Multiple Sclerosis

Prior to 1993, a multiple sclerosis (MS) diagnosis could often mean an abbreviated lifespan marked by progressive disability and loss of function. That changed when the Food and Drug Administration approved interferon beta-1b (Betaseron) in 1993, which revolutionized MS therapy and gave hope to the entire MS community.

"The most surprising thing about MS management over the last 30 years is that we’ve been able to treat MS – especially relapsing MS,” said Fred D. Lublin, MD, professor of neurology and director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis in Mount Sinai in New York. “The approval of interferon was a major therapeutic advancement because it was the first treatment for what was an untreatable disease.”

Mark Gudesblatt, MD, medical director of the Comprehensive MS Care Center of South Shore Neurologic Associates in Patchogue, N.Y., agrees.

“For people with MS, it’s an extraordinarily lucky and amazingly optimistic time,” he said. “Before interferon beta-1b, MS was called ‘the crippler of young adults’ because more than 50% of these people would require a walker 10 years after diagnosis, and a large number of young and middle-age patients with MS were residing in nursing homes.”

Treatment options, treatment challenges

Dr. Gudesblatt points out that having numerous therapies from which to choose is both a blessing and a problem.

“The good news is that there are so many options for treating relapsing MS today,” he said. “The bad news is there are so many options. Like doctors who are treating high blood pressure, doctors managing patients with MS often struggle to determine which medication is best for individual patients.”

Despite the promise of vastly better outcomes and prolonged lifespan, MS therapy still faces its share of challenges, including effective therapies for progressive MS and reparative-restorative therapies.

“Choice in route of administration and timing of administration allow for larger and broader discussions to try to meet patients’ needs,” Dr. Lublin said. “We’ve been extremely successful at treating relapses, but not as successful in treating progressive disease.”

The unclear mechanism of pathogenesis amplifies the challenges clinicians face in successful management of patients with MS. For example, experts agree that the therapies for progressive MS have only proven moderately effective at best. The paucity of therapies available for progressive MS and the limitations of the current therapies further limit the outcomes.
 

Looking ahead

Experts expressed optimistic views about the future of MS therapy as a whole. From Dr. Lublin’s perspective, the MS community stands to gain valuable insights from emerging research focused on treating progressive disease along with new testing to understand the underlying mechanism of progressive disease. Enhanced understanding of the underlying pathogenesis of progressive MS coupled with the ability to diagnose MS – such as improved MRI techniques – have facilitated this process.

Among the therapies with novel mechanisms of action in the pipeline include agents that generate myelin sheath repair. Another potential therapeutic class on the horizon, known as TPK inhibitors, addresses the smoldering of the disease. With these and other therapeutic advances, Dr. Lublin hopes to see better control of progressive disease.
 

An agenda for the future

In addition, barriers such as access to care, cost, insurance coverage, and tolerance remain ongoing stressors that will likely continue weighing on the MS community and its stakeholders into the future.

Dr. Gudesblatt concluded that advancing MS outcomes in the future hinges on several additional factors.

“We need medicines that are better for relapse and progression; medicines that are better tolerated and safer; and better medicine to address the underlying disease as well as its symptoms. But we also need to appreciate, recognize, and address cognitive impairment along the MS continuum and develop effective reparative options,” he said.

Regardless, he emphasized that these “amazing advancements” in MS therapy have renewed hope that research may identify and expand effective treatments for multiple other neurologic conditions such as muscular dystrophies, neurodegenerative and genetic disorders, movement disorders, and dysautonomia-related diseases. Like MS, all of these conditions have limited therapies, some of which have minimal efficacy. But none of these other disorders has disease-modifying therapies currently available.
 

‘A beacon of hope’

“MS is the beacon of hope for multiple disease states because it’s cracked the door wide open,” Dr. Gudesblatt said. Relapse no longer gauges the prognosis of today’s MS patient – a prognosis both experts think will only continue to improve with forthcoming innovations.

While the challenges for MS still exist, the bright future that lies ahead may eventually eclipse them.

Prior to 1993, a multiple sclerosis (MS) diagnosis could often mean an abbreviated lifespan marked by progressive disability and loss of function. That changed when the Food and Drug Administration approved interferon beta-1b (Betaseron) in 1993, which revolutionized MS therapy and gave hope to the entire MS community.

"The most surprising thing about MS management over the last 30 years is that we’ve been able to treat MS – especially relapsing MS,” said Fred D. Lublin, MD, professor of neurology and director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis in Mount Sinai in New York. “The approval of interferon was a major therapeutic advancement because it was the first treatment for what was an untreatable disease.”

Mark Gudesblatt, MD, medical director of the Comprehensive MS Care Center of South Shore Neurologic Associates in Patchogue, N.Y., agrees.

“For people with MS, it’s an extraordinarily lucky and amazingly optimistic time,” he said. “Before interferon beta-1b, MS was called ‘the crippler of young adults’ because more than 50% of these people would require a walker 10 years after diagnosis, and a large number of young and middle-age patients with MS were residing in nursing homes.”

Treatment options, treatment challenges

Dr. Gudesblatt points out that having numerous therapies from which to choose is both a blessing and a problem.

“The good news is that there are so many options for treating relapsing MS today,” he said. “The bad news is there are so many options. Like doctors who are treating high blood pressure, doctors managing patients with MS often struggle to determine which medication is best for individual patients.”

Despite the promise of vastly better outcomes and prolonged lifespan, MS therapy still faces its share of challenges, including effective therapies for progressive MS and reparative-restorative therapies.

“Choice in route of administration and timing of administration allow for larger and broader discussions to try to meet patients’ needs,” Dr. Lublin said. “We’ve been extremely successful at treating relapses, but not as successful in treating progressive disease.”

The unclear mechanism of pathogenesis amplifies the challenges clinicians face in successful management of patients with MS. For example, experts agree that the therapies for progressive MS have only proven moderately effective at best. The paucity of therapies available for progressive MS and the limitations of the current therapies further limit the outcomes.
 

Looking ahead

Experts expressed optimistic views about the future of MS therapy as a whole. From Dr. Lublin’s perspective, the MS community stands to gain valuable insights from emerging research focused on treating progressive disease along with new testing to understand the underlying mechanism of progressive disease. Enhanced understanding of the underlying pathogenesis of progressive MS coupled with the ability to diagnose MS – such as improved MRI techniques – have facilitated this process.

Among the therapies with novel mechanisms of action in the pipeline include agents that generate myelin sheath repair. Another potential therapeutic class on the horizon, known as TPK inhibitors, addresses the smoldering of the disease. With these and other therapeutic advances, Dr. Lublin hopes to see better control of progressive disease.
 

An agenda for the future

In addition, barriers such as access to care, cost, insurance coverage, and tolerance remain ongoing stressors that will likely continue weighing on the MS community and its stakeholders into the future.

Dr. Gudesblatt concluded that advancing MS outcomes in the future hinges on several additional factors.

“We need medicines that are better for relapse and progression; medicines that are better tolerated and safer; and better medicine to address the underlying disease as well as its symptoms. But we also need to appreciate, recognize, and address cognitive impairment along the MS continuum and develop effective reparative options,” he said.

Regardless, he emphasized that these “amazing advancements” in MS therapy have renewed hope that research may identify and expand effective treatments for multiple other neurologic conditions such as muscular dystrophies, neurodegenerative and genetic disorders, movement disorders, and dysautonomia-related diseases. Like MS, all of these conditions have limited therapies, some of which have minimal efficacy. But none of these other disorders has disease-modifying therapies currently available.
 

‘A beacon of hope’

“MS is the beacon of hope for multiple disease states because it’s cracked the door wide open,” Dr. Gudesblatt said. Relapse no longer gauges the prognosis of today’s MS patient – a prognosis both experts think will only continue to improve with forthcoming innovations.

