ICYMI Multiple Sclerosis

I had the privilege of attending and speaking at the recent MSVirtual2020—the 8^th Joint ACTRIMS-ECTRIMS Meeting. I came away with a wealth of knowledge, much of which can be put to immediate use in practice, and some that shows the promise of eventual clinical utility.

Dr. Helen Tremlett, PhD, kicked off the meeting with a keynote address covering her important work on the MS prodrome.  The Canada research chair in neuroepidemiology and multiple sclerosis at the University of British Columbia summarized her team’s research to date and offered her thoughts on clinical implications.

Dr. Tremlett’s group has observed that in the five years before an MS symptom onset, individuals who would ultimately be diagnosed tended to experience more hospitalizations, visit their provider more, and fill more prescriptions than did those in the general population. The team dug deeper and found that these individuals experienced a range of issues prior to symptom onset, including pain, headache, migraine, fibromyalgia, irritable bowel syndrome, sleep disturbances, depression/anxiety, and dermatologic issues.

Interestingly, females in this group were less likely to become pregnant and more likely than healthy females to fill an oral contraceptive prescription, suggesting that they were trying to delay pregnancy due to these prodromal symptoms.

Dr. Tremlett noted that the more immediate implications of her group’s work are for clinical researchers, who can now use these findings to understand that there is a prodromal stage as they conduct clinical trials. The ultimate aim is to use this work to develop a diagnostic tool, but that will take more time and study.

COVID-19’s Impact on MS

The impact on COVID-19 on individuals with MS was addressed in a number of sessions. I presented data that clearly shows the risk of infection from COVID-19 is similar to that of the population at large.

• A critical evaluation of MS disease modifying therapies (DMTs) and their potential effects on COVID-19 that I published with my colleagues at the University of Pennsylvania suggested that DMTs might not increase the risk of morbidity and mortality associated with COVID-19 as some had feared. We based this conclusion on an evaluation of pathogenesis of COVID, the importance of the innate immune system in control of exposure to a novel pathogen, and the likely effects, both salutary and pernicious, of DMTs on COVID morbidity and mortality.
•  Investigators from Italy looked at 232 patients from 38 centers with MS and confirmed or suspected COVID and found that the vast majority of them (96%) had mild disease consisting of no or mild pneumonia. The remainder had either severe (2%) or critical (3%) disease.  These investigators have since expanded their observations and suggested that anti-CD20 monoclonal antibody treatment may be associated with a higher risk of hospitalization, though there did not appear to be an increase in the risk of death with their use.  Importantly, the anti-CD20 monoclonal antibody therapies are the DMTs routinely used in patients with progressive MS, generally, the MS population at greatest risk of hospitalization with COVID-19 due to their older age, co-morbidities, and level of debility.
• Recently, French researchers evaluated 347 individuals with MS and COVID by COVID disease severity. They found that there was a higher proportion of patients with severe COVID not receiving DMT compared with individuals receiving treatment (46% and 15%, respectively).

The Increasing Importance of sNfL Concentration

Serum neurofilament light chain (sNfL) concentration continues to be a hot topic. Dr. Jens Kuhle, head of the Multiple Sclerosis Centre at the University of Basel, and colleagues have demonstrated that sNfL levels can play a role in monitoring MS treatment in practice. They evaluated more than 1000 individuals who were taking DMTs, measuring sNfL and deriving a score that reflected how participants fared relative to healthy controls of the same age. Among their findings:

• The resulting score predicted clinical events in the following year, with the effect escalating in magnitude in those whose scores were higher.
• This same predictive effect was seen with respect to future new/enlarging T2 lesions and brain volume loss.
• Score change in patients with NEDA-03 status was linked with a 37% increased risk of clinical events in the following year.

New Radiologic Techniques

Encouraging findings on new radiologic techniques were presented. I found three studies extremely informative. The first two have immediate or near-immediate clinical implications, and the third shows promise.

