Multiple Sclerosis Hub

A blood test that measures elevations in neurofilament light chain (NfL) levels in patients with multiple sclerosis (MS) could warn of worsening disability up to 2 years before it occurs, a new study suggests.

Rising NfL levels are a known indicator of neuroaxonal injury and correlate with MS disease activity. Levels rise in the presence of an MS relapse or MRI activity and fall following treatment with disease-modifying therapies. But the link between NfL levels and worsening disability was less understood.

This new analysis of NfL in two large MS cohorts found that elevated levels of the neuronal protein at baseline were associated with large increases in future disability risk, even in patients with no clinical relapse.

“This rising of NfL up to 2 years before signs of disability worsening represents the window when interventions may prevent worsening,” lead investigator Ahmed Abdelhak, MD, department of neurology, University of California, San Francisco, said in a press release.

The findings were published online in JAMA Neurology.
 

Early warning system?

The study included data on 1,899 patients with nearly 13,000 patient visits from two observational, long-term, real-world cohorts: the U.S.-based Expression, Proteomics, Imaging, Clinical (EPIC) study (n = 609 patients), and the Swiss Multiple Sclerosis Cohort trial (SMSC; n = 1,290 patients).

Investigators analyzed longitudinal serum NfL measurements in conjunction with clinical disability worsening, defined as 6 months or more of increased impairment as measured by the Expanded Disability Status Scale.

Researchers also assessed the temporal association between NfL measurements and the risk of increased disability and distinguished between disability with and without relapse.

Worsening disability was reported in 227 patients in the EPIC group and 435 in the SMSC trial.

Elevated NfL at baseline was associated with a 70% higher risk for worsening disability with relapse about 11 months later in the SMSC study (hazard ratio, 1.70; P = .02). In the EPIC trial, there was trend toward a 91% higher risk for worsening disability with relapse at 12.6 months, although the findings did not meet statistical significance (HR, 1.91; P = .07).

The risk of future disability progression independent of clinical relapse was 40% higher in those with high NfL at baseline in the EPIC study 12 months after baseline (HR, 1.40; P = .02) and 49% higher in the SMSC trial 21 months later (HR, 1.49; P < .001).

The early elevation of NfL levels suggests a slower degradation of nerve cells and could be a possible early warning system of future progression of disability, allowing time for interventions that could slow or even halt further disability.

“Monitoring NfL levels might be able to detect disease activity with higher sensitivity than clinical exam or conventional imaging,” senior author Jens Kuhle, MD, PhD, leader of the Swiss cohort and head of the Multiple Sclerosis Center at University Hospital and University of Basel, said in a statement.
 

Challenges for clinicians

Commenting on the findings, Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research, Neurological Institute, Cleveland Clinic, said that, while there is a clinical test to measure NfL levels, incorporating that test into standard of care isn’t straightforward.

“The challenge for the practicing clinician is to translate these population-level studies to individual patient management decisions,” said Dr. Fox, who was not a part of the study.

“The published prediction curves corrected for age, sex, disease course, disease-modifying treatment, relapse within the past 90 days, and current disability status, the combination of which makes it rather challenging to calculate and interpret adjusted z score NfL levels in routine practice and then use it in clinical decision-making.”

The investigators said the study underscores the importance of NfL as an MS biomarker and “points to the existence of different windows of dynamic central nervous system pathology” that precedes worsening disability with or without relapse. But there may be a simpler explanation, Dr. Fox suggested.

“We know MRI activity occurs 5-10 times more frequently than relapses, and we know that MRI activity is associated with both NfL increases and future disability progression,” Dr. Fox said. “It is quite likely that the elevations in NfL seen here are reflective of new MRI disease activity, which frequently is seen without symptoms of an MS relapse,” he said

The study was funded by the Westridge Foundation, F. Hoffmann–La Roche, the Fishman Family, the Swiss National Research Foundation, the National Institutes of Health/National Institute of Neurological Disorders and Stroke, and the Valhalla Foundation. Dr. Abdelhak reported receiving grants from the German Multiple Sclerosis Society and the Weill Institute for Neurosciences outside the submitted work. Dr. Kuhle has received grants from Swiss MS Society, the Swiss National Research Foundation, the Progressive MS Alliance, Biogen, Merck, Celgene, Bristol-Myers Squibb, Novartis, Octave Bioscience, Roche, Sanofi, Alnylam, Bayer, Immunic, Quanterix, Neurogenesis, Stata DX, and the University of Basel outside the submitted work. Dr. Fox reported receiving consulting fees from Siemens and Roche.

A version of this article appeared on Medscape.com.

A blood test that measures elevations in neurofilament light chain (NfL) levels in patients with multiple sclerosis (MS) could warn of worsening disability up to 2 years before it occurs, a new study suggests.

Rising NfL levels are a known indicator of neuroaxonal injury and correlate with MS disease activity. Levels rise in the presence of an MS relapse or MRI activity and fall following treatment with disease-modifying therapies. But the link between NfL levels and worsening disability was less understood.

This new analysis of NfL in two large MS cohorts found that elevated levels of the neuronal protein at baseline were associated with large increases in future disability risk, even in patients with no clinical relapse.

“This rising of NfL up to 2 years before signs of disability worsening represents the window when interventions may prevent worsening,” lead investigator Ahmed Abdelhak, MD, department of neurology, University of California, San Francisco, said in a press release.

The findings were published online in JAMA Neurology.
 

Early warning system?

The study included data on 1,899 patients with nearly 13,000 patient visits from two observational, long-term, real-world cohorts: the U.S.-based Expression, Proteomics, Imaging, Clinical (EPIC) study (n = 609 patients), and the Swiss Multiple Sclerosis Cohort trial (SMSC; n = 1,290 patients).

Investigators analyzed longitudinal serum NfL measurements in conjunction with clinical disability worsening, defined as 6 months or more of increased impairment as measured by the Expanded Disability Status Scale.

Researchers also assessed the temporal association between NfL measurements and the risk of increased disability and distinguished between disability with and without relapse.

Worsening disability was reported in 227 patients in the EPIC group and 435 in the SMSC trial.

Elevated NfL at baseline was associated with a 70% higher risk for worsening disability with relapse about 11 months later in the SMSC study (hazard ratio, 1.70; P = .02). In the EPIC trial, there was trend toward a 91% higher risk for worsening disability with relapse at 12.6 months, although the findings did not meet statistical significance (HR, 1.91; P = .07).

The risk of future disability progression independent of clinical relapse was 40% higher in those with high NfL at baseline in the EPIC study 12 months after baseline (HR, 1.40; P = .02) and 49% higher in the SMSC trial 21 months later (HR, 1.49; P < .001).

The early elevation of NfL levels suggests a slower degradation of nerve cells and could be a possible early warning system of future progression of disability, allowing time for interventions that could slow or even halt further disability.

“Monitoring NfL levels might be able to detect disease activity with higher sensitivity than clinical exam or conventional imaging,” senior author Jens Kuhle, MD, PhD, leader of the Swiss cohort and head of the Multiple Sclerosis Center at University Hospital and University of Basel, said in a statement.
 

Challenges for clinicians

Commenting on the findings, Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research, Neurological Institute, Cleveland Clinic, said that, while there is a clinical test to measure NfL levels, incorporating that test into standard of care isn’t straightforward.

“The challenge for the practicing clinician is to translate these population-level studies to individual patient management decisions,” said Dr. Fox, who was not a part of the study.

“The published prediction curves corrected for age, sex, disease course, disease-modifying treatment, relapse within the past 90 days, and current disability status, the combination of which makes it rather challenging to calculate and interpret adjusted z score NfL levels in routine practice and then use it in clinical decision-making.”

The investigators said the study underscores the importance of NfL as an MS biomarker and “points to the existence of different windows of dynamic central nervous system pathology” that precedes worsening disability with or without relapse. But there may be a simpler explanation, Dr. Fox suggested.

“We know MRI activity occurs 5-10 times more frequently than relapses, and we know that MRI activity is associated with both NfL increases and future disability progression,” Dr. Fox said. “It is quite likely that the elevations in NfL seen here are reflective of new MRI disease activity, which frequently is seen without symptoms of an MS relapse,” he said

The study was funded by the Westridge Foundation, F. Hoffmann–La Roche, the Fishman Family, the Swiss National Research Foundation, the National Institutes of Health/National Institute of Neurological Disorders and Stroke, and the Valhalla Foundation. Dr. Abdelhak reported receiving grants from the German Multiple Sclerosis Society and the Weill Institute for Neurosciences outside the submitted work. Dr. Kuhle has received grants from Swiss MS Society, the Swiss National Research Foundation, the Progressive MS Alliance, Biogen, Merck, Celgene, Bristol-Myers Squibb, Novartis, Octave Bioscience, Roche, Sanofi, Alnylam, Bayer, Immunic, Quanterix, Neurogenesis, Stata DX, and the University of Basel outside the submitted work. Dr. Fox reported receiving consulting fees from Siemens and Roche.

A version of this article appeared on Medscape.com.

A blood test that measures elevations in neurofilament light chain (NfL) levels in patients with multiple sclerosis (MS) could warn of worsening disability up to 2 years before it occurs, a new study suggests.

Rising NfL levels are a known indicator of neuroaxonal injury and correlate with MS disease activity. Levels rise in the presence of an MS relapse or MRI activity and fall following treatment with disease-modifying therapies. But the link between NfL levels and worsening disability was less understood.

This new analysis of NfL in two large MS cohorts found that elevated levels of the neuronal protein at baseline were associated with large increases in future disability risk, even in patients with no clinical relapse.

“This rising of NfL up to 2 years before signs of disability worsening represents the window when interventions may prevent worsening,” lead investigator Ahmed Abdelhak, MD, department of neurology, University of California, San Francisco, said in a press release.

The findings were published online in JAMA Neurology.
 

Early warning system?

The study included data on 1,899 patients with nearly 13,000 patient visits from two observational, long-term, real-world cohorts: the U.S.-based Expression, Proteomics, Imaging, Clinical (EPIC) study (n = 609 patients), and the Swiss Multiple Sclerosis Cohort trial (SMSC; n = 1,290 patients).

Investigators analyzed longitudinal serum NfL measurements in conjunction with clinical disability worsening, defined as 6 months or more of increased impairment as measured by the Expanded Disability Status Scale.

Researchers also assessed the temporal association between NfL measurements and the risk of increased disability and distinguished between disability with and without relapse.

Worsening disability was reported in 227 patients in the EPIC group and 435 in the SMSC trial.

Elevated NfL at baseline was associated with a 70% higher risk for worsening disability with relapse about 11 months later in the SMSC study (hazard ratio, 1.70; P = .02). In the EPIC trial, there was trend toward a 91% higher risk for worsening disability with relapse at 12.6 months, although the findings did not meet statistical significance (HR, 1.91; P = .07).

The risk of future disability progression independent of clinical relapse was 40% higher in those with high NfL at baseline in the EPIC study 12 months after baseline (HR, 1.40; P = .02) and 49% higher in the SMSC trial 21 months later (HR, 1.49; P < .001).

The early elevation of NfL levels suggests a slower degradation of nerve cells and could be a possible early warning system of future progression of disability, allowing time for interventions that could slow or even halt further disability.

“Monitoring NfL levels might be able to detect disease activity with higher sensitivity than clinical exam or conventional imaging,” senior author Jens Kuhle, MD, PhD, leader of the Swiss cohort and head of the Multiple Sclerosis Center at University Hospital and University of Basel, said in a statement.
 

Challenges for clinicians

Commenting on the findings, Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research, Neurological Institute, Cleveland Clinic, said that, while there is a clinical test to measure NfL levels, incorporating that test into standard of care isn’t straightforward.

“The challenge for the practicing clinician is to translate these population-level studies to individual patient management decisions,” said Dr. Fox, who was not a part of the study.

“The published prediction curves corrected for age, sex, disease course, disease-modifying treatment, relapse within the past 90 days, and current disability status, the combination of which makes it rather challenging to calculate and interpret adjusted z score NfL levels in routine practice and then use it in clinical decision-making.”

The investigators said the study underscores the importance of NfL as an MS biomarker and “points to the existence of different windows of dynamic central nervous system pathology” that precedes worsening disability with or without relapse. But there may be a simpler explanation, Dr. Fox suggested.

“We know MRI activity occurs 5-10 times more frequently than relapses, and we know that MRI activity is associated with both NfL increases and future disability progression,” Dr. Fox said. “It is quite likely that the elevations in NfL seen here are reflective of new MRI disease activity, which frequently is seen without symptoms of an MS relapse,” he said

The study was funded by the Westridge Foundation, F. Hoffmann–La Roche, the Fishman Family, the Swiss National Research Foundation, the National Institutes of Health/National Institute of Neurological Disorders and Stroke, and the Valhalla Foundation. Dr. Abdelhak reported receiving grants from the German Multiple Sclerosis Society and the Weill Institute for Neurosciences outside the submitted work. Dr. Kuhle has received grants from Swiss MS Society, the Swiss National Research Foundation, the Progressive MS Alliance, Biogen, Merck, Celgene, Bristol-Myers Squibb, Novartis, Octave Bioscience, Roche, Sanofi, Alnylam, Bayer, Immunic, Quanterix, Neurogenesis, Stata DX, and the University of Basel outside the submitted work. Dr. Fox reported receiving consulting fees from Siemens and Roche.

A version of this article appeared on Medscape.com.

TOPLINE:

The disease-modifying treatment (DMT) delays conversion to clinical multiple sclerosis (MS) for patients with radiologically isolated syndrome (RIS) and has a reassuring long-term safety profile, new research shows.

METHODOLOGY:

Early use of DMTs is typically recommended for patients with established MS, but mounting evidence, including the ARISE trial, which assessed Tecfidera, suggests these agents benefit patients with RIS, the earliest detectable preclinical MS stage.

The new study, known as Teriflunomide in Radiologically Isolated Syndrome (TERIS), included 89 adult patients with RIS (mean age, 37.8 years) from centers in France, Switzerland, and Turkey. Participants were randomly assigned to receive placebo or teriflunomide 14 mg daily. Teriflunomide is an oral immunomodulator approved for treating relapsing remitting MS.

Investigators performed MRI at baseline and at weeks 48, 96, and 144 and at any time during the study if warranted.

Researchers adjusted for potential confounders, including sex, age at RIS diagnosis, MS family history, brain T2-weighted hyperintense lesion volume, and presence of Gd+/− lesions.

The primary outcome was time to a first acute or progressive neurologic event resulting from central nervous system demyelination, expressed as a rate of conversion to clinical MS.
 

TAKEAWAY:

Eighteen participants – nine in each group – discontinued the study, resulting in a dropout rate of 20%.

The risk of a first clinical event was significantly reduced in the teriflunomide arm (mean time to event, 128.2 weeks) with 8 clinical events (6 acute, 2 progressive) in comparison with the placebo arm (mean time to event, 109.6 weeks) with 20 clinical events (18 acute, 2 progressive) and an adjusted hazard ratio of 0.28 (95% CI, 0.11-0.71; P = .007).

All secondary MRI measures, including the cumulative number of new and/or newly enlarging T2 lesions and the cumulative number of Gd+ lesions, did not reach statistical significance, although these were numerically lower in the teriflunomide arm, possibly because participants with early events switched to the treatment arm.

The most common adverse events that occurred more often in patients treated with teriflunomide were gastrointestinal disorders (11.4%), dysmenorrhea (9.1%), benign respiratory infections (6.8%), general disorders/conditions (6.8%), and transient increase of transaminases (4.5%).
 

IN PRACTICE:

“These results suggest that for the first time, we may have an opportunity to better identify those at risk for a primary progressive clinical course at this preclinical stage and prevent or delay clinical progression from the onset, which is a clear unmet need in MS clinical practice,” wrote the authors.

SOURCE:

The study was carried out by Christine Lebrun-Frénay MD, PhD, head of the inflammatory neurological disorders clinical research unit and MS center at the University of Nice (France). It was published online in JAMA Neurology.

LIMITATIONS:

The investigators could not stratify at-risk subgroups according to risk factors for developing MS, mainly because of power issues. The study was prematurely discontinued by its financial sponsor (Sanofi), owing primarily to slow enrollment that resulted from national regulations on activating recruitment sites and the impact of the COVID-19 pandemic. Another challenge for the study was that some individuals with RIS had already been exposed to a DMT or hesitated to participate in a clinical trial. The financial sponsor, which provided the study drug and placebo tablets, terminated their availability, given the anticipated release of generic teriflunomide.

DISCLOSURES:

The study was supported by Sanofi, the University Hospital of Nice, University Cote d’Azur, and the Radiologically Isolated Syndrome Consortium. Lebrun-Frénay has no relevant conflicts of interest.

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

TOPLINE:

The disease-modifying treatment (DMT) delays conversion to clinical multiple sclerosis (MS) for patients with radiologically isolated syndrome (RIS) and has a reassuring long-term safety profile, new research shows.

METHODOLOGY:

Early use of DMTs is typically recommended for patients with established MS, but mounting evidence, including the ARISE trial, which assessed Tecfidera, suggests these agents benefit patients with RIS, the earliest detectable preclinical MS stage.

The new study, known as Teriflunomide in Radiologically Isolated Syndrome (TERIS), included 89 adult patients with RIS (mean age, 37.8 years) from centers in France, Switzerland, and Turkey. Participants were randomly assigned to receive placebo or teriflunomide 14 mg daily. Teriflunomide is an oral immunomodulator approved for treating relapsing remitting MS.

Investigators performed MRI at baseline and at weeks 48, 96, and 144 and at any time during the study if warranted.

Researchers adjusted for potential confounders, including sex, age at RIS diagnosis, MS family history, brain T2-weighted hyperintense lesion volume, and presence of Gd+/− lesions.

The primary outcome was time to a first acute or progressive neurologic event resulting from central nervous system demyelination, expressed as a rate of conversion to clinical MS.
 

TAKEAWAY:

Eighteen participants – nine in each group – discontinued the study, resulting in a dropout rate of 20%.