While the challenges for MS still exist, the bright future that lies ahead may eventually eclipse them.

Prior to 1993, a multiple sclerosis (MS) diagnosis could often mean an abbreviated lifespan marked by progressive disability and loss of function. That changed when the Food and Drug Administration approved interferon beta-1b (Betaseron) in 1993, which revolutionized MS therapy and gave hope to the entire MS community.

"The most surprising thing about MS management over the last 30 years is that we’ve been able to treat MS – especially relapsing MS,” said Fred D. Lublin, MD, professor of neurology and director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis in Mount Sinai in New York. “The approval of interferon was a major therapeutic advancement because it was the first treatment for what was an untreatable disease.”

Mark Gudesblatt, MD, medical director of the Comprehensive MS Care Center of South Shore Neurologic Associates in Patchogue, N.Y., agrees.

“For people with MS, it’s an extraordinarily lucky and amazingly optimistic time,” he said. “Before interferon beta-1b, MS was called ‘the crippler of young adults’ because more than 50% of these people would require a walker 10 years after diagnosis, and a large number of young and middle-age patients with MS were residing in nursing homes.”

Treatment options, treatment challenges

Dr. Gudesblatt points out that having numerous therapies from which to choose is both a blessing and a problem.

“The good news is that there are so many options for treating relapsing MS today,” he said. “The bad news is there are so many options. Like doctors who are treating high blood pressure, doctors managing patients with MS often struggle to determine which medication is best for individual patients.”

Despite the promise of vastly better outcomes and prolonged lifespan, MS therapy still faces its share of challenges, including effective therapies for progressive MS and reparative-restorative therapies.

“Choice in route of administration and timing of administration allow for larger and broader discussions to try to meet patients’ needs,” Dr. Lublin said. “We’ve been extremely successful at treating relapses, but not as successful in treating progressive disease.”

The unclear mechanism of pathogenesis amplifies the challenges clinicians face in successful management of patients with MS. For example, experts agree that the therapies for progressive MS have only proven moderately effective at best. The paucity of therapies available for progressive MS and the limitations of the current therapies further limit the outcomes.
 

Looking ahead

Experts expressed optimistic views about the future of MS therapy as a whole. From Dr. Lublin’s perspective, the MS community stands to gain valuable insights from emerging research focused on treating progressive disease along with new testing to understand the underlying mechanism of progressive disease. Enhanced understanding of the underlying pathogenesis of progressive MS coupled with the ability to diagnose MS – such as improved MRI techniques – have facilitated this process.

Among the therapies with novel mechanisms of action in the pipeline include agents that generate myelin sheath repair. Another potential therapeutic class on the horizon, known as TPK inhibitors, addresses the smoldering of the disease. With these and other therapeutic advances, Dr. Lublin hopes to see better control of progressive disease.
 

An agenda for the future

In addition, barriers such as access to care, cost, insurance coverage, and tolerance remain ongoing stressors that will likely continue weighing on the MS community and its stakeholders into the future.

Dr. Gudesblatt concluded that advancing MS outcomes in the future hinges on several additional factors.

“We need medicines that are better for relapse and progression; medicines that are better tolerated and safer; and better medicine to address the underlying disease as well as its symptoms. But we also need to appreciate, recognize, and address cognitive impairment along the MS continuum and develop effective reparative options,” he said.

Regardless, he emphasized that these “amazing advancements” in MS therapy have renewed hope that research may identify and expand effective treatments for multiple other neurologic conditions such as muscular dystrophies, neurodegenerative and genetic disorders, movement disorders, and dysautonomia-related diseases. Like MS, all of these conditions have limited therapies, some of which have minimal efficacy. But none of these other disorders has disease-modifying therapies currently available.
 

‘A beacon of hope’

“MS is the beacon of hope for multiple disease states because it’s cracked the door wide open,” Dr. Gudesblatt said. Relapse no longer gauges the prognosis of today’s MS patient – a prognosis both experts think will only continue to improve with forthcoming innovations.

While the challenges for MS still exist, the bright future that lies ahead may eventually eclipse them.

Autologous hematopoietic stem cell transplantation (AHSCT) is linked to less disability and lower relapse rates in secondary progressive multiple sclerosis (SPMS) versus other disease-modifying therapies (DMTs), new research suggests.

Results from a retrospective study show that more than 60% of patients with SPMS who received AHSCT were free from disability progression at 5 years. Also for these patients, improvement was more likely to be maintained for years after treatment.

The investigators noted that patients with secondary progressive disease often show little benefit from other DMTs, so interest in other treatments is high. While AHSCT is known to offer good results for patients with relapsing remitting MS, studies of its efficacy for SPMS have yielded conflicting results.

The new findings suggest it may be time to take another look at this therapy for patients with active, more severe disease, the researchers wrote.

“AHSCT may become a treatment option in secondary progressive MS patients with inflammatory activity who have failed available treatments,” said coinvestigator Matilde Inglese, MD, PhD, professor of neurology at the University of Genoa (Italy).

“Patients selection is very important to ensure the best treatment response and minimize safety issues, including transplant-related mortality,” Dr. Inglese added.

The findings were published online in Neurology.
 

Class III evidence

In the retrospective, propensity-matching study, researchers used two Italian registries to identify 79 patients who were treated off label with AHSCT and 1,975 patients who received another therapy.

Other DMTs included in the control-group analysis were beta-interferons, azathioprine, glatiramer acetate, mitoxantrone, fingolimod, natalizumab, methotrexate, teriflunomide, cyclophosphamide, dimethyl fumarate, or alemtuzumab.

Results showed that time to first disability progression was significantly longer for patients who had received transplants (hazard ratio, 0.5; P = .005); 61.7% of the AHSCT group were free of disability progression at 5 years versus 46.3% of the control group.

Among patients who received AHSCT, relapse rates were lower in comparison with those who received other DMTs (P < .001), and disability scores were lower over 10 years (P < .001).

The transplant group was also significantly more likely than the other-DMTs group to achieve sustained improvement in disability 3 years after treatment (34.7% vs. 4.6%; P < .001).

“This study provides Class III evidence that autologous hematopoietic stem cell transplants prolonged the time to confirmed disability progression compared to other disease-modifying therapies,” the investigators wrote.
 

Extends the treatment population

Commenting on the study, Jeff Cohen, MD, director of experimental therapeutics at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, said the research “extends the population for which hematopoietic stem cell transplant should be considered.”

Although previous studies did not show a benefit for patients with severe progressive MS, participants in the current study had secondary progressive MS and superimposed relapse activity, said Dr. Cohen, who was not involved with the research.

“We think that indicates a greater likelihood of benefit” from AHSCT, he noted. “The fact that someone has overt progression or somewhat more severe disability doesn’t preclude the use of stem cell transplant.”

Dr. Cohen pointed out, however, that the study is not without limitations. The exclusion of patients taking B-cell therapies from the SPMS control group raises the question of whether similar results would come from a comparison with AHSCT.

In addition, Dr. Cohen noted there are safety concerns about the therapy, which has yielded higher transplant-related mortality among patients with SPMS – although only one patient in the current study died following the transplant.

Still, the findings are promising, Dr. Cohen added.

“I think as more data accumulate that supports its benefit and reasonable safety in a variety of populations, we’ll see it used more,” he said.

The study was funded by the Italian Multiple Sclerosis Foundation. Dr. Inglese has received fees for consultation from Roche, Genzyme, Merck, Biogen, and Novartis. Dr. Cohen reported no relevant financial relationships.

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

Autologous hematopoietic stem cell transplantation (AHSCT) is linked to less disability and lower relapse rates in secondary progressive multiple sclerosis (SPMS) versus other disease-modifying therapies (DMTs), new research suggests.

Results from a retrospective study show that more than 60% of patients with SPMS who received AHSCT were free from disability progression at 5 years. Also for these patients, improvement was more likely to be maintained for years after treatment.