• In a comparison of patients with MS and healthy individuals who underwent brain 3T MRI to assess lesions and atrophy, R. Bonacchi and colleagues from Milan, Italy found that cardiovascular (CV) risk factors are linked with brain atrophy in patients with MS, even those <50 years of age. Specifically, the presence of at least two CV risk factors was linked with reduced normalized grey matter volume, white matter volume, and brain volume.
• Another comparison of individuals with MS and healthy controls—this one from O. Al-Louzi and colleagues at the National Institute of Neurological Disorders and Stroke—looked at the central vein sign (CVS) biomarker and determined that excluding lesions only if all dimensions of 3T MRI results were less than threshold (versus if any dimension was less than threshold) led to the inclusion of more CVS-positive lesions. Investigators suggested this work could lead to modified clinical guidelines.
• In an evaluation of patients with MS using 3T MRI, F. LaRosa and colleagues from Lausanne, Switzerland reported that RimNet, a prototype built upon two convolutional neural networks, was better than two alternative methods at detecting pragmatic rim lesions, which are linked with higher disease burden. Compared with expert raters, RimNet had higher sensitivity (87% vs 76%) but lower specificity (91% vs 99%).

There were many other valuable presentations at MSVirtual2020, but perhaps the most appreciated experience was the ability to hear more experts deliver their important work. Unlike a live meeting, I was able to easily attend parallel sessions and to do so at my leisure. ECTRIMS has become so big that I often left the live meeting feeling as if I missed out on a lot. Not this year. I heard almost all of it and came away with a greater appreciation of the breadth and depth of the meeting.  I hope that in the future, even following the return of in-person meetings, a virtual format coexists to afford attendees and those unable to attend live the opportunity to experience the totality of the meeting.

I had the privilege of attending and speaking at the recent MSVirtual2020—the 8^th Joint ACTRIMS-ECTRIMS Meeting. I came away with a wealth of knowledge, much of which can be put to immediate use in practice, and some that shows the promise of eventual clinical utility.

Dr. Helen Tremlett, PhD, kicked off the meeting with a keynote address covering her important work on the MS prodrome.  The Canada research chair in neuroepidemiology and multiple sclerosis at the University of British Columbia summarized her team’s research to date and offered her thoughts on clinical implications.

Dr. Tremlett’s group has observed that in the five years before an MS symptom onset, individuals who would ultimately be diagnosed tended to experience more hospitalizations, visit their provider more, and fill more prescriptions than did those in the general population. The team dug deeper and found that these individuals experienced a range of issues prior to symptom onset, including pain, headache, migraine, fibromyalgia, irritable bowel syndrome, sleep disturbances, depression/anxiety, and dermatologic issues.

Interestingly, females in this group were less likely to become pregnant and more likely than healthy females to fill an oral contraceptive prescription, suggesting that they were trying to delay pregnancy due to these prodromal symptoms.

Dr. Tremlett noted that the more immediate implications of her group’s work are for clinical researchers, who can now use these findings to understand that there is a prodromal stage as they conduct clinical trials. The ultimate aim is to use this work to develop a diagnostic tool, but that will take more time and study.

COVID-19’s Impact on MS

The impact on COVID-19 on individuals with MS was addressed in a number of sessions. I presented data that clearly shows the risk of infection from COVID-19 is similar to that of the population at large.

• A critical evaluation of MS disease modifying therapies (DMTs) and their potential effects on COVID-19 that I published with my colleagues at the University of Pennsylvania suggested that DMTs might not increase the risk of morbidity and mortality associated with COVID-19 as some had feared. We based this conclusion on an evaluation of pathogenesis of COVID, the importance of the innate immune system in control of exposure to a novel pathogen, and the likely effects, both salutary and pernicious, of DMTs on COVID morbidity and mortality.
•  Investigators from Italy looked at 232 patients from 38 centers with MS and confirmed or suspected COVID and found that the vast majority of them (96%) had mild disease consisting of no or mild pneumonia. The remainder had either severe (2%) or critical (3%) disease.  These investigators have since expanded their observations and suggested that anti-CD20 monoclonal antibody treatment may be associated with a higher risk of hospitalization, though there did not appear to be an increase in the risk of death with their use.  Importantly, the anti-CD20 monoclonal antibody therapies are the DMTs routinely used in patients with progressive MS, generally, the MS population at greatest risk of hospitalization with COVID-19 due to their older age, co-morbidities, and level of debility.
• Recently, French researchers evaluated 347 individuals with MS and COVID by COVID disease severity. They found that there was a higher proportion of patients with severe COVID not receiving DMT compared with individuals receiving treatment (46% and 15%, respectively).

