TBD Meeting (5317-20)

“It is time that the prodromal phase of multiple sclerosis [MS] is formally recognized.” That was the conclusion of Helen Tremlett, PhD, delivering the opening plenary session lecture at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

“There is now no doubt that there is an MS prodrome measurable by increased healthcare usage and lifestyle changes that are recognizable 5-10 years before the clinical recognition of MS. There is a myriad of prodromal features but none that are specific to MS,” Dr. Tremlett said.

“These findings show that in future there could be an earlier window of opportunity to identify and manage MS,” she suggested.

In an interview, Dr. Tremlett, who is professor and Canada Research Chair in Neuroepidemiology and Multiple Sclerosis at the University of British Columbia, Vancouver, explained that for MS a prodrome is a relatively new concept. “Right up until the year 2000, MS leaders were specifically saying that a prodrome did not exist,” she said. “But things have changed. Studies started emerging in the last decade suggestive of a prodrome, and I think we can now say there is definitely proof that a prodrome does exist. If you ask MS patients, the vast majority of them will say they had an increase in health issues in the years before diagnosis.”

In her plenary talk, Dr. Tremlett summarized the available evidence showing that, in the years before the first demyelinating event, patients are more likely to be have multiple health issues and an increase in hospitalizations and physician visits.

In a 2018 study, her group analyzed data from four Canadian provinces, including 14,000 patients with MS and 75,000 matched controls, and found a 75% increase in the rate of hospitalization, a 88% higher rate of physician service use, and a 49% increase in prescription numbers in the 5 years before the first demyelinating event in the patients with MS, compared with controls.

This included a 50% increase in mental health visits to physicians and increased rates of fibromyalgia, pain, headache, migraine, sleep disturbances, urology, and dermatology referrals, as well as irritable bowel syndrome. In addition, there were fewer pregnancies and increased prescriptions for contraception in the female patients later diagnosed with MS.

“There is a huge range of nonspecific symptoms in the 5 years before MS diagnosis, and some of these are really intriguing and unanticipated,” Dr. Tremlett said. “We are not surprised by the findings that fatigue, mental health issues, and bladder and bowel symptoms are increased, but the finding that there are more visits to a dermatologist and an increase in prescriptions for skin conditions was completely unexpected.”

The researchers found that dermatology referrals increased in patients who went on to develop relapsing remitting but not primary progressive forms of MS, which correlates with the established knowledge that the relapsing form has an inflammatory component not seen in progressive MS.

In a large U.K. population study of 10,000 patients with MS and 39,000 matched controls sourced from primary care doctors’ records, there was an increase in gastrointestinal and urinary issues, pain, anxiety and depression, insomnia, and fatigue in the 10 years before the first diagnosis of MS or clinically isolated syndrome (CIS) in patients later diagnosed with those conditions, compared with controls, Dr. Tremlett reported.

Other data have suggested that sex and age may affect the prodrome. In a study published this year, anemia was increased in the year before the first demyelinating event and pain was increased for 5 years beforehand. But anemia was more common in male patients later diagnosed with MS/CIS (odds ratio compared with controls, 2.4) than in female patients (OR compared with controls, 1.2).

The increase in pain seemed to be greater with age, with ORs of 1.8 for those younger than 30 years, 2.1 for those age 30-49 years, and 2.4 for those older than 50 years compared with controls.

A Norwegian military study in men that included 900 patients with MS and 19,000 matched controls found that cognitive performance was reduced in the 2 years before MS symptoms developed and up to 20 years before symptoms in those who developed primary progressive MS. “This suggests that primary progressive MS could start decades before the first apparent symptoms become obvious,” Dr. Tremlett commented.

A study in pediatric MS found that the mothers of the patients had higher use of health care (rate ratio, 1.16) and mental health (rate ratio, 1.33) services in the 5 years before their children had their first demyelinating event.

A study in Bavaria, Germany, including 10,000 patients with MS and 73,000 controls, concluded that “many physician visits before MS diagnosis were, in hindsight, likely a demyelinating event,” with the implication that this is evidence of missed opportunity for earlier diagnosis, Dr. Tremlett noted.

In a 2019 study, psychiatric symptoms were more common before MS diagnosis across various different immune-mediated disease (MS, rheumatoid arthritis, inflammatory bowel disease), with an incidence rate ratio of 1.6. The rate was even increased 10 years before diagnosis (incidence rate ratio, 1.5).

“This is evidence for shared prodromal features across immune diseases, but there isn’t a single feature specific to MS,” Dr. Tremlett said. She also referred to evidence that the blood biomarker of neuronal damage, neurofilament light chain (NfL), is raised several years before MS diagnosis. In a U.S. military study that examined serum repository samples, NfL was increased for 6 years before disease onset in 30 patients with MS, compared with 30 matched controls.
 

What are the implications?

Dr. Tremlett said the immediate impact of these observations about the prodrome is focused on research, particularly investigation of risk factors for MS. “If we want to know what causes MS, we have to be very careful that we are not detecting prodromal symptoms and mistaking that for a causal MS risk factor. We need to make sure we look further back than just the last few years when looking for risk factors.”

She gave the example of the observation that women in the years before MS diagnosis are less likely to have a pregnancy and more likely to fill a prescription for contraception. “This has led to the idea that avoiding pregnancy and using contraceptives increases the risk of MS, but I interpret it as these women know that something odd is going on and make the lifestyle decision not to become pregnant.”

She believes the longer-term impact of the prodrome is going to require much thought. “There is no such diagnosis of prodromal MS at the moment, but there could be in future. But the idea that we can use this information to detect MS earlier is going to require collaboration from many international stakeholders and MS organizations. We can’t automatically suspect MS in people who have these symptoms because they are so nonspecific. I think to request an MRI in patients experiencing headaches/fatigue/bowel issues is jumping the gun at the present moment as these symptoms are very common.”

On the idea of measuring NfL in patients with some of these symptoms, she believes that may be a possibility in the future but much more data are required.“We do have some evidence suggesting that the NfL blood biomarker is raised before MS diagnosis, and this was from a very well-designed study, but it was small so I think it is too early to start looking at this in clinical practice,” she said. “But it does justify doing this as part of a research study. We definitely need more data on this. We must be cautious as NfL is not specific for MS – many other conditions are also associated with raised levels, but it is certainly an interesting marker if used carefully.”
 

Following in the footsteps of Parkinson disease

She suggested that the way forward will be to package up these symptoms with information on biomarkers, such as NfL and imaging information, to enhance the ability to identify prodromal MS. “We could create a risk score and when a certain level of confidence is reached that this could be prodromal MS, then these patients could be enrolled in an intervention research study.”

Dr. Tremlett pointed out that, in the Parkinson disease field, a set of validated criteria for a prodrome have already been identified. “This is not used in clinical practice yet, but it is being used to identify patients for enrollment into clinical trials. I’m hoping that MS will follow in their footsteps.”

Commenting on the presentation, ACTRIMS president, Jeffrey Cohen, MD, Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, said: “There is no doubt that the MS disease process begins prior to the first attack (in the case of relapsing MS) or the onset of overt disability progression (in the case of primary progressive MS).”

He explained that this is demonstrated by the presence of old lesions on MRI in most patients at the time of presentation, the existence of so-called radiologically isolated syndrome (patients without symptoms of MS who undergo MRI for another reason and are found to have lesions suggesting of MS, many of whom go on to develop MS at a later date), and the occurrence of a variety of symptoms 5-10 years before presentation to a neurologist.

“Those symptoms are ones that are common in MS, though not specific for MS,” Dr. Cohen noted. “The main implication is that the timeline for MS needs to be moved earlier – for diagnosis, categorization of disease course, prognostic studies, and treatment. The issue is that the symptoms of the prodrome are rather nonspecific and most people with those symptoms do not have MS.”

New incoming president of ECTRIMS, Maria Pia Amato, MD, professor of neurology at the University of Florence (Italy), added: “The million-dollar question is when does progression really begin? This plenary talk tells us the disease is there years and years before it manifests itself with first demyelinating event. This opens up an immense opportunity for research and to open the window to the possibility of earlier diagnosis and treatment.”

Dr. Tremlett reports an investment in Precision NanoSystems.

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

“It is time that the prodromal phase of multiple sclerosis [MS] is formally recognized.” That was the conclusion of Helen Tremlett, PhD, delivering the opening plenary session lecture at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

“There is now no doubt that there is an MS prodrome measurable by increased healthcare usage and lifestyle changes that are recognizable 5-10 years before the clinical recognition of MS. There is a myriad of prodromal features but none that are specific to MS,” Dr. Tremlett said.

“These findings show that in future there could be an earlier window of opportunity to identify and manage MS,” she suggested.

In an interview, Dr. Tremlett, who is professor and Canada Research Chair in Neuroepidemiology and Multiple Sclerosis at the University of British Columbia, Vancouver, explained that for MS a prodrome is a relatively new concept. “Right up until the year 2000, MS leaders were specifically saying that a prodrome did not exist,” she said. “But things have changed. Studies started emerging in the last decade suggestive of a prodrome, and I think we can now say there is definitely proof that a prodrome does exist. If you ask MS patients, the vast majority of them will say they had an increase in health issues in the years before diagnosis.”

In her plenary talk, Dr. Tremlett summarized the available evidence showing that, in the years before the first demyelinating event, patients are more likely to be have multiple health issues and an increase in hospitalizations and physician visits.

In a 2018 study, her group analyzed data from four Canadian provinces, including 14,000 patients with MS and 75,000 matched controls, and found a 75% increase in the rate of hospitalization, a 88% higher rate of physician service use, and a 49% increase in prescription numbers in the 5 years before the first demyelinating event in the patients with MS, compared with controls.

This included a 50% increase in mental health visits to physicians and increased rates of fibromyalgia, pain, headache, migraine, sleep disturbances, urology, and dermatology referrals, as well as irritable bowel syndrome. In addition, there were fewer pregnancies and increased prescriptions for contraception in the female patients later diagnosed with MS.

“There is a huge range of nonspecific symptoms in the 5 years before MS diagnosis, and some of these are really intriguing and unanticipated,” Dr. Tremlett said. “We are not surprised by the findings that fatigue, mental health issues, and bladder and bowel symptoms are increased, but the finding that there are more visits to a dermatologist and an increase in prescriptions for skin conditions was completely unexpected.”

The researchers found that dermatology referrals increased in patients who went on to develop relapsing remitting but not primary progressive forms of MS, which correlates with the established knowledge that the relapsing form has an inflammatory component not seen in progressive MS.

In a large U.K. population study of 10,000 patients with MS and 39,000 matched controls sourced from primary care doctors’ records, there was an increase in gastrointestinal and urinary issues, pain, anxiety and depression, insomnia, and fatigue in the 10 years before the first diagnosis of MS or clinically isolated syndrome (CIS) in patients later diagnosed with those conditions, compared with controls, Dr. Tremlett reported.

Other data have suggested that sex and age may affect the prodrome. In a study published this year, anemia was increased in the year before the first demyelinating event and pain was increased for 5 years beforehand. But anemia was more common in male patients later diagnosed with MS/CIS (odds ratio compared with controls, 2.4) than in female patients (OR compared with controls, 1.2).

The increase in pain seemed to be greater with age, with ORs of 1.8 for those younger than 30 years, 2.1 for those age 30-49 years, and 2.4 for those older than 50 years compared with controls.

A Norwegian military study in men that included 900 patients with MS and 19,000 matched controls found that cognitive performance was reduced in the 2 years before MS symptoms developed and up to 20 years before symptoms in those who developed primary progressive MS. “This suggests that primary progressive MS could start decades before the first apparent symptoms become obvious,” Dr. Tremlett commented.

A study in pediatric MS found that the mothers of the patients had higher use of health care (rate ratio, 1.16) and mental health (rate ratio, 1.33) services in the 5 years before their children had their first demyelinating event.

A study in Bavaria, Germany, including 10,000 patients with MS and 73,000 controls, concluded that “many physician visits before MS diagnosis were, in hindsight, likely a demyelinating event,” with the implication that this is evidence of missed opportunity for earlier diagnosis, Dr. Tremlett noted.

In a 2019 study, psychiatric symptoms were more common before MS diagnosis across various different immune-mediated disease (MS, rheumatoid arthritis, inflammatory bowel disease), with an incidence rate ratio of 1.6. The rate was even increased 10 years before diagnosis (incidence rate ratio, 1.5).

“This is evidence for shared prodromal features across immune diseases, but there isn’t a single feature specific to MS,” Dr. Tremlett said. She also referred to evidence that the blood biomarker of neuronal damage, neurofilament light chain (NfL), is raised several years before MS diagnosis. In a U.S. military study that examined serum repository samples, NfL was increased for 6 years before disease onset in 30 patients with MS, compared with 30 matched controls.
 

What are the implications?

Dr. Tremlett said the immediate impact of these observations about the prodrome is focused on research, particularly investigation of risk factors for MS. “If we want to know what causes MS, we have to be very careful that we are not detecting prodromal symptoms and mistaking that for a causal MS risk factor. We need to make sure we look further back than just the last few years when looking for risk factors.”

She gave the example of the observation that women in the years before MS diagnosis are less likely to have a pregnancy and more likely to fill a prescription for contraception. “This has led to the idea that avoiding pregnancy and using contraceptives increases the risk of MS, but I interpret it as these women know that something odd is going on and make the lifestyle decision not to become pregnant.”

She believes the longer-term impact of the prodrome is going to require much thought. “There is no such diagnosis of prodromal MS at the moment, but there could be in future. But the idea that we can use this information to detect MS earlier is going to require collaboration from many international stakeholders and MS organizations. We can’t automatically suspect MS in people who have these symptoms because they are so nonspecific. I think to request an MRI in patients experiencing headaches/fatigue/bowel issues is jumping the gun at the present moment as these symptoms are very common.”