The investigators noted that patients with secondary progressive disease often show little benefit from other DMTs, so interest in other treatments is high. While AHSCT is known to offer good results for patients with relapsing remitting MS, studies of its efficacy for SPMS have yielded conflicting results.

The new findings suggest it may be time to take another look at this therapy for patients with active, more severe disease, the researchers wrote.

“AHSCT may become a treatment option in secondary progressive MS patients with inflammatory activity who have failed available treatments,” said coinvestigator Matilde Inglese, MD, PhD, professor of neurology at the University of Genoa (Italy).

“Patients selection is very important to ensure the best treatment response and minimize safety issues, including transplant-related mortality,” Dr. Inglese added.

The findings were published online in Neurology.
 

Class III evidence

In the retrospective, propensity-matching study, researchers used two Italian registries to identify 79 patients who were treated off label with AHSCT and 1,975 patients who received another therapy.

Other DMTs included in the control-group analysis were beta-interferons, azathioprine, glatiramer acetate, mitoxantrone, fingolimod, natalizumab, methotrexate, teriflunomide, cyclophosphamide, dimethyl fumarate, or alemtuzumab.

Results showed that time to first disability progression was significantly longer for patients who had received transplants (hazard ratio, 0.5; P = .005); 61.7% of the AHSCT group were free of disability progression at 5 years versus 46.3% of the control group.

Among patients who received AHSCT, relapse rates were lower in comparison with those who received other DMTs (P < .001), and disability scores were lower over 10 years (P < .001).

The transplant group was also significantly more likely than the other-DMTs group to achieve sustained improvement in disability 3 years after treatment (34.7% vs. 4.6%; P < .001).

“This study provides Class III evidence that autologous hematopoietic stem cell transplants prolonged the time to confirmed disability progression compared to other disease-modifying therapies,” the investigators wrote.
 

Extends the treatment population

Commenting on the study, Jeff Cohen, MD, director of experimental therapeutics at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, said the research “extends the population for which hematopoietic stem cell transplant should be considered.”

Although previous studies did not show a benefit for patients with severe progressive MS, participants in the current study had secondary progressive MS and superimposed relapse activity, said Dr. Cohen, who was not involved with the research.

“We think that indicates a greater likelihood of benefit” from AHSCT, he noted. “The fact that someone has overt progression or somewhat more severe disability doesn’t preclude the use of stem cell transplant.”

Dr. Cohen pointed out, however, that the study is not without limitations. The exclusion of patients taking B-cell therapies from the SPMS control group raises the question of whether similar results would come from a comparison with AHSCT.

In addition, Dr. Cohen noted there are safety concerns about the therapy, which has yielded higher transplant-related mortality among patients with SPMS – although only one patient in the current study died following the transplant.

Still, the findings are promising, Dr. Cohen added.

“I think as more data accumulate that supports its benefit and reasonable safety in a variety of populations, we’ll see it used more,” he said.

The study was funded by the Italian Multiple Sclerosis Foundation. Dr. Inglese has received fees for consultation from Roche, Genzyme, Merck, Biogen, and Novartis. Dr. Cohen reported no relevant financial relationships.

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

Autologous hematopoietic stem cell transplantation (AHSCT) is linked to less disability and lower relapse rates in secondary progressive multiple sclerosis (SPMS) versus other disease-modifying therapies (DMTs), new research suggests.

Results from a retrospective study show that more than 60% of patients with SPMS who received AHSCT were free from disability progression at 5 years. Also for these patients, improvement was more likely to be maintained for years after treatment.

The investigators noted that patients with secondary progressive disease often show little benefit from other DMTs, so interest in other treatments is high. While AHSCT is known to offer good results for patients with relapsing remitting MS, studies of its efficacy for SPMS have yielded conflicting results.

The new findings suggest it may be time to take another look at this therapy for patients with active, more severe disease, the researchers wrote.

“AHSCT may become a treatment option in secondary progressive MS patients with inflammatory activity who have failed available treatments,” said coinvestigator Matilde Inglese, MD, PhD, professor of neurology at the University of Genoa (Italy).

“Patients selection is very important to ensure the best treatment response and minimize safety issues, including transplant-related mortality,” Dr. Inglese added.

The findings were published online in Neurology.
 

Class III evidence

In the retrospective, propensity-matching study, researchers used two Italian registries to identify 79 patients who were treated off label with AHSCT and 1,975 patients who received another therapy.

Other DMTs included in the control-group analysis were beta-interferons, azathioprine, glatiramer acetate, mitoxantrone, fingolimod, natalizumab, methotrexate, teriflunomide, cyclophosphamide, dimethyl fumarate, or alemtuzumab.

Results showed that time to first disability progression was significantly longer for patients who had received transplants (hazard ratio, 0.5; P = .005); 61.7% of the AHSCT group were free of disability progression at 5 years versus 46.3% of the control group.

Among patients who received AHSCT, relapse rates were lower in comparison with those who received other DMTs (P < .001), and disability scores were lower over 10 years (P < .001).

The transplant group was also significantly more likely than the other-DMTs group to achieve sustained improvement in disability 3 years after treatment (34.7% vs. 4.6%; P < .001).

“This study provides Class III evidence that autologous hematopoietic stem cell transplants prolonged the time to confirmed disability progression compared to other disease-modifying therapies,” the investigators wrote.
 

Extends the treatment population

Commenting on the study, Jeff Cohen, MD, director of experimental therapeutics at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, said the research “extends the population for which hematopoietic stem cell transplant should be considered.”

Although previous studies did not show a benefit for patients with severe progressive MS, participants in the current study had secondary progressive MS and superimposed relapse activity, said Dr. Cohen, who was not involved with the research.

“We think that indicates a greater likelihood of benefit” from AHSCT, he noted. “The fact that someone has overt progression or somewhat more severe disability doesn’t preclude the use of stem cell transplant.”

Dr. Cohen pointed out, however, that the study is not without limitations. The exclusion of patients taking B-cell therapies from the SPMS control group raises the question of whether similar results would come from a comparison with AHSCT.

In addition, Dr. Cohen noted there are safety concerns about the therapy, which has yielded higher transplant-related mortality among patients with SPMS – although only one patient in the current study died following the transplant.

Still, the findings are promising, Dr. Cohen added.

“I think as more data accumulate that supports its benefit and reasonable safety in a variety of populations, we’ll see it used more,” he said.

The study was funded by the Italian Multiple Sclerosis Foundation. Dr. Inglese has received fees for consultation from Roche, Genzyme, Merck, Biogen, and Novartis. Dr. Cohen reported no relevant financial relationships.

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

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.

Black and Latinx older adults are up to three times as likely to develop Alzheimer’s disease than non-Latinx White adults and tend to experience onset at a younger age with more severe symptoms, according to Monica Rivera-Mindt, PhD, a professor of psychology at Fordham University and the Icahn School of Medicine at Mount Sinai, New York. Looking ahead, that means by 2030, nearly 40% of the 8.4 million Americans affected by Alzheimer’s disease will be Black and/or Latinx, she said. These facts were among the stark disparities in health care outcomes Dr. Rivera-Mindt discussed in her presentation on brain health equity at the 2022 annual meeting of the American Neurological Association.

Dr. Rivera-Mindt’s presentation opened the ANA’s plenary session on health disparities and inequities. The plenary, “Advancing Neurologic Equity: Challenges and Paths Forward,” did not simply enumerate racial and ethnic disparities that exist with various neurological conditions. Rather it went beyond the discussion of what disparities exist into understanding the roots of them as well as tips, tools, and resources that can aid clinicians in addressing or ameliorating them.