The Increasing Importance of sNfL Concentration

Serum neurofilament light chain (sNfL) concentration continues to be a hot topic. Dr. Jens Kuhle, head of the Multiple Sclerosis Centre at the University of Basel, and colleagues have demonstrated that sNfL levels can play a role in monitoring MS treatment in practice. They evaluated more than 1000 individuals who were taking DMTs, measuring sNfL and deriving a score that reflected how participants fared relative to healthy controls of the same age. Among their findings:

• The resulting score predicted clinical events in the following year, with the effect escalating in magnitude in those whose scores were higher.
• This same predictive effect was seen with respect to future new/enlarging T2 lesions and brain volume loss.
• Score change in patients with NEDA-03 status was linked with a 37% increased risk of clinical events in the following year.

New Radiologic Techniques

Encouraging findings on new radiologic techniques were presented. I found three studies extremely informative. The first two have immediate or near-immediate clinical implications, and the third shows promise.

• In a comparison of patients with MS and healthy individuals who underwent brain 3T MRI to assess lesions and atrophy, R. Bonacchi and colleagues from Milan, Italy found that cardiovascular (CV) risk factors are linked with brain atrophy in patients with MS, even those <50 years of age. Specifically, the presence of at least two CV risk factors was linked with reduced normalized grey matter volume, white matter volume, and brain volume.
• Another comparison of individuals with MS and healthy controls—this one from O. Al-Louzi and colleagues at the National Institute of Neurological Disorders and Stroke—looked at the central vein sign (CVS) biomarker and determined that excluding lesions only if all dimensions of 3T MRI results were less than threshold (versus if any dimension was less than threshold) led to the inclusion of more CVS-positive lesions. Investigators suggested this work could lead to modified clinical guidelines.
• In an evaluation of patients with MS using 3T MRI, F. LaRosa and colleagues from Lausanne, Switzerland reported that RimNet, a prototype built upon two convolutional neural networks, was better than two alternative methods at detecting pragmatic rim lesions, which are linked with higher disease burden. Compared with expert raters, RimNet had higher sensitivity (87% vs 76%) but lower specificity (91% vs 99%).

There were many other valuable presentations at MSVirtual2020, but perhaps the most appreciated experience was the ability to hear more experts deliver their important work. Unlike a live meeting, I was able to easily attend parallel sessions and to do so at my leisure. ECTRIMS has become so big that I often left the live meeting feeling as if I missed out on a lot. Not this year. I heard almost all of it and came away with a greater appreciation of the breadth and depth of the meeting.  I hope that in the future, even following the return of in-person meetings, a virtual format coexists to afford attendees and those unable to attend live the opportunity to experience the totality of the meeting.

I had the privilege of attending and speaking at the recent MSVirtual2020—the 8^th Joint ACTRIMS-ECTRIMS Meeting. I came away with a wealth of knowledge, much of which can be put to immediate use in practice, and some that shows the promise of eventual clinical utility.

Dr. Helen Tremlett, PhD, kicked off the meeting with a keynote address covering her important work on the MS prodrome.  The Canada research chair in neuroepidemiology and multiple sclerosis at the University of British Columbia summarized her team’s research to date and offered her thoughts on clinical implications.

Dr. Tremlett’s group has observed that in the five years before an MS symptom onset, individuals who would ultimately be diagnosed tended to experience more hospitalizations, visit their provider more, and fill more prescriptions than did those in the general population. The team dug deeper and found that these individuals experienced a range of issues prior to symptom onset, including pain, headache, migraine, fibromyalgia, irritable bowel syndrome, sleep disturbances, depression/anxiety, and dermatologic issues.

Interestingly, females in this group were less likely to become pregnant and more likely than healthy females to fill an oral contraceptive prescription, suggesting that they were trying to delay pregnancy due to these prodromal symptoms.

Dr. Tremlett noted that the more immediate implications of her group’s work are for clinical researchers, who can now use these findings to understand that there is a prodromal stage as they conduct clinical trials. The ultimate aim is to use this work to develop a diagnostic tool, but that will take more time and study.

COVID-19’s Impact on MS

The impact on COVID-19 on individuals with MS was addressed in a number of sessions. I presented data that clearly shows the risk of infection from COVID-19 is similar to that of the population at large.