The risk of a first clinical event was significantly reduced in the teriflunomide arm (mean time to event, 128.2 weeks) with 8 clinical events (6 acute, 2 progressive) in comparison with the placebo arm (mean time to event, 109.6 weeks) with 20 clinical events (18 acute, 2 progressive) and an adjusted hazard ratio of 0.28 (95% CI, 0.11-0.71; P = .007).

All secondary MRI measures, including the cumulative number of new and/or newly enlarging T2 lesions and the cumulative number of Gd+ lesions, did not reach statistical significance, although these were numerically lower in the teriflunomide arm, possibly because participants with early events switched to the treatment arm.

The most common adverse events that occurred more often in patients treated with teriflunomide were gastrointestinal disorders (11.4%), dysmenorrhea (9.1%), benign respiratory infections (6.8%), general disorders/conditions (6.8%), and transient increase of transaminases (4.5%).
 

IN PRACTICE:

“These results suggest that for the first time, we may have an opportunity to better identify those at risk for a primary progressive clinical course at this preclinical stage and prevent or delay clinical progression from the onset, which is a clear unmet need in MS clinical practice,” wrote the authors.

SOURCE:

The study was carried out by Christine Lebrun-Frénay MD, PhD, head of the inflammatory neurological disorders clinical research unit and MS center at the University of Nice (France). It was published online in JAMA Neurology.

LIMITATIONS:

The investigators could not stratify at-risk subgroups according to risk factors for developing MS, mainly because of power issues. The study was prematurely discontinued by its financial sponsor (Sanofi), owing primarily to slow enrollment that resulted from national regulations on activating recruitment sites and the impact of the COVID-19 pandemic. Another challenge for the study was that some individuals with RIS had already been exposed to a DMT or hesitated to participate in a clinical trial. The financial sponsor, which provided the study drug and placebo tablets, terminated their availability, given the anticipated release of generic teriflunomide.

DISCLOSURES:

The study was supported by Sanofi, the University Hospital of Nice, University Cote d’Azur, and the Radiologically Isolated Syndrome Consortium. Lebrun-Frénay has no relevant conflicts of interest.

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

TOPLINE:

The disease-modifying treatment (DMT) delays conversion to clinical multiple sclerosis (MS) for patients with radiologically isolated syndrome (RIS) and has a reassuring long-term safety profile, new research shows.

METHODOLOGY:

Early use of DMTs is typically recommended for patients with established MS, but mounting evidence, including the ARISE trial, which assessed Tecfidera, suggests these agents benefit patients with RIS, the earliest detectable preclinical MS stage.

The new study, known as Teriflunomide in Radiologically Isolated Syndrome (TERIS), included 89 adult patients with RIS (mean age, 37.8 years) from centers in France, Switzerland, and Turkey. Participants were randomly assigned to receive placebo or teriflunomide 14 mg daily. Teriflunomide is an oral immunomodulator approved for treating relapsing remitting MS.

Investigators performed MRI at baseline and at weeks 48, 96, and 144 and at any time during the study if warranted.

Researchers adjusted for potential confounders, including sex, age at RIS diagnosis, MS family history, brain T2-weighted hyperintense lesion volume, and presence of Gd+/− lesions.

The primary outcome was time to a first acute or progressive neurologic event resulting from central nervous system demyelination, expressed as a rate of conversion to clinical MS.
 

TAKEAWAY:

Eighteen participants – nine in each group – discontinued the study, resulting in a dropout rate of 20%.

The risk of a first clinical event was significantly reduced in the teriflunomide arm (mean time to event, 128.2 weeks) with 8 clinical events (6 acute, 2 progressive) in comparison with the placebo arm (mean time to event, 109.6 weeks) with 20 clinical events (18 acute, 2 progressive) and an adjusted hazard ratio of 0.28 (95% CI, 0.11-0.71; P = .007).

All secondary MRI measures, including the cumulative number of new and/or newly enlarging T2 lesions and the cumulative number of Gd+ lesions, did not reach statistical significance, although these were numerically lower in the teriflunomide arm, possibly because participants with early events switched to the treatment arm.

The most common adverse events that occurred more often in patients treated with teriflunomide were gastrointestinal disorders (11.4%), dysmenorrhea (9.1%), benign respiratory infections (6.8%), general disorders/conditions (6.8%), and transient increase of transaminases (4.5%).
 

IN PRACTICE:

“These results suggest that for the first time, we may have an opportunity to better identify those at risk for a primary progressive clinical course at this preclinical stage and prevent or delay clinical progression from the onset, which is a clear unmet need in MS clinical practice,” wrote the authors.

SOURCE:

The study was carried out by Christine Lebrun-Frénay MD, PhD, head of the inflammatory neurological disorders clinical research unit and MS center at the University of Nice (France). It was published online in JAMA Neurology.

LIMITATIONS:

The investigators could not stratify at-risk subgroups according to risk factors for developing MS, mainly because of power issues. The study was prematurely discontinued by its financial sponsor (Sanofi), owing primarily to slow enrollment that resulted from national regulations on activating recruitment sites and the impact of the COVID-19 pandemic. Another challenge for the study was that some individuals with RIS had already been exposed to a DMT or hesitated to participate in a clinical trial. The financial sponsor, which provided the study drug and placebo tablets, terminated their availability, given the anticipated release of generic teriflunomide.

DISCLOSURES:

The study was supported by Sanofi, the University Hospital of Nice, University Cote d’Azur, and the Radiologically Isolated Syndrome Consortium. Lebrun-Frénay has no relevant conflicts of interest.

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

Initiating treatment for multiple sclerosis (MS) within 6 months of the first symptoms is associated with a significantly lower risk for severe disability 1 decade later, a new study suggests.

Patients who received early treatment had a 45% lower risk of reaching a disability score of 3 and a 60% lower risk of advancing to secondary progressive MS compared with those who began treatment 18 months or more after symptoms presented.

Those with a score of 3 can still walk unassisted but have moderate disability in one of eight areas, such as motor function, vision or thinking skills, or mild disability in three or four areas.

“With a very early treatment, within 6 months from the first symptoms and even before the MS diagnosis, we are now able to decrease long-term disability. This means the earlier the better – time is brain,” lead author Alvaro Cobo-Calvo, MD, PhD, clinical neurologists and researcher with the Multiple Sclerosis Center of Catalonia in Barcelona and the Universitat Autonoma de Barcelona, said in an interview.

The findings were published online in Neurology.
 

Measuring disability

The observational, retrospective study included people aged 50 years or younger who received MS treatment within 6 months of their first clinical demyelinating event (n = 194), 6-16 months later (n = 192), or more than 16 months after the initial symptoms presented (n = 194).

The investigators noted that this cohort is one of the few that is considered “deeply phenotyped,” meaning it is followed prospectively over time with strict quality controls and systematic data collection methods.

MRIs were done within 3-5 months of the first symptoms, again at 12 months after the first event, and every 5 years over a median 11.2-year follow-up.

Disability levels were measured using the Expanded Disability Status Scale, with scores ranging from 0-10 and higher scores indicating more disability.

Patients who received treatment within 6 months of first symptoms were 45% less likely to have a disability score of 3 by the end of the study than did those who received treatment more than 16 months after that first event (hazard ratio, 0.55; 95% confidence interval, 0.32-0.97).

The earliest-treatment group also had a 60% lower risk of advancing to secondary progressive MS than did people in the latest-treatment group (HR, 0.40; 95% CI, 0.19-0.85).
 

Better disease stability

The researchers also found that earlier treatment was associated with a 53% better chance of disease stability 1 year after initial treatment (HR, 0.47; 95% CI, 0.28-0.80).

The early-treatment group also had a lower disability progression rate and lower severe disability in a self-reported test, compared with those who were treated later.

The investigators also found that patients who received early treatment were at lower risk for disability, even those with a higher baseline radiologic burden.

Current guidelines recommend early treatment of MS, but it is unclear whether disease-modifying treatments (DMTs) should be prescribed after the first MS symptoms or after a definitive MS diagnosis.

Earlier studies often evaluated treatment efficacy after MS diagnosis. This study began tracking efficacy when therapy began after the first symptoms. In some cases, that was before a diagnosis was given.

“It is important to be cautious when starting treatment and we need to know if the patient will evolve to MS or if the patient is diagnosed with MS based on current McDonald criteria.

“In our study, 70% of patients had MS at the time of the first symptoms according to McDonald 201, but the remainder started treatment without an ‘official’ diagnosis but with an event highly suggestive of MS,” Dr. Cobo-Calvo said.

He added that very early treatment after first symptoms is key to preserving neurologic functionality.
 

Controversy remains

Adding MRI results as a clinical variable is a novel approach, but the MRI risk score used in the study is a new tool that has not yet been validated, the authors of an accompanying editorial noted.

“The results of this study show that in order to achieve a balance between compared groups, matching on MRI has little to add to good-quality balancing on patients’ clinical and demographic features,” wrote Erin Longbrake, MD, PhD, of the department of neurology, Yale University, New Haven, Conn., and Tomas Kalincik, MD, PhD, of the Neuroimmunology Centre, department of neurology, Royal Melbourne Hospital and the CORe unit, department of medicine, University of Melbourne.

Despite growing evidence pointing to improved outcomes from administering DMTs soon after diagnosis, the timing and sequence of therapy remains an area of controversy, they added.

“While these uncertain diagnostic scenarios may tempt neurologists to ‘wait and see,’ the data presented here remind us that these patients remain at risk of accumulating disability,” the authors wrote. “Neurologists must therefore remain vigilant to ensure that diagnosis is made promptly, that patients are followed up effectively and that effective treatments are used liberally.”

The study was funded by the European Regional Development Fund, Instituto de Salud Carlos III. Dr. Cobo-Calvo has received a grant from Instituto de Salud Carlos III. Dr. Longbrake has consulted for Genentech and NGM Bio and received research support from Biogen & Genentech. Dr. Kalincik has received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi Genzyme, Teva, BioCSL, and Merck, and has received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene, and Merck.

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

Initiating treatment for multiple sclerosis (MS) within 6 months of the first symptoms is associated with a significantly lower risk for severe disability 1 decade later, a new study suggests.

Patients who received early treatment had a 45% lower risk of reaching a disability score of 3 and a 60% lower risk of advancing to secondary progressive MS compared with those who began treatment 18 months or more after symptoms presented.

Those with a score of 3 can still walk unassisted but have moderate disability in one of eight areas, such as motor function, vision or thinking skills, or mild disability in three or four areas.

“With a very early treatment, within 6 months from the first symptoms and even before the MS diagnosis, we are now able to decrease long-term disability. This means the earlier the better – time is brain,” lead author Alvaro Cobo-Calvo, MD, PhD, clinical neurologists and researcher with the Multiple Sclerosis Center of Catalonia in Barcelona and the Universitat Autonoma de Barcelona, said in an interview.

The findings were published online in Neurology.
 

Measuring disability

The observational, retrospective study included people aged 50 years or younger who received MS treatment within 6 months of their first clinical demyelinating event (n = 194), 6-16 months later (n = 192), or more than 16 months after the initial symptoms presented (n = 194).

The investigators noted that this cohort is one of the few that is considered “deeply phenotyped,” meaning it is followed prospectively over time with strict quality controls and systematic data collection methods.

MRIs were done within 3-5 months of the first symptoms, again at 12 months after the first event, and every 5 years over a median 11.2-year follow-up.

Disability levels were measured using the Expanded Disability Status Scale, with scores ranging from 0-10 and higher scores indicating more disability.

Patients who received treatment within 6 months of first symptoms were 45% less likely to have a disability score of 3 by the end of the study than did those who received treatment more than 16 months after that first event (hazard ratio, 0.55; 95% confidence interval, 0.32-0.97).

The earliest-treatment group also had a 60% lower risk of advancing to secondary progressive MS than did people in the latest-treatment group (HR, 0.40; 95% CI, 0.19-0.85).
 

Better disease stability

The researchers also found that earlier treatment was associated with a 53% better chance of disease stability 1 year after initial treatment (HR, 0.47; 95% CI, 0.28-0.80).

The early-treatment group also had a lower disability progression rate and lower severe disability in a self-reported test, compared with those who were treated later.

The investigators also found that patients who received early treatment were at lower risk for disability, even those with a higher baseline radiologic burden.

Current guidelines recommend early treatment of MS, but it is unclear whether disease-modifying treatments (DMTs) should be prescribed after the first MS symptoms or after a definitive MS diagnosis.

Earlier studies often evaluated treatment efficacy after MS diagnosis. This study began tracking efficacy when therapy began after the first symptoms. In some cases, that was before a diagnosis was given.

“It is important to be cautious when starting treatment and we need to know if the patient will evolve to MS or if the patient is diagnosed with MS based on current McDonald criteria.

“In our study, 70% of patients had MS at the time of the first symptoms according to McDonald 201, but the remainder started treatment without an ‘official’ diagnosis but with an event highly suggestive of MS,” Dr. Cobo-Calvo said.

He added that very early treatment after first symptoms is key to preserving neurologic functionality.
 

Controversy remains

Adding MRI results as a clinical variable is a novel approach, but the MRI risk score used in the study is a new tool that has not yet been validated, the authors of an accompanying editorial noted.

“The results of this study show that in order to achieve a balance between compared groups, matching on MRI has little to add to good-quality balancing on patients’ clinical and demographic features,” wrote Erin Longbrake, MD, PhD, of the department of neurology, Yale University, New Haven, Conn., and Tomas Kalincik, MD, PhD, of the Neuroimmunology Centre, department of neurology, Royal Melbourne Hospital and the CORe unit, department of medicine, University of Melbourne.

Despite growing evidence pointing to improved outcomes from administering DMTs soon after diagnosis, the timing and sequence of therapy remains an area of controversy, they added.

“While these uncertain diagnostic scenarios may tempt neurologists to ‘wait and see,’ the data presented here remind us that these patients remain at risk of accumulating disability,” the authors wrote. “Neurologists must therefore remain vigilant to ensure that diagnosis is made promptly, that patients are followed up effectively and that effective treatments are used liberally.”

The study was funded by the European Regional Development Fund, Instituto de Salud Carlos III. Dr. Cobo-Calvo has received a grant from Instituto de Salud Carlos III. Dr. Longbrake has consulted for Genentech and NGM Bio and received research support from Biogen & Genentech. Dr. Kalincik has received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi Genzyme, Teva, BioCSL, and Merck, and has received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene, and Merck.

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

Initiating treatment for multiple sclerosis (MS) within 6 months of the first symptoms is associated with a significantly lower risk for severe disability 1 decade later, a new study suggests.

Patients who received early treatment had a 45% lower risk of reaching a disability score of 3 and a 60% lower risk of advancing to secondary progressive MS compared with those who began treatment 18 months or more after symptoms presented.

Those with a score of 3 can still walk unassisted but have moderate disability in one of eight areas, such as motor function, vision or thinking skills, or mild disability in three or four areas.

“With a very early treatment, within 6 months from the first symptoms and even before the MS diagnosis, we are now able to decrease long-term disability. This means the earlier the better – time is brain,” lead author Alvaro Cobo-Calvo, MD, PhD, clinical neurologists and researcher with the Multiple Sclerosis Center of Catalonia in Barcelona and the Universitat Autonoma de Barcelona, said in an interview.

The findings were published online in Neurology.
 

Measuring disability

The observational, retrospective study included people aged 50 years or younger who received MS treatment within 6 months of their first clinical demyelinating event (n = 194), 6-16 months later (n = 192), or more than 16 months after the initial symptoms presented (n = 194).

The investigators noted that this cohort is one of the few that is considered “deeply phenotyped,” meaning it is followed prospectively over time with strict quality controls and systematic data collection methods.

MRIs were done within 3-5 months of the first symptoms, again at 12 months after the first event, and every 5 years over a median 11.2-year follow-up.

Disability levels were measured using the Expanded Disability Status Scale, with scores ranging from 0-10 and higher scores indicating more disability.

Patients who received treatment within 6 months of first symptoms were 45% less likely to have a disability score of 3 by the end of the study than did those who received treatment more than 16 months after that first event (hazard ratio, 0.55; 95% confidence interval, 0.32-0.97).

The earliest-treatment group also had a 60% lower risk of advancing to secondary progressive MS than did people in the latest-treatment group (HR, 0.40; 95% CI, 0.19-0.85).
 

Better disease stability

The researchers also found that earlier treatment was associated with a 53% better chance of disease stability 1 year after initial treatment (HR, 0.47; 95% CI, 0.28-0.80).

The early-treatment group also had a lower disability progression rate and lower severe disability in a self-reported test, compared with those who were treated later.

The investigators also found that patients who received early treatment were at lower risk for disability, even those with a higher baseline radiologic burden.

Current guidelines recommend early treatment of MS, but it is unclear whether disease-modifying treatments (DMTs) should be prescribed after the first MS symptoms or after a definitive MS diagnosis.

Earlier studies often evaluated treatment efficacy after MS diagnosis. This study began tracking efficacy when therapy began after the first symptoms. In some cases, that was before a diagnosis was given.

“It is important to be cautious when starting treatment and we need to know if the patient will evolve to MS or if the patient is diagnosed with MS based on current McDonald criteria.

“In our study, 70% of patients had MS at the time of the first symptoms according to McDonald 201, but the remainder started treatment without an ‘official’ diagnosis but with an event highly suggestive of MS,” Dr. Cobo-Calvo said.

He added that very early treatment after first symptoms is key to preserving neurologic functionality.
 

Controversy remains

Adding MRI results as a clinical variable is a novel approach, but the MRI risk score used in the study is a new tool that has not yet been validated, the authors of an accompanying editorial noted.

“The results of this study show that in order to achieve a balance between compared groups, matching on MRI has little to add to good-quality balancing on patients’ clinical and demographic features,” wrote Erin Longbrake, MD, PhD, of the department of neurology, Yale University, New Haven, Conn., and Tomas Kalincik, MD, PhD, of the Neuroimmunology Centre, department of neurology, Royal Melbourne Hospital and the CORe unit, department of medicine, University of Melbourne.

Despite growing evidence pointing to improved outcomes from administering DMTs soon after diagnosis, the timing and sequence of therapy remains an area of controversy, they added.