“Our most prevalent, most burdensome diseases in neurology disproportionately affect persons from minoritized and marginalized backgrounds,” Roy Hamilton, MD, an associate professor of neurology and physical medicine and rehabilitation at the University of Pennsylvania, Philadelphia, said. “If clinicians are unaware of these disparities or don’t have any sense of how to start to address or think about them, then they’re really missing out on an important component of their education as persons who take care of patients with brain disorders.”

Dr. Hamilton, who organized the plenary, noted that awareness of these disparities is crucial to comprehensively caring for patients.
 

Missed opportunities

“We’re talking about disadvantages that are structural and large scale, but those disadvantages play themselves out in the individual encounter,” Dr. Hamilton said. “When physicians see patients, they have to treat the whole patient in front of them,” which means being aware of the risks and factors that could affect a patient’s clinical presentation. “Being aware of disparities has practical impacts on physician judgment,” he said.

For example, recent research in multiple sclerosis (MS) has highlighted how clinicians may be missing diagnosis of this condition in non-White populations because the condition has been regarded for so long as a “White person’s” disease, Dr. Hamilton said. In non-White patients exhibiting MS symptoms, then, clinicians may have been less likely to consider MS as a possibility, thereby delaying diagnosis and treatment.

Those patterns may partly explain why the mortality rate for MS is greater in Black patients, who also show more rapid neurodegeneration than White patients with MS, Lilyana Amezcua, MD, an associate professor of neurology at the University of Southern California, Los Angeles, reported in the plenary’s second presentation.
 

Transgender issues

The third session, presented by Nicole Rosendale, MD, an assistant professor of neurology at the University of California, San Francisco, and director of the San Francisco General Hospital neurology inpatient services, examined disparities in neurology within the LGBTQ+ community through representative case studies and then offered specific ways that neurologists could make their practices more inclusive and equitable for sexual and gender minorities.

Her first case study was a 52-year-old man who presented with new-onset seizures, right hemiparesis, and aphasia. A brain biopsy consistent with adenocarcinoma eventually led his physician to discover he had metastatic breast cancer. It turned out the man was transgender and, despite a family history of breast cancer, hadn’t been advised to get breast cancer screenings.

“Breast cancer was not initially on the differential as no one had identified that the patient was transmasculine,” Dr. Rosendale said. A major challenge to providing care to transgender patients is a dearth of data on risks and screening recommendations. Another barrier is low knowledge of LGBTQ+ health among neurologists, Dr. Rosendale said while sharing findings from her 2019 study on the topic and calling for more research in LGBTQ+ populations.

Dr. Rosendale’s second case study dealt with a nonbinary patient who suffered from debilitating headaches for decades, first because they lacked access to health insurance and then because negative experiences with providers dissuaded them from seeking care. In data from the Center for American Progress she shared, 8% of LGB respondents and 22% of transgender respondents said they had avoided or delayed care because of fear of discrimination or mistreatment.

“So it’s not only access but also what experiences people are having when they go in and whether they’re actually even getting access to care or being taken care of,” Dr. Rosendale said. Other findings from the CAP found that:

• 8% of LGB patients and 29% of transgender patients reported having a clinician refuse to see them.
• 6% of LGB patients and 12% of transgender patients reported that a clinician refused to give them health care.
• 9% of LGB patients and 21% of transgender patients experienced harsh or abusive language during a health care experience.
• 7% of LGB patients and nearly a third (29%) of transgender patients experienced unwanted physical contact, such as fondling or sexual assault.

Reducing the disparities

Adys Mendizabal, MD, an assistant professor of neurology at the Institute of Society and Genetics at the University of California, Los Angeles, who attended the presentation, was grateful to see how the various lectures enriched the discussion beyond stating the fact of racial/ethnic disparities and dug into the nuances on how to think about and address these disparities. She particularly appreciated discussion about the need to go out of the way to recruit diverse patient populations for clinical trials while also providing them care.

“It is definitely complicated, but it’s not impossible for an individual neurologist or an individual department to do something to reduce some of the disparities,” Dr. Mendizabal said. “It starts with just knowing that they exist and being aware of some of the things that may be impacting care for a particular patient.”
 

Tools to counter disparity

In the final presentation, Amy Kind, MD, PhD, the associate dean for social health sciences and programs at the University of Wisconsin–Madison, rounded out the discussion by exploring social determinants of health and their influence on outcomes.

“Social determinants impact brain health, and brain health is not distributed equally,” Dr. Kind told attendees. “We have known this for decades, yet disparities persist.”

Dr. Kind described the “exposome,” a “measure of all the exposures of an individual in a lifetime and how those exposures relate to health,” according to the CDC, and then introduced a tool clinicians can use to better understand social determinants of health in specific geographic areas. The Neighborhood Atlas, which Dr. Kind described in the New England Journal of Medicine in 2018, measures 17 social determinants across small population-sensitive areas and provides an area deprivation index. A high area deprivation index is linked to a range of negative outcomes, including reshopitalization, later diagnoses, less comprehensive diagnostic evaluation, increased risk of postsurgical complications, and decreased life expectancy.

“One of the things that really stood out to me about Dr. Kind’s discussion of the use of the area deprivation index was the fact that understanding and quantifying these kinds of risks and exposures is the vehicle for creating the kinds of social changes, including policy changes, that will actually lead to addressing and mitigating some of these lifelong risks and exposures,” Dr. Hamilton said. “It is implausible to think that a specific group of people would be genetically more susceptible to basically every disease that we know,” he added. “It makes much more sense to think that groups of individuals have been subjected systematically to conditions that impair health in a variety of ways.”
 

Not just race, ethnicity, sex, and gender

Following the four presentations from researchers in health inequities was an Emerging Scholar presentation in which Jay B. Lusk, an MD/MBA candidate at Duke University, Durham, N.C., shared new research findings on the role of neighborhood disadvantage in predicting mortality from coma, stroke, and other neurologic conditions. His findings revealed that living in a neighborhood with greater deprivation substantially increased risk of mortality even after accounting for individual wealth and demographics.

Maria Eugenia Diaz-Ortiz, PhD, of the department of neurology, University of Pennsylvania, Philadelphia, said she found the five presentations to be an excellent introduction to people like herself who are in the earlier stages of learning about health equity research.

“I think they introduced various important concepts and frameworks and provided tools for people who don’t know about them,” Dr. Diaz-Ortiz said. “Then they asked important questions and provided some solutions to them.”

Dr. Diaz-Ortiz also appreciated seemingly minor but actually important details in how the speakers presented themselves, such as Dr. Rivera-Mindt opening with a land acknowledgment and her disclosures of “positionality.” The former recognized the traditional Native American custodians of the land on which she lives and works, and the latter revealed details about her as an individual – such as being the Afro-Latinx daughter of immigrants yet being cisgender, able-bodied, and U.S.-born – that show where she falls on the axis of adversity and axis of privilege.
 

Implications for research

The biggest takeaway for Dr. Diaz-Ortiz, however, came from the first Q&A session when someone asked how to increase underrepresented populations in dementia research. Dr. Rivera-Mindt described her experience engaging these communities by employing “community-based participatory research practices, which involves making yourself a part of the community and making the community active participants in the research,” Dr. Diaz-Ortiz said. “It’s an evidence-based approach that has been shown to increase participation in research not only in her work but in the work of others.”

Preaching to the choir

Dr. Diaz-Ortiz was pleased overall with the plenary but disappointed in its placement at the end of the meeting, when attendance is always lower as attendees head home.

“The people who stayed were people who already know and recognize the value of health equity work, so I think that was a missed opportunity where the session could have been included on day one or two to boost attendance and also to educate like a broader group of neurologists,” Dr. Diaz-Ortiz said in an interview.

Dr. Mendizabal felt similarly, appreciating the plenary but noting it was “definitely overdue” and that it should not be the last session. Instead, sessions on health equity should be as easy as possible to attend to bring in larger audiences. “Perhaps having that session on a Saturday or Sunday would have a higher likelihood of greater attendance than on a Tuesday,” she said. That said, Dr. Mendizabal also noticed that greater attention to health care disparities was woven into many other sessions throughout the conference, which is “the best way of addressing health equity instead of trying to just designate a session,” she said.