• A critical evaluation of MS disease modifying therapies (DMTs) and their potential effects on COVID-19 that I published with my colleagues at the University of Pennsylvania suggested that DMTs might not increase the risk of morbidity and mortality associated with COVID-19 as some had feared. We based this conclusion on an evaluation of pathogenesis of COVID, the importance of the innate immune system in control of exposure to a novel pathogen, and the likely effects, both salutary and pernicious, of DMTs on COVID morbidity and mortality.
•  Investigators from Italy looked at 232 patients from 38 centers with MS and confirmed or suspected COVID and found that the vast majority of them (96%) had mild disease consisting of no or mild pneumonia. The remainder had either severe (2%) or critical (3%) disease.  These investigators have since expanded their observations and suggested that anti-CD20 monoclonal antibody treatment may be associated with a higher risk of hospitalization, though there did not appear to be an increase in the risk of death with their use.  Importantly, the anti-CD20 monoclonal antibody therapies are the DMTs routinely used in patients with progressive MS, generally, the MS population at greatest risk of hospitalization with COVID-19 due to their older age, co-morbidities, and level of debility.
• Recently, French researchers evaluated 347 individuals with MS and COVID by COVID disease severity. They found that there was a higher proportion of patients with severe COVID not receiving DMT compared with individuals receiving treatment (46% and 15%, respectively).

The Increasing Importance of sNfL Concentration

Serum neurofilament light chain (sNfL) concentration continues to be a hot topic. Dr. Jens Kuhle, head of the Multiple Sclerosis Centre at the University of Basel, and colleagues have demonstrated that sNfL levels can play a role in monitoring MS treatment in practice. They evaluated more than 1000 individuals who were taking DMTs, measuring sNfL and deriving a score that reflected how participants fared relative to healthy controls of the same age. Among their findings:

• The resulting score predicted clinical events in the following year, with the effect escalating in magnitude in those whose scores were higher.
• This same predictive effect was seen with respect to future new/enlarging T2 lesions and brain volume loss.
• Score change in patients with NEDA-03 status was linked with a 37% increased risk of clinical events in the following year.

New Radiologic Techniques

Encouraging findings on new radiologic techniques were presented. I found three studies extremely informative. The first two have immediate or near-immediate clinical implications, and the third shows promise.

• In a comparison of patients with MS and healthy individuals who underwent brain 3T MRI to assess lesions and atrophy, R. Bonacchi and colleagues from Milan, Italy found that cardiovascular (CV) risk factors are linked with brain atrophy in patients with MS, even those <50 years of age. Specifically, the presence of at least two CV risk factors was linked with reduced normalized grey matter volume, white matter volume, and brain volume.
• Another comparison of individuals with MS and healthy controls—this one from O. Al-Louzi and colleagues at the National Institute of Neurological Disorders and Stroke—looked at the central vein sign (CVS) biomarker and determined that excluding lesions only if all dimensions of 3T MRI results were less than threshold (versus if any dimension was less than threshold) led to the inclusion of more CVS-positive lesions. Investigators suggested this work could lead to modified clinical guidelines.
• In an evaluation of patients with MS using 3T MRI, F. LaRosa and colleagues from Lausanne, Switzerland reported that RimNet, a prototype built upon two convolutional neural networks, was better than two alternative methods at detecting pragmatic rim lesions, which are linked with higher disease burden. Compared with expert raters, RimNet had higher sensitivity (87% vs 76%) but lower specificity (91% vs 99%).

There were many other valuable presentations at MSVirtual2020, but perhaps the most appreciated experience was the ability to hear more experts deliver their important work. Unlike a live meeting, I was able to easily attend parallel sessions and to do so at my leisure. ECTRIMS has become so big that I often left the live meeting feeling as if I missed out on a lot. Not this year. I heard almost all of it and came away with a greater appreciation of the breadth and depth of the meeting.  I hope that in the future, even following the return of in-person meetings, a virtual format coexists to afford attendees and those unable to attend live the opportunity to experience the totality of the meeting.

Key clinical point: Increased high-density lipoprotein cholesterol (HDL-C) is associated with decreased gray matter and cortical atrophy in patients with multiple sclerosis (MS) after adjusting for baseline serum neurofilaments (sNfL).

Major finding: Gray matter volume and cortical volume had significant associations with percent change in HDL-C (P = .0024 and P less than .001, respectively) after adjusting for sNfL as a predictor.

Study details: This prospective longitudinal study assessed patients with relapsing-remitting MS (n = 75) and progressive multiple sclerosis (n = 37) over a 5-year follow-up period.

