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MS and Epstein-Barr Virus: What Do We Know and Where Do We Go From Here?
The Epstein-Barr virus (EBV) is our constant companion, infecting an estimated 90%-95% of adults. Many of us are first infected as children, when the germ may trigger cold and flu symptoms. EBV also causes mononucleosis, or kissing disease, a glandular fever that has afflicted generations of amorous young people.
Post infection, EBV settles in for the long haul and remains in the body until death. It’s thought to be largely innocuous, but EBV is now implicated as a cause of several types of cancer — including lymphoma and nasopharyngeal tumors – and multiple sclerosis (MS). In 2022, a landmark study in Science suggested that previous EBV infection is the primary cause of MS.
While there aren’t many implications for current treatment, greater insight into the origin story of MS may eventually help neurologists better diagnose and treat patients, experts said. The goal is to uncover clues that “can help us understand MS a little bit better and reveal insights that could lead to new disease-modifying therapy,” Bruce Bebo, PhD, executive vice president of research with the National MS Society, said in an interview.
EBV Boosts MS Risk 32-Fold
EBV was first linked to MS back in 1981. For the 2022 study, researchers at the Harvard T.H. Chan School of Public Health and Harvard Medical School, Boston, analyzed blood serum from 10 million active-duty members of the US military. They focused on 801 recruits with MS and matched them with more than 1500 controls. All but one of those with MS had been infected with EBV; infection appeared to boost the risk for MS 32-fold (95% CI, 4.3-245.3; P < .001).
Neurologist and associate professor Michael Levy, MD, PhD, of Harvard Medical School and Massachusetts General Hospital, said in an interview that the findings are “groundbreaking” and confirm that EBV is “likely the primary cause of MS.”
According to Dr. Levy, there are two main theories about why EBV causes MS. The first hypothesis, known as the “molecular mimicry” theory, suggests that “EBV is a trigger of MS, possibly when the immune system mistakes a viral protein for a myelin protein and then attacks myelin,” Dr. Levy said. In MS, the immune system attacks the protective myelin sheath and the axons it insulates.
“After that point, the virus is not necessary to maintain the disease state and eradicating the virus likely won’t have much effect since the immune response is already triggered,” he said.
The second theory is that “EBV is a driver of MS where there is an ongoing, lifelong immunological response to EBV that continuously causes damage in the central nervous system [CNS]. In theory, if we could eradicate the virus, the destructive immune response could also resolve. Thus, an EBV antiviral treatment could potentially treat and maybe cure MS,” Dr. Levy explained, noting that “removing the pathogenic antigen may be a more effective strategy than removing the immune response.”
However, “we don’t yet know which hypothesis is correct,” he said. But “there is preliminary evidence in favor of each one.”
‘Additional Fuses Must Be Ignited’
It’s also unclear why most people infected with EBV do not develop MS. It appears that “additional fuses must be ignited,” for MS to take hold, according to a commentary accompanying the landmark 2022 study.
“As far as clinical implications, knowing whether a patient has a medical or family history of mononucleosis may be a small clue, a small piece of evidence, to help with diagnosis,” Dr. Bebo said.
He agreed with Dr. Levy that an antiviral could be a promising approach “If the problem in MS is a dysfunctional immune response to EBV.”
Natalia Drosu, MD, PhD, a postdoctoral fellow at Harvard-MIT Biomedical Engineering Center, said that a clinical trial of a non-immunosuppressive antiviral targeting EBV in patients with MS would be a crucial step toward better understanding the MS-EBV connection. “If we learn that antivirals are effective in MS, we should develop non-immunosuppressive therapies for patients with MS as soon as possible,” she said.
Stanford University’s Lawrence Steinman, MD, professor of neurology and neurological sciences, pediatrics, and genetics, who coauthored the commentary on the original Science paper, agreed that it’s worth investigating whether antiviral therapies targeting EBV will benefit patients who already have MS. But he cautioned against clinicians experimenting on their own outside of a research study. “You’d want to use the right antiviral and a properly designed trial,” he said.
Antivirals May Place a Crucial Role in MS Control
While there are no approved therapies for EBV, several MS disease-modifying therapies have anti-EBV effects, Dr. Levy said, citing anti-CD20 therapy as a clear example. It depletes B cells from the circulation, and it depletes EBV because the virus lives in the B-cell compartment. “Some MS treatments may be inadvertent EBV antivirals,” he said.
Researchers are also thinking about how they might exploit the MS-EBV link to prevent MS from developing in the first place, but there are uncertainties on that front too.
Conceivably, there may be some way to intervene in patients to treat EBV and prevent MS, such as a unique treatment for infectious mononucleosis (IM), Dr. Levy said.
Researchers are especially intrigued by signs that the timing of infection may play a role, with people infected with EBV via IM after early childhood at especially a high risk of developing MS. A 2022 German study calculated that people who developed IM were almost twice as likely as those who didn’t to develop MS within 10 years, although the risks in both groups were very small. Subgroup analysis revealed the strongest association between IM and MS was in the group infected between age 14 and 20 years (hazard ratio, 3.52; 95% CI, 1.00-12.37). They also saw a stronger association in men than in women.
The authors of a 2023 review in Clinical & Translational Immunology wrote that “further understanding of IM may be critical in solving the mystery” of EBV’s role in MS.
Dr. Levy said this line of questioning is important.
However, “remember that while most of the world gets EBV infections, only 1 in 1000 will get MS. So, it might not be feasible to test everyone before neurological manifestations occur,” he said.
More Questions to Answer About EBV and MS
Researchers hope to answer several questions moving forward. For one, why is EBV uniquely connected to MS? “You would think that if there were cross-reactivity to myelin, there are many viruses that could cause MS. But the association seems to be very restricted to EBV,” Dr. Levy said. “It is probably due to the fact that EBV is one of the only human viruses that can infect B cells, which play important roles in controlling immune responses.”
The molecular mimicry theory also opens up a potential treatment pathway.
A 2022 study reported “high-affinity molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and the central nervous system protein glial cell adhesion molecule (GlialCAM)”. Antibodies against EBNA1 and GlialCAM are prevalent in patients with MS. In a mouse model of MS, the researchers showed that EBNA1 immunization exacerbates disease. The authors wrote that “Our results provide a mechanistic link for the association between MS and EBV and could guide the development of new MS therapies.”
Could an EBV Vaccine Be the Answer?
On the prevention front, perhaps the most obvious question is whether an EBV vaccine could eliminate MS for good?
Dr. Bebo, from the National MS Society, said it will be important to determine which kind of vaccine is best. Is it one that neutralizes infection with EBV? Or is it enough to simply prevent clinical manifestations?
Both types of vaccines are in development, and at least two clinical trials are now in the works. The National Institute of Allergy and Infectious Diseases is sponsoring a phase 1 study of an adjuvanted EBV gp350-Ferritin nanoparticle vaccine. Forty subjects aged 18-29 years will take part: 20 with EBV and 20 who are not infected. The study is expected to end in 2025.
There is also a phase 1 placebo-controlled study in progress testing an EBV vaccine based on mRNA-1189 in 422 subjects aged 12-30 years. This trial is also due to end in 2025.
“This is very exciting, but it may take a decade or two to determine whether a vaccine is effective at preventing MS,” Dr. Levy said.
Dr. Levy, Dr. Steinman, Dr. Drosu, and Dr. Bebo had no disclosures.
A version of this article appeared on Medscape.com.
The Epstein-Barr virus (EBV) is our constant companion, infecting an estimated 90%-95% of adults. Many of us are first infected as children, when the germ may trigger cold and flu symptoms. EBV also causes mononucleosis, or kissing disease, a glandular fever that has afflicted generations of amorous young people.
Post infection, EBV settles in for the long haul and remains in the body until death. It’s thought to be largely innocuous, but EBV is now implicated as a cause of several types of cancer — including lymphoma and nasopharyngeal tumors – and multiple sclerosis (MS). In 2022, a landmark study in Science suggested that previous EBV infection is the primary cause of MS.
While there aren’t many implications for current treatment, greater insight into the origin story of MS may eventually help neurologists better diagnose and treat patients, experts said. The goal is to uncover clues that “can help us understand MS a little bit better and reveal insights that could lead to new disease-modifying therapy,” Bruce Bebo, PhD, executive vice president of research with the National MS Society, said in an interview.
EBV Boosts MS Risk 32-Fold
EBV was first linked to MS back in 1981. For the 2022 study, researchers at the Harvard T.H. Chan School of Public Health and Harvard Medical School, Boston, analyzed blood serum from 10 million active-duty members of the US military. They focused on 801 recruits with MS and matched them with more than 1500 controls. All but one of those with MS had been infected with EBV; infection appeared to boost the risk for MS 32-fold (95% CI, 4.3-245.3; P < .001).
Neurologist and associate professor Michael Levy, MD, PhD, of Harvard Medical School and Massachusetts General Hospital, said in an interview that the findings are “groundbreaking” and confirm that EBV is “likely the primary cause of MS.”
According to Dr. Levy, there are two main theories about why EBV causes MS. The first hypothesis, known as the “molecular mimicry” theory, suggests that “EBV is a trigger of MS, possibly when the immune system mistakes a viral protein for a myelin protein and then attacks myelin,” Dr. Levy said. In MS, the immune system attacks the protective myelin sheath and the axons it insulates.
“After that point, the virus is not necessary to maintain the disease state and eradicating the virus likely won’t have much effect since the immune response is already triggered,” he said.
The second theory is that “EBV is a driver of MS where there is an ongoing, lifelong immunological response to EBV that continuously causes damage in the central nervous system [CNS]. In theory, if we could eradicate the virus, the destructive immune response could also resolve. Thus, an EBV antiviral treatment could potentially treat and maybe cure MS,” Dr. Levy explained, noting that “removing the pathogenic antigen may be a more effective strategy than removing the immune response.”
However, “we don’t yet know which hypothesis is correct,” he said. But “there is preliminary evidence in favor of each one.”
‘Additional Fuses Must Be Ignited’
It’s also unclear why most people infected with EBV do not develop MS. It appears that “additional fuses must be ignited,” for MS to take hold, according to a commentary accompanying the landmark 2022 study.
“As far as clinical implications, knowing whether a patient has a medical or family history of mononucleosis may be a small clue, a small piece of evidence, to help with diagnosis,” Dr. Bebo said.
He agreed with Dr. Levy that an antiviral could be a promising approach “If the problem in MS is a dysfunctional immune response to EBV.”
Natalia Drosu, MD, PhD, a postdoctoral fellow at Harvard-MIT Biomedical Engineering Center, said that a clinical trial of a non-immunosuppressive antiviral targeting EBV in patients with MS would be a crucial step toward better understanding the MS-EBV connection. “If we learn that antivirals are effective in MS, we should develop non-immunosuppressive therapies for patients with MS as soon as possible,” she said.
Stanford University’s Lawrence Steinman, MD, professor of neurology and neurological sciences, pediatrics, and genetics, who coauthored the commentary on the original Science paper, agreed that it’s worth investigating whether antiviral therapies targeting EBV will benefit patients who already have MS. But he cautioned against clinicians experimenting on their own outside of a research study. “You’d want to use the right antiviral and a properly designed trial,” he said.
Antivirals May Place a Crucial Role in MS Control
While there are no approved therapies for EBV, several MS disease-modifying therapies have anti-EBV effects, Dr. Levy said, citing anti-CD20 therapy as a clear example. It depletes B cells from the circulation, and it depletes EBV because the virus lives in the B-cell compartment. “Some MS treatments may be inadvertent EBV antivirals,” he said.
Researchers are also thinking about how they might exploit the MS-EBV link to prevent MS from developing in the first place, but there are uncertainties on that front too.
Conceivably, there may be some way to intervene in patients to treat EBV and prevent MS, such as a unique treatment for infectious mononucleosis (IM), Dr. Levy said.
Researchers are especially intrigued by signs that the timing of infection may play a role, with people infected with EBV via IM after early childhood at especially a high risk of developing MS. A 2022 German study calculated that people who developed IM were almost twice as likely as those who didn’t to develop MS within 10 years, although the risks in both groups were very small. Subgroup analysis revealed the strongest association between IM and MS was in the group infected between age 14 and 20 years (hazard ratio, 3.52; 95% CI, 1.00-12.37). They also saw a stronger association in men than in women.
The authors of a 2023 review in Clinical & Translational Immunology wrote that “further understanding of IM may be critical in solving the mystery” of EBV’s role in MS.
Dr. Levy said this line of questioning is important.
However, “remember that while most of the world gets EBV infections, only 1 in 1000 will get MS. So, it might not be feasible to test everyone before neurological manifestations occur,” he said.
More Questions to Answer About EBV and MS
Researchers hope to answer several questions moving forward. For one, why is EBV uniquely connected to MS? “You would think that if there were cross-reactivity to myelin, there are many viruses that could cause MS. But the association seems to be very restricted to EBV,” Dr. Levy said. “It is probably due to the fact that EBV is one of the only human viruses that can infect B cells, which play important roles in controlling immune responses.”
The molecular mimicry theory also opens up a potential treatment pathway.
A 2022 study reported “high-affinity molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and the central nervous system protein glial cell adhesion molecule (GlialCAM)”. Antibodies against EBNA1 and GlialCAM are prevalent in patients with MS. In a mouse model of MS, the researchers showed that EBNA1 immunization exacerbates disease. The authors wrote that “Our results provide a mechanistic link for the association between MS and EBV and could guide the development of new MS therapies.”
Could an EBV Vaccine Be the Answer?
On the prevention front, perhaps the most obvious question is whether an EBV vaccine could eliminate MS for good?
Dr. Bebo, from the National MS Society, said it will be important to determine which kind of vaccine is best. Is it one that neutralizes infection with EBV? Or is it enough to simply prevent clinical manifestations?
Both types of vaccines are in development, and at least two clinical trials are now in the works. The National Institute of Allergy and Infectious Diseases is sponsoring a phase 1 study of an adjuvanted EBV gp350-Ferritin nanoparticle vaccine. Forty subjects aged 18-29 years will take part: 20 with EBV and 20 who are not infected. The study is expected to end in 2025.
There is also a phase 1 placebo-controlled study in progress testing an EBV vaccine based on mRNA-1189 in 422 subjects aged 12-30 years. This trial is also due to end in 2025.
“This is very exciting, but it may take a decade or two to determine whether a vaccine is effective at preventing MS,” Dr. Levy said.
Dr. Levy, Dr. Steinman, Dr. Drosu, and Dr. Bebo had no disclosures.
A version of this article appeared on Medscape.com.
The Epstein-Barr virus (EBV) is our constant companion, infecting an estimated 90%-95% of adults. Many of us are first infected as children, when the germ may trigger cold and flu symptoms. EBV also causes mononucleosis, or kissing disease, a glandular fever that has afflicted generations of amorous young people.
Post infection, EBV settles in for the long haul and remains in the body until death. It’s thought to be largely innocuous, but EBV is now implicated as a cause of several types of cancer — including lymphoma and nasopharyngeal tumors – and multiple sclerosis (MS). In 2022, a landmark study in Science suggested that previous EBV infection is the primary cause of MS.
While there aren’t many implications for current treatment, greater insight into the origin story of MS may eventually help neurologists better diagnose and treat patients, experts said. The goal is to uncover clues that “can help us understand MS a little bit better and reveal insights that could lead to new disease-modifying therapy,” Bruce Bebo, PhD, executive vice president of research with the National MS Society, said in an interview.
EBV Boosts MS Risk 32-Fold
EBV was first linked to MS back in 1981. For the 2022 study, researchers at the Harvard T.H. Chan School of Public Health and Harvard Medical School, Boston, analyzed blood serum from 10 million active-duty members of the US military. They focused on 801 recruits with MS and matched them with more than 1500 controls. All but one of those with MS had been infected with EBV; infection appeared to boost the risk for MS 32-fold (95% CI, 4.3-245.3; P < .001).
Neurologist and associate professor Michael Levy, MD, PhD, of Harvard Medical School and Massachusetts General Hospital, said in an interview that the findings are “groundbreaking” and confirm that EBV is “likely the primary cause of MS.”
According to Dr. Levy, there are two main theories about why EBV causes MS. The first hypothesis, known as the “molecular mimicry” theory, suggests that “EBV is a trigger of MS, possibly when the immune system mistakes a viral protein for a myelin protein and then attacks myelin,” Dr. Levy said. In MS, the immune system attacks the protective myelin sheath and the axons it insulates.
“After that point, the virus is not necessary to maintain the disease state and eradicating the virus likely won’t have much effect since the immune response is already triggered,” he said.
The second theory is that “EBV is a driver of MS where there is an ongoing, lifelong immunological response to EBV that continuously causes damage in the central nervous system [CNS]. In theory, if we could eradicate the virus, the destructive immune response could also resolve. Thus, an EBV antiviral treatment could potentially treat and maybe cure MS,” Dr. Levy explained, noting that “removing the pathogenic antigen may be a more effective strategy than removing the immune response.”
However, “we don’t yet know which hypothesis is correct,” he said. But “there is preliminary evidence in favor of each one.”
‘Additional Fuses Must Be Ignited’
It’s also unclear why most people infected with EBV do not develop MS. It appears that “additional fuses must be ignited,” for MS to take hold, according to a commentary accompanying the landmark 2022 study.
“As far as clinical implications, knowing whether a patient has a medical or family history of mononucleosis may be a small clue, a small piece of evidence, to help with diagnosis,” Dr. Bebo said.
He agreed with Dr. Levy that an antiviral could be a promising approach “If the problem in MS is a dysfunctional immune response to EBV.”
Natalia Drosu, MD, PhD, a postdoctoral fellow at Harvard-MIT Biomedical Engineering Center, said that a clinical trial of a non-immunosuppressive antiviral targeting EBV in patients with MS would be a crucial step toward better understanding the MS-EBV connection. “If we learn that antivirals are effective in MS, we should develop non-immunosuppressive therapies for patients with MS as soon as possible,” she said.
Stanford University’s Lawrence Steinman, MD, professor of neurology and neurological sciences, pediatrics, and genetics, who coauthored the commentary on the original Science paper, agreed that it’s worth investigating whether antiviral therapies targeting EBV will benefit patients who already have MS. But he cautioned against clinicians experimenting on their own outside of a research study. “You’d want to use the right antiviral and a properly designed trial,” he said.