On the idea of measuring NfL in patients with some of these symptoms, she believes that may be a possibility in the future but much more data are required.“We do have some evidence suggesting that the NfL blood biomarker is raised before MS diagnosis, and this was from a very well-designed study, but it was small so I think it is too early to start looking at this in clinical practice,” she said. “But it does justify doing this as part of a research study. We definitely need more data on this. We must be cautious as NfL is not specific for MS – many other conditions are also associated with raised levels, but it is certainly an interesting marker if used carefully.”
 

Following in the footsteps of Parkinson disease

She suggested that the way forward will be to package up these symptoms with information on biomarkers, such as NfL and imaging information, to enhance the ability to identify prodromal MS. “We could create a risk score and when a certain level of confidence is reached that this could be prodromal MS, then these patients could be enrolled in an intervention research study.”

Dr. Tremlett pointed out that, in the Parkinson disease field, a set of validated criteria for a prodrome have already been identified. “This is not used in clinical practice yet, but it is being used to identify patients for enrollment into clinical trials. I’m hoping that MS will follow in their footsteps.”

Commenting on the presentation, ACTRIMS president, Jeffrey Cohen, MD, Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, said: “There is no doubt that the MS disease process begins prior to the first attack (in the case of relapsing MS) or the onset of overt disability progression (in the case of primary progressive MS).”

He explained that this is demonstrated by the presence of old lesions on MRI in most patients at the time of presentation, the existence of so-called radiologically isolated syndrome (patients without symptoms of MS who undergo MRI for another reason and are found to have lesions suggesting of MS, many of whom go on to develop MS at a later date), and the occurrence of a variety of symptoms 5-10 years before presentation to a neurologist.

“Those symptoms are ones that are common in MS, though not specific for MS,” Dr. Cohen noted. “The main implication is that the timeline for MS needs to be moved earlier – for diagnosis, categorization of disease course, prognostic studies, and treatment. The issue is that the symptoms of the prodrome are rather nonspecific and most people with those symptoms do not have MS.”

New incoming president of ECTRIMS, Maria Pia Amato, MD, professor of neurology at the University of Florence (Italy), added: “The million-dollar question is when does progression really begin? This plenary talk tells us the disease is there years and years before it manifests itself with first demyelinating event. This opens up an immense opportunity for research and to open the window to the possibility of earlier diagnosis and treatment.”

Dr. Tremlett reports an investment in Precision NanoSystems.

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

“It is time that the prodromal phase of multiple sclerosis [MS] is formally recognized.” That was the conclusion of Helen Tremlett, PhD, delivering the opening plenary session lecture at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

“There is now no doubt that there is an MS prodrome measurable by increased healthcare usage and lifestyle changes that are recognizable 5-10 years before the clinical recognition of MS. There is a myriad of prodromal features but none that are specific to MS,” Dr. Tremlett said.

“These findings show that in future there could be an earlier window of opportunity to identify and manage MS,” she suggested.

In an interview, Dr. Tremlett, who is professor and Canada Research Chair in Neuroepidemiology and Multiple Sclerosis at the University of British Columbia, Vancouver, explained that for MS a prodrome is a relatively new concept. “Right up until the year 2000, MS leaders were specifically saying that a prodrome did not exist,” she said. “But things have changed. Studies started emerging in the last decade suggestive of a prodrome, and I think we can now say there is definitely proof that a prodrome does exist. If you ask MS patients, the vast majority of them will say they had an increase in health issues in the years before diagnosis.”

In her plenary talk, Dr. Tremlett summarized the available evidence showing that, in the years before the first demyelinating event, patients are more likely to be have multiple health issues and an increase in hospitalizations and physician visits.

In a 2018 study, her group analyzed data from four Canadian provinces, including 14,000 patients with MS and 75,000 matched controls, and found a 75% increase in the rate of hospitalization, a 88% higher rate of physician service use, and a 49% increase in prescription numbers in the 5 years before the first demyelinating event in the patients with MS, compared with controls.

This included a 50% increase in mental health visits to physicians and increased rates of fibromyalgia, pain, headache, migraine, sleep disturbances, urology, and dermatology referrals, as well as irritable bowel syndrome. In addition, there were fewer pregnancies and increased prescriptions for contraception in the female patients later diagnosed with MS.

“There is a huge range of nonspecific symptoms in the 5 years before MS diagnosis, and some of these are really intriguing and unanticipated,” Dr. Tremlett said. “We are not surprised by the findings that fatigue, mental health issues, and bladder and bowel symptoms are increased, but the finding that there are more visits to a dermatologist and an increase in prescriptions for skin conditions was completely unexpected.”

The researchers found that dermatology referrals increased in patients who went on to develop relapsing remitting but not primary progressive forms of MS, which correlates with the established knowledge that the relapsing form has an inflammatory component not seen in progressive MS.

In a large U.K. population study of 10,000 patients with MS and 39,000 matched controls sourced from primary care doctors’ records, there was an increase in gastrointestinal and urinary issues, pain, anxiety and depression, insomnia, and fatigue in the 10 years before the first diagnosis of MS or clinically isolated syndrome (CIS) in patients later diagnosed with those conditions, compared with controls, Dr. Tremlett reported.

Other data have suggested that sex and age may affect the prodrome. In a study published this year, anemia was increased in the year before the first demyelinating event and pain was increased for 5 years beforehand. But anemia was more common in male patients later diagnosed with MS/CIS (odds ratio compared with controls, 2.4) than in female patients (OR compared with controls, 1.2).

The increase in pain seemed to be greater with age, with ORs of 1.8 for those younger than 30 years, 2.1 for those age 30-49 years, and 2.4 for those older than 50 years compared with controls.

A Norwegian military study in men that included 900 patients with MS and 19,000 matched controls found that cognitive performance was reduced in the 2 years before MS symptoms developed and up to 20 years before symptoms in those who developed primary progressive MS. “This suggests that primary progressive MS could start decades before the first apparent symptoms become obvious,” Dr. Tremlett commented.

A study in pediatric MS found that the mothers of the patients had higher use of health care (rate ratio, 1.16) and mental health (rate ratio, 1.33) services in the 5 years before their children had their first demyelinating event.

A study in Bavaria, Germany, including 10,000 patients with MS and 73,000 controls, concluded that “many physician visits before MS diagnosis were, in hindsight, likely a demyelinating event,” with the implication that this is evidence of missed opportunity for earlier diagnosis, Dr. Tremlett noted.

In a 2019 study, psychiatric symptoms were more common before MS diagnosis across various different immune-mediated disease (MS, rheumatoid arthritis, inflammatory bowel disease), with an incidence rate ratio of 1.6. The rate was even increased 10 years before diagnosis (incidence rate ratio, 1.5).

“This is evidence for shared prodromal features across immune diseases, but there isn’t a single feature specific to MS,” Dr. Tremlett said. She also referred to evidence that the blood biomarker of neuronal damage, neurofilament light chain (NfL), is raised several years before MS diagnosis. In a U.S. military study that examined serum repository samples, NfL was increased for 6 years before disease onset in 30 patients with MS, compared with 30 matched controls.
 

What are the implications?

Dr. Tremlett said the immediate impact of these observations about the prodrome is focused on research, particularly investigation of risk factors for MS. “If we want to know what causes MS, we have to be very careful that we are not detecting prodromal symptoms and mistaking that for a causal MS risk factor. We need to make sure we look further back than just the last few years when looking for risk factors.”

She gave the example of the observation that women in the years before MS diagnosis are less likely to have a pregnancy and more likely to fill a prescription for contraception. “This has led to the idea that avoiding pregnancy and using contraceptives increases the risk of MS, but I interpret it as these women know that something odd is going on and make the lifestyle decision not to become pregnant.”

She believes the longer-term impact of the prodrome is going to require much thought. “There is no such diagnosis of prodromal MS at the moment, but there could be in future. But the idea that we can use this information to detect MS earlier is going to require collaboration from many international stakeholders and MS organizations. We can’t automatically suspect MS in people who have these symptoms because they are so nonspecific. I think to request an MRI in patients experiencing headaches/fatigue/bowel issues is jumping the gun at the present moment as these symptoms are very common.”

On the idea of measuring NfL in patients with some of these symptoms, she believes that may be a possibility in the future but much more data are required.“We do have some evidence suggesting that the NfL blood biomarker is raised before MS diagnosis, and this was from a very well-designed study, but it was small so I think it is too early to start looking at this in clinical practice,” she said. “But it does justify doing this as part of a research study. We definitely need more data on this. We must be cautious as NfL is not specific for MS – many other conditions are also associated with raised levels, but it is certainly an interesting marker if used carefully.”
 

Following in the footsteps of Parkinson disease

She suggested that the way forward will be to package up these symptoms with information on biomarkers, such as NfL and imaging information, to enhance the ability to identify prodromal MS. “We could create a risk score and when a certain level of confidence is reached that this could be prodromal MS, then these patients could be enrolled in an intervention research study.”

Dr. Tremlett pointed out that, in the Parkinson disease field, a set of validated criteria for a prodrome have already been identified. “This is not used in clinical practice yet, but it is being used to identify patients for enrollment into clinical trials. I’m hoping that MS will follow in their footsteps.”

Commenting on the presentation, ACTRIMS president, Jeffrey Cohen, MD, Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, said: “There is no doubt that the MS disease process begins prior to the first attack (in the case of relapsing MS) or the onset of overt disability progression (in the case of primary progressive MS).”

He explained that this is demonstrated by the presence of old lesions on MRI in most patients at the time of presentation, the existence of so-called radiologically isolated syndrome (patients without symptoms of MS who undergo MRI for another reason and are found to have lesions suggesting of MS, many of whom go on to develop MS at a later date), and the occurrence of a variety of symptoms 5-10 years before presentation to a neurologist.

“Those symptoms are ones that are common in MS, though not specific for MS,” Dr. Cohen noted. “The main implication is that the timeline for MS needs to be moved earlier – for diagnosis, categorization of disease course, prognostic studies, and treatment. The issue is that the symptoms of the prodrome are rather nonspecific and most people with those symptoms do not have MS.”

New incoming president of ECTRIMS, Maria Pia Amato, MD, professor of neurology at the University of Florence (Italy), added: “The million-dollar question is when does progression really begin? This plenary talk tells us the disease is there years and years before it manifests itself with first demyelinating event. This opens up an immense opportunity for research and to open the window to the possibility of earlier diagnosis and treatment.”

Dr. Tremlett reports an investment in Precision NanoSystems.

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

A high level of glial fibrillary acidic protein (GFAP) in the blood may predict worsening disability in patients with secondary progressive multiple sclerosis (MS), according to investigators. The biomarker appears to have a stronger correlation with disability in people with nonactive disease, compared with those with active disease. These data were presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Astroglial injury and activation is one of the characteristic features of progressive MS. Following such injury, GFAP is released into the cerebrospinal fluid and blood.

“It may be that GFAP plays an especially important role in patients without focal inflammatory activity and is more associated with insidious progression,” said Jens Kuhle, MD, PhD, head of the MS center at University Hospital Basel (Switzerland). “This [finding] needs to be investigated further within the same cohort, but also [within] additional well-characterized other cohorts.”

Dr. Kuhle and colleagues examined GFAP as a prognostic biomarker of disability worsening by analyzing data for patients with active or nonactive secondary progressive MS who participated in the phase 3 EXPAND study, which compared siponimod with placebo. In this post hoc analysis, the investigators quantified baseline GFAP in plasma samples using single-molecule array technology. They categorized GFAP as high or low according to the gender-stratified 80th percentile.

Dr. Kuhle’s group assessed the effect of GFAP on time to an Expanded Disability Status Scale score of 7 (i.e., restriction to wheelchair) using a Cox regression model adjusted for age, gender, disease duration, treatment, relapses in the 24 months prior to study start, and baseline EDSS. In addition, they performed subgroup analyses in patients with active secondary progressive MS and those with nonactive secondary progressive MS. They defined active disease as having relapses at 24 or fewer months before study entry or gadolinium-enhancing T1 lesions at baseline. Participants without these characteristics were classified as having nonactive disease. The investigators also stratified the results by gender.
 

Correlation was strongest in nonactive disease

The current analysis included samples for 1,405 of the 1,651 patients who had been randomly assigned to treatment in the EXPAND study. The median GFAP level was 119.6 pg/mL among men and 141.4 pg/mL among women.

The risk of reaching an EDSS score of 7 was higher in patients with a high baseline GFAP level. Of 281 (12.1%) participants with a high baseline GFAP level, 34 reached this endpoint, compared with 54 of 1,117 (4.8%) participants with a low baseline GFAP level. For patients with a high GFAP level at baseline, the hazard ratio of this outcome was 1.96.

Subgroup analyses indicated that the increased risk of reaching an EDSS score of 7 was seen mainly in women. Of 169 women (13.6%) with high baseline GFAP level, 23 reached this endpoint, compared with 34 of 673 women (5.1%) without a high baseline GFAP level (HR, 2.22). Among men, the difference was not significant. Of 112 men (9.8%) with a high baseline GFAP level, 11 reached an EDSS score of 7, compared with 20 of 444 men (4.5%) without a high baseline GFAP level (HR, 1.45). The reason for this sex difference is unknown, said Dr. Kuhle. “A next important step is to ensure this [finding] is not influenced by other hidden factors.”

Dr. Kuhle and colleagues also found that the increase in risk of reaching an EDSS score of 7 was mainly observed in patients with nonactive secondary progressive MS. Among 133 such patients with a high baseline GFAP level, 14 (10.5%) reached this endpoint, compared with 22 of 570 patients (3.9%) without a high baseline GFAP level (HR, 3.40). The difference among patients with active secondary progressive MS was not significant (20 of 144 patients [13.9%] with high baseline GFAP level, compared with 30 of 521 patients [5.8%] without a high baseline GFAP level; HR, 1.58). Dr. Kuhle and colleagues found similar trends in the associations between baseline GFAP levels and time to 6-month confirmed disability progression, but these trends were less pronounced.