“While these uncertain diagnostic scenarios may tempt neurologists to ‘wait and see,’ the data presented here remind us that these patients remain at risk of accumulating disability,” the authors wrote. “Neurologists must therefore remain vigilant to ensure that diagnosis is made promptly, that patients are followed up effectively and that effective treatments are used liberally.”

The study was funded by the European Regional Development Fund, Instituto de Salud Carlos III. Dr. Cobo-Calvo has received a grant from Instituto de Salud Carlos III. Dr. Longbrake has consulted for Genentech and NGM Bio and received research support from Biogen & Genentech. Dr. Kalincik has received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi Genzyme, Teva, BioCSL, and Merck, and has received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene, and Merck.

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

Retinal thickness may be a potential biomarker for predicting disability for patients newly diagnosed with relapsing multiple sclerosis (MS), new research suggests.

The researchers measured retinal thickness using optical coherence tomography (OCT) within 3 months of diagnosis for more than 230 patients with MS and found that thinning of the retina was associated with a more than fourfold increased risk of Expanded Disability Status Scale (EDSS) scores of at least 3.0.

The OCT “basically tells you how much nerve layer is left in the glass,” said study investigator Gabriel Bsteh, MD, PhD, department of neurology, Medical University of Vienna.

This “could potentially inform treatment strategies, but that is another direction which will be investigated hopefully in the near future,” he added. However, the imaging technique cannot be used for all patients and is currently not widely available.

Dr. Bsteh presented the results at the annual meeting of the European Academy of Neurology.


 

Retinal layers of interest

OCT produces images of the retina and measures its thickness, Dr. Bsteh explained. Of greatest interest and relevance to patients with MS are two layers – the peripapillary retinal nerve fiber layer (pRNFL) and the ganglion cell and inner plexiform layer (GCL), which are associated with “future physical and cognitive disability and brain atrophy, and are reliable biomarkers of axonal damage.”

However, he said, what is not yet known is whether the baseline thickness of these two layers independently predicts progression of disability in patients with newly diagnosed disease within the framework of all of the other known risk factors.

To investigate, the team used data from ViennOCTiMS, an ongoing prospective observational cohort study conducted in Vienna and Innsbruck. For the analysis, they included patients newly diagnosed with relapsing MS using the 2017 McDonald criteria.

Study participants were required to undergo a spectral-domain OCT scan within 90 days of diagnosis and within 270 days of symptom onset. They also had to undergo follow-up of at least 12 months.

Among 231 patients included in the study, 74 were female, and the mean age was 30.3 years.

Dr. Bsteh noted that disease duration was short. There was a median of 45 days between initial diagnosis and the OCT scan. The median number of T2 lesions on MRI was 11, with 59.3% of patients had at least 10 lesions.

At baseline, 13.0% of patients were not receiving drug therapy, although they were advised to do so, said Dr. Bsteh. A total of 59.7% of patients received “moderately effective” disease-modifying treatments, while 27.3% were treated with “highly effective” DMTs.
 

Independent predictors of disability

To determine the contribution of retinal thickness to the risk of developing EDSS of 3.0 or more, the researchers conducted a multivariate analysis that accounted for patient age and sex, the type of first relapse, the remission of first relapse symptoms, the presence of oligoclonal bands, the baseline number of T2 lesions, and the use and type of DMT.

After approximately 96 months of follow-up, a pRNFL thickness of 88 mcm or less at baseline was associated with a hazard ratio for EDSS of at least 3.0 versus a thickness of greater than 88 mcm of 4.0 (P < .001), Dr. Bsteh reported.

Similarly, a GCL thickness of less than 77 mcm at baseline was associated with a HR for EDSS of at least 3.0 of 5.1 (P < .001).

Subgroup analysis indicated that both measures of retinal thickness were indeed independent predictors of EDSS. Dr. Bsteh said: “It was encouraging to see that all the unknown prognostic factor factors performed within the expected framework.”

For example, there was a notable association between the risk of EDSS of at least 3.0 and patient age, as well as with incomplete remission and a greater number of lesions on MRI.

Dr. Bsteh said it was also “very encouraging” to find that high-efficacy DMT was associated with a reduced risk of EDSS of at least 3.0.
 

Strengths, limitations

Turning to the relatively recently described progression independent of relapse activity, Dr. Bsteh showed that both pRNFL of 88 mcm or less and GCL less than 77 mcm were significantly associated with the development of PIRA, compared with greater thickness, at HRs of 3.1 and 4.1, respectively (P < .001 for both).

Subgroup analysis again supported the independent contribution of retinal thickness to the risk of PIRA and revealed similar associations with known risk factors, although the contribution of highly effective DMT was of borderline significance for this outcome.

Interestingly, neither pRNFL of 88 mcm or less nor GCL less than 77 mcm was significantly associated with the time to second clinical attack, “which is basically the correlation of the inflammatory activity” in MS, said Dr. Bsteh.

This, he continued, “goes back to the basic theory that EDSS, PIRA, and neurodegenerative problems are associated with the OCT but not the degree of inflammatory activity.

“As good as all that sounds, there are of course, some limitations” to the study, Dr. Bsteh acknowledged.

The most important limitation is that the changes measured on OCT were “not specific to multiple sclerosis,” and the thickness of the layers “can be influenced by a lot of other factors,” in particular by eye conditions such as glaucoma and diabetes mellitus.

In addition, OCT is not reliable for patients with myopia of more than four to six diopters and for those with retinal comorbidities, such as optic drusen. Dr. Bsteh also pointed out that automatic segmentation in OCT requires stringent quality control.

However, the “biggest problem for the deployment of OCT in the clinical routine is its lack of availability. It’s not very easy for neurologists to procure an OCT,” said Dr. Bsteh.

“You can always create it with your ophthalmologist of trust, but you have to know what you’re looking for,” he added.
 

Important research

Commenting on the study, Giancarlo Comi, MD, honorary professor of neurology at the Università Vita Salute San Raffaele and founder and director of the Institute of Experimental Neurology at the Scientific Institute San Raffaele, both in Milan, characterized the research as “very, very important and interesting.”

However, he said that he was a “bit surprised” that it showed no association between OCT measures and the second clinical attack, noting that longitudinal research by his team found such an association.

Dr. Comi added that the “key point” from the current study is that there was no such association in the early phase of the disease, which suggests that the amount of inflammatory activity “is not so relevant” in determining the degree of damage seen on OCT at that point.

Dr. Bsteh said he partially agreed with Dr. Comi, adding that “it depends on what you adjust for.

“If we did the same analysis without adjusting for the number of MRI lesions, we would see an association with second clinical attack,” he said. However, the aim of the current study was to determine the independent contribution of retinal thickness, “and that’s why we tried to adjust to everything which was available to us.”

Dr. Bsteh also underlined that it was a cross-sectional analysis conducted “very, very early” in the MS disease course, and “so the inflammatory activity did not yet have a chance to influence the thickness on the OCT.”

Had OCT been performed later in the disease course, inflammatory activity might have influenced the findings, but the intention of the study was to use it “as an early marker to try to stratify patients who are at risk, and [those] who are maybe a little less at risk, and inform the treatment strategy.”

Maria Assunta Rocca, MD, associate professor of neurology at Università Vita Salute San Raffaele, and head of neuroimaging of the CNS white matter unit at IRCCS San Raffaele Scientific Institute, Milan, who cochaired the session in which the study was presented, asked whether the researchers analyzed patients with optic neuritis separately from those without and whether it affected the predictive factors.

Dr. Bsteh said that OCT cannot be used for patients with bilateral optic neuritis and so they were excluded from the study, but for patients who were affected unilaterally, the contralateral eye was assessed.

This underlines why OCT contributes the most when used early on the disease course. “The longer the disease has time, the higher the likelihood that optic neuritis has developed,” he said.

Funding for the study was provided by Mindset Technologies. All authors are, or were, employees and/or shareholders of Mindset Technologies. Dr. Bsteh has relationships with Biogen, Celgene/Bristol-Myers Squibb, Lilly, Merck, Novartis, Roche, Sanofi Genzyme, and Teva.

A version of this article appeared on Medscape.com.

Retinal thickness may be a potential biomarker for predicting disability for patients newly diagnosed with relapsing multiple sclerosis (MS), new research suggests.

The researchers measured retinal thickness using optical coherence tomography (OCT) within 3 months of diagnosis for more than 230 patients with MS and found that thinning of the retina was associated with a more than fourfold increased risk of Expanded Disability Status Scale (EDSS) scores of at least 3.0.

The OCT “basically tells you how much nerve layer is left in the glass,” said study investigator Gabriel Bsteh, MD, PhD, department of neurology, Medical University of Vienna.

This “could potentially inform treatment strategies, but that is another direction which will be investigated hopefully in the near future,” he added. However, the imaging technique cannot be used for all patients and is currently not widely available.

Dr. Bsteh presented the results at the annual meeting of the European Academy of Neurology.


 

Retinal layers of interest

OCT produces images of the retina and measures its thickness, Dr. Bsteh explained. Of greatest interest and relevance to patients with MS are two layers – the peripapillary retinal nerve fiber layer (pRNFL) and the ganglion cell and inner plexiform layer (GCL), which are associated with “future physical and cognitive disability and brain atrophy, and are reliable biomarkers of axonal damage.”

However, he said, what is not yet known is whether the baseline thickness of these two layers independently predicts progression of disability in patients with newly diagnosed disease within the framework of all of the other known risk factors.

To investigate, the team used data from ViennOCTiMS, an ongoing prospective observational cohort study conducted in Vienna and Innsbruck. For the analysis, they included patients newly diagnosed with relapsing MS using the 2017 McDonald criteria.

Study participants were required to undergo a spectral-domain OCT scan within 90 days of diagnosis and within 270 days of symptom onset. They also had to undergo follow-up of at least 12 months.

Among 231 patients included in the study, 74 were female, and the mean age was 30.3 years.

Dr. Bsteh noted that disease duration was short. There was a median of 45 days between initial diagnosis and the OCT scan. The median number of T2 lesions on MRI was 11, with 59.3% of patients had at least 10 lesions.

At baseline, 13.0% of patients were not receiving drug therapy, although they were advised to do so, said Dr. Bsteh. A total of 59.7% of patients received “moderately effective” disease-modifying treatments, while 27.3% were treated with “highly effective” DMTs.
 

Independent predictors of disability

To determine the contribution of retinal thickness to the risk of developing EDSS of 3.0 or more, the researchers conducted a multivariate analysis that accounted for patient age and sex, the type of first relapse, the remission of first relapse symptoms, the presence of oligoclonal bands, the baseline number of T2 lesions, and the use and type of DMT.

After approximately 96 months of follow-up, a pRNFL thickness of 88 mcm or less at baseline was associated with a hazard ratio for EDSS of at least 3.0 versus a thickness of greater than 88 mcm of 4.0 (P < .001), Dr. Bsteh reported.

Similarly, a GCL thickness of less than 77 mcm at baseline was associated with a HR for EDSS of at least 3.0 of 5.1 (P < .001).

Subgroup analysis indicated that both measures of retinal thickness were indeed independent predictors of EDSS. Dr. Bsteh said: “It was encouraging to see that all the unknown prognostic factor factors performed within the expected framework.”

For example, there was a notable association between the risk of EDSS of at least 3.0 and patient age, as well as with incomplete remission and a greater number of lesions on MRI.

Dr. Bsteh said it was also “very encouraging” to find that high-efficacy DMT was associated with a reduced risk of EDSS of at least 3.0.
 

Strengths, limitations

Turning to the relatively recently described progression independent of relapse activity, Dr. Bsteh showed that both pRNFL of 88 mcm or less and GCL less than 77 mcm were significantly associated with the development of PIRA, compared with greater thickness, at HRs of 3.1 and 4.1, respectively (P < .001 for both).

Subgroup analysis again supported the independent contribution of retinal thickness to the risk of PIRA and revealed similar associations with known risk factors, although the contribution of highly effective DMT was of borderline significance for this outcome.

Interestingly, neither pRNFL of 88 mcm or less nor GCL less than 77 mcm was significantly associated with the time to second clinical attack, “which is basically the correlation of the inflammatory activity” in MS, said Dr. Bsteh.

This, he continued, “goes back to the basic theory that EDSS, PIRA, and neurodegenerative problems are associated with the OCT but not the degree of inflammatory activity.

“As good as all that sounds, there are of course, some limitations” to the study, Dr. Bsteh acknowledged.

The most important limitation is that the changes measured on OCT were “not specific to multiple sclerosis,” and the thickness of the layers “can be influenced by a lot of other factors,” in particular by eye conditions such as glaucoma and diabetes mellitus.

In addition, OCT is not reliable for patients with myopia of more than four to six diopters and for those with retinal comorbidities, such as optic drusen. Dr. Bsteh also pointed out that automatic segmentation in OCT requires stringent quality control.

However, the “biggest problem for the deployment of OCT in the clinical routine is its lack of availability. It’s not very easy for neurologists to procure an OCT,” said Dr. Bsteh.

“You can always create it with your ophthalmologist of trust, but you have to know what you’re looking for,” he added.
 

Important research

Commenting on the study, Giancarlo Comi, MD, honorary professor of neurology at the Università Vita Salute San Raffaele and founder and director of the Institute of Experimental Neurology at the Scientific Institute San Raffaele, both in Milan, characterized the research as “very, very important and interesting.”

However, he said that he was a “bit surprised” that it showed no association between OCT measures and the second clinical attack, noting that longitudinal research by his team found such an association.

Dr. Comi added that the “key point” from the current study is that there was no such association in the early phase of the disease, which suggests that the amount of inflammatory activity “is not so relevant” in determining the degree of damage seen on OCT at that point.

Dr. Bsteh said he partially agreed with Dr. Comi, adding that “it depends on what you adjust for.

“If we did the same analysis without adjusting for the number of MRI lesions, we would see an association with second clinical attack,” he said. However, the aim of the current study was to determine the independent contribution of retinal thickness, “and that’s why we tried to adjust to everything which was available to us.”

Dr. Bsteh also underlined that it was a cross-sectional analysis conducted “very, very early” in the MS disease course, and “so the inflammatory activity did not yet have a chance to influence the thickness on the OCT.”

Had OCT been performed later in the disease course, inflammatory activity might have influenced the findings, but the intention of the study was to use it “as an early marker to try to stratify patients who are at risk, and [those] who are maybe a little less at risk, and inform the treatment strategy.”

Maria Assunta Rocca, MD, associate professor of neurology at Università Vita Salute San Raffaele, and head of neuroimaging of the CNS white matter unit at IRCCS San Raffaele Scientific Institute, Milan, who cochaired the session in which the study was presented, asked whether the researchers analyzed patients with optic neuritis separately from those without and whether it affected the predictive factors.

Dr. Bsteh said that OCT cannot be used for patients with bilateral optic neuritis and so they were excluded from the study, but for patients who were affected unilaterally, the contralateral eye was assessed.

This underlines why OCT contributes the most when used early on the disease course. “The longer the disease has time, the higher the likelihood that optic neuritis has developed,” he said.

Funding for the study was provided by Mindset Technologies. All authors are, or were, employees and/or shareholders of Mindset Technologies. Dr. Bsteh has relationships with Biogen, Celgene/Bristol-Myers Squibb, Lilly, Merck, Novartis, Roche, Sanofi Genzyme, and Teva.

A version of this article appeared on Medscape.com.

Retinal thickness may be a potential biomarker for predicting disability for patients newly diagnosed with relapsing multiple sclerosis (MS), new research suggests.

The researchers measured retinal thickness using optical coherence tomography (OCT) within 3 months of diagnosis for more than 230 patients with MS and found that thinning of the retina was associated with a more than fourfold increased risk of Expanded Disability Status Scale (EDSS) scores of at least 3.0.

The OCT “basically tells you how much nerve layer is left in the glass,” said study investigator Gabriel Bsteh, MD, PhD, department of neurology, Medical University of Vienna.

This “could potentially inform treatment strategies, but that is another direction which will be investigated hopefully in the near future,” he added. However, the imaging technique cannot be used for all patients and is currently not widely available.

Dr. Bsteh presented the results at the annual meeting of the European Academy of Neurology.


 

Retinal layers of interest

OCT produces images of the retina and measures its thickness, Dr. Bsteh explained. Of greatest interest and relevance to patients with MS are two layers – the peripapillary retinal nerve fiber layer (pRNFL) and the ganglion cell and inner plexiform layer (GCL), which are associated with “future physical and cognitive disability and brain atrophy, and are reliable biomarkers of axonal damage.”

However, he said, what is not yet known is whether the baseline thickness of these two layers independently predicts progression of disability in patients with newly diagnosed disease within the framework of all of the other known risk factors.

To investigate, the team used data from ViennOCTiMS, an ongoing prospective observational cohort study conducted in Vienna and Innsbruck. For the analysis, they included patients newly diagnosed with relapsing MS using the 2017 McDonald criteria.

Study participants were required to undergo a spectral-domain OCT scan within 90 days of diagnosis and within 270 days of symptom onset. They also had to undergo follow-up of at least 12 months.

Among 231 patients included in the study, 74 were female, and the mean age was 30.3 years.

Dr. Bsteh noted that disease duration was short. There was a median of 45 days between initial diagnosis and the OCT scan. The median number of T2 lesions on MRI was 11, with 59.3% of patients had at least 10 lesions.

At baseline, 13.0% of patients were not receiving drug therapy, although they were advised to do so, said Dr. Bsteh. A total of 59.7% of patients received “moderately effective” disease-modifying treatments, while 27.3% were treated with “highly effective” DMTs.
 

Independent predictors of disability

To determine the contribution of retinal thickness to the risk of developing EDSS of 3.0 or more, the researchers conducted a multivariate analysis that accounted for patient age and sex, the type of first relapse, the remission of first relapse symptoms, the presence of oligoclonal bands, the baseline number of T2 lesions, and the use and type of DMT.

After approximately 96 months of follow-up, a pRNFL thickness of 88 mcm or less at baseline was associated with a hazard ratio for EDSS of at least 3.0 versus a thickness of greater than 88 mcm of 4.0 (P < .001), Dr. Bsteh reported.