Disclosures: The study was funded by the National Center for Advancing Translational Sciences of the National Institutes of Health. B Weinstock-Guttman, J Kuhle, R Zivadinov and M Ramanathan reported ties with multiple pharmaceutical companies. The remaining authors declared no conflicts of interest.

Citation: McComb M et al. Mult Scler Relat Disord. 2020 Jul 11. doi: 10.1016/j.msard.2020.102389.

Key clinical point: Increased high-density lipoprotein cholesterol (HDL-C) is associated with decreased gray matter and cortical atrophy in patients with multiple sclerosis (MS) after adjusting for baseline serum neurofilaments (sNfL).

Major finding: Gray matter volume and cortical volume had significant associations with percent change in HDL-C (P = .0024 and P less than .001, respectively) after adjusting for sNfL as a predictor.

Study details: This prospective longitudinal study assessed patients with relapsing-remitting MS (n = 75) and progressive multiple sclerosis (n = 37) over a 5-year follow-up period.

Disclosures: The study was funded by the National Center for Advancing Translational Sciences of the National Institutes of Health. B Weinstock-Guttman, J Kuhle, R Zivadinov and M Ramanathan reported ties with multiple pharmaceutical companies. The remaining authors declared no conflicts of interest.

Citation: McComb M et al. Mult Scler Relat Disord. 2020 Jul 11. doi: 10.1016/j.msard.2020.102389.

Key clinical point: Increased high-density lipoprotein cholesterol (HDL-C) is associated with decreased gray matter and cortical atrophy in patients with multiple sclerosis (MS) after adjusting for baseline serum neurofilaments (sNfL).

Major finding: Gray matter volume and cortical volume had significant associations with percent change in HDL-C (P = .0024 and P less than .001, respectively) after adjusting for sNfL as a predictor.

Study details: This prospective longitudinal study assessed patients with relapsing-remitting MS (n = 75) and progressive multiple sclerosis (n = 37) over a 5-year follow-up period.

Disclosures: The study was funded by the National Center for Advancing Translational Sciences of the National Institutes of Health. B Weinstock-Guttman, J Kuhle, R Zivadinov and M Ramanathan reported ties with multiple pharmaceutical companies. The remaining authors declared no conflicts of interest.

Citation: McComb M et al. Mult Scler Relat Disord. 2020 Jul 11. doi: 10.1016/j.msard.2020.102389.

Key clinical point: Early and continuous ocrelizumab treatment can provide sustained benefit on clinical and magnetic resonance imaging measures for disease progression in patients with relapsing multiple sclerosis (MS).

Major finding: At 5 years, the cumulative proportion of patients with 24-week confirmed disability progression was lower among those who continued ocrelizumab vs those who switched from interferon (IFN) β-1a to ocrelizumab (16.1% vs 21.3%; P = .014). Similarly, brain atrophy was significantly lower among those who continued ocrelizumab than in those who switched to ocrelizumab (P less than .01).

Study details: The OPERA open label extension study evaluated long-term efficacy and safety (5 years follow-up) of ocrelizumab (600 mg) in adults with relapsing MS. Patients previously assigned to INF β-1a  (n = 829) and ocrelizumab (n = 827) entered the open-label extension phase in this study, of which 623 switched to ocrelizumab and 702 continued ocrelizumab, respectively

Disclosures: This study was supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland. The lead author reporting receiving travel reimbursement and writing assistance from F. Hoffmann-La Roche Ltd for CD20-related meetings and presentations. Some of his coinvestigators reported owning stock in, being an employee of, receiving support from, and/or serving on scientific advisory board for F. Hoffmann-La Roche Ltd.

Citation: Hauser SL et al. Neurology. 2020 Jul 20. doi: 10.1212/WNL.0000000000010376.

Key clinical point: Early and continuous ocrelizumab treatment can provide sustained benefit on clinical and magnetic resonance imaging measures for disease progression in patients with relapsing multiple sclerosis (MS).

Major finding: At 5 years, the cumulative proportion of patients with 24-week confirmed disability progression was lower among those who continued ocrelizumab vs those who switched from interferon (IFN) β-1a to ocrelizumab (16.1% vs 21.3%; P = .014). Similarly, brain atrophy was significantly lower among those who continued ocrelizumab than in those who switched to ocrelizumab (P less than .01).

