ICYMI Multiple Sclerosis

Any of four variants of genes associated with immunity can significantly increase a carrier’s risk for developing progressive multifocal leukoencephalopathy (PML) after exposure to immunosuppressing drugs, a team of European and U.S. investigators reported.

The four-gene signature could be used to screen patients who are currently taking or are candidates for drugs know to increase risk for PML, a rare but frequently lethal demyelinating disorder of the central nervous system, according to Eli Hatchwell, MD, PhD, from Population BIO UK in Oxfordshire, England, and colleagues.

“Due to the seriousness of a PML diagnosis – particularly because it often leads to life-threatening outcomes and the lack of treatment options once it develops – it would seem unethical not to test individuals considering immunosuppressive therapies with PML risk for our top four variants, and advising those with a positive result to consider an alternative therapy or treatment strategy,” they wrote in a study published in Frontiers in Neurology.
 

Benign virus, bad disease

PML is caused by reactivation of the otherwise benign JC virus (JCV), also known as human polyomavirus 2. (The “J” and “C” in the virus’ common name stand for John Cunningham, a man with Hodgkin lymphoma from whose brain the virus was first isolated, in 1971.)

The estimated prevalence of JCV infection ranges from 40% to 70% of the population worldwide, although PML itself is rare, with an incidence of approximately 1 in 200,000.

PML is a complication of treatment with targeted monoclonal antibodies, such as natalizumab (Tysabri), rituximab (Rituxan), alemtuzumab (Campath; Lemtrada), and other agents with immunosuppressive properties, such as dimethyl fumarate and mycophenolate mofetil.

In addition, PML can occur among patients with diseases that disrupt or inhibit natural immunity, such as HIV/AIDS, hematologic cancers, and autoimmune diseases.
 

Predisposing variants suspected

Dr. Hatchwell and colleagues hypothesized that some patients may have rare genetic variants in immune-system genes that predispose them to increased risk for PML. The researchers had previously shown an association between PML and 19 genetic risk variants among 184 patients with PML.

In the current study, they looked at variants in an additional 152 patients with PML who served as a validation sample. Of the 19 risk variants they had previously identified, the investigators narrowed the field down to 4 variants in both population controls and in a matched control set consisting of patients with multiple sclerosis (MS) who were positive for JCV and who were on therapy with a PML-linked drug for at least 2 years.

The four variants they identified, all linked to immune viral defense, were C8B, 1-57409459-C-A, rs139498867; LY9 (a checkpoint regulator also known as SLAMF3), 1-160769595-AG-A, rs763811636; FCN2, 9-137779251-G-A, rs76267164; and STXBP2, 19-7712287-G-C, rs35490401.

In all, 10.9% of patients with PML carried at least one of the variants.

The investigators reported that carriers of any one of the variants has a nearly ninefold risk for developing PML after exposure to a PML-linked drug compared with non-carriers with similar drug exposures (odds ratio, 8.7; P < .001).

“Measures of clinical validity and utility compare favorably to other genetic risk tests, such as BRCA1 and BRCA2 screening for breast cancer risk and HLA-B_15:02 pharmacogenetic screening for pharmacovigilance of carbamazepine to prevent Stevens-Johnson syndrome and toxic epidermal necrolysis,” the authors noted.
 

Screening? Maybe

In a press release, Lawrence Steinman, MD, from Stanford (Calif.) University, who was not involved in the study, stated that “preventative screening for these variants should become part of the standard of care. I wish we had more powerful tools like this for other therapies.”

But another neurologist who was not involved in the study commented that the finding, while “exciting” as a confirmation study, is not as yet practice changing.

“It does give us very good confidence that these four genes are indeed risk factors that increase the risk of this brain infection by quite a bit, so that makes it very exciting,” said Robert Fox, MD, from the Neurological Institute at the Cleveland Clinic.

“Indeed, we are trying to risk-stratify patients to try to reduce the risk of PML in the patients treated with our MS drugs. So for natalizumab we risk stratify by testing them for JC virus serology. Half of people don’t have it and we say ‘OK, you’re good to go.’ With other drugs like Tecfidera – dimethyl fumarate – we follow their lymphocyte counts, so when their lymphocyte counts drop too low we say ‘OK, you need to come off the drug because of the risk of PML,’ ” he said in an interview.

The four-gene signature, however, only identifies about 11% of patients with PML, which is not a sufficiently large enough effect to be clinically useful. For example, the risk for PML in patients treated with natalizumab is about 1%, and if the test can only detect enhanced risk in about 11% of those patients, the risk would drop from 1% to 0.9%, which “doesn’t really the move needle much,” he pointed out.

Dr. Fox also noted that neurologists now have a large formulary of drugs to offer their patients, including agents (such as interferon-beta and corticosteroids that are not associated with increased risk for PML).

The study was funded by Emerald Lake Safety and Population Bio. Dr. Hatchwell and several coauthors are employees of the respective companies, and several are inventors of genetic screening methods for PML. Dr. Steiman has disclosed consulting for TG Therapeutics. Dr. Fox reported consulting for manufacturers of MS therapies.

Any of four variants of genes associated with immunity can significantly increase a carrier’s risk for developing progressive multifocal leukoencephalopathy (PML) after exposure to immunosuppressing drugs, a team of European and U.S. investigators reported.

The four-gene signature could be used to screen patients who are currently taking or are candidates for drugs know to increase risk for PML, a rare but frequently lethal demyelinating disorder of the central nervous system, according to Eli Hatchwell, MD, PhD, from Population BIO UK in Oxfordshire, England, and colleagues.

“Due to the seriousness of a PML diagnosis – particularly because it often leads to life-threatening outcomes and the lack of treatment options once it develops – it would seem unethical not to test individuals considering immunosuppressive therapies with PML risk for our top four variants, and advising those with a positive result to consider an alternative therapy or treatment strategy,” they wrote in a study published in Frontiers in Neurology.
 

Benign virus, bad disease

PML is caused by reactivation of the otherwise benign JC virus (JCV), also known as human polyomavirus 2. (The “J” and “C” in the virus’ common name stand for John Cunningham, a man with Hodgkin lymphoma from whose brain the virus was first isolated, in 1971.)

The estimated prevalence of JCV infection ranges from 40% to 70% of the population worldwide, although PML itself is rare, with an incidence of approximately 1 in 200,000.

PML is a complication of treatment with targeted monoclonal antibodies, such as natalizumab (Tysabri), rituximab (Rituxan), alemtuzumab (Campath; Lemtrada), and other agents with immunosuppressive properties, such as dimethyl fumarate and mycophenolate mofetil.

In addition, PML can occur among patients with diseases that disrupt or inhibit natural immunity, such as HIV/AIDS, hematologic cancers, and autoimmune diseases.
 

Predisposing variants suspected

Dr. Hatchwell and colleagues hypothesized that some patients may have rare genetic variants in immune-system genes that predispose them to increased risk for PML. The researchers had previously shown an association between PML and 19 genetic risk variants among 184 patients with PML.

In the current study, they looked at variants in an additional 152 patients with PML who served as a validation sample. Of the 19 risk variants they had previously identified, the investigators narrowed the field down to 4 variants in both population controls and in a matched control set consisting of patients with multiple sclerosis (MS) who were positive for JCV and who were on therapy with a PML-linked drug for at least 2 years.

The four variants they identified, all linked to immune viral defense, were C8B, 1-57409459-C-A, rs139498867; LY9 (a checkpoint regulator also known as SLAMF3), 1-160769595-AG-A, rs763811636; FCN2, 9-137779251-G-A, rs76267164; and STXBP2, 19-7712287-G-C, rs35490401.

In all, 10.9% of patients with PML carried at least one of the variants.

The investigators reported that carriers of any one of the variants has a nearly ninefold risk for developing PML after exposure to a PML-linked drug compared with non-carriers with similar drug exposures (odds ratio, 8.7; P < .001).

“Measures of clinical validity and utility compare favorably to other genetic risk tests, such as BRCA1 and BRCA2 screening for breast cancer risk and HLA-B_15:02 pharmacogenetic screening for pharmacovigilance of carbamazepine to prevent Stevens-Johnson syndrome and toxic epidermal necrolysis,” the authors noted.
 

Screening? Maybe

In a press release, Lawrence Steinman, MD, from Stanford (Calif.) University, who was not involved in the study, stated that “preventative screening for these variants should become part of the standard of care. I wish we had more powerful tools like this for other therapies.”

But another neurologist who was not involved in the study commented that the finding, while “exciting” as a confirmation study, is not as yet practice changing.

“It does give us very good confidence that these four genes are indeed risk factors that increase the risk of this brain infection by quite a bit, so that makes it very exciting,” said Robert Fox, MD, from the Neurological Institute at the Cleveland Clinic.

“Indeed, we are trying to risk-stratify patients to try to reduce the risk of PML in the patients treated with our MS drugs. So for natalizumab we risk stratify by testing them for JC virus serology. Half of people don’t have it and we say ‘OK, you’re good to go.’ With other drugs like Tecfidera – dimethyl fumarate – we follow their lymphocyte counts, so when their lymphocyte counts drop too low we say ‘OK, you need to come off the drug because of the risk of PML,’ ” he said in an interview.

The four-gene signature, however, only identifies about 11% of patients with PML, which is not a sufficiently large enough effect to be clinically useful. For example, the risk for PML in patients treated with natalizumab is about 1%, and if the test can only detect enhanced risk in about 11% of those patients, the risk would drop from 1% to 0.9%, which “doesn’t really the move needle much,” he pointed out.

Dr. Fox also noted that neurologists now have a large formulary of drugs to offer their patients, including agents (such as interferon-beta and corticosteroids that are not associated with increased risk for PML).

The study was funded by Emerald Lake Safety and Population Bio. Dr. Hatchwell and several coauthors are employees of the respective companies, and several are inventors of genetic screening methods for PML. Dr. Steiman has disclosed consulting for TG Therapeutics. Dr. Fox reported consulting for manufacturers of MS therapies.

Any of four variants of genes associated with immunity can significantly increase a carrier’s risk for developing progressive multifocal leukoencephalopathy (PML) after exposure to immunosuppressing drugs, a team of European and U.S. investigators reported.

The four-gene signature could be used to screen patients who are currently taking or are candidates for drugs know to increase risk for PML, a rare but frequently lethal demyelinating disorder of the central nervous system, according to Eli Hatchwell, MD, PhD, from Population BIO UK in Oxfordshire, England, and colleagues.

“Due to the seriousness of a PML diagnosis – particularly because it often leads to life-threatening outcomes and the lack of treatment options once it develops – it would seem unethical not to test individuals considering immunosuppressive therapies with PML risk for our top four variants, and advising those with a positive result to consider an alternative therapy or treatment strategy,” they wrote in a study published in Frontiers in Neurology.
 

Benign virus, bad disease

PML is caused by reactivation of the otherwise benign JC virus (JCV), also known as human polyomavirus 2. (The “J” and “C” in the virus’ common name stand for John Cunningham, a man with Hodgkin lymphoma from whose brain the virus was first isolated, in 1971.)

The estimated prevalence of JCV infection ranges from 40% to 70% of the population worldwide, although PML itself is rare, with an incidence of approximately 1 in 200,000.

PML is a complication of treatment with targeted monoclonal antibodies, such as natalizumab (Tysabri), rituximab (Rituxan), alemtuzumab (Campath; Lemtrada), and other agents with immunosuppressive properties, such as dimethyl fumarate and mycophenolate mofetil.

In addition, PML can occur among patients with diseases that disrupt or inhibit natural immunity, such as HIV/AIDS, hematologic cancers, and autoimmune diseases.
 

Predisposing variants suspected

Dr. Hatchwell and colleagues hypothesized that some patients may have rare genetic variants in immune-system genes that predispose them to increased risk for PML. The researchers had previously shown an association between PML and 19 genetic risk variants among 184 patients with PML.

In the current study, they looked at variants in an additional 152 patients with PML who served as a validation sample. Of the 19 risk variants they had previously identified, the investigators narrowed the field down to 4 variants in both population controls and in a matched control set consisting of patients with multiple sclerosis (MS) who were positive for JCV and who were on therapy with a PML-linked drug for at least 2 years.

The four variants they identified, all linked to immune viral defense, were C8B, 1-57409459-C-A, rs139498867; LY9 (a checkpoint regulator also known as SLAMF3), 1-160769595-AG-A, rs763811636; FCN2, 9-137779251-G-A, rs76267164; and STXBP2, 19-7712287-G-C, rs35490401.

In all, 10.9% of patients with PML carried at least one of the variants.

The investigators reported that carriers of any one of the variants has a nearly ninefold risk for developing PML after exposure to a PML-linked drug compared with non-carriers with similar drug exposures (odds ratio, 8.7; P < .001).

“Measures of clinical validity and utility compare favorably to other genetic risk tests, such as BRCA1 and BRCA2 screening for breast cancer risk and HLA-B_15:02 pharmacogenetic screening for pharmacovigilance of carbamazepine to prevent Stevens-Johnson syndrome and toxic epidermal necrolysis,” the authors noted.
 

Screening? Maybe

In a press release, Lawrence Steinman, MD, from Stanford (Calif.) University, who was not involved in the study, stated that “preventative screening for these variants should become part of the standard of care. I wish we had more powerful tools like this for other therapies.”

But another neurologist who was not involved in the study commented that the finding, while “exciting” as a confirmation study, is not as yet practice changing.

“It does give us very good confidence that these four genes are indeed risk factors that increase the risk of this brain infection by quite a bit, so that makes it very exciting,” said Robert Fox, MD, from the Neurological Institute at the Cleveland Clinic.

“Indeed, we are trying to risk-stratify patients to try to reduce the risk of PML in the patients treated with our MS drugs. So for natalizumab we risk stratify by testing them for JC virus serology. Half of people don’t have it and we say ‘OK, you’re good to go.’ With other drugs like Tecfidera – dimethyl fumarate – we follow their lymphocyte counts, so when their lymphocyte counts drop too low we say ‘OK, you need to come off the drug because of the risk of PML,’ ” he said in an interview.

The four-gene signature, however, only identifies about 11% of patients with PML, which is not a sufficiently large enough effect to be clinically useful. For example, the risk for PML in patients treated with natalizumab is about 1%, and if the test can only detect enhanced risk in about 11% of those patients, the risk would drop from 1% to 0.9%, which “doesn’t really the move needle much,” he pointed out.

Dr. Fox also noted that neurologists now have a large formulary of drugs to offer their patients, including agents (such as interferon-beta and corticosteroids that are not associated with increased risk for PML).

The study was funded by Emerald Lake Safety and Population Bio. Dr. Hatchwell and several coauthors are employees of the respective companies, and several are inventors of genetic screening methods for PML. Dr. Steiman has disclosed consulting for TG Therapeutics. Dr. Fox reported consulting for manufacturers of MS therapies.

Sir Augustus d’Este (1794-1848) described the circumstances preceding his development of neurological symptoms as follows:¹ “I travelled from Ramsgate to the Highlands of Scotland for the purpose of passing some days with a Relation for whom I had the affection of a Son. On my arrival I found him dead. Shortly after the funeral I was obliged to have my letters read to me, and their answers written for me, as my eyes were so attacked that when fixed upon minute objects indistinctness of vision was the consequence: Soon after I went to Ireland, and without any thing having been done to my eyes, they completely recovered their strength and distinctness of vision…" He then described a clinical course of relapsing-remitting neurologic symptoms merging into a progressive stage of unrelenting illness, most fitting with what we know today as multiple sclerosis (MS).¹ Why did Sir Augustus d'Este connect the event of the unexpected death to the onset of a lifelong neurologic disease?

Jean-Martin Charcot first described MS in a way close to what we know it as today. Charcot considered stress a factor in MS. He linked grief, vexation, and adverse changes in social circumstances to the onset of MS at that time.² I, as a practicing MS specialist, am surprised neither by Sir Augustus d'Este's diary nor by Charcot's earlier assessments of MS triggers.³ As I write this narrative, I think of the many times I heard from people diagnosed with MS. "It happened to me because of stress" is a statement not estranged from my daily clinical practice

MS as a multifactorial disease

It is tempting to make a case for emotional stress as a cause of MS, but one must remember that MS is a very complex disease with unclear etiologies. MS, a treatable but not yet curable disease, is the interplay between the genetics of the host and numerous environmental factors that exploit a susceptible immune system leading to unrelenting immune dysregulation.⁴ Recent studies have brought some pieces of this intricate puzzle together. The role of Epstein-Barr virus (EBV) in the pathogenesis of MS is being dissected.⁵ The possible synergy between vitamin D deficiency, EBV, and certain genetic variations is being studied.⁶ The roles of smoking, environmental toxins, obesity, diet, Western lifestyle, and the gut microbiome are some of the top areas of clinical, translational, and basic research.^7-11 But what about emotional stress? Where does it fit, if anywhere, in the current research paradigm?

Emotional stress and MS—Causality or not?

In the scientific method, several criteria must be proven for an element to be suspected in the etiology of a disease.¹² First, the suspect element must be present before the disease starts—i.e., a temporal association. Second, there must be a plausible biological explanation of how the suspect element acts in the disease's causation. Third, other variables that could confound the picture must be controlled for or dismissed. It is clear that no single factor is the cause of MS. By now, MS is agreed upon as a disease caused by multiple factors, some of which remain to be unraveled.⁹ The term "cause" has been utilized more recently by many authors when referring to EBV in relation to MS development, reasoning that in one study, in a small number of individuals with MS, EBV infection preceded the MS clinical diagnosis.¹³ Thus, the temporal association was provided. But does MS start at the onset of clinical symptoms?