Antivirals May Place a Crucial Role in MS Control
While there are no approved therapies for EBV, several MS disease-modifying therapies have anti-EBV effects, Dr. Levy said, citing anti-CD20 therapy as a clear example. It depletes B cells from the circulation, and it depletes EBV because the virus lives in the B-cell compartment. “Some MS treatments may be inadvertent EBV antivirals,” he said.
Researchers are also thinking about how they might exploit the MS-EBV link to prevent MS from developing in the first place, but there are uncertainties on that front too.
Conceivably, there may be some way to intervene in patients to treat EBV and prevent MS, such as a unique treatment for infectious mononucleosis (IM), Dr. Levy said.
Researchers are especially intrigued by signs that the timing of infection may play a role, with people infected with EBV via IM after early childhood at especially a high risk of developing MS. A 2022 German study calculated that people who developed IM were almost twice as likely as those who didn’t to develop MS within 10 years, although the risks in both groups were very small. Subgroup analysis revealed the strongest association between IM and MS was in the group infected between age 14 and 20 years (hazard ratio, 3.52; 95% CI, 1.00-12.37). They also saw a stronger association in men than in women.
The authors of a 2023 review in Clinical & Translational Immunology wrote that “further understanding of IM may be critical in solving the mystery” of EBV’s role in MS.
Dr. Levy said this line of questioning is important.
However, “remember that while most of the world gets EBV infections, only 1 in 1000 will get MS. So, it might not be feasible to test everyone before neurological manifestations occur,” he said.
More Questions to Answer About EBV and MS
Researchers hope to answer several questions moving forward. For one, why is EBV uniquely connected to MS? “You would think that if there were cross-reactivity to myelin, there are many viruses that could cause MS. But the association seems to be very restricted to EBV,” Dr. Levy said. “It is probably due to the fact that EBV is one of the only human viruses that can infect B cells, which play important roles in controlling immune responses.”
The molecular mimicry theory also opens up a potential treatment pathway.
A 2022 study reported “high-affinity molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and the central nervous system protein glial cell adhesion molecule (GlialCAM)”. Antibodies against EBNA1 and GlialCAM are prevalent in patients with MS. In a mouse model of MS, the researchers showed that EBNA1 immunization exacerbates disease. The authors wrote that “Our results provide a mechanistic link for the association between MS and EBV and could guide the development of new MS therapies.”
Could an EBV Vaccine Be the Answer?
On the prevention front, perhaps the most obvious question is whether an EBV vaccine could eliminate MS for good?
Dr. Bebo, from the National MS Society, said it will be important to determine which kind of vaccine is best. Is it one that neutralizes infection with EBV? Or is it enough to simply prevent clinical manifestations?
Both types of vaccines are in development, and at least two clinical trials are now in the works. The National Institute of Allergy and Infectious Diseases is sponsoring a phase 1 study of an adjuvanted EBV gp350-Ferritin nanoparticle vaccine. Forty subjects aged 18-29 years will take part: 20 with EBV and 20 who are not infected. The study is expected to end in 2025.
There is also a phase 1 placebo-controlled study in progress testing an EBV vaccine based on mRNA-1189 in 422 subjects aged 12-30 years. This trial is also due to end in 2025.
“This is very exciting, but it may take a decade or two to determine whether a vaccine is effective at preventing MS,” Dr. Levy said.
Dr. Levy, Dr. Steinman, Dr. Drosu, and Dr. Bebo had no disclosures.
A version of this article appeared on Medscape.com.
When Does a Disease Become Its Own Specialty?
Once upon a time, treating multiple sclerosis (MS) was easy — steroids.
Then, in the 1990s, came Betaseron, then Avonex, then Copaxone. Suddenly we had three options to choose from, though overall roughly similar in efficacy (yeah, I’m leaving Novantrone out; it’s a niche drug). Treatment required some decision making, though not a huge amount. I usually laid out the different schedules and side effect to patients and let them decide.
MS treatment was uncomplicated enough that I knew family doctors who treated MS patients on their own, and I can’t say I could have done any better. If you’ve got a clear MRI, then prescribe Betaseron and hope.
Then came Rebif, then Tysabri, and then pretty much an explosion of new drugs which hasn’t slowed down. Next up are the BTK agents. An embarrassment of riches, though for patients, their families, and neurologists, a very welcome one.
But as more drugs come out, with different mechanisms of action and monitoring requirements, the treatment of MS becomes more complicated, slowly moving from the realm of a general neurologist to an MS subspecialist.
At some point it raises the question of when does a disease become its own specialty? Perhaps this is a bit of hyperbole — I’m pretty sure I’ll be seeing MS patients for a long time to come — but it’s a valid point. Especially as further research may subdivide MS treatment by genetics and other breakdowns.
Alzheimer’s disease may follow a similar (albeit very welcome) trajectory. While nothing really game-changing has come out in the 20 years, the number of new drugs and different mechanisms of action in development is large. Granted, not all of them will work, but hopefully some will. At some point it may come down to treating patients with a cocktail of drugs with separate ways of managing the disease, with guidance based on genetic or clinical profiles.
And that’s a good thing, but it may, again, move the disease from the province of general neurologists to subspecialists. Maybe that would be a good, maybe not. Probably will depend on the patient, their families, and other factors.
Of course, I may be overthinking this. The number of drugs we have for MS is nothing compared with the available treatments we have for hypertension, yet it’s certainly well within the capabilities of most internists to treat without referring to a cardiologist or nephrologist.
Perhaps the new drugs won’t make a difference except in a handful of cases. As new drugs come out we also move on from the old ones, dropping them from our mental armamentarium except in rare cases. When was the last time you prescribed Betaseron?
These drugs are very welcome, and very needed. I will be happy if we can beat back some of the diseases neurologist see, regardless of whom the patients and up seeing.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Once upon a time, treating multiple sclerosis (MS) was easy — steroids.
Then, in the 1990s, came Betaseron, then Avonex, then Copaxone. Suddenly we had three options to choose from, though overall roughly similar in efficacy (yeah, I’m leaving Novantrone out; it’s a niche drug). Treatment required some decision making, though not a huge amount. I usually laid out the different schedules and side effect to patients and let them decide.
MS treatment was uncomplicated enough that I knew family doctors who treated MS patients on their own, and I can’t say I could have done any better. If you’ve got a clear MRI, then prescribe Betaseron and hope.
Then came Rebif, then Tysabri, and then pretty much an explosion of new drugs which hasn’t slowed down. Next up are the BTK agents. An embarrassment of riches, though for patients, their families, and neurologists, a very welcome one.
But as more drugs come out, with different mechanisms of action and monitoring requirements, the treatment of MS becomes more complicated, slowly moving from the realm of a general neurologist to an MS subspecialist.
At some point it raises the question of when does a disease become its own specialty? Perhaps this is a bit of hyperbole — I’m pretty sure I’ll be seeing MS patients for a long time to come — but it’s a valid point. Especially as further research may subdivide MS treatment by genetics and other breakdowns.
Alzheimer’s disease may follow a similar (albeit very welcome) trajectory. While nothing really game-changing has come out in the 20 years, the number of new drugs and different mechanisms of action in development is large. Granted, not all of them will work, but hopefully some will. At some point it may come down to treating patients with a cocktail of drugs with separate ways of managing the disease, with guidance based on genetic or clinical profiles.
And that’s a good thing, but it may, again, move the disease from the province of general neurologists to subspecialists. Maybe that would be a good, maybe not. Probably will depend on the patient, their families, and other factors.
Of course, I may be overthinking this. The number of drugs we have for MS is nothing compared with the available treatments we have for hypertension, yet it’s certainly well within the capabilities of most internists to treat without referring to a cardiologist or nephrologist.
Perhaps the new drugs won’t make a difference except in a handful of cases. As new drugs come out we also move on from the old ones, dropping them from our mental armamentarium except in rare cases. When was the last time you prescribed Betaseron?
These drugs are very welcome, and very needed. I will be happy if we can beat back some of the diseases neurologist see, regardless of whom the patients and up seeing.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Once upon a time, treating multiple sclerosis (MS) was easy — steroids.
Then, in the 1990s, came Betaseron, then Avonex, then Copaxone. Suddenly we had three options to choose from, though overall roughly similar in efficacy (yeah, I’m leaving Novantrone out; it’s a niche drug). Treatment required some decision making, though not a huge amount. I usually laid out the different schedules and side effect to patients and let them decide.
MS treatment was uncomplicated enough that I knew family doctors who treated MS patients on their own, and I can’t say I could have done any better. If you’ve got a clear MRI, then prescribe Betaseron and hope.
Then came Rebif, then Tysabri, and then pretty much an explosion of new drugs which hasn’t slowed down. Next up are the BTK agents. An embarrassment of riches, though for patients, their families, and neurologists, a very welcome one.
But as more drugs come out, with different mechanisms of action and monitoring requirements, the treatment of MS becomes more complicated, slowly moving from the realm of a general neurologist to an MS subspecialist.
At some point it raises the question of when does a disease become its own specialty? Perhaps this is a bit of hyperbole — I’m pretty sure I’ll be seeing MS patients for a long time to come — but it’s a valid point. Especially as further research may subdivide MS treatment by genetics and other breakdowns.
Alzheimer’s disease may follow a similar (albeit very welcome) trajectory. While nothing really game-changing has come out in the 20 years, the number of new drugs and different mechanisms of action in development is large. Granted, not all of them will work, but hopefully some will. At some point it may come down to treating patients with a cocktail of drugs with separate ways of managing the disease, with guidance based on genetic or clinical profiles.
And that’s a good thing, but it may, again, move the disease from the province of general neurologists to subspecialists. Maybe that would be a good, maybe not. Probably will depend on the patient, their families, and other factors.
Of course, I may be overthinking this. The number of drugs we have for MS is nothing compared with the available treatments we have for hypertension, yet it’s certainly well within the capabilities of most internists to treat without referring to a cardiologist or nephrologist.
Perhaps the new drugs won’t make a difference except in a handful of cases. As new drugs come out we also move on from the old ones, dropping them from our mental armamentarium except in rare cases. When was the last time you prescribed Betaseron?
These drugs are very welcome, and very needed. I will be happy if we can beat back some of the diseases neurologist see, regardless of whom the patients and up seeing.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Autoimmunity’s Female Bias and the Mysteries of Xist
Female bias in autoimmune disease can be profound, with nine females developing lupus for every male affected, and nearly twice that ratio seen in Sjögren disease.
For years, researchers have worked to determine the reasons for sex-linked differences in immune response and autoimmunity, with environmental factors, sex hormones, and X-chromosome inactivation — the process by which a second X chromosome is silenced — all seen as having roles.
More recently, different groups of researchers have homed in on a long noncoding RNA fragment called X-inactive specific transcript, or Xist, as a potential driver of sex bias in autoimmune disease. Xist, which occurs in female mammals, has been known since the 1990s as the master regulator of X-chromosome inactivation, the process by which the second X chromosome is silenced, averting a fatal double dose of X-linked genes.
The inactivation process, which scientists liken to wrapping the extra X with a fluffy cloud of proteins, occurs early in embryonic development. After its initial work silencing the X, Xist is produced throughout the female’s life, allowing X inactivation to be maintained.
But is it possible that Xist, and the many dozens of proteins it recruits to keep that extra X chromosome silent, can also provoke autoimmunity? This is the question that several teams of researchers have been grappling with, resulting in provocative findings and opening exciting new avenues of discovery.
Xist Protein Complexes Make Male Mice Vulnerable to Lupus
In February, researchers Howard Chang, MD, PhD, and Diana Dou, PhD, of Stanford University in Stanford, California, made worldwide news when they published results from an experiment using male mice genetically engineered to carry a non-silencing form of Xist on one of their chromosomes.
Xist acts like a scaffold, recruiting multiple protein complexes to help it do its job. Dr. Dou explained in an interview that her team has been eyeing suspiciously for years the dozens of proteins Xist recruits in the process of X-chromosome inactivation, many of which are known autoantigens.
When the mice were injected with pristane, a chemical that induces lupus-like autoimmunity in mice, the Xist-producing males developed symptoms at a rate similar to that of females, while wild-type male mice did not.
By using a male model, the scientists could determine whether Xist could cause an increased vulnerability for autoimmunity absent the influence of female hormones and development. “Everything else about the animal is male,” Dr. Dou commented. “You just add the formation of the Xist ribonucleoprotein particles — Xist RNA plus the associating proteins — to male cells that would not ordinarily have these particles. Is just having the particles present in these animals sufficient to increase their autoimmunity? This is what our paper showed: That just having expression of Xist, the presence of these Xist [ribonucleoproteins], is enough in permissive genetic backgrounds to invoke higher incidence and severity of autoimmune disease development in our pristane-induced lupus model.”
The Stanford group sees the Xist protein complex, which they have studied extensively, as a key to understanding how Xist might provoke autoimmunity. Nonetheless, Dr. Dou said, “It’s important to note that there are other contributing factors, which is why not all females develop autoimmunity, and we had very different results in our autoimmune-resistant mouse strain compared to the more autoimmune-prone strain. Xist is a factor, but many factors are required to subvert the checkpoints in immune balance and allow the progression to full-blown autoimmunity.”
Faulty X Inactivation and Gene Escape
The understanding that Xist might be implicated in autoimmune disease — and explain some of its female bias — is not new.
About a decade ago, Montserrat Anguera, PhD, a biologist at the University of Pennsylvania, Philadelphia, began looking at the relationship of X-chromosome inactivation, which by definition involves Xist, and lupus.
Dr. Anguera hypothesized that imperfect X inactivation allowed for greater escape of genes associated with immunity and autoimmunity. Studying patients with lupus, Dr. Anguera found that the silencing process was abnormal, allowing more of these genes to escape the silenced X — including toll-like receptor 7 (TLR-7) and other genes implicated in the pathogenesis of lupus.
“If you get increased expression of certain genes from the [silenced] X, like TLR-7, it can result in autoimmune disease,” Dr. Anguera said. “So what we think is that in the lupus patients, because the silencing is impacted, you’re going to have more expression happening from the inactive X. And then in conjunction with the active X, that’s going to throw off the dosage [of autoimmunity-linked genes]. You’re changing the dosage of genes, and that’s what’s critical.”
Even among patients with lupus whose symptoms are well controlled with medication, “if you look at their T cells and B cells, they still have messed up X inactivation,” Dr. Anguera said. “The Xist RNA that’s supposed to be tethered to the inactive X in a fluffy cloud is not localized, and instead is dispersed all over the nucleus.”
Dr. Anguera pointed out that autoimmune diseases are complex and can result from a combination of factors. “You also have a host of hormonal and environmental contributors, such as previous viral infections,” she said. And of course men can also develop lupus, meaning that the X chromosome cannot explain everything.
Dr. Anguera said that, while the findings by the Stanford scientists do not explain the full pathogenesis of lupus and related diseases, they still support a strong role for Xist in sex-biased autoimmune diseases. “It’s sort of another take on it,” she said.
Is It the Proteins, the RNA, or Both?
The Stanford team points to the proteins recruited by Xist in the process of X-chromosome inactivation as the likely trigger of autoimmunity. However, a group of researchers at Johns Hopkins University in Baltimore, Maryland, made the case in a 2022 paper that Xist RNA itself was dangerous. They found that numerous short RNA sequences within the Xist molecule serve as ligands for TLR-7. And TLR-7 ligation causes plasmacytoid dendritic cells to overproduce type 1 interferon, a classic hallmark of lupus.
“Within rheumatology, the diseases that tend to be most female biased are the ones that are antibody positive and have this presence of upregulated interferon,” explained Brendan Antiochos, MD. “Lupus is an example of that. Sjögren’s syndrome is another. So there’s always been this quest to want to understand the mechanisms that explain why women would have more autoimmunity. And are there specific pathways which could contribute? One of the key pathways that’s been shown in humans and in mice to be important in lupus is toll-like receptor signaling.” Most convincingly, one recent study showed that people who have a gain-of-function mutation in their TLR-7 gene get a spontaneous form of lupus.
These findings led Erika Darrah, PhD, and her colleague Dr. Antiochos to begin looking more deeply into which RNAs could be triggering this signaling pathway. “We started to think: Well, there is this sex bias. Could it be that women have unique RNAs that could potentially act as triggers for TLR-7 signaling?” Dr. Darrah said.
Dr. Darrah and Dr. Antiochos looked at publicly available genetic data to identify sex-biased sources of self-RNA containing TLR-7 ligands. Xist, they found, was chock full of them. “Every time we analyzed that data, no matter what filter we applied, Xist kept popping out over and over again as the most highly female skewed RNA, the RNA most likely to contain these TLR-7 binding motifs,” Dr. Darrah said. “We started to formulate the hypothesis that Xist was actually promoting responses that were dangerous and pathogenic in lupus.”
That finding led the team to conduct in-vitro experiments that showed different fragments of Xist can activate TLR-7, resulting in higher interferon production. Finally, they looked at blood and kidney cells from women with lupus and found that higher Xist expression correlated with more interferon production, and higher disease activity. “The more Xist, the sicker people were,” Dr. Darrah said.
Xist’s Other Functions
Xist was first studied in the 1990s, and most research has centered on its primary role in X-chromosome inactivation. A research group led by Kathrin Plath, PhD, at the University of California, Los Angeles, has been occupied for years with untangling exactly how Xist does what it does. “It’s a very clever RNA, right? It can silence the whole chromosome,” Dr. Plath said in an interview.
In 2021, Dr. Plath and her colleagues established in detail how Xist executes silencing, setting down pairs of molecules in specific spots along the chromosome and building huge protein clouds around them. “We worked on learning where Xist binds and what proteins it binds, drilling down to understand how these proteins and the RNA are coming together.”
Dr. Plath has long suspected that Xist has other functions besides X inactivation, and she and her colleagues are starting to identify them. Early this year they published the surprising finding that Xist can regulate gene expression in autosomes, or non–sex-linked chromosomes, “which it might well also do in cancer cells and lymphocytes,” Dr. Plath said. “And now there is this new evidence of an autoimmune function,” she said. “It’s a super exciting time.”
The different hypotheses surrounding Xist’s role in sex-biased autoimmunity aren’t mutually exclusive, Dr. Plath said. “There’s a tremendous enrichment of proteins occurring” during X inactivation, she said, supporting the Stanford team’s hypothesis that proteins are triggering autoimmunity. As for the Johns Hopkins researchers’ understanding that Xist RNA itself is the trigger, “I’m totally open to that,” she said. “Why can’t it be an autoantigen?”
