’ because I don’t know any neurologist that knows how to look in the back of the eye, and I don’t know any neurologist that has an OCT in their office,” said Dr. Pless, professor of ophthalmology and a neurologist at Mayo Clinic in Jacksonville, Fla.

The panelists generally agreed with his point, although the hot mic picked up when one panelist whispered to another, ‘I have one,’ referring to an office OCT. “Using OCT in that regard, but also collaborating with your neuro-ophthalmologist and ophthalmologist is critical,” said Dr. Balcer.

Dr. Barkhof has financial relationships with Biogen, Merck, Roche, EISAI, Prothena, IXICO, Jansen, Combinostics, Novartis, GE, Queen Square, and Analytics. Dr. Vidal-Jordana has financial relationships with Roche, Novartis, Merck, and Sanofi. Dr. Balcer has no relevant financial disclosures. Dr. Brownlee has financial relationships with Biogen, Celgene, Merck, Mylan, Novartis, Roche, and Sanofi.

The McDonald criteria for diagnosing multiple sclerosis (MS) has been around since 2001, with revisions in 2005, 2010, and 2017. They focus on lesions disseminated in space (DIS) and disseminated in time (DIT). As with any diagnostic, new science and methods inform changes. Although optic nerve lesions (ONL) have been considered in past revisions, they have yet to be adopted as a key diagnostic measure of MS.

At the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), several speakers made the case for the addition of ONL to the next McDonald revision. Arguments ranged from the inherent injustice that patients with a diagnosis of optic lesions should have to meet three symptoms of MS to get a diagnosis, while other patients require only two, to the possibility that early presentation with ocular symptoms could be an indicator of a more severe prognosis.

Still, many conditions can mimic the symptoms of ONL, so it is critical to be sure of the diagnosis before considering it a symptom of MS. For example, central serious maculopathy in young to middle-aged patients is often painless and could lead to an inadvertent MS diagnosis if it were added to the criteria. However, treatment with steroids can make it worse, according to Laura Balcer, MD, who spoke at the session. Dr. Balcer is a neuro-ophthalmologist at NYU Langone Health.
 

Adding ONL to McDonald

In the first talk of the session, Frederik Barkhof, MD, PhD, discussed some of the history of the McDonald criteria and laid a groundwork for why it should be updated. He began by pointing out that the latest criteria require either symptomatic or asymptomatic MRI lesions to determine DIS or DIT.

Dr. Barkhof has led the Magnetic Imaging in Multiple Sclerosis (MAGNIMS) group, which had some doubts about the 2017 revision to the McDonald criteria. “We discussed this and said, ‘Well, that is interesting. So you can have a brainstem lesion, which can be the symptomatic lesion and then you need one further region, so you have two regions, and then you have MS. But now if you have an optic nerve presentation, and you can find the optic nerve, it doesn’t count, and then you need two more regions. So there’s a bit of an imbalance. Why would you need three regions if you have an optic nerve, and only two if you have a spinal cord or a brainstem presentation?” recalled Dr. Barkhof, professor of radiology and neuroscience at Vrije Universiteit Amsterdam.

Identifying optic nerve lesions requires a good MRI that should use fat-saturation techniques.

Dr. Barkhof pointed out that the ONLs are a common presentation among MS patients. “We’re now preparing for the next revisions of the McDonnell criteria, and I’m confident and hopeful that we’ll make it this time,” said Dr. Barkhof.
 

Confirm the MS diagnosis

In the second talk, Angela Vidal-Jordana, MD, PhD, discussed ways to implement ONLs in the clinic. She emphasized the importance of ruling out other causes. “Even when a patient comes to us with a diagnosis of optic neuritis, we should question that. Different studies have shown that the optic neuritis overdiagnosis rate at referral might be as high as 60% of the cases,” said Dr. Vidal-Jordana, a neurologist at Centre d’Esclerosi Multiple de Catalunya in Barcelona. Studies show that about half of those are due to misinterpretation of the clinical history and examination, she said.

“So when presenting new visual symptoms, we should ask whether this is suggestive of an inflammatory etiology or not, and whether they are typical for MS or not. If both answers to these questions are yes, then we should apply the diagnostic criteria,” said Dr. Vidal-Jordana.