For Sir Augustus d'Este, the disease may have started years before he visited the Highlands of Scotland, but only at that visit did MS become clinically apparent. So, the emotional trauma may have acted as a "trigger" for an MS flare-up rather than being a "cause" of MS. This might be a more plausible explanation of the association between emotional trauma and MS development. However, MS pathogenesis is complex, and one could argue that the disease starts many years before the first clinical symptoms that lead to diagnosis.

The MS prodrome has been demonstrated by several studies that suggest that MS may start many years before the clinical diagnosis.¹⁴ Radiologically isolated syndrome (RIS) further argues that MS may be clinically dormant for years, and clinical symptoms may not appear until later in the disease process.¹⁵ One may think that immune attacks on the optic nerves, spinal cord, or areas of the brainstem might be readily symptomatic compared to attacks on other structures of the central nervous system (e.g., periventricular or juxtacortical brain areas) that may be clinically silent. So, while for Sir Augustus d'Este it seemed that the disease started at the time of his visit to the Highlands of Scotland, it is equally plausible that it started years before the first clinical attack. Nevertheless, how could emotional stress play a role in the pathophysiology of MS?

Stress and the Immune System

At times of chronic stress, one may become more susceptible to infections. Reactivation of certain viruses can lead to oral ulcers, increased common cold symptoms, or other illnesses. For example, stress can reactivate herpes simplex type 1 and interestingly, EBV.^16,17 In MS, the immune system is dysregulated and has an autoimmune component. The effect of acute emotional stress differs from that of chronic stress.¹⁸ Several studies have examined the immune responses to both forms of stress.^19-21

Interestingly, acute stress activates cell-mediated immunity, increases immune cell trafficking to areas of injury, and, importantly, increases blood-brain barrier (BBB) permeability by activating resident mast cells in the brain and other areas, including the optic nerves.^22,23 Mast cell activation leads to BBB disruption, which is a key early step in the pathogenesis of MS. Thus, it is plausible that the proinflammatory changes associated with acute stress could be implicated in the pathogenesis of MS. This contrasts with chronic stress, which attenuates various immune responses, including suppressing cell-mediated immunity, but also dysregulate the immune system.

One could establish a biological plausibility for stress playing a role in the proinflammatory responses in MS. Whether it is causal or not, scientists can further explore the potential biologic explanations. While studying the association between acute stress and MS development or disease activity is difficult, several groups have examined the potential association. Many studies, however, have limitations due to the difficult nature of studying such an association, especially in quantifying or defining acute stress in general.

A limited number of studies on MS and stress: What do we know? And what are the challenges?

Rare studies have reported a potential association between MS development and stressful life events, while others reported no association.^24-26 Also, some studies observed an increase in MS relapses or the development of new magnetic resonance imaging (MRI) lesions following stressful life events or wartime, while others failed to show such an association.^26-30 There are few studies directly addressing the potential association between acute emotional stress and MS. The results of published studies are variable, and limitations are numerous. Limitations include the difficulty in measuring acute emotional stress, difficulty in its prediction, and ethical challenges of experimental design and recruiting participants. So, studies have focused on observational aspects, retrospective reviews, and surveys of memories prone to various biases. Rarely was the design of these clinical studies prospective. A few prospective studies reported an association between stressful life events and increased MS relapses and increased number of brain lesions.^27,31,32 Rare clinical trials have attempted to test stress reduction strategies and reported on the modest improvement of patient-reported outcomes and, in one study, a modest improvement in new MRI lesions.^33-35

Overall, several lines of evidence support a potential association between acute emotional stress and MS. Yet, the association is challenging to study, and future research might focus on stress-mitigation strategies and improving coping mechanisms in persons living with MS. It is important to note that it will be very difficult to design prospective studies to examine the potential association between acute emotional trauma and the development of de novo MS. Such studies will require a large number of participants (e.g., hundreds of thousands), long durations of follow-up (e.g., decades), and ways to classify repeated stressful events. An alternative approach is to ask persons newly diagnosed with MS at the time of initial diagnosis about any temporal association between their first symptom and stressful life events. However, this approach would provide some information on any association between the two, but not on causality of the disease itself.

Conclusion

The potential association between acute emotional stress and MS dates to the times of early descriptions of MS. Yet, research has been very limited and challenging. To date, the potential association remains elusive. Lines of evidence, while with limitations, have provided possible biologic explanations for the relationship between MS symptom onset and acute emotional stress. Although avoiding acute emotional stress is nearly impossible, incorporating global stress-coping strategies in early childhood education and secondary education might theoretically have potential beneficial effects on the subsequent risk of MS development or symptom flare-up, depending on a variety of factors.

But for now, when patients and colleagues ask me, “Can acute emotional stress be a ‘trigger’ for MS symptomology?,” my answer will remain, “Potentially, until proven otherwise.”

Sir Augustus d’Este (1794-1848) described the circumstances preceding his development of neurological symptoms as follows:¹ “I travelled from Ramsgate to the Highlands of Scotland for the purpose of passing some days with a Relation for whom I had the affection of a Son. On my arrival I found him dead. Shortly after the funeral I was obliged to have my letters read to me, and their answers written for me, as my eyes were so attacked that when fixed upon minute objects indistinctness of vision was the consequence: Soon after I went to Ireland, and without any thing having been done to my eyes, they completely recovered their strength and distinctness of vision…" He then described a clinical course of relapsing-remitting neurologic symptoms merging into a progressive stage of unrelenting illness, most fitting with what we know today as multiple sclerosis (MS).¹ Why did Sir Augustus d'Este connect the event of the unexpected death to the onset of a lifelong neurologic disease?

Jean-Martin Charcot first described MS in a way close to what we know it as today. Charcot considered stress a factor in MS. He linked grief, vexation, and adverse changes in social circumstances to the onset of MS at that time.² I, as a practicing MS specialist, am surprised neither by Sir Augustus d'Este's diary nor by Charcot's earlier assessments of MS triggers.³ As I write this narrative, I think of the many times I heard from people diagnosed with MS. "It happened to me because of stress" is a statement not estranged from my daily clinical practice

MS as a multifactorial disease

It is tempting to make a case for emotional stress as a cause of MS, but one must remember that MS is a very complex disease with unclear etiologies. MS, a treatable but not yet curable disease, is the interplay between the genetics of the host and numerous environmental factors that exploit a susceptible immune system leading to unrelenting immune dysregulation.⁴ Recent studies have brought some pieces of this intricate puzzle together. The role of Epstein-Barr virus (EBV) in the pathogenesis of MS is being dissected.⁵ The possible synergy between vitamin D deficiency, EBV, and certain genetic variations is being studied.⁶ The roles of smoking, environmental toxins, obesity, diet, Western lifestyle, and the gut microbiome are some of the top areas of clinical, translational, and basic research.^7-11 But what about emotional stress? Where does it fit, if anywhere, in the current research paradigm?

Emotional stress and MS—Causality or not?

In the scientific method, several criteria must be proven for an element to be suspected in the etiology of a disease.¹² First, the suspect element must be present before the disease starts—i.e., a temporal association. Second, there must be a plausible biological explanation of how the suspect element acts in the disease's causation. Third, other variables that could confound the picture must be controlled for or dismissed. It is clear that no single factor is the cause of MS. By now, MS is agreed upon as a disease caused by multiple factors, some of which remain to be unraveled.⁹ The term "cause" has been utilized more recently by many authors when referring to EBV in relation to MS development, reasoning that in one study, in a small number of individuals with MS, EBV infection preceded the MS clinical diagnosis.¹³ Thus, the temporal association was provided. But does MS start at the onset of clinical symptoms?

For Sir Augustus d'Este, the disease may have started years before he visited the Highlands of Scotland, but only at that visit did MS become clinically apparent. So, the emotional trauma may have acted as a "trigger" for an MS flare-up rather than being a "cause" of MS. This might be a more plausible explanation of the association between emotional trauma and MS development. However, MS pathogenesis is complex, and one could argue that the disease starts many years before the first clinical symptoms that lead to diagnosis.

The MS prodrome has been demonstrated by several studies that suggest that MS may start many years before the clinical diagnosis.¹⁴ Radiologically isolated syndrome (RIS) further argues that MS may be clinically dormant for years, and clinical symptoms may not appear until later in the disease process.¹⁵ One may think that immune attacks on the optic nerves, spinal cord, or areas of the brainstem might be readily symptomatic compared to attacks on other structures of the central nervous system (e.g., periventricular or juxtacortical brain areas) that may be clinically silent. So, while for Sir Augustus d'Este it seemed that the disease started at the time of his visit to the Highlands of Scotland, it is equally plausible that it started years before the first clinical attack. Nevertheless, how could emotional stress play a role in the pathophysiology of MS?

Stress and the Immune System

At times of chronic stress, one may become more susceptible to infections. Reactivation of certain viruses can lead to oral ulcers, increased common cold symptoms, or other illnesses. For example, stress can reactivate herpes simplex type 1 and interestingly, EBV.^16,17 In MS, the immune system is dysregulated and has an autoimmune component. The effect of acute emotional stress differs from that of chronic stress.¹⁸ Several studies have examined the immune responses to both forms of stress.^19-21

Interestingly, acute stress activates cell-mediated immunity, increases immune cell trafficking to areas of injury, and, importantly, increases blood-brain barrier (BBB) permeability by activating resident mast cells in the brain and other areas, including the optic nerves.^22,23 Mast cell activation leads to BBB disruption, which is a key early step in the pathogenesis of MS. Thus, it is plausible that the proinflammatory changes associated with acute stress could be implicated in the pathogenesis of MS. This contrasts with chronic stress, which attenuates various immune responses, including suppressing cell-mediated immunity, but also dysregulate the immune system.

One could establish a biological plausibility for stress playing a role in the proinflammatory responses in MS. Whether it is causal or not, scientists can further explore the potential biologic explanations. While studying the association between acute stress and MS development or disease activity is difficult, several groups have examined the potential association. Many studies, however, have limitations due to the difficult nature of studying such an association, especially in quantifying or defining acute stress in general.

A limited number of studies on MS and stress: What do we know? And what are the challenges?

Rare studies have reported a potential association between MS development and stressful life events, while others reported no association.^24-26 Also, some studies observed an increase in MS relapses or the development of new magnetic resonance imaging (MRI) lesions following stressful life events or wartime, while others failed to show such an association.^26-30 There are few studies directly addressing the potential association between acute emotional stress and MS. The results of published studies are variable, and limitations are numerous. Limitations include the difficulty in measuring acute emotional stress, difficulty in its prediction, and ethical challenges of experimental design and recruiting participants. So, studies have focused on observational aspects, retrospective reviews, and surveys of memories prone to various biases. Rarely was the design of these clinical studies prospective. A few prospective studies reported an association between stressful life events and increased MS relapses and increased number of brain lesions.^27,31,32 Rare clinical trials have attempted to test stress reduction strategies and reported on the modest improvement of patient-reported outcomes and, in one study, a modest improvement in new MRI lesions.^33-35

Overall, several lines of evidence support a potential association between acute emotional stress and MS. Yet, the association is challenging to study, and future research might focus on stress-mitigation strategies and improving coping mechanisms in persons living with MS. It is important to note that it will be very difficult to design prospective studies to examine the potential association between acute emotional trauma and the development of de novo MS. Such studies will require a large number of participants (e.g., hundreds of thousands), long durations of follow-up (e.g., decades), and ways to classify repeated stressful events. An alternative approach is to ask persons newly diagnosed with MS at the time of initial diagnosis about any temporal association between their first symptom and stressful life events. However, this approach would provide some information on any association between the two, but not on causality of the disease itself.

Conclusion

The potential association between acute emotional stress and MS dates to the times of early descriptions of MS. Yet, research has been very limited and challenging. To date, the potential association remains elusive. Lines of evidence, while with limitations, have provided possible biologic explanations for the relationship between MS symptom onset and acute emotional stress. Although avoiding acute emotional stress is nearly impossible, incorporating global stress-coping strategies in early childhood education and secondary education might theoretically have potential beneficial effects on the subsequent risk of MS development or symptom flare-up, depending on a variety of factors.

But for now, when patients and colleagues ask me, “Can acute emotional stress be a ‘trigger’ for MS symptomology?,” my answer will remain, “Potentially, until proven otherwise.”

Sir Augustus d’Este (1794-1848) described the circumstances preceding his development of neurological symptoms as follows:¹ “I travelled from Ramsgate to the Highlands of Scotland for the purpose of passing some days with a Relation for whom I had the affection of a Son. On my arrival I found him dead. Shortly after the funeral I was obliged to have my letters read to me, and their answers written for me, as my eyes were so attacked that when fixed upon minute objects indistinctness of vision was the consequence: Soon after I went to Ireland, and without any thing having been done to my eyes, they completely recovered their strength and distinctness of vision…" He then described a clinical course of relapsing-remitting neurologic symptoms merging into a progressive stage of unrelenting illness, most fitting with what we know today as multiple sclerosis (MS).¹ Why did Sir Augustus d'Este connect the event of the unexpected death to the onset of a lifelong neurologic disease?

Jean-Martin Charcot first described MS in a way close to what we know it as today. Charcot considered stress a factor in MS. He linked grief, vexation, and adverse changes in social circumstances to the onset of MS at that time.² I, as a practicing MS specialist, am surprised neither by Sir Augustus d'Este's diary nor by Charcot's earlier assessments of MS triggers.³ As I write this narrative, I think of the many times I heard from people diagnosed with MS. "It happened to me because of stress" is a statement not estranged from my daily clinical practice

MS as a multifactorial disease

It is tempting to make a case for emotional stress as a cause of MS, but one must remember that MS is a very complex disease with unclear etiologies. MS, a treatable but not yet curable disease, is the interplay between the genetics of the host and numerous environmental factors that exploit a susceptible immune system leading to unrelenting immune dysregulation.⁴ Recent studies have brought some pieces of this intricate puzzle together. The role of Epstein-Barr virus (EBV) in the pathogenesis of MS is being dissected.⁵ The possible synergy between vitamin D deficiency, EBV, and certain genetic variations is being studied.⁶ The roles of smoking, environmental toxins, obesity, diet, Western lifestyle, and the gut microbiome are some of the top areas of clinical, translational, and basic research.^7-11 But what about emotional stress? Where does it fit, if anywhere, in the current research paradigm?

Emotional stress and MS—Causality or not?

In the scientific method, several criteria must be proven for an element to be suspected in the etiology of a disease.¹² First, the suspect element must be present before the disease starts—i.e., a temporal association. Second, there must be a plausible biological explanation of how the suspect element acts in the disease's causation. Third, other variables that could confound the picture must be controlled for or dismissed. It is clear that no single factor is the cause of MS. By now, MS is agreed upon as a disease caused by multiple factors, some of which remain to be unraveled.⁹ The term "cause" has been utilized more recently by many authors when referring to EBV in relation to MS development, reasoning that in one study, in a small number of individuals with MS, EBV infection preceded the MS clinical diagnosis.¹³ Thus, the temporal association was provided. But does MS start at the onset of clinical symptoms?

For Sir Augustus d'Este, the disease may have started years before he visited the Highlands of Scotland, but only at that visit did MS become clinically apparent. So, the emotional trauma may have acted as a "trigger" for an MS flare-up rather than being a "cause" of MS. This might be a more plausible explanation of the association between emotional trauma and MS development. However, MS pathogenesis is complex, and one could argue that the disease starts many years before the first clinical symptoms that lead to diagnosis.

The MS prodrome has been demonstrated by several studies that suggest that MS may start many years before the clinical diagnosis.¹⁴ Radiologically isolated syndrome (RIS) further argues that MS may be clinically dormant for years, and clinical symptoms may not appear until later in the disease process.¹⁵ One may think that immune attacks on the optic nerves, spinal cord, or areas of the brainstem might be readily symptomatic compared to attacks on other structures of the central nervous system (e.g., periventricular or juxtacortical brain areas) that may be clinically silent. So, while for Sir Augustus d'Este it seemed that the disease started at the time of his visit to the Highlands of Scotland, it is equally plausible that it started years before the first clinical attack. Nevertheless, how could emotional stress play a role in the pathophysiology of MS?

Stress and the Immune System

At times of chronic stress, one may become more susceptible to infections. Reactivation of certain viruses can lead to oral ulcers, increased common cold symptoms, or other illnesses. For example, stress can reactivate herpes simplex type 1 and interestingly, EBV.^16,17 In MS, the immune system is dysregulated and has an autoimmune component. The effect of acute emotional stress differs from that of chronic stress.¹⁸ Several studies have examined the immune responses to both forms of stress.^19-21

Interestingly, acute stress activates cell-mediated immunity, increases immune cell trafficking to areas of injury, and, importantly, increases blood-brain barrier (BBB) permeability by activating resident mast cells in the brain and other areas, including the optic nerves.^22,23 Mast cell activation leads to BBB disruption, which is a key early step in the pathogenesis of MS. Thus, it is plausible that the proinflammatory changes associated with acute stress could be implicated in the pathogenesis of MS. This contrasts with chronic stress, which attenuates various immune responses, including suppressing cell-mediated immunity, but also dysregulate the immune system.

One could establish a biological plausibility for stress playing a role in the proinflammatory responses in MS. Whether it is causal or not, scientists can further explore the potential biologic explanations. While studying the association between acute stress and MS development or disease activity is difficult, several groups have examined the potential association. Many studies, however, have limitations due to the difficult nature of studying such an association, especially in quantifying or defining acute stress in general.

A limited number of studies on MS and stress: What do we know? And what are the challenges?