Dr. Mendizabal hopes that plenaries like this one and the weaving of health equity issues into presentations throughout neurology conferences continue.

“After the racial reckoning in 2020, there was a big impetus and a big wave of energy in addressing health disparities in the field, and I hope that that momentum is not starting to wane,” Dr. Mendizabal said. “It’s important because not talking about is not going to make this issue go away.”

Dr. Hamilton agreed that it is important that the conversation continue and that physicians recognize the importance of understanding health care disparities and determinants of health, regardless of where they fall on the political spectrum or whether they choose to get involved in policy or advocacy.

“Irrespective of whether you think race or ethnicity or socioeconomic status are political issues or not, it is the case that you’re obligated to have an objective understanding of the factors that contribute to your patient’s health and as points of intervention,” Dr. Hamilton said. “So even if you don’t want to sit down and jot off that email to your senator, you still have to take these factors into account when you’re treating the person who’s sitting right in front of you, and that’s not political. That’s the promise of being a physician.”

Dr. Amezcua has received personal compensation for consulting, speaking, or serving on steering committees or advisory boards for Biogen Idec, Novartis, Genentech, and EMD Serono, and she has received research support from Biogen Idec and Bristol Myers Squibb Foundation. Dr. Kind reported support from the Alzheimer’s Association. Dr. Diaz-Ortiz is coinventor of a provisional patent submitted by the University of Pennsylvania that relates to a potential therapeutic in Parkinson’s disease. Mr. Lusk reported fellowship support from American Heart Association and travel support from the American Neurological Association. No other speakers or sources had relevant disclosures.
 

Black and Latinx older adults are up to three times as likely to develop Alzheimer’s disease than non-Latinx White adults and tend to experience onset at a younger age with more severe symptoms, according to Monica Rivera-Mindt, PhD, a professor of psychology at Fordham University and the Icahn School of Medicine at Mount Sinai, New York. Looking ahead, that means by 2030, nearly 40% of the 8.4 million Americans affected by Alzheimer’s disease will be Black and/or Latinx, she said. These facts were among the stark disparities in health care outcomes Dr. Rivera-Mindt discussed in her presentation on brain health equity at the 2022 annual meeting of the American Neurological Association.

Dr. Rivera-Mindt’s presentation opened the ANA’s plenary session on health disparities and inequities. The plenary, “Advancing Neurologic Equity: Challenges and Paths Forward,” did not simply enumerate racial and ethnic disparities that exist with various neurological conditions. Rather it went beyond the discussion of what disparities exist into understanding the roots of them as well as tips, tools, and resources that can aid clinicians in addressing or ameliorating them.

“Our most prevalent, most burdensome diseases in neurology disproportionately affect persons from minoritized and marginalized backgrounds,” Roy Hamilton, MD, an associate professor of neurology and physical medicine and rehabilitation at the University of Pennsylvania, Philadelphia, said. “If clinicians are unaware of these disparities or don’t have any sense of how to start to address or think about them, then they’re really missing out on an important component of their education as persons who take care of patients with brain disorders.”

Dr. Hamilton, who organized the plenary, noted that awareness of these disparities is crucial to comprehensively caring for patients.
 

Missed opportunities

“We’re talking about disadvantages that are structural and large scale, but those disadvantages play themselves out in the individual encounter,” Dr. Hamilton said. “When physicians see patients, they have to treat the whole patient in front of them,” which means being aware of the risks and factors that could affect a patient’s clinical presentation. “Being aware of disparities has practical impacts on physician judgment,” he said.

For example, recent research in multiple sclerosis (MS) has highlighted how clinicians may be missing diagnosis of this condition in non-White populations because the condition has been regarded for so long as a “White person’s” disease, Dr. Hamilton said. In non-White patients exhibiting MS symptoms, then, clinicians may have been less likely to consider MS as a possibility, thereby delaying diagnosis and treatment.

Those patterns may partly explain why the mortality rate for MS is greater in Black patients, who also show more rapid neurodegeneration than White patients with MS, Lilyana Amezcua, MD, an associate professor of neurology at the University of Southern California, Los Angeles, reported in the plenary’s second presentation.
 

Transgender issues

The third session, presented by Nicole Rosendale, MD, an assistant professor of neurology at the University of California, San Francisco, and director of the San Francisco General Hospital neurology inpatient services, examined disparities in neurology within the LGBTQ+ community through representative case studies and then offered specific ways that neurologists could make their practices more inclusive and equitable for sexual and gender minorities.

Her first case study was a 52-year-old man who presented with new-onset seizures, right hemiparesis, and aphasia. A brain biopsy consistent with adenocarcinoma eventually led his physician to discover he had metastatic breast cancer. It turned out the man was transgender and, despite a family history of breast cancer, hadn’t been advised to get breast cancer screenings.

“Breast cancer was not initially on the differential as no one had identified that the patient was transmasculine,” Dr. Rosendale said. A major challenge to providing care to transgender patients is a dearth of data on risks and screening recommendations. Another barrier is low knowledge of LGBTQ+ health among neurologists, Dr. Rosendale said while sharing findings from her 2019 study on the topic and calling for more research in LGBTQ+ populations.

Dr. Rosendale’s second case study dealt with a nonbinary patient who suffered from debilitating headaches for decades, first because they lacked access to health insurance and then because negative experiences with providers dissuaded them from seeking care. In data from the Center for American Progress she shared, 8% of LGB respondents and 22% of transgender respondents said they had avoided or delayed care because of fear of discrimination or mistreatment.

“So it’s not only access but also what experiences people are having when they go in and whether they’re actually even getting access to care or being taken care of,” Dr. Rosendale said. Other findings from the CAP found that:

• 8% of LGB patients and 29% of transgender patients reported having a clinician refuse to see them.
• 6% of LGB patients and 12% of transgender patients reported that a clinician refused to give them health care.
• 9% of LGB patients and 21% of transgender patients experienced harsh or abusive language during a health care experience.
• 7% of LGB patients and nearly a third (29%) of transgender patients experienced unwanted physical contact, such as fondling or sexual assault.

Reducing the disparities

Adys Mendizabal, MD, an assistant professor of neurology at the Institute of Society and Genetics at the University of California, Los Angeles, who attended the presentation, was grateful to see how the various lectures enriched the discussion beyond stating the fact of racial/ethnic disparities and dug into the nuances on how to think about and address these disparities. She particularly appreciated discussion about the need to go out of the way to recruit diverse patient populations for clinical trials while also providing them care.

“It is definitely complicated, but it’s not impossible for an individual neurologist or an individual department to do something to reduce some of the disparities,” Dr. Mendizabal said. “It starts with just knowing that they exist and being aware of some of the things that may be impacting care for a particular patient.”
 

Tools to counter disparity

In the final presentation, Amy Kind, MD, PhD, the associate dean for social health sciences and programs at the University of Wisconsin–Madison, rounded out the discussion by exploring social determinants of health and their influence on outcomes.

“Social determinants impact brain health, and brain health is not distributed equally,” Dr. Kind told attendees. “We have known this for decades, yet disparities persist.”

Dr. Kind described the “exposome,” a “measure of all the exposures of an individual in a lifetime and how those exposures relate to health,” according to the CDC, and then introduced a tool clinicians can use to better understand social determinants of health in specific geographic areas. The Neighborhood Atlas, which Dr. Kind described in the New England Journal of Medicine in 2018, measures 17 social determinants across small population-sensitive areas and provides an area deprivation index. A high area deprivation index is linked to a range of negative outcomes, including reshopitalization, later diagnoses, less comprehensive diagnostic evaluation, increased risk of postsurgical complications, and decreased life expectancy.