She presented results from a longitudinal, prospective study conducted within the MAGNIMS network supporting the inclusion of ONL into DIS criteria for MS. It included use of optic nerve MRI, OCT, and VEP [visual evoked potential]. “All of the modified DIS criteria, that is including one of the tests at each time, or a combination of them, led to a higher sensitivity of the diagnostic criteria (when optic nerve involvement was included), albeit with a small decrease in specificity which mainly was due to the fact that we only had 3 years of follow-up. The same held true when analyzing the secondary outcome of new T2 lesions or second relapse during the follow up,” said Dr. Vidal-Jordana.

“As a summary, I would say for sure we will need first of all an MRI, and we need to know if we can evaluate the optic nerve by MRI or not. If not, and we still do not have a diagnosis of a MS, maybe we can order VEP or OCT and then the test selection should be based on the time elapsed since first CIS [clinically isolated syndrome]. If it’s less than 3 months, I would go for a VEP. If it’s more than 3 months, then I probably want to go for OCT,” said Dr. Vidal-Jordana.
 

An aid to earlier diagnosis

In the last talk, Dr. Balcer discussed non-MRI methods for assessing ONLs. She noted that in about 25% of MS patients, ONLs are the first clinical demyelinating event. “Adding the optic nerve to the MS diagnostic criteria will allow us to diagnose our patients even earlier, (it) may help their vision, and could also help us to reduce the overall burden of MS disability over a lifetime. Importantly, entry into MS diagnosis can be delayed among patients for whom optic neuritis or even asymptomatic optic nerve lesions are noted at presentation, and there has been an enormous amount of data that have emerged over the past 5 years demonstrating the importance of the optic nerve in the MS diagnosis with implications for early therapy,” said Dr. Balcer.

She discussed optical coherence tomography (OCT), which is a key technique for diagnosing optic neuropathy. It measures the thickness of the retinal nerve fiber and ganglion cell layers, which have been associated with vision impairment and can reveal asymptomatic involvement of optic nerves in MS.
 

Beware of misdiagnosis

In the Q&A period following the talks, much of the discussion turned to reliability of ONL diagnoses.

“Misdiagnosis is a huge problem. That’s my experience: People who are referred to me with optic neuritis often don’t have optic neuritis,” said comoderator Wallace Brownlee, MBChB, PhD, a consultant neurologist at Cleveland Clinic London. Misha Pless, MD, spoke up from the audience to second that. “I’m delighted that the optic nerve will finally get a place at the table. I’ve been practicing neuro-ophthalmology and I have also [been] an MS doctor for about 25 years. What I see here in this fantastic discussion is that a lot of neurologists are going to be – I hate to use the word ‘misled’ – into relying on technology like OCT, VEP, and MRI to make the diagnosis. I will submit to this panel that that will lead to a number of MS misdiagnoses because I have been doing this for 25 years and the number of patients that I’ve received with rule-out optic neuritis that had macular disease, optical changes, or corneal abrasions are too numerous to count. If you’re going to add optic neuritis in the list of criteria [for MS], you definitely have to have a little asterisk in my opinion and say, ‘with prior blessing from an ophthalmologist to rule out ocular disease,’ because I don’t know any neurologist that knows how to look in the back of the eye, and I don’t know any neurologist that has an OCT in their office,” said Dr. Pless, professor of ophthalmology and a neurologist at Mayo Clinic in Jacksonville, Fla.

The panelists generally agreed with his point, although the hot mic picked up when one panelist whispered to another, ‘I have one,’ referring to an office OCT. “Using OCT in that regard, but also collaborating with your neuro-ophthalmologist and ophthalmologist is critical,” said Dr. Balcer.

Dr. Barkhof has financial relationships with Biogen, Merck, Roche, EISAI, Prothena, IXICO, Jansen, Combinostics, Novartis, GE, Queen Square, and Analytics. Dr. Vidal-Jordana has financial relationships with Roche, Novartis, Merck, and Sanofi. Dr. Balcer has no relevant financial disclosures. Dr. Brownlee has financial relationships with Biogen, Celgene, Merck, Mylan, Novartis, Roche, and Sanofi.