Rare studies have reported a potential association between MS development and stressful life events, while others reported no association.^24-26 Also, some studies observed an increase in MS relapses or the development of new magnetic resonance imaging (MRI) lesions following stressful life events or wartime, while others failed to show such an association.^26-30 There are few studies directly addressing the potential association between acute emotional stress and MS. The results of published studies are variable, and limitations are numerous. Limitations include the difficulty in measuring acute emotional stress, difficulty in its prediction, and ethical challenges of experimental design and recruiting participants. So, studies have focused on observational aspects, retrospective reviews, and surveys of memories prone to various biases. Rarely was the design of these clinical studies prospective. A few prospective studies reported an association between stressful life events and increased MS relapses and increased number of brain lesions.^27,31,32 Rare clinical trials have attempted to test stress reduction strategies and reported on the modest improvement of patient-reported outcomes and, in one study, a modest improvement in new MRI lesions.^33-35

Overall, several lines of evidence support a potential association between acute emotional stress and MS. Yet, the association is challenging to study, and future research might focus on stress-mitigation strategies and improving coping mechanisms in persons living with MS. It is important to note that it will be very difficult to design prospective studies to examine the potential association between acute emotional trauma and the development of de novo MS. Such studies will require a large number of participants (e.g., hundreds of thousands), long durations of follow-up (e.g., decades), and ways to classify repeated stressful events. An alternative approach is to ask persons newly diagnosed with MS at the time of initial diagnosis about any temporal association between their first symptom and stressful life events. However, this approach would provide some information on any association between the two, but not on causality of the disease itself.

Conclusion

The potential association between acute emotional stress and MS dates to the times of early descriptions of MS. Yet, research has been very limited and challenging. To date, the potential association remains elusive. Lines of evidence, while with limitations, have provided possible biologic explanations for the relationship between MS symptom onset and acute emotional stress. Although avoiding acute emotional stress is nearly impossible, incorporating global stress-coping strategies in early childhood education and secondary education might theoretically have potential beneficial effects on the subsequent risk of MS development or symptom flare-up, depending on a variety of factors.

But for now, when patients and colleagues ask me, “Can acute emotional stress be a ‘trigger’ for MS symptomology?,” my answer will remain, “Potentially, until proven otherwise.”

Because of the high out-of-pocket costs of new-to-market neurologic drugs that are of similar benefit as older agents, only a small percentage of patients with neurologic disorders have access to these cutting-edge medications, new research shows.

“Our study of people with neurologic conditions found that fewer than 20% were being treated with new medications,” study author Brian C. Callaghan, MD, with University of Michigan Health in Ann Arbor, said in a statement.

“For new, high-cost medications that have similar effectiveness to older drugs, limited use is likely appropriate. However, future studies are needed to look into whether the high costs are barriers to those new medications that can really make a difference for people living with neurologic disease,” Dr. Callaghan said.

The study was published online in Neurology.
 

Most expensive drugs

Using insurance claims data, the investigators compared the utilization and costs of new-to-market drugs from 2014 to 2018 with those for existing guideline-supported medications for treating 11 neurologic conditions.

The new drugs included:

• erenumab, fremanezumab, and galcanezumab for migraine.
• ocrelizumab and peginterferon beta-1a for multiple sclerosis (MS).
• pimavanserin and safinamide for Parkinson’s disease.
• droxidopa for orthostatic hypertension.
• eculizumab for myasthenia gravis (MG).
• edaravone for amyotrophic lateral sclerosis (ALS).
• deutetrabenazine and valbenazine for Huntington’s disease and tardive dyskinesia.
• patisiran and inotersen for transthyretin amyloidosis (ATTR).
• eteplirsen and deflazacort for Duchenne disease.
• nusinersen for spinal muscular atrophy (SMA).

Utilization of new drugs was modest – they accounted for one in five prescriptions for every condition except tardive dyskinesia (32% for valbenazine), the researchers noted.

Mean out-of-pocket costs were significantly higher for the new medications, although there was large variability among individual drugs.

The two most expensive drugs were edaravone, for ALS, with a mean out-of-pocket cost of $713 for a 30-day supply, and eculizumab, for MG, which costs $91 per month.

“For new-to-market medications, the distribution of out-of-pocket costs were highly variable and the trends over time were unpredictable compared with existing guideline-supported medications,” the authors reported.

They noted that potential reasons for low utilization of newer agents include delay in provider uptake and prescriber and/or patient avoidance because of high cost.

Given that most of the new neurologic agents offer little advantage compared with existing treatments – exceptions being new drugs for SMA and ATTR – drug costs should be a key consideration in prescribing decisions, Dr. Callaghan and colleagues concluded.

One limitation of the study is that follow-up time was short for some of the recently approved medications. Another limitation is that the number of people in the study who had rare diseases was small.
 

Revolution in neurotherapeutics

“We are living in a time when new treatments bring hope to people with neurologic diseases and disorders,” Orly Avitzur, MD, president of the American Academy of Neurology, said in a statement.

“However, even existing prescription medication can be expensive and drug prices continue to rise. In order for neurologists to provide people with the highest quality care, it is imperative that new drugs are accessible and affordable to the people who need them,” Dr. Avitzur added.

Writing in a linked editorial, A. Gordon Smith, MD, professor and chair, department of neurology, Virginia Commonwealth University, Richmond, said there is a revolution in neurotherapeutics, with particularly robust growth in new drug approvals for orphan diseases (those affecting < 200,000 Americans).

“This study adds to a growing literature indicating rising drug prices are a threat to the health care system. No matter how effective a disease-modifying therapy may be, if a patient cannot afford the cost, it doesn’t work,” Dr. Smith wrote.

He added that neurologists must be “diligent in assessing for financial toxicity and appropriately tailor individual treatment recommendations. We must insist on development of point-of-care tools to accurately estimate each patient’s potential financial toxicity including RTBT [real-time benefit tools].

“Neurologists’ primary obligation is to the individual patient, but we are also compelled to support access to high-quality care for all people, which requires advocacy for appropriate policy reforms to ensure value based and fair drug pricing and treatment success,” Dr. Smith added.

The study was funded by the American Academy of Neurology Health Services Research Subcommittee. Dr. Callaghan consults for a PCORI grant, DynaMed, receives research support from the American Academy of Neurology, and performs medical/legal consultations, including consultations for the Vaccine Injury Compensation Program. Dr. Smith has disclosed no relevant financial relationships.

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

Because of the high out-of-pocket costs of new-to-market neurologic drugs that are of similar benefit as older agents, only a small percentage of patients with neurologic disorders have access to these cutting-edge medications, new research shows.

“Our study of people with neurologic conditions found that fewer than 20% were being treated with new medications,” study author Brian C. Callaghan, MD, with University of Michigan Health in Ann Arbor, said in a statement.

“For new, high-cost medications that have similar effectiveness to older drugs, limited use is likely appropriate. However, future studies are needed to look into whether the high costs are barriers to those new medications that can really make a difference for people living with neurologic disease,” Dr. Callaghan said.

The study was published online in Neurology.
 

Most expensive drugs

Using insurance claims data, the investigators compared the utilization and costs of new-to-market drugs from 2014 to 2018 with those for existing guideline-supported medications for treating 11 neurologic conditions.

The new drugs included:

• erenumab, fremanezumab, and galcanezumab for migraine.
• ocrelizumab and peginterferon beta-1a for multiple sclerosis (MS).
• pimavanserin and safinamide for Parkinson’s disease.
• droxidopa for orthostatic hypertension.
• eculizumab for myasthenia gravis (MG).
• edaravone for amyotrophic lateral sclerosis (ALS).
• deutetrabenazine and valbenazine for Huntington’s disease and tardive dyskinesia.
• patisiran and inotersen for transthyretin amyloidosis (ATTR).
• eteplirsen and deflazacort for Duchenne disease.
• nusinersen for spinal muscular atrophy (SMA).

Utilization of new drugs was modest – they accounted for one in five prescriptions for every condition except tardive dyskinesia (32% for valbenazine), the researchers noted.

Mean out-of-pocket costs were significantly higher for the new medications, although there was large variability among individual drugs.

The two most expensive drugs were edaravone, for ALS, with a mean out-of-pocket cost of $713 for a 30-day supply, and eculizumab, for MG, which costs $91 per month.

“For new-to-market medications, the distribution of out-of-pocket costs were highly variable and the trends over time were unpredictable compared with existing guideline-supported medications,” the authors reported.

They noted that potential reasons for low utilization of newer agents include delay in provider uptake and prescriber and/or patient avoidance because of high cost.

Given that most of the new neurologic agents offer little advantage compared with existing treatments – exceptions being new drugs for SMA and ATTR – drug costs should be a key consideration in prescribing decisions, Dr. Callaghan and colleagues concluded.

One limitation of the study is that follow-up time was short for some of the recently approved medications. Another limitation is that the number of people in the study who had rare diseases was small.
 

Revolution in neurotherapeutics

“We are living in a time when new treatments bring hope to people with neurologic diseases and disorders,” Orly Avitzur, MD, president of the American Academy of Neurology, said in a statement.

“However, even existing prescription medication can be expensive and drug prices continue to rise. In order for neurologists to provide people with the highest quality care, it is imperative that new drugs are accessible and affordable to the people who need them,” Dr. Avitzur added.

Writing in a linked editorial, A. Gordon Smith, MD, professor and chair, department of neurology, Virginia Commonwealth University, Richmond, said there is a revolution in neurotherapeutics, with particularly robust growth in new drug approvals for orphan diseases (those affecting < 200,000 Americans).

“This study adds to a growing literature indicating rising drug prices are a threat to the health care system. No matter how effective a disease-modifying therapy may be, if a patient cannot afford the cost, it doesn’t work,” Dr. Smith wrote.

He added that neurologists must be “diligent in assessing for financial toxicity and appropriately tailor individual treatment recommendations. We must insist on development of point-of-care tools to accurately estimate each patient’s potential financial toxicity including RTBT [real-time benefit tools].

“Neurologists’ primary obligation is to the individual patient, but we are also compelled to support access to high-quality care for all people, which requires advocacy for appropriate policy reforms to ensure value based and fair drug pricing and treatment success,” Dr. Smith added.

The study was funded by the American Academy of Neurology Health Services Research Subcommittee. Dr. Callaghan consults for a PCORI grant, DynaMed, receives research support from the American Academy of Neurology, and performs medical/legal consultations, including consultations for the Vaccine Injury Compensation Program. Dr. Smith has disclosed no relevant financial relationships.

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

Because of the high out-of-pocket costs of new-to-market neurologic drugs that are of similar benefit as older agents, only a small percentage of patients with neurologic disorders have access to these cutting-edge medications, new research shows.

“Our study of people with neurologic conditions found that fewer than 20% were being treated with new medications,” study author Brian C. Callaghan, MD, with University of Michigan Health in Ann Arbor, said in a statement.

“For new, high-cost medications that have similar effectiveness to older drugs, limited use is likely appropriate. However, future studies are needed to look into whether the high costs are barriers to those new medications that can really make a difference for people living with neurologic disease,” Dr. Callaghan said.

The study was published online in Neurology.
 

Most expensive drugs

Using insurance claims data, the investigators compared the utilization and costs of new-to-market drugs from 2014 to 2018 with those for existing guideline-supported medications for treating 11 neurologic conditions.

The new drugs included:

• erenumab, fremanezumab, and galcanezumab for migraine.
• ocrelizumab and peginterferon beta-1a for multiple sclerosis (MS).
• pimavanserin and safinamide for Parkinson’s disease.
• droxidopa for orthostatic hypertension.
• eculizumab for myasthenia gravis (MG).
• edaravone for amyotrophic lateral sclerosis (ALS).
• deutetrabenazine and valbenazine for Huntington’s disease and tardive dyskinesia.
• patisiran and inotersen for transthyretin amyloidosis (ATTR).
• eteplirsen and deflazacort for Duchenne disease.
• nusinersen for spinal muscular atrophy (SMA).

Utilization of new drugs was modest – they accounted for one in five prescriptions for every condition except tardive dyskinesia (32% for valbenazine), the researchers noted.

Mean out-of-pocket costs were significantly higher for the new medications, although there was large variability among individual drugs.

The two most expensive drugs were edaravone, for ALS, with a mean out-of-pocket cost of $713 for a 30-day supply, and eculizumab, for MG, which costs $91 per month.

“For new-to-market medications, the distribution of out-of-pocket costs were highly variable and the trends over time were unpredictable compared with existing guideline-supported medications,” the authors reported.

They noted that potential reasons for low utilization of newer agents include delay in provider uptake and prescriber and/or patient avoidance because of high cost.

Given that most of the new neurologic agents offer little advantage compared with existing treatments – exceptions being new drugs for SMA and ATTR – drug costs should be a key consideration in prescribing decisions, Dr. Callaghan and colleagues concluded.

One limitation of the study is that follow-up time was short for some of the recently approved medications. Another limitation is that the number of people in the study who had rare diseases was small.
 

Revolution in neurotherapeutics

“We are living in a time when new treatments bring hope to people with neurologic diseases and disorders,” Orly Avitzur, MD, president of the American Academy of Neurology, said in a statement.

“However, even existing prescription medication can be expensive and drug prices continue to rise. In order for neurologists to provide people with the highest quality care, it is imperative that new drugs are accessible and affordable to the people who need them,” Dr. Avitzur added.

Writing in a linked editorial, A. Gordon Smith, MD, professor and chair, department of neurology, Virginia Commonwealth University, Richmond, said there is a revolution in neurotherapeutics, with particularly robust growth in new drug approvals for orphan diseases (those affecting < 200,000 Americans).

“This study adds to a growing literature indicating rising drug prices are a threat to the health care system. No matter how effective a disease-modifying therapy may be, if a patient cannot afford the cost, it doesn’t work,” Dr. Smith wrote.

He added that neurologists must be “diligent in assessing for financial toxicity and appropriately tailor individual treatment recommendations. We must insist on development of point-of-care tools to accurately estimate each patient’s potential financial toxicity including RTBT [real-time benefit tools].

“Neurologists’ primary obligation is to the individual patient, but we are also compelled to support access to high-quality care for all people, which requires advocacy for appropriate policy reforms to ensure value based and fair drug pricing and treatment success,” Dr. Smith added.

The study was funded by the American Academy of Neurology Health Services Research Subcommittee. Dr. Callaghan consults for a PCORI grant, DynaMed, receives research support from the American Academy of Neurology, and performs medical/legal consultations, including consultations for the Vaccine Injury Compensation Program. Dr. Smith has disclosed no relevant financial relationships.

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

An international panel of experts has proposed a new way to classify multiple sclerosis (MS) that would ultimately change the way patients are diagnosed and treated. The goal is to eventually move away from the current system, which classifies MS based on disease progression into distinct relapsing-remitting, secondary progressive, and primary progressive subtypes.

Members of the International Advisory Committee on Clinical Trials in Multiple Sclerosis, which developed the framework, note the new framework is based on underlying biology of disease and acknowledges the different trajectories of individual patients. “The categorization of patients into distinct subtypes or stages is artificial,” said framework coauthor Jeffrey Cohen, MD, director of experimental therapeutics, Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic. “The rationale for the new framework was recent studies demonstrating that the biologic processes that underlie relapses and progression are present to varying degrees throughout the disease course, representing a continuum.”

The proposal was published online in The Lancet Neurology.
 

A more responsive system

Since the current MS classification, dubbed the Lublin-Reingold descriptors, was introduced, there have been calls for a different system that is more responsive to biological changes inherent in MS. The committee, which is jointly sponsored by the European Committee for Treatment and Research in Multiple Sclerosis and the U.S. National Multiple Sclerosis Society, responded by clarifying clinical course descriptions published in 1996 and 2013. The proposed framework grew out of that process.

“One of the main points is the concept that patients don’t evolve into secondary progressive MS,” Dr. Cohen said. “The processes that underlie progression and the findings of proxy measures of progression are present from the earliest stages of the disease.”

In its report, the committee reviews current data on the pathophysiology of injury and compensatory mechanisms in MS, presenting findings that suggest disease progression is caused not by a single disease mechanism, but from a combination of several processes that vary from patient to patient.

Current research studies highlighted in the report include those focused on mechanisms of injury, such as acute and chronic inflammation, myelin loss, nerve fiber and neuron loss, and mitochondrial dysfunction. How the body responds to that injury is likely to determine how MS evolves in each patient, the committee wrote.

Studies point to a range of factors that influence how MS manifests and progresses, including patients’ age at onset, biological sex, genes, race, ethnicity, comorbid health conditions, health behaviors, therapies, and social and environmental exposures.
 

Potential for better treatments

Any new framework for classifying the disease in the future would enable the development and approval of more biologically based treatment approaches, Dr. Cohen said. “One anticipated advantage of the new framework is that treatments should be evaluated based on their efficacy on biologic processes, not in artificial categories of patients.”

Dr. Cohen and other committee members acknowledged that developing the framework is just a first step in what would likely be a long and complicated process. “This proposal is among many initiatives that the committee has supported over the years as part of its overarching aim to constantly improve, update, and enhance clinical trial design and inform clinical care delivery for people living with MS and their health care teams,” committee chair Ruth Ann Marrie, MD, PhD, director of the Multiple Sclerosis Clinic at the University of Manitoba Health Sciences Center, Winnipeg, said in a press release.

Commenting on the proposal, Tony Reder, MD, professor of neurology at the University of Chicago Medicine, said the paper offers a “good framework for all trialists attempting to go beyond the usual markers.”
 

The time is right for reclassifying MS

The authors “have good reasons to propose the need for a new mechanism-driven framework to define MS progression,” wrote Takashi Yamamura, MD, PhD, director and chief of the Neuroimmunology Section and director of Multiple Sclerosis Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan, in an accompanying commentary.