“The measurement of plasma or blood neurofilament light chain [NfL] is certainly closer to a potential clinical application than [the measurement of] GFAP,” Dr. Kuhle admitted. “However, highly sensitive platforms open the field to the fascinating possibility of finding meaningful biomarkers in the blood compartment in MS.” This development should be developed further. It is necessary to validate the significance of GFAP measures in individual patients and describe them with greater precision before they can be applied clinically. It also is necessary to create normative data and explore for the impact of other variables like age and comorbidities, he added.

“We are currently analyzing the EXPAND data further to see which characteristics at baseline and at end of study are driving plasma GFAP concentrations,” said Dr. Kuhle. “We also need to investigate whether progression events are captured accurately by GFAP in plasma. It will also be important to combine the GFAP data with NfL measures that are already available in this cohort.”
 

Study addresses a clinical need

“There is great need for a reliable, easy-to-measure, and relevant fluid biomarker for use in MS,” said Robert J. Fox, MD, staff neurologist at the Cleveland Clinic’s Mellen Center for MS. Neurofilaments have been a leading candidate among biomarkers, but researchers are exploring other candidates as well. An advantage of the present study is that Dr. Kuhle and colleagues examined a large number of patients with secondary progressive MS who underwent highly structured follow-up over several years, Dr. Fox said.

“What is most interesting is that the predictive capacity was greater in nonrelapsing secondary progressive MS, and so may have advantages over neurofilament in this group of patients,” he added. “Currently, GFAP is a research test and isn’t available for clinical practice.”

Researchers should investigate other ways in which GFAP is related to future disease activity (e.g., in the form of relapses or new MRI lesions) as well as to other measures of disability progression besides restriction to a wheelchair, said Dr. Fox. “Future research needs to examine whether this biomarker is helpful at the individual patient level. Can it guide a patient’s clinician toward treatment recommendations?”

This study was funded by Novartis. Neither Dr. Kuhle nor Dr. Fox had no relevant disclosures to report.

egreb@mdedge.com

This article was updated 9/14/2020.

A high level of glial fibrillary acidic protein (GFAP) in the blood may predict worsening disability in patients with secondary progressive multiple sclerosis (MS), according to investigators. The biomarker appears to have a stronger correlation with disability in people with nonactive disease, compared with those with active disease. These data were presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Astroglial injury and activation is one of the characteristic features of progressive MS. Following such injury, GFAP is released into the cerebrospinal fluid and blood.

“It may be that GFAP plays an especially important role in patients without focal inflammatory activity and is more associated with insidious progression,” said Jens Kuhle, MD, PhD, head of the MS center at University Hospital Basel (Switzerland). “This [finding] needs to be investigated further within the same cohort, but also [within] additional well-characterized other cohorts.”

Dr. Kuhle and colleagues examined GFAP as a prognostic biomarker of disability worsening by analyzing data for patients with active or nonactive secondary progressive MS who participated in the phase 3 EXPAND study, which compared siponimod with placebo. In this post hoc analysis, the investigators quantified baseline GFAP in plasma samples using single-molecule array technology. They categorized GFAP as high or low according to the gender-stratified 80th percentile.

Dr. Kuhle’s group assessed the effect of GFAP on time to an Expanded Disability Status Scale score of 7 (i.e., restriction to wheelchair) using a Cox regression model adjusted for age, gender, disease duration, treatment, relapses in the 24 months prior to study start, and baseline EDSS. In addition, they performed subgroup analyses in patients with active secondary progressive MS and those with nonactive secondary progressive MS. They defined active disease as having relapses at 24 or fewer months before study entry or gadolinium-enhancing T1 lesions at baseline. Participants without these characteristics were classified as having nonactive disease. The investigators also stratified the results by gender.
 

Correlation was strongest in nonactive disease

The current analysis included samples for 1,405 of the 1,651 patients who had been randomly assigned to treatment in the EXPAND study. The median GFAP level was 119.6 pg/mL among men and 141.4 pg/mL among women.

The risk of reaching an EDSS score of 7 was higher in patients with a high baseline GFAP level. Of 281 (12.1%) participants with a high baseline GFAP level, 34 reached this endpoint, compared with 54 of 1,117 (4.8%) participants with a low baseline GFAP level. For patients with a high GFAP level at baseline, the hazard ratio of this outcome was 1.96.

Subgroup analyses indicated that the increased risk of reaching an EDSS score of 7 was seen mainly in women. Of 169 women (13.6%) with high baseline GFAP level, 23 reached this endpoint, compared with 34 of 673 women (5.1%) without a high baseline GFAP level (HR, 2.22). Among men, the difference was not significant. Of 112 men (9.8%) with a high baseline GFAP level, 11 reached an EDSS score of 7, compared with 20 of 444 men (4.5%) without a high baseline GFAP level (HR, 1.45). The reason for this sex difference is unknown, said Dr. Kuhle. “A next important step is to ensure this [finding] is not influenced by other hidden factors.”

Dr. Kuhle and colleagues also found that the increase in risk of reaching an EDSS score of 7 was mainly observed in patients with nonactive secondary progressive MS. Among 133 such patients with a high baseline GFAP level, 14 (10.5%) reached this endpoint, compared with 22 of 570 patients (3.9%) without a high baseline GFAP level (HR, 3.40). The difference among patients with active secondary progressive MS was not significant (20 of 144 patients [13.9%] with high baseline GFAP level, compared with 30 of 521 patients [5.8%] without a high baseline GFAP level; HR, 1.58). Dr. Kuhle and colleagues found similar trends in the associations between baseline GFAP levels and time to 6-month confirmed disability progression, but these trends were less pronounced.

“The measurement of plasma or blood neurofilament light chain [NfL] is certainly closer to a potential clinical application than [the measurement of] GFAP,” Dr. Kuhle admitted. “However, highly sensitive platforms open the field to the fascinating possibility of finding meaningful biomarkers in the blood compartment in MS.” This development should be developed further. It is necessary to validate the significance of GFAP measures in individual patients and describe them with greater precision before they can be applied clinically. It also is necessary to create normative data and explore for the impact of other variables like age and comorbidities, he added.

“We are currently analyzing the EXPAND data further to see which characteristics at baseline and at end of study are driving plasma GFAP concentrations,” said Dr. Kuhle. “We also need to investigate whether progression events are captured accurately by GFAP in plasma. It will also be important to combine the GFAP data with NfL measures that are already available in this cohort.”
 

Study addresses a clinical need

“There is great need for a reliable, easy-to-measure, and relevant fluid biomarker for use in MS,” said Robert J. Fox, MD, staff neurologist at the Cleveland Clinic’s Mellen Center for MS. Neurofilaments have been a leading candidate among biomarkers, but researchers are exploring other candidates as well. An advantage of the present study is that Dr. Kuhle and colleagues examined a large number of patients with secondary progressive MS who underwent highly structured follow-up over several years, Dr. Fox said.

“What is most interesting is that the predictive capacity was greater in nonrelapsing secondary progressive MS, and so may have advantages over neurofilament in this group of patients,” he added. “Currently, GFAP is a research test and isn’t available for clinical practice.”

Researchers should investigate other ways in which GFAP is related to future disease activity (e.g., in the form of relapses or new MRI lesions) as well as to other measures of disability progression besides restriction to a wheelchair, said Dr. Fox. “Future research needs to examine whether this biomarker is helpful at the individual patient level. Can it guide a patient’s clinician toward treatment recommendations?”

This study was funded by Novartis. Neither Dr. Kuhle nor Dr. Fox had no relevant disclosures to report.

egreb@mdedge.com

This article was updated 9/14/2020.

A high level of glial fibrillary acidic protein (GFAP) in the blood may predict worsening disability in patients with secondary progressive multiple sclerosis (MS), according to investigators. The biomarker appears to have a stronger correlation with disability in people with nonactive disease, compared with those with active disease. These data were presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Astroglial injury and activation is one of the characteristic features of progressive MS. Following such injury, GFAP is released into the cerebrospinal fluid and blood.

“It may be that GFAP plays an especially important role in patients without focal inflammatory activity and is more associated with insidious progression,” said Jens Kuhle, MD, PhD, head of the MS center at University Hospital Basel (Switzerland). “This [finding] needs to be investigated further within the same cohort, but also [within] additional well-characterized other cohorts.”

Dr. Kuhle and colleagues examined GFAP as a prognostic biomarker of disability worsening by analyzing data for patients with active or nonactive secondary progressive MS who participated in the phase 3 EXPAND study, which compared siponimod with placebo. In this post hoc analysis, the investigators quantified baseline GFAP in plasma samples using single-molecule array technology. They categorized GFAP as high or low according to the gender-stratified 80th percentile.

Dr. Kuhle’s group assessed the effect of GFAP on time to an Expanded Disability Status Scale score of 7 (i.e., restriction to wheelchair) using a Cox regression model adjusted for age, gender, disease duration, treatment, relapses in the 24 months prior to study start, and baseline EDSS. In addition, they performed subgroup analyses in patients with active secondary progressive MS and those with nonactive secondary progressive MS. They defined active disease as having relapses at 24 or fewer months before study entry or gadolinium-enhancing T1 lesions at baseline. Participants without these characteristics were classified as having nonactive disease. The investigators also stratified the results by gender.
 

Correlation was strongest in nonactive disease

The current analysis included samples for 1,405 of the 1,651 patients who had been randomly assigned to treatment in the EXPAND study. The median GFAP level was 119.6 pg/mL among men and 141.4 pg/mL among women.

The risk of reaching an EDSS score of 7 was higher in patients with a high baseline GFAP level. Of 281 (12.1%) participants with a high baseline GFAP level, 34 reached this endpoint, compared with 54 of 1,117 (4.8%) participants with a low baseline GFAP level. For patients with a high GFAP level at baseline, the hazard ratio of this outcome was 1.96.

Subgroup analyses indicated that the increased risk of reaching an EDSS score of 7 was seen mainly in women. Of 169 women (13.6%) with high baseline GFAP level, 23 reached this endpoint, compared with 34 of 673 women (5.1%) without a high baseline GFAP level (HR, 2.22). Among men, the difference was not significant. Of 112 men (9.8%) with a high baseline GFAP level, 11 reached an EDSS score of 7, compared with 20 of 444 men (4.5%) without a high baseline GFAP level (HR, 1.45). The reason for this sex difference is unknown, said Dr. Kuhle. “A next important step is to ensure this [finding] is not influenced by other hidden factors.”

Dr. Kuhle and colleagues also found that the increase in risk of reaching an EDSS score of 7 was mainly observed in patients with nonactive secondary progressive MS. Among 133 such patients with a high baseline GFAP level, 14 (10.5%) reached this endpoint, compared with 22 of 570 patients (3.9%) without a high baseline GFAP level (HR, 3.40). The difference among patients with active secondary progressive MS was not significant (20 of 144 patients [13.9%] with high baseline GFAP level, compared with 30 of 521 patients [5.8%] without a high baseline GFAP level; HR, 1.58). Dr. Kuhle and colleagues found similar trends in the associations between baseline GFAP levels and time to 6-month confirmed disability progression, but these trends were less pronounced.

“The measurement of plasma or blood neurofilament light chain [NfL] is certainly closer to a potential clinical application than [the measurement of] GFAP,” Dr. Kuhle admitted. “However, highly sensitive platforms open the field to the fascinating possibility of finding meaningful biomarkers in the blood compartment in MS.” This development should be developed further. It is necessary to validate the significance of GFAP measures in individual patients and describe them with greater precision before they can be applied clinically. It also is necessary to create normative data and explore for the impact of other variables like age and comorbidities, he added.

“We are currently analyzing the EXPAND data further to see which characteristics at baseline and at end of study are driving plasma GFAP concentrations,” said Dr. Kuhle. “We also need to investigate whether progression events are captured accurately by GFAP in plasma. It will also be important to combine the GFAP data with NfL measures that are already available in this cohort.”
 

Study addresses a clinical need

“There is great need for a reliable, easy-to-measure, and relevant fluid biomarker for use in MS,” said Robert J. Fox, MD, staff neurologist at the Cleveland Clinic’s Mellen Center for MS. Neurofilaments have been a leading candidate among biomarkers, but researchers are exploring other candidates as well. An advantage of the present study is that Dr. Kuhle and colleagues examined a large number of patients with secondary progressive MS who underwent highly structured follow-up over several years, Dr. Fox said.

“What is most interesting is that the predictive capacity was greater in nonrelapsing secondary progressive MS, and so may have advantages over neurofilament in this group of patients,” he added. “Currently, GFAP is a research test and isn’t available for clinical practice.”

Researchers should investigate other ways in which GFAP is related to future disease activity (e.g., in the form of relapses or new MRI lesions) as well as to other measures of disability progression besides restriction to a wheelchair, said Dr. Fox. “Future research needs to examine whether this biomarker is helpful at the individual patient level. Can it guide a patient’s clinician toward treatment recommendations?”

This study was funded by Novartis. Neither Dr. Kuhle nor Dr. Fox had no relevant disclosures to report.

egreb@mdedge.com

This article was updated 9/14/2020.

Investigators in Switzerland are testing an application for smartphones that they hope will elucidate subtle signs of disease progression in multiple sclerosis (MS)—beyond what standard imaging and clinical biomarkers can tell them.

At the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020, researchers at the University Hospital and University of Basel in Switzerland, presented data on their dreaMS app. The investigators are validating the app in a nonblinded cohort of 30 people with MS in the early to middle stages of progression and 30 controls without MS.

The application comprises a series of active tests measuring movement, fine motor skills, cognition, and vision, as well as questionnaires to assess quality of life, walking ability, and fatigue in people with Expanded Disability Status Scale (EDSS) scores of 6.5 or lower. A wrist device, used concurrently with the app, passively monitors subjects’ step count, heart rate, and different measures of activity.