The other model in the field, Dr. Plath noted, is the one proposed by Dr. Anguera — “that there’s [gene] escape from X-inactivation — that females have more escape expression, and that Xist is more dispersed in the lymphocytes [of patients with lupus]. In fact, Xist becoming a little dispersed might make it a better antigen. So I do think everything is possible.”
The plethora of new findings related to autoimmunity has caused Dr. Plath to consider redirecting her lab’s focus toward more translational work, “because we are obviously good at studying Xist.” Among the mysteries Dr. Plath would like to solve is how some genes manage to escape the Xist cloud.
What is needed, she said, is collaboration. “Everyone will come up with different ideas. So I think it’s good to have more people look at things together. Then the field will achieve a breakthrough treatment.”
Female bias in autoimmune disease can be profound, with nine females developing lupus for every male affected, and nearly twice that ratio seen in Sjögren disease.
For years, researchers have worked to determine the reasons for sex-linked differences in immune response and autoimmunity, with environmental factors, sex hormones, and X-chromosome inactivation — the process by which a second X chromosome is silenced — all seen as having roles.
More recently, different groups of researchers have homed in on a long noncoding RNA fragment called X-inactive specific transcript, or Xist, as a potential driver of sex bias in autoimmune disease. Xist, which occurs in female mammals, has been known since the 1990s as the master regulator of X-chromosome inactivation, the process by which the second X chromosome is silenced, averting a fatal double dose of X-linked genes.
The inactivation process, which scientists liken to wrapping the extra X with a fluffy cloud of proteins, occurs early in embryonic development. After its initial work silencing the X, Xist is produced throughout the female’s life, allowing X inactivation to be maintained.
But is it possible that Xist, and the many dozens of proteins it recruits to keep that extra X chromosome silent, can also provoke autoimmunity? This is the question that several teams of researchers have been grappling with, resulting in provocative findings and opening exciting new avenues of discovery.
Xist Protein Complexes Make Male Mice Vulnerable to Lupus
In February, researchers Howard Chang, MD, PhD, and Diana Dou, PhD, of Stanford University in Stanford, California, made worldwide news when they published results from an experiment using male mice genetically engineered to carry a non-silencing form of Xist on one of their chromosomes.
Xist acts like a scaffold, recruiting multiple protein complexes to help it do its job. Dr. Dou explained in an interview that her team has been eyeing suspiciously for years the dozens of proteins Xist recruits in the process of X-chromosome inactivation, many of which are known autoantigens.
When the mice were injected with pristane, a chemical that induces lupus-like autoimmunity in mice, the Xist-producing males developed symptoms at a rate similar to that of females, while wild-type male mice did not.
By using a male model, the scientists could determine whether Xist could cause an increased vulnerability for autoimmunity absent the influence of female hormones and development. “Everything else about the animal is male,” Dr. Dou commented. “You just add the formation of the Xist ribonucleoprotein particles — Xist RNA plus the associating proteins — to male cells that would not ordinarily have these particles. Is just having the particles present in these animals sufficient to increase their autoimmunity? This is what our paper showed: That just having expression of Xist, the presence of these Xist [ribonucleoproteins], is enough in permissive genetic backgrounds to invoke higher incidence and severity of autoimmune disease development in our pristane-induced lupus model.”
The Stanford group sees the Xist protein complex, which they have studied extensively, as a key to understanding how Xist might provoke autoimmunity. Nonetheless, Dr. Dou said, “It’s important to note that there are other contributing factors, which is why not all females develop autoimmunity, and we had very different results in our autoimmune-resistant mouse strain compared to the more autoimmune-prone strain. Xist is a factor, but many factors are required to subvert the checkpoints in immune balance and allow the progression to full-blown autoimmunity.”
Faulty X Inactivation and Gene Escape
The understanding that Xist might be implicated in autoimmune disease — and explain some of its female bias — is not new.
About a decade ago, Montserrat Anguera, PhD, a biologist at the University of Pennsylvania, Philadelphia, began looking at the relationship of X-chromosome inactivation, which by definition involves Xist, and lupus.
Dr. Anguera hypothesized that imperfect X inactivation allowed for greater escape of genes associated with immunity and autoimmunity. Studying patients with lupus, Dr. Anguera found that the silencing process was abnormal, allowing more of these genes to escape the silenced X — including toll-like receptor 7 (TLR-7) and other genes implicated in the pathogenesis of lupus.
“If you get increased expression of certain genes from the [silenced] X, like TLR-7, it can result in autoimmune disease,” Dr. Anguera said. “So what we think is that in the lupus patients, because the silencing is impacted, you’re going to have more expression happening from the inactive X. And then in conjunction with the active X, that’s going to throw off the dosage [of autoimmunity-linked genes]. You’re changing the dosage of genes, and that’s what’s critical.”
Even among patients with lupus whose symptoms are well controlled with medication, “if you look at their T cells and B cells, they still have messed up X inactivation,” Dr. Anguera said. “The Xist RNA that’s supposed to be tethered to the inactive X in a fluffy cloud is not localized, and instead is dispersed all over the nucleus.”
Dr. Anguera pointed out that autoimmune diseases are complex and can result from a combination of factors. “You also have a host of hormonal and environmental contributors, such as previous viral infections,” she said. And of course men can also develop lupus, meaning that the X chromosome cannot explain everything.
Dr. Anguera said that, while the findings by the Stanford scientists do not explain the full pathogenesis of lupus and related diseases, they still support a strong role for Xist in sex-biased autoimmune diseases. “It’s sort of another take on it,” she said.
Is It the Proteins, the RNA, or Both?
The Stanford team points to the proteins recruited by Xist in the process of X-chromosome inactivation as the likely trigger of autoimmunity. However, a group of researchers at Johns Hopkins University in Baltimore, Maryland, made the case in a 2022 paper that Xist RNA itself was dangerous. They found that numerous short RNA sequences within the Xist molecule serve as ligands for TLR-7. And TLR-7 ligation causes plasmacytoid dendritic cells to overproduce type 1 interferon, a classic hallmark of lupus.
“Within rheumatology, the diseases that tend to be most female biased are the ones that are antibody positive and have this presence of upregulated interferon,” explained Brendan Antiochos, MD. “Lupus is an example of that. Sjögren’s syndrome is another. So there’s always been this quest to want to understand the mechanisms that explain why women would have more autoimmunity. And are there specific pathways which could contribute? One of the key pathways that’s been shown in humans and in mice to be important in lupus is toll-like receptor signaling.” Most convincingly, one recent study showed that people who have a gain-of-function mutation in their TLR-7 gene get a spontaneous form of lupus.
These findings led Erika Darrah, PhD, and her colleague Dr. Antiochos to begin looking more deeply into which RNAs could be triggering this signaling pathway. “We started to think: Well, there is this sex bias. Could it be that women have unique RNAs that could potentially act as triggers for TLR-7 signaling?” Dr. Darrah said.
Dr. Darrah and Dr. Antiochos looked at publicly available genetic data to identify sex-biased sources of self-RNA containing TLR-7 ligands. Xist, they found, was chock full of them. “Every time we analyzed that data, no matter what filter we applied, Xist kept popping out over and over again as the most highly female skewed RNA, the RNA most likely to contain these TLR-7 binding motifs,” Dr. Darrah said. “We started to formulate the hypothesis that Xist was actually promoting responses that were dangerous and pathogenic in lupus.”
That finding led the team to conduct in-vitro experiments that showed different fragments of Xist can activate TLR-7, resulting in higher interferon production. Finally, they looked at blood and kidney cells from women with lupus and found that higher Xist expression correlated with more interferon production, and higher disease activity. “The more Xist, the sicker people were,” Dr. Darrah said.
Xist’s Other Functions
Xist was first studied in the 1990s, and most research has centered on its primary role in X-chromosome inactivation. A research group led by Kathrin Plath, PhD, at the University of California, Los Angeles, has been occupied for years with untangling exactly how Xist does what it does. “It’s a very clever RNA, right? It can silence the whole chromosome,” Dr. Plath said in an interview.
In 2021, Dr. Plath and her colleagues established in detail how Xist executes silencing, setting down pairs of molecules in specific spots along the chromosome and building huge protein clouds around them. “We worked on learning where Xist binds and what proteins it binds, drilling down to understand how these proteins and the RNA are coming together.”
Dr. Plath has long suspected that Xist has other functions besides X inactivation, and she and her colleagues are starting to identify them. Early this year they published the surprising finding that Xist can regulate gene expression in autosomes, or non–sex-linked chromosomes, “which it might well also do in cancer cells and lymphocytes,” Dr. Plath said. “And now there is this new evidence of an autoimmune function,” she said. “It’s a super exciting time.”
The different hypotheses surrounding Xist’s role in sex-biased autoimmunity aren’t mutually exclusive, Dr. Plath said. “There’s a tremendous enrichment of proteins occurring” during X inactivation, she said, supporting the Stanford team’s hypothesis that proteins are triggering autoimmunity. As for the Johns Hopkins researchers’ understanding that Xist RNA itself is the trigger, “I’m totally open to that,” she said. “Why can’t it be an autoantigen?”
The other model in the field, Dr. Plath noted, is the one proposed by Dr. Anguera — “that there’s [gene] escape from X-inactivation — that females have more escape expression, and that Xist is more dispersed in the lymphocytes [of patients with lupus]. In fact, Xist becoming a little dispersed might make it a better antigen. So I do think everything is possible.”
The plethora of new findings related to autoimmunity has caused Dr. Plath to consider redirecting her lab’s focus toward more translational work, “because we are obviously good at studying Xist.” Among the mysteries Dr. Plath would like to solve is how some genes manage to escape the Xist cloud.
What is needed, she said, is collaboration. “Everyone will come up with different ideas. So I think it’s good to have more people look at things together. Then the field will achieve a breakthrough treatment.”
Female bias in autoimmune disease can be profound, with nine females developing lupus for every male affected, and nearly twice that ratio seen in Sjögren disease.
For years, researchers have worked to determine the reasons for sex-linked differences in immune response and autoimmunity, with environmental factors, sex hormones, and X-chromosome inactivation — the process by which a second X chromosome is silenced — all seen as having roles.
More recently, different groups of researchers have homed in on a long noncoding RNA fragment called X-inactive specific transcript, or Xist, as a potential driver of sex bias in autoimmune disease. Xist, which occurs in female mammals, has been known since the 1990s as the master regulator of X-chromosome inactivation, the process by which the second X chromosome is silenced, averting a fatal double dose of X-linked genes.
The inactivation process, which scientists liken to wrapping the extra X with a fluffy cloud of proteins, occurs early in embryonic development. After its initial work silencing the X, Xist is produced throughout the female’s life, allowing X inactivation to be maintained.
But is it possible that Xist, and the many dozens of proteins it recruits to keep that extra X chromosome silent, can also provoke autoimmunity? This is the question that several teams of researchers have been grappling with, resulting in provocative findings and opening exciting new avenues of discovery.
Xist Protein Complexes Make Male Mice Vulnerable to Lupus
In February, researchers Howard Chang, MD, PhD, and Diana Dou, PhD, of Stanford University in Stanford, California, made worldwide news when they published results from an experiment using male mice genetically engineered to carry a non-silencing form of Xist on one of their chromosomes.
Xist acts like a scaffold, recruiting multiple protein complexes to help it do its job. Dr. Dou explained in an interview that her team has been eyeing suspiciously for years the dozens of proteins Xist recruits in the process of X-chromosome inactivation, many of which are known autoantigens.
When the mice were injected with pristane, a chemical that induces lupus-like autoimmunity in mice, the Xist-producing males developed symptoms at a rate similar to that of females, while wild-type male mice did not.
By using a male model, the scientists could determine whether Xist could cause an increased vulnerability for autoimmunity absent the influence of female hormones and development. “Everything else about the animal is male,” Dr. Dou commented. “You just add the formation of the Xist ribonucleoprotein particles — Xist RNA plus the associating proteins — to male cells that would not ordinarily have these particles. Is just having the particles present in these animals sufficient to increase their autoimmunity? This is what our paper showed: That just having expression of Xist, the presence of these Xist [ribonucleoproteins], is enough in permissive genetic backgrounds to invoke higher incidence and severity of autoimmune disease development in our pristane-induced lupus model.”
The Stanford group sees the Xist protein complex, which they have studied extensively, as a key to understanding how Xist might provoke autoimmunity. Nonetheless, Dr. Dou said, “It’s important to note that there are other contributing factors, which is why not all females develop autoimmunity, and we had very different results in our autoimmune-resistant mouse strain compared to the more autoimmune-prone strain. Xist is a factor, but many factors are required to subvert the checkpoints in immune balance and allow the progression to full-blown autoimmunity.”
Faulty X Inactivation and Gene Escape
The understanding that Xist might be implicated in autoimmune disease — and explain some of its female bias — is not new.
About a decade ago, Montserrat Anguera, PhD, a biologist at the University of Pennsylvania, Philadelphia, began looking at the relationship of X-chromosome inactivation, which by definition involves Xist, and lupus.
Dr. Anguera hypothesized that imperfect X inactivation allowed for greater escape of genes associated with immunity and autoimmunity. Studying patients with lupus, Dr. Anguera found that the silencing process was abnormal, allowing more of these genes to escape the silenced X — including toll-like receptor 7 (TLR-7) and other genes implicated in the pathogenesis of lupus.
“If you get increased expression of certain genes from the [silenced] X, like TLR-7, it can result in autoimmune disease,” Dr. Anguera said. “So what we think is that in the lupus patients, because the silencing is impacted, you’re going to have more expression happening from the inactive X. And then in conjunction with the active X, that’s going to throw off the dosage [of autoimmunity-linked genes]. You’re changing the dosage of genes, and that’s what’s critical.”
Even among patients with lupus whose symptoms are well controlled with medication, “if you look at their T cells and B cells, they still have messed up X inactivation,” Dr. Anguera said. “The Xist RNA that’s supposed to be tethered to the inactive X in a fluffy cloud is not localized, and instead is dispersed all over the nucleus.”
Dr. Anguera pointed out that autoimmune diseases are complex and can result from a combination of factors. “You also have a host of hormonal and environmental contributors, such as previous viral infections,” she said. And of course men can also develop lupus, meaning that the X chromosome cannot explain everything.
Dr. Anguera said that, while the findings by the Stanford scientists do not explain the full pathogenesis of lupus and related diseases, they still support a strong role for Xist in sex-biased autoimmune diseases. “It’s sort of another take on it,” she said.
Is It the Proteins, the RNA, or Both?
The Stanford team points to the proteins recruited by Xist in the process of X-chromosome inactivation as the likely trigger of autoimmunity. However, a group of researchers at Johns Hopkins University in Baltimore, Maryland, made the case in a 2022 paper that Xist RNA itself was dangerous. They found that numerous short RNA sequences within the Xist molecule serve as ligands for TLR-7. And TLR-7 ligation causes plasmacytoid dendritic cells to overproduce type 1 interferon, a classic hallmark of lupus.
“Within rheumatology, the diseases that tend to be most female biased are the ones that are antibody positive and have this presence of upregulated interferon,” explained Brendan Antiochos, MD. “Lupus is an example of that. Sjögren’s syndrome is another. So there’s always been this quest to want to understand the mechanisms that explain why women would have more autoimmunity. And are there specific pathways which could contribute? One of the key pathways that’s been shown in humans and in mice to be important in lupus is toll-like receptor signaling.” Most convincingly, one recent study showed that people who have a gain-of-function mutation in their TLR-7 gene get a spontaneous form of lupus.
These findings led Erika Darrah, PhD, and her colleague Dr. Antiochos to begin looking more deeply into which RNAs could be triggering this signaling pathway. “We started to think: Well, there is this sex bias. Could it be that women have unique RNAs that could potentially act as triggers for TLR-7 signaling?” Dr. Darrah said.
Dr. Darrah and Dr. Antiochos looked at publicly available genetic data to identify sex-biased sources of self-RNA containing TLR-7 ligands. Xist, they found, was chock full of them. “Every time we analyzed that data, no matter what filter we applied, Xist kept popping out over and over again as the most highly female skewed RNA, the RNA most likely to contain these TLR-7 binding motifs,” Dr. Darrah said. “We started to formulate the hypothesis that Xist was actually promoting responses that were dangerous and pathogenic in lupus.”
That finding led the team to conduct in-vitro experiments that showed different fragments of Xist can activate TLR-7, resulting in higher interferon production. Finally, they looked at blood and kidney cells from women with lupus and found that higher Xist expression correlated with more interferon production, and higher disease activity. “The more Xist, the sicker people were,” Dr. Darrah said.
Xist’s Other Functions
Xist was first studied in the 1990s, and most research has centered on its primary role in X-chromosome inactivation. A research group led by Kathrin Plath, PhD, at the University of California, Los Angeles, has been occupied for years with untangling exactly how Xist does what it does. “It’s a very clever RNA, right? It can silence the whole chromosome,” Dr. Plath said in an interview.
In 2021, Dr. Plath and her colleagues established in detail how Xist executes silencing, setting down pairs of molecules in specific spots along the chromosome and building huge protein clouds around them. “We worked on learning where Xist binds and what proteins it binds, drilling down to understand how these proteins and the RNA are coming together.”
Dr. Plath has long suspected that Xist has other functions besides X inactivation, and she and her colleagues are starting to identify them. Early this year they published the surprising finding that Xist can regulate gene expression in autosomes, or non–sex-linked chromosomes, “which it might well also do in cancer cells and lymphocytes,” Dr. Plath said. “And now there is this new evidence of an autoimmune function,” she said. “It’s a super exciting time.”
The different hypotheses surrounding Xist’s role in sex-biased autoimmunity aren’t mutually exclusive, Dr. Plath said. “There’s a tremendous enrichment of proteins occurring” during X inactivation, she said, supporting the Stanford team’s hypothesis that proteins are triggering autoimmunity. As for the Johns Hopkins researchers’ understanding that Xist RNA itself is the trigger, “I’m totally open to that,” she said. “Why can’t it be an autoantigen?”
The other model in the field, Dr. Plath noted, is the one proposed by Dr. Anguera — “that there’s [gene] escape from X-inactivation — that females have more escape expression, and that Xist is more dispersed in the lymphocytes [of patients with lupus]. In fact, Xist becoming a little dispersed might make it a better antigen. So I do think everything is possible.”