Adopting biologically based definitions of MS progression will be challenging to implement, the authors admitted. The current subtype classification is woven into clinical care and research models and is the basis for regulatory approval of new therapeutics. Replacing it will take time and require external validation in the clinic and the lab.

“Although the goal is distant and many obstacles might arise (such as reaching a consensus between physicians, academia, and stakeholders), the time seems right to launch initiatives to reframe the classification of MS subtypes,” Dr. Yamamura added.

The study was supported by the German Research Foundation and the Intramural Research Program of NINDS. Dr. Cohen reported personal compensation for consulting for Biogen, Convelo, EMD Serono, Gossamer Bio, Mylan, and PSI. Dr. Yamamura has received support from AMED-CREST, Novartis, and Chiome Bioscience, and speaker honoraria from Novartis, Biogen, Chugai, Alexion, Mitsubishi-Tanabe, and Takeda.

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

An international panel of experts has proposed a new way to classify multiple sclerosis (MS) that would ultimately change the way patients are diagnosed and treated. The goal is to eventually move away from the current system, which classifies MS based on disease progression into distinct relapsing-remitting, secondary progressive, and primary progressive subtypes.

Members of the International Advisory Committee on Clinical Trials in Multiple Sclerosis, which developed the framework, note the new framework is based on underlying biology of disease and acknowledges the different trajectories of individual patients. “The categorization of patients into distinct subtypes or stages is artificial,” said framework coauthor Jeffrey Cohen, MD, director of experimental therapeutics, Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic. “The rationale for the new framework was recent studies demonstrating that the biologic processes that underlie relapses and progression are present to varying degrees throughout the disease course, representing a continuum.”

The proposal was published online in The Lancet Neurology.
 

A more responsive system

Since the current MS classification, dubbed the Lublin-Reingold descriptors, was introduced, there have been calls for a different system that is more responsive to biological changes inherent in MS. The committee, which is jointly sponsored by the European Committee for Treatment and Research in Multiple Sclerosis and the U.S. National Multiple Sclerosis Society, responded by clarifying clinical course descriptions published in 1996 and 2013. The proposed framework grew out of that process.

“One of the main points is the concept that patients don’t evolve into secondary progressive MS,” Dr. Cohen said. “The processes that underlie progression and the findings of proxy measures of progression are present from the earliest stages of the disease.”

In its report, the committee reviews current data on the pathophysiology of injury and compensatory mechanisms in MS, presenting findings that suggest disease progression is caused not by a single disease mechanism, but from a combination of several processes that vary from patient to patient.

Current research studies highlighted in the report include those focused on mechanisms of injury, such as acute and chronic inflammation, myelin loss, nerve fiber and neuron loss, and mitochondrial dysfunction. How the body responds to that injury is likely to determine how MS evolves in each patient, the committee wrote.

Studies point to a range of factors that influence how MS manifests and progresses, including patients’ age at onset, biological sex, genes, race, ethnicity, comorbid health conditions, health behaviors, therapies, and social and environmental exposures.
 

Potential for better treatments

Any new framework for classifying the disease in the future would enable the development and approval of more biologically based treatment approaches, Dr. Cohen said. “One anticipated advantage of the new framework is that treatments should be evaluated based on their efficacy on biologic processes, not in artificial categories of patients.”

Dr. Cohen and other committee members acknowledged that developing the framework is just a first step in what would likely be a long and complicated process. “This proposal is among many initiatives that the committee has supported over the years as part of its overarching aim to constantly improve, update, and enhance clinical trial design and inform clinical care delivery for people living with MS and their health care teams,” committee chair Ruth Ann Marrie, MD, PhD, director of the Multiple Sclerosis Clinic at the University of Manitoba Health Sciences Center, Winnipeg, said in a press release.

Commenting on the proposal, Tony Reder, MD, professor of neurology at the University of Chicago Medicine, said the paper offers a “good framework for all trialists attempting to go beyond the usual markers.”
 

The time is right for reclassifying MS

The authors “have good reasons to propose the need for a new mechanism-driven framework to define MS progression,” wrote Takashi Yamamura, MD, PhD, director and chief of the Neuroimmunology Section and director of Multiple Sclerosis Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan, in an accompanying commentary.

Adopting biologically based definitions of MS progression will be challenging to implement, the authors admitted. The current subtype classification is woven into clinical care and research models and is the basis for regulatory approval of new therapeutics. Replacing it will take time and require external validation in the clinic and the lab.

“Although the goal is distant and many obstacles might arise (such as reaching a consensus between physicians, academia, and stakeholders), the time seems right to launch initiatives to reframe the classification of MS subtypes,” Dr. Yamamura added.

The study was supported by the German Research Foundation and the Intramural Research Program of NINDS. Dr. Cohen reported personal compensation for consulting for Biogen, Convelo, EMD Serono, Gossamer Bio, Mylan, and PSI. Dr. Yamamura has received support from AMED-CREST, Novartis, and Chiome Bioscience, and speaker honoraria from Novartis, Biogen, Chugai, Alexion, Mitsubishi-Tanabe, and Takeda.

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

An international panel of experts has proposed a new way to classify multiple sclerosis (MS) that would ultimately change the way patients are diagnosed and treated. The goal is to eventually move away from the current system, which classifies MS based on disease progression into distinct relapsing-remitting, secondary progressive, and primary progressive subtypes.

Members of the International Advisory Committee on Clinical Trials in Multiple Sclerosis, which developed the framework, note the new framework is based on underlying biology of disease and acknowledges the different trajectories of individual patients. “The categorization of patients into distinct subtypes or stages is artificial,” said framework coauthor Jeffrey Cohen, MD, director of experimental therapeutics, Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic. “The rationale for the new framework was recent studies demonstrating that the biologic processes that underlie relapses and progression are present to varying degrees throughout the disease course, representing a continuum.”

The proposal was published online in The Lancet Neurology.
 

A more responsive system

Since the current MS classification, dubbed the Lublin-Reingold descriptors, was introduced, there have been calls for a different system that is more responsive to biological changes inherent in MS. The committee, which is jointly sponsored by the European Committee for Treatment and Research in Multiple Sclerosis and the U.S. National Multiple Sclerosis Society, responded by clarifying clinical course descriptions published in 1996 and 2013. The proposed framework grew out of that process.

“One of the main points is the concept that patients don’t evolve into secondary progressive MS,” Dr. Cohen said. “The processes that underlie progression and the findings of proxy measures of progression are present from the earliest stages of the disease.”

In its report, the committee reviews current data on the pathophysiology of injury and compensatory mechanisms in MS, presenting findings that suggest disease progression is caused not by a single disease mechanism, but from a combination of several processes that vary from patient to patient.

Current research studies highlighted in the report include those focused on mechanisms of injury, such as acute and chronic inflammation, myelin loss, nerve fiber and neuron loss, and mitochondrial dysfunction. How the body responds to that injury is likely to determine how MS evolves in each patient, the committee wrote.

Studies point to a range of factors that influence how MS manifests and progresses, including patients’ age at onset, biological sex, genes, race, ethnicity, comorbid health conditions, health behaviors, therapies, and social and environmental exposures.
 

Potential for better treatments

Any new framework for classifying the disease in the future would enable the development and approval of more biologically based treatment approaches, Dr. Cohen said. “One anticipated advantage of the new framework is that treatments should be evaluated based on their efficacy on biologic processes, not in artificial categories of patients.”

Dr. Cohen and other committee members acknowledged that developing the framework is just a first step in what would likely be a long and complicated process. “This proposal is among many initiatives that the committee has supported over the years as part of its overarching aim to constantly improve, update, and enhance clinical trial design and inform clinical care delivery for people living with MS and their health care teams,” committee chair Ruth Ann Marrie, MD, PhD, director of the Multiple Sclerosis Clinic at the University of Manitoba Health Sciences Center, Winnipeg, said in a press release.

Commenting on the proposal, Tony Reder, MD, professor of neurology at the University of Chicago Medicine, said the paper offers a “good framework for all trialists attempting to go beyond the usual markers.”
 

The time is right for reclassifying MS

The authors “have good reasons to propose the need for a new mechanism-driven framework to define MS progression,” wrote Takashi Yamamura, MD, PhD, director and chief of the Neuroimmunology Section and director of Multiple Sclerosis Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan, in an accompanying commentary.

Adopting biologically based definitions of MS progression will be challenging to implement, the authors admitted. The current subtype classification is woven into clinical care and research models and is the basis for regulatory approval of new therapeutics. Replacing it will take time and require external validation in the clinic and the lab.

“Although the goal is distant and many obstacles might arise (such as reaching a consensus between physicians, academia, and stakeholders), the time seems right to launch initiatives to reframe the classification of MS subtypes,” Dr. Yamamura added.

The study was supported by the German Research Foundation and the Intramural Research Program of NINDS. Dr. Cohen reported personal compensation for consulting for Biogen, Convelo, EMD Serono, Gossamer Bio, Mylan, and PSI. Dr. Yamamura has received support from AMED-CREST, Novartis, and Chiome Bioscience, and speaker honoraria from Novartis, Biogen, Chugai, Alexion, Mitsubishi-Tanabe, and Takeda.

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

Nondisabling relapses that occur early in the course of relapsing-remitting multiple sclerosis (RRMS) signal faster accumulation of disability relative to no early relapses, new research suggests. However, in the large registry study, this association was not found in patients treated with high-efficacy, disease-modifying therapies (DMTs) early on.

The results suggest that nondisabling relapses “should be considered in decisions to initiate or escalate treatment, including with high-efficacy therapies,” said lead author Cyrus Daruwalla, MD, department of clinical neurosciences at the University of Cambridge, and Addenbrooke’s Hospital, Cambridge, England.

Dr. Daruwalla presented the findings at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

Questioning EMA restrictions 

“We designed this project because regulators, including EMA [European Medicines Agency], restrict the use of certain DMTs to only those with disabling relapses. In particular, natalizumab [Tysabri] and fingolimod [Gilenya] can only be used as the first-line therapy for people with rapidly evolving, severe MS – which includes having two disabling relapses in a year,” Dr. Daruwalla noted.

“In clinic, when we see somebody who has a nondisabling relapse, we’re left with the question of what is the prognostic significance of that relapse, and how should it influence treatment decisions,” he added.

Using prospectively collected data from the MSBase international registry, the researchers examined data on individuals with RRMS and complete early relapse severity information. 

They compared patients with exclusively nondisabling relapses in the 2 years after definitive RRMS diagnosis with peers with no relapses within this time frame.

To mitigate the confounding effect of DMT use, the investigators performed analyses in participants untreated during follow-up, and then in those who received only older or “platform” therapies (interferon-beta, glatiramer acetate, dimethyl fumarate, or teriflunomide) during follow-up.

In the untreated cohort, 285 patients had nondisabling relapses and 4,717 had no relapses during the 2 years after diagnosis. Those with early nondisabling relapses had a significantly increased risk for disability accumulation (adjusted hazard ratio [aHR], 1.29; 95% confidence interval [CI], 1.00-1.68).

In the treated cohort, 1,074 patients had nondisabling early relapses and 7,262 did not. 

In this cohort, those treated with “platform” DMTs who had nondisabling relapses showed a significantly increased risk for disability accumulation compared with treated peers who had no relapses (aHR, 1.33; 95% CI, 1.15-1.54).

Notably, said Dr. Daruwalla, in patients treated at any point during follow-up with high-efficacy DMTs, including monoclonal antibodies, sphingosphine-1 phosphate modulators, and hematopoietic stem cell transplantation, there was no difference in disability accumulation between patients who did and did not experience nondisabling relapses (aHR, 0.90; 95% CI, 0.71-1.13).

The data clearly show that early nondisabling relapses are associated with a higher risk of disability accumulation than no early relapses in people with relapsing remitting MS,” Dr. Daruwalla said.

However, he noted, treatment with high-efficacy DMTs offers protection against disability accumulations.

“Therefore, contrary to EMA guidance, nondisabling relapses should be considered in decisions to initiate or escalate treatment, including with high-efficacy therapies,” he added.
 

Valuable, confirmatory data

Patricia Coyle, MD, professor of neurology and director of the MS Comprehensive Care Center at Stony Brook (N.Y.) University, called the study “valuable.”

“It confirms prior data that having relapses is bad in MS even if they are mild, and provides additional modest data in support of high-efficacy versus moderate-efficacy DMT,” said Dr. Coyle, who was not involved with the research.

“Although certainly not definitive, it adds to data supporting high-efficacy as preferred treatment [and] addresses a completely arbitrary governmental limitation to DMT use in Europe,” she added.

The study had no commercial funding. Dr. Daruwalla has reported no relevant financial relationships. Dr. Coyle reports having received consulting fees from Accordant, Biogen, Bristol-Myers Squibb, Celgene, Genentech/Roche, GlaxoSmithKline, Horizon, Janssen, Novartis, Sanofi Genzyme, and Viela Bio; and grant funding from Actelion, Alkermes, Bristol-Myers Squibb, CorEvitas, Genentech/Roche, Sanofi Genzyme, MedDay, and Novartis.

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

Nondisabling relapses that occur early in the course of relapsing-remitting multiple sclerosis (RRMS) signal faster accumulation of disability relative to no early relapses, new research suggests. However, in the large registry study, this association was not found in patients treated with high-efficacy, disease-modifying therapies (DMTs) early on.

The results suggest that nondisabling relapses “should be considered in decisions to initiate or escalate treatment, including with high-efficacy therapies,” said lead author Cyrus Daruwalla, MD, department of clinical neurosciences at the University of Cambridge, and Addenbrooke’s Hospital, Cambridge, England.

Dr. Daruwalla presented the findings at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

Questioning EMA restrictions 

“We designed this project because regulators, including EMA [European Medicines Agency], restrict the use of certain DMTs to only those with disabling relapses. In particular, natalizumab [Tysabri] and fingolimod [Gilenya] can only be used as the first-line therapy for people with rapidly evolving, severe MS – which includes having two disabling relapses in a year,” Dr. Daruwalla noted.

“In clinic, when we see somebody who has a nondisabling relapse, we’re left with the question of what is the prognostic significance of that relapse, and how should it influence treatment decisions,” he added.

Using prospectively collected data from the MSBase international registry, the researchers examined data on individuals with RRMS and complete early relapse severity information. 

They compared patients with exclusively nondisabling relapses in the 2 years after definitive RRMS diagnosis with peers with no relapses within this time frame.

To mitigate the confounding effect of DMT use, the investigators performed analyses in participants untreated during follow-up, and then in those who received only older or “platform” therapies (interferon-beta, glatiramer acetate, dimethyl fumarate, or teriflunomide) during follow-up.

In the untreated cohort, 285 patients had nondisabling relapses and 4,717 had no relapses during the 2 years after diagnosis. Those with early nondisabling relapses had a significantly increased risk for disability accumulation (adjusted hazard ratio [aHR], 1.29; 95% confidence interval [CI], 1.00-1.68).

In the treated cohort, 1,074 patients had nondisabling early relapses and 7,262 did not. 

In this cohort, those treated with “platform” DMTs who had nondisabling relapses showed a significantly increased risk for disability accumulation compared with treated peers who had no relapses (aHR, 1.33; 95% CI, 1.15-1.54).

Notably, said Dr. Daruwalla, in patients treated at any point during follow-up with high-efficacy DMTs, including monoclonal antibodies, sphingosphine-1 phosphate modulators, and hematopoietic stem cell transplantation, there was no difference in disability accumulation between patients who did and did not experience nondisabling relapses (aHR, 0.90; 95% CI, 0.71-1.13).

The data clearly show that early nondisabling relapses are associated with a higher risk of disability accumulation than no early relapses in people with relapsing remitting MS,” Dr. Daruwalla said.

However, he noted, treatment with high-efficacy DMTs offers protection against disability accumulations.

“Therefore, contrary to EMA guidance, nondisabling relapses should be considered in decisions to initiate or escalate treatment, including with high-efficacy therapies,” he added.
 

Valuable, confirmatory data

Patricia Coyle, MD, professor of neurology and director of the MS Comprehensive Care Center at Stony Brook (N.Y.) University, called the study “valuable.”

“It confirms prior data that having relapses is bad in MS even if they are mild, and provides additional modest data in support of high-efficacy versus moderate-efficacy DMT,” said Dr. Coyle, who was not involved with the research.

“Although certainly not definitive, it adds to data supporting high-efficacy as preferred treatment [and] addresses a completely arbitrary governmental limitation to DMT use in Europe,” she added.

The study had no commercial funding. Dr. Daruwalla has reported no relevant financial relationships. Dr. Coyle reports having received consulting fees from Accordant, Biogen, Bristol-Myers Squibb, Celgene, Genentech/Roche, GlaxoSmithKline, Horizon, Janssen, Novartis, Sanofi Genzyme, and Viela Bio; and grant funding from Actelion, Alkermes, Bristol-Myers Squibb, CorEvitas, Genentech/Roche, Sanofi Genzyme, MedDay, and Novartis.

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

Nondisabling relapses that occur early in the course of relapsing-remitting multiple sclerosis (RRMS) signal faster accumulation of disability relative to no early relapses, new research suggests. However, in the large registry study, this association was not found in patients treated with high-efficacy, disease-modifying therapies (DMTs) early on.

The results suggest that nondisabling relapses “should be considered in decisions to initiate or escalate treatment, including with high-efficacy therapies,” said lead author Cyrus Daruwalla, MD, department of clinical neurosciences at the University of Cambridge, and Addenbrooke’s Hospital, Cambridge, England.