If validated, such smartphone-based “digital biomarkers” will provide clinicians and investigators with a steadier flow of information for assessing MS disease progression and informing clinical decision-making. In June, Ludwig Kappos, MD, the app study’s senior researcher, co-authored an analysis of randomized trial data that argued for discarding the standard categories of relapsing and progressive MS in favor of seeing the disease as a continuum, in which progression can and does occur in the absence of relapses.

The digital biomarker work builds on that more unified view of the disease, Dr. Kappos said in an interview.

Outside of disease exacerbations or relapses, “progression can be very difficult to capture, especially in the first stage of the disease because of compensation in the central nervous system,” he said. “Our ability to see these very slight changes during a neurological examination is limited even if we do it very thoroughly. But by having these more frequent assessments we may be able to.”

Smartphone-gleaned biomarkers may have implications for prognosis and for choice of therapy, Dr. Kappos added. “We expect that these digital biomarkers will be even more sensitive and to be able to recognize before severe deficits are evident who is a candidate for a more intensive treatment and who is not.”

At the MSVirtual2020 congress, Dr. Kappos’s colleagues at the university Johannes Lorscheider, MD, and Yvonne Naegelin, MD, presented their feasibility and acceptance study currently underway in 60 volunteers. One of the concerns the investigators have had was whether engaged users would remain with the app. “We have designed the tests as little challenges to help keep people interested—we want to make these tests as appealing as possible,” Dr. Kappos said.

In this study, the reliability of each test is determined by intra-class correlation and median coefficient of variation. Preliminary reliability testing with healthy controls showed intra-class correlation coefficients of greater than 60% for the digital biomarkers and greater than 80% for at least one in every domain.

Once the best tests are selected and the app is fine-tuned, the group intends to embark on larger studies of the digital biomarkers. The next, planned for 2021, will recruit approximately 400 patients from the Swiss MS cohort, whose 1,000-some MS participants are followed with standardized examination and imaging protocols across healthcare centers.

“This is a very well characterized group of patients who are followed continuously with state-of-the-art neurological examinations, high-end MRI, and blood biomarkers,” Dr. Kappos said. “We want to see if we can add value by using digital biomarkers.”

The dreaMS app project is an independent investigator-initiated venture in cooperation with a technological partner. The study was supported by the Swiss Innovation Agency. The University Hospital Basel has received research funding for clinical trials from a number of pharmaceutical manufacturers.

SOURCE: Lorscheider J, et al. MSVirtual2020. Abstract P0069.

Investigators in Switzerland are testing an application for smartphones that they hope will elucidate subtle signs of disease progression in multiple sclerosis (MS)—beyond what standard imaging and clinical biomarkers can tell them.

At the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020, researchers at the University Hospital and University of Basel in Switzerland, presented data on their dreaMS app. The investigators are validating the app in a nonblinded cohort of 30 people with MS in the early to middle stages of progression and 30 controls without MS.

The application comprises a series of active tests measuring movement, fine motor skills, cognition, and vision, as well as questionnaires to assess quality of life, walking ability, and fatigue in people with Expanded Disability Status Scale (EDSS) scores of 6.5 or lower. A wrist device, used concurrently with the app, passively monitors subjects’ step count, heart rate, and different measures of activity.

If validated, such smartphone-based “digital biomarkers” will provide clinicians and investigators with a steadier flow of information for assessing MS disease progression and informing clinical decision-making. In June, Ludwig Kappos, MD, the app study’s senior researcher, co-authored an analysis of randomized trial data that argued for discarding the standard categories of relapsing and progressive MS in favor of seeing the disease as a continuum, in which progression can and does occur in the absence of relapses.

The digital biomarker work builds on that more unified view of the disease, Dr. Kappos said in an interview.

Outside of disease exacerbations or relapses, “progression can be very difficult to capture, especially in the first stage of the disease because of compensation in the central nervous system,” he said. “Our ability to see these very slight changes during a neurological examination is limited even if we do it very thoroughly. But by having these more frequent assessments we may be able to.”

Smartphone-gleaned biomarkers may have implications for prognosis and for choice of therapy, Dr. Kappos added. “We expect that these digital biomarkers will be even more sensitive and to be able to recognize before severe deficits are evident who is a candidate for a more intensive treatment and who is not.”

At the MSVirtual2020 congress, Dr. Kappos’s colleagues at the university Johannes Lorscheider, MD, and Yvonne Naegelin, MD, presented their feasibility and acceptance study currently underway in 60 volunteers. One of the concerns the investigators have had was whether engaged users would remain with the app. “We have designed the tests as little challenges to help keep people interested—we want to make these tests as appealing as possible,” Dr. Kappos said.

In this study, the reliability of each test is determined by intra-class correlation and median coefficient of variation. Preliminary reliability testing with healthy controls showed intra-class correlation coefficients of greater than 60% for the digital biomarkers and greater than 80% for at least one in every domain.

Once the best tests are selected and the app is fine-tuned, the group intends to embark on larger studies of the digital biomarkers. The next, planned for 2021, will recruit approximately 400 patients from the Swiss MS cohort, whose 1,000-some MS participants are followed with standardized examination and imaging protocols across healthcare centers.

“This is a very well characterized group of patients who are followed continuously with state-of-the-art neurological examinations, high-end MRI, and blood biomarkers,” Dr. Kappos said. “We want to see if we can add value by using digital biomarkers.”

The dreaMS app project is an independent investigator-initiated venture in cooperation with a technological partner. The study was supported by the Swiss Innovation Agency. The University Hospital Basel has received research funding for clinical trials from a number of pharmaceutical manufacturers.

SOURCE: Lorscheider J, et al. MSVirtual2020. Abstract P0069.

Investigators in Switzerland are testing an application for smartphones that they hope will elucidate subtle signs of disease progression in multiple sclerosis (MS)—beyond what standard imaging and clinical biomarkers can tell them.

At the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020, researchers at the University Hospital and University of Basel in Switzerland, presented data on their dreaMS app. The investigators are validating the app in a nonblinded cohort of 30 people with MS in the early to middle stages of progression and 30 controls without MS.

The application comprises a series of active tests measuring movement, fine motor skills, cognition, and vision, as well as questionnaires to assess quality of life, walking ability, and fatigue in people with Expanded Disability Status Scale (EDSS) scores of 6.5 or lower. A wrist device, used concurrently with the app, passively monitors subjects’ step count, heart rate, and different measures of activity.

If validated, such smartphone-based “digital biomarkers” will provide clinicians and investigators with a steadier flow of information for assessing MS disease progression and informing clinical decision-making. In June, Ludwig Kappos, MD, the app study’s senior researcher, co-authored an analysis of randomized trial data that argued for discarding the standard categories of relapsing and progressive MS in favor of seeing the disease as a continuum, in which progression can and does occur in the absence of relapses.

The digital biomarker work builds on that more unified view of the disease, Dr. Kappos said in an interview.

Outside of disease exacerbations or relapses, “progression can be very difficult to capture, especially in the first stage of the disease because of compensation in the central nervous system,” he said. “Our ability to see these very slight changes during a neurological examination is limited even if we do it very thoroughly. But by having these more frequent assessments we may be able to.”

Smartphone-gleaned biomarkers may have implications for prognosis and for choice of therapy, Dr. Kappos added. “We expect that these digital biomarkers will be even more sensitive and to be able to recognize before severe deficits are evident who is a candidate for a more intensive treatment and who is not.”

At the MSVirtual2020 congress, Dr. Kappos’s colleagues at the university Johannes Lorscheider, MD, and Yvonne Naegelin, MD, presented their feasibility and acceptance study currently underway in 60 volunteers. One of the concerns the investigators have had was whether engaged users would remain with the app. “We have designed the tests as little challenges to help keep people interested—we want to make these tests as appealing as possible,” Dr. Kappos said.

In this study, the reliability of each test is determined by intra-class correlation and median coefficient of variation. Preliminary reliability testing with healthy controls showed intra-class correlation coefficients of greater than 60% for the digital biomarkers and greater than 80% for at least one in every domain.

Once the best tests are selected and the app is fine-tuned, the group intends to embark on larger studies of the digital biomarkers. The next, planned for 2021, will recruit approximately 400 patients from the Swiss MS cohort, whose 1,000-some MS participants are followed with standardized examination and imaging protocols across healthcare centers.

“This is a very well characterized group of patients who are followed continuously with state-of-the-art neurological examinations, high-end MRI, and blood biomarkers,” Dr. Kappos said. “We want to see if we can add value by using digital biomarkers.”

The dreaMS app project is an independent investigator-initiated venture in cooperation with a technological partner. The study was supported by the Swiss Innovation Agency. The University Hospital Basel has received research funding for clinical trials from a number of pharmaceutical manufacturers.

SOURCE: Lorscheider J, et al. MSVirtual2020. Abstract P0069.

Compared with placebo, satralizumab reduces the risk of severe relapse in patients with neuromyelitis optica spectrum disorder (NMOSD), according to investigators. The drug also was associated with a lower likelihood of using acute relapse therapy.

These results were presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

NMOSD is characterized by acute relapses that are unpredictable and lead to the accumulation of disability. “Patients with NMOSD often recover poorly from relapses, therefore, the primary goal for disease management is to reduce attack frequency,” said Ingo Kleiter, MD, medical director of Marianne-Strauß-Klinik in Berg, Germany. “In the two phase 3 trials SAkuraSky and SAkuraStar, the IL-6 receptor inhibitor satralizumab was found to significantly reduce the risk of relapses versus placebo.” Satralizumab is a humanized, monoclonal, recycling antibody that targets the interleukin-6 receptor.

Dr. Kleiter and colleagues examined pooled data from the two phase 3 trials of satralizumab to determine the treatment’s effect on relapse severity in patients with NMOSD. Participants in those trials received placebo or 120 mg of satralizumab at weeks 0, 2, 4, and every 4 weeks thereafter.

For their research, the investigators analyzed data from the pooled intention-to-treat population in the double-blind periods of both studies. To evaluate the severity of protocol-defined relapses, they compared patients’ Expanded Disability Status Scale (EDSS) scores at the time of relapse with their scores before the relapse (i.e., their scores at the last scheduled study visit). Using the visual Functional Systems Score (FSS), Dr. Kleiter and colleagues performed a similar analysis on optic neuritis relapses. They categorized a protocol-defined relapse as severe if it entailed a change of two or more points on the EDSS or visual FSS. The investigators conducted Kaplan-Meier analyses to evaluate the time to first severe protocol-defined relapse. They also compared the number of patients receiving acute therapy for any relapse between treatment groups.
 

Safety profile confirmed

Dr. Kleiter and colleagues included 178 patients in their analyses. A total of 27 of 104 patients (26%) who received satralizumab had a protocol-defined relapse, compared with 34 of 74 patients (46%) who received placebo. The number and proportion of severe protocol-defined relapses were lower in the satralizumab group (5 of 27 events [19%]), compared with the placebo group (12 of 34 events [35%]). In addition, the number and proportion of severe protocol-defined optic neuritis relapses were lower in patients receiving satralizumab (2 of 8 events [25%]), compared with those receiving placebo (5 of 13 events [39%]). Compared with placebo, satralizumab was associated with a 79% reduction in the risk of severe protocol-defined relapse (hazard ratio, 0.21).

A lower proportion of patients receiving satralizumab was prescribed acute relapse therapy (38%), compared with patients receiving placebo (58%). The odds ratio of receiving a prescription of acute relapse therapy was 0.46 among patients receiving satralizumab.

The activity of IL-6 may cause neurologic damage in patients with NMOSD through astrocytic damage, disruption of the blood–brain barrier, and T cell polarization. “It is proposed that through inhibiting IL-6 across these multiple mechanisms, satralizumab reduces the risk and severity of NMOSD attacks,” Dr. Kleiter said.

To date, the rates of infection and serious infection for patients treated with satralizumab in the combined double-blind and open-label extension periods have been consistent with those for patients treated with satralizumab in the double-blind portion. These rates have not increased over time. Satralizumab is administered as a subcutaneous injection every 4 weeks, and treatment can be self-administered at the discretion of the managing physician. “These data provide reassurance to physicians about the overall profile of satralizumab, with respect to efficacy and safety in the longer term,” said Dr. Kleiter.
 

Does satralizumab differ from other new agents?

The main strength of the study is that sufficient numbers of relapses were available for analysis in the active and control groups, said Achim Berthele, MD, associate professor of neurology at the Technical University of Munich. This allowed the researchers to examine whether satralizumab led to a better outcome after each relapse, which it did. “A weakness is how the severity of relapses was quantified,” said Dr. Berthele. “The EDSS as a measure is not linear, and its functional systems are not clinically equivalent. However, the whole NMOSD community is struggling with this problem.”

The study’s implications for neurologists’ clinical practice are unclear, however. “Although the results presented are encouraging, the data are still too small to say with certainty that satralizumab does indeed improve the outcome of relapses,” said Dr. Berthele. “It is also an open question whether satralizumab differs in this respect from the other new immunotherapeutic agents.”

Investigators must collect further data on the outcome of relapses that occur during treatment with modern immunomodulatory therapy, Dr. Berthele added. Future research could examine whether the new anti-inflammatory immunotherapeutic agents also are suitable drugs for relapse therapy. Another salient question is whether clinical vigilance or relapse therapy in NMOSD has improved in general. “This is what Kleiter and colleagues show as well: The number of severe relapses under placebo was much lower than expected,” said Dr. Berthele.

Chugai/Roche funded the study. Dr. Kleiter has received compensation for consulting, speaking, or serving on advisory boards for Alexion, Biogen, Celgene, Merck, and Roche. Dr. Berthele was not involved in any of the satralizumab trials, but is an investigator and coauthor of the PREVENT trial of eculizumab.

egreb@mdedge.com

SOURCE: Kleiter I, et al. MSVirtual2020. Abstract FC01.03.