The plethora of new findings related to autoimmunity has caused Dr. Plath to consider redirecting her lab’s focus toward more translational work, “because we are obviously good at studying Xist.” Among the mysteries Dr. Plath would like to solve is how some genes manage to escape the Xist cloud.
What is needed, she said, is collaboration. “Everyone will come up with different ideas. So I think it’s good to have more people look at things together. Then the field will achieve a breakthrough treatment.”
Improved Communication Center Stage in Multiple Sclerosis
This transcript has been edited for clarity.
Joseph R. Berger, MD: Hi. I'm Dr Joseph Berger, and I'm joined for this Care Cues conversation with my patient, Michelle Biloon, who has had multiple sclerosis (MS) for the past 6 years. Hello, Michelle. Welcome.
Michelle Biloon: Thank you, Dr Berger.
Berger: Can you tell us a little bit about yourself, how you came to understand you had MS, and how you've done since the diagnosis was rendered?
Biloon: Yeah. It was a very short diagnosis period for me. In the winter of 2017, I started experiencing dizzy spells, and I didn't really know why. I eventually went to my primary care clinic where my doctor is, and they did blood work. Then, they did a CT and didn't see anything, and I just kind of kept feeling worse.
Then, finally, I went to an ENT just to see if it was maybe related to my ears. The ENT actually said, "You need to go to the ER and get an MRI." And while I was in the MRI, I could feel the dizzy spells. And I thought, Well, something is happening. I don't know what it is. And then a resident came in and said that they saw lesions on my brain, and they knew that it was going to be MS or something like it.
Berger: How did you feel about that?
Biloon: At the time, I was kind of glad to hear it was something. And I just asked her if, like, you die from it. That was the first thing I asked. It was like falling off a cliff.
It was making it hard for me to function in what I was doing, which was stand-up comedy, because of the cognitive issues I was having, the cognitive fog. That was how I ended up with you. Right away, you talked to me and were actually able to introduce to me some new medications that are out and are phenomenally better for MS plus were not pills or shots every day. It's made my MS over the years a lot more manageable.
Berger: I'd like to pick up on a couple of things you said.
Biloon: Sure.
Berger: One is, because most people envision MS as this terrible, crippling illness that's going to leave them wheelchair-bound, deprived of their profession, finding it difficult to stay in a marriage it's vested with what has been termed "lamentable results." And one of the first things that we as physicians have to do is to calm people down and say, "You know what. You have MS. You're going to be just fine. Trust me. We have wonderful medications for what you have, and we'll take care of it." In fact, I've made a habit of telling people quit worrying. You hired me to worry for you.
Biloon: Yep.
Berger: And I think that's helpful.
Biloon: I've been just so appreciative of that. There's a balance of being condescended to — do you know what I mean — and also being given information. I'm very sensitive to that balance because I consider myself an intelligent person. And you're being put in a position where someone knows more than you, and you have to listen.
Berger: One of the other challenges we face is getting somebody on a treatment. And we elected to put you on an intravenous therapy every 6 months.
Biloon: Especially because as a stand-up comedian, I was traveling a lot, doing these every-6-months infusion, especially with the high efficacy rate that it had been reported from what we had read and the low amount of side effects. I mean, just those things together was just something that seemed the easiest for me.
Berger: So did you encounter any challenges when we first got you started on the infusion therapy?
Biloon: The first infusion I got was at the hospital. But then after that, I had to go to the suburbs, to a center out there for the infusion. That was difficult because to get a ride out there and a ride back — it was a long trip for someone to wait with me. Taking an Uber is expensive, so was it for me to drive. You don't feel good for a couple of days after. So that was how it was, and I complained about it. Probably at every appointment we had, I complained about it.
Berger: Yeah. So some of the challenges you talked about are very, very common. As a physician on medications myself, I can tell you that I am not particularly compliant. And what I love about infusion therapies is that I know that the patient is getting their medicine. Because when they don't show up for a scheduled appointment, I'm called, and I know.
Biloon: I do have a bit of an allergic reaction to the drug. But that's been easily managed over time. Now, the drug infusions are actually being done at my home, which makes the whole process twice-a-year–world's better.
Berger: But there are other barriers that people confront other than the initiation of drugs. Had you encountered any?
Biloon: I think the problem that I had more so was finding the drugs that would manage some of my symptoms. It took a couple of years to sort of figure out what that would be, both with figuring them out and both dealing with insurance on certain medications.
Berger: That's one sort of problem that we confront. The other, of course, are those individuals who, for a variety of reasons, have difficulty with the diagnosis because of their backgrounds. And they may be sociocultural in nature. Every time you go to the physical therapist, it's some degree of money.
Now for some people, it's trivial. But for others, it's a considerable amount of money, relative to what it is that they earn. And you simply have to work within those confines as best you can.
We do have various programs that help people. So we try to employ them. There are, in addition to the sociocultural barriers, language barriers that we often confront. We, in our situation here in a large city, have a very large migrant population.
Fortunately, most of the people speak languages that either you speak as well, or there's somebody in the next room that speaks pretty well. But that's not always the case. So we do have an interpreter service that has to be employed.
Biloon: I cannot imagine the nuance in speaking to people from different ages and different backgrounds, who have different types of lifestyles, for them to understand.
Berger: I don't write at a computer. I think that really degrades the patient-physician relationship. What I do is I obtain a history. I do it on a piece of paper with a pen or a pencil.
I recapitulate them to the patient in paraphrasing it, to make sure that I have gotten it right and that they understand what I think I heard. That, I think, has been enormously helpful in helping people understand what may happen in the absence of treatment and why the treatment is important. That you can do, regardless of what the person's background is. So that's how I approach it.
Biloon: How do you deal with patients when they're not on the same page with you?
Berger: One important thing is that you have to be patient. That is something that it took me 50 years in medicine to learn. And then accepting the patient's opinion and saying, "All right, go home and think about it," because you often don't convince them when they're in the office with you.
Biloon: I did have a little bit of a cushion between my diagnosis and when we actually saw each other, where I was able to really sit in my thoughts on the different treatments and stuff. By the time that we were able to talk, it reassured me on that was the right plan.
Berger: I'm curious what your experience has been with our MS center.
Biloon: Through the portal, every time I need something, I'm usually reaching out, keeping you up-to-date on my primary care or whether it's trying to get a refill on one of my medications that I have to reach out. I really do feel that having that team there, being able to reach out, that's been extremely helpful to have and keeps me very secure because that's all I really need, especially during the pandemic, right? Because then I was very isolated and dealing with going through MS. So it was great to at least — and I did — shoot off emails or texts in the portal, and that's usually primarily how I communicated.
Berger: I will tell you, in my opinion, maybe nine out of 10 messages in the portal or calls that we get simply require reassurance.
Biloon: Yes.
Berger: You just either pick up the phone or shoot back a note, say, "This is not your MS. Don't worry about it." I mean, the most important thing for me is to keep people from worrying because that doesn't solve any problem.
Biloon: No, and it causes stress, which causes fatigue. I mean, it's a bad cycle.
Berger: In the past year, you've actually felt better, and you've gone back to performing. It sounds like the volume of performances has gotten back to what it was pre-illness. What do you see for the future?
Biloon: What I see is traveling more for stand-up and doing the sort of clubs and cities that I had kind of stopped doing from before I was diagnosed, so 2017 and prior to that. And then also even working on other things, writing and maybe even doing sort of books or one-person shows that even talk about sort of my struggles with MS and kind of coming back to where I am. I'm looking forward to the future, and I hope that that's the track I can keep going on.
Berger: I see no reason why you shouldn't.
Biloon: Thank you.
Berger: Michelle, thank you very much for joining me today in this conversation.
Biloon: Thank you so much for having me. It's been really wonderful to be able to sit down here with you.
Joseph R. Berger, MD, has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Celgene/Bristol-Myers Squibb; Cellevolve; EMD Serono/Merck/Genentech; Genzyme; Janssen/Johnson & Johnson; Morphic; Novartis; Roche; Sanofi; Takeda; TG Therapeutics; MAPI; Excision Bio
Received research grant from: Genentech/Roche
Michelle Biloon has disclosed no relevant financial relationships
This transcript has been edited for clarity.
Joseph R. Berger, MD: Hi. I'm Dr Joseph Berger, and I'm joined for this Care Cues conversation with my patient, Michelle Biloon, who has had multiple sclerosis (MS) for the past 6 years. Hello, Michelle. Welcome.
Michelle Biloon: Thank you, Dr Berger.
Berger: Can you tell us a little bit about yourself, how you came to understand you had MS, and how you've done since the diagnosis was rendered?
Biloon: Yeah. It was a very short diagnosis period for me. In the winter of 2017, I started experiencing dizzy spells, and I didn't really know why. I eventually went to my primary care clinic where my doctor is, and they did blood work. Then, they did a CT and didn't see anything, and I just kind of kept feeling worse.
Then, finally, I went to an ENT just to see if it was maybe related to my ears. The ENT actually said, "You need to go to the ER and get an MRI." And while I was in the MRI, I could feel the dizzy spells. And I thought, Well, something is happening. I don't know what it is. And then a resident came in and said that they saw lesions on my brain, and they knew that it was going to be MS or something like it.
Berger: How did you feel about that?
Biloon: At the time, I was kind of glad to hear it was something. And I just asked her if, like, you die from it. That was the first thing I asked. It was like falling off a cliff.
It was making it hard for me to function in what I was doing, which was stand-up comedy, because of the cognitive issues I was having, the cognitive fog. That was how I ended up with you. Right away, you talked to me and were actually able to introduce to me some new medications that are out and are phenomenally better for MS plus were not pills or shots every day. It's made my MS over the years a lot more manageable.
Berger: I'd like to pick up on a couple of things you said.
Biloon: Sure.
Berger: One is, because most people envision MS as this terrible, crippling illness that's going to leave them wheelchair-bound, deprived of their profession, finding it difficult to stay in a marriage it's vested with what has been termed "lamentable results." And one of the first things that we as physicians have to do is to calm people down and say, "You know what. You have MS. You're going to be just fine. Trust me. We have wonderful medications for what you have, and we'll take care of it." In fact, I've made a habit of telling people quit worrying. You hired me to worry for you.
Biloon: Yep.
Berger: And I think that's helpful.
Biloon: I've been just so appreciative of that. There's a balance of being condescended to — do you know what I mean — and also being given information. I'm very sensitive to that balance because I consider myself an intelligent person. And you're being put in a position where someone knows more than you, and you have to listen.
Berger: One of the other challenges we face is getting somebody on a treatment. And we elected to put you on an intravenous therapy every 6 months.
Biloon: Especially because as a stand-up comedian, I was traveling a lot, doing these every-6-months infusion, especially with the high efficacy rate that it had been reported from what we had read and the low amount of side effects. I mean, just those things together was just something that seemed the easiest for me.
Berger: So did you encounter any challenges when we first got you started on the infusion therapy?
Biloon: The first infusion I got was at the hospital. But then after that, I had to go to the suburbs, to a center out there for the infusion. That was difficult because to get a ride out there and a ride back — it was a long trip for someone to wait with me. Taking an Uber is expensive, so was it for me to drive. You don't feel good for a couple of days after. So that was how it was, and I complained about it. Probably at every appointment we had, I complained about it.
Berger: Yeah. So some of the challenges you talked about are very, very common. As a physician on medications myself, I can tell you that I am not particularly compliant. And what I love about infusion therapies is that I know that the patient is getting their medicine. Because when they don't show up for a scheduled appointment, I'm called, and I know.
Biloon: I do have a bit of an allergic reaction to the drug. But that's been easily managed over time. Now, the drug infusions are actually being done at my home, which makes the whole process twice-a-year–world's better.
Berger: But there are other barriers that people confront other than the initiation of drugs. Had you encountered any?
Biloon: I think the problem that I had more so was finding the drugs that would manage some of my symptoms. It took a couple of years to sort of figure out what that would be, both with figuring them out and both dealing with insurance on certain medications.
Berger: That's one sort of problem that we confront. The other, of course, are those individuals who, for a variety of reasons, have difficulty with the diagnosis because of their backgrounds. And they may be sociocultural in nature. Every time you go to the physical therapist, it's some degree of money.
Now for some people, it's trivial. But for others, it's a considerable amount of money, relative to what it is that they earn. And you simply have to work within those confines as best you can.
We do have various programs that help people. So we try to employ them. There are, in addition to the sociocultural barriers, language barriers that we often confront. We, in our situation here in a large city, have a very large migrant population.
Fortunately, most of the people speak languages that either you speak as well, or there's somebody in the next room that speaks pretty well. But that's not always the case. So we do have an interpreter service that has to be employed.
Biloon: I cannot imagine the nuance in speaking to people from different ages and different backgrounds, who have different types of lifestyles, for them to understand.
Berger: I don't write at a computer. I think that really degrades the patient-physician relationship. What I do is I obtain a history. I do it on a piece of paper with a pen or a pencil.
I recapitulate them to the patient in paraphrasing it, to make sure that I have gotten it right and that they understand what I think I heard. That, I think, has been enormously helpful in helping people understand what may happen in the absence of treatment and why the treatment is important. That you can do, regardless of what the person's background is. So that's how I approach it.
Biloon: How do you deal with patients when they're not on the same page with you?
Berger: One important thing is that you have to be patient. That is something that it took me 50 years in medicine to learn. And then accepting the patient's opinion and saying, "All right, go home and think about it," because you often don't convince them when they're in the office with you.
Biloon: I did have a little bit of a cushion between my diagnosis and when we actually saw each other, where I was able to really sit in my thoughts on the different treatments and stuff. By the time that we were able to talk, it reassured me on that was the right plan.
Berger: I'm curious what your experience has been with our MS center.
Biloon: Through the portal, every time I need something, I'm usually reaching out, keeping you up-to-date on my primary care or whether it's trying to get a refill on one of my medications that I have to reach out. I really do feel that having that team there, being able to reach out, that's been extremely helpful to have and keeps me very secure because that's all I really need, especially during the pandemic, right? Because then I was very isolated and dealing with going through MS. So it was great to at least — and I did — shoot off emails or texts in the portal, and that's usually primarily how I communicated.
Berger: I will tell you, in my opinion, maybe nine out of 10 messages in the portal or calls that we get simply require reassurance.
Biloon: Yes.
Berger: You just either pick up the phone or shoot back a note, say, "This is not your MS. Don't worry about it." I mean, the most important thing for me is to keep people from worrying because that doesn't solve any problem.
Biloon: No, and it causes stress, which causes fatigue. I mean, it's a bad cycle.
Berger: In the past year, you've actually felt better, and you've gone back to performing. It sounds like the volume of performances has gotten back to what it was pre-illness. What do you see for the future?
Biloon: What I see is traveling more for stand-up and doing the sort of clubs and cities that I had kind of stopped doing from before I was diagnosed, so 2017 and prior to that. And then also even working on other things, writing and maybe even doing sort of books or one-person shows that even talk about sort of my struggles with MS and kind of coming back to where I am. I'm looking forward to the future, and I hope that that's the track I can keep going on.
Berger: I see no reason why you shouldn't.
Biloon: Thank you.
Berger: Michelle, thank you very much for joining me today in this conversation.
Biloon: Thank you so much for having me. It's been really wonderful to be able to sit down here with you.
Joseph R. Berger, MD, has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Celgene/Bristol-Myers Squibb; Cellevolve; EMD Serono/Merck/Genentech; Genzyme; Janssen/Johnson & Johnson; Morphic; Novartis; Roche; Sanofi; Takeda; TG Therapeutics; MAPI; Excision Bio
Received research grant from: Genentech/Roche
Michelle Biloon has disclosed no relevant financial relationships
This transcript has been edited for clarity.
Joseph R. Berger, MD: Hi. I'm Dr Joseph Berger, and I'm joined for this Care Cues conversation with my patient, Michelle Biloon, who has had multiple sclerosis (MS) for the past 6 years. Hello, Michelle. Welcome.
Michelle Biloon: Thank you, Dr Berger.
Berger: Can you tell us a little bit about yourself, how you came to understand you had MS, and how you've done since the diagnosis was rendered?
Biloon: Yeah. It was a very short diagnosis period for me. In the winter of 2017, I started experiencing dizzy spells, and I didn't really know why. I eventually went to my primary care clinic where my doctor is, and they did blood work. Then, they did a CT and didn't see anything, and I just kind of kept feeling worse.
Then, finally, I went to an ENT just to see if it was maybe related to my ears. The ENT actually said, "You need to go to the ER and get an MRI." And while I was in the MRI, I could feel the dizzy spells. And I thought, Well, something is happening. I don't know what it is. And then a resident came in and said that they saw lesions on my brain, and they knew that it was going to be MS or something like it.
Berger: How did you feel about that?
Biloon: At the time, I was kind of glad to hear it was something. And I just asked her if, like, you die from it. That was the first thing I asked. It was like falling off a cliff.
It was making it hard for me to function in what I was doing, which was stand-up comedy, because of the cognitive issues I was having, the cognitive fog. That was how I ended up with you. Right away, you talked to me and were actually able to introduce to me some new medications that are out and are phenomenally better for MS plus were not pills or shots every day. It's made my MS over the years a lot more manageable.
Berger: I'd like to pick up on a couple of things you said.
Biloon: Sure.
Berger: One is, because most people envision MS as this terrible, crippling illness that's going to leave them wheelchair-bound, deprived of their profession, finding it difficult to stay in a marriage it's vested with what has been termed "lamentable results." And one of the first things that we as physicians have to do is to calm people down and say, "You know what. You have MS. You're going to be just fine. Trust me. We have wonderful medications for what you have, and we'll take care of it." In fact, I've made a habit of telling people quit worrying. You hired me to worry for you.
Biloon: Yep.
Berger: And I think that's helpful.
Biloon: I've been just so appreciative of that. There's a balance of being condescended to — do you know what I mean — and also being given information. I'm very sensitive to that balance because I consider myself an intelligent person. And you're being put in a position where someone knows more than you, and you have to listen.
Berger: One of the other challenges we face is getting somebody on a treatment. And we elected to put you on an intravenous therapy every 6 months.
Biloon: Especially because as a stand-up comedian, I was traveling a lot, doing these every-6-months infusion, especially with the high efficacy rate that it had been reported from what we had read and the low amount of side effects. I mean, just those things together was just something that seemed the easiest for me.
Berger: So did you encounter any challenges when we first got you started on the infusion therapy?