Similarly, a GCL thickness of less than 77 mcm at baseline was associated with a HR for EDSS of at least 3.0 of 5.1 (P < .001).

Subgroup analysis indicated that both measures of retinal thickness were indeed independent predictors of EDSS. Dr. Bsteh said: “It was encouraging to see that all the unknown prognostic factor factors performed within the expected framework.”

For example, there was a notable association between the risk of EDSS of at least 3.0 and patient age, as well as with incomplete remission and a greater number of lesions on MRI.

Dr. Bsteh said it was also “very encouraging” to find that high-efficacy DMT was associated with a reduced risk of EDSS of at least 3.0.
 

Strengths, limitations

Turning to the relatively recently described progression independent of relapse activity, Dr. Bsteh showed that both pRNFL of 88 mcm or less and GCL less than 77 mcm were significantly associated with the development of PIRA, compared with greater thickness, at HRs of 3.1 and 4.1, respectively (P < .001 for both).

Subgroup analysis again supported the independent contribution of retinal thickness to the risk of PIRA and revealed similar associations with known risk factors, although the contribution of highly effective DMT was of borderline significance for this outcome.

Interestingly, neither pRNFL of 88 mcm or less nor GCL less than 77 mcm was significantly associated with the time to second clinical attack, “which is basically the correlation of the inflammatory activity” in MS, said Dr. Bsteh.

This, he continued, “goes back to the basic theory that EDSS, PIRA, and neurodegenerative problems are associated with the OCT but not the degree of inflammatory activity.

“As good as all that sounds, there are of course, some limitations” to the study, Dr. Bsteh acknowledged.

The most important limitation is that the changes measured on OCT were “not specific to multiple sclerosis,” and the thickness of the layers “can be influenced by a lot of other factors,” in particular by eye conditions such as glaucoma and diabetes mellitus.

In addition, OCT is not reliable for patients with myopia of more than four to six diopters and for those with retinal comorbidities, such as optic drusen. Dr. Bsteh also pointed out that automatic segmentation in OCT requires stringent quality control.

However, the “biggest problem for the deployment of OCT in the clinical routine is its lack of availability. It’s not very easy for neurologists to procure an OCT,” said Dr. Bsteh.

“You can always create it with your ophthalmologist of trust, but you have to know what you’re looking for,” he added.
 

Important research

Commenting on the study, Giancarlo Comi, MD, honorary professor of neurology at the Università Vita Salute San Raffaele and founder and director of the Institute of Experimental Neurology at the Scientific Institute San Raffaele, both in Milan, characterized the research as “very, very important and interesting.”

However, he said that he was a “bit surprised” that it showed no association between OCT measures and the second clinical attack, noting that longitudinal research by his team found such an association.

Dr. Comi added that the “key point” from the current study is that there was no such association in the early phase of the disease, which suggests that the amount of inflammatory activity “is not so relevant” in determining the degree of damage seen on OCT at that point.

Dr. Bsteh said he partially agreed with Dr. Comi, adding that “it depends on what you adjust for.

“If we did the same analysis without adjusting for the number of MRI lesions, we would see an association with second clinical attack,” he said. However, the aim of the current study was to determine the independent contribution of retinal thickness, “and that’s why we tried to adjust to everything which was available to us.”

Dr. Bsteh also underlined that it was a cross-sectional analysis conducted “very, very early” in the MS disease course, and “so the inflammatory activity did not yet have a chance to influence the thickness on the OCT.”

Had OCT been performed later in the disease course, inflammatory activity might have influenced the findings, but the intention of the study was to use it “as an early marker to try to stratify patients who are at risk, and [those] who are maybe a little less at risk, and inform the treatment strategy.”

Maria Assunta Rocca, MD, associate professor of neurology at Università Vita Salute San Raffaele, and head of neuroimaging of the CNS white matter unit at IRCCS San Raffaele Scientific Institute, Milan, who cochaired the session in which the study was presented, asked whether the researchers analyzed patients with optic neuritis separately from those without and whether it affected the predictive factors.

Dr. Bsteh said that OCT cannot be used for patients with bilateral optic neuritis and so they were excluded from the study, but for patients who were affected unilaterally, the contralateral eye was assessed.

This underlines why OCT contributes the most when used early on the disease course. “The longer the disease has time, the higher the likelihood that optic neuritis has developed,” he said.

Funding for the study was provided by Mindset Technologies. All authors are, or were, employees and/or shareholders of Mindset Technologies. Dr. Bsteh has relationships with Biogen, Celgene/Bristol-Myers Squibb, Lilly, Merck, Novartis, Roche, Sanofi Genzyme, and Teva.

A version of this article appeared on Medscape.com.

High-efficacy therapies for multiple sclerosis (MS) have improved disease outcomes for many patients, but physicians are uncertain when to use them. Despite better long-term disease outcomes, there are concerns over long-term safety, and some physicians and patients remain wary of these medications.

High-efficacy therapies were the subject of a session at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Key topics included patient selection, timing of escalation to high-efficacy therapies, and initial use of high-efficacy therapies. The session produced a compelling message, according to moderator Patricia Coyle, MD. “I think [the speakers provided] accumulating data that this is a smart thing to do: Use high-efficacy therapies early to get the maximum bang for the buck,” Dr. Coyle said in an interview. She is professor of neurology and director of the MS Comprehensive Care Center at Stony Brook (N.Y.) University.
 

Consider baseline characteristics

In the first talk, Xavier Montalban, MD, PhD, noted that a statement from the ECTRIMS/EAN (European Academy of Neurology) guideline update in 2021 said that a high-efficacy disease-modifying therapy (DMT) should be considered early in the disease course. A key question is whether any baseline characteristics can be used to select patients, and studies have shown worse prognosis with older age, male sex, low levels of vitamin D, and smoking status, among various other factors.

He presented subgroup analyses from trials of fingolimod and ozanimod, which showed that the drugs did not work as well in patients with poor prognostic factors such as an Expanded Disability Status Scale (EDSS) score of 4 or above and age over 40 years. Lower doses also tend to have less efficacy in males. “If you have [a patient with] bad baseline prognostic factors, you need high-efficacy medication at the right dose, because a lower dose will not work well. It is the same phenomenon for age,” Dr. Montalban said in his talk. On the other hand, he showed the results of a study of ofatumumab and ocrelizumab, both of which showed high efficacy even in patients with poor prognostic factors.

Among patients with secondary progressive MS, clinical or MRI evidence of inflammatory activity is the only poor prognostic factor that appears to be a good predictor of treatment response.

Dr. Montalban also addressed the timing of intervention with DMTs. A study from his group prospectively followed 1,015 patients treated with DMTs. “Interestingly, what we observed is that patients who were treated with DMTs just after the first attack did better than those who were treated after the second attack, and you have to take into consideration that we treat those patients after the first attack, those who had the worst prognostic factors, so treatment was very effective in that sense,” said Dr. Montalban, director of the Multiple Sclerosis Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona.
 

Switching DMTs

In the second presentation, Dalia Rotstein, MD, discussed how to incorporate prognostic factors when switching a patient to high-efficacy therapies as a result of new disease activity while on another therapy.

Patients with favorable prognostic factors at baseline may be started out on immunomodulatory therapy. “Essentially, we want to match the intensity of the therapy to the intensity of the disease of the patient in front of us,” Dr. Rotstein said in her talk. Nevertheless, the course of MS is unpredictable, and the first year or two of immunomodulatory therapy can give physicians clues about the longer-term course of the disease. “We need to observe closely for disease activity in the first year, but even up to 2 years on therapy to determine a need for early escalation,” said Dr. Rotstein, assistant professor of medicine at University of Toronto.

For switching to high-efficacy therapies, any relapse, disability progression, or an EDSS change of 1 point or more could be a consideration. MRI indicators are more controversial, but one to three new T2 lesions also could prompt a switch.

Serum neural filament light chain (sNFL) is a useful biomarker for monitoring disease activity as it correlates well with new disease activity within the next year. It can be monitored every 3-4 months and adjusted for clinical factors and monitored for changing levels. A concerning finding can be followed up with an MRI or in-person visit.

When switching to a high-efficacy therapy, it’s important to administer any vaccines well in advance to ensure a good immune response.

When it comes to a washout period, physicians need to consider both the risk of immunosuppression and breakthrough disease activity. “But in general, we’ve observed that we can minimize the duration of the washout when stopping initial immunomodulator therapy to reduce the risk of breakthrough disease activity. We need to pay particular attention to the risk of rebound activity with longer washouts after stopping sphingosine-1 phosphate (S1P) receptor modulators because the rebound activity can be devastating,” said Dr. Rotstein.

A study of timing of relapses after fingolimod washout, carried out by Dr. Rotstein’s group, found a stark signal. “We observed that when the washout after fingolimod discontinuation was 30 days or more, there is a very high risk of early relapse,” she said.
 

The case for induction therapy

In the third talk, Gavin Giovannoni, MBBCh, PhD, discussed “flipping the pyramid” – that is, starting patients off immediately with high-efficacy therapies rather than waiting until they progress on other therapies. He likened such a decision to a gambler, because MS patients on less-effective therapy can suffer irreversible, long-term physical consequences, as well as social consequences such as unemployment due to cognitive effects.

“We always tend to put up a graph about the risks and benefits of a specific treatment, and we forget about the risks of untreated or undertreated MS. Keep that in mind when making decisions about high-efficacy therapies,” said Dr. Giovannoni, professor of neurology at Queen Mary University of London.

About 80% of patients on tier 1, or low-efficacy therapies, will have breakthrough activity on MRI within 4 years. Moving up a tier gets to about a 60% rate of breakthrough activity. High-efficacy therapies attain an efficacy of about 80% at 6 months. “If you have MS, you’ve got to realize that if you had to roll the dice, which tier would you want to be in? By putting all of them [on high-efficacy therapies], you’re going to get the majority responding and a few of them will break through,” said Dr. Giovannoni.

He presented some real-world evidence to back up the argument: A study comparing outcomes in Sweden and Denmark, which have similar demographics. In Denmark, 7.6% of patients with MS received high-efficacy therapies initially, while in Sweden the proportion was 34.5%. Patients with MS treated in Sweden had a 29% lower probability of progressing to disability (P = .004) and there were 22% fewer discontinuations of DMTs (P < .001). Since that study, the proportion of patients receiving high-efficacy therapies to begin with is closer to 70%. “This is compelling evidence that you want to be on a [high-efficacy therapy] early. If I had MS, I would want to live in Sweden,” said Dr. Giovannoni.

Historical treatments focused on reducing relapses, and more recently on eliminating evidence of inflammatory disease. He said that physicians are prioritizing brain volume loss to improve long-term outcomes in MS, and some are studying long-term disability. “We know that brain volume loss in MS is a prognostic sign both at baseline and at follow-up. It predicts poor outcome, poor cognition and employment, poor quality of life, et cetera,” said Dr. Giovannoni.

He cited data from studies of alemtuzumab that showed a significant reduction in brain volume loss. “The rate is about 0.2% per annum, which is kind of getting into the normal range for age-matched controls. Those people who were started off on interferons in the study lost a lot of brain volume in those first 2 years, and that’s irreversible,” said Dr. Giovannoni.

He pointed out that studies of hematopoietic stem cell therapy showed similar brain-volume outcomes. “So flipping the pyramid with the two most highly effective therapies almost normalizes brain volume loss in people with MS,” said Dr. Giovannoni.

There is also evidence in other autoimmune diseases that early use of high-efficacy therapies improves outcomes. More aggressive therapy in rheumatoid arthritis has reduced joint replacements by 90%.

“I think you really, really need to give your patients the opportunity of flipping the pyramid. You shouldn’t decide that for them,” said Dr. Giovannoni.

Dr. Coyle has consulted for nearly all pharmaceutical companies developing drugs in the MS space. Dr. Montalban has financial relationships with Biogen Idec, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva, Roche, Celgene, Actelion, Mylan, BMS, and Sandoz. Dr. Rotstein has financial ties with Roche Canada, Alexion, Biogen, EMD Serono, Novartis, Roche, and Sanofi Aventis. Dr. Giovannoni has financial ties with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, GW Pharma, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co., Merck KGaA/EMD Serono, Moderna, Novartis, Sanofi, Roche/Genentech, and Teva.

High-efficacy therapies for multiple sclerosis (MS) have improved disease outcomes for many patients, but physicians are uncertain when to use them. Despite better long-term disease outcomes, there are concerns over long-term safety, and some physicians and patients remain wary of these medications.

High-efficacy therapies were the subject of a session at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Key topics included patient selection, timing of escalation to high-efficacy therapies, and initial use of high-efficacy therapies. The session produced a compelling message, according to moderator Patricia Coyle, MD. “I think [the speakers provided] accumulating data that this is a smart thing to do: Use high-efficacy therapies early to get the maximum bang for the buck,” Dr. Coyle said in an interview. She is professor of neurology and director of the MS Comprehensive Care Center at Stony Brook (N.Y.) University.
 

Consider baseline characteristics

In the first talk, Xavier Montalban, MD, PhD, noted that a statement from the ECTRIMS/EAN (European Academy of Neurology) guideline update in 2021 said that a high-efficacy disease-modifying therapy (DMT) should be considered early in the disease course. A key question is whether any baseline characteristics can be used to select patients, and studies have shown worse prognosis with older age, male sex, low levels of vitamin D, and smoking status, among various other factors.

He presented subgroup analyses from trials of fingolimod and ozanimod, which showed that the drugs did not work as well in patients with poor prognostic factors such as an Expanded Disability Status Scale (EDSS) score of 4 or above and age over 40 years. Lower doses also tend to have less efficacy in males. “If you have [a patient with] bad baseline prognostic factors, you need high-efficacy medication at the right dose, because a lower dose will not work well. It is the same phenomenon for age,” Dr. Montalban said in his talk. On the other hand, he showed the results of a study of ofatumumab and ocrelizumab, both of which showed high efficacy even in patients with poor prognostic factors.

Among patients with secondary progressive MS, clinical or MRI evidence of inflammatory activity is the only poor prognostic factor that appears to be a good predictor of treatment response.

Dr. Montalban also addressed the timing of intervention with DMTs. A study from his group prospectively followed 1,015 patients treated with DMTs. “Interestingly, what we observed is that patients who were treated with DMTs just after the first attack did better than those who were treated after the second attack, and you have to take into consideration that we treat those patients after the first attack, those who had the worst prognostic factors, so treatment was very effective in that sense,” said Dr. Montalban, director of the Multiple Sclerosis Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona.
 

Switching DMTs

In the second presentation, Dalia Rotstein, MD, discussed how to incorporate prognostic factors when switching a patient to high-efficacy therapies as a result of new disease activity while on another therapy.

Patients with favorable prognostic factors at baseline may be started out on immunomodulatory therapy. “Essentially, we want to match the intensity of the therapy to the intensity of the disease of the patient in front of us,” Dr. Rotstein said in her talk. Nevertheless, the course of MS is unpredictable, and the first year or two of immunomodulatory therapy can give physicians clues about the longer-term course of the disease. “We need to observe closely for disease activity in the first year, but even up to 2 years on therapy to determine a need for early escalation,” said Dr. Rotstein, assistant professor of medicine at University of Toronto.

For switching to high-efficacy therapies, any relapse, disability progression, or an EDSS change of 1 point or more could be a consideration. MRI indicators are more controversial, but one to three new T2 lesions also could prompt a switch.

Serum neural filament light chain (sNFL) is a useful biomarker for monitoring disease activity as it correlates well with new disease activity within the next year. It can be monitored every 3-4 months and adjusted for clinical factors and monitored for changing levels. A concerning finding can be followed up with an MRI or in-person visit.

When switching to a high-efficacy therapy, it’s important to administer any vaccines well in advance to ensure a good immune response.

When it comes to a washout period, physicians need to consider both the risk of immunosuppression and breakthrough disease activity. “But in general, we’ve observed that we can minimize the duration of the washout when stopping initial immunomodulator therapy to reduce the risk of breakthrough disease activity. We need to pay particular attention to the risk of rebound activity with longer washouts after stopping sphingosine-1 phosphate (S1P) receptor modulators because the rebound activity can be devastating,” said Dr. Rotstein.

A study of timing of relapses after fingolimod washout, carried out by Dr. Rotstein’s group, found a stark signal. “We observed that when the washout after fingolimod discontinuation was 30 days or more, there is a very high risk of early relapse,” she said.
 

The case for induction therapy

In the third talk, Gavin Giovannoni, MBBCh, PhD, discussed “flipping the pyramid” – that is, starting patients off immediately with high-efficacy therapies rather than waiting until they progress on other therapies. He likened such a decision to a gambler, because MS patients on less-effective therapy can suffer irreversible, long-term physical consequences, as well as social consequences such as unemployment due to cognitive effects.

“We always tend to put up a graph about the risks and benefits of a specific treatment, and we forget about the risks of untreated or undertreated MS. Keep that in mind when making decisions about high-efficacy therapies,” said Dr. Giovannoni, professor of neurology at Queen Mary University of London.

About 80% of patients on tier 1, or low-efficacy therapies, will have breakthrough activity on MRI within 4 years. Moving up a tier gets to about a 60% rate of breakthrough activity. High-efficacy therapies attain an efficacy of about 80% at 6 months. “If you have MS, you’ve got to realize that if you had to roll the dice, which tier would you want to be in? By putting all of them [on high-efficacy therapies], you’re going to get the majority responding and a few of them will break through,” said Dr. Giovannoni.

He presented some real-world evidence to back up the argument: A study comparing outcomes in Sweden and Denmark, which have similar demographics. In Denmark, 7.6% of patients with MS received high-efficacy therapies initially, while in Sweden the proportion was 34.5%. Patients with MS treated in Sweden had a 29% lower probability of progressing to disability (P = .004) and there were 22% fewer discontinuations of DMTs (P < .001). Since that study, the proportion of patients receiving high-efficacy therapies to begin with is closer to 70%. “This is compelling evidence that you want to be on a [high-efficacy therapy] early. If I had MS, I would want to live in Sweden,” said Dr. Giovannoni.