Compared with placebo, satralizumab reduces the risk of severe relapse in patients with neuromyelitis optica spectrum disorder (NMOSD), according to investigators. The drug also was associated with a lower likelihood of using acute relapse therapy.

These results were presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

NMOSD is characterized by acute relapses that are unpredictable and lead to the accumulation of disability. “Patients with NMOSD often recover poorly from relapses, therefore, the primary goal for disease management is to reduce attack frequency,” said Ingo Kleiter, MD, medical director of Marianne-Strauß-Klinik in Berg, Germany. “In the two phase 3 trials SAkuraSky and SAkuraStar, the IL-6 receptor inhibitor satralizumab was found to significantly reduce the risk of relapses versus placebo.” Satralizumab is a humanized, monoclonal, recycling antibody that targets the interleukin-6 receptor.

Dr. Kleiter and colleagues examined pooled data from the two phase 3 trials of satralizumab to determine the treatment’s effect on relapse severity in patients with NMOSD. Participants in those trials received placebo or 120 mg of satralizumab at weeks 0, 2, 4, and every 4 weeks thereafter.

For their research, the investigators analyzed data from the pooled intention-to-treat population in the double-blind periods of both studies. To evaluate the severity of protocol-defined relapses, they compared patients’ Expanded Disability Status Scale (EDSS) scores at the time of relapse with their scores before the relapse (i.e., their scores at the last scheduled study visit). Using the visual Functional Systems Score (FSS), Dr. Kleiter and colleagues performed a similar analysis on optic neuritis relapses. They categorized a protocol-defined relapse as severe if it entailed a change of two or more points on the EDSS or visual FSS. The investigators conducted Kaplan-Meier analyses to evaluate the time to first severe protocol-defined relapse. They also compared the number of patients receiving acute therapy for any relapse between treatment groups.
 

Safety profile confirmed

Dr. Kleiter and colleagues included 178 patients in their analyses. A total of 27 of 104 patients (26%) who received satralizumab had a protocol-defined relapse, compared with 34 of 74 patients (46%) who received placebo. The number and proportion of severe protocol-defined relapses were lower in the satralizumab group (5 of 27 events [19%]), compared with the placebo group (12 of 34 events [35%]). In addition, the number and proportion of severe protocol-defined optic neuritis relapses were lower in patients receiving satralizumab (2 of 8 events [25%]), compared with those receiving placebo (5 of 13 events [39%]). Compared with placebo, satralizumab was associated with a 79% reduction in the risk of severe protocol-defined relapse (hazard ratio, 0.21).

A lower proportion of patients receiving satralizumab was prescribed acute relapse therapy (38%), compared with patients receiving placebo (58%). The odds ratio of receiving a prescription of acute relapse therapy was 0.46 among patients receiving satralizumab.

The activity of IL-6 may cause neurologic damage in patients with NMOSD through astrocytic damage, disruption of the blood–brain barrier, and T cell polarization. “It is proposed that through inhibiting IL-6 across these multiple mechanisms, satralizumab reduces the risk and severity of NMOSD attacks,” Dr. Kleiter said.

To date, the rates of infection and serious infection for patients treated with satralizumab in the combined double-blind and open-label extension periods have been consistent with those for patients treated with satralizumab in the double-blind portion. These rates have not increased over time. Satralizumab is administered as a subcutaneous injection every 4 weeks, and treatment can be self-administered at the discretion of the managing physician. “These data provide reassurance to physicians about the overall profile of satralizumab, with respect to efficacy and safety in the longer term,” said Dr. Kleiter.
 

Does satralizumab differ from other new agents?

The main strength of the study is that sufficient numbers of relapses were available for analysis in the active and control groups, said Achim Berthele, MD, associate professor of neurology at the Technical University of Munich. This allowed the researchers to examine whether satralizumab led to a better outcome after each relapse, which it did. “A weakness is how the severity of relapses was quantified,” said Dr. Berthele. “The EDSS as a measure is not linear, and its functional systems are not clinically equivalent. However, the whole NMOSD community is struggling with this problem.”

The study’s implications for neurologists’ clinical practice are unclear, however. “Although the results presented are encouraging, the data are still too small to say with certainty that satralizumab does indeed improve the outcome of relapses,” said Dr. Berthele. “It is also an open question whether satralizumab differs in this respect from the other new immunotherapeutic agents.”

Investigators must collect further data on the outcome of relapses that occur during treatment with modern immunomodulatory therapy, Dr. Berthele added. Future research could examine whether the new anti-inflammatory immunotherapeutic agents also are suitable drugs for relapse therapy. Another salient question is whether clinical vigilance or relapse therapy in NMOSD has improved in general. “This is what Kleiter and colleagues show as well: The number of severe relapses under placebo was much lower than expected,” said Dr. Berthele.

Chugai/Roche funded the study. Dr. Kleiter has received compensation for consulting, speaking, or serving on advisory boards for Alexion, Biogen, Celgene, Merck, and Roche. Dr. Berthele was not involved in any of the satralizumab trials, but is an investigator and coauthor of the PREVENT trial of eculizumab.

egreb@mdedge.com

SOURCE: Kleiter I, et al. MSVirtual2020. Abstract FC01.03.

Compared with placebo, satralizumab reduces the risk of severe relapse in patients with neuromyelitis optica spectrum disorder (NMOSD), according to investigators. The drug also was associated with a lower likelihood of using acute relapse therapy.

These results were presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

NMOSD is characterized by acute relapses that are unpredictable and lead to the accumulation of disability. “Patients with NMOSD often recover poorly from relapses, therefore, the primary goal for disease management is to reduce attack frequency,” said Ingo Kleiter, MD, medical director of Marianne-Strauß-Klinik in Berg, Germany. “In the two phase 3 trials SAkuraSky and SAkuraStar, the IL-6 receptor inhibitor satralizumab was found to significantly reduce the risk of relapses versus placebo.” Satralizumab is a humanized, monoclonal, recycling antibody that targets the interleukin-6 receptor.

Dr. Kleiter and colleagues examined pooled data from the two phase 3 trials of satralizumab to determine the treatment’s effect on relapse severity in patients with NMOSD. Participants in those trials received placebo or 120 mg of satralizumab at weeks 0, 2, 4, and every 4 weeks thereafter.

For their research, the investigators analyzed data from the pooled intention-to-treat population in the double-blind periods of both studies. To evaluate the severity of protocol-defined relapses, they compared patients’ Expanded Disability Status Scale (EDSS) scores at the time of relapse with their scores before the relapse (i.e., their scores at the last scheduled study visit). Using the visual Functional Systems Score (FSS), Dr. Kleiter and colleagues performed a similar analysis on optic neuritis relapses. They categorized a protocol-defined relapse as severe if it entailed a change of two or more points on the EDSS or visual FSS. The investigators conducted Kaplan-Meier analyses to evaluate the time to first severe protocol-defined relapse. They also compared the number of patients receiving acute therapy for any relapse between treatment groups.
 

Safety profile confirmed

Dr. Kleiter and colleagues included 178 patients in their analyses. A total of 27 of 104 patients (26%) who received satralizumab had a protocol-defined relapse, compared with 34 of 74 patients (46%) who received placebo. The number and proportion of severe protocol-defined relapses were lower in the satralizumab group (5 of 27 events [19%]), compared with the placebo group (12 of 34 events [35%]). In addition, the number and proportion of severe protocol-defined optic neuritis relapses were lower in patients receiving satralizumab (2 of 8 events [25%]), compared with those receiving placebo (5 of 13 events [39%]). Compared with placebo, satralizumab was associated with a 79% reduction in the risk of severe protocol-defined relapse (hazard ratio, 0.21).

A lower proportion of patients receiving satralizumab was prescribed acute relapse therapy (38%), compared with patients receiving placebo (58%). The odds ratio of receiving a prescription of acute relapse therapy was 0.46 among patients receiving satralizumab.

The activity of IL-6 may cause neurologic damage in patients with NMOSD through astrocytic damage, disruption of the blood–brain barrier, and T cell polarization. “It is proposed that through inhibiting IL-6 across these multiple mechanisms, satralizumab reduces the risk and severity of NMOSD attacks,” Dr. Kleiter said.

To date, the rates of infection and serious infection for patients treated with satralizumab in the combined double-blind and open-label extension periods have been consistent with those for patients treated with satralizumab in the double-blind portion. These rates have not increased over time. Satralizumab is administered as a subcutaneous injection every 4 weeks, and treatment can be self-administered at the discretion of the managing physician. “These data provide reassurance to physicians about the overall profile of satralizumab, with respect to efficacy and safety in the longer term,” said Dr. Kleiter.
 

Does satralizumab differ from other new agents?

The main strength of the study is that sufficient numbers of relapses were available for analysis in the active and control groups, said Achim Berthele, MD, associate professor of neurology at the Technical University of Munich. This allowed the researchers to examine whether satralizumab led to a better outcome after each relapse, which it did. “A weakness is how the severity of relapses was quantified,” said Dr. Berthele. “The EDSS as a measure is not linear, and its functional systems are not clinically equivalent. However, the whole NMOSD community is struggling with this problem.”

The study’s implications for neurologists’ clinical practice are unclear, however. “Although the results presented are encouraging, the data are still too small to say with certainty that satralizumab does indeed improve the outcome of relapses,” said Dr. Berthele. “It is also an open question whether satralizumab differs in this respect from the other new immunotherapeutic agents.”

Investigators must collect further data on the outcome of relapses that occur during treatment with modern immunomodulatory therapy, Dr. Berthele added. Future research could examine whether the new anti-inflammatory immunotherapeutic agents also are suitable drugs for relapse therapy. Another salient question is whether clinical vigilance or relapse therapy in NMOSD has improved in general. “This is what Kleiter and colleagues show as well: The number of severe relapses under placebo was much lower than expected,” said Dr. Berthele.

Chugai/Roche funded the study. Dr. Kleiter has received compensation for consulting, speaking, or serving on advisory boards for Alexion, Biogen, Celgene, Merck, and Roche. Dr. Berthele was not involved in any of the satralizumab trials, but is an investigator and coauthor of the PREVENT trial of eculizumab.

egreb@mdedge.com

SOURCE: Kleiter I, et al. MSVirtual2020. Abstract FC01.03.

The presence of cardiovascular risk factors in patients with multiple sclerosis (MS) is associated with a greater degree of brain atrophy even in young patients who are unlikely to have small vessel disease, a new study has shown.

The results were presented by Raffaello Bonacchi, MD, Vita-Salute San Raffaele University, Milan, Italy, at at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020. .

“Our results suggest that even low levels of exposure to cardiovascular risk factors are important in MS and might affect brain atrophy—and therefore long-term disability—even in young patients,” Dr. Bonacchi said. 

“It is not only smoking,” he added. “Other cardiovascular risk factors also appear to be implicated. We found a synergistic effect of the different risk factors.”

These are only preliminary data and need to be confirmed in other studies,” he said, “but it does suggest that MS neurologists need to pay attention to comprehensive care—not just MS disease activity.

“They also need to be discussing lifestyle with their patients, evaluating their cardiovascular risk factors, and giving advice on stopping smoking, lowering blood pressure, cholesterol, etc.”
 

Brain changes

Dr. Bonacchi explained that previous studies have suggested a relationship between cardiovascular risk factors and changes on magnetic resonance imaging (MRI) and clinical outcomes in patients with MS that may be mediated by small vessel disease and/or inflammation.  

“Small vessel disease is widespread in the population over 50 years of age, but in this study we wanted to look at the impact of cardiovascular risk factors in younger patients with MS who are not likely to have much small vessel disease to try and see whether there is still a relationship with brain atrophy or white/gray matter lesions,” he said.

Previous studies have not set an age limit for examining this relationship and they have also assessed the presence versus absence of cardiovascular risk factors, without attempting to grade the strength of exposure, he noted.

For the current study, the researchers examined several cardiovascular risk factors and in addition to just being present or absent. They also graded each risk factor as being stringent or not depending on a certain threshold.

For example, smoking was defined as a threshold of 5 pack-years (smoking 5 cigarettes a day for 20 years or 20 cigarettes a day for 5 years). And the more stringent definition was 10 pack-years.

For hypertension, the stringent definition was consistently high blood pressure levels and use of antihypertensive medication, with similar definitions used for cholesterol and diabetes.

This was a cross-sectional observational study in 124 patients with MS and 95 healthy controls. The researchers examined MRI scans and neurological exams and investigated whether the amount of cardiovascular risk factors a patient was exposed to was associated with degree of brain atrophy and white matter/gray matter volume. Results were adjusted for age, sex, disease duration, phenotype (relapsing-remitting versus progressive MS) and treatment.

Results showed no significant difference if patients were exposed to at least one classical risk factor versus no risk factors. But if a patient had at least two classical risk factors, significant differences were found in gray matter, white matter, and total brain volume.

Patients with MS and no risk factors had a mean brain volume of 1524 mL versus 1481 mL in those with at least two risk factors, a difference that was significant (P = 0.003). Mean gray matter volume was 856 mL in MS patients without cardiovascular risk factors and 836 mL in those with at least two risk factors (P = 0.01) Mean white matter volume was 668 mL in MS patients without cardiovascular risk factors and 845 mL in those with at least two risk factors (P = 0.03).

“This is one of the first studies to have graded degrees of risk factors and we found one stringent risk factor was associated with the same effects on brain atrophy as two less stringent risk factors,” Dr. Bonacchi reported.

Healthy controls showed no differences in any of the brain volume outcomes in those with or without cardiovascular risk factors.

“As our population was under aged 50 years, who are unlikely to have much small vessel disease, our results suggest that the influence of cardiovascular risk factors on brain atrophy in MS is not just mediated through small vessel disease and is probably also mediated by increased inflammation,” Dr. Bonacchi suggested. 
 