Dr. Daruwalla presented the findings at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

Questioning EMA restrictions 

“We designed this project because regulators, including EMA [European Medicines Agency], restrict the use of certain DMTs to only those with disabling relapses. In particular, natalizumab [Tysabri] and fingolimod [Gilenya] can only be used as the first-line therapy for people with rapidly evolving, severe MS – which includes having two disabling relapses in a year,” Dr. Daruwalla noted.

“In clinic, when we see somebody who has a nondisabling relapse, we’re left with the question of what is the prognostic significance of that relapse, and how should it influence treatment decisions,” he added.

Using prospectively collected data from the MSBase international registry, the researchers examined data on individuals with RRMS and complete early relapse severity information. 

They compared patients with exclusively nondisabling relapses in the 2 years after definitive RRMS diagnosis with peers with no relapses within this time frame.

To mitigate the confounding effect of DMT use, the investigators performed analyses in participants untreated during follow-up, and then in those who received only older or “platform” therapies (interferon-beta, glatiramer acetate, dimethyl fumarate, or teriflunomide) during follow-up.

In the untreated cohort, 285 patients had nondisabling relapses and 4,717 had no relapses during the 2 years after diagnosis. Those with early nondisabling relapses had a significantly increased risk for disability accumulation (adjusted hazard ratio [aHR], 1.29; 95% confidence interval [CI], 1.00-1.68).

In the treated cohort, 1,074 patients had nondisabling early relapses and 7,262 did not. 

In this cohort, those treated with “platform” DMTs who had nondisabling relapses showed a significantly increased risk for disability accumulation compared with treated peers who had no relapses (aHR, 1.33; 95% CI, 1.15-1.54).

Notably, said Dr. Daruwalla, in patients treated at any point during follow-up with high-efficacy DMTs, including monoclonal antibodies, sphingosphine-1 phosphate modulators, and hematopoietic stem cell transplantation, there was no difference in disability accumulation between patients who did and did not experience nondisabling relapses (aHR, 0.90; 95% CI, 0.71-1.13).

The data clearly show that early nondisabling relapses are associated with a higher risk of disability accumulation than no early relapses in people with relapsing remitting MS,” Dr. Daruwalla said.

However, he noted, treatment with high-efficacy DMTs offers protection against disability accumulations.

“Therefore, contrary to EMA guidance, nondisabling relapses should be considered in decisions to initiate or escalate treatment, including with high-efficacy therapies,” he added.
 

Valuable, confirmatory data

Patricia Coyle, MD, professor of neurology and director of the MS Comprehensive Care Center at Stony Brook (N.Y.) University, called the study “valuable.”

“It confirms prior data that having relapses is bad in MS even if they are mild, and provides additional modest data in support of high-efficacy versus moderate-efficacy DMT,” said Dr. Coyle, who was not involved with the research.

“Although certainly not definitive, it adds to data supporting high-efficacy as preferred treatment [and] addresses a completely arbitrary governmental limitation to DMT use in Europe,” she added.

The study had no commercial funding. Dr. Daruwalla has reported no relevant financial relationships. Dr. Coyle reports having received consulting fees from Accordant, Biogen, Bristol-Myers Squibb, Celgene, Genentech/Roche, GlaxoSmithKline, Horizon, Janssen, Novartis, Sanofi Genzyme, and Viela Bio; and grant funding from Actelion, Alkermes, Bristol-Myers Squibb, CorEvitas, Genentech/Roche, Sanofi Genzyme, MedDay, and Novartis.

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

In two retrospective studies that drew from the international MSBase registry, autologous hematopoietic stem cell therapy (AHSCT) did not outperform a disease-modifying therapy (DMT) in patients with multiple sclerosis. One study looked at progressive MS and found no evidence of superiority. Another study in relapsing-remitting MS showed a reduction in relapses compared with treatment with the immune reconstitution therapies alemtuzumab and cladribine, though the results were not definitive.

Scant evidence supporting AHSCT for progressive MS

Some previous, small retrospective studies had suggested that AHSCT could benefit progressive MS. For example, a study published in Neurology looked at outcomes following AHSCT in 210 patients with MS and found a disability worsening–free survival of 85.5% at 5 years in relapsing-remitting MS and 71.0% in progressive MS. However, such studies are prone to bias, according to Bruce Cree, MD, PhD, who was asked to comment on the progressive MS study. Both studies were presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

AHSCT has attracted interest as a treatment for both relapsing-remitting and progressive MS, and some retrospective studies have reported signals of efficacy for both. Despite that, the biology of progressive MS is inconsistent with an expectation of success, said Tomas Kalincik, MD, PhD, who presented the two studies. “AHSCT is primarily a very potent anti-inflammatory therapy. Therefore, it is assumed that where localized, episodic inflammation is not part of the clinical picture, such as nonactive progressive MS forms, AHSCT should not be more effective than standard DMTs. In fact, in these scenarios, the potent DMTs also show at best marginal effect on disability outcomes. Therefore, the lack of evidence for superiority of the effectiveness of AHSCT over natalizumab in progressive MS is not surprising. The clinical implications of our study therefore are that the use of AHSCT in inactive progressive MS cannot be justified based on the presently available data,” said Dr. Kalincik, who is head of neuroimmunology at Royal Melbourne Hospital and head of the Clinical Outcomes Research Unit at the University of Melbourne, in an email exchange.

Dr. Cree agreed. “Right now, based on this very, very large data set that MSBase can afford, there really doesn’t seem to be a basis for this presumption that you’re going to get the therapeutic bang for the buck that you want to see with HSCT,” he said.

Despite the scientific attention that AHSCT has received, Dr. Cree has never been convinced that AHSCT is likely to be broadly useful in MS. “The simple concept is that MS is an autoimmune disease, so if you can reset the immune system, that you would eradicate MS in that individual, and then that individual would be fine thereafter. It’s a bit naive, but nonetheless, it’s an OK concept to begin a series of studies for investigation. I think there’s a potential place for this in relapsing disease, but when it comes to a cure for progressive MS, everything that we understand about this disease is pointing away from a peripheral immune system inflammatory etiology as the driver for what is causing progression, and so we have to, in my opinion, think about other possible etiologies for what might be driving and underlying disability worsening in progressive MS,” said Dr. Cree.
 

Two studies

In the progressive MS study, the researchers conducted a propensity-matched analysis of 39 patients treated with AHSCT and 65 who were treated with natalizumab. There were no significant differences between the two groups in overall annualized relapse rate or annual relapse rate by year. Disability outcomes were also similar, with no differences in worsening or improvement.

In the relapsing-remitting MS study, Dr. Kalincik’s group drew on data from 6 centers as well as the MSBase registry. They compared outcomes following AHSCT with outcomes of patients taking the immune-reconstitution DMTs mitoxantrone, alemtuzumab, and cladribine. The study included matched cohorts of 135 patients treated with AHSCT versus 312 treated with alemtuzumab, 72 treated with AHSCT versus 164 treated with cladribine, and 30 treated with AHSCT versus 100 treated with mitoxantrone. All groups had similar outcomes, with the exception of a greater likelihood of confirmed disability improvement in treatment with AHSCT versus alemtuzumab (hazard ratio, 1.63; P = .02). The cumulative probability of improvement was higher in the AHSCT group both at year 2 (28% versus 19%) and year 4 (30% versus 22%).

“The analysis suggested trends that may favor the effectiveness AHSCT over alemtuzumab, cladribine, and mitoxantrone, but the analysis was not fully powered. More research with larger cohorts is needed,” said Dr. Kalincik.

Dr. Cree has consulted for Biogen. Dr. Kalincik has financial relationships with Merck, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Biogen, Eisai, Teva, BioCSL, and Celgene.
 

In two retrospective studies that drew from the international MSBase registry, autologous hematopoietic stem cell therapy (AHSCT) did not outperform a disease-modifying therapy (DMT) in patients with multiple sclerosis. One study looked at progressive MS and found no evidence of superiority. Another study in relapsing-remitting MS showed a reduction in relapses compared with treatment with the immune reconstitution therapies alemtuzumab and cladribine, though the results were not definitive.

Scant evidence supporting AHSCT for progressive MS

Some previous, small retrospective studies had suggested that AHSCT could benefit progressive MS. For example, a study published in Neurology looked at outcomes following AHSCT in 210 patients with MS and found a disability worsening–free survival of 85.5% at 5 years in relapsing-remitting MS and 71.0% in progressive MS. However, such studies are prone to bias, according to Bruce Cree, MD, PhD, who was asked to comment on the progressive MS study. Both studies were presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

AHSCT has attracted interest as a treatment for both relapsing-remitting and progressive MS, and some retrospective studies have reported signals of efficacy for both. Despite that, the biology of progressive MS is inconsistent with an expectation of success, said Tomas Kalincik, MD, PhD, who presented the two studies. “AHSCT is primarily a very potent anti-inflammatory therapy. Therefore, it is assumed that where localized, episodic inflammation is not part of the clinical picture, such as nonactive progressive MS forms, AHSCT should not be more effective than standard DMTs. In fact, in these scenarios, the potent DMTs also show at best marginal effect on disability outcomes. Therefore, the lack of evidence for superiority of the effectiveness of AHSCT over natalizumab in progressive MS is not surprising. The clinical implications of our study therefore are that the use of AHSCT in inactive progressive MS cannot be justified based on the presently available data,” said Dr. Kalincik, who is head of neuroimmunology at Royal Melbourne Hospital and head of the Clinical Outcomes Research Unit at the University of Melbourne, in an email exchange.

Dr. Cree agreed. “Right now, based on this very, very large data set that MSBase can afford, there really doesn’t seem to be a basis for this presumption that you’re going to get the therapeutic bang for the buck that you want to see with HSCT,” he said.

Despite the scientific attention that AHSCT has received, Dr. Cree has never been convinced that AHSCT is likely to be broadly useful in MS. “The simple concept is that MS is an autoimmune disease, so if you can reset the immune system, that you would eradicate MS in that individual, and then that individual would be fine thereafter. It’s a bit naive, but nonetheless, it’s an OK concept to begin a series of studies for investigation. I think there’s a potential place for this in relapsing disease, but when it comes to a cure for progressive MS, everything that we understand about this disease is pointing away from a peripheral immune system inflammatory etiology as the driver for what is causing progression, and so we have to, in my opinion, think about other possible etiologies for what might be driving and underlying disability worsening in progressive MS,” said Dr. Cree.
 

Two studies

In the progressive MS study, the researchers conducted a propensity-matched analysis of 39 patients treated with AHSCT and 65 who were treated with natalizumab. There were no significant differences between the two groups in overall annualized relapse rate or annual relapse rate by year. Disability outcomes were also similar, with no differences in worsening or improvement.

In the relapsing-remitting MS study, Dr. Kalincik’s group drew on data from 6 centers as well as the MSBase registry. They compared outcomes following AHSCT with outcomes of patients taking the immune-reconstitution DMTs mitoxantrone, alemtuzumab, and cladribine. The study included matched cohorts of 135 patients treated with AHSCT versus 312 treated with alemtuzumab, 72 treated with AHSCT versus 164 treated with cladribine, and 30 treated with AHSCT versus 100 treated with mitoxantrone. All groups had similar outcomes, with the exception of a greater likelihood of confirmed disability improvement in treatment with AHSCT versus alemtuzumab (hazard ratio, 1.63; P = .02). The cumulative probability of improvement was higher in the AHSCT group both at year 2 (28% versus 19%) and year 4 (30% versus 22%).

“The analysis suggested trends that may favor the effectiveness AHSCT over alemtuzumab, cladribine, and mitoxantrone, but the analysis was not fully powered. More research with larger cohorts is needed,” said Dr. Kalincik.

Dr. Cree has consulted for Biogen. Dr. Kalincik has financial relationships with Merck, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Biogen, Eisai, Teva, BioCSL, and Celgene.
 

In two retrospective studies that drew from the international MSBase registry, autologous hematopoietic stem cell therapy (AHSCT) did not outperform a disease-modifying therapy (DMT) in patients with multiple sclerosis. One study looked at progressive MS and found no evidence of superiority. Another study in relapsing-remitting MS showed a reduction in relapses compared with treatment with the immune reconstitution therapies alemtuzumab and cladribine, though the results were not definitive.

Scant evidence supporting AHSCT for progressive MS

Some previous, small retrospective studies had suggested that AHSCT could benefit progressive MS. For example, a study published in Neurology looked at outcomes following AHSCT in 210 patients with MS and found a disability worsening–free survival of 85.5% at 5 years in relapsing-remitting MS and 71.0% in progressive MS. However, such studies are prone to bias, according to Bruce Cree, MD, PhD, who was asked to comment on the progressive MS study. Both studies were presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

AHSCT has attracted interest as a treatment for both relapsing-remitting and progressive MS, and some retrospective studies have reported signals of efficacy for both. Despite that, the biology of progressive MS is inconsistent with an expectation of success, said Tomas Kalincik, MD, PhD, who presented the two studies. “AHSCT is primarily a very potent anti-inflammatory therapy. Therefore, it is assumed that where localized, episodic inflammation is not part of the clinical picture, such as nonactive progressive MS forms, AHSCT should not be more effective than standard DMTs. In fact, in these scenarios, the potent DMTs also show at best marginal effect on disability outcomes. Therefore, the lack of evidence for superiority of the effectiveness of AHSCT over natalizumab in progressive MS is not surprising. The clinical implications of our study therefore are that the use of AHSCT in inactive progressive MS cannot be justified based on the presently available data,” said Dr. Kalincik, who is head of neuroimmunology at Royal Melbourne Hospital and head of the Clinical Outcomes Research Unit at the University of Melbourne, in an email exchange.

Dr. Cree agreed. “Right now, based on this very, very large data set that MSBase can afford, there really doesn’t seem to be a basis for this presumption that you’re going to get the therapeutic bang for the buck that you want to see with HSCT,” he said.

Despite the scientific attention that AHSCT has received, Dr. Cree has never been convinced that AHSCT is likely to be broadly useful in MS. “The simple concept is that MS is an autoimmune disease, so if you can reset the immune system, that you would eradicate MS in that individual, and then that individual would be fine thereafter. It’s a bit naive, but nonetheless, it’s an OK concept to begin a series of studies for investigation. I think there’s a potential place for this in relapsing disease, but when it comes to a cure for progressive MS, everything that we understand about this disease is pointing away from a peripheral immune system inflammatory etiology as the driver for what is causing progression, and so we have to, in my opinion, think about other possible etiologies for what might be driving and underlying disability worsening in progressive MS,” said Dr. Cree.
 

Two studies

In the progressive MS study, the researchers conducted a propensity-matched analysis of 39 patients treated with AHSCT and 65 who were treated with natalizumab. There were no significant differences between the two groups in overall annualized relapse rate or annual relapse rate by year. Disability outcomes were also similar, with no differences in worsening or improvement.

In the relapsing-remitting MS study, Dr. Kalincik’s group drew on data from 6 centers as well as the MSBase registry. They compared outcomes following AHSCT with outcomes of patients taking the immune-reconstitution DMTs mitoxantrone, alemtuzumab, and cladribine. The study included matched cohorts of 135 patients treated with AHSCT versus 312 treated with alemtuzumab, 72 treated with AHSCT versus 164 treated with cladribine, and 30 treated with AHSCT versus 100 treated with mitoxantrone. All groups had similar outcomes, with the exception of a greater likelihood of confirmed disability improvement in treatment with AHSCT versus alemtuzumab (hazard ratio, 1.63; P = .02). The cumulative probability of improvement was higher in the AHSCT group both at year 2 (28% versus 19%) and year 4 (30% versus 22%).

“The analysis suggested trends that may favor the effectiveness AHSCT over alemtuzumab, cladribine, and mitoxantrone, but the analysis was not fully powered. More research with larger cohorts is needed,” said Dr. Kalincik.

Dr. Cree has consulted for Biogen. Dr. Kalincik has financial relationships with Merck, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Biogen, Eisai, Teva, BioCSL, and Celgene.
 

Epstein-Barr Virus (EBV) is a suspect in the development of multiple sclerosis (MS), and recent research developments have strengthened that connection. In 2022, two studies received quite a bit of attention. One showed that EBV seroconversion occurs in the years prior to MS diagnosis in virtually every patient, and that serum levels of the neuronal damage biomarker neurofilament light (NfL) rose following EBV infection. Another paper showed anti-EBNA (Epstein-Barr nuclear antigen) antibodies in the cerebrospinal fluid cross-react with the central nervous system antigen GlialCAM in some MS patients.

Based on those studies, “it’s tempting to speculate that primary EBV infection could be a trigger to the autoimmune process suspected for MS,” said Tilman Schneider-Hohendorf, PhD, during a presentation at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Dr. Schneider-Hohendorf, who is a postdoctoral fellow at the University of Münster, Germany, presented a new study that added more evidence that EBV may be a key player in MS pathogenesis. He and colleagues conducted a genetic analysis of patient T cells and found evidence that EBV viral activity may be occurring during MS.
 

A viral pathway to MS

Asked for comment, Bruce Cree, MD, PhD, said: “I think it is a very interesting one, because what we know about EBV is that it’s a risk factor for MS. So many studies performed over the last 20 years have shown a very strong association between EBV infection and the occurrence of MS. Studies have shown quite conclusively that EBV infection precedes MS in almost every patient, and that EBV infection is followed by a rise in serum NfL, which is a biomarker of neuronal damage. You have EBV infection, and then typically several years later a rise in serum concentrations of this marker of neuronal injury, and this is all in a presymptomatic state. Then that is followed by the onset of clinical symptoms in MS. That temporal sequence, I think, is very convincing,” said Dr. Cree, who is a professor of clinical neurology at the University of California, San Francisco.