Historical treatments focused on reducing relapses, and more recently on eliminating evidence of inflammatory disease. He said that physicians are prioritizing brain volume loss to improve long-term outcomes in MS, and some are studying long-term disability. “We know that brain volume loss in MS is a prognostic sign both at baseline and at follow-up. It predicts poor outcome, poor cognition and employment, poor quality of life, et cetera,” said Dr. Giovannoni.

He cited data from studies of alemtuzumab that showed a significant reduction in brain volume loss. “The rate is about 0.2% per annum, which is kind of getting into the normal range for age-matched controls. Those people who were started off on interferons in the study lost a lot of brain volume in those first 2 years, and that’s irreversible,” said Dr. Giovannoni.

He pointed out that studies of hematopoietic stem cell therapy showed similar brain-volume outcomes. “So flipping the pyramid with the two most highly effective therapies almost normalizes brain volume loss in people with MS,” said Dr. Giovannoni.

There is also evidence in other autoimmune diseases that early use of high-efficacy therapies improves outcomes. More aggressive therapy in rheumatoid arthritis has reduced joint replacements by 90%.

“I think you really, really need to give your patients the opportunity of flipping the pyramid. You shouldn’t decide that for them,” said Dr. Giovannoni.

Dr. Coyle has consulted for nearly all pharmaceutical companies developing drugs in the MS space. Dr. Montalban has financial relationships with Biogen Idec, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva, Roche, Celgene, Actelion, Mylan, BMS, and Sandoz. Dr. Rotstein has financial ties with Roche Canada, Alexion, Biogen, EMD Serono, Novartis, Roche, and Sanofi Aventis. Dr. Giovannoni has financial ties with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, GW Pharma, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co., Merck KGaA/EMD Serono, Moderna, Novartis, Sanofi, Roche/Genentech, and Teva.

High-efficacy therapies for multiple sclerosis (MS) have improved disease outcomes for many patients, but physicians are uncertain when to use them. Despite better long-term disease outcomes, there are concerns over long-term safety, and some physicians and patients remain wary of these medications.

High-efficacy therapies were the subject of a session at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Key topics included patient selection, timing of escalation to high-efficacy therapies, and initial use of high-efficacy therapies. The session produced a compelling message, according to moderator Patricia Coyle, MD. “I think [the speakers provided] accumulating data that this is a smart thing to do: Use high-efficacy therapies early to get the maximum bang for the buck,” Dr. Coyle said in an interview. She is professor of neurology and director of the MS Comprehensive Care Center at Stony Brook (N.Y.) University.
 

Consider baseline characteristics

In the first talk, Xavier Montalban, MD, PhD, noted that a statement from the ECTRIMS/EAN (European Academy of Neurology) guideline update in 2021 said that a high-efficacy disease-modifying therapy (DMT) should be considered early in the disease course. A key question is whether any baseline characteristics can be used to select patients, and studies have shown worse prognosis with older age, male sex, low levels of vitamin D, and smoking status, among various other factors.

He presented subgroup analyses from trials of fingolimod and ozanimod, which showed that the drugs did not work as well in patients with poor prognostic factors such as an Expanded Disability Status Scale (EDSS) score of 4 or above and age over 40 years. Lower doses also tend to have less efficacy in males. “If you have [a patient with] bad baseline prognostic factors, you need high-efficacy medication at the right dose, because a lower dose will not work well. It is the same phenomenon for age,” Dr. Montalban said in his talk. On the other hand, he showed the results of a study of ofatumumab and ocrelizumab, both of which showed high efficacy even in patients with poor prognostic factors.

Among patients with secondary progressive MS, clinical or MRI evidence of inflammatory activity is the only poor prognostic factor that appears to be a good predictor of treatment response.

Dr. Montalban also addressed the timing of intervention with DMTs. A study from his group prospectively followed 1,015 patients treated with DMTs. “Interestingly, what we observed is that patients who were treated with DMTs just after the first attack did better than those who were treated after the second attack, and you have to take into consideration that we treat those patients after the first attack, those who had the worst prognostic factors, so treatment was very effective in that sense,” said Dr. Montalban, director of the Multiple Sclerosis Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona.
 

Switching DMTs

In the second presentation, Dalia Rotstein, MD, discussed how to incorporate prognostic factors when switching a patient to high-efficacy therapies as a result of new disease activity while on another therapy.

Patients with favorable prognostic factors at baseline may be started out on immunomodulatory therapy. “Essentially, we want to match the intensity of the therapy to the intensity of the disease of the patient in front of us,” Dr. Rotstein said in her talk. Nevertheless, the course of MS is unpredictable, and the first year or two of immunomodulatory therapy can give physicians clues about the longer-term course of the disease. “We need to observe closely for disease activity in the first year, but even up to 2 years on therapy to determine a need for early escalation,” said Dr. Rotstein, assistant professor of medicine at University of Toronto.

For switching to high-efficacy therapies, any relapse, disability progression, or an EDSS change of 1 point or more could be a consideration. MRI indicators are more controversial, but one to three new T2 lesions also could prompt a switch.

Serum neural filament light chain (sNFL) is a useful biomarker for monitoring disease activity as it correlates well with new disease activity within the next year. It can be monitored every 3-4 months and adjusted for clinical factors and monitored for changing levels. A concerning finding can be followed up with an MRI or in-person visit.

When switching to a high-efficacy therapy, it’s important to administer any vaccines well in advance to ensure a good immune response.

When it comes to a washout period, physicians need to consider both the risk of immunosuppression and breakthrough disease activity. “But in general, we’ve observed that we can minimize the duration of the washout when stopping initial immunomodulator therapy to reduce the risk of breakthrough disease activity. We need to pay particular attention to the risk of rebound activity with longer washouts after stopping sphingosine-1 phosphate (S1P) receptor modulators because the rebound activity can be devastating,” said Dr. Rotstein.

A study of timing of relapses after fingolimod washout, carried out by Dr. Rotstein’s group, found a stark signal. “We observed that when the washout after fingolimod discontinuation was 30 days or more, there is a very high risk of early relapse,” she said.
 

The case for induction therapy

In the third talk, Gavin Giovannoni, MBBCh, PhD, discussed “flipping the pyramid” – that is, starting patients off immediately with high-efficacy therapies rather than waiting until they progress on other therapies. He likened such a decision to a gambler, because MS patients on less-effective therapy can suffer irreversible, long-term physical consequences, as well as social consequences such as unemployment due to cognitive effects.

“We always tend to put up a graph about the risks and benefits of a specific treatment, and we forget about the risks of untreated or undertreated MS. Keep that in mind when making decisions about high-efficacy therapies,” said Dr. Giovannoni, professor of neurology at Queen Mary University of London.

About 80% of patients on tier 1, or low-efficacy therapies, will have breakthrough activity on MRI within 4 years. Moving up a tier gets to about a 60% rate of breakthrough activity. High-efficacy therapies attain an efficacy of about 80% at 6 months. “If you have MS, you’ve got to realize that if you had to roll the dice, which tier would you want to be in? By putting all of them [on high-efficacy therapies], you’re going to get the majority responding and a few of them will break through,” said Dr. Giovannoni.

He presented some real-world evidence to back up the argument: A study comparing outcomes in Sweden and Denmark, which have similar demographics. In Denmark, 7.6% of patients with MS received high-efficacy therapies initially, while in Sweden the proportion was 34.5%. Patients with MS treated in Sweden had a 29% lower probability of progressing to disability (P = .004) and there were 22% fewer discontinuations of DMTs (P < .001). Since that study, the proportion of patients receiving high-efficacy therapies to begin with is closer to 70%. “This is compelling evidence that you want to be on a [high-efficacy therapy] early. If I had MS, I would want to live in Sweden,” said Dr. Giovannoni.

Historical treatments focused on reducing relapses, and more recently on eliminating evidence of inflammatory disease. He said that physicians are prioritizing brain volume loss to improve long-term outcomes in MS, and some are studying long-term disability. “We know that brain volume loss in MS is a prognostic sign both at baseline and at follow-up. It predicts poor outcome, poor cognition and employment, poor quality of life, et cetera,” said Dr. Giovannoni.

He cited data from studies of alemtuzumab that showed a significant reduction in brain volume loss. “The rate is about 0.2% per annum, which is kind of getting into the normal range for age-matched controls. Those people who were started off on interferons in the study lost a lot of brain volume in those first 2 years, and that’s irreversible,” said Dr. Giovannoni.

He pointed out that studies of hematopoietic stem cell therapy showed similar brain-volume outcomes. “So flipping the pyramid with the two most highly effective therapies almost normalizes brain volume loss in people with MS,” said Dr. Giovannoni.

There is also evidence in other autoimmune diseases that early use of high-efficacy therapies improves outcomes. More aggressive therapy in rheumatoid arthritis has reduced joint replacements by 90%.

“I think you really, really need to give your patients the opportunity of flipping the pyramid. You shouldn’t decide that for them,” said Dr. Giovannoni.

Dr. Coyle has consulted for nearly all pharmaceutical companies developing drugs in the MS space. Dr. Montalban has financial relationships with Biogen Idec, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva, Roche, Celgene, Actelion, Mylan, BMS, and Sandoz. Dr. Rotstein has financial ties with Roche Canada, Alexion, Biogen, EMD Serono, Novartis, Roche, and Sanofi Aventis. Dr. Giovannoni has financial ties with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, GW Pharma, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co., Merck KGaA/EMD Serono, Moderna, Novartis, Sanofi, Roche/Genentech, and Teva.

Patients with relapsing multiple sclerosis (MS) treated with intravenous ublituximab had fewer relapses and brain lesions compared with those treated with oral teriflunomide, although both therapies resulted in similar rates of worsening disability, according to results of the two identical phase 3 ULTIMATE I and II trials.

“In these two 96-week trials involving participants with MS, annualized relapse rates were lower with intravenous ublituximab than with oral teriflunomide. Ublituximab was associated with infusion-related reactions. Larger and longer trials are required to determine the efficacy and safety of ublituximab in patients with relapsing MS, including comparison with other disease-modifying treatments such as existing anti-CD20 monoclonal antibodies,” noted lead author Lawrence Steinman, MD, professor of neurology and neurological sciences, pediatrics, and genetics at Stanford (Calif.) University, and colleagues.

Two trials

The double-blind, double-dummy ULTIMATE I and II trials enrolled 549 and 545 participants respectively, with a median follow-up of 95 weeks. Subjects, aged between 18 and 55 years, were randomized to receive either oral placebo and intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72), or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary endpoint was the annualized relapse rate, defined as the number of confirmed MS relapses per participant-year, with a range of secondary end points including number of lesions on magnetic resonance imaging (MRI) by 96 weeks, and worsening of disability confirmed at 12 weeks.

Prevention and management of infusion-related reactions was with oral antihistamine and dexamethasone, administered 30 to 60 minutes before each intravenous dose of ublituximab or placebo, as well as reductions in infusion flow rates and discretionary acetaminophen.

Results for the primary endpoint in ULTIMATE I showed the adjusted annualized relapse rate over a period of 96 weeks was 0.08 in the ublituximab group and 0.19 in the teriflunomide group (rate ratio, 0.41; P < .001). Corresponding rates for ULTIMATE II were 0.09 and 0.18 (rate ratio, 0.51; P = .002).

The mean number of lesions in both ublituximab arms of the trials was 0.02 and 0.01 compared with 0.49 and 0.25 in the teriflunomide arms (rate ratios 0.03 and 0.04 respectively; P < .001 for both).
 

Similar disability worsening in both groups

A pooled analysis of the two trials showed worsening disability in 5.2% of the ublituximab group, and 5.9% of the teriflunomide group (hazard ratio, 0.84; P = 0.51). “In both trials, teriflunomide was associated with a numerically lower rate of worsening of disability than that reported in previous studies with this drug, but no conclusions can be drawn from these comparisons,” noted the authors.

Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group, consisting mainly of mild to moderate pyrexia, headache, chills, and influenza-like illness. “The reactions may have been related to cytokine release from immune cells (B and NK cells) on interaction of the Fc antibody domain with Fc gamma receptors on effector cells,” they suggested.

Although no opportunistic infections occurred, a higher frequency of infections, including serious infections, was observed with ublituximab (5.0%) than with teriflunomide (2.9%).

While the ULTIMATE trials showed no difference between ublituximab and teriflunomide in confirmed worsening of disability, only a small percentage of participants in either arm showed deterioration, Dr. Coyle remarked. “In a relatively short trial (96 weeks), in a relapsing population on active treatment, this result was not surprising … If the study was bigger, or longer it would increase the chances of seeing a progressive slow worsening component to affect the EDSS [Expanded Disability Status Scale],” she added.
 

Equivalent efficacy

Ultimately, “it appears likely” that ublituximab is “equivalent in efficacy” to the earlier anti-CD20 agents ocrelizumab and ofatumumab, Dr. Coyle said. While all three agents target B-cells, “ublituximab targets a novel CD20 binding site, and is bioengineered to have a particularly potent antibody dependent cell cytotoxicity lysis mechanism,” she added. “It has been touted to ultimately allow a short infusion of 1 hour.”

Although the serious infection rate is slightly higher with ublituximab (5.0% vs. 2.5% for ofatumumab, and 1.3% for ocrelizumab), “it is still low,” and infusion-related reactions are also higher with ublituximab, she added (47.7% vs. 20.2% and 34.3%, respectively). She suggested factors that might influence which treatment is chosen for a given patient might include cost, convenience, whether it is more or less likely to cause low IgG, interference with vaccination, or influence on cancer or COVID risk.

The trials were supported by TG Therapeutics.

Dr. Coyle has 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 LLD, Genentech/Roche, Sanofi Genzyme, MedDay, NINDS, and Novartis.

Patients with relapsing multiple sclerosis (MS) treated with intravenous ublituximab had fewer relapses and brain lesions compared with those treated with oral teriflunomide, although both therapies resulted in similar rates of worsening disability, according to results of the two identical phase 3 ULTIMATE I and II trials.

“In these two 96-week trials involving participants with MS, annualized relapse rates were lower with intravenous ublituximab than with oral teriflunomide. Ublituximab was associated with infusion-related reactions. Larger and longer trials are required to determine the efficacy and safety of ublituximab in patients with relapsing MS, including comparison with other disease-modifying treatments such as existing anti-CD20 monoclonal antibodies,” noted lead author Lawrence Steinman, MD, professor of neurology and neurological sciences, pediatrics, and genetics at Stanford (Calif.) University, and colleagues.

Two trials

The double-blind, double-dummy ULTIMATE I and II trials enrolled 549 and 545 participants respectively, with a median follow-up of 95 weeks. Subjects, aged between 18 and 55 years, were randomized to receive either oral placebo and intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72), or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary endpoint was the annualized relapse rate, defined as the number of confirmed MS relapses per participant-year, with a range of secondary end points including number of lesions on magnetic resonance imaging (MRI) by 96 weeks, and worsening of disability confirmed at 12 weeks.

Prevention and management of infusion-related reactions was with oral antihistamine and dexamethasone, administered 30 to 60 minutes before each intravenous dose of ublituximab or placebo, as well as reductions in infusion flow rates and discretionary acetaminophen.

Results for the primary endpoint in ULTIMATE I showed the adjusted annualized relapse rate over a period of 96 weeks was 0.08 in the ublituximab group and 0.19 in the teriflunomide group (rate ratio, 0.41; P < .001). Corresponding rates for ULTIMATE II were 0.09 and 0.18 (rate ratio, 0.51; P = .002).

The mean number of lesions in both ublituximab arms of the trials was 0.02 and 0.01 compared with 0.49 and 0.25 in the teriflunomide arms (rate ratios 0.03 and 0.04 respectively; P < .001 for both).
 

Similar disability worsening in both groups

A pooled analysis of the two trials showed worsening disability in 5.2% of the ublituximab group, and 5.9% of the teriflunomide group (hazard ratio, 0.84; P = 0.51). “In both trials, teriflunomide was associated with a numerically lower rate of worsening of disability than that reported in previous studies with this drug, but no conclusions can be drawn from these comparisons,” noted the authors.

Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group, consisting mainly of mild to moderate pyrexia, headache, chills, and influenza-like illness. “The reactions may have been related to cytokine release from immune cells (B and NK cells) on interaction of the Fc antibody domain with Fc gamma receptors on effector cells,” they suggested.

Although no opportunistic infections occurred, a higher frequency of infections, including serious infections, was observed with ublituximab (5.0%) than with teriflunomide (2.9%).

While the ULTIMATE trials showed no difference between ublituximab and teriflunomide in confirmed worsening of disability, only a small percentage of participants in either arm showed deterioration, Dr. Coyle remarked. “In a relatively short trial (96 weeks), in a relapsing population on active treatment, this result was not surprising … If the study was bigger, or longer it would increase the chances of seeing a progressive slow worsening component to affect the EDSS [Expanded Disability Status Scale],” she added.
 

Equivalent efficacy

Ultimately, “it appears likely” that ublituximab is “equivalent in efficacy” to the earlier anti-CD20 agents ocrelizumab and ofatumumab, Dr. Coyle said. While all three agents target B-cells, “ublituximab targets a novel CD20 binding site, and is bioengineered to have a particularly potent antibody dependent cell cytotoxicity lysis mechanism,” she added. “It has been touted to ultimately allow a short infusion of 1 hour.”

Although the serious infection rate is slightly higher with ublituximab (5.0% vs. 2.5% for ofatumumab, and 1.3% for ocrelizumab), “it is still low,” and infusion-related reactions are also higher with ublituximab, she added (47.7% vs. 20.2% and 34.3%, respectively). She suggested factors that might influence which treatment is chosen for a given patient might include cost, convenience, whether it is more or less likely to cause low IgG, interference with vaccination, or influence on cancer or COVID risk.

The trials were supported by TG Therapeutics.

Dr. Coyle has 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 LLD, Genentech/Roche, Sanofi Genzyme, MedDay, NINDS, and Novartis.