Impact of CV risk factors

Commenting on the study, Dalia Rotstein, MD, assistant professor, department of neurology, University of Toronto, Ontario, Canada, session cochair, said: “This is an interesting study that captures the impact of cardiovascular risk factors on various measures of brain atrophy in MS.”

The cohort was quite young, under age 50, and the effect on brain atrophy was increased with more severe cardiovascular risk factors, she noted.

“The investigators compared these effects to a population of healthy controls and did not observe as substantial an effect in controls. However, they were likely underpowered for the analysis in the healthy controls because of a relatively small number of subjects with cardiovascular risk factors in this group,” Dr. Rotstein noted.

“More research is needed to determine whether the observed relationship is unique to MS and whether treating cardiovascular risk factors may help protect against neurodegeneration in MS,” she added.

Dr. Bonacchi has reported no relevant financial relationships. Dr. Rotstein has reported acting as a consultant for Roche, Alexion, Novartis, EMD Serono, and Sanofi Aventis.

SOURCE: Bonacchi R. et al. MSVirtual2020. Session PS04.05.

This article originally appeared on Medscape.com .

The presence of cardiovascular risk factors in patients with multiple sclerosis (MS) is associated with a greater degree of brain atrophy even in young patients who are unlikely to have small vessel disease, a new study has shown.

The results were presented by Raffaello Bonacchi, MD, Vita-Salute San Raffaele University, Milan, Italy, at at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020. .

“Our results suggest that even low levels of exposure to cardiovascular risk factors are important in MS and might affect brain atrophy—and therefore long-term disability—even in young patients,” Dr. Bonacchi said. 

“It is not only smoking,” he added. “Other cardiovascular risk factors also appear to be implicated. We found a synergistic effect of the different risk factors.”

These are only preliminary data and need to be confirmed in other studies,” he said, “but it does suggest that MS neurologists need to pay attention to comprehensive care—not just MS disease activity.

“They also need to be discussing lifestyle with their patients, evaluating their cardiovascular risk factors, and giving advice on stopping smoking, lowering blood pressure, cholesterol, etc.”
 

Brain changes

Dr. Bonacchi explained that previous studies have suggested a relationship between cardiovascular risk factors and changes on magnetic resonance imaging (MRI) and clinical outcomes in patients with MS that may be mediated by small vessel disease and/or inflammation.  

“Small vessel disease is widespread in the population over 50 years of age, but in this study we wanted to look at the impact of cardiovascular risk factors in younger patients with MS who are not likely to have much small vessel disease to try and see whether there is still a relationship with brain atrophy or white/gray matter lesions,” he said.

Previous studies have not set an age limit for examining this relationship and they have also assessed the presence versus absence of cardiovascular risk factors, without attempting to grade the strength of exposure, he noted.

For the current study, the researchers examined several cardiovascular risk factors and in addition to just being present or absent. They also graded each risk factor as being stringent or not depending on a certain threshold.

For example, smoking was defined as a threshold of 5 pack-years (smoking 5 cigarettes a day for 20 years or 20 cigarettes a day for 5 years). And the more stringent definition was 10 pack-years.

For hypertension, the stringent definition was consistently high blood pressure levels and use of antihypertensive medication, with similar definitions used for cholesterol and diabetes.

This was a cross-sectional observational study in 124 patients with MS and 95 healthy controls. The researchers examined MRI scans and neurological exams and investigated whether the amount of cardiovascular risk factors a patient was exposed to was associated with degree of brain atrophy and white matter/gray matter volume. Results were adjusted for age, sex, disease duration, phenotype (relapsing-remitting versus progressive MS) and treatment.

Results showed no significant difference if patients were exposed to at least one classical risk factor versus no risk factors. But if a patient had at least two classical risk factors, significant differences were found in gray matter, white matter, and total brain volume.

Patients with MS and no risk factors had a mean brain volume of 1524 mL versus 1481 mL in those with at least two risk factors, a difference that was significant (P = 0.003). Mean gray matter volume was 856 mL in MS patients without cardiovascular risk factors and 836 mL in those with at least two risk factors (P = 0.01) Mean white matter volume was 668 mL in MS patients without cardiovascular risk factors and 845 mL in those with at least two risk factors (P = 0.03).

“This is one of the first studies to have graded degrees of risk factors and we found one stringent risk factor was associated with the same effects on brain atrophy as two less stringent risk factors,” Dr. Bonacchi reported.

Healthy controls showed no differences in any of the brain volume outcomes in those with or without cardiovascular risk factors.

“As our population was under aged 50 years, who are unlikely to have much small vessel disease, our results suggest that the influence of cardiovascular risk factors on brain atrophy in MS is not just mediated through small vessel disease and is probably also mediated by increased inflammation,” Dr. Bonacchi suggested. 
 

Impact of CV risk factors

Commenting on the study, Dalia Rotstein, MD, assistant professor, department of neurology, University of Toronto, Ontario, Canada, session cochair, said: “This is an interesting study that captures the impact of cardiovascular risk factors on various measures of brain atrophy in MS.”

The cohort was quite young, under age 50, and the effect on brain atrophy was increased with more severe cardiovascular risk factors, she noted.

“The investigators compared these effects to a population of healthy controls and did not observe as substantial an effect in controls. However, they were likely underpowered for the analysis in the healthy controls because of a relatively small number of subjects with cardiovascular risk factors in this group,” Dr. Rotstein noted.

“More research is needed to determine whether the observed relationship is unique to MS and whether treating cardiovascular risk factors may help protect against neurodegeneration in MS,” she added.

Dr. Bonacchi has reported no relevant financial relationships. Dr. Rotstein has reported acting as a consultant for Roche, Alexion, Novartis, EMD Serono, and Sanofi Aventis.

SOURCE: Bonacchi R. et al. MSVirtual2020. Session PS04.05.

This article originally appeared on Medscape.com .

The presence of cardiovascular risk factors in patients with multiple sclerosis (MS) is associated with a greater degree of brain atrophy even in young patients who are unlikely to have small vessel disease, a new study has shown.

The results were presented by Raffaello Bonacchi, MD, Vita-Salute San Raffaele University, Milan, Italy, at at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020. .

“Our results suggest that even low levels of exposure to cardiovascular risk factors are important in MS and might affect brain atrophy—and therefore long-term disability—even in young patients,” Dr. Bonacchi said. 

“It is not only smoking,” he added. “Other cardiovascular risk factors also appear to be implicated. We found a synergistic effect of the different risk factors.”

These are only preliminary data and need to be confirmed in other studies,” he said, “but it does suggest that MS neurologists need to pay attention to comprehensive care—not just MS disease activity.

“They also need to be discussing lifestyle with their patients, evaluating their cardiovascular risk factors, and giving advice on stopping smoking, lowering blood pressure, cholesterol, etc.”
 

Brain changes

Dr. Bonacchi explained that previous studies have suggested a relationship between cardiovascular risk factors and changes on magnetic resonance imaging (MRI) and clinical outcomes in patients with MS that may be mediated by small vessel disease and/or inflammation.  

“Small vessel disease is widespread in the population over 50 years of age, but in this study we wanted to look at the impact of cardiovascular risk factors in younger patients with MS who are not likely to have much small vessel disease to try and see whether there is still a relationship with brain atrophy or white/gray matter lesions,” he said.

Previous studies have not set an age limit for examining this relationship and they have also assessed the presence versus absence of cardiovascular risk factors, without attempting to grade the strength of exposure, he noted.

For the current study, the researchers examined several cardiovascular risk factors and in addition to just being present or absent. They also graded each risk factor as being stringent or not depending on a certain threshold.

For example, smoking was defined as a threshold of 5 pack-years (smoking 5 cigarettes a day for 20 years or 20 cigarettes a day for 5 years). And the more stringent definition was 10 pack-years.

For hypertension, the stringent definition was consistently high blood pressure levels and use of antihypertensive medication, with similar definitions used for cholesterol and diabetes.

This was a cross-sectional observational study in 124 patients with MS and 95 healthy controls. The researchers examined MRI scans and neurological exams and investigated whether the amount of cardiovascular risk factors a patient was exposed to was associated with degree of brain atrophy and white matter/gray matter volume. Results were adjusted for age, sex, disease duration, phenotype (relapsing-remitting versus progressive MS) and treatment.

Results showed no significant difference if patients were exposed to at least one classical risk factor versus no risk factors. But if a patient had at least two classical risk factors, significant differences were found in gray matter, white matter, and total brain volume.

Patients with MS and no risk factors had a mean brain volume of 1524 mL versus 1481 mL in those with at least two risk factors, a difference that was significant (P = 0.003). Mean gray matter volume was 856 mL in MS patients without cardiovascular risk factors and 836 mL in those with at least two risk factors (P = 0.01) Mean white matter volume was 668 mL in MS patients without cardiovascular risk factors and 845 mL in those with at least two risk factors (P = 0.03).

“This is one of the first studies to have graded degrees of risk factors and we found one stringent risk factor was associated with the same effects on brain atrophy as two less stringent risk factors,” Dr. Bonacchi reported.

Healthy controls showed no differences in any of the brain volume outcomes in those with or without cardiovascular risk factors.

“As our population was under aged 50 years, who are unlikely to have much small vessel disease, our results suggest that the influence of cardiovascular risk factors on brain atrophy in MS is not just mediated through small vessel disease and is probably also mediated by increased inflammation,” Dr. Bonacchi suggested. 
 

Impact of CV risk factors

Commenting on the study, Dalia Rotstein, MD, assistant professor, department of neurology, University of Toronto, Ontario, Canada, session cochair, said: “This is an interesting study that captures the impact of cardiovascular risk factors on various measures of brain atrophy in MS.”

The cohort was quite young, under age 50, and the effect on brain atrophy was increased with more severe cardiovascular risk factors, she noted.

“The investigators compared these effects to a population of healthy controls and did not observe as substantial an effect in controls. However, they were likely underpowered for the analysis in the healthy controls because of a relatively small number of subjects with cardiovascular risk factors in this group,” Dr. Rotstein noted.

“More research is needed to determine whether the observed relationship is unique to MS and whether treating cardiovascular risk factors may help protect against neurodegeneration in MS,” she added.

Dr. Bonacchi has reported no relevant financial relationships. Dr. Rotstein has reported acting as a consultant for Roche, Alexion, Novartis, EMD Serono, and Sanofi Aventis.

SOURCE: Bonacchi R. et al. MSVirtual2020. Session PS04.05.

This article originally appeared on Medscape.com .

Two important lessons about managing patients with multiple sclerosis (MS) and COVID-19 have emerged from a hospital clinic in Madrid that managed COVID-infected patients with MS through the peak of the pandemic: Combined polymeric chain reaction and serology testing helped avoid disease reactivation in asymptomatic carriers during the pandemic peak, although after the peak PCR alone proved just as effective; and infected MS patients could stay on their MS medications while being treated for COVID-19, as fewer than one in five required hospitalization.

Virginia Meca-Lallana, MD, a neurologist and coordinator of the demyelinating diseases unit at the Hospital of the University of the Princess in Madrid, and colleagues presented their findings in two posters at the Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

“MS treatments don’t seem to make the prognosis of COVID-19 worse, but it is very important to evaluate other risk factors,” Dr. Meca-Lallana said in an interview. “MS treatments prevent the patients’ disability, and it is very important not to stop them if it isn’t necessary.”

The results arose from a multidisciplinary safety protocol involving neurology, microbiology, and preventive medicine that the University of Princess physicians developed to keep MS stable in patients diagnosed with SARS-CoV-2.

The researchers obtained 152 PCR nasopharyngeal swabs and 140 serology tests in 90 patients with MS over 3 months before starting a variety of MS treatments: Natalizumab (96 tests), ocrelizumab (36), rituximab (3), methylprednisolone (7), cladribine (4), and dimethyl fumarate (3). The protocol identified 7 asymptomatic carriers—7.8% of the total population—5 of whom had positive immunoglobulin M and G serology. The study also confirmed 5 patients with positive IgM+IgG serology post-infection, but no COVID-19 reactivations were detected after implementation of the protocol.

“The safety protocol reached its objective of avoiding disease reactivation and clinical activation in asymptomatic carriers,” Dr. Meca-Lallana said.

The second poster she presented reported on the real-world experience with SARS-CoV-2 in the MS unit at her hospital. The observational, prospective study included 41 cases, 38 of which were relapsing-remitting MS and the remainder progressive MS. The patients had MS for an average of 9 years.

“We need more patients to draw more robust conclusions, but in our patients, MS treatments seem safe in this situation,” Dr. Meca-Lallana said. “We did not discontinue treatments, and after our first results, we only delayed treatments in patients with any additional comorbidity or when coming to the hospital was not safe.”

A total of 39 patients were taking disease-modifying therapies (DMTs): 46.3% with oral agents, 39% with monoclonal antibodies, and 10% with injectable agents; 27 patients were previously treated with other DMTs. The median Expanded Disability Status Scale (EDSS) was 2.5, and 11 patients had clinical activity the previous year. Eighteen cases were confirmed by PCR or serology, or both, and 23 were diagnosed clinically.

Among the patients with MS and COVID-19, 17% were admitted to the hospital. Six patients had pneumonia, but none required admission to the intensive care unit, and no deaths occurred. Three patients had other comorbidities. Admitted patients tended to be older and had higher EDSS scores, although the difference was not statistically significant. MS worsened in 7 patients, and 10 patients stopped or paused DMTs because of the infection.

“Multiple sclerosis is a weakening illness,” Dr. Meca-Lallana said. “MS treatments do not seem to make the prognosis of COVID-19 worse, but it is very important to evaluate other risk factors.”

The SARS-CoV-2 infection does not seem to result in a more aggressive form of the disease in MS patients, and selective immunosuppression may improve their outcomes, she noted.

“MS treatments avoid the patient’s disability,” the investigator added, “and it is very important not to stop them if it isn’t necessary.”