Study details: The OPERA open label extension study evaluated long-term efficacy and safety (5 years follow-up) of ocrelizumab (600 mg) in adults with relapsing MS. Patients previously assigned to INF β-1a  (n = 829) and ocrelizumab (n = 827) entered the open-label extension phase in this study, of which 623 switched to ocrelizumab and 702 continued ocrelizumab, respectively

Disclosures: This study was supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland. The lead author reporting receiving travel reimbursement and writing assistance from F. Hoffmann-La Roche Ltd for CD20-related meetings and presentations. Some of his coinvestigators reported owning stock in, being an employee of, receiving support from, and/or serving on scientific advisory board for F. Hoffmann-La Roche Ltd.

Citation: Hauser SL et al. Neurology. 2020 Jul 20. doi: 10.1212/WNL.0000000000010376.

Key clinical point: Early and continuous ocrelizumab treatment can provide sustained benefit on clinical and magnetic resonance imaging measures for disease progression in patients with relapsing multiple sclerosis (MS).

Major finding: At 5 years, the cumulative proportion of patients with 24-week confirmed disability progression was lower among those who continued ocrelizumab vs those who switched from interferon (IFN) β-1a to ocrelizumab (16.1% vs 21.3%; P = .014). Similarly, brain atrophy was significantly lower among those who continued ocrelizumab than in those who switched to ocrelizumab (P less than .01).

Study details: The OPERA open label extension study evaluated long-term efficacy and safety (5 years follow-up) of ocrelizumab (600 mg) in adults with relapsing MS. Patients previously assigned to INF β-1a  (n = 829) and ocrelizumab (n = 827) entered the open-label extension phase in this study, of which 623 switched to ocrelizumab and 702 continued ocrelizumab, respectively

Disclosures: This study was supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland. The lead author reporting receiving travel reimbursement and writing assistance from F. Hoffmann-La Roche Ltd for CD20-related meetings and presentations. Some of his coinvestigators reported owning stock in, being an employee of, receiving support from, and/or serving on scientific advisory board for F. Hoffmann-La Roche Ltd.

Citation: Hauser SL et al. Neurology. 2020 Jul 20. doi: 10.1212/WNL.0000000000010376.

Key clinical point: Real-world data demonstrates effectiveness of rituximab in reducing disease activity and maintaining long-term treatment in patients with multiple sclerosis (MS).

Major finding: The odds for experiencing a clinical relapse, contrast-enhancing lesions (CEL), and/or new T2 lesions were greater with fingolimod  (adjusted odds ratio [aOR], 3.17; P less than .001)  and dimethyl fumarate (aOR, 2.68; P less than .001) compared with rituximab. Similarly, natalizimab vs rituximab showed higher odds for disease activity (aOR, 1.36; P = 0.216). The odds for discontinuation were higher for fingolimod (aOR, 2.02; P = .005) and dimethyl fumarate (aOR, 3.27; P less than .001) compared with rituximab.

Study details: A retrospective real-world study included MS patients who were initiated on rituximab (n = 182), natalizumab (n = 451), fingolimod (n = 271) or dimethyl fumarate (n = 342) and followed for 2 years.

Disclosures: This study received no funding. KV Nair, JR Corboy, T Vollmer and E Alvarez reported relationships with multiple pharmaceutical companies.

Citation: Vollmer BL et al. Ann Clin Transl Neurol. 2020 Aug 6. doi: 10.1002/acn3.51111.

Key clinical point: Real-world data demonstrates effectiveness of rituximab in reducing disease activity and maintaining long-term treatment in patients with multiple sclerosis (MS).

Major finding: The odds for experiencing a clinical relapse, contrast-enhancing lesions (CEL), and/or new T2 lesions were greater with fingolimod  (adjusted odds ratio [aOR], 3.17; P less than .001)  and dimethyl fumarate (aOR, 2.68; P less than .001) compared with rituximab. Similarly, natalizimab vs rituximab showed higher odds for disease activity (aOR, 1.36; P = 0.216). The odds for discontinuation were higher for fingolimod (aOR, 2.02; P = .005) and dimethyl fumarate (aOR, 3.27; P less than .001) compared with rituximab.

Study details: A retrospective real-world study included MS patients who were initiated on rituximab (n = 182), natalizumab (n = 451), fingolimod (n = 271) or dimethyl fumarate (n = 342) and followed for 2 years.

Disclosures: This study received no funding. KV Nair, JR Corboy, T Vollmer and E Alvarez reported relationships with multiple pharmaceutical companies.