Patients with relapsing multiple sclerosis (MS) treated with intravenous ublituximab had fewer relapses and brain lesions compared with those treated with oral teriflunomide, although both therapies resulted in similar rates of worsening disability, according to results of the two identical phase 3 ULTIMATE I and II trials.

“In these two 96-week trials involving participants with MS, annualized relapse rates were lower with intravenous ublituximab than with oral teriflunomide. Ublituximab was associated with infusion-related reactions. Larger and longer trials are required to determine the efficacy and safety of ublituximab in patients with relapsing MS, including comparison with other disease-modifying treatments such as existing anti-CD20 monoclonal antibodies,” noted lead author Lawrence Steinman, MD, professor of neurology and neurological sciences, pediatrics, and genetics at Stanford (Calif.) University, and colleagues.

Two trials

The double-blind, double-dummy ULTIMATE I and II trials enrolled 549 and 545 participants respectively, with a median follow-up of 95 weeks. Subjects, aged between 18 and 55 years, were randomized to receive either oral placebo and intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72), or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary endpoint was the annualized relapse rate, defined as the number of confirmed MS relapses per participant-year, with a range of secondary end points including number of lesions on magnetic resonance imaging (MRI) by 96 weeks, and worsening of disability confirmed at 12 weeks.

Prevention and management of infusion-related reactions was with oral antihistamine and dexamethasone, administered 30 to 60 minutes before each intravenous dose of ublituximab or placebo, as well as reductions in infusion flow rates and discretionary acetaminophen.

Results for the primary endpoint in ULTIMATE I showed the adjusted annualized relapse rate over a period of 96 weeks was 0.08 in the ublituximab group and 0.19 in the teriflunomide group (rate ratio, 0.41; P < .001). Corresponding rates for ULTIMATE II were 0.09 and 0.18 (rate ratio, 0.51; P = .002).

The mean number of lesions in both ublituximab arms of the trials was 0.02 and 0.01 compared with 0.49 and 0.25 in the teriflunomide arms (rate ratios 0.03 and 0.04 respectively; P < .001 for both).
 

Similar disability worsening in both groups

A pooled analysis of the two trials showed worsening disability in 5.2% of the ublituximab group, and 5.9% of the teriflunomide group (hazard ratio, 0.84; P = 0.51). “In both trials, teriflunomide was associated with a numerically lower rate of worsening of disability than that reported in previous studies with this drug, but no conclusions can be drawn from these comparisons,” noted the authors.

Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group, consisting mainly of mild to moderate pyrexia, headache, chills, and influenza-like illness. “The reactions may have been related to cytokine release from immune cells (B and NK cells) on interaction of the Fc antibody domain with Fc gamma receptors on effector cells,” they suggested.

Although no opportunistic infections occurred, a higher frequency of infections, including serious infections, was observed with ublituximab (5.0%) than with teriflunomide (2.9%).

While the ULTIMATE trials showed no difference between ublituximab and teriflunomide in confirmed worsening of disability, only a small percentage of participants in either arm showed deterioration, Dr. Coyle remarked. “In a relatively short trial (96 weeks), in a relapsing population on active treatment, this result was not surprising … If the study was bigger, or longer it would increase the chances of seeing a progressive slow worsening component to affect the EDSS [Expanded Disability Status Scale],” she added.
 

Equivalent efficacy

Ultimately, “it appears likely” that ublituximab is “equivalent in efficacy” to the earlier anti-CD20 agents ocrelizumab and ofatumumab, Dr. Coyle said. While all three agents target B-cells, “ublituximab targets a novel CD20 binding site, and is bioengineered to have a particularly potent antibody dependent cell cytotoxicity lysis mechanism,” she added. “It has been touted to ultimately allow a short infusion of 1 hour.”

Although the serious infection rate is slightly higher with ublituximab (5.0% vs. 2.5% for ofatumumab, and 1.3% for ocrelizumab), “it is still low,” and infusion-related reactions are also higher with ublituximab, she added (47.7% vs. 20.2% and 34.3%, respectively). She suggested factors that might influence which treatment is chosen for a given patient might include cost, convenience, whether it is more or less likely to cause low IgG, interference with vaccination, or influence on cancer or COVID risk.

The trials were supported by TG Therapeutics.

Dr. Coyle has 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 LLD, Genentech/Roche, Sanofi Genzyme, MedDay, NINDS, and Novartis.

Cognitive impairment is a good predictor of physical disability progression in patients with multiple sclerosis (MS), new research suggests. In an analysis of more than 1,600 patients with secondary-progressive MS (SPMS), the likelihood of needing a wheelchair was almost doubled in those who had the worst scores on cognitive testing measures, compared with their counterparts who had the best scores.

“These findings should change our world view of MS,” study investigator Gavin Giovannoni, PhD, professor of neurology, Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, told attendees at the Congress of the European Academy of Neurology.

Expand data

Cognitive impairment occurs very early in the course of MS and is part of the disease, although to a greater or lesser degree depending on the patient, Dr. Giovannoni noted. Such impairment has a significant impact on quality of life for patients dealing with this disease, he added.

EXPAND was a phase 3 study of siponimod. Results showed the now-approved oral selective sphingosine 1–phosphate receptor modulator significantly reduced the risk for disability progression in patients with SPMS.

Using the EXPAND clinical trial database, the current researchers assessed 1,628 participants for an association between cognitive processing speed, as measured with the Symbol Digit Modality Test (SDMT), and physical disability progression, as measured with the Expanded Disability Status Scale (EDSS). A score of 7 or more on the EDSS indicates wheelchair dependence.

Dr. Giovannoni noted that cognitive processing speed is considered an indirect measure of thalamic network efficiency and functional brain reserve.

Investigators looked at both the core study, in which all patients continued on treatment or placebo for up to 37 months, and the core plus extension part, in which patients received treatment for up to 5 years.

They separated SDMT scores into quartiles: from worst (n = 435) to two intermediate quartiles (n = 808) to the best quartile (n = 385).
 

Wheelchair dependence

In addition, the researchers examined the predictive value by baseline SDMT, adjusting for treatment, age, gender, baseline EDSS score, baseline SCMT quartile, and treatment-by-baseline SCMT quartile interaction. On-study SDMT change (month 0-24) was also assessed after adjusting for treatment, age, gender, baseline EDS, baseline SCMT, and on-study change in SCMT quartile.

In the core study, those in the worst SDMT quartile at baseline were numerically more likely to reach deterioration to EDSS 7 or greater (wheelchair dependent), compared with patients in the best SDMT quartile (hazard ratio, 1.31; 95% confidence interval, .72-2.38; P = .371).

The short-term predictive value of baseline SDMT for reaching sustained EDSS of at least 7 was more obvious in the placebo arm than in the treatment arm.

Dr. Giovannoni said this is likely due to the treatment effect of siponimod preventing relatively more events in the worse quartile, and so reducing the risk for wheelchair dependency.

In the core plus extension part, there was an almost twofold increased risk for wheelchair dependence in the worse versus best SDMT groups (HR, 1.81; 95% CI, 1.17-2.78; P = .007).

Both baseline SDMT (HR, 1.81; P = .007) and on-study change in SDMT (HR, 1.73; P = .046) predicted wheelchair dependence in the long-term.
 

‘More important than a walking stick’

Measuring cognitive change over time “may be a more important predictor than a walking stick in terms of quality of life and outcomes, and it affects clinical decisionmaking,” said Dr. Giovannoni.

The findings are not novel, as post hoc analyses of other studies showed similar results. However, this new analysis adds more evidence to the importance of cognition in MS, Dr. Giovannoni noted.

“I have patients with EDSS of 0 or 1 who are profoundly disabled because of cognition. You shouldn’t just assume someone is not disabled because they don’t have physical disability,” he said.

However, Dr. Giovannoni noted that the study found an association and does not necessarily indicate a cause.
 

‘Valuable’ insights

Antonia Lefter, MD, of NeuroHope, Monza Oncologic Hospital, Bucharest, Romania, cochaired the session highlighting the research. Commenting on the study, she called this analysis from the “renowned” EXPAND study “valuable.”

In addition, it “underscores” the importance of assessing cognitive processing speed, as it may predict long-term disability progression in patients with SPMS, Dr. Lefter said.

The study was funded by Novartis Pharma AG, Basel, Switzerland. Dr. Giovannoni, a steering committee member of the EXPAND trial, reported receiving consulting fees from AbbVie, Actelion, Atara Bio, Biogen, Celgene, Sanofi-Genzyme, Genentech, GlaxoSmithKline, Merck-Serono, Novartis, Roche, and Reva. He has also received compensation for research from Biogen, Roche, Merck-Serono, Novartis, Sanofi-Genzyme, and Takeda. Dr. Lefter has reported no relevant financial relationships.

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

Cognitive impairment is a good predictor of physical disability progression in patients with multiple sclerosis (MS), new research suggests. In an analysis of more than 1,600 patients with secondary-progressive MS (SPMS), the likelihood of needing a wheelchair was almost doubled in those who had the worst scores on cognitive testing measures, compared with their counterparts who had the best scores.

“These findings should change our world view of MS,” study investigator Gavin Giovannoni, PhD, professor of neurology, Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, told attendees at the Congress of the European Academy of Neurology.

Expand data

Cognitive impairment occurs very early in the course of MS and is part of the disease, although to a greater or lesser degree depending on the patient, Dr. Giovannoni noted. Such impairment has a significant impact on quality of life for patients dealing with this disease, he added.

EXPAND was a phase 3 study of siponimod. Results showed the now-approved oral selective sphingosine 1–phosphate receptor modulator significantly reduced the risk for disability progression in patients with SPMS.

Using the EXPAND clinical trial database, the current researchers assessed 1,628 participants for an association between cognitive processing speed, as measured with the Symbol Digit Modality Test (SDMT), and physical disability progression, as measured with the Expanded Disability Status Scale (EDSS). A score of 7 or more on the EDSS indicates wheelchair dependence.

Dr. Giovannoni noted that cognitive processing speed is considered an indirect measure of thalamic network efficiency and functional brain reserve.

Investigators looked at both the core study, in which all patients continued on treatment or placebo for up to 37 months, and the core plus extension part, in which patients received treatment for up to 5 years.

They separated SDMT scores into quartiles: from worst (n = 435) to two intermediate quartiles (n = 808) to the best quartile (n = 385).
 

Wheelchair dependence

In addition, the researchers examined the predictive value by baseline SDMT, adjusting for treatment, age, gender, baseline EDSS score, baseline SCMT quartile, and treatment-by-baseline SCMT quartile interaction. On-study SDMT change (month 0-24) was also assessed after adjusting for treatment, age, gender, baseline EDS, baseline SCMT, and on-study change in SCMT quartile.

In the core study, those in the worst SDMT quartile at baseline were numerically more likely to reach deterioration to EDSS 7 or greater (wheelchair dependent), compared with patients in the best SDMT quartile (hazard ratio, 1.31; 95% confidence interval, .72-2.38; P = .371).

The short-term predictive value of baseline SDMT for reaching sustained EDSS of at least 7 was more obvious in the placebo arm than in the treatment arm.

Dr. Giovannoni said this is likely due to the treatment effect of siponimod preventing relatively more events in the worse quartile, and so reducing the risk for wheelchair dependency.

In the core plus extension part, there was an almost twofold increased risk for wheelchair dependence in the worse versus best SDMT groups (HR, 1.81; 95% CI, 1.17-2.78; P = .007).

Both baseline SDMT (HR, 1.81; P = .007) and on-study change in SDMT (HR, 1.73; P = .046) predicted wheelchair dependence in the long-term.
 

‘More important than a walking stick’

Measuring cognitive change over time “may be a more important predictor than a walking stick in terms of quality of life and outcomes, and it affects clinical decisionmaking,” said Dr. Giovannoni.

The findings are not novel, as post hoc analyses of other studies showed similar results. However, this new analysis adds more evidence to the importance of cognition in MS, Dr. Giovannoni noted.

“I have patients with EDSS of 0 or 1 who are profoundly disabled because of cognition. You shouldn’t just assume someone is not disabled because they don’t have physical disability,” he said.

However, Dr. Giovannoni noted that the study found an association and does not necessarily indicate a cause.
 

‘Valuable’ insights

Antonia Lefter, MD, of NeuroHope, Monza Oncologic Hospital, Bucharest, Romania, cochaired the session highlighting the research. Commenting on the study, she called this analysis from the “renowned” EXPAND study “valuable.”

In addition, it “underscores” the importance of assessing cognitive processing speed, as it may predict long-term disability progression in patients with SPMS, Dr. Lefter said.

The study was funded by Novartis Pharma AG, Basel, Switzerland. Dr. Giovannoni, a steering committee member of the EXPAND trial, reported receiving consulting fees from AbbVie, Actelion, Atara Bio, Biogen, Celgene, Sanofi-Genzyme, Genentech, GlaxoSmithKline, Merck-Serono, Novartis, Roche, and Reva. He has also received compensation for research from Biogen, Roche, Merck-Serono, Novartis, Sanofi-Genzyme, and Takeda. Dr. Lefter has reported no relevant financial relationships.

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

Cognitive impairment is a good predictor of physical disability progression in patients with multiple sclerosis (MS), new research suggests. In an analysis of more than 1,600 patients with secondary-progressive MS (SPMS), the likelihood of needing a wheelchair was almost doubled in those who had the worst scores on cognitive testing measures, compared with their counterparts who had the best scores.

“These findings should change our world view of MS,” study investigator Gavin Giovannoni, PhD, professor of neurology, Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, told attendees at the Congress of the European Academy of Neurology.

Expand data

Cognitive impairment occurs very early in the course of MS and is part of the disease, although to a greater or lesser degree depending on the patient, Dr. Giovannoni noted. Such impairment has a significant impact on quality of life for patients dealing with this disease, he added.

EXPAND was a phase 3 study of siponimod. Results showed the now-approved oral selective sphingosine 1–phosphate receptor modulator significantly reduced the risk for disability progression in patients with SPMS.

Using the EXPAND clinical trial database, the current researchers assessed 1,628 participants for an association between cognitive processing speed, as measured with the Symbol Digit Modality Test (SDMT), and physical disability progression, as measured with the Expanded Disability Status Scale (EDSS). A score of 7 or more on the EDSS indicates wheelchair dependence.

Dr. Giovannoni noted that cognitive processing speed is considered an indirect measure of thalamic network efficiency and functional brain reserve.

Investigators looked at both the core study, in which all patients continued on treatment or placebo for up to 37 months, and the core plus extension part, in which patients received treatment for up to 5 years.

They separated SDMT scores into quartiles: from worst (n = 435) to two intermediate quartiles (n = 808) to the best quartile (n = 385).
 

Wheelchair dependence

In addition, the researchers examined the predictive value by baseline SDMT, adjusting for treatment, age, gender, baseline EDSS score, baseline SCMT quartile, and treatment-by-baseline SCMT quartile interaction. On-study SDMT change (month 0-24) was also assessed after adjusting for treatment, age, gender, baseline EDS, baseline SCMT, and on-study change in SCMT quartile.

In the core study, those in the worst SDMT quartile at baseline were numerically more likely to reach deterioration to EDSS 7 or greater (wheelchair dependent), compared with patients in the best SDMT quartile (hazard ratio, 1.31; 95% confidence interval, .72-2.38; P = .371).

The short-term predictive value of baseline SDMT for reaching sustained EDSS of at least 7 was more obvious in the placebo arm than in the treatment arm.

Dr. Giovannoni said this is likely due to the treatment effect of siponimod preventing relatively more events in the worse quartile, and so reducing the risk for wheelchair dependency.

In the core plus extension part, there was an almost twofold increased risk for wheelchair dependence in the worse versus best SDMT groups (HR, 1.81; 95% CI, 1.17-2.78; P = .007).

Both baseline SDMT (HR, 1.81; P = .007) and on-study change in SDMT (HR, 1.73; P = .046) predicted wheelchair dependence in the long-term.
 

‘More important than a walking stick’

Measuring cognitive change over time “may be a more important predictor than a walking stick in terms of quality of life and outcomes, and it affects clinical decisionmaking,” said Dr. Giovannoni.

The findings are not novel, as post hoc analyses of other studies showed similar results. However, this new analysis adds more evidence to the importance of cognition in MS, Dr. Giovannoni noted.

“I have patients with EDSS of 0 or 1 who are profoundly disabled because of cognition. You shouldn’t just assume someone is not disabled because they don’t have physical disability,” he said.

However, Dr. Giovannoni noted that the study found an association and does not necessarily indicate a cause.
 

‘Valuable’ insights

Antonia Lefter, MD, of NeuroHope, Monza Oncologic Hospital, Bucharest, Romania, cochaired the session highlighting the research. Commenting on the study, she called this analysis from the “renowned” EXPAND study “valuable.”

In addition, it “underscores” the importance of assessing cognitive processing speed, as it may predict long-term disability progression in patients with SPMS, Dr. Lefter said.

The study was funded by Novartis Pharma AG, Basel, Switzerland. Dr. Giovannoni, a steering committee member of the EXPAND trial, reported receiving consulting fees from AbbVie, Actelion, Atara Bio, Biogen, Celgene, Sanofi-Genzyme, Genentech, GlaxoSmithKline, Merck-Serono, Novartis, Roche, and Reva. He has also received compensation for research from Biogen, Roche, Merck-Serono, Novartis, Sanofi-Genzyme, and Takeda. Dr. Lefter has reported no relevant financial relationships.

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

NATIONAL HARBOR, MD – How often do patients with multiple sclerosis (MS) end up taking drugs that could dangerously interact with other medications they’re taking? A new German study provides a disturbing hint, a pharmacist who spoke at the annual meeting of the Consortium of Multiple Sclerosis Centers told colleagues: Out of 627 patients who took an average of 5.3 drugs each, about 1 in 25 faced a potentially severe interaction, and nearly two-thirds had at least one potentially risky interaction.

It’s crucial to “work on identifying those interactions,” said Jenelle H. Montgomery, PharmD, of Duke University Hospital, Durham, N.C., and to understand the risks. As she noted, interactions don’t just put patients at risk of adverse effects and hospitalization. They can also lead to secondary comorbidities and therapeutic failures.
 