Dr. Meca-Lallana had no relevant financial disclosures.

Two important lessons about managing patients with multiple sclerosis (MS) and COVID-19 have emerged from a hospital clinic in Madrid that managed COVID-infected patients with MS through the peak of the pandemic: Combined polymeric chain reaction and serology testing helped avoid disease reactivation in asymptomatic carriers during the pandemic peak, although after the peak PCR alone proved just as effective; and infected MS patients could stay on their MS medications while being treated for COVID-19, as fewer than one in five required hospitalization.

Virginia Meca-Lallana, MD, a neurologist and coordinator of the demyelinating diseases unit at the Hospital of the University of the Princess in Madrid, and colleagues presented their findings in two posters at the Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

“MS treatments don’t seem to make the prognosis of COVID-19 worse, but it is very important to evaluate other risk factors,” Dr. Meca-Lallana said in an interview. “MS treatments prevent the patients’ disability, and it is very important not to stop them if it isn’t necessary.”

The results arose from a multidisciplinary safety protocol involving neurology, microbiology, and preventive medicine that the University of Princess physicians developed to keep MS stable in patients diagnosed with SARS-CoV-2.

The researchers obtained 152 PCR nasopharyngeal swabs and 140 serology tests in 90 patients with MS over 3 months before starting a variety of MS treatments: Natalizumab (96 tests), ocrelizumab (36), rituximab (3), methylprednisolone (7), cladribine (4), and dimethyl fumarate (3). The protocol identified 7 asymptomatic carriers—7.8% of the total population—5 of whom had positive immunoglobulin M and G serology. The study also confirmed 5 patients with positive IgM+IgG serology post-infection, but no COVID-19 reactivations were detected after implementation of the protocol.

“The safety protocol reached its objective of avoiding disease reactivation and clinical activation in asymptomatic carriers,” Dr. Meca-Lallana said.

The second poster she presented reported on the real-world experience with SARS-CoV-2 in the MS unit at her hospital. The observational, prospective study included 41 cases, 38 of which were relapsing-remitting MS and the remainder progressive MS. The patients had MS for an average of 9 years.

“We need more patients to draw more robust conclusions, but in our patients, MS treatments seem safe in this situation,” Dr. Meca-Lallana said. “We did not discontinue treatments, and after our first results, we only delayed treatments in patients with any additional comorbidity or when coming to the hospital was not safe.”

A total of 39 patients were taking disease-modifying therapies (DMTs): 46.3% with oral agents, 39% with monoclonal antibodies, and 10% with injectable agents; 27 patients were previously treated with other DMTs. The median Expanded Disability Status Scale (EDSS) was 2.5, and 11 patients had clinical activity the previous year. Eighteen cases were confirmed by PCR or serology, or both, and 23 were diagnosed clinically.

Among the patients with MS and COVID-19, 17% were admitted to the hospital. Six patients had pneumonia, but none required admission to the intensive care unit, and no deaths occurred. Three patients had other comorbidities. Admitted patients tended to be older and had higher EDSS scores, although the difference was not statistically significant. MS worsened in 7 patients, and 10 patients stopped or paused DMTs because of the infection.

“Multiple sclerosis is a weakening illness,” Dr. Meca-Lallana said. “MS treatments do not seem to make the prognosis of COVID-19 worse, but it is very important to evaluate other risk factors.”

The SARS-CoV-2 infection does not seem to result in a more aggressive form of the disease in MS patients, and selective immunosuppression may improve their outcomes, she noted.

“MS treatments avoid the patient’s disability,” the investigator added, “and it is very important not to stop them if it isn’t necessary.”

Dr. Meca-Lallana had no relevant financial disclosures.

Two important lessons about managing patients with multiple sclerosis (MS) and COVID-19 have emerged from a hospital clinic in Madrid that managed COVID-infected patients with MS through the peak of the pandemic: Combined polymeric chain reaction and serology testing helped avoid disease reactivation in asymptomatic carriers during the pandemic peak, although after the peak PCR alone proved just as effective; and infected MS patients could stay on their MS medications while being treated for COVID-19, as fewer than one in five required hospitalization.

Virginia Meca-Lallana, MD, a neurologist and coordinator of the demyelinating diseases unit at the Hospital of the University of the Princess in Madrid, and colleagues presented their findings in two posters at the Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

“MS treatments don’t seem to make the prognosis of COVID-19 worse, but it is very important to evaluate other risk factors,” Dr. Meca-Lallana said in an interview. “MS treatments prevent the patients’ disability, and it is very important not to stop them if it isn’t necessary.”

The results arose from a multidisciplinary safety protocol involving neurology, microbiology, and preventive medicine that the University of Princess physicians developed to keep MS stable in patients diagnosed with SARS-CoV-2.

The researchers obtained 152 PCR nasopharyngeal swabs and 140 serology tests in 90 patients with MS over 3 months before starting a variety of MS treatments: Natalizumab (96 tests), ocrelizumab (36), rituximab (3), methylprednisolone (7), cladribine (4), and dimethyl fumarate (3). The protocol identified 7 asymptomatic carriers—7.8% of the total population—5 of whom had positive immunoglobulin M and G serology. The study also confirmed 5 patients with positive IgM+IgG serology post-infection, but no COVID-19 reactivations were detected after implementation of the protocol.

“The safety protocol reached its objective of avoiding disease reactivation and clinical activation in asymptomatic carriers,” Dr. Meca-Lallana said.

The second poster she presented reported on the real-world experience with SARS-CoV-2 in the MS unit at her hospital. The observational, prospective study included 41 cases, 38 of which were relapsing-remitting MS and the remainder progressive MS. The patients had MS for an average of 9 years.

“We need more patients to draw more robust conclusions, but in our patients, MS treatments seem safe in this situation,” Dr. Meca-Lallana said. “We did not discontinue treatments, and after our first results, we only delayed treatments in patients with any additional comorbidity or when coming to the hospital was not safe.”

A total of 39 patients were taking disease-modifying therapies (DMTs): 46.3% with oral agents, 39% with monoclonal antibodies, and 10% with injectable agents; 27 patients were previously treated with other DMTs. The median Expanded Disability Status Scale (EDSS) was 2.5, and 11 patients had clinical activity the previous year. Eighteen cases were confirmed by PCR or serology, or both, and 23 were diagnosed clinically.

Among the patients with MS and COVID-19, 17% were admitted to the hospital. Six patients had pneumonia, but none required admission to the intensive care unit, and no deaths occurred. Three patients had other comorbidities. Admitted patients tended to be older and had higher EDSS scores, although the difference was not statistically significant. MS worsened in 7 patients, and 10 patients stopped or paused DMTs because of the infection.

“Multiple sclerosis is a weakening illness,” Dr. Meca-Lallana said. “MS treatments do not seem to make the prognosis of COVID-19 worse, but it is very important to evaluate other risk factors.”

The SARS-CoV-2 infection does not seem to result in a more aggressive form of the disease in MS patients, and selective immunosuppression may improve their outcomes, she noted.

“MS treatments avoid the patient’s disability,” the investigator added, “and it is very important not to stop them if it isn’t necessary.”

Dr. Meca-Lallana had no relevant financial disclosures.

For patients with primary progressive multiple sclerosis (MS), longer exposure to disease-modifying therapy (DMT) may delay the time at which a patient is restricted to a wheelchair. Reducing the delay to treatment initiation, as well as treating younger patients, might improve long-term disability outcomes, according to a new study. 

“To optimize treatment decision-making in primary progressive MS, further profiling of the best candidates for treatment is needed,” said the researchers. The study was presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Ocrelizumab remains the only treatment available for patients with primary progressive MS. In clinical trials, other drugs have failed to reduce disability progression in this population. Mattia Fonderico, a doctoral student and research assistant at the University of Florence (Italy), and colleagues reviewed data from the Italian MS Registry to examine whether DMT affects the attainment of given disability outcomes.

Patients with longer exposure were younger at baseline

Patients eligible for inclusion in the study had primary progressive MS, at least three evaluations using the Expanded Disability Status Scale (EDSS), and 3 years’ follow-up. The investigators defined the baseline for untreated patients as the first EDSS evaluation. For treated patients, the baseline was the date of DMT initiation.

Using multivariable Cox regression models, Ms. Fonderico and colleagues examined the effect of DMT on the risk of reaching EDSS scores of 6 (i.e., requirement for intermittent or unilateral constant walking assistance) and 7 (i.e., restriction to a wheelchair) as a dichotomous variable and as a time-dependent covariate. The researchers adjusted the data for age at baseline, sex, first EDSS score, symptoms at onset, annualized visit rate, and annualized relapse rate. They compared outcomes with an as-treated analysis and chose cohorts with similar baseline characteristics using propensity-score matching. In addition, Ms. Fonderico and colleagues also analyzed quartiles of DMT exposure.

The investigators included 1,214 patients (671 women) in their analysis. The population’s mean age at baseline was 48.7 years, and its mean EDSS score was 4.1. A total of 626 patients (52%) received DMT during follow-up. Approximately 57% of DMTs were platform therapies, and 43% were high-efficacy therapies.

Mean follow-up duration was 11.6 years. By the end of follow-up, 994 patients (82%) reached an EDSS score of 6, and 539 (44%) reached an EDSS score of 7. Multivariable Cox regression models indicated that DMT, analyzed as a dichotomous variable, did not affect the risk of reaching EDSS 6 (adjusted hazard ratio, 1.1) or EDSS 7 (aHR, 0.93). Longer DMT exposure, however, significantly reduced the risk of reaching EDSS 7 (aHR, 0.73).

Compared with patients with shorter exposure to DMT, patients in the highest quartile of DMT exposure were younger at baseline (mean age, 44.1 years) and initiated DMT closer to disease onset (mean time to DMT initiation was 6.8 years). The propensity score matching analysis confirmed these findings.

The investigators did not consider MRI variables, which Ms. Fonderico acknowledged was a weakness of the study. In addition, they did not analyze the effect of superimposed relapses.

 

A new perspective on primary progressive MS?

These results suggest that primary progressive MS behaves like relapsing-remitting MS, said Gavin Giovannoni, MD, PhD, chair of neurology at Queen Mary University of London. That is, they suggest that primary progressive MS “is modifiable by a DMT and that the earlier you treat, the better the outcome.” The results also indicate that neurologists commonly prescribe DMT off label in Italy, he added.

A weakness of the study is that it was not randomized. Furthermore, “EDSS [evaluations] tend not be done properly in routine clinical practice,” said Dr. Giovannoni. Still, the study raises an important question for future research. “Why have we missed the treatment effect in previous trials?” asked Dr. Giovannoni. Whether previous trials were too short or underpowered could be investigated, he added.

Study funding was not reported. Ms. Fonderico had no relevant disclosures. Dr. Giovannoni had no relevant disclosures.

egreb@mdedge.com

For patients with primary progressive multiple sclerosis (MS), longer exposure to disease-modifying therapy (DMT) may delay the time at which a patient is restricted to a wheelchair. Reducing the delay to treatment initiation, as well as treating younger patients, might improve long-term disability outcomes, according to a new study. 

“To optimize treatment decision-making in primary progressive MS, further profiling of the best candidates for treatment is needed,” said the researchers. The study was presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Ocrelizumab remains the only treatment available for patients with primary progressive MS. In clinical trials, other drugs have failed to reduce disability progression in this population. Mattia Fonderico, a doctoral student and research assistant at the University of Florence (Italy), and colleagues reviewed data from the Italian MS Registry to examine whether DMT affects the attainment of given disability outcomes.

Patients with longer exposure were younger at baseline

Patients eligible for inclusion in the study had primary progressive MS, at least three evaluations using the Expanded Disability Status Scale (EDSS), and 3 years’ follow-up. The investigators defined the baseline for untreated patients as the first EDSS evaluation. For treated patients, the baseline was the date of DMT initiation.

Using multivariable Cox regression models, Ms. Fonderico and colleagues examined the effect of DMT on the risk of reaching EDSS scores of 6 (i.e., requirement for intermittent or unilateral constant walking assistance) and 7 (i.e., restriction to a wheelchair) as a dichotomous variable and as a time-dependent covariate. The researchers adjusted the data for age at baseline, sex, first EDSS score, symptoms at onset, annualized visit rate, and annualized relapse rate. They compared outcomes with an as-treated analysis and chose cohorts with similar baseline characteristics using propensity-score matching. In addition, Ms. Fonderico and colleagues also analyzed quartiles of DMT exposure.

The investigators included 1,214 patients (671 women) in their analysis. The population’s mean age at baseline was 48.7 years, and its mean EDSS score was 4.1. A total of 626 patients (52%) received DMT during follow-up. Approximately 57% of DMTs were platform therapies, and 43% were high-efficacy therapies.

Mean follow-up duration was 11.6 years. By the end of follow-up, 994 patients (82%) reached an EDSS score of 6, and 539 (44%) reached an EDSS score of 7. Multivariable Cox regression models indicated that DMT, analyzed as a dichotomous variable, did not affect the risk of reaching EDSS 6 (adjusted hazard ratio, 1.1) or EDSS 7 (aHR, 0.93). Longer DMT exposure, however, significantly reduced the risk of reaching EDSS 7 (aHR, 0.73).

Compared with patients with shorter exposure to DMT, patients in the highest quartile of DMT exposure were younger at baseline (mean age, 44.1 years) and initiated DMT closer to disease onset (mean time to DMT initiation was 6.8 years). The propensity score matching analysis confirmed these findings.

The investigators did not consider MRI variables, which Ms. Fonderico acknowledged was a weakness of the study. In addition, they did not analyze the effect of superimposed relapses.

 

A new perspective on primary progressive MS?

These results suggest that primary progressive MS behaves like relapsing-remitting MS, said Gavin Giovannoni, MD, PhD, chair of neurology at Queen Mary University of London. That is, they suggest that primary progressive MS “is modifiable by a DMT and that the earlier you treat, the better the outcome.” The results also indicate that neurologists commonly prescribe DMT off label in Italy, he added.