He pointed out that EBV is not the sole causal pathway of MS, since genetic and environmental factors are known to be involved. “Nonetheless, it’s very strong evidence to indicate that this virus is involved in disease pathogenesis,” said Dr. Cree.

The new research takes the work a step further by revealing a population of T cells in MS patients that appear to be responding directly to EBV during active viral disease. That could be telling because most people who experience an EBV infection and experience mononucleosis recover, and some never even realize they have been infected. As a herpes virus, EBV remains in a latent state in B cells and other immune cells. “We know that you need an EBV infection (to trigger MS), but is EBV in some way continuing to be active in MS?” said Dr. Cree.

Other groups have looked for such evidence, but results have been mixed. Dr. Cree’s own group looked for evidence of EBV in spinal fluid of MS patients when they first present with symptoms, and could find no evidence. On the other hand, an autopsy study of MS patients has found evidence of chronic EBV infection in and around the brain, including the meninges, which could implicate the B cells found in that region. Another study found EBV-targeting antibodies that cross react with neuronal antigens in the cerebral spinal fluid of MS patients. “So depending on the assay used and the types of investigation, there is variable evidence to indicate that EBV has a role in ongoing MS pathogenesis – that it isn’t just a risk factor for MS that triggers the disease but potentially has a role in determining the course of MS,” said Dr. Cree.
 

IS EBV part of MS pathogenesis?

The new study presented at ECTRIMS by Dr. Schneider-Hohendorf offered evidence that MS patients have excess CD8-positive T cells that recognize EBV antigens typically shed during active viral infection. The results suggest “that the immune system is responding to that chronic infection,” said Dr. Cree.

The findings have some implications for a clinical study now in progress, called EMBOLD, which is looking at whether a heterologous infusion of T cells that have been primed to attack EBV could improve symptoms of progressive MS. “The hypothesis there is that chronically infected cells within the body are causing progressive MS and that if we could eradicate those cells, both within the central nervous system and within the periphery, perhaps we could see improvement in MS functional outcomes,” said Dr. Cree, who is a co-investigator for the EMBOLD study. The trial is using T cells from donors that are matched for the human leukocyte antigen complex, which is hoped will target and kill EBV-infected cells.

The study presented by Dr. Schneider-Hohendorf supports the approach. “There is an implication from this study that the trial that that’s currently being conducted might actually possibly have a benefit in the sense that there’s now another piece of evidence to indicate that EBV is not only a risk factor for MS, but may actually participate during the course of the disease as part of the pathogenesis,” said Dr. Cree.

In the new study, the researchers sequenced the T-cell receptor variable beta-chain (TRBV) peripheral repertoire among three cohorts of MS patients: A discovery cohort with 1,336 patients with MS and 229 controls; a validation cohort with 59 patients with MS and 51 controls; and 35 monozygotic twins who were discordant for MS. They identified sequences known to bind to EBV, SARS-CoV-2, cytomegalovirus, and influenza A, and used the latter three viruses as a proof of concept to demonstrate the validity of the approach. EBV-specific MHC-1 restricted CD8 TRBV in the serum of MS patients, with large effect sizes in the discovery (+2.2), validation (+2.1), and MS twin (+1.6) populations. The findings in the twin population rule out a genetic or environmental explanation for the findings in the discovery and validation cohorts, according to Dr. Schneider-Hohendorf.

The researchers also sequenced CSF among six healthy donors and five patients with MS and found significant differences. The T-cell populations had more lytic properties that suggested ongoing immune surveillance. “We can conclude that we found a broader response that could indicate an aberrant immune response. This could be a remnant of disease triggering an event or it could indicate an ongoing immune response to EBV. Is this EBV activity? We really don’t know. To find out, we would expand our pathogen-specific sequences, we would assess CNS tissue and lesions, and we would define the primary response in pediatric cohorts to better understand what might go wrong,” Dr. Schneider-Hohendorf concluded.

Dr. Cree has a financial relationship with Biogen and is a co-investigator for the EMBOLD trial. Dr. Schneider-Hohendorf has financial relationships with Biogen, Novartis, and Roche.

Epstein-Barr Virus (EBV) is a suspect in the development of multiple sclerosis (MS), and recent research developments have strengthened that connection. In 2022, two studies received quite a bit of attention. One showed that EBV seroconversion occurs in the years prior to MS diagnosis in virtually every patient, and that serum levels of the neuronal damage biomarker neurofilament light (NfL) rose following EBV infection. Another paper showed anti-EBNA (Epstein-Barr nuclear antigen) antibodies in the cerebrospinal fluid cross-react with the central nervous system antigen GlialCAM in some MS patients.

Based on those studies, “it’s tempting to speculate that primary EBV infection could be a trigger to the autoimmune process suspected for MS,” said Tilman Schneider-Hohendorf, PhD, during a presentation at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Dr. Schneider-Hohendorf, who is a postdoctoral fellow at the University of Münster, Germany, presented a new study that added more evidence that EBV may be a key player in MS pathogenesis. He and colleagues conducted a genetic analysis of patient T cells and found evidence that EBV viral activity may be occurring during MS.
 

A viral pathway to MS

Asked for comment, Bruce Cree, MD, PhD, said: “I think it is a very interesting one, because what we know about EBV is that it’s a risk factor for MS. So many studies performed over the last 20 years have shown a very strong association between EBV infection and the occurrence of MS. Studies have shown quite conclusively that EBV infection precedes MS in almost every patient, and that EBV infection is followed by a rise in serum NfL, which is a biomarker of neuronal damage. You have EBV infection, and then typically several years later a rise in serum concentrations of this marker of neuronal injury, and this is all in a presymptomatic state. Then that is followed by the onset of clinical symptoms in MS. That temporal sequence, I think, is very convincing,” said Dr. Cree, who is a professor of clinical neurology at the University of California, San Francisco.

He pointed out that EBV is not the sole causal pathway of MS, since genetic and environmental factors are known to be involved. “Nonetheless, it’s very strong evidence to indicate that this virus is involved in disease pathogenesis,” said Dr. Cree.

The new research takes the work a step further by revealing a population of T cells in MS patients that appear to be responding directly to EBV during active viral disease. That could be telling because most people who experience an EBV infection and experience mononucleosis recover, and some never even realize they have been infected. As a herpes virus, EBV remains in a latent state in B cells and other immune cells. “We know that you need an EBV infection (to trigger MS), but is EBV in some way continuing to be active in MS?” said Dr. Cree.

Other groups have looked for such evidence, but results have been mixed. Dr. Cree’s own group looked for evidence of EBV in spinal fluid of MS patients when they first present with symptoms, and could find no evidence. On the other hand, an autopsy study of MS patients has found evidence of chronic EBV infection in and around the brain, including the meninges, which could implicate the B cells found in that region. Another study found EBV-targeting antibodies that cross react with neuronal antigens in the cerebral spinal fluid of MS patients. “So depending on the assay used and the types of investigation, there is variable evidence to indicate that EBV has a role in ongoing MS pathogenesis – that it isn’t just a risk factor for MS that triggers the disease but potentially has a role in determining the course of MS,” said Dr. Cree.
 

IS EBV part of MS pathogenesis?

The new study presented at ECTRIMS by Dr. Schneider-Hohendorf offered evidence that MS patients have excess CD8-positive T cells that recognize EBV antigens typically shed during active viral infection. The results suggest “that the immune system is responding to that chronic infection,” said Dr. Cree.

The findings have some implications for a clinical study now in progress, called EMBOLD, which is looking at whether a heterologous infusion of T cells that have been primed to attack EBV could improve symptoms of progressive MS. “The hypothesis there is that chronically infected cells within the body are causing progressive MS and that if we could eradicate those cells, both within the central nervous system and within the periphery, perhaps we could see improvement in MS functional outcomes,” said Dr. Cree, who is a co-investigator for the EMBOLD study. The trial is using T cells from donors that are matched for the human leukocyte antigen complex, which is hoped will target and kill EBV-infected cells.

The study presented by Dr. Schneider-Hohendorf supports the approach. “There is an implication from this study that the trial that that’s currently being conducted might actually possibly have a benefit in the sense that there’s now another piece of evidence to indicate that EBV is not only a risk factor for MS, but may actually participate during the course of the disease as part of the pathogenesis,” said Dr. Cree.

In the new study, the researchers sequenced the T-cell receptor variable beta-chain (TRBV) peripheral repertoire among three cohorts of MS patients: A discovery cohort with 1,336 patients with MS and 229 controls; a validation cohort with 59 patients with MS and 51 controls; and 35 monozygotic twins who were discordant for MS. They identified sequences known to bind to EBV, SARS-CoV-2, cytomegalovirus, and influenza A, and used the latter three viruses as a proof of concept to demonstrate the validity of the approach. EBV-specific MHC-1 restricted CD8 TRBV in the serum of MS patients, with large effect sizes in the discovery (+2.2), validation (+2.1), and MS twin (+1.6) populations. The findings in the twin population rule out a genetic or environmental explanation for the findings in the discovery and validation cohorts, according to Dr. Schneider-Hohendorf.

The researchers also sequenced CSF among six healthy donors and five patients with MS and found significant differences. The T-cell populations had more lytic properties that suggested ongoing immune surveillance. “We can conclude that we found a broader response that could indicate an aberrant immune response. This could be a remnant of disease triggering an event or it could indicate an ongoing immune response to EBV. Is this EBV activity? We really don’t know. To find out, we would expand our pathogen-specific sequences, we would assess CNS tissue and lesions, and we would define the primary response in pediatric cohorts to better understand what might go wrong,” Dr. Schneider-Hohendorf concluded.

Dr. Cree has a financial relationship with Biogen and is a co-investigator for the EMBOLD trial. Dr. Schneider-Hohendorf has financial relationships with Biogen, Novartis, and Roche.

Epstein-Barr Virus (EBV) is a suspect in the development of multiple sclerosis (MS), and recent research developments have strengthened that connection. In 2022, two studies received quite a bit of attention. One showed that EBV seroconversion occurs in the years prior to MS diagnosis in virtually every patient, and that serum levels of the neuronal damage biomarker neurofilament light (NfL) rose following EBV infection. Another paper showed anti-EBNA (Epstein-Barr nuclear antigen) antibodies in the cerebrospinal fluid cross-react with the central nervous system antigen GlialCAM in some MS patients.

Based on those studies, “it’s tempting to speculate that primary EBV infection could be a trigger to the autoimmune process suspected for MS,” said Tilman Schneider-Hohendorf, PhD, during a presentation at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Dr. Schneider-Hohendorf, who is a postdoctoral fellow at the University of Münster, Germany, presented a new study that added more evidence that EBV may be a key player in MS pathogenesis. He and colleagues conducted a genetic analysis of patient T cells and found evidence that EBV viral activity may be occurring during MS.
 

A viral pathway to MS

Asked for comment, Bruce Cree, MD, PhD, said: “I think it is a very interesting one, because what we know about EBV is that it’s a risk factor for MS. So many studies performed over the last 20 years have shown a very strong association between EBV infection and the occurrence of MS. Studies have shown quite conclusively that EBV infection precedes MS in almost every patient, and that EBV infection is followed by a rise in serum NfL, which is a biomarker of neuronal damage. You have EBV infection, and then typically several years later a rise in serum concentrations of this marker of neuronal injury, and this is all in a presymptomatic state. Then that is followed by the onset of clinical symptoms in MS. That temporal sequence, I think, is very convincing,” said Dr. Cree, who is a professor of clinical neurology at the University of California, San Francisco.

He pointed out that EBV is not the sole causal pathway of MS, since genetic and environmental factors are known to be involved. “Nonetheless, it’s very strong evidence to indicate that this virus is involved in disease pathogenesis,” said Dr. Cree.

The new research takes the work a step further by revealing a population of T cells in MS patients that appear to be responding directly to EBV during active viral disease. That could be telling because most people who experience an EBV infection and experience mononucleosis recover, and some never even realize they have been infected. As a herpes virus, EBV remains in a latent state in B cells and other immune cells. “We know that you need an EBV infection (to trigger MS), but is EBV in some way continuing to be active in MS?” said Dr. Cree.

Other groups have looked for such evidence, but results have been mixed. Dr. Cree’s own group looked for evidence of EBV in spinal fluid of MS patients when they first present with symptoms, and could find no evidence. On the other hand, an autopsy study of MS patients has found evidence of chronic EBV infection in and around the brain, including the meninges, which could implicate the B cells found in that region. Another study found EBV-targeting antibodies that cross react with neuronal antigens in the cerebral spinal fluid of MS patients. “So depending on the assay used and the types of investigation, there is variable evidence to indicate that EBV has a role in ongoing MS pathogenesis – that it isn’t just a risk factor for MS that triggers the disease but potentially has a role in determining the course of MS,” said Dr. Cree.
 

IS EBV part of MS pathogenesis?

The new study presented at ECTRIMS by Dr. Schneider-Hohendorf offered evidence that MS patients have excess CD8-positive T cells that recognize EBV antigens typically shed during active viral infection. The results suggest “that the immune system is responding to that chronic infection,” said Dr. Cree.

The findings have some implications for a clinical study now in progress, called EMBOLD, which is looking at whether a heterologous infusion of T cells that have been primed to attack EBV could improve symptoms of progressive MS. “The hypothesis there is that chronically infected cells within the body are causing progressive MS and that if we could eradicate those cells, both within the central nervous system and within the periphery, perhaps we could see improvement in MS functional outcomes,” said Dr. Cree, who is a co-investigator for the EMBOLD study. The trial is using T cells from donors that are matched for the human leukocyte antigen complex, which is hoped will target and kill EBV-infected cells.

The study presented by Dr. Schneider-Hohendorf supports the approach. “There is an implication from this study that the trial that that’s currently being conducted might actually possibly have a benefit in the sense that there’s now another piece of evidence to indicate that EBV is not only a risk factor for MS, but may actually participate during the course of the disease as part of the pathogenesis,” said Dr. Cree.

In the new study, the researchers sequenced the T-cell receptor variable beta-chain (TRBV) peripheral repertoire among three cohorts of MS patients: A discovery cohort with 1,336 patients with MS and 229 controls; a validation cohort with 59 patients with MS and 51 controls; and 35 monozygotic twins who were discordant for MS. They identified sequences known to bind to EBV, SARS-CoV-2, cytomegalovirus, and influenza A, and used the latter three viruses as a proof of concept to demonstrate the validity of the approach. EBV-specific MHC-1 restricted CD8 TRBV in the serum of MS patients, with large effect sizes in the discovery (+2.2), validation (+2.1), and MS twin (+1.6) populations. The findings in the twin population rule out a genetic or environmental explanation for the findings in the discovery and validation cohorts, according to Dr. Schneider-Hohendorf.

The researchers also sequenced CSF among six healthy donors and five patients with MS and found significant differences. The T-cell populations had more lytic properties that suggested ongoing immune surveillance. “We can conclude that we found a broader response that could indicate an aberrant immune response. This could be a remnant of disease triggering an event or it could indicate an ongoing immune response to EBV. Is this EBV activity? We really don’t know. To find out, we would expand our pathogen-specific sequences, we would assess CNS tissue and lesions, and we would define the primary response in pediatric cohorts to better understand what might go wrong,” Dr. Schneider-Hohendorf concluded.

Dr. Cree has a financial relationship with Biogen and is a co-investigator for the EMBOLD trial. Dr. Schneider-Hohendorf has financial relationships with Biogen, Novartis, and Roche.

New research confirms the importance of COVID-19 mRNA booster doses for patients with multiple sclerosis (MS) who are receiving the anti-CD20 monoclonal antibody ocrelizumab (Ocrevus), as currently recommended.

“We have shown that even MS patients whose B cells were depleted from circulation with ocrelizumab can mount immune responses to COVID-19 vaccines,” said lead study author Ilya Kister, MD, of NYU Langone’s Multiple Sclerosis Comprehensive Care Center in New York.

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

VIOLA study

The data stem from VIOLA, an ongoing prospective study of humoral and cellular immune responses to COVID-19 vaccines in 60 patients with MS receiving ocrelizumab at MS care centers at NYU Langone and the University of Colorado Denver.

The mean age of participants was 38 years, 73% were women, all had been taking ocrelizumab for a mean of 1.7 years, and 45% had had COVID-19 prior to vaccination.

The researchers examined antibody and cellular responses to the two-dose series of mRNA COVID-19 vaccine (80% received the Pfizer-BioNTech vaccine, 18% the Moderna vaccine, and 2% unknown) over 24 weeks. In addition, 57% of the participants received the third dose/booster.

Results showed that antibody and cellular responses to SARS-CoV-2 spike protein significantly increased after the two-dose mRNA COVID-19 vaccination, though antibody responses tended to peak between 4 and 12 weeks and declined thereafter. There was no significant decline in cellular responses at week 24.

“The third dose ‘booster’ again significantly increased antibody and cellular responses compared with the pre–third dose levels,” Dr. Kister said.

“Importantly, cellular responses remained elevated or even increased from 4 weeks to 12 weeks after third dose/booster. Overall, these data strongly support the need for a third dose in MS patients on ocrelizumab,” Dr. Kister added.

Participants with “hybrid immunity” (those who had been infected with SARS-CoV-2 and who had also been vaccinated for COVID) had markedly higher SARS-CoV-2–specific antibody and cellular responses than those of peers with vaccine-only immunity.
 

CDC recs

Looking ahead, Dr. Kister said the VIOLA investigators plan to present data on the durability of COVID-19 vaccines in ocrelizumab-treated patients up to 48 weeks after the third dose.