Newer versus older drugs

Drug interactions in MS have become more common as disease-modifying therapies have evolved, she said. Some older drugs – such as glatiramer acetate, beta-interferons, and fumarates – have low interaction profiles. But newer drugs have more drug interactions caused in part by their side-effect profiles, oral routes of administration, and immunosuppressive instead of immunomodulatory effects, she said. Teriflunomide, for example, interacts with rosuvastatin and warfarin.

S1P modulators are especially complex on the interaction front, Dr. Montgomery said. Cardiology consults are recommended for patients taking siponimod, ozanimod, and ponesimod, and there are a number of potential interactions between these drugs and other medications.

In regard to other MS drugs, other medications can disrupt the metabolism of cladribine, she said, and the manufacturer recommends separating any other oral drug doses by 3 hours. Even MS-related drugs can interact: carbamazepine, used to treat MS-related neuropathic pain, interacts with drugs such as siponimod.
 

Who is most at risk?

How can medical professionals prevent harmful drug interactions in MS? One strategy could be to focus on patients who may be more susceptible. Dr. Montgomery highlighted the kinds of patients who were most at risk of polypharmacy, per the 2022 German study: older people, those with lower education levels, and those with more disability. And she pointed out that 77% of all drug interactions were between prescription drugs. Another 19% were between prescription drugs and over-the-counter medications, and 4% were between OTC drugs.

She also emphasized the importance of asking about everything that a patient is taking, including herbal supplements, as nearly 60% of people aged 20 and over take them, and about 75% of those over 60. A quarter of people over age 60 take at least four supplements.

Information about interactions with supplements isn’t always available, she said, but she did mention concerns about St. John’s wort interactions with siponimod and cladribine.

Dr. Montgomery also offered several tips: Periodically ask patients to bring in medication bottles or pillboxes; encourage annual checkups with primary physicians; and use drug resources such as Facts and Comparisons, Lexicomp, Clinical Pharmacology, Micromedex, and Natural Medicines.

Disclosures for Dr. Montgomery were not available.

NATIONAL HARBOR, MD – How often do patients with multiple sclerosis (MS) end up taking drugs that could dangerously interact with other medications they’re taking? A new German study provides a disturbing hint, a pharmacist who spoke at the annual meeting of the Consortium of Multiple Sclerosis Centers told colleagues: Out of 627 patients who took an average of 5.3 drugs each, about 1 in 25 faced a potentially severe interaction, and nearly two-thirds had at least one potentially risky interaction.

It’s crucial to “work on identifying those interactions,” said Jenelle H. Montgomery, PharmD, of Duke University Hospital, Durham, N.C., and to understand the risks. As she noted, interactions don’t just put patients at risk of adverse effects and hospitalization. They can also lead to secondary comorbidities and therapeutic failures.
 

Newer versus older drugs

Drug interactions in MS have become more common as disease-modifying therapies have evolved, she said. Some older drugs – such as glatiramer acetate, beta-interferons, and fumarates – have low interaction profiles. But newer drugs have more drug interactions caused in part by their side-effect profiles, oral routes of administration, and immunosuppressive instead of immunomodulatory effects, she said. Teriflunomide, for example, interacts with rosuvastatin and warfarin.

S1P modulators are especially complex on the interaction front, Dr. Montgomery said. Cardiology consults are recommended for patients taking siponimod, ozanimod, and ponesimod, and there are a number of potential interactions between these drugs and other medications.

In regard to other MS drugs, other medications can disrupt the metabolism of cladribine, she said, and the manufacturer recommends separating any other oral drug doses by 3 hours. Even MS-related drugs can interact: carbamazepine, used to treat MS-related neuropathic pain, interacts with drugs such as siponimod.
 

Who is most at risk?

How can medical professionals prevent harmful drug interactions in MS? One strategy could be to focus on patients who may be more susceptible. Dr. Montgomery highlighted the kinds of patients who were most at risk of polypharmacy, per the 2022 German study: older people, those with lower education levels, and those with more disability. And she pointed out that 77% of all drug interactions were between prescription drugs. Another 19% were between prescription drugs and over-the-counter medications, and 4% were between OTC drugs.

She also emphasized the importance of asking about everything that a patient is taking, including herbal supplements, as nearly 60% of people aged 20 and over take them, and about 75% of those over 60. A quarter of people over age 60 take at least four supplements.

Information about interactions with supplements isn’t always available, she said, but she did mention concerns about St. John’s wort interactions with siponimod and cladribine.

Dr. Montgomery also offered several tips: Periodically ask patients to bring in medication bottles or pillboxes; encourage annual checkups with primary physicians; and use drug resources such as Facts and Comparisons, Lexicomp, Clinical Pharmacology, Micromedex, and Natural Medicines.

Disclosures for Dr. Montgomery were not available.

NATIONAL HARBOR, MD – How often do patients with multiple sclerosis (MS) end up taking drugs that could dangerously interact with other medications they’re taking? A new German study provides a disturbing hint, a pharmacist who spoke at the annual meeting of the Consortium of Multiple Sclerosis Centers told colleagues: Out of 627 patients who took an average of 5.3 drugs each, about 1 in 25 faced a potentially severe interaction, and nearly two-thirds had at least one potentially risky interaction.

It’s crucial to “work on identifying those interactions,” said Jenelle H. Montgomery, PharmD, of Duke University Hospital, Durham, N.C., and to understand the risks. As she noted, interactions don’t just put patients at risk of adverse effects and hospitalization. They can also lead to secondary comorbidities and therapeutic failures.
 

Newer versus older drugs

Drug interactions in MS have become more common as disease-modifying therapies have evolved, she said. Some older drugs – such as glatiramer acetate, beta-interferons, and fumarates – have low interaction profiles. But newer drugs have more drug interactions caused in part by their side-effect profiles, oral routes of administration, and immunosuppressive instead of immunomodulatory effects, she said. Teriflunomide, for example, interacts with rosuvastatin and warfarin.

S1P modulators are especially complex on the interaction front, Dr. Montgomery said. Cardiology consults are recommended for patients taking siponimod, ozanimod, and ponesimod, and there are a number of potential interactions between these drugs and other medications.

In regard to other MS drugs, other medications can disrupt the metabolism of cladribine, she said, and the manufacturer recommends separating any other oral drug doses by 3 hours. Even MS-related drugs can interact: carbamazepine, used to treat MS-related neuropathic pain, interacts with drugs such as siponimod.
 

Who is most at risk?

How can medical professionals prevent harmful drug interactions in MS? One strategy could be to focus on patients who may be more susceptible. Dr. Montgomery highlighted the kinds of patients who were most at risk of polypharmacy, per the 2022 German study: older people, those with lower education levels, and those with more disability. And she pointed out that 77% of all drug interactions were between prescription drugs. Another 19% were between prescription drugs and over-the-counter medications, and 4% were between OTC drugs.

She also emphasized the importance of asking about everything that a patient is taking, including herbal supplements, as nearly 60% of people aged 20 and over take them, and about 75% of those over 60. A quarter of people over age 60 take at least four supplements.

Information about interactions with supplements isn’t always available, she said, but she did mention concerns about St. John’s wort interactions with siponimod and cladribine.

Dr. Montgomery also offered several tips: Periodically ask patients to bring in medication bottles or pillboxes; encourage annual checkups with primary physicians; and use drug resources such as Facts and Comparisons, Lexicomp, Clinical Pharmacology, Micromedex, and Natural Medicines.

Disclosures for Dr. Montgomery were not available.

NATIONAL HARBOR, MD. – Treatment guidelines are helpful in treating relapsing-remitting multiple sclerosis (RRMS), a neurologist told colleagues, but they’re only useful to an extent. Consider his 40-year-old female patient who’s averse to vaccines, often misses appointments, and seems to be unable to take blood pressure drugs as prescribed. In this case, the best strategy may not be the drug with the highest efficacy.

“There’s no pharmaceutical insert that’s going to tell you what to do with all of this information,” John R. Rinker II, MD, of the University of Alabama at Birmingham, said in a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers. “It’s important to not only know about the disease and the specifics of the pharmaceuticals, but also about the patient’s personal circumstances, their comorbidities, their social situation, and how it all ties together.”

Fortunately, he said, there are about two dozen medication options now available for RRMS. Noting that his scale is at best “a crude approximation of reality,” he said their efficacy runs the gamut from low (glatiramer acetate and beta-interferons) to high (cladribine, alemtuzumab). He places sphingosine-1 phosphate (SIP1) modulators in the mid-range in terms of efficacy and B cell-depleting agents and natalizumab toward the high side.
 

Why go low?

Why put someone on a low-efficacy drug? One reason is because they’re the safest options, he said, while the two highest-efficacy drugs – cladribine and alemtuzumab – are the least safe. But even the older, safer drugs can cause problems: Beta interferons can cause flu-like symptoms early on along with depression and miscarriage, and glatiramer acetate can spur injection site reactions and acute post injection syndrome “that can feel like a panic attack or even a heart attack.”

Dimethyl fumarate “is probably the easiest of the oral agents to initiate because there’s no extra doctor’s appointments. And there’s no concerns really about hair loss, liver failure, or birth defects,” he said. “But it’s one of the oral agents that has the most side effects associated with it.” Flushing is almost universal but “rarely a cause of discontinuation,” while gastrointestinal symptoms can lead to discontinuation.

Alemtuzumab, a high-efficacy drug that’s administered in two annual cycles, he said, is especially convenient but monthly labs are required for years to check for problems due to its dampening of the immune system. Patients on ocrelizumab must be closely monitored for the same reason.

There are other factors to consider. Lower-efficacy drugs tend to be better options in younger patients – “they’re more resilient, and they tend to recover a little bit better after their early relapses,” Dr. Rinker said.

The drugs are especially helpful in patients who recover well after their initial episodes and who have sensory instead of motor symptoms, he said.
 

The case for high efficacy

Higher-efficacy drugs are best for older patients and those with heavy disease burden.

What about the 40-year-old patient? She’s female (women get less sick from MS) and has low disease burden, suggesting that a lower-efficacy drug may be appropriate, he said. “On the other hand, she has an incomplete recovery, and she’s got spinal cord disease and motor symptoms, so the tendency is going to be more towards the higher-efficacy end of the [drug] spectrum.”

But which drug? S1P modulators aren’t a good option since they require redosing or titration if doses are missed: “It’s important that you don’t prescribe them to patients where you have concerns about compliance.”

Also, he said, “we don’t think we’re to the point that we’re willing to put her at risk of severe medical complications by putting her on medicines with a high monitoring burden like cladribine or alemtuzumab.”

The best option may be teriflunomide, a once-daily pill, he said. It’s forgiving if a patient misses a dose since the medication stays in the body for a long time.

“There’s no single right answer,” Dr. Rinker said. “But there are ways to eliminate a lot of the choices based upon what we know about the medications and what we know about the patient. Then we can tailor a specific range of medications for a specific patient.”

Dr. Rinker disclosed research support from GW Pharmaceuticals.

NATIONAL HARBOR, MD. – Treatment guidelines are helpful in treating relapsing-remitting multiple sclerosis (RRMS), a neurologist told colleagues, but they’re only useful to an extent. Consider his 40-year-old female patient who’s averse to vaccines, often misses appointments, and seems to be unable to take blood pressure drugs as prescribed. In this case, the best strategy may not be the drug with the highest efficacy.

“There’s no pharmaceutical insert that’s going to tell you what to do with all of this information,” John R. Rinker II, MD, of the University of Alabama at Birmingham, said in a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers. “It’s important to not only know about the disease and the specifics of the pharmaceuticals, but also about the patient’s personal circumstances, their comorbidities, their social situation, and how it all ties together.”

Fortunately, he said, there are about two dozen medication options now available for RRMS. Noting that his scale is at best “a crude approximation of reality,” he said their efficacy runs the gamut from low (glatiramer acetate and beta-interferons) to high (cladribine, alemtuzumab). He places sphingosine-1 phosphate (SIP1) modulators in the mid-range in terms of efficacy and B cell-depleting agents and natalizumab toward the high side.
 

Why go low?

Why put someone on a low-efficacy drug? One reason is because they’re the safest options, he said, while the two highest-efficacy drugs – cladribine and alemtuzumab – are the least safe. But even the older, safer drugs can cause problems: Beta interferons can cause flu-like symptoms early on along with depression and miscarriage, and glatiramer acetate can spur injection site reactions and acute post injection syndrome “that can feel like a panic attack or even a heart attack.”

Dimethyl fumarate “is probably the easiest of the oral agents to initiate because there’s no extra doctor’s appointments. And there’s no concerns really about hair loss, liver failure, or birth defects,” he said. “But it’s one of the oral agents that has the most side effects associated with it.” Flushing is almost universal but “rarely a cause of discontinuation,” while gastrointestinal symptoms can lead to discontinuation.

Alemtuzumab, a high-efficacy drug that’s administered in two annual cycles, he said, is especially convenient but monthly labs are required for years to check for problems due to its dampening of the immune system. Patients on ocrelizumab must be closely monitored for the same reason.

There are other factors to consider. Lower-efficacy drugs tend to be better options in younger patients – “they’re more resilient, and they tend to recover a little bit better after their early relapses,” Dr. Rinker said.

The drugs are especially helpful in patients who recover well after their initial episodes and who have sensory instead of motor symptoms, he said.
 

The case for high efficacy

Higher-efficacy drugs are best for older patients and those with heavy disease burden.

What about the 40-year-old patient? She’s female (women get less sick from MS) and has low disease burden, suggesting that a lower-efficacy drug may be appropriate, he said. “On the other hand, she has an incomplete recovery, and she’s got spinal cord disease and motor symptoms, so the tendency is going to be more towards the higher-efficacy end of the [drug] spectrum.”

But which drug? S1P modulators aren’t a good option since they require redosing or titration if doses are missed: “It’s important that you don’t prescribe them to patients where you have concerns about compliance.”

Also, he said, “we don’t think we’re to the point that we’re willing to put her at risk of severe medical complications by putting her on medicines with a high monitoring burden like cladribine or alemtuzumab.”

The best option may be teriflunomide, a once-daily pill, he said. It’s forgiving if a patient misses a dose since the medication stays in the body for a long time.

“There’s no single right answer,” Dr. Rinker said. “But there are ways to eliminate a lot of the choices based upon what we know about the medications and what we know about the patient. Then we can tailor a specific range of medications for a specific patient.”

Dr. Rinker disclosed research support from GW Pharmaceuticals.

NATIONAL HARBOR, MD. – Treatment guidelines are helpful in treating relapsing-remitting multiple sclerosis (RRMS), a neurologist told colleagues, but they’re only useful to an extent. Consider his 40-year-old female patient who’s averse to vaccines, often misses appointments, and seems to be unable to take blood pressure drugs as prescribed. In this case, the best strategy may not be the drug with the highest efficacy.

“There’s no pharmaceutical insert that’s going to tell you what to do with all of this information,” John R. Rinker II, MD, of the University of Alabama at Birmingham, said in a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers. “It’s important to not only know about the disease and the specifics of the pharmaceuticals, but also about the patient’s personal circumstances, their comorbidities, their social situation, and how it all ties together.”

Fortunately, he said, there are about two dozen medication options now available for RRMS. Noting that his scale is at best “a crude approximation of reality,” he said their efficacy runs the gamut from low (glatiramer acetate and beta-interferons) to high (cladribine, alemtuzumab). He places sphingosine-1 phosphate (SIP1) modulators in the mid-range in terms of efficacy and B cell-depleting agents and natalizumab toward the high side.
 

Why go low?

Why put someone on a low-efficacy drug? One reason is because they’re the safest options, he said, while the two highest-efficacy drugs – cladribine and alemtuzumab – are the least safe. But even the older, safer drugs can cause problems: Beta interferons can cause flu-like symptoms early on along with depression and miscarriage, and glatiramer acetate can spur injection site reactions and acute post injection syndrome “that can feel like a panic attack or even a heart attack.”

Dimethyl fumarate “is probably the easiest of the oral agents to initiate because there’s no extra doctor’s appointments. And there’s no concerns really about hair loss, liver failure, or birth defects,” he said. “But it’s one of the oral agents that has the most side effects associated with it.” Flushing is almost universal but “rarely a cause of discontinuation,” while gastrointestinal symptoms can lead to discontinuation.

Alemtuzumab, a high-efficacy drug that’s administered in two annual cycles, he said, is especially convenient but monthly labs are required for years to check for problems due to its dampening of the immune system. Patients on ocrelizumab must be closely monitored for the same reason.

There are other factors to consider. Lower-efficacy drugs tend to be better options in younger patients – “they’re more resilient, and they tend to recover a little bit better after their early relapses,” Dr. Rinker said.

The drugs are especially helpful in patients who recover well after their initial episodes and who have sensory instead of motor symptoms, he said.
 

The case for high efficacy

Higher-efficacy drugs are best for older patients and those with heavy disease burden.

What about the 40-year-old patient? She’s female (women get less sick from MS) and has low disease burden, suggesting that a lower-efficacy drug may be appropriate, he said. “On the other hand, she has an incomplete recovery, and she’s got spinal cord disease and motor symptoms, so the tendency is going to be more towards the higher-efficacy end of the [drug] spectrum.”

But which drug? S1P modulators aren’t a good option since they require redosing or titration if doses are missed: “It’s important that you don’t prescribe them to patients where you have concerns about compliance.”

Also, he said, “we don’t think we’re to the point that we’re willing to put her at risk of severe medical complications by putting her on medicines with a high monitoring burden like cladribine or alemtuzumab.”

The best option may be teriflunomide, a once-daily pill, he said. It’s forgiving if a patient misses a dose since the medication stays in the body for a long time.

“There’s no single right answer,” Dr. Rinker said. “But there are ways to eliminate a lot of the choices based upon what we know about the medications and what we know about the patient. Then we can tailor a specific range of medications for a specific patient.”

Dr. Rinker disclosed research support from GW Pharmaceuticals.