Biloon: The first infusion I got was at the hospital. But then after that, I had to go to the suburbs, to a center out there for the infusion. That was difficult because to get a ride out there and a ride back — it was a long trip for someone to wait with me. Taking an Uber is expensive, so was it for me to drive. You don't feel good for a couple of days after. So that was how it was, and I complained about it. Probably at every appointment we had, I complained about it.
Berger: Yeah. So some of the challenges you talked about are very, very common. As a physician on medications myself, I can tell you that I am not particularly compliant. And what I love about infusion therapies is that I know that the patient is getting their medicine. Because when they don't show up for a scheduled appointment, I'm called, and I know.
Biloon: I do have a bit of an allergic reaction to the drug. But that's been easily managed over time. Now, the drug infusions are actually being done at my home, which makes the whole process twice-a-year–world's better.
Berger: But there are other barriers that people confront other than the initiation of drugs. Had you encountered any?
Biloon: I think the problem that I had more so was finding the drugs that would manage some of my symptoms. It took a couple of years to sort of figure out what that would be, both with figuring them out and both dealing with insurance on certain medications.
Berger: That's one sort of problem that we confront. The other, of course, are those individuals who, for a variety of reasons, have difficulty with the diagnosis because of their backgrounds. And they may be sociocultural in nature. Every time you go to the physical therapist, it's some degree of money.
Now for some people, it's trivial. But for others, it's a considerable amount of money, relative to what it is that they earn. And you simply have to work within those confines as best you can.
We do have various programs that help people. So we try to employ them. There are, in addition to the sociocultural barriers, language barriers that we often confront. We, in our situation here in a large city, have a very large migrant population.
Fortunately, most of the people speak languages that either you speak as well, or there's somebody in the next room that speaks pretty well. But that's not always the case. So we do have an interpreter service that has to be employed.
Biloon: I cannot imagine the nuance in speaking to people from different ages and different backgrounds, who have different types of lifestyles, for them to understand.
Berger: I don't write at a computer. I think that really degrades the patient-physician relationship. What I do is I obtain a history. I do it on a piece of paper with a pen or a pencil.
I recapitulate them to the patient in paraphrasing it, to make sure that I have gotten it right and that they understand what I think I heard. That, I think, has been enormously helpful in helping people understand what may happen in the absence of treatment and why the treatment is important. That you can do, regardless of what the person's background is. So that's how I approach it.
Biloon: How do you deal with patients when they're not on the same page with you?
Berger: One important thing is that you have to be patient. That is something that it took me 50 years in medicine to learn. And then accepting the patient's opinion and saying, "All right, go home and think about it," because you often don't convince them when they're in the office with you.
Biloon: I did have a little bit of a cushion between my diagnosis and when we actually saw each other, where I was able to really sit in my thoughts on the different treatments and stuff. By the time that we were able to talk, it reassured me on that was the right plan.
Berger: I'm curious what your experience has been with our MS center.
Biloon: Through the portal, every time I need something, I'm usually reaching out, keeping you up-to-date on my primary care or whether it's trying to get a refill on one of my medications that I have to reach out. I really do feel that having that team there, being able to reach out, that's been extremely helpful to have and keeps me very secure because that's all I really need, especially during the pandemic, right? Because then I was very isolated and dealing with going through MS. So it was great to at least — and I did — shoot off emails or texts in the portal, and that's usually primarily how I communicated.
Berger: I will tell you, in my opinion, maybe nine out of 10 messages in the portal or calls that we get simply require reassurance.
Biloon: Yes.
Berger: You just either pick up the phone or shoot back a note, say, "This is not your MS. Don't worry about it." I mean, the most important thing for me is to keep people from worrying because that doesn't solve any problem.
Biloon: No, and it causes stress, which causes fatigue. I mean, it's a bad cycle.
Berger: In the past year, you've actually felt better, and you've gone back to performing. It sounds like the volume of performances has gotten back to what it was pre-illness. What do you see for the future?
Biloon: What I see is traveling more for stand-up and doing the sort of clubs and cities that I had kind of stopped doing from before I was diagnosed, so 2017 and prior to that. And then also even working on other things, writing and maybe even doing sort of books or one-person shows that even talk about sort of my struggles with MS and kind of coming back to where I am. I'm looking forward to the future, and I hope that that's the track I can keep going on.
Berger: I see no reason why you shouldn't.
Biloon: Thank you.
Berger: Michelle, thank you very much for joining me today in this conversation.
Biloon: Thank you so much for having me. It's been really wonderful to be able to sit down here with you.
Joseph R. Berger, MD, has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Celgene/Bristol-Myers Squibb; Cellevolve; EMD Serono/Merck/Genentech; Genzyme; Janssen/Johnson & Johnson; Morphic; Novartis; Roche; Sanofi; Takeda; TG Therapeutics; MAPI; Excision Bio
Received research grant from: Genentech/Roche
Michelle Biloon has disclosed no relevant financial relationships
Infant Exposure to MS Drugs via Breastfeeding: New Data
, new research confirmed.
Registry data showed no differences in health or development in the first 3 years of life among infants exposed to natalizumab, ocrelizumab, rituximab, or ofatumumab, compared with unexposed infants.
“Most monoclonal antibody medications for multiple sclerosis are not currently approved for use while a mother is breastfeeding,” even though the disease can develop during a person’s reproductive years, study investigator Kerstin Hellwig, MD, with Ruhr University in Bochum, Germany, said in a news release.
“Our data show infants exposed to these medications through breastfeeding experienced no negative effects on health or development within the first 3 years of life,” Dr. Hellwig said.
The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
Registry Data and Analysis
Using the German MS and Pregnancy Registry, researchers identified 183 infants born to mothers taking mAbs while breastfeeding — 180 with a diagnosis of MS and three with a diagnosis of NMOSD. The infants were matched to 183 unexposed infants (control group).
Exposure to mAbs during lactation started a median of 19 days postpartum and lasted for a median of 172 days. The most commonly used mAb during lactation was natalizumab (125 women), followed by ocrelizumab (34 women), rituximab (11 women), and ofatumumab (10 women).
Among the entire infant cohort, two were first exposed to natalizumab and then ocrelizumab; one was exposed to rituximab and then ocrelizumab; three had been previously breastfed on glatiramer acetate and two on interferons.
The primary outcomes were hospitalizations, antibiotic use, developmental delay, and weight during the first 3 years of life in mAb-exposed versus unexposed infants.
In adjusted regression analyses, mAb exposure during breastfeeding was not significantly associated with annual hospitalization (rate ratio [RR], 1.23; P = .473), annual systemic antibiotic use (RR, 1.55; P = .093), developmental delay (odds ratio, 1.16; P = .716), or weight.
A limitation of the study was that only about a third of the infants were followed for the full 3 years. Therefore, Dr. Hellwig said, the results for the third year of life are less meaningful than for years 1 and 2.
‘Reassuring’ Data
Reached for comment, Edith L. Graham, MD, Department of Neurology, Multiple Sclerosis and Neuroimmunology, Northwestern University, Chicago, Illinois, noted that this is the largest group of breastfed infants exposed to mAbs used to treat MS and said the data provide “reassuring infant outcomes with no increase in hospitalization, antibiotic use, or developmental delay.”
Dr. Graham noted that recent publications have reported more on the use of anti-CD20 mAbs (ocrelizumab/rituximab/ofatumumab) while breastfeeding, “and this study adds data for patients on natalizumab.”
“It will be important to know how infusion timing after birth impacts transfer of monoclonal antibodies depending on the milk stage as it transitions from colostrum to mature milk in the first month postpartum,” Dr. Graham said.
“While infection rates of infants are reassuring, data on allergies in the exposed infants would be interesting to look at as well,” she added. “While these infusions are not orally bioavailable, we do not know the full extent of impact on the neonatal gut microbiome.”
In addition, Dr. Graham said it would be important to know whether drugs administered monthly, such as natalizumab and ofatumumab, accumulate in the breast milk at higher levels than medications such as ocrelizumab and rituximab, which are administered twice a year.
The German MS and pregnancy registry was partly supported by the Innovation Fund of the Federal Joint Committee, Almirall Hermal GmbH, Biogen GmbH Germany, Hexal AG, Merck Serono GmbH, Novartis Pharma GmbH, Roche Deutschland GmbH, Sanofi Genzyme, and Teva GmbH. Dr. Hellwig and Dr. Graham had no relevant disclosures.
A version of this article appeared on Medscape.com.
, new research confirmed.
Registry data showed no differences in health or development in the first 3 years of life among infants exposed to natalizumab, ocrelizumab, rituximab, or ofatumumab, compared with unexposed infants.
“Most monoclonal antibody medications for multiple sclerosis are not currently approved for use while a mother is breastfeeding,” even though the disease can develop during a person’s reproductive years, study investigator Kerstin Hellwig, MD, with Ruhr University in Bochum, Germany, said in a news release.
“Our data show infants exposed to these medications through breastfeeding experienced no negative effects on health or development within the first 3 years of life,” Dr. Hellwig said.
The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
Registry Data and Analysis
Using the German MS and Pregnancy Registry, researchers identified 183 infants born to mothers taking mAbs while breastfeeding — 180 with a diagnosis of MS and three with a diagnosis of NMOSD. The infants were matched to 183 unexposed infants (control group).
Exposure to mAbs during lactation started a median of 19 days postpartum and lasted for a median of 172 days. The most commonly used mAb during lactation was natalizumab (125 women), followed by ocrelizumab (34 women), rituximab (11 women), and ofatumumab (10 women).
Among the entire infant cohort, two were first exposed to natalizumab and then ocrelizumab; one was exposed to rituximab and then ocrelizumab; three had been previously breastfed on glatiramer acetate and two on interferons.
The primary outcomes were hospitalizations, antibiotic use, developmental delay, and weight during the first 3 years of life in mAb-exposed versus unexposed infants.
In adjusted regression analyses, mAb exposure during breastfeeding was not significantly associated with annual hospitalization (rate ratio [RR], 1.23; P = .473), annual systemic antibiotic use (RR, 1.55; P = .093), developmental delay (odds ratio, 1.16; P = .716), or weight.
A limitation of the study was that only about a third of the infants were followed for the full 3 years. Therefore, Dr. Hellwig said, the results for the third year of life are less meaningful than for years 1 and 2.
‘Reassuring’ Data
Reached for comment, Edith L. Graham, MD, Department of Neurology, Multiple Sclerosis and Neuroimmunology, Northwestern University, Chicago, Illinois, noted that this is the largest group of breastfed infants exposed to mAbs used to treat MS and said the data provide “reassuring infant outcomes with no increase in hospitalization, antibiotic use, or developmental delay.”
Dr. Graham noted that recent publications have reported more on the use of anti-CD20 mAbs (ocrelizumab/rituximab/ofatumumab) while breastfeeding, “and this study adds data for patients on natalizumab.”
“It will be important to know how infusion timing after birth impacts transfer of monoclonal antibodies depending on the milk stage as it transitions from colostrum to mature milk in the first month postpartum,” Dr. Graham said.
“While infection rates of infants are reassuring, data on allergies in the exposed infants would be interesting to look at as well,” she added. “While these infusions are not orally bioavailable, we do not know the full extent of impact on the neonatal gut microbiome.”
In addition, Dr. Graham said it would be important to know whether drugs administered monthly, such as natalizumab and ofatumumab, accumulate in the breast milk at higher levels than medications such as ocrelizumab and rituximab, which are administered twice a year.
The German MS and pregnancy registry was partly supported by the Innovation Fund of the Federal Joint Committee, Almirall Hermal GmbH, Biogen GmbH Germany, Hexal AG, Merck Serono GmbH, Novartis Pharma GmbH, Roche Deutschland GmbH, Sanofi Genzyme, and Teva GmbH. Dr. Hellwig and Dr. Graham had no relevant disclosures.
A version of this article appeared on Medscape.com.
, new research confirmed.
Registry data showed no differences in health or development in the first 3 years of life among infants exposed to natalizumab, ocrelizumab, rituximab, or ofatumumab, compared with unexposed infants.
“Most monoclonal antibody medications for multiple sclerosis are not currently approved for use while a mother is breastfeeding,” even though the disease can develop during a person’s reproductive years, study investigator Kerstin Hellwig, MD, with Ruhr University in Bochum, Germany, said in a news release.
“Our data show infants exposed to these medications through breastfeeding experienced no negative effects on health or development within the first 3 years of life,” Dr. Hellwig said.
The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
Registry Data and Analysis
Using the German MS and Pregnancy Registry, researchers identified 183 infants born to mothers taking mAbs while breastfeeding — 180 with a diagnosis of MS and three with a diagnosis of NMOSD. The infants were matched to 183 unexposed infants (control group).
Exposure to mAbs during lactation started a median of 19 days postpartum and lasted for a median of 172 days. The most commonly used mAb during lactation was natalizumab (125 women), followed by ocrelizumab (34 women), rituximab (11 women), and ofatumumab (10 women).
Among the entire infant cohort, two were first exposed to natalizumab and then ocrelizumab; one was exposed to rituximab and then ocrelizumab; three had been previously breastfed on glatiramer acetate and two on interferons.
The primary outcomes were hospitalizations, antibiotic use, developmental delay, and weight during the first 3 years of life in mAb-exposed versus unexposed infants.
In adjusted regression analyses, mAb exposure during breastfeeding was not significantly associated with annual hospitalization (rate ratio [RR], 1.23; P = .473), annual systemic antibiotic use (RR, 1.55; P = .093), developmental delay (odds ratio, 1.16; P = .716), or weight.
A limitation of the study was that only about a third of the infants were followed for the full 3 years. Therefore, Dr. Hellwig said, the results for the third year of life are less meaningful than for years 1 and 2.
‘Reassuring’ Data
Reached for comment, Edith L. Graham, MD, Department of Neurology, Multiple Sclerosis and Neuroimmunology, Northwestern University, Chicago, Illinois, noted that this is the largest group of breastfed infants exposed to mAbs used to treat MS and said the data provide “reassuring infant outcomes with no increase in hospitalization, antibiotic use, or developmental delay.”
Dr. Graham noted that recent publications have reported more on the use of anti-CD20 mAbs (ocrelizumab/rituximab/ofatumumab) while breastfeeding, “and this study adds data for patients on natalizumab.”
“It will be important to know how infusion timing after birth impacts transfer of monoclonal antibodies depending on the milk stage as it transitions from colostrum to mature milk in the first month postpartum,” Dr. Graham said.
“While infection rates of infants are reassuring, data on allergies in the exposed infants would be interesting to look at as well,” she added. “While these infusions are not orally bioavailable, we do not know the full extent of impact on the neonatal gut microbiome.”
In addition, Dr. Graham said it would be important to know whether drugs administered monthly, such as natalizumab and ofatumumab, accumulate in the breast milk at higher levels than medications such as ocrelizumab and rituximab, which are administered twice a year.
The German MS and pregnancy registry was partly supported by the Innovation Fund of the Federal Joint Committee, Almirall Hermal GmbH, Biogen GmbH Germany, Hexal AG, Merck Serono GmbH, Novartis Pharma GmbH, Roche Deutschland GmbH, Sanofi Genzyme, and Teva GmbH. Dr. Hellwig and Dr. Graham had no relevant disclosures.
A version of this article appeared on Medscape.com.
Multiple Sclerosis Highlights From ACTRIMS 2024
Andrew Solomon, MD, from the University of Vermont in Burlington, highlights key findings presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024.
Dr Solomon begins by discussing a study on the potential benefits of antipyretics to manage overheating associated with exercise, a common symptom among MS patients. Results showed that MS patients who took aspirin or acetaminophen had less increase in body temperature after a maximal exercise test than those who took placebo.
He next reports on a study that examined whether a combination of two imaging biomarkers specific for MS, namely the central vein sign and the paramagnetic rim lesion, could improve diagnostic specificity. This study found that the presence of at least one of the signs contributed to improved diagnosis.
Dr Solomon then discusses a post hoc analysis of the ULTIMATE I and II trials which reconsidered how to confirm relapses of MS. The study found that follow-up MRI could distinguish relapse from pseudoexacerbations.
Finally, he reports on a study that examined the feasibility and tolerability of low-field brain MRI in MS. The equipment is smaller, portable, and more cost-effective than standard MRI and has high acceptability from patients. Although the precision of these devices needs further testing, Dr Solomon suggests that portable MRI could make MS diagnosis and monitoring available to broader populations.
--
Andrew J. Solomon, MD, Professor, Neurological Sciences, Larner College of Medicine, University of Vermont; Division Chief, Multiple Sclerosis, University Health Center, Burlington, Vermont
Andrew J. Solomon, MD, has disclosed the following relevant financial relationships: Received research grant from: Bristol Myers Squibb
Andrew Solomon, MD, from the University of Vermont in Burlington, highlights key findings presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024.
Dr Solomon begins by discussing a study on the potential benefits of antipyretics to manage overheating associated with exercise, a common symptom among MS patients. Results showed that MS patients who took aspirin or acetaminophen had less increase in body temperature after a maximal exercise test than those who took placebo.
He next reports on a study that examined whether a combination of two imaging biomarkers specific for MS, namely the central vein sign and the paramagnetic rim lesion, could improve diagnostic specificity. This study found that the presence of at least one of the signs contributed to improved diagnosis.
Dr Solomon then discusses a post hoc analysis of the ULTIMATE I and II trials which reconsidered how to confirm relapses of MS. The study found that follow-up MRI could distinguish relapse from pseudoexacerbations.
Finally, he reports on a study that examined the feasibility and tolerability of low-field brain MRI in MS. The equipment is smaller, portable, and more cost-effective than standard MRI and has high acceptability from patients. Although the precision of these devices needs further testing, Dr Solomon suggests that portable MRI could make MS diagnosis and monitoring available to broader populations.
--
Andrew J. Solomon, MD, Professor, Neurological Sciences, Larner College of Medicine, University of Vermont; Division Chief, Multiple Sclerosis, University Health Center, Burlington, Vermont
Andrew J. Solomon, MD, has disclosed the following relevant financial relationships: Received research grant from: Bristol Myers Squibb
Andrew Solomon, MD, from the University of Vermont in Burlington, highlights key findings presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024.
Dr Solomon begins by discussing a study on the potential benefits of antipyretics to manage overheating associated with exercise, a common symptom among MS patients. Results showed that MS patients who took aspirin or acetaminophen had less increase in body temperature after a maximal exercise test than those who took placebo.