For immunocompromised patients, such as those taking ocrelizumab, the Centers for Disease Control and Prevention considers the third dose of mRNA vaccine not as a “booster” but as part of the regular vaccine series.

“In other words, all these patients should receive three doses as part of their ‘primary’ series,” Dr. Kister noted.

The CDC also recommends receiving the updated booster for COVID-19 that became available in September 2022 (the fourth dose of the vaccine).

“Our study did not evaluate the efficacy of this fourth dose; but based on our results, it is reasonable to suppose that the fourth dose would also lead to a further increase in immune defenses,” Dr. Kister said.

The VIOLA study is an investigator-initiated collaboration supported by F. Hoffmann-La Roche Ltd/Genentech Inc. Dr. Kister has reported no relevant financial relationships.

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

New research confirms the importance of COVID-19 mRNA booster doses for patients with multiple sclerosis (MS) who are receiving the anti-CD20 monoclonal antibody ocrelizumab (Ocrevus), as currently recommended.

“We have shown that even MS patients whose B cells were depleted from circulation with ocrelizumab can mount immune responses to COVID-19 vaccines,” said lead study author Ilya Kister, MD, of NYU Langone’s Multiple Sclerosis Comprehensive Care Center in New York.

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

VIOLA study

The data stem from VIOLA, an ongoing prospective study of humoral and cellular immune responses to COVID-19 vaccines in 60 patients with MS receiving ocrelizumab at MS care centers at NYU Langone and the University of Colorado Denver.

The mean age of participants was 38 years, 73% were women, all had been taking ocrelizumab for a mean of 1.7 years, and 45% had had COVID-19 prior to vaccination.

The researchers examined antibody and cellular responses to the two-dose series of mRNA COVID-19 vaccine (80% received the Pfizer-BioNTech vaccine, 18% the Moderna vaccine, and 2% unknown) over 24 weeks. In addition, 57% of the participants received the third dose/booster.

Results showed that antibody and cellular responses to SARS-CoV-2 spike protein significantly increased after the two-dose mRNA COVID-19 vaccination, though antibody responses tended to peak between 4 and 12 weeks and declined thereafter. There was no significant decline in cellular responses at week 24.

“The third dose ‘booster’ again significantly increased antibody and cellular responses compared with the pre–third dose levels,” Dr. Kister said.

“Importantly, cellular responses remained elevated or even increased from 4 weeks to 12 weeks after third dose/booster. Overall, these data strongly support the need for a third dose in MS patients on ocrelizumab,” Dr. Kister added.

Participants with “hybrid immunity” (those who had been infected with SARS-CoV-2 and who had also been vaccinated for COVID) had markedly higher SARS-CoV-2–specific antibody and cellular responses than those of peers with vaccine-only immunity.
 

CDC recs

Looking ahead, Dr. Kister said the VIOLA investigators plan to present data on the durability of COVID-19 vaccines in ocrelizumab-treated patients up to 48 weeks after the third dose.

For immunocompromised patients, such as those taking ocrelizumab, the Centers for Disease Control and Prevention considers the third dose of mRNA vaccine not as a “booster” but as part of the regular vaccine series.

“In other words, all these patients should receive three doses as part of their ‘primary’ series,” Dr. Kister noted.

The CDC also recommends receiving the updated booster for COVID-19 that became available in September 2022 (the fourth dose of the vaccine).

“Our study did not evaluate the efficacy of this fourth dose; but based on our results, it is reasonable to suppose that the fourth dose would also lead to a further increase in immune defenses,” Dr. Kister said.

The VIOLA study is an investigator-initiated collaboration supported by F. Hoffmann-La Roche Ltd/Genentech Inc. Dr. Kister has reported no relevant financial relationships.

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

New research confirms the importance of COVID-19 mRNA booster doses for patients with multiple sclerosis (MS) who are receiving the anti-CD20 monoclonal antibody ocrelizumab (Ocrevus), as currently recommended.

“We have shown that even MS patients whose B cells were depleted from circulation with ocrelizumab can mount immune responses to COVID-19 vaccines,” said lead study author Ilya Kister, MD, of NYU Langone’s Multiple Sclerosis Comprehensive Care Center in New York.

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

VIOLA study

The data stem from VIOLA, an ongoing prospective study of humoral and cellular immune responses to COVID-19 vaccines in 60 patients with MS receiving ocrelizumab at MS care centers at NYU Langone and the University of Colorado Denver.

The mean age of participants was 38 years, 73% were women, all had been taking ocrelizumab for a mean of 1.7 years, and 45% had had COVID-19 prior to vaccination.

The researchers examined antibody and cellular responses to the two-dose series of mRNA COVID-19 vaccine (80% received the Pfizer-BioNTech vaccine, 18% the Moderna vaccine, and 2% unknown) over 24 weeks. In addition, 57% of the participants received the third dose/booster.

Results showed that antibody and cellular responses to SARS-CoV-2 spike protein significantly increased after the two-dose mRNA COVID-19 vaccination, though antibody responses tended to peak between 4 and 12 weeks and declined thereafter. There was no significant decline in cellular responses at week 24.

“The third dose ‘booster’ again significantly increased antibody and cellular responses compared with the pre–third dose levels,” Dr. Kister said.

“Importantly, cellular responses remained elevated or even increased from 4 weeks to 12 weeks after third dose/booster. Overall, these data strongly support the need for a third dose in MS patients on ocrelizumab,” Dr. Kister added.

Participants with “hybrid immunity” (those who had been infected with SARS-CoV-2 and who had also been vaccinated for COVID) had markedly higher SARS-CoV-2–specific antibody and cellular responses than those of peers with vaccine-only immunity.
 

CDC recs

Looking ahead, Dr. Kister said the VIOLA investigators plan to present data on the durability of COVID-19 vaccines in ocrelizumab-treated patients up to 48 weeks after the third dose.

For immunocompromised patients, such as those taking ocrelizumab, the Centers for Disease Control and Prevention considers the third dose of mRNA vaccine not as a “booster” but as part of the regular vaccine series.

“In other words, all these patients should receive three doses as part of their ‘primary’ series,” Dr. Kister noted.

The CDC also recommends receiving the updated booster for COVID-19 that became available in September 2022 (the fourth dose of the vaccine).

“Our study did not evaluate the efficacy of this fourth dose; but based on our results, it is reasonable to suppose that the fourth dose would also lead to a further increase in immune defenses,” Dr. Kister said.

The VIOLA study is an investigator-initiated collaboration supported by F. Hoffmann-La Roche Ltd/Genentech Inc. Dr. Kister has reported no relevant financial relationships.

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

Neurofilament light chain (NfL) is a biomarker for both disease progression and treatment response in multiple sclerosis (MS), but the search continues for additional biomarkers to distinguish between disease activity and progression.

At a session of the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), researchers presented evidence that serum glial fibrillary acid protein (GFAP) could be a useful complement to NfL in MS, although it is not ready for the clinic. Acceptance of NfL wasn’t universal, either.

Patients with MS follow wide-ranging disease courses, and disability arises due to two partially independent mechanisms, according to Stephanie Meier, who presented results suggests from a study of two cohorts. “Firstly, the acute disease activity leading to relapse associated worsening or RAW (relapse-associated worsening), and secondly the chronic deterioration of neurologic functions leading to progression independent of relapse activity,” said Ms. Meier, a PhD student at University of Basel, Switzerland.
 

GFAP and NfL may be complementary biomarkers

NfL is a structural protein of neurons, while GFAP is a structure protein of astrocytes. NfL therefore reflects neuronal damage, while GFAP is an indicator of astrogliosis and astrocytic damage. GFAP has been shown to be increased in progressive MS and has been applied in traumatic brain injury and neuromyelitis optica spectrum disorder, according to Ms. Meier.

Her group examined data from two cohorts with “extreme” phenotypes. One cohort included 169 patients with stable MS and 184 with worsening disease progression but no sign of relapses. The other was a focal inflammation cohort that comprised paired samples from 66 patients: One sample from an active time point characterized by a relapse or at least one contrast-enhancing lesion (CEL) detected in the previous 30 days, and one remission sample when there was no relapse in the past year and no CEL in the previous 6 months.

The focal inflammation cohort demonstrated an association between raised NfL levels, with a 53% increase in predicted serum NfL during the active state after a multivariate analysis (P < .0001). GFAP values, on the other hand, were nearly identical.

In the progression cohort, there was more total yearly brain loss in the worsening group (0.42% vs. 0.14%; P = .0005). Baseline GFAP predicted gray matter atrophy (–0.24% per year, P < .0001) but NfL did not. The reverse was true for white matter atrophy, with NfL being predictive (–0.26% per year; P < .0001) but not GFAP.

“The use of biomarkers such as NfL and GFAP could be useful to understand the MS disease course by detecting disease activity that is not usually measurable with standard methods,” said Ms. Meier.

“We found that NfL was strongly associated with acute inflammation and prognosticated white matter volume loss, while GFAP has a potential as a prognostic biomarker for disease worsening, including progression independent of relapse activity, and baseline GFAP also prognosticated gray matter volume loss. From this we can conclude that serum GFAP is a promising biomarker reflecting progression in MS and it is complementary to NfL, as NfL is more strongly associated with acute inflammatory activity,” said Ms. Meier.
 

A biomarker of disease progression

In another presentation, Mark Wessels, MD, PhD, discussed use of GFAP as a biomarker of disease progression among patients treated with natalizumab. He noted that heightened levels of GFAP are found in astrocytes in chronic MS lesions. Serum GFAP also has been linked to lesion load and clinical outcomes in relapsing-remitting MS.

“The overall aim of our study was to evaluate the value of serum GFAP to monitor disability progression and treatment response in a natalizumab-treated cohort in which disease activity is effectively suppressed, and we did this by investigating GFAP as biomarker for progression despite suppression of inflammation,” said Dr. Wessels, a neurologist at Amsterdam University Medical Center.

The researchers evaluated data from an observational cohort at their institution in Amsterdam. GFAP decreased significantly after 3 months of treatment in both groups, then stabilized, but there was no difference between the groups. GFAP correlated with ventricle fraction at all time points with the exception of the last follow-up. It also correlated with lesion volume. However, GFAP did not correlate with whole brain parenchyma volume over time. There was no difference in GFAP among treatment responders and nonresponders.

Baseline serum GFAP predicted the annualized rate of ventricle volume change (P = .009). At 12 months it predicted both annualized rate of ventricle volume change (P = .009) and thalamus volume (P = .025).

“We’ve been struggling with how to interpret this data. We did see that GFAP and inflammation appear to be associated with each other. What supports this interpretation is that the GFAP decreased significantly after starting high efficacy treatments, namely natalizumab. We also found some clues that GFAP and brain atrophy may have a relationship with each other. Our conclusions weren’t entirely conclusive, possibly due to our smaller cohort sizes, and the use of various MRI scans over the years. And then the question of today was whether GFAP should be implemented in the clinic. Unfortunately, we couldn’t find evidence for use of GFAP as a disease progression biomarker, but we did find some clues of its use as both monitoring lesion volume and monitoring brain atrophy, making it still an interesting biomarker,” said Dr. Wessels.
 

What does it all mean?

In the Q&A session following the talks, one audience member challenged some of the assumptions behind the use of NfL and GFAP. “We don’t really know what these proteins actually do, and what they truly measure,” he said. Another criticism voiced by the commenter was that the platforms used to measure high and low values may be inconsistent. Finally, there are questions about the underlying theory. “I think our simplistic model for thinking that these are all just measurements of damage is potentially something that we have to reassess … or the assumption that these measures have to correlate to brain atrophy, as if that’s a gold standard. We all know that brain atrophy has totally failed us in the clinic and been incapable of giving us anything that’s useful for monitoring our patients,” said the questioner.

Elias Sotirchos, MD, who presented on NfL values and brain atrophy MS patients, agreed that it’s important to compare values across platforms to ensure consistency. He also cited potential issues with reference populations, since there may be a variety of contributors to neurotoxicity based on behaviors such as smoking, drinking, or comorbidities. “The selection of the reference population is important to be a representative of the MS population in which we are trying to apply that measurement of that normative value,” said Dr. Sotirchos, assistant professor of neurology at Johns Hopkins Medicine, Baltimore.

Ms. Basel and Dr. Wessels have no relevant financial disclosures. Dr. Sotirchos has financial relationships with Alexion, Viela Bio, Horizon Therapeutics, Genentech, Biogen, and Ad Scientiam.

Neurofilament light chain (NfL) is a biomarker for both disease progression and treatment response in multiple sclerosis (MS), but the search continues for additional biomarkers to distinguish between disease activity and progression.

At a session of the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), researchers presented evidence that serum glial fibrillary acid protein (GFAP) could be a useful complement to NfL in MS, although it is not ready for the clinic. Acceptance of NfL wasn’t universal, either.

Patients with MS follow wide-ranging disease courses, and disability arises due to two partially independent mechanisms, according to Stephanie Meier, who presented results suggests from a study of two cohorts. “Firstly, the acute disease activity leading to relapse associated worsening or RAW (relapse-associated worsening), and secondly the chronic deterioration of neurologic functions leading to progression independent of relapse activity,” said Ms. Meier, a PhD student at University of Basel, Switzerland.
 

GFAP and NfL may be complementary biomarkers

NfL is a structural protein of neurons, while GFAP is a structure protein of astrocytes. NfL therefore reflects neuronal damage, while GFAP is an indicator of astrogliosis and astrocytic damage. GFAP has been shown to be increased in progressive MS and has been applied in traumatic brain injury and neuromyelitis optica spectrum disorder, according to Ms. Meier.

Her group examined data from two cohorts with “extreme” phenotypes. One cohort included 169 patients with stable MS and 184 with worsening disease progression but no sign of relapses. The other was a focal inflammation cohort that comprised paired samples from 66 patients: One sample from an active time point characterized by a relapse or at least one contrast-enhancing lesion (CEL) detected in the previous 30 days, and one remission sample when there was no relapse in the past year and no CEL in the previous 6 months.

The focal inflammation cohort demonstrated an association between raised NfL levels, with a 53% increase in predicted serum NfL during the active state after a multivariate analysis (P < .0001). GFAP values, on the other hand, were nearly identical.

In the progression cohort, there was more total yearly brain loss in the worsening group (0.42% vs. 0.14%; P = .0005). Baseline GFAP predicted gray matter atrophy (–0.24% per year, P < .0001) but NfL did not. The reverse was true for white matter atrophy, with NfL being predictive (–0.26% per year; P < .0001) but not GFAP.

“The use of biomarkers such as NfL and GFAP could be useful to understand the MS disease course by detecting disease activity that is not usually measurable with standard methods,” said Ms. Meier.

“We found that NfL was strongly associated with acute inflammation and prognosticated white matter volume loss, while GFAP has a potential as a prognostic biomarker for disease worsening, including progression independent of relapse activity, and baseline GFAP also prognosticated gray matter volume loss. From this we can conclude that serum GFAP is a promising biomarker reflecting progression in MS and it is complementary to NfL, as NfL is more strongly associated with acute inflammatory activity,” said Ms. Meier.
 

A biomarker of disease progression

In another presentation, Mark Wessels, MD, PhD, discussed use of GFAP as a biomarker of disease progression among patients treated with natalizumab. He noted that heightened levels of GFAP are found in astrocytes in chronic MS lesions. Serum GFAP also has been linked to lesion load and clinical outcomes in relapsing-remitting MS.

“The overall aim of our study was to evaluate the value of serum GFAP to monitor disability progression and treatment response in a natalizumab-treated cohort in which disease activity is effectively suppressed, and we did this by investigating GFAP as biomarker for progression despite suppression of inflammation,” said Dr. Wessels, a neurologist at Amsterdam University Medical Center.

The researchers evaluated data from an observational cohort at their institution in Amsterdam. GFAP decreased significantly after 3 months of treatment in both groups, then stabilized, but there was no difference between the groups. GFAP correlated with ventricle fraction at all time points with the exception of the last follow-up. It also correlated with lesion volume. However, GFAP did not correlate with whole brain parenchyma volume over time. There was no difference in GFAP among treatment responders and nonresponders.

Baseline serum GFAP predicted the annualized rate of ventricle volume change (P = .009). At 12 months it predicted both annualized rate of ventricle volume change (P = .009) and thalamus volume (P = .025).

“We’ve been struggling with how to interpret this data. We did see that GFAP and inflammation appear to be associated with each other. What supports this interpretation is that the GFAP decreased significantly after starting high efficacy treatments, namely natalizumab. We also found some clues that GFAP and brain atrophy may have a relationship with each other. Our conclusions weren’t entirely conclusive, possibly due to our smaller cohort sizes, and the use of various MRI scans over the years. And then the question of today was whether GFAP should be implemented in the clinic. Unfortunately, we couldn’t find evidence for use of GFAP as a disease progression biomarker, but we did find some clues of its use as both monitoring lesion volume and monitoring brain atrophy, making it still an interesting biomarker,” said Dr. Wessels.
 

What does it all mean?

In the Q&A session following the talks, one audience member challenged some of the assumptions behind the use of NfL and GFAP. “We don’t really know what these proteins actually do, and what they truly measure,” he said. Another criticism voiced by the commenter was that the platforms used to measure high and low values may be inconsistent. Finally, there are questions about the underlying theory. “I think our simplistic model for thinking that these are all just measurements of damage is potentially something that we have to reassess … or the assumption that these measures have to correlate to brain atrophy, as if that’s a gold standard. We all know that brain atrophy has totally failed us in the clinic and been incapable of giving us anything that’s useful for monitoring our patients,” said the questioner.