“One of the things that really stood out to me about Dr. Kind’s discussion of the use of the area deprivation index was the fact that understanding and quantifying these kinds of risks and exposures is the vehicle for creating the kinds of social changes, including policy changes, that will actually lead to addressing and mitigating some of these lifelong risks and exposures,” Dr. Hamilton said. “It is implausible to think that a specific group of people would be genetically more susceptible to basically every disease that we know,” he added. “It makes much more sense to think that groups of individuals have been subjected systematically to conditions that impair health in a variety of ways.”
 

Not just race, ethnicity, sex, and gender

Following the four presentations from researchers in health inequities was an Emerging Scholar presentation in which Jay B. Lusk, an MD/MBA candidate at Duke University, Durham, N.C., shared new research findings on the role of neighborhood disadvantage in predicting mortality from coma, stroke, and other neurologic conditions. His findings revealed that living in a neighborhood with greater deprivation substantially increased risk of mortality even after accounting for individual wealth and demographics.

Maria Eugenia Diaz-Ortiz, PhD, of the department of neurology, University of Pennsylvania, Philadelphia, said she found the five presentations to be an excellent introduction to people like herself who are in the earlier stages of learning about health equity research.

“I think they introduced various important concepts and frameworks and provided tools for people who don’t know about them,” Dr. Diaz-Ortiz said. “Then they asked important questions and provided some solutions to them.”

Dr. Diaz-Ortiz also appreciated seemingly minor but actually important details in how the speakers presented themselves, such as Dr. Rivera-Mindt opening with a land acknowledgment and her disclosures of “positionality.” The former recognized the traditional Native American custodians of the land on which she lives and works, and the latter revealed details about her as an individual – such as being the Afro-Latinx daughter of immigrants yet being cisgender, able-bodied, and U.S.-born – that show where she falls on the axis of adversity and axis of privilege.
 

Implications for research

The biggest takeaway for Dr. Diaz-Ortiz, however, came from the first Q&A session when someone asked how to increase underrepresented populations in dementia research. Dr. Rivera-Mindt described her experience engaging these communities by employing “community-based participatory research practices, which involves making yourself a part of the community and making the community active participants in the research,” Dr. Diaz-Ortiz said. “It’s an evidence-based approach that has been shown to increase participation in research not only in her work but in the work of others.”

Preaching to the choir

Dr. Diaz-Ortiz was pleased overall with the plenary but disappointed in its placement at the end of the meeting, when attendance is always lower as attendees head home.

“The people who stayed were people who already know and recognize the value of health equity work, so I think that was a missed opportunity where the session could have been included on day one or two to boost attendance and also to educate like a broader group of neurologists,” Dr. Diaz-Ortiz said in an interview.

Dr. Mendizabal felt similarly, appreciating the plenary but noting it was “definitely overdue” and that it should not be the last session. Instead, sessions on health equity should be as easy as possible to attend to bring in larger audiences. “Perhaps having that session on a Saturday or Sunday would have a higher likelihood of greater attendance than on a Tuesday,” she said. That said, Dr. Mendizabal also noticed that greater attention to health care disparities was woven into many other sessions throughout the conference, which is “the best way of addressing health equity instead of trying to just designate a session,” she said.

Dr. Mendizabal hopes that plenaries like this one and the weaving of health equity issues into presentations throughout neurology conferences continue.

“After the racial reckoning in 2020, there was a big impetus and a big wave of energy in addressing health disparities in the field, and I hope that that momentum is not starting to wane,” Dr. Mendizabal said. “It’s important because not talking about is not going to make this issue go away.”

Dr. Hamilton agreed that it is important that the conversation continue and that physicians recognize the importance of understanding health care disparities and determinants of health, regardless of where they fall on the political spectrum or whether they choose to get involved in policy or advocacy.

“Irrespective of whether you think race or ethnicity or socioeconomic status are political issues or not, it is the case that you’re obligated to have an objective understanding of the factors that contribute to your patient’s health and as points of intervention,” Dr. Hamilton said. “So even if you don’t want to sit down and jot off that email to your senator, you still have to take these factors into account when you’re treating the person who’s sitting right in front of you, and that’s not political. That’s the promise of being a physician.”

Dr. Amezcua has received personal compensation for consulting, speaking, or serving on steering committees or advisory boards for Biogen Idec, Novartis, Genentech, and EMD Serono, and she has received research support from Biogen Idec and Bristol Myers Squibb Foundation. Dr. Kind reported support from the Alzheimer’s Association. Dr. Diaz-Ortiz is coinventor of a provisional patent submitted by the University of Pennsylvania that relates to a potential therapeutic in Parkinson’s disease. Mr. Lusk reported fellowship support from American Heart Association and travel support from the American Neurological Association. No other speakers or sources had relevant disclosures.
 

Black and Latinx older adults are up to three times as likely to develop Alzheimer’s disease than non-Latinx White adults and tend to experience onset at a younger age with more severe symptoms, according to Monica Rivera-Mindt, PhD, a professor of psychology at Fordham University and the Icahn School of Medicine at Mount Sinai, New York. Looking ahead, that means by 2030, nearly 40% of the 8.4 million Americans affected by Alzheimer’s disease will be Black and/or Latinx, she said. These facts were among the stark disparities in health care outcomes Dr. Rivera-Mindt discussed in her presentation on brain health equity at the 2022 annual meeting of the American Neurological Association.

Dr. Rivera-Mindt’s presentation opened the ANA’s plenary session on health disparities and inequities. The plenary, “Advancing Neurologic Equity: Challenges and Paths Forward,” did not simply enumerate racial and ethnic disparities that exist with various neurological conditions. Rather it went beyond the discussion of what disparities exist into understanding the roots of them as well as tips, tools, and resources that can aid clinicians in addressing or ameliorating them.

“Our most prevalent, most burdensome diseases in neurology disproportionately affect persons from minoritized and marginalized backgrounds,” Roy Hamilton, MD, an associate professor of neurology and physical medicine and rehabilitation at the University of Pennsylvania, Philadelphia, said. “If clinicians are unaware of these disparities or don’t have any sense of how to start to address or think about them, then they’re really missing out on an important component of their education as persons who take care of patients with brain disorders.”

Dr. Hamilton, who organized the plenary, noted that awareness of these disparities is crucial to comprehensively caring for patients.
 

Missed opportunities

“We’re talking about disadvantages that are structural and large scale, but those disadvantages play themselves out in the individual encounter,” Dr. Hamilton said. “When physicians see patients, they have to treat the whole patient in front of them,” which means being aware of the risks and factors that could affect a patient’s clinical presentation. “Being aware of disparities has practical impacts on physician judgment,” he said.

For example, recent research in multiple sclerosis (MS) has highlighted how clinicians may be missing diagnosis of this condition in non-White populations because the condition has been regarded for so long as a “White person’s” disease, Dr. Hamilton said. In non-White patients exhibiting MS symptoms, then, clinicians may have been less likely to consider MS as a possibility, thereby delaying diagnosis and treatment.

Those patterns may partly explain why the mortality rate for MS is greater in Black patients, who also show more rapid neurodegeneration than White patients with MS, Lilyana Amezcua, MD, an associate professor of neurology at the University of Southern California, Los Angeles, reported in the plenary’s second presentation.
 

Transgender issues

The third session, presented by Nicole Rosendale, MD, an assistant professor of neurology at the University of California, San Francisco, and director of the San Francisco General Hospital neurology inpatient services, examined disparities in neurology within the LGBTQ+ community through representative case studies and then offered specific ways that neurologists could make their practices more inclusive and equitable for sexual and gender minorities.

Her first case study was a 52-year-old man who presented with new-onset seizures, right hemiparesis, and aphasia. A brain biopsy consistent with adenocarcinoma eventually led his physician to discover he had metastatic breast cancer. It turned out the man was transgender and, despite a family history of breast cancer, hadn’t been advised to get breast cancer screenings.