NATIONAL HARBOR, MD. – Treating neuromyelitis optica spectrum disorder (NMOSD) with the recently approved monoclonal antibody inebilizumab (Uplizna, Horizon Therapeutics) is effective across patient genotypes – including a common genetic variation linked to reduced response to anti-CD20 therapies, new research shows.

The phase 3 N-MOmentum Study previously showed safety and efficacy for inebilizumab over placebo in more than 200 adults with NMOSD.

A new analysis focused on participants who were carriers of either the F/F allele, which is known to reduce the effectiveness of certain monoclonal antibodies, or the rs396991 V-allele, which has not been associated with a reduced response.

Results showed no significant differences between the two carrier groups in NMOSD activity, including annual rates of new/enlarging T2 lesions, during the trial and up to 6 months after treatment with inebilizumab.

“These data illustrate how mechanistic precision in treatment design can help patients gain benefit from their regimen regardless of the genetic make-up of their immune systems,” coinvestigator Bruce Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco, Weill Institute for Neurosciences, said in a press release.

“The combination of efficacy, safety, and ease of administration with twice-yearly infusions make this product an excellent choice for first-line therapy in NMOSD,” Dr. Cree said.

The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

B-cell depletion

Inebilizumab has also been approved in China, Japan, and South Korea for the treatment of NMOSD, a rare and severe autoantibody-mediated disease of the central nervous system that includes NMO and related syndromes.

The drug’s B-cell depletion capability is credited with reducing inflammation, lesion formation, and astrocyte damage. The latter can cause severe effects in an NMOSD attack, affecting the optic nerve, spinal cord, and brain.

Manifestations can range from loss of vision to paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain or respiratory failure. Attacks can also result in cumulative damage and disability, the researchers noted.

Results from the original double-blind trial of 230 adults with NMOSD showed that treatment with inebilizumab demonstrated efficacy and safety over placebo. However, questions have remained regarding the treatment’s effectiveness, specifically among patients with the FCGR3A (F/F) allele, a genetic variant that encodes the low-affinity Fc gamma receptor IIIa.

This genotype is known to reduce the effectiveness of certain monoclonal antibodies and anti-CD20 therapies, notably rituximab, in disorders such as NMOSD.

With up to 40% of White and Black individuals known to carry the F/F allele, inebilizumab was designed specifically with that risk in mind, with strong binding to the allele.

Although inebilizumab joins two other Food and Drug Administration–approved treatments for NMOSD – eculizumab and satralizumab – neither of those have a mechanism involving the FCGRA3 receptor. Therefore, those drugs are not a concern for individuals with those genotypes.

To evaluate inebilizumab’s effects among patients with the F/F allele, Dr. Cree and colleagues assessed data on a subset of 142 patients from the N-MOmentum trial.

The study included a 28-week randomized controlled period in which adults with NMOSD received either 300 mg of intravenous inebilizumab or placebo on days 1 and 15, followed by an optional open-label period of at least 2 years. During the open-label phase, all patients received 300 mg of IV inebilizumab every 26 weeks.

Of the 142 patients in the genetic analysis, 104 received inebilizumab and 38 received placebo. In addition, 68 group participants were carriers of the F/F allele, while 74 carried the rs396991 V-allele.
 

No significant differences

Prior to the trial, annualized attack rates (AARs) and disability, as assessed by change in the Expanded Disability Status Scale (EDSS) scores, were nominally higher in the V allele group from disease onset to trial enrollment.

During the trial’s first 6 months, AARs and annual rates of new/enlarging T2 lesions were nominally lower in inebilizumab-treated V allele participants compared with the F/F allele participants, although the differences were not statistically significant.

The AAR was 0.1 for the V allele group vs. 0.3 for the F/F allele group (hazard ratio, 0.40; P = .17). The annual rate of new/enlarging T2 lesions was 1.4 vs. 1.7 (risk ratio, 0.91; P = .88), respectively.

However, at the end of the randomized controlled period, there were no significant differences between the two genotype groups. There was also little difference in clinical metrics of NMOSD activity or B-cell depletion between the two genotype groups during the open-label period involving the long-term repeated inebilizumab dosing.

“Though greater B-cell depletion was observed in inebilizumab-treated V allele participants, compared with F/F participants during the first 6 months, no significant difference in NMOSD activity was observed during this time period,” the investigators reported.

“No differences in B-cell depletion or NMOSD disease activity were observed after 6 months of inebilizumab treatment,” they added.

Dr. Cree noted the study showed that, overall, inebiluzumab’s efficacy was not adversely affected by a polymorphism in the Fc gamma receptor. “These types of genetic analyses may help inform future screening mechanisms to tailor treatment strategies that can optimize the response rate for each patient,” he said.

Dr. Cree added the higher degree of disease activity among those carrying the alleles at baseline is notable and deserves further investigation. That finding “suggests that the presence of the F/F allele is to some extent protective of the detrimental effects the auto-antibody directed against aquaporin-4 that underlies NMOSD pathogenesis,” he said.
 

A new era?

Commenting on the study, Marcelo Matiello, MD, assistant professor of neurology at Harvard Medical School and associate director of the Neuromyelitis Optica clinic at Massachusetts General Hospital, both in Boston, said the findings provide valuable insights into risks for key patient subgroups.

“The data is quite important because we know that with other conditions, such as rheumatoid arthritis, people with this particular genotype do have lower response and are more likely to be refractory,” said Dr. Matiello, who was not involved with the research.

He noted that rituximab is the most commonly used medication in the United States for NMOSD. “It’s not FDA approved, but because of extensive experience, and many case series and small prospective studies, most NMO patients are using rituximab,” Dr. Matiello said. However, the drug’s mechanism “can be compromised” by the F/F allele, he added.

The new findings “provide a good understanding that this medication would likely be superior to patients with this genotype,” he said.

“I think it’s a new era,” Dr. Matiello added. “Not only do we have approved medication for this very severe disease, but we can find out who can benefit most. So, I think this is exciting and is a major step in more individualized appropriate use.”

The study was funded by Horizon Therapeutics. Dr. Cree has consulted for Horizon Therapeutics. Dr. Matiello reported no relevant financial relationships.

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

NATIONAL HARBOR, MD. – Treating neuromyelitis optica spectrum disorder (NMOSD) with the recently approved monoclonal antibody inebilizumab (Uplizna, Horizon Therapeutics) is effective across patient genotypes – including a common genetic variation linked to reduced response to anti-CD20 therapies, new research shows.

The phase 3 N-MOmentum Study previously showed safety and efficacy for inebilizumab over placebo in more than 200 adults with NMOSD.

A new analysis focused on participants who were carriers of either the F/F allele, which is known to reduce the effectiveness of certain monoclonal antibodies, or the rs396991 V-allele, which has not been associated with a reduced response.

Results showed no significant differences between the two carrier groups in NMOSD activity, including annual rates of new/enlarging T2 lesions, during the trial and up to 6 months after treatment with inebilizumab.

“These data illustrate how mechanistic precision in treatment design can help patients gain benefit from their regimen regardless of the genetic make-up of their immune systems,” coinvestigator Bruce Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco, Weill Institute for Neurosciences, said in a press release.

“The combination of efficacy, safety, and ease of administration with twice-yearly infusions make this product an excellent choice for first-line therapy in NMOSD,” Dr. Cree said.

The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

B-cell depletion

Inebilizumab has also been approved in China, Japan, and South Korea for the treatment of NMOSD, a rare and severe autoantibody-mediated disease of the central nervous system that includes NMO and related syndromes.

The drug’s B-cell depletion capability is credited with reducing inflammation, lesion formation, and astrocyte damage. The latter can cause severe effects in an NMOSD attack, affecting the optic nerve, spinal cord, and brain.

Manifestations can range from loss of vision to paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain or respiratory failure. Attacks can also result in cumulative damage and disability, the researchers noted.

Results from the original double-blind trial of 230 adults with NMOSD showed that treatment with inebilizumab demonstrated efficacy and safety over placebo. However, questions have remained regarding the treatment’s effectiveness, specifically among patients with the FCGR3A (F/F) allele, a genetic variant that encodes the low-affinity Fc gamma receptor IIIa.

This genotype is known to reduce the effectiveness of certain monoclonal antibodies and anti-CD20 therapies, notably rituximab, in disorders such as NMOSD.

With up to 40% of White and Black individuals known to carry the F/F allele, inebilizumab was designed specifically with that risk in mind, with strong binding to the allele.

Although inebilizumab joins two other Food and Drug Administration–approved treatments for NMOSD – eculizumab and satralizumab – neither of those have a mechanism involving the FCGRA3 receptor. Therefore, those drugs are not a concern for individuals with those genotypes.

To evaluate inebilizumab’s effects among patients with the F/F allele, Dr. Cree and colleagues assessed data on a subset of 142 patients from the N-MOmentum trial.

The study included a 28-week randomized controlled period in which adults with NMOSD received either 300 mg of intravenous inebilizumab or placebo on days 1 and 15, followed by an optional open-label period of at least 2 years. During the open-label phase, all patients received 300 mg of IV inebilizumab every 26 weeks.

Of the 142 patients in the genetic analysis, 104 received inebilizumab and 38 received placebo. In addition, 68 group participants were carriers of the F/F allele, while 74 carried the rs396991 V-allele.
 

No significant differences

Prior to the trial, annualized attack rates (AARs) and disability, as assessed by change in the Expanded Disability Status Scale (EDSS) scores, were nominally higher in the V allele group from disease onset to trial enrollment.

During the trial’s first 6 months, AARs and annual rates of new/enlarging T2 lesions were nominally lower in inebilizumab-treated V allele participants compared with the F/F allele participants, although the differences were not statistically significant.

The AAR was 0.1 for the V allele group vs. 0.3 for the F/F allele group (hazard ratio, 0.40; P = .17). The annual rate of new/enlarging T2 lesions was 1.4 vs. 1.7 (risk ratio, 0.91; P = .88), respectively.

However, at the end of the randomized controlled period, there were no significant differences between the two genotype groups. There was also little difference in clinical metrics of NMOSD activity or B-cell depletion between the two genotype groups during the open-label period involving the long-term repeated inebilizumab dosing.

“Though greater B-cell depletion was observed in inebilizumab-treated V allele participants, compared with F/F participants during the first 6 months, no significant difference in NMOSD activity was observed during this time period,” the investigators reported.

“No differences in B-cell depletion or NMOSD disease activity were observed after 6 months of inebilizumab treatment,” they added.

Dr. Cree noted the study showed that, overall, inebiluzumab’s efficacy was not adversely affected by a polymorphism in the Fc gamma receptor. “These types of genetic analyses may help inform future screening mechanisms to tailor treatment strategies that can optimize the response rate for each patient,” he said.

Dr. Cree added the higher degree of disease activity among those carrying the alleles at baseline is notable and deserves further investigation. That finding “suggests that the presence of the F/F allele is to some extent protective of the detrimental effects the auto-antibody directed against aquaporin-4 that underlies NMOSD pathogenesis,” he said.
 

A new era?

Commenting on the study, Marcelo Matiello, MD, assistant professor of neurology at Harvard Medical School and associate director of the Neuromyelitis Optica clinic at Massachusetts General Hospital, both in Boston, said the findings provide valuable insights into risks for key patient subgroups.

“The data is quite important because we know that with other conditions, such as rheumatoid arthritis, people with this particular genotype do have lower response and are more likely to be refractory,” said Dr. Matiello, who was not involved with the research.

He noted that rituximab is the most commonly used medication in the United States for NMOSD. “It’s not FDA approved, but because of extensive experience, and many case series and small prospective studies, most NMO patients are using rituximab,” Dr. Matiello said. However, the drug’s mechanism “can be compromised” by the F/F allele, he added.

The new findings “provide a good understanding that this medication would likely be superior to patients with this genotype,” he said.

“I think it’s a new era,” Dr. Matiello added. “Not only do we have approved medication for this very severe disease, but we can find out who can benefit most. So, I think this is exciting and is a major step in more individualized appropriate use.”

The study was funded by Horizon Therapeutics. Dr. Cree has consulted for Horizon Therapeutics. Dr. Matiello reported no relevant financial relationships.

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

NATIONAL HARBOR, MD. – Treating neuromyelitis optica spectrum disorder (NMOSD) with the recently approved monoclonal antibody inebilizumab (Uplizna, Horizon Therapeutics) is effective across patient genotypes – including a common genetic variation linked to reduced response to anti-CD20 therapies, new research shows.

The phase 3 N-MOmentum Study previously showed safety and efficacy for inebilizumab over placebo in more than 200 adults with NMOSD.

A new analysis focused on participants who were carriers of either the F/F allele, which is known to reduce the effectiveness of certain monoclonal antibodies, or the rs396991 V-allele, which has not been associated with a reduced response.

Results showed no significant differences between the two carrier groups in NMOSD activity, including annual rates of new/enlarging T2 lesions, during the trial and up to 6 months after treatment with inebilizumab.

“These data illustrate how mechanistic precision in treatment design can help patients gain benefit from their regimen regardless of the genetic make-up of their immune systems,” coinvestigator Bruce Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco, Weill Institute for Neurosciences, said in a press release.

“The combination of efficacy, safety, and ease of administration with twice-yearly infusions make this product an excellent choice for first-line therapy in NMOSD,” Dr. Cree said.

The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

B-cell depletion

Inebilizumab has also been approved in China, Japan, and South Korea for the treatment of NMOSD, a rare and severe autoantibody-mediated disease of the central nervous system that includes NMO and related syndromes.

The drug’s B-cell depletion capability is credited with reducing inflammation, lesion formation, and astrocyte damage. The latter can cause severe effects in an NMOSD attack, affecting the optic nerve, spinal cord, and brain.

Manifestations can range from loss of vision to paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain or respiratory failure. Attacks can also result in cumulative damage and disability, the researchers noted.

Results from the original double-blind trial of 230 adults with NMOSD showed that treatment with inebilizumab demonstrated efficacy and safety over placebo. However, questions have remained regarding the treatment’s effectiveness, specifically among patients with the FCGR3A (F/F) allele, a genetic variant that encodes the low-affinity Fc gamma receptor IIIa.

This genotype is known to reduce the effectiveness of certain monoclonal antibodies and anti-CD20 therapies, notably rituximab, in disorders such as NMOSD.

With up to 40% of White and Black individuals known to carry the F/F allele, inebilizumab was designed specifically with that risk in mind, with strong binding to the allele.

Although inebilizumab joins two other Food and Drug Administration–approved treatments for NMOSD – eculizumab and satralizumab – neither of those have a mechanism involving the FCGRA3 receptor. Therefore, those drugs are not a concern for individuals with those genotypes.

To evaluate inebilizumab’s effects among patients with the F/F allele, Dr. Cree and colleagues assessed data on a subset of 142 patients from the N-MOmentum trial.

The study included a 28-week randomized controlled period in which adults with NMOSD received either 300 mg of intravenous inebilizumab or placebo on days 1 and 15, followed by an optional open-label period of at least 2 years. During the open-label phase, all patients received 300 mg of IV inebilizumab every 26 weeks.

Of the 142 patients in the genetic analysis, 104 received inebilizumab and 38 received placebo. In addition, 68 group participants were carriers of the F/F allele, while 74 carried the rs396991 V-allele.
 

No significant differences

Prior to the trial, annualized attack rates (AARs) and disability, as assessed by change in the Expanded Disability Status Scale (EDSS) scores, were nominally higher in the V allele group from disease onset to trial enrollment.

During the trial’s first 6 months, AARs and annual rates of new/enlarging T2 lesions were nominally lower in inebilizumab-treated V allele participants compared with the F/F allele participants, although the differences were not statistically significant.

The AAR was 0.1 for the V allele group vs. 0.3 for the F/F allele group (hazard ratio, 0.40; P = .17). The annual rate of new/enlarging T2 lesions was 1.4 vs. 1.7 (risk ratio, 0.91; P = .88), respectively.

However, at the end of the randomized controlled period, there were no significant differences between the two genotype groups. There was also little difference in clinical metrics of NMOSD activity or B-cell depletion between the two genotype groups during the open-label period involving the long-term repeated inebilizumab dosing.

“Though greater B-cell depletion was observed in inebilizumab-treated V allele participants, compared with F/F participants during the first 6 months, no significant difference in NMOSD activity was observed during this time period,” the investigators reported.

“No differences in B-cell depletion or NMOSD disease activity were observed after 6 months of inebilizumab treatment,” they added.

Dr. Cree noted the study showed that, overall, inebiluzumab’s efficacy was not adversely affected by a polymorphism in the Fc gamma receptor. “These types of genetic analyses may help inform future screening mechanisms to tailor treatment strategies that can optimize the response rate for each patient,” he said.

Dr. Cree added the higher degree of disease activity among those carrying the alleles at baseline is notable and deserves further investigation. That finding “suggests that the presence of the F/F allele is to some extent protective of the detrimental effects the auto-antibody directed against aquaporin-4 that underlies NMOSD pathogenesis,” he said.
 

A new era?

Commenting on the study, Marcelo Matiello, MD, assistant professor of neurology at Harvard Medical School and associate director of the Neuromyelitis Optica clinic at Massachusetts General Hospital, both in Boston, said the findings provide valuable insights into risks for key patient subgroups.

“The data is quite important because we know that with other conditions, such as rheumatoid arthritis, people with this particular genotype do have lower response and are more likely to be refractory,” said Dr. Matiello, who was not involved with the research.

He noted that rituximab is the most commonly used medication in the United States for NMOSD. “It’s not FDA approved, but because of extensive experience, and many case series and small prospective studies, most NMO patients are using rituximab,” Dr. Matiello said. However, the drug’s mechanism “can be compromised” by the F/F allele, he added.

The new findings “provide a good understanding that this medication would likely be superior to patients with this genotype,” he said.

“I think it’s a new era,” Dr. Matiello added. “Not only do we have approved medication for this very severe disease, but we can find out who can benefit most. So, I think this is exciting and is a major step in more individualized appropriate use.”

The study was funded by Horizon Therapeutics. Dr. Cree has consulted for Horizon Therapeutics. Dr. Matiello reported no relevant financial relationships.

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