Elias Sotirchos, MD, who presented on NfL values and brain atrophy MS patients, agreed that it’s important to compare values across platforms to ensure consistency. He also cited potential issues with reference populations, since there may be a variety of contributors to neurotoxicity based on behaviors such as smoking, drinking, or comorbidities. “The selection of the reference population is important to be a representative of the MS population in which we are trying to apply that measurement of that normative value,” said Dr. Sotirchos, assistant professor of neurology at Johns Hopkins Medicine, Baltimore.

Ms. Basel and Dr. Wessels have no relevant financial disclosures. Dr. Sotirchos has financial relationships with Alexion, Viela Bio, Horizon Therapeutics, Genentech, Biogen, and Ad Scientiam.

Neurofilament light chain (NfL) is a biomarker for both disease progression and treatment response in multiple sclerosis (MS), but the search continues for additional biomarkers to distinguish between disease activity and progression.

At a session of the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), researchers presented evidence that serum glial fibrillary acid protein (GFAP) could be a useful complement to NfL in MS, although it is not ready for the clinic. Acceptance of NfL wasn’t universal, either.

Patients with MS follow wide-ranging disease courses, and disability arises due to two partially independent mechanisms, according to Stephanie Meier, who presented results suggests from a study of two cohorts. “Firstly, the acute disease activity leading to relapse associated worsening or RAW (relapse-associated worsening), and secondly the chronic deterioration of neurologic functions leading to progression independent of relapse activity,” said Ms. Meier, a PhD student at University of Basel, Switzerland.
 

GFAP and NfL may be complementary biomarkers

NfL is a structural protein of neurons, while GFAP is a structure protein of astrocytes. NfL therefore reflects neuronal damage, while GFAP is an indicator of astrogliosis and astrocytic damage. GFAP has been shown to be increased in progressive MS and has been applied in traumatic brain injury and neuromyelitis optica spectrum disorder, according to Ms. Meier.

Her group examined data from two cohorts with “extreme” phenotypes. One cohort included 169 patients with stable MS and 184 with worsening disease progression but no sign of relapses. The other was a focal inflammation cohort that comprised paired samples from 66 patients: One sample from an active time point characterized by a relapse or at least one contrast-enhancing lesion (CEL) detected in the previous 30 days, and one remission sample when there was no relapse in the past year and no CEL in the previous 6 months.

The focal inflammation cohort demonstrated an association between raised NfL levels, with a 53% increase in predicted serum NfL during the active state after a multivariate analysis (P < .0001). GFAP values, on the other hand, were nearly identical.

In the progression cohort, there was more total yearly brain loss in the worsening group (0.42% vs. 0.14%; P = .0005). Baseline GFAP predicted gray matter atrophy (–0.24% per year, P < .0001) but NfL did not. The reverse was true for white matter atrophy, with NfL being predictive (–0.26% per year; P < .0001) but not GFAP.

“The use of biomarkers such as NfL and GFAP could be useful to understand the MS disease course by detecting disease activity that is not usually measurable with standard methods,” said Ms. Meier.

“We found that NfL was strongly associated with acute inflammation and prognosticated white matter volume loss, while GFAP has a potential as a prognostic biomarker for disease worsening, including progression independent of relapse activity, and baseline GFAP also prognosticated gray matter volume loss. From this we can conclude that serum GFAP is a promising biomarker reflecting progression in MS and it is complementary to NfL, as NfL is more strongly associated with acute inflammatory activity,” said Ms. Meier.
 

A biomarker of disease progression

In another presentation, Mark Wessels, MD, PhD, discussed use of GFAP as a biomarker of disease progression among patients treated with natalizumab. He noted that heightened levels of GFAP are found in astrocytes in chronic MS lesions. Serum GFAP also has been linked to lesion load and clinical outcomes in relapsing-remitting MS.

“The overall aim of our study was to evaluate the value of serum GFAP to monitor disability progression and treatment response in a natalizumab-treated cohort in which disease activity is effectively suppressed, and we did this by investigating GFAP as biomarker for progression despite suppression of inflammation,” said Dr. Wessels, a neurologist at Amsterdam University Medical Center.

The researchers evaluated data from an observational cohort at their institution in Amsterdam. GFAP decreased significantly after 3 months of treatment in both groups, then stabilized, but there was no difference between the groups. GFAP correlated with ventricle fraction at all time points with the exception of the last follow-up. It also correlated with lesion volume. However, GFAP did not correlate with whole brain parenchyma volume over time. There was no difference in GFAP among treatment responders and nonresponders.

Baseline serum GFAP predicted the annualized rate of ventricle volume change (P = .009). At 12 months it predicted both annualized rate of ventricle volume change (P = .009) and thalamus volume (P = .025).

“We’ve been struggling with how to interpret this data. We did see that GFAP and inflammation appear to be associated with each other. What supports this interpretation is that the GFAP decreased significantly after starting high efficacy treatments, namely natalizumab. We also found some clues that GFAP and brain atrophy may have a relationship with each other. Our conclusions weren’t entirely conclusive, possibly due to our smaller cohort sizes, and the use of various MRI scans over the years. And then the question of today was whether GFAP should be implemented in the clinic. Unfortunately, we couldn’t find evidence for use of GFAP as a disease progression biomarker, but we did find some clues of its use as both monitoring lesion volume and monitoring brain atrophy, making it still an interesting biomarker,” said Dr. Wessels.
 

What does it all mean?

In the Q&A session following the talks, one audience member challenged some of the assumptions behind the use of NfL and GFAP. “We don’t really know what these proteins actually do, and what they truly measure,” he said. Another criticism voiced by the commenter was that the platforms used to measure high and low values may be inconsistent. Finally, there are questions about the underlying theory. “I think our simplistic model for thinking that these are all just measurements of damage is potentially something that we have to reassess … or the assumption that these measures have to correlate to brain atrophy, as if that’s a gold standard. We all know that brain atrophy has totally failed us in the clinic and been incapable of giving us anything that’s useful for monitoring our patients,” said the questioner.

Elias Sotirchos, MD, who presented on NfL values and brain atrophy MS patients, agreed that it’s important to compare values across platforms to ensure consistency. He also cited potential issues with reference populations, since there may be a variety of contributors to neurotoxicity based on behaviors such as smoking, drinking, or comorbidities. “The selection of the reference population is important to be a representative of the MS population in which we are trying to apply that measurement of that normative value,” said Dr. Sotirchos, assistant professor of neurology at Johns Hopkins Medicine, Baltimore.

Ms. Basel and Dr. Wessels have no relevant financial disclosures. Dr. Sotirchos has financial relationships with Alexion, Viela Bio, Horizon Therapeutics, Genentech, Biogen, and Ad Scientiam.

Dimethyl fumarate could delay – or even prevent – clinical symptoms in patients with radiologically isolated syndrome (RIS), the earliest detected preclinical phase of multiple sclerosis (MS). Researchers found that dimethyl fumarate reduced the risk of a first acute or progressive event related to CNS demyelination by more than 80%, compared with placebo.

Patients with RIS have incidental MRI abnormalities typical of MS but have no symptoms of the disease. The condition is usually detected when a patient seeks treatment for another issue, such as migraines or head trauma.

The study is the first randomized clinical trial to examine efficacy of a disease-modifying therapy in delaying symptoms in RIS. “It really supports the concept of the benefit of early treatment intervention within this given MS disease spectrum,” lead investigator Darin Okuda, MD, professor of neurology at the University of Texas Southwestern Medical Center in Dallas, told delegates attending the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis.
 

Topic of debate

RIS was first identified by Dr. Okuda in 2008. Increased use of brain imaging led to the detection of patients with incidental white-matter pathology in the central nervous system on MRI. Some of the findings were nonspecific, but others were highly suggestive of demyelinating pathology based on their location and morphology in the central nervous system.

Although the prevalence of RIS is unknown, incidentally discovered white matter lesions resembling demyelination occur in an estimated 0.1%-0.7% of the general population. Up to half of patients with RIS experience a first clinical MS event within 10 years.

Diagnostic criteria and whether to treat patients with RIS prophylactically has long been a topic of debate among neurologists and radiologists.

Researchers conducted the multicenter, randomized, double-blinded, placebo-controlled ARISE study in 2016, recruiting 87 patients with RIS. The majority of participants were women, and most were diagnosed in their early 40s.

Patients received oral dimethyl fumarate at 240 mg twice daily or placebo and were followed for 96 weeks (1 year, 10 months). Clinical assessments were completed at baseline, at weeks 48 and 96, and at the time of the first clinical event. MRI scans were performed only at the beginning and end of the study.

Those who received dimethyl fumarate had a significantly lower risk of experiencing a first clinical demyelinating event during the study period (adjusted hazard ratio, 0.07; P = .005).

After adjusting for the number of gadolinium-enhancing lesions at baseline, there was a significant reduction in the number of new or newly enlarged T2-weighted hyperintense lesions, a secondary endpoint, in the dimethyl fumarate group, compared with those on placebo (HR, 0.20; P = .042).

“In the future we’d like to see further studies performed to assess the impact on disability outcome measures following treatment for a meaningful amount of time,” Dr. Okuda said.
 

‘Striking’ findings

Barbara Giesser, MD, a neurologist at Pacific Neuroscience Institute in Santa Monica, Calif., called the results “striking,” but noted that questions remain.

“Up until this study we haven’t had anything like it to guide us in determining whether we should treat RIS or not,” she said. “Obviously, larger studies are needed, but I think this is a very important and well-done study.”

In addition to the small sample size, Dr. Giesser noted that the study lacked data on the presence of risk factors that are known to increase RIS patients’ risk of developing MS, such as evidence of spinal cord lesions. That issue was also raised during discussion of the paper in Amsterdam.

“I don’t think this means you should treat everybody with RIS necessarily,” Dr. Giesser said. “But I think it suggests that in people with RIS, particularly if they do have risk factors, you could consider treatment with dimethyl fumarate.”

The study was funded by Biogen. Dr. Okuda has received support from Biogen and EMD Serono/Merck; and consulting fees from Alexion, Biogen, EMD Serono, Genzyme, Novartis, RVL Pharmaceuticals, TG Therapeutics, Viela Bio, Celgene/Bristol Myers Squibb, Genentech, Janssen Pharmaceuticals, and Osmotica Pharmaceuticals. Dr. Giesser reports no relevant financial relationships.

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

Dimethyl fumarate could delay – or even prevent – clinical symptoms in patients with radiologically isolated syndrome (RIS), the earliest detected preclinical phase of multiple sclerosis (MS). Researchers found that dimethyl fumarate reduced the risk of a first acute or progressive event related to CNS demyelination by more than 80%, compared with placebo.

Patients with RIS have incidental MRI abnormalities typical of MS but have no symptoms of the disease. The condition is usually detected when a patient seeks treatment for another issue, such as migraines or head trauma.

The study is the first randomized clinical trial to examine efficacy of a disease-modifying therapy in delaying symptoms in RIS. “It really supports the concept of the benefit of early treatment intervention within this given MS disease spectrum,” lead investigator Darin Okuda, MD, professor of neurology at the University of Texas Southwestern Medical Center in Dallas, told delegates attending the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis.
 

Topic of debate

RIS was first identified by Dr. Okuda in 2008. Increased use of brain imaging led to the detection of patients with incidental white-matter pathology in the central nervous system on MRI. Some of the findings were nonspecific, but others were highly suggestive of demyelinating pathology based on their location and morphology in the central nervous system.

Although the prevalence of RIS is unknown, incidentally discovered white matter lesions resembling demyelination occur in an estimated 0.1%-0.7% of the general population. Up to half of patients with RIS experience a first clinical MS event within 10 years.

Diagnostic criteria and whether to treat patients with RIS prophylactically has long been a topic of debate among neurologists and radiologists.

Researchers conducted the multicenter, randomized, double-blinded, placebo-controlled ARISE study in 2016, recruiting 87 patients with RIS. The majority of participants were women, and most were diagnosed in their early 40s.

Patients received oral dimethyl fumarate at 240 mg twice daily or placebo and were followed for 96 weeks (1 year, 10 months). Clinical assessments were completed at baseline, at weeks 48 and 96, and at the time of the first clinical event. MRI scans were performed only at the beginning and end of the study.

Those who received dimethyl fumarate had a significantly lower risk of experiencing a first clinical demyelinating event during the study period (adjusted hazard ratio, 0.07; P = .005).

After adjusting for the number of gadolinium-enhancing lesions at baseline, there was a significant reduction in the number of new or newly enlarged T2-weighted hyperintense lesions, a secondary endpoint, in the dimethyl fumarate group, compared with those on placebo (HR, 0.20; P = .042).

“In the future we’d like to see further studies performed to assess the impact on disability outcome measures following treatment for a meaningful amount of time,” Dr. Okuda said.
 

‘Striking’ findings

Barbara Giesser, MD, a neurologist at Pacific Neuroscience Institute in Santa Monica, Calif., called the results “striking,” but noted that questions remain.

“Up until this study we haven’t had anything like it to guide us in determining whether we should treat RIS or not,” she said. “Obviously, larger studies are needed, but I think this is a very important and well-done study.”

In addition to the small sample size, Dr. Giesser noted that the study lacked data on the presence of risk factors that are known to increase RIS patients’ risk of developing MS, such as evidence of spinal cord lesions. That issue was also raised during discussion of the paper in Amsterdam.

“I don’t think this means you should treat everybody with RIS necessarily,” Dr. Giesser said. “But I think it suggests that in people with RIS, particularly if they do have risk factors, you could consider treatment with dimethyl fumarate.”

The study was funded by Biogen. Dr. Okuda has received support from Biogen and EMD Serono/Merck; and consulting fees from Alexion, Biogen, EMD Serono, Genzyme, Novartis, RVL Pharmaceuticals, TG Therapeutics, Viela Bio, Celgene/Bristol Myers Squibb, Genentech, Janssen Pharmaceuticals, and Osmotica Pharmaceuticals. Dr. Giesser reports no relevant financial relationships.

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

Dimethyl fumarate could delay – or even prevent – clinical symptoms in patients with radiologically isolated syndrome (RIS), the earliest detected preclinical phase of multiple sclerosis (MS). Researchers found that dimethyl fumarate reduced the risk of a first acute or progressive event related to CNS demyelination by more than 80%, compared with placebo.

Patients with RIS have incidental MRI abnormalities typical of MS but have no symptoms of the disease. The condition is usually detected when a patient seeks treatment for another issue, such as migraines or head trauma.

The study is the first randomized clinical trial to examine efficacy of a disease-modifying therapy in delaying symptoms in RIS. “It really supports the concept of the benefit of early treatment intervention within this given MS disease spectrum,” lead investigator Darin Okuda, MD, professor of neurology at the University of Texas Southwestern Medical Center in Dallas, told delegates attending the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis.
 

Topic of debate

RIS was first identified by Dr. Okuda in 2008. Increased use of brain imaging led to the detection of patients with incidental white-matter pathology in the central nervous system on MRI. Some of the findings were nonspecific, but others were highly suggestive of demyelinating pathology based on their location and morphology in the central nervous system.

Although the prevalence of RIS is unknown, incidentally discovered white matter lesions resembling demyelination occur in an estimated 0.1%-0.7% of the general population. Up to half of patients with RIS experience a first clinical MS event within 10 years.

Diagnostic criteria and whether to treat patients with RIS prophylactically has long been a topic of debate among neurologists and radiologists.

Researchers conducted the multicenter, randomized, double-blinded, placebo-controlled ARISE study in 2016, recruiting 87 patients with RIS. The majority of participants were women, and most were diagnosed in their early 40s.

Patients received oral dimethyl fumarate at 240 mg twice daily or placebo and were followed for 96 weeks (1 year, 10 months). Clinical assessments were completed at baseline, at weeks 48 and 96, and at the time of the first clinical event. MRI scans were performed only at the beginning and end of the study.

Those who received dimethyl fumarate had a significantly lower risk of experiencing a first clinical demyelinating event during the study period (adjusted hazard ratio, 0.07; P = .005).

After adjusting for the number of gadolinium-enhancing lesions at baseline, there was a significant reduction in the number of new or newly enlarged T2-weighted hyperintense lesions, a secondary endpoint, in the dimethyl fumarate group, compared with those on placebo (HR, 0.20; P = .042).

“In the future we’d like to see further studies performed to assess the impact on disability outcome measures following treatment for a meaningful amount of time,” Dr. Okuda said.
 

‘Striking’ findings

Barbara Giesser, MD, a neurologist at Pacific Neuroscience Institute in Santa Monica, Calif., called the results “striking,” but noted that questions remain.

“Up until this study we haven’t had anything like it to guide us in determining whether we should treat RIS or not,” she said. “Obviously, larger studies are needed, but I think this is a very important and well-done study.”

In addition to the small sample size, Dr. Giesser noted that the study lacked data on the presence of risk factors that are known to increase RIS patients’ risk of developing MS, such as evidence of spinal cord lesions. That issue was also raised during discussion of the paper in Amsterdam.

“I don’t think this means you should treat everybody with RIS necessarily,” Dr. Giesser said. “But I think it suggests that in people with RIS, particularly if they do have risk factors, you could consider treatment with dimethyl fumarate.”

The study was funded by Biogen. Dr. Okuda has received support from Biogen and EMD Serono/Merck; and consulting fees from Alexion, Biogen, EMD Serono, Genzyme, Novartis, RVL Pharmaceuticals, TG Therapeutics, Viela Bio, Celgene/Bristol Myers Squibb, Genentech, Janssen Pharmaceuticals, and Osmotica Pharmaceuticals. Dr. Giesser reports no relevant financial relationships.

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