“Breast cancer was not initially on the differential as no one had identified that the patient was transmasculine,” Dr. Rosendale said. A major challenge to providing care to transgender patients is a dearth of data on risks and screening recommendations. Another barrier is low knowledge of LGBTQ+ health among neurologists, Dr. Rosendale said while sharing findings from her 2019 study on the topic and calling for more research in LGBTQ+ populations.

Dr. Rosendale’s second case study dealt with a nonbinary patient who suffered from debilitating headaches for decades, first because they lacked access to health insurance and then because negative experiences with providers dissuaded them from seeking care. In data from the Center for American Progress she shared, 8% of LGB respondents and 22% of transgender respondents said they had avoided or delayed care because of fear of discrimination or mistreatment.

“So it’s not only access but also what experiences people are having when they go in and whether they’re actually even getting access to care or being taken care of,” Dr. Rosendale said. Other findings from the CAP found that:

• 8% of LGB patients and 29% of transgender patients reported having a clinician refuse to see them.
• 6% of LGB patients and 12% of transgender patients reported that a clinician refused to give them health care.
• 9% of LGB patients and 21% of transgender patients experienced harsh or abusive language during a health care experience.
• 7% of LGB patients and nearly a third (29%) of transgender patients experienced unwanted physical contact, such as fondling or sexual assault.

Reducing the disparities

Adys Mendizabal, MD, an assistant professor of neurology at the Institute of Society and Genetics at the University of California, Los Angeles, who attended the presentation, was grateful to see how the various lectures enriched the discussion beyond stating the fact of racial/ethnic disparities and dug into the nuances on how to think about and address these disparities. She particularly appreciated discussion about the need to go out of the way to recruit diverse patient populations for clinical trials while also providing them care.

“It is definitely complicated, but it’s not impossible for an individual neurologist or an individual department to do something to reduce some of the disparities,” Dr. Mendizabal said. “It starts with just knowing that they exist and being aware of some of the things that may be impacting care for a particular patient.”
 

Tools to counter disparity

In the final presentation, Amy Kind, MD, PhD, the associate dean for social health sciences and programs at the University of Wisconsin–Madison, rounded out the discussion by exploring social determinants of health and their influence on outcomes.

“Social determinants impact brain health, and brain health is not distributed equally,” Dr. Kind told attendees. “We have known this for decades, yet disparities persist.”

Dr. Kind described the “exposome,” a “measure of all the exposures of an individual in a lifetime and how those exposures relate to health,” according to the CDC, and then introduced a tool clinicians can use to better understand social determinants of health in specific geographic areas. The Neighborhood Atlas, which Dr. Kind described in the New England Journal of Medicine in 2018, measures 17 social determinants across small population-sensitive areas and provides an area deprivation index. A high area deprivation index is linked to a range of negative outcomes, including reshopitalization, later diagnoses, less comprehensive diagnostic evaluation, increased risk of postsurgical complications, and decreased life expectancy.

“One of the things that really stood out to me about Dr. Kind’s discussion of the use of the area deprivation index was the fact that understanding and quantifying these kinds of risks and exposures is the vehicle for creating the kinds of social changes, including policy changes, that will actually lead to addressing and mitigating some of these lifelong risks and exposures,” Dr. Hamilton said. “It is implausible to think that a specific group of people would be genetically more susceptible to basically every disease that we know,” he added. “It makes much more sense to think that groups of individuals have been subjected systematically to conditions that impair health in a variety of ways.”
 

Not just race, ethnicity, sex, and gender

Following the four presentations from researchers in health inequities was an Emerging Scholar presentation in which Jay B. Lusk, an MD/MBA candidate at Duke University, Durham, N.C., shared new research findings on the role of neighborhood disadvantage in predicting mortality from coma, stroke, and other neurologic conditions. His findings revealed that living in a neighborhood with greater deprivation substantially increased risk of mortality even after accounting for individual wealth and demographics.

Maria Eugenia Diaz-Ortiz, PhD, of the department of neurology, University of Pennsylvania, Philadelphia, said she found the five presentations to be an excellent introduction to people like herself who are in the earlier stages of learning about health equity research.

“I think they introduced various important concepts and frameworks and provided tools for people who don’t know about them,” Dr. Diaz-Ortiz said. “Then they asked important questions and provided some solutions to them.”

Dr. Diaz-Ortiz also appreciated seemingly minor but actually important details in how the speakers presented themselves, such as Dr. Rivera-Mindt opening with a land acknowledgment and her disclosures of “positionality.” The former recognized the traditional Native American custodians of the land on which she lives and works, and the latter revealed details about her as an individual – such as being the Afro-Latinx daughter of immigrants yet being cisgender, able-bodied, and U.S.-born – that show where she falls on the axis of adversity and axis of privilege.
 

Implications for research

The biggest takeaway for Dr. Diaz-Ortiz, however, came from the first Q&A session when someone asked how to increase underrepresented populations in dementia research. Dr. Rivera-Mindt described her experience engaging these communities by employing “community-based participatory research practices, which involves making yourself a part of the community and making the community active participants in the research,” Dr. Diaz-Ortiz said. “It’s an evidence-based approach that has been shown to increase participation in research not only in her work but in the work of others.”

Preaching to the choir

Dr. Diaz-Ortiz was pleased overall with the plenary but disappointed in its placement at the end of the meeting, when attendance is always lower as attendees head home.

“The people who stayed were people who already know and recognize the value of health equity work, so I think that was a missed opportunity where the session could have been included on day one or two to boost attendance and also to educate like a broader group of neurologists,” Dr. Diaz-Ortiz said in an interview.

Dr. Mendizabal felt similarly, appreciating the plenary but noting it was “definitely overdue” and that it should not be the last session. Instead, sessions on health equity should be as easy as possible to attend to bring in larger audiences. “Perhaps having that session on a Saturday or Sunday would have a higher likelihood of greater attendance than on a Tuesday,” she said. That said, Dr. Mendizabal also noticed that greater attention to health care disparities was woven into many other sessions throughout the conference, which is “the best way of addressing health equity instead of trying to just designate a session,” she said.

Dr. Mendizabal hopes that plenaries like this one and the weaving of health equity issues into presentations throughout neurology conferences continue.

“After the racial reckoning in 2020, there was a big impetus and a big wave of energy in addressing health disparities in the field, and I hope that that momentum is not starting to wane,” Dr. Mendizabal said. “It’s important because not talking about is not going to make this issue go away.”

Dr. Hamilton agreed that it is important that the conversation continue and that physicians recognize the importance of understanding health care disparities and determinants of health, regardless of where they fall on the political spectrum or whether they choose to get involved in policy or advocacy.

“Irrespective of whether you think race or ethnicity or socioeconomic status are political issues or not, it is the case that you’re obligated to have an objective understanding of the factors that contribute to your patient’s health and as points of intervention,” Dr. Hamilton said. “So even if you don’t want to sit down and jot off that email to your senator, you still have to take these factors into account when you’re treating the person who’s sitting right in front of you, and that’s not political. That’s the promise of being a physician.”

Dr. Amezcua has received personal compensation for consulting, speaking, or serving on steering committees or advisory boards for Biogen Idec, Novartis, Genentech, and EMD Serono, and she has received research support from Biogen Idec and Bristol Myers Squibb Foundation. Dr. Kind reported support from the Alzheimer’s Association. Dr. Diaz-Ortiz is coinventor of a provisional patent submitted by the University of Pennsylvania that relates to a potential therapeutic in Parkinson’s disease. Mr. Lusk reported fellowship support from American Heart Association and travel support from the American Neurological Association. No other speakers or sources had relevant disclosures.
 