He next reports on a study that examined whether a combination of two imaging biomarkers specific for MS, namely the central vein sign and the paramagnetic rim lesion, could improve diagnostic specificity. This study found that the presence of at least one of the signs contributed to improved diagnosis.
Dr Solomon then discusses a post hoc analysis of the ULTIMATE I and II trials which reconsidered how to confirm relapses of MS. The study found that follow-up MRI could distinguish relapse from pseudoexacerbations.
Finally, he reports on a study that examined the feasibility and tolerability of low-field brain MRI in MS. The equipment is smaller, portable, and more cost-effective than standard MRI and has high acceptability from patients. Although the precision of these devices needs further testing, Dr Solomon suggests that portable MRI could make MS diagnosis and monitoring available to broader populations.
--
Andrew J. Solomon, MD, Professor, Neurological Sciences, Larner College of Medicine, University of Vermont; Division Chief, Multiple Sclerosis, University Health Center, Burlington, Vermont
Andrew J. Solomon, MD, has disclosed the following relevant financial relationships: Received research grant from: Bristol Myers Squibb
In Unexpected Finding, Clemastine Fumarate Linked to Worsening Symptoms in MS
WEST PALM BEACH, FLORIDA — An over-the-counter antihistamine that had shown potential for treatment of multiple sclerosis (MS) in animal studies was linked to significant worsening of symptoms in humans, new trial data suggested.
,” investigators said.
The inexpensive antihistamine had been touted as a potential MS treatment following promising early findings, and some patients are reportedly taking it on an off-label basis. It was one of four approved drugs in an ongoing trial led by the National Institute of Allergy and Infectious Diseases (NIAID) to investigate the drugs’ efficacy in the treatment of MS.
“Most patients on the other drugs progressed much slower compared to their baseline,” said senior investigator Bibi Bielekova, MD, with NIAID. “When we compare the results in clemastine arm with all other patients treated with the remaining drugs, the probability that our patients progressed by chance is lower than 0.01%.”
The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
TRAP-MS Trial
The OTC antihistamine clemastine has been available for decades under the brand names Tavist and Dayhist. In addition to findings from mouse studies, results from a small clinical trial reported in 2017 suggested that clemastine may promote myelin repair. Other animal studies and another small study with healthy volunteers also suggested the drug may reduce immune activity.
Clemastine fumarate is one of four drugs in the ongoing TRAP-MS phase 1/2 trial, which is sponsored by NIAID. The study is designed to determine what effects, if any, the drugs have on MS biomarkers either alone or in combination.
Other drugs in the study include the diabetes drug pioglitazone (Actos), the muscle relaxant dantrolene (Ryanodex, Revonto, and Dantrium), and the idiopathic pulmonary fibrosis drug pirfenidone (Pirespa).
An estimated 250 adults with MS were expected to be enrolled in the trial, which began in 2017 and is scheduled to reach its primary completion in 2025.
Per the study protocol, nine patients in the clemastine arm were assigned to receive 8 mg/d (divided into three doses of 2, 2, and 4 mg). Cerebrospinal fluid samples were collected at baseline and 6 months after clemastine treatment began.
Worsening Symptoms
The three patients whose worsening symptoms triggered stopping criteria when they demonstrated increased disability five times faster than their 18-month baseline, researchers reported.
These participants had increased levels of C-reactive protein and erythrocyte sedimentation rate and gained weight, which study authors said were “suggestive of systemic pro-inflammatory state.”
“We found that clemastine treatment causes significant changes in purinergic metabolism,” lead author Joanna Kocot, PhD, a NIAID fellow, said during the ACTRIMS presentation. “We also confirmed that this toxic effect of clemastine was because of pyroptosis,” a form of cell death.
None of the remaining 55 patients treated with other TRAP-MS therapies triggered safety criteria, which study authors said offered “evidence for clemastine toxicity.”
Demographic information was not provided, but the patients on clemastine with worsening symptoms were older, more disabled, and more obese than the other six patients in the clemastine arm, Dr. Bielekova said during the conference presentation.
‘Undesirable’ or ‘Premature’?
Commenting on the findings, Paul J. Tesar, PhD, professor of innovative therapeutics at Case Western Reserve University School of Medicine in Cleveland, said the findings are unexpected.
“Compared to previous trials, the TRAP-MS trial included different patient populations and treated them with clemastine for a longer time period, so it is hard to make direct comparisons,” said Dr. Tesar, who studies MS and did not take part in the new study. “From the limited data disclosed thus far, it does seem likely that clemastine is causing toxicity, possibly through increased inflammation, and accelerating disease progression.”
In the big picture, he said, “while clemastine trials have been important steps toward a first-in-class remyelinating drug, the promiscuous nature of clemastine — it binds to many protein targets — and its known side effects make it undesirable as a mainstay treatment for people with multiple sclerosis.”
Hundreds or perhaps thousands of patients with MS may already take the drug because of the early positive findings, said Ari Green, MD, medical director of the University of California at San Francisco Multiple Sclerosis Center and lead author of the initial 2017 clinical trial on clemastine and myelin repair.
Dr. Green, who was not involved in the new study, said he is skeptical of the findings.
“We can’t conclude much about an effect based on three patients, and the risk that this is a chance effect is extraordinarily high,” he said. “It’s premature to make any attribution of what they saw to clemastine itself.”
Dr. Bielekova disagreed, and said she stands by the findings.
The pyroptosis score, derived from CSF biomarkers, was elevated in MS and higher in progressive MS than in relapsing-remitting MS, she said, adding that pyroptosis correlates with how fast people with MS accumulate disability.
“From all drugs we tested, only clemastine increased this CSF pyroptosis score,” Dr. Bielekova said.
Regardless, Dr. Green urged caution when considering whether to use the drug.
“Nobody should take clemastine without the supervision of a doctor,” he said. “It’s actually best done in the context of clinical trials.”
NIAID funded the study, and the authors had no disclosures. Dr. Tesar is cofounder of Convelo Therapeutics, a biotechnology company developing remyelinating therapeutics for MS. Dr. Green said he is conducting studies related to clemastine, but they do not have industry funding.
A version of this article appeared on Medscape.com.
WEST PALM BEACH, FLORIDA — An over-the-counter antihistamine that had shown potential for treatment of multiple sclerosis (MS) in animal studies was linked to significant worsening of symptoms in humans, new trial data suggested.
,” investigators said.
The inexpensive antihistamine had been touted as a potential MS treatment following promising early findings, and some patients are reportedly taking it on an off-label basis. It was one of four approved drugs in an ongoing trial led by the National Institute of Allergy and Infectious Diseases (NIAID) to investigate the drugs’ efficacy in the treatment of MS.
“Most patients on the other drugs progressed much slower compared to their baseline,” said senior investigator Bibi Bielekova, MD, with NIAID. “When we compare the results in clemastine arm with all other patients treated with the remaining drugs, the probability that our patients progressed by chance is lower than 0.01%.”
The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
TRAP-MS Trial
The OTC antihistamine clemastine has been available for decades under the brand names Tavist and Dayhist. In addition to findings from mouse studies, results from a small clinical trial reported in 2017 suggested that clemastine may promote myelin repair. Other animal studies and another small study with healthy volunteers also suggested the drug may reduce immune activity.
Clemastine fumarate is one of four drugs in the ongoing TRAP-MS phase 1/2 trial, which is sponsored by NIAID. The study is designed to determine what effects, if any, the drugs have on MS biomarkers either alone or in combination.
Other drugs in the study include the diabetes drug pioglitazone (Actos), the muscle relaxant dantrolene (Ryanodex, Revonto, and Dantrium), and the idiopathic pulmonary fibrosis drug pirfenidone (Pirespa).
An estimated 250 adults with MS were expected to be enrolled in the trial, which began in 2017 and is scheduled to reach its primary completion in 2025.
Per the study protocol, nine patients in the clemastine arm were assigned to receive 8 mg/d (divided into three doses of 2, 2, and 4 mg). Cerebrospinal fluid samples were collected at baseline and 6 months after clemastine treatment began.
Worsening Symptoms
The three patients whose worsening symptoms triggered stopping criteria when they demonstrated increased disability five times faster than their 18-month baseline, researchers reported.
These participants had increased levels of C-reactive protein and erythrocyte sedimentation rate and gained weight, which study authors said were “suggestive of systemic pro-inflammatory state.”
“We found that clemastine treatment causes significant changes in purinergic metabolism,” lead author Joanna Kocot, PhD, a NIAID fellow, said during the ACTRIMS presentation. “We also confirmed that this toxic effect of clemastine was because of pyroptosis,” a form of cell death.
None of the remaining 55 patients treated with other TRAP-MS therapies triggered safety criteria, which study authors said offered “evidence for clemastine toxicity.”
Demographic information was not provided, but the patients on clemastine with worsening symptoms were older, more disabled, and more obese than the other six patients in the clemastine arm, Dr. Bielekova said during the conference presentation.
‘Undesirable’ or ‘Premature’?
Commenting on the findings, Paul J. Tesar, PhD, professor of innovative therapeutics at Case Western Reserve University School of Medicine in Cleveland, said the findings are unexpected.
“Compared to previous trials, the TRAP-MS trial included different patient populations and treated them with clemastine for a longer time period, so it is hard to make direct comparisons,” said Dr. Tesar, who studies MS and did not take part in the new study. “From the limited data disclosed thus far, it does seem likely that clemastine is causing toxicity, possibly through increased inflammation, and accelerating disease progression.”
In the big picture, he said, “while clemastine trials have been important steps toward a first-in-class remyelinating drug, the promiscuous nature of clemastine — it binds to many protein targets — and its known side effects make it undesirable as a mainstay treatment for people with multiple sclerosis.”
Hundreds or perhaps thousands of patients with MS may already take the drug because of the early positive findings, said Ari Green, MD, medical director of the University of California at San Francisco Multiple Sclerosis Center and lead author of the initial 2017 clinical trial on clemastine and myelin repair.
Dr. Green, who was not involved in the new study, said he is skeptical of the findings.
“We can’t conclude much about an effect based on three patients, and the risk that this is a chance effect is extraordinarily high,” he said. “It’s premature to make any attribution of what they saw to clemastine itself.”
Dr. Bielekova disagreed, and said she stands by the findings.
The pyroptosis score, derived from CSF biomarkers, was elevated in MS and higher in progressive MS than in relapsing-remitting MS, she said, adding that pyroptosis correlates with how fast people with MS accumulate disability.
“From all drugs we tested, only clemastine increased this CSF pyroptosis score,” Dr. Bielekova said.
Regardless, Dr. Green urged caution when considering whether to use the drug.
“Nobody should take clemastine without the supervision of a doctor,” he said. “It’s actually best done in the context of clinical trials.”
NIAID funded the study, and the authors had no disclosures. Dr. Tesar is cofounder of Convelo Therapeutics, a biotechnology company developing remyelinating therapeutics for MS. Dr. Green said he is conducting studies related to clemastine, but they do not have industry funding.
A version of this article appeared on Medscape.com.
WEST PALM BEACH, FLORIDA — An over-the-counter antihistamine that had shown potential for treatment of multiple sclerosis (MS) in animal studies was linked to significant worsening of symptoms in humans, new trial data suggested.
,” investigators said.
The inexpensive antihistamine had been touted as a potential MS treatment following promising early findings, and some patients are reportedly taking it on an off-label basis. It was one of four approved drugs in an ongoing trial led by the National Institute of Allergy and Infectious Diseases (NIAID) to investigate the drugs’ efficacy in the treatment of MS.
“Most patients on the other drugs progressed much slower compared to their baseline,” said senior investigator Bibi Bielekova, MD, with NIAID. “When we compare the results in clemastine arm with all other patients treated with the remaining drugs, the probability that our patients progressed by chance is lower than 0.01%.”
The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
TRAP-MS Trial
The OTC antihistamine clemastine has been available for decades under the brand names Tavist and Dayhist. In addition to findings from mouse studies, results from a small clinical trial reported in 2017 suggested that clemastine may promote myelin repair. Other animal studies and another small study with healthy volunteers also suggested the drug may reduce immune activity.
Clemastine fumarate is one of four drugs in the ongoing TRAP-MS phase 1/2 trial, which is sponsored by NIAID. The study is designed to determine what effects, if any, the drugs have on MS biomarkers either alone or in combination.
Other drugs in the study include the diabetes drug pioglitazone (Actos), the muscle relaxant dantrolene (Ryanodex, Revonto, and Dantrium), and the idiopathic pulmonary fibrosis drug pirfenidone (Pirespa).
An estimated 250 adults with MS were expected to be enrolled in the trial, which began in 2017 and is scheduled to reach its primary completion in 2025.
Per the study protocol, nine patients in the clemastine arm were assigned to receive 8 mg/d (divided into three doses of 2, 2, and 4 mg). Cerebrospinal fluid samples were collected at baseline and 6 months after clemastine treatment began.
Worsening Symptoms
The three patients whose worsening symptoms triggered stopping criteria when they demonstrated increased disability five times faster than their 18-month baseline, researchers reported.
These participants had increased levels of C-reactive protein and erythrocyte sedimentation rate and gained weight, which study authors said were “suggestive of systemic pro-inflammatory state.”
“We found that clemastine treatment causes significant changes in purinergic metabolism,” lead author Joanna Kocot, PhD, a NIAID fellow, said during the ACTRIMS presentation. “We also confirmed that this toxic effect of clemastine was because of pyroptosis,” a form of cell death.
None of the remaining 55 patients treated with other TRAP-MS therapies triggered safety criteria, which study authors said offered “evidence for clemastine toxicity.”
Demographic information was not provided, but the patients on clemastine with worsening symptoms were older, more disabled, and more obese than the other six patients in the clemastine arm, Dr. Bielekova said during the conference presentation.
‘Undesirable’ or ‘Premature’?
Commenting on the findings, Paul J. Tesar, PhD, professor of innovative therapeutics at Case Western Reserve University School of Medicine in Cleveland, said the findings are unexpected.
“Compared to previous trials, the TRAP-MS trial included different patient populations and treated them with clemastine for a longer time period, so it is hard to make direct comparisons,” said Dr. Tesar, who studies MS and did not take part in the new study. “From the limited data disclosed thus far, it does seem likely that clemastine is causing toxicity, possibly through increased inflammation, and accelerating disease progression.”
In the big picture, he said, “while clemastine trials have been important steps toward a first-in-class remyelinating drug, the promiscuous nature of clemastine — it binds to many protein targets — and its known side effects make it undesirable as a mainstay treatment for people with multiple sclerosis.”
Hundreds or perhaps thousands of patients with MS may already take the drug because of the early positive findings, said Ari Green, MD, medical director of the University of California at San Francisco Multiple Sclerosis Center and lead author of the initial 2017 clinical trial on clemastine and myelin repair.
Dr. Green, who was not involved in the new study, said he is skeptical of the findings.
“We can’t conclude much about an effect based on three patients, and the risk that this is a chance effect is extraordinarily high,” he said. “It’s premature to make any attribution of what they saw to clemastine itself.”
Dr. Bielekova disagreed, and said she stands by the findings.
The pyroptosis score, derived from CSF biomarkers, was elevated in MS and higher in progressive MS than in relapsing-remitting MS, she said, adding that pyroptosis correlates with how fast people with MS accumulate disability.
“From all drugs we tested, only clemastine increased this CSF pyroptosis score,” Dr. Bielekova said.
Regardless, Dr. Green urged caution when considering whether to use the drug.
“Nobody should take clemastine without the supervision of a doctor,” he said. “It’s actually best done in the context of clinical trials.”
NIAID funded the study, and the authors had no disclosures. Dr. Tesar is cofounder of Convelo Therapeutics, a biotechnology company developing remyelinating therapeutics for MS. Dr. Green said he is conducting studies related to clemastine, but they do not have industry funding.
A version of this article appeared on Medscape.com.
FROM ACTRIMS FORUM 2024
An Easy, Effective Solution to Exercise-Induced Heat Sensitivity in RRMS?
WEST PALM BEACH, CALIFORNIA — , results from a new phase 3 trial suggested.
The findings from the randomized, placebo-controlled, double-blind study could solve this common problem, known clinically as Uhthoff’s phenomenon, that causes temporary worsening of MS symptoms with heat exposure.
“This could be a game changer,” said study investigator Victoria M. Leavitt, PhD, assistant professor of neuropsychology of Columbia University Irving Medical Center in New York City.
The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) and published online in the Journal of Neurology.
A Common Condition
Research suggested that 60%-80% of MS patients experience heat sensitivity. However, while the exact cause is unknown, some evidence suggested it may be related to hypothalamic dysregulation or lesions of the hypothalamus.
Researchers have explored cooling strategies such as liquid-cooled clothing, but available tools can be hard to find, expensive, and cumbersome. Although aspirin has been linked to some symptom improvement in MS, its utility and that of acetaminophen for the condition has not been studied, Dr. Leavitt said.
For the single-center study, researchers recruited 60 patients (81% female; average age, 42 years; 73% White individuals) between 2019 and 2022. Overall, 37 completed at least one study visit, and 29 completed two to three visits. The average disease duration was 6 years.
Participants received oral administration of 650 mg aspirin, acetaminophen, or placebo at each of three study visits over 3 weeks, separated by at least 1 week. At each visit, they took part in a maximal exercise test conducted on a cycle ergometer and were asked to cycle at 50-60 revolutions/min for as long as possible.
Compared with placebo, body temperature increase from baseline to exercise stoppage was significantly reduced with aspirin (0.006 °F vs 0.68 °F; P < .001) and with acetaminophen (0.31 °F vs 0.68 °F; P < .004)
Neither medication was associated with a significant difference in time to exhaustion, and there were no serious adverse events.
“This is really nice because some people might have an adverse reaction to aspirin,” such as gastrointestinal issues. Acetaminophen has a different side-effect profile,” Dr. Leavitt said.
Both medications are inexpensive and available over the counter. The 650-mg acetaminophen dose used in the study is available in an extended-release formula. Typically aspirin isn’t available in doses larger than 325 mg. The 650-mg dose used in the study is considered safe but large.
Dr. Leavitt said she would like to study daily aspirin in people with MS to see if it can boost physical activity. “That’s the test of whether this will meaningfully affect the lives of people with MS,” she said.