A weakness of the study is that it was not randomized. Furthermore, “EDSS [evaluations] tend not be done properly in routine clinical practice,” said Dr. Giovannoni. Still, the study raises an important question for future research. “Why have we missed the treatment effect in previous trials?” asked Dr. Giovannoni. Whether previous trials were too short or underpowered could be investigated, he added.

Study funding was not reported. Ms. Fonderico had no relevant disclosures. Dr. Giovannoni had no relevant disclosures.

egreb@mdedge.com

For patients with primary progressive multiple sclerosis (MS), longer exposure to disease-modifying therapy (DMT) may delay the time at which a patient is restricted to a wheelchair. Reducing the delay to treatment initiation, as well as treating younger patients, might improve long-term disability outcomes, according to a new study. 

“To optimize treatment decision-making in primary progressive MS, further profiling of the best candidates for treatment is needed,” said the researchers. The study was presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Ocrelizumab remains the only treatment available for patients with primary progressive MS. In clinical trials, other drugs have failed to reduce disability progression in this population. Mattia Fonderico, a doctoral student and research assistant at the University of Florence (Italy), and colleagues reviewed data from the Italian MS Registry to examine whether DMT affects the attainment of given disability outcomes.

Patients with longer exposure were younger at baseline

Patients eligible for inclusion in the study had primary progressive MS, at least three evaluations using the Expanded Disability Status Scale (EDSS), and 3 years’ follow-up. The investigators defined the baseline for untreated patients as the first EDSS evaluation. For treated patients, the baseline was the date of DMT initiation.

Using multivariable Cox regression models, Ms. Fonderico and colleagues examined the effect of DMT on the risk of reaching EDSS scores of 6 (i.e., requirement for intermittent or unilateral constant walking assistance) and 7 (i.e., restriction to a wheelchair) as a dichotomous variable and as a time-dependent covariate. The researchers adjusted the data for age at baseline, sex, first EDSS score, symptoms at onset, annualized visit rate, and annualized relapse rate. They compared outcomes with an as-treated analysis and chose cohorts with similar baseline characteristics using propensity-score matching. In addition, Ms. Fonderico and colleagues also analyzed quartiles of DMT exposure.

The investigators included 1,214 patients (671 women) in their analysis. The population’s mean age at baseline was 48.7 years, and its mean EDSS score was 4.1. A total of 626 patients (52%) received DMT during follow-up. Approximately 57% of DMTs were platform therapies, and 43% were high-efficacy therapies.

Mean follow-up duration was 11.6 years. By the end of follow-up, 994 patients (82%) reached an EDSS score of 6, and 539 (44%) reached an EDSS score of 7. Multivariable Cox regression models indicated that DMT, analyzed as a dichotomous variable, did not affect the risk of reaching EDSS 6 (adjusted hazard ratio, 1.1) or EDSS 7 (aHR, 0.93). Longer DMT exposure, however, significantly reduced the risk of reaching EDSS 7 (aHR, 0.73).

Compared with patients with shorter exposure to DMT, patients in the highest quartile of DMT exposure were younger at baseline (mean age, 44.1 years) and initiated DMT closer to disease onset (mean time to DMT initiation was 6.8 years). The propensity score matching analysis confirmed these findings.

The investigators did not consider MRI variables, which Ms. Fonderico acknowledged was a weakness of the study. In addition, they did not analyze the effect of superimposed relapses.

 

A new perspective on primary progressive MS?

These results suggest that primary progressive MS behaves like relapsing-remitting MS, said Gavin Giovannoni, MD, PhD, chair of neurology at Queen Mary University of London. That is, they suggest that primary progressive MS “is modifiable by a DMT and that the earlier you treat, the better the outcome.” The results also indicate that neurologists commonly prescribe DMT off label in Italy, he added.

A weakness of the study is that it was not randomized. Furthermore, “EDSS [evaluations] tend not be done properly in routine clinical practice,” said Dr. Giovannoni. Still, the study raises an important question for future research. “Why have we missed the treatment effect in previous trials?” asked Dr. Giovannoni. Whether previous trials were too short or underpowered could be investigated, he added.

Study funding was not reported. Ms. Fonderico had no relevant disclosures. Dr. Giovannoni had no relevant disclosures.

egreb@mdedge.com

A new study has found that patients with multiple sclerosis (MS) who smoke cigarettes regularly have an increased risk of higher plasma neurofilament light levels (pNfL), which is associated with increased disease activity and reduced response to treatment. At the same time, patients who have stopped smoking have notably lower risk that correlates to how long ago they quit.

“Before, all the studies that were looking at the association between smoking and MS – especially in terms of severity – were using indications like the Expanded Disability Status Scale and the Multiple Sclerosis Severity Score,” said first author Ali Manouchehrinia, PhD, assistant professor at the Karolinska Institute, Stockholm. “Now, we have NfL as a biomarker for disease activity, and we can see the effect of smoking on that biomarker.”

The ultimate goal, he added, “is to tease out the effects of MS severity and disease activity from NfL, to make sure that changes or differences in NfL levels are truly caused by MS and nothing else.”

Dr. Manouchehrinia presented his team’s findings at the virtual annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

To determine any associations between smoking and pNfL levels, the researchers began a retrospective, population-based cohort study of 2,572 Swedish MS patients with a self-reported history of cigarette smoking. Their average age was 38.2 years, slightly more than 71% were women, and their average disease duration was 4.13 years.

Blood samples were collected at each patients’ time of diagnosis to analyze concentrations of pNfL. Three age-stratified pNfL levels were classified: above the 80th (>C80), 95th (>C95), and 99th (>C99) of 1,026 non-MS controls’ percentiles.

Of the 2,572 MS patients, 292 (11.4%) were current regular smokers and 714 (27.8%) were past regular smokers. The past smokers’ median time since quitting was 2 years. Being a current smoker was associated with much higher odds of having pNfL levels at >C99, compared with never smokers (odds ratio, 1.52; 95% confidence interval, 1.12-2.05; P = .007) and past smokers (OR, 1.42; 95% CI, 1.01-1.99; P = .043).

For past smokers who quit between 6 and 10 years ago, the risk of having pNfL levels at >C99 was considerably lower (OR, 0.53; 95% CI, 0.29-0.93; P = .032), compared with current smokers, as was the risk for past smokers who quit more than 10 years ago (OR, 0.50; 95% CI, 0.29-0.84; P = .010). The odds were also lower, though not significantly, for patients who quit 1-5 years ago (OR, 0.84; 95% CI, 0.58-1.22; P = .359).

“It looks like, after 10 years, you go back to the baseline and have the same risk as the never smokers,” Dr. Manouchehrinia said. “But the damage may have already been done. Quitting smoking is good, but it’s better to not smoke at all.”

Dr. Manouchehrinia acknowledged the study’s limitations, including the need to learn more about the role NfL levels – especially plasma NfL levels – play across MS patients, along with the complications surrounding smoking as an environmental factor. He noted that, in Sweden, many people get their nicotine from snuff rather than cigarettes. “Among our MS population, we’ve seen a recent shift toward female snuff users,” which lessens the amount they smoke and could confound the results. In fact, the study indicated that snuff users had less risk of pNfL levels at >C95, compared with nonsnuff users (OR, 0.71; 95% CI, 0.51-0.97; P = .034).

The authors reported several potential conflicts of interest, including receiving research grants and lecture honoraria and serving on advisory boards for various pharmaceutical companies.

A new study has found that patients with multiple sclerosis (MS) who smoke cigarettes regularly have an increased risk of higher plasma neurofilament light levels (pNfL), which is associated with increased disease activity and reduced response to treatment. At the same time, patients who have stopped smoking have notably lower risk that correlates to how long ago they quit.

“Before, all the studies that were looking at the association between smoking and MS – especially in terms of severity – were using indications like the Expanded Disability Status Scale and the Multiple Sclerosis Severity Score,” said first author Ali Manouchehrinia, PhD, assistant professor at the Karolinska Institute, Stockholm. “Now, we have NfL as a biomarker for disease activity, and we can see the effect of smoking on that biomarker.”

The ultimate goal, he added, “is to tease out the effects of MS severity and disease activity from NfL, to make sure that changes or differences in NfL levels are truly caused by MS and nothing else.”

Dr. Manouchehrinia presented his team’s findings at the virtual annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

To determine any associations between smoking and pNfL levels, the researchers began a retrospective, population-based cohort study of 2,572 Swedish MS patients with a self-reported history of cigarette smoking. Their average age was 38.2 years, slightly more than 71% were women, and their average disease duration was 4.13 years.

Blood samples were collected at each patients’ time of diagnosis to analyze concentrations of pNfL. Three age-stratified pNfL levels were classified: above the 80th (>C80), 95th (>C95), and 99th (>C99) of 1,026 non-MS controls’ percentiles.

Of the 2,572 MS patients, 292 (11.4%) were current regular smokers and 714 (27.8%) were past regular smokers. The past smokers’ median time since quitting was 2 years. Being a current smoker was associated with much higher odds of having pNfL levels at >C99, compared with never smokers (odds ratio, 1.52; 95% confidence interval, 1.12-2.05; P = .007) and past smokers (OR, 1.42; 95% CI, 1.01-1.99; P = .043).

For past smokers who quit between 6 and 10 years ago, the risk of having pNfL levels at >C99 was considerably lower (OR, 0.53; 95% CI, 0.29-0.93; P = .032), compared with current smokers, as was the risk for past smokers who quit more than 10 years ago (OR, 0.50; 95% CI, 0.29-0.84; P = .010). The odds were also lower, though not significantly, for patients who quit 1-5 years ago (OR, 0.84; 95% CI, 0.58-1.22; P = .359).

“It looks like, after 10 years, you go back to the baseline and have the same risk as the never smokers,” Dr. Manouchehrinia said. “But the damage may have already been done. Quitting smoking is good, but it’s better to not smoke at all.”

Dr. Manouchehrinia acknowledged the study’s limitations, including the need to learn more about the role NfL levels – especially plasma NfL levels – play across MS patients, along with the complications surrounding smoking as an environmental factor. He noted that, in Sweden, many people get their nicotine from snuff rather than cigarettes. “Among our MS population, we’ve seen a recent shift toward female snuff users,” which lessens the amount they smoke and could confound the results. In fact, the study indicated that snuff users had less risk of pNfL levels at >C95, compared with nonsnuff users (OR, 0.71; 95% CI, 0.51-0.97; P = .034).

The authors reported several potential conflicts of interest, including receiving research grants and lecture honoraria and serving on advisory boards for various pharmaceutical companies.

A new study has found that patients with multiple sclerosis (MS) who smoke cigarettes regularly have an increased risk of higher plasma neurofilament light levels (pNfL), which is associated with increased disease activity and reduced response to treatment. At the same time, patients who have stopped smoking have notably lower risk that correlates to how long ago they quit.

“Before, all the studies that were looking at the association between smoking and MS – especially in terms of severity – were using indications like the Expanded Disability Status Scale and the Multiple Sclerosis Severity Score,” said first author Ali Manouchehrinia, PhD, assistant professor at the Karolinska Institute, Stockholm. “Now, we have NfL as a biomarker for disease activity, and we can see the effect of smoking on that biomarker.”

The ultimate goal, he added, “is to tease out the effects of MS severity and disease activity from NfL, to make sure that changes or differences in NfL levels are truly caused by MS and nothing else.”

Dr. Manouchehrinia presented his team’s findings at the virtual annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

To determine any associations between smoking and pNfL levels, the researchers began a retrospective, population-based cohort study of 2,572 Swedish MS patients with a self-reported history of cigarette smoking. Their average age was 38.2 years, slightly more than 71% were women, and their average disease duration was 4.13 years.

Blood samples were collected at each patients’ time of diagnosis to analyze concentrations of pNfL. Three age-stratified pNfL levels were classified: above the 80th (>C80), 95th (>C95), and 99th (>C99) of 1,026 non-MS controls’ percentiles.

Of the 2,572 MS patients, 292 (11.4%) were current regular smokers and 714 (27.8%) were past regular smokers. The past smokers’ median time since quitting was 2 years. Being a current smoker was associated with much higher odds of having pNfL levels at >C99, compared with never smokers (odds ratio, 1.52; 95% confidence interval, 1.12-2.05; P = .007) and past smokers (OR, 1.42; 95% CI, 1.01-1.99; P = .043).

For past smokers who quit between 6 and 10 years ago, the risk of having pNfL levels at >C99 was considerably lower (OR, 0.53; 95% CI, 0.29-0.93; P = .032), compared with current smokers, as was the risk for past smokers who quit more than 10 years ago (OR, 0.50; 95% CI, 0.29-0.84; P = .010). The odds were also lower, though not significantly, for patients who quit 1-5 years ago (OR, 0.84; 95% CI, 0.58-1.22; P = .359).

“It looks like, after 10 years, you go back to the baseline and have the same risk as the never smokers,” Dr. Manouchehrinia said. “But the damage may have already been done. Quitting smoking is good, but it’s better to not smoke at all.”

Dr. Manouchehrinia acknowledged the study’s limitations, including the need to learn more about the role NfL levels – especially plasma NfL levels – play across MS patients, along with the complications surrounding smoking as an environmental factor. He noted that, in Sweden, many people get their nicotine from snuff rather than cigarettes. “Among our MS population, we’ve seen a recent shift toward female snuff users,” which lessens the amount they smoke and could confound the results. In fact, the study indicated that snuff users had less risk of pNfL levels at >C95, compared with nonsnuff users (OR, 0.71; 95% CI, 0.51-0.97; P = .034).

The authors reported several potential conflicts of interest, including receiving research grants and lecture honoraria and serving on advisory boards for various pharmaceutical companies.