Based on this patient's history and presentation, the likely diagnosis is primary progressive multiple sclerosis (PPMS). PPMS represents around 10% of MS cases and tends to develop about a decade later than relapsing MS. Unlike other forms of MS, this phenotype progresses steadily instead of in an episodic fashion like relapsing forms of MS. Most patients with PPMS present with gait difficulty because lesions often develop on the spinal cord. While relapsing-remitting MS (RRMS) is much more common among women than men, men with MS are more likely to have the progressive form. 

Although this patient's MRI ultimately points to multiple sclerosis, his functional deficits may initially suggest other conditions in the differential diagnosis. Brainstem gliomas typically manifest in unsteady gait, weakness, double vision, difficulty swallowing, dysarthria, headache, drowsiness, nausea, and vomiting. Transverse myelitis often presents with rapid-onset weakness, sensory deficits, and bowel/bladder dysfunction. Musculoskeletal and neurologic symptoms are common in Lyme disease. B12 deficiency can present with worsening weakness and a sensory ataxia that can present as balance difficulties, but it would not cause focal lesions on the MRI, nor would it present with bladder symptoms. In addition, the patient's steady decline in function rules out RRMS.

PPMS is diagnosed with confirmation of gradual change in functional ability (often ambulation) over time without remission or relapse. These criteria include 1 full year of worsening neurologic function without asymptomatic periods as well as two of these signs of disease: brain lesion, two or more spinal cord lesions, and oligoclonal bands or elevated Immunoglobulin G index. These timing-specific criteria can delay diagnosis, as seen here. 

Ocrelizumab is the only FDA-approved disease-modifying therapy (DMT) proven to alter disease progression in ambulatory patients with PPMS. American Academy of Neurology guidelines recommend ocrelizumab for patients with PPMS who are likely to benefit from this therapy. While it is thought that DMTs are more effective at targeting inflammation in RRMS than nerve degeneration in PPMS, these agents may show benefit for patients with active PPMS (relapse and/or evidence of new MRI activity) rather than inactive disease. A recent PPMS study concluded that among patients with relapse or disease activity, DMTs were associated with a significant reduction of long-term disability risk. Together with immunomodulatory therapy, rehabilitation can help manage symptoms.

Krupa Pandey, MD, Director, Multiple Sclerosis Center, Department of Neurology & Neuroscience Institute, Hackensack University Medical Center; Neurologist, Department of Neurology, Hackensack Meridian Health, Hackensack, NJ.

Krupa Pandey, MD, has serve(d) as a speaker or a member of a speakers bureau for: Bristol-Myers Squibb; Biogen; Alexion; Genentech; Sanofi-Genzyme.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Based on this patient's history and presentation, the likely diagnosis is primary progressive multiple sclerosis (PPMS). PPMS represents around 10% of MS cases and tends to develop about a decade later than relapsing MS. Unlike other forms of MS, this phenotype progresses steadily instead of in an episodic fashion like relapsing forms of MS. Most patients with PPMS present with gait difficulty because lesions often develop on the spinal cord. While relapsing-remitting MS (RRMS) is much more common among women than men, men with MS are more likely to have the progressive form. 

Although this patient's MRI ultimately points to multiple sclerosis, his functional deficits may initially suggest other conditions in the differential diagnosis. Brainstem gliomas typically manifest in unsteady gait, weakness, double vision, difficulty swallowing, dysarthria, headache, drowsiness, nausea, and vomiting. Transverse myelitis often presents with rapid-onset weakness, sensory deficits, and bowel/bladder dysfunction. Musculoskeletal and neurologic symptoms are common in Lyme disease. B12 deficiency can present with worsening weakness and a sensory ataxia that can present as balance difficulties, but it would not cause focal lesions on the MRI, nor would it present with bladder symptoms. In addition, the patient's steady decline in function rules out RRMS.

PPMS is diagnosed with confirmation of gradual change in functional ability (often ambulation) over time without remission or relapse. These criteria include 1 full year of worsening neurologic function without asymptomatic periods as well as two of these signs of disease: brain lesion, two or more spinal cord lesions, and oligoclonal bands or elevated Immunoglobulin G index. These timing-specific criteria can delay diagnosis, as seen here. 

Ocrelizumab is the only FDA-approved disease-modifying therapy (DMT) proven to alter disease progression in ambulatory patients with PPMS. American Academy of Neurology guidelines recommend ocrelizumab for patients with PPMS who are likely to benefit from this therapy. While it is thought that DMTs are more effective at targeting inflammation in RRMS than nerve degeneration in PPMS, these agents may show benefit for patients with active PPMS (relapse and/or evidence of new MRI activity) rather than inactive disease. A recent PPMS study concluded that among patients with relapse or disease activity, DMTs were associated with a significant reduction of long-term disability risk. Together with immunomodulatory therapy, rehabilitation can help manage symptoms.

Krupa Pandey, MD, Director, Multiple Sclerosis Center, Department of Neurology & Neuroscience Institute, Hackensack University Medical Center; Neurologist, Department of Neurology, Hackensack Meridian Health, Hackensack, NJ.

Krupa Pandey, MD, has serve(d) as a speaker or a member of a speakers bureau for: Bristol-Myers Squibb; Biogen; Alexion; Genentech; Sanofi-Genzyme.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Based on this patient's history and presentation, the likely diagnosis is primary progressive multiple sclerosis (PPMS). PPMS represents around 10% of MS cases and tends to develop about a decade later than relapsing MS. Unlike other forms of MS, this phenotype progresses steadily instead of in an episodic fashion like relapsing forms of MS. Most patients with PPMS present with gait difficulty because lesions often develop on the spinal cord. While relapsing-remitting MS (RRMS) is much more common among women than men, men with MS are more likely to have the progressive form. 

Although this patient's MRI ultimately points to multiple sclerosis, his functional deficits may initially suggest other conditions in the differential diagnosis. Brainstem gliomas typically manifest in unsteady gait, weakness, double vision, difficulty swallowing, dysarthria, headache, drowsiness, nausea, and vomiting. Transverse myelitis often presents with rapid-onset weakness, sensory deficits, and bowel/bladder dysfunction. Musculoskeletal and neurologic symptoms are common in Lyme disease. B12 deficiency can present with worsening weakness and a sensory ataxia that can present as balance difficulties, but it would not cause focal lesions on the MRI, nor would it present with bladder symptoms. In addition, the patient's steady decline in function rules out RRMS.

PPMS is diagnosed with confirmation of gradual change in functional ability (often ambulation) over time without remission or relapse. These criteria include 1 full year of worsening neurologic function without asymptomatic periods as well as two of these signs of disease: brain lesion, two or more spinal cord lesions, and oligoclonal bands or elevated Immunoglobulin G index. These timing-specific criteria can delay diagnosis, as seen here. 

Ocrelizumab is the only FDA-approved disease-modifying therapy (DMT) proven to alter disease progression in ambulatory patients with PPMS. American Academy of Neurology guidelines recommend ocrelizumab for patients with PPMS who are likely to benefit from this therapy. While it is thought that DMTs are more effective at targeting inflammation in RRMS than nerve degeneration in PPMS, these agents may show benefit for patients with active PPMS (relapse and/or evidence of new MRI activity) rather than inactive disease. A recent PPMS study concluded that among patients with relapse or disease activity, DMTs were associated with a significant reduction of long-term disability risk. Together with immunomodulatory therapy, rehabilitation can help manage symptoms.

Krupa Pandey, MD, Director, Multiple Sclerosis Center, Department of Neurology & Neuroscience Institute, Hackensack University Medical Center; Neurologist, Department of Neurology, Hackensack Meridian Health, Hackensack, NJ.

Krupa Pandey, MD, has serve(d) as a speaker or a member of a speakers bureau for: Bristol-Myers Squibb; Biogen; Alexion; Genentech; Sanofi-Genzyme.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

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.