No Harm From Overheating
Commenting on the findings, Katherine Knox, MD, associate professor of physical medicine and rehabilitation at the University of Saskatchewan, Canada, noted that “the intervention maybe be initially helpful for the person fearful of getting weaker when they get ‘hot’ with exercise.”
Dr. Knox, who wasn’t involved in the research, added that it’s important for patients with MS to overcome initial barriers and fears about exercise.
“However, for most people the effects of being warm with exercise are less concerning for them after education that the weakness is temporary and does not cause harm if one takes the right precautions such as planning ahead to avoid a fall,” she said. Also, inexpensive interventions such as a fan or a wet cotton headband can be helpful, she said.
The study “provides further evidence that the ‘overheating’ is not causing harm since the time to exhaustion was unchanged,” Dr. Knox added.
The study was funded by the National Institutes of Health. The authors had no disclosures. Disclosure information for Dr. Knox was not available.
A version of this article appeared on Medscape.com.
WEST PALM BEACH, CALIFORNIA — , results from a new phase 3 trial suggested.
The findings from the randomized, placebo-controlled, double-blind study could solve this common problem, known clinically as Uhthoff’s phenomenon, that causes temporary worsening of MS symptoms with heat exposure.
“This could be a game changer,” said study investigator Victoria M. Leavitt, PhD, assistant professor of neuropsychology of Columbia University Irving Medical Center in New York City.
The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) and published online in the Journal of Neurology.
A Common Condition
Research suggested that 60%-80% of MS patients experience heat sensitivity. However, while the exact cause is unknown, some evidence suggested it may be related to hypothalamic dysregulation or lesions of the hypothalamus.
Researchers have explored cooling strategies such as liquid-cooled clothing, but available tools can be hard to find, expensive, and cumbersome. Although aspirin has been linked to some symptom improvement in MS, its utility and that of acetaminophen for the condition has not been studied, Dr. Leavitt said.
For the single-center study, researchers recruited 60 patients (81% female; average age, 42 years; 73% White individuals) between 2019 and 2022. Overall, 37 completed at least one study visit, and 29 completed two to three visits. The average disease duration was 6 years.
Participants received oral administration of 650 mg aspirin, acetaminophen, or placebo at each of three study visits over 3 weeks, separated by at least 1 week. At each visit, they took part in a maximal exercise test conducted on a cycle ergometer and were asked to cycle at 50-60 revolutions/min for as long as possible.
Compared with placebo, body temperature increase from baseline to exercise stoppage was significantly reduced with aspirin (0.006 °F vs 0.68 °F; P < .001) and with acetaminophen (0.31 °F vs 0.68 °F; P < .004)
Neither medication was associated with a significant difference in time to exhaustion, and there were no serious adverse events.
“This is really nice because some people might have an adverse reaction to aspirin,” such as gastrointestinal issues. Acetaminophen has a different side-effect profile,” Dr. Leavitt said.
Both medications are inexpensive and available over the counter. The 650-mg acetaminophen dose used in the study is available in an extended-release formula. Typically aspirin isn’t available in doses larger than 325 mg. The 650-mg dose used in the study is considered safe but large.
Dr. Leavitt said she would like to study daily aspirin in people with MS to see if it can boost physical activity. “That’s the test of whether this will meaningfully affect the lives of people with MS,” she said.
No Harm From Overheating
Commenting on the findings, Katherine Knox, MD, associate professor of physical medicine and rehabilitation at the University of Saskatchewan, Canada, noted that “the intervention maybe be initially helpful for the person fearful of getting weaker when they get ‘hot’ with exercise.”
Dr. Knox, who wasn’t involved in the research, added that it’s important for patients with MS to overcome initial barriers and fears about exercise.
“However, for most people the effects of being warm with exercise are less concerning for them after education that the weakness is temporary and does not cause harm if one takes the right precautions such as planning ahead to avoid a fall,” she said. Also, inexpensive interventions such as a fan or a wet cotton headband can be helpful, she said.
The study “provides further evidence that the ‘overheating’ is not causing harm since the time to exhaustion was unchanged,” Dr. Knox added.
The study was funded by the National Institutes of Health. The authors had no disclosures. Disclosure information for Dr. Knox was not available.
A version of this article appeared on Medscape.com.
WEST PALM BEACH, CALIFORNIA — , results from a new phase 3 trial suggested.
The findings from the randomized, placebo-controlled, double-blind study could solve this common problem, known clinically as Uhthoff’s phenomenon, that causes temporary worsening of MS symptoms with heat exposure.
“This could be a game changer,” said study investigator Victoria M. Leavitt, PhD, assistant professor of neuropsychology of Columbia University Irving Medical Center in New York City.
The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) and published online in the Journal of Neurology.
A Common Condition
Research suggested that 60%-80% of MS patients experience heat sensitivity. However, while the exact cause is unknown, some evidence suggested it may be related to hypothalamic dysregulation or lesions of the hypothalamus.
Researchers have explored cooling strategies such as liquid-cooled clothing, but available tools can be hard to find, expensive, and cumbersome. Although aspirin has been linked to some symptom improvement in MS, its utility and that of acetaminophen for the condition has not been studied, Dr. Leavitt said.
For the single-center study, researchers recruited 60 patients (81% female; average age, 42 years; 73% White individuals) between 2019 and 2022. Overall, 37 completed at least one study visit, and 29 completed two to three visits. The average disease duration was 6 years.
Participants received oral administration of 650 mg aspirin, acetaminophen, or placebo at each of three study visits over 3 weeks, separated by at least 1 week. At each visit, they took part in a maximal exercise test conducted on a cycle ergometer and were asked to cycle at 50-60 revolutions/min for as long as possible.
Compared with placebo, body temperature increase from baseline to exercise stoppage was significantly reduced with aspirin (0.006 °F vs 0.68 °F; P < .001) and with acetaminophen (0.31 °F vs 0.68 °F; P < .004)
Neither medication was associated with a significant difference in time to exhaustion, and there were no serious adverse events.
“This is really nice because some people might have an adverse reaction to aspirin,” such as gastrointestinal issues. Acetaminophen has a different side-effect profile,” Dr. Leavitt said.
Both medications are inexpensive and available over the counter. The 650-mg acetaminophen dose used in the study is available in an extended-release formula. Typically aspirin isn’t available in doses larger than 325 mg. The 650-mg dose used in the study is considered safe but large.
Dr. Leavitt said she would like to study daily aspirin in people with MS to see if it can boost physical activity. “That’s the test of whether this will meaningfully affect the lives of people with MS,” she said.
No Harm From Overheating
Commenting on the findings, Katherine Knox, MD, associate professor of physical medicine and rehabilitation at the University of Saskatchewan, Canada, noted that “the intervention maybe be initially helpful for the person fearful of getting weaker when they get ‘hot’ with exercise.”
Dr. Knox, who wasn’t involved in the research, added that it’s important for patients with MS to overcome initial barriers and fears about exercise.
“However, for most people the effects of being warm with exercise are less concerning for them after education that the weakness is temporary and does not cause harm if one takes the right precautions such as planning ahead to avoid a fall,” she said. Also, inexpensive interventions such as a fan or a wet cotton headband can be helpful, she said.
The study “provides further evidence that the ‘overheating’ is not causing harm since the time to exhaustion was unchanged,” Dr. Knox added.
The study was funded by the National Institutes of Health. The authors had no disclosures. Disclosure information for Dr. Knox was not available.
A version of this article appeared on Medscape.com.
FROM ACTRIMS FORUM 2024
Not Even Secondary Endpoints Support BTK Inhibitor in Phase 3 MS Trial
WEST PALM BEACH, FLORIDA — Top-line results of two phase 3 trials evaluating the BTK inhibitor evobrutinib for treatment of multiple sclerosis (MS) were negative when released several months ago, but the hope for a signal of benefit on secondary endpoints was dashed when the full results of the trials were presented at the 2024 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum.
Based on prior drug development, including the promise seen in a phase 2 trial, “these negative results were quite disappointing,” reported Xavier Montalban, MD, director, department of neurology, Catalunya Center for Multiple Sclerosis, Hospital Universitario Vall d’Hebron, Barcelona, Spain.
In the evolutionRMS1 and 2 phase 3 trials, 2285 relapsing-remitting MS patients with active disease were randomized to 45 mg of twice-daily oral evobrutinib or 14 mg once-daily teriflunomide, a pyrimidine synthesis inhibitor already widely used for the treatment of MS. The trial, conducted in 52 countries, was double-blind and double-dummy.
When released at the end of 2023, the primary endpoints of the annualized relapse rate (ARR) were identical or nearly identical for evobrutinib relative to teriflunomide in RMS1 (0.15 vs 0.14) and RMS2 (0.11 vs 0.11).
Yet, many researchers were still hoping to see some greater advantage for the BTK inhibitor, which modulates B cell activity and inhibits activation of inflammatory cells in the central nervous system, on one or more secondary endpoints.
“The primary ARR endpoint was mandated by the regulatory agencies,” explained Mark S. Freedman, MD, director of the MS Research Unit, University of Ottawa, Canada. Although he was not greatly surprised that evobrutinib failed to show superiority over the already low ARR rates typically achieved on teriflunomide, he had held out hope that a benefit on one or more secondary outcomes would support BTK inhibition as an MS target.
However, the time to confirmed disability progression and time to confirmed disability improvement among the two treatment groups traced the same course over 24 weeks. Graphically, the lines were nearly superimposed.
No Outcome Supported an Evobrutinib Advantage
Numerically, the mean number of T1 gadolinium-enhancing lesions was greater among those randomized to evobrutinib while the mean number of new or enlarging T2 lesions was lower. However, none of these differences in either study reached statistical significance.
The lower serum neurofilament light chain (sNfL) levels were significant (P = .032) in one of the two trials, but the difference was modest, and Dr. Montalban stated that the difference “was probably not clinically significant.”
Almost all of the patients had multiple relapses before being enrolled in the study, but only 36.5% had received a prior disease-modifying therapy. According to Dr. Montalban, the baseline characteristics of the patients enrolled were “nothing special,” in that they were very much “like the types of patients enrolled in trials like these.”
In general, both drugs were well tolerated with a comparable safety profile. The exception was a greater proportion of patients randomized to evobrutinib who developed elevated liver function tests, including a greater proportion with a level at least 5 times the upper limit of normal. All normalized after treatment was discontinued.
This is the first phase 3 trial of a BTK inhibitor in MS, according to Dr. Montalban, who pointed out that evobrutinib did perform as well as a highly active agent, even if it could not show superiority.
There is limited likelihood that further ongoing analyses will uncover meaningful activity not detected in the primary and secondary outcomes, but Dr. Montalban said that there is a possibility that a higher dose or a BTK inhibitor with different characteristics might still produce the types of clinical benefits hypothesized in this initial trial.
Asked to speculate about the results if the RM1 and RM2 trials had a noninferiority rather than a superiority design been employed, Dr. Montalban said that evobrutinib relative to teriflunomide appears to be “similar but more toxic.”
The recent excitement building for the potential of BTK inhibitors in MS was not helped by a second, but much smaller, late-breaker study that evaluated tolebrutinib. The primary endpoint of that study, conducted with just seven patients, was complete resolution of paramagnetic rim lesions (PRL), a prognostically important composition of macrophages, microglia, and iron seen in the central nervous system (CNS) on imaging.
No Resolution of CNS Lesions
Even after 48 weeks, none of the lesions had resolved, according to Maria I. Gaitán, MD, acting director of the Translational Neuroradiology Unit of the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland.
Again, although these findings were disappointing, Dr. Gaitán said there are a number of explanations for the result that do not preclude a benefit from BTK inhibitors in future studies.
“Complete resolution of PRL might be a bar that was too high,” she said, noting that favorable changes in these lesions could have occurred even if the characteristic iron deposits persisted. She also suggested that dosing might not have been optimized to halt or reverse disease activity in the CNS. Like Dr. Montalban, she suggested that BTK inhibitors with different characteristics might succeed where tolebrutinib failed.
Dr. Freedman, current president of ACTRIMS, agreed that these data should not be interpreted as ruling out a clinical role for BTK inhibitors. Pointing to the substantial body of data supporting this mechanism for reversing inflammation in the CNS, he declared that “the story is not over.”
Dr. Montalban reported financial relationships with Actelion, Alexion, Bayer, Biogen, Bristol-Myers Squibb, Celgene, EMD Serono, Hoffman La Roche, Immunic, Janssen, Mylan, NervGen, Novartis, Sanofi-Genzyme, Teva, TG Therapeutics, and Merck, which provided funding for the RMS 1 and 2 trials. Dr. Freedman reported financial relationships with Actelion, Alexion, Bayer, Biogen, Celgene, EMD Serono, Hoffman La Roche, Merck, Novartis, and Teva Canada Innovation. Dr. Gaitán reported no potential conflicts of interest.
WEST PALM BEACH, FLORIDA — Top-line results of two phase 3 trials evaluating the BTK inhibitor evobrutinib for treatment of multiple sclerosis (MS) were negative when released several months ago, but the hope for a signal of benefit on secondary endpoints was dashed when the full results of the trials were presented at the 2024 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum.
Based on prior drug development, including the promise seen in a phase 2 trial, “these negative results were quite disappointing,” reported Xavier Montalban, MD, director, department of neurology, Catalunya Center for Multiple Sclerosis, Hospital Universitario Vall d’Hebron, Barcelona, Spain.
In the evolutionRMS1 and 2 phase 3 trials, 2285 relapsing-remitting MS patients with active disease were randomized to 45 mg of twice-daily oral evobrutinib or 14 mg once-daily teriflunomide, a pyrimidine synthesis inhibitor already widely used for the treatment of MS. The trial, conducted in 52 countries, was double-blind and double-dummy.
When released at the end of 2023, the primary endpoints of the annualized relapse rate (ARR) were identical or nearly identical for evobrutinib relative to teriflunomide in RMS1 (0.15 vs 0.14) and RMS2 (0.11 vs 0.11).
Yet, many researchers were still hoping to see some greater advantage for the BTK inhibitor, which modulates B cell activity and inhibits activation of inflammatory cells in the central nervous system, on one or more secondary endpoints.
“The primary ARR endpoint was mandated by the regulatory agencies,” explained Mark S. Freedman, MD, director of the MS Research Unit, University of Ottawa, Canada. Although he was not greatly surprised that evobrutinib failed to show superiority over the already low ARR rates typically achieved on teriflunomide, he had held out hope that a benefit on one or more secondary outcomes would support BTK inhibition as an MS target.
However, the time to confirmed disability progression and time to confirmed disability improvement among the two treatment groups traced the same course over 24 weeks. Graphically, the lines were nearly superimposed.
No Outcome Supported an Evobrutinib Advantage
Numerically, the mean number of T1 gadolinium-enhancing lesions was greater among those randomized to evobrutinib while the mean number of new or enlarging T2 lesions was lower. However, none of these differences in either study reached statistical significance.
The lower serum neurofilament light chain (sNfL) levels were significant (P = .032) in one of the two trials, but the difference was modest, and Dr. Montalban stated that the difference “was probably not clinically significant.”
Almost all of the patients had multiple relapses before being enrolled in the study, but only 36.5% had received a prior disease-modifying therapy. According to Dr. Montalban, the baseline characteristics of the patients enrolled were “nothing special,” in that they were very much “like the types of patients enrolled in trials like these.”
In general, both drugs were well tolerated with a comparable safety profile. The exception was a greater proportion of patients randomized to evobrutinib who developed elevated liver function tests, including a greater proportion with a level at least 5 times the upper limit of normal. All normalized after treatment was discontinued.
This is the first phase 3 trial of a BTK inhibitor in MS, according to Dr. Montalban, who pointed out that evobrutinib did perform as well as a highly active agent, even if it could not show superiority.
There is limited likelihood that further ongoing analyses will uncover meaningful activity not detected in the primary and secondary outcomes, but Dr. Montalban said that there is a possibility that a higher dose or a BTK inhibitor with different characteristics might still produce the types of clinical benefits hypothesized in this initial trial.
Asked to speculate about the results if the RM1 and RM2 trials had a noninferiority rather than a superiority design been employed, Dr. Montalban said that evobrutinib relative to teriflunomide appears to be “similar but more toxic.”
The recent excitement building for the potential of BTK inhibitors in MS was not helped by a second, but much smaller, late-breaker study that evaluated tolebrutinib. The primary endpoint of that study, conducted with just seven patients, was complete resolution of paramagnetic rim lesions (PRL), a prognostically important composition of macrophages, microglia, and iron seen in the central nervous system (CNS) on imaging.
No Resolution of CNS Lesions
Even after 48 weeks, none of the lesions had resolved, according to Maria I. Gaitán, MD, acting director of the Translational Neuroradiology Unit of the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland.
Again, although these findings were disappointing, Dr. Gaitán said there are a number of explanations for the result that do not preclude a benefit from BTK inhibitors in future studies.
“Complete resolution of PRL might be a bar that was too high,” she said, noting that favorable changes in these lesions could have occurred even if the characteristic iron deposits persisted. She also suggested that dosing might not have been optimized to halt or reverse disease activity in the CNS. Like Dr. Montalban, she suggested that BTK inhibitors with different characteristics might succeed where tolebrutinib failed.
Dr. Freedman, current president of ACTRIMS, agreed that these data should not be interpreted as ruling out a clinical role for BTK inhibitors. Pointing to the substantial body of data supporting this mechanism for reversing inflammation in the CNS, he declared that “the story is not over.”
Dr. Montalban reported financial relationships with Actelion, Alexion, Bayer, Biogen, Bristol-Myers Squibb, Celgene, EMD Serono, Hoffman La Roche, Immunic, Janssen, Mylan, NervGen, Novartis, Sanofi-Genzyme, Teva, TG Therapeutics, and Merck, which provided funding for the RMS 1 and 2 trials. Dr. Freedman reported financial relationships with Actelion, Alexion, Bayer, Biogen, Celgene, EMD Serono, Hoffman La Roche, Merck, Novartis, and Teva Canada Innovation. Dr. Gaitán reported no potential conflicts of interest.
WEST PALM BEACH, FLORIDA — Top-line results of two phase 3 trials evaluating the BTK inhibitor evobrutinib for treatment of multiple sclerosis (MS) were negative when released several months ago, but the hope for a signal of benefit on secondary endpoints was dashed when the full results of the trials were presented at the 2024 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum.
Based on prior drug development, including the promise seen in a phase 2 trial, “these negative results were quite disappointing,” reported Xavier Montalban, MD, director, department of neurology, Catalunya Center for Multiple Sclerosis, Hospital Universitario Vall d’Hebron, Barcelona, Spain.
In the evolutionRMS1 and 2 phase 3 trials, 2285 relapsing-remitting MS patients with active disease were randomized to 45 mg of twice-daily oral evobrutinib or 14 mg once-daily teriflunomide, a pyrimidine synthesis inhibitor already widely used for the treatment of MS. The trial, conducted in 52 countries, was double-blind and double-dummy.
When released at the end of 2023, the primary endpoints of the annualized relapse rate (ARR) were identical or nearly identical for evobrutinib relative to teriflunomide in RMS1 (0.15 vs 0.14) and RMS2 (0.11 vs 0.11).
Yet, many researchers were still hoping to see some greater advantage for the BTK inhibitor, which modulates B cell activity and inhibits activation of inflammatory cells in the central nervous system, on one or more secondary endpoints.
“The primary ARR endpoint was mandated by the regulatory agencies,” explained Mark S. Freedman, MD, director of the MS Research Unit, University of Ottawa, Canada. Although he was not greatly surprised that evobrutinib failed to show superiority over the already low ARR rates typically achieved on teriflunomide, he had held out hope that a benefit on one or more secondary outcomes would support BTK inhibition as an MS target.
However, the time to confirmed disability progression and time to confirmed disability improvement among the two treatment groups traced the same course over 24 weeks. Graphically, the lines were nearly superimposed.
No Outcome Supported an Evobrutinib Advantage
Numerically, the mean number of T1 gadolinium-enhancing lesions was greater among those randomized to evobrutinib while the mean number of new or enlarging T2 lesions was lower. However, none of these differences in either study reached statistical significance.
The lower serum neurofilament light chain (sNfL) levels were significant (P = .032) in one of the two trials, but the difference was modest, and Dr. Montalban stated that the difference “was probably not clinically significant.”
Almost all of the patients had multiple relapses before being enrolled in the study, but only 36.5% had received a prior disease-modifying therapy. According to Dr. Montalban, the baseline characteristics of the patients enrolled were “nothing special,” in that they were very much “like the types of patients enrolled in trials like these.”
In general, both drugs were well tolerated with a comparable safety profile. The exception was a greater proportion of patients randomized to evobrutinib who developed elevated liver function tests, including a greater proportion with a level at least 5 times the upper limit of normal. All normalized after treatment was discontinued.
This is the first phase 3 trial of a BTK inhibitor in MS, according to Dr. Montalban, who pointed out that evobrutinib did perform as well as a highly active agent, even if it could not show superiority.
There is limited likelihood that further ongoing analyses will uncover meaningful activity not detected in the primary and secondary outcomes, but Dr. Montalban said that there is a possibility that a higher dose or a BTK inhibitor with different characteristics might still produce the types of clinical benefits hypothesized in this initial trial.
Asked to speculate about the results if the RM1 and RM2 trials had a noninferiority rather than a superiority design been employed, Dr. Montalban said that evobrutinib relative to teriflunomide appears to be “similar but more toxic.”
The recent excitement building for the potential of BTK inhibitors in MS was not helped by a second, but much smaller, late-breaker study that evaluated tolebrutinib. The primary endpoint of that study, conducted with just seven patients, was complete resolution of paramagnetic rim lesions (PRL), a prognostically important composition of macrophages, microglia, and iron seen in the central nervous system (CNS) on imaging.
No Resolution of CNS Lesions
Even after 48 weeks, none of the lesions had resolved, according to Maria I. Gaitán, MD, acting director of the Translational Neuroradiology Unit of the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland.
Again, although these findings were disappointing, Dr. Gaitán said there are a number of explanations for the result that do not preclude a benefit from BTK inhibitors in future studies.
“Complete resolution of PRL might be a bar that was too high,” she said, noting that favorable changes in these lesions could have occurred even if the characteristic iron deposits persisted. She also suggested that dosing might not have been optimized to halt or reverse disease activity in the CNS. Like Dr. Montalban, she suggested that BTK inhibitors with different characteristics might succeed where tolebrutinib failed.
Dr. Freedman, current president of ACTRIMS, agreed that these data should not be interpreted as ruling out a clinical role for BTK inhibitors. Pointing to the substantial body of data supporting this mechanism for reversing inflammation in the CNS, he declared that “the story is not over.”
Dr. Montalban reported financial relationships with Actelion, Alexion, Bayer, Biogen, Bristol-Myers Squibb, Celgene, EMD Serono, Hoffman La Roche, Immunic, Janssen, Mylan, NervGen, Novartis, Sanofi-Genzyme, Teva, TG Therapeutics, and Merck, which provided funding for the RMS 1 and 2 trials. Dr. Freedman reported financial relationships with Actelion, Alexion, Bayer, Biogen, Celgene, EMD Serono, Hoffman La Roche, Merck, Novartis, and Teva Canada Innovation. Dr. Gaitán reported no potential conflicts of interest.
FROM ACTRIMS FORUM 2024
Neurological Disorders Now Top Global Cause of Illness, Disability
, a new comprehensive analysis showed.
In 2021, neurological conditions were responsible for 443 million years of healthy life lost due to illness, disability, and premature death — a measurement known as disability-adjusted life years (DALY) — making them the top contributor to the global disease burden, ahead of cardiovascular diseases.
Some 3.4 billion people — 43% of the entire global population — had a neurological illness in 2021, the report noted.
“As the world’s leading cause of overall disease burden, and with case numbers rising 59% globally since 1990, nervous system conditions must be addressed through effective, culturally acceptable, and affordable prevention, treatment, rehabilitation, and long-term care strategies,” lead author Jaimie Steinmetz, PhD, from the Institute of Health Metrics and Evaluation (IHME), University of Washington, Seattle, said in a news release.
The findings, from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2021, “have important health service and policy implications and serve as evidence that global neurological heath loss has been under-recognized and is increasing and unevenly distributed geographically and socioeconomically,” the authors noted.
The study was published online in The Lancet: Neurology.
The Top 10
The top 10 contributors to neurological health loss in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer’s disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications from preterm birth, autistic spectrum disorders, and nervous system cancers.
Neurological consequences of COVID-19 ranked 20th out of 37 unique conditions assessed.
In 2021, there were more than 23 million global cases of COVID-19 with long-term cognitive symptoms or Guillain-Barré syndrome, accounting for 57% of all infectious neurological disease cases and contributing to 2.48 million years of healthy life lost, the study found.
The most prevalent neurological disorders were tension-type headache (about 2 billion cases) and migraine (about 1.1 billion cases), while diabetic neuropathy is the fastest-growing of all neurological conditions.
“The number of people with diabetic neuropathy has more than tripled globally since 1990, rising to 206 million in 2021. This is in line with the increase in the global prevalence of diabetes,” co-senior author Liane Ong, PhD, from IHME, said in the release.
The data showed striking differences in the burden of neurological conditions between world regions and national income levels, with over 80% of neurological deaths and health loss occurring in low- and middle-income countries.
Regions with the highest burden of neurological conditions were central and western sub-Saharan Africa, while high-income Asia Pacific and Australasia had the lowest burden.
“Nervous system health loss disproportionately impacts many of the poorest countries partly due to the higher prevalence of conditions affecting neonates and children under 5, especially birth-related complications and infections,” co-senior author Tarun Dua, MD, with the World Health Organization (WHO) brain health unit, noted in the news release.
“Improved infant survival has led to an increase in long-term disability, while limited access to treatment and rehabilitation services is contributing to the much higher proportion of deaths in these countries,” Dr. Dua said.
Prioritize Prevention
The analysis also provides estimates of the proportion of neurological conditions that are potentially preventable by eliminating known risk factors for stroke, dementia, multiple sclerosis, Parkinson’s disease, encephalitis, meningitis, and intellectual disability.
It shows that modifying 18 risk factors over a person’s lifetime — most importantly high systolic blood pressure — could prevent 84% of global DALYs from stroke. Controlling lead exposure could lower intellectual disability cases by 63% and reducing high fasting plasma glucose to normal levels could cut dementia by roughly 15%.
“Because many neurological conditions lack cures, and access to medical care is often limited, understanding modifiable risk factors and the potentially avoidable neurological condition burden is essential to help curb this global health crisis,” co-lead author Katrin Seeher, PhD, mental health specialist with WHO’s brain health unit, said in the release.
It’s important to note that nervous system conditions include infectious and vector-borne diseases and injuries as well as noncommunicable diseases and injuries, Dr. Steinmetz said, “demanding different strategies for prevention and treatment throughout life.”
“We hope that our findings can help policymakers more comprehensively understand the impact of neurological conditions on both adults and children to inform more targeted interventions in individual countries, as well as guide ongoing awareness and advocacy efforts around the world,” Dr. Steinmetz added.
In an accompanying editorial, Wolfgang Grisold, MD, president of the World Federation of Neurology, London, noted that the study builds on previous findings and expands the number of neurological conditions studied from 15 to 37.
“This important new GBD report highlights that the burden of neurological conditions is greater than previously thought,” wrote Dr. Grisold, who was not a part of the study. “In the next iteration, more attention should be given to neuromuscular diseases, the effects of cancer in the nervous system, and neuropathic pain. Comparing the disability caused by conditions with episodic occurrence versus those that cause permanent and progressive disease will remain challenging because the effects on the individuals vary substantially.”
The study was funded by the Bill and Melinda Gates Foundation. Full disclosures are included in the original article.
A version of this article appeared on Medscape.com.
, a new comprehensive analysis showed.
In 2021, neurological conditions were responsible for 443 million years of healthy life lost due to illness, disability, and premature death — a measurement known as disability-adjusted life years (DALY) — making them the top contributor to the global disease burden, ahead of cardiovascular diseases.
Some 3.4 billion people — 43% of the entire global population — had a neurological illness in 2021, the report noted.
“As the world’s leading cause of overall disease burden, and with case numbers rising 59% globally since 1990, nervous system conditions must be addressed through effective, culturally acceptable, and affordable prevention, treatment, rehabilitation, and long-term care strategies,” lead author Jaimie Steinmetz, PhD, from the Institute of Health Metrics and Evaluation (IHME), University of Washington, Seattle, said in a news release.
The findings, from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2021, “have important health service and policy implications and serve as evidence that global neurological heath loss has been under-recognized and is increasing and unevenly distributed geographically and socioeconomically,” the authors noted.
The study was published online in The Lancet: Neurology.
The Top 10
The top 10 contributors to neurological health loss in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer’s disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications from preterm birth, autistic spectrum disorders, and nervous system cancers.
Neurological consequences of COVID-19 ranked 20th out of 37 unique conditions assessed.
In 2021, there were more than 23 million global cases of COVID-19 with long-term cognitive symptoms or Guillain-Barré syndrome, accounting for 57% of all infectious neurological disease cases and contributing to 2.48 million years of healthy life lost, the study found.
The most prevalent neurological disorders were tension-type headache (about 2 billion cases) and migraine (about 1.1 billion cases), while diabetic neuropathy is the fastest-growing of all neurological conditions.
“The number of people with diabetic neuropathy has more than tripled globally since 1990, rising to 206 million in 2021. This is in line with the increase in the global prevalence of diabetes,” co-senior author Liane Ong, PhD, from IHME, said in the release.
The data showed striking differences in the burden of neurological conditions between world regions and national income levels, with over 80% of neurological deaths and health loss occurring in low- and middle-income countries.
Regions with the highest burden of neurological conditions were central and western sub-Saharan Africa, while high-income Asia Pacific and Australasia had the lowest burden.
“Nervous system health loss disproportionately impacts many of the poorest countries partly due to the higher prevalence of conditions affecting neonates and children under 5, especially birth-related complications and infections,” co-senior author Tarun Dua, MD, with the World Health Organization (WHO) brain health unit, noted in the news release.
“Improved infant survival has led to an increase in long-term disability, while limited access to treatment and rehabilitation services is contributing to the much higher proportion of deaths in these countries,” Dr. Dua said.
Prioritize Prevention
The analysis also provides estimates of the proportion of neurological conditions that are potentially preventable by eliminating known risk factors for stroke, dementia, multiple sclerosis, Parkinson’s disease, encephalitis, meningitis, and intellectual disability.
It shows that modifying 18 risk factors over a person’s lifetime — most importantly high systolic blood pressure — could prevent 84% of global DALYs from stroke. Controlling lead exposure could lower intellectual disability cases by 63% and reducing high fasting plasma glucose to normal levels could cut dementia by roughly 15%.
“Because many neurological conditions lack cures, and access to medical care is often limited, understanding modifiable risk factors and the potentially avoidable neurological condition burden is essential to help curb this global health crisis,” co-lead author Katrin Seeher, PhD, mental health specialist with WHO’s brain health unit, said in the release.
It’s important to note that nervous system conditions include infectious and vector-borne diseases and injuries as well as noncommunicable diseases and injuries, Dr. Steinmetz said, “demanding different strategies for prevention and treatment throughout life.”
“We hope that our findings can help policymakers more comprehensively understand the impact of neurological conditions on both adults and children to inform more targeted interventions in individual countries, as well as guide ongoing awareness and advocacy efforts around the world,” Dr. Steinmetz added.
In an accompanying editorial, Wolfgang Grisold, MD, president of the World Federation of Neurology, London, noted that the study builds on previous findings and expands the number of neurological conditions studied from 15 to 37.
“This important new GBD report highlights that the burden of neurological conditions is greater than previously thought,” wrote Dr. Grisold, who was not a part of the study. “In the next iteration, more attention should be given to neuromuscular diseases, the effects of cancer in the nervous system, and neuropathic pain. Comparing the disability caused by conditions with episodic occurrence versus those that cause permanent and progressive disease will remain challenging because the effects on the individuals vary substantially.”
The study was funded by the Bill and Melinda Gates Foundation. Full disclosures are included in the original article.
A version of this article appeared on Medscape.com.
, a new comprehensive analysis showed.
In 2021, neurological conditions were responsible for 443 million years of healthy life lost due to illness, disability, and premature death — a measurement known as disability-adjusted life years (DALY) — making them the top contributor to the global disease burden, ahead of cardiovascular diseases.
Some 3.4 billion people — 43% of the entire global population — had a neurological illness in 2021, the report noted.
“As the world’s leading cause of overall disease burden, and with case numbers rising 59% globally since 1990, nervous system conditions must be addressed through effective, culturally acceptable, and affordable prevention, treatment, rehabilitation, and long-term care strategies,” lead author Jaimie Steinmetz, PhD, from the Institute of Health Metrics and Evaluation (IHME), University of Washington, Seattle, said in a news release.
The findings, from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2021, “have important health service and policy implications and serve as evidence that global neurological heath loss has been under-recognized and is increasing and unevenly distributed geographically and socioeconomically,” the authors noted.
The study was published online in The Lancet: Neurology.
The Top 10
The top 10 contributors to neurological health loss in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer’s disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications from preterm birth, autistic spectrum disorders, and nervous system cancers.
Neurological consequences of COVID-19 ranked 20th out of 37 unique conditions assessed.
In 2021, there were more than 23 million global cases of COVID-19 with long-term cognitive symptoms or Guillain-Barré syndrome, accounting for 57% of all infectious neurological disease cases and contributing to 2.48 million years of healthy life lost, the study found.
The most prevalent neurological disorders were tension-type headache (about 2 billion cases) and migraine (about 1.1 billion cases), while diabetic neuropathy is the fastest-growing of all neurological conditions.
“The number of people with diabetic neuropathy has more than tripled globally since 1990, rising to 206 million in 2021. This is in line with the increase in the global prevalence of diabetes,” co-senior author Liane Ong, PhD, from IHME, said in the release.
The data showed striking differences in the burden of neurological conditions between world regions and national income levels, with over 80% of neurological deaths and health loss occurring in low- and middle-income countries.
Regions with the highest burden of neurological conditions were central and western sub-Saharan Africa, while high-income Asia Pacific and Australasia had the lowest burden.
“Nervous system health loss disproportionately impacts many of the poorest countries partly due to the higher prevalence of conditions affecting neonates and children under 5, especially birth-related complications and infections,” co-senior author Tarun Dua, MD, with the World Health Organization (WHO) brain health unit, noted in the news release.
“Improved infant survival has led to an increase in long-term disability, while limited access to treatment and rehabilitation services is contributing to the much higher proportion of deaths in these countries,” Dr. Dua said.
Prioritize Prevention
The analysis also provides estimates of the proportion of neurological conditions that are potentially preventable by eliminating known risk factors for stroke, dementia, multiple sclerosis, Parkinson’s disease, encephalitis, meningitis, and intellectual disability.
It shows that modifying 18 risk factors over a person’s lifetime — most importantly high systolic blood pressure — could prevent 84% of global DALYs from stroke. Controlling lead exposure could lower intellectual disability cases by 63% and reducing high fasting plasma glucose to normal levels could cut dementia by roughly 15%.
“Because many neurological conditions lack cures, and access to medical care is often limited, understanding modifiable risk factors and the potentially avoidable neurological condition burden is essential to help curb this global health crisis,” co-lead author Katrin Seeher, PhD, mental health specialist with WHO’s brain health unit, said in the release.
It’s important to note that nervous system conditions include infectious and vector-borne diseases and injuries as well as noncommunicable diseases and injuries, Dr. Steinmetz said, “demanding different strategies for prevention and treatment throughout life.”
“We hope that our findings can help policymakers more comprehensively understand the impact of neurological conditions on both adults and children to inform more targeted interventions in individual countries, as well as guide ongoing awareness and advocacy efforts around the world,” Dr. Steinmetz added.
In an accompanying editorial, Wolfgang Grisold, MD, president of the World Federation of Neurology, London, noted that the study builds on previous findings and expands the number of neurological conditions studied from 15 to 37.
“This important new GBD report highlights that the burden of neurological conditions is greater than previously thought,” wrote Dr. Grisold, who was not a part of the study. “In the next iteration, more attention should be given to neuromuscular diseases, the effects of cancer in the nervous system, and neuropathic pain. Comparing the disability caused by conditions with episodic occurrence versus those that cause permanent and progressive disease will remain challenging because the effects on the individuals vary substantially.”
The study was funded by the Bill and Melinda Gates Foundation. Full disclosures are included in the original article.
A version of this article appeared on Medscape.com.
FROM THE LANCET NEUROLOGY