Citation: Vollmer BL et al. Ann Clin Transl Neurol. 2020 Aug 6. doi: 10.1002/acn3.51111.

Key clinical point: Real-world data demonstrates effectiveness of rituximab in reducing disease activity and maintaining long-term treatment in patients with multiple sclerosis (MS).

Major finding: The odds for experiencing a clinical relapse, contrast-enhancing lesions (CEL), and/or new T2 lesions were greater with fingolimod  (adjusted odds ratio [aOR], 3.17; P less than .001)  and dimethyl fumarate (aOR, 2.68; P less than .001) compared with rituximab. Similarly, natalizimab vs rituximab showed higher odds for disease activity (aOR, 1.36; P = 0.216). The odds for discontinuation were higher for fingolimod (aOR, 2.02; P = .005) and dimethyl fumarate (aOR, 3.27; P less than .001) compared with rituximab.

Study details: A retrospective real-world study included MS patients who were initiated on rituximab (n = 182), natalizumab (n = 451), fingolimod (n = 271) or dimethyl fumarate (n = 342) and followed for 2 years.

Disclosures: This study received no funding. KV Nair, JR Corboy, T Vollmer and E Alvarez reported relationships with multiple pharmaceutical companies.

Citation: Vollmer BL et al. Ann Clin Transl Neurol. 2020 Aug 6. doi: 10.1002/acn3.51111.

Key clinical point: Elevated blood lipid parameters in patients with multiple sclerosis (MS) may harm cognitive functions.

Major finding: A negative correlation was observed between cholesterol and general cognitive functioning score after rehabilitation and the Expanded Disability Status Scale scores (Cronbach alpha, 0.60 and 0.65, respectively). Triglyceride scores also has a negative correlation with working memory scores before and after rehabilitation (Cronbach alpha, 0.36 and 0.40, respectively). Furthermore, body mass index scores had a negative correlation with the visuospatial ability (Cronbach alpha, 0.59)

Study details: The study included 90 inpatients with relapsing remitting, primary and secondary progressive MS who underwent intense neurorehabilitation training.

Disclosures: The study received no funding. The authors reported no conflicts of interest.

Citation: Andaloro A et al. Int J Neurosci. 2020 Aug 7. doi: 10.1080/00207454.2020.1807980.

Key clinical point: Elevated blood lipid parameters in patients with multiple sclerosis (MS) may harm cognitive functions.

Major finding: A negative correlation was observed between cholesterol and general cognitive functioning score after rehabilitation and the Expanded Disability Status Scale scores (Cronbach alpha, 0.60 and 0.65, respectively). Triglyceride scores also has a negative correlation with working memory scores before and after rehabilitation (Cronbach alpha, 0.36 and 0.40, respectively). Furthermore, body mass index scores had a negative correlation with the visuospatial ability (Cronbach alpha, 0.59)

Study details: The study included 90 inpatients with relapsing remitting, primary and secondary progressive MS who underwent intense neurorehabilitation training.

Disclosures: The study received no funding. The authors reported no conflicts of interest.

Citation: Andaloro A et al. Int J Neurosci. 2020 Aug 7. doi: 10.1080/00207454.2020.1807980.

Key clinical point: Elevated blood lipid parameters in patients with multiple sclerosis (MS) may harm cognitive functions.

Major finding: A negative correlation was observed between cholesterol and general cognitive functioning score after rehabilitation and the Expanded Disability Status Scale scores (Cronbach alpha, 0.60 and 0.65, respectively). Triglyceride scores also has a negative correlation with working memory scores before and after rehabilitation (Cronbach alpha, 0.36 and 0.40, respectively). Furthermore, body mass index scores had a negative correlation with the visuospatial ability (Cronbach alpha, 0.59)

Study details: The study included 90 inpatients with relapsing remitting, primary and secondary progressive MS who underwent intense neurorehabilitation training.

Disclosures: The study received no funding. The authors reported no conflicts of interest.

Citation: Andaloro A et al. Int J Neurosci. 2020 Aug 7. doi: 10.1080/00207454.2020.1807980.

In patients with pediatric-onset multiple sclerosis (MS), increased abundance of Blautia stercoris and its variants in the gut is associated with an increased risk of relapse. No broad differences in gut bacterial composition, however, are associated with risk of relapse, according to the investigators. The findings 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.

Previous research has found an association between Blautia stercoris and disease activity in other immune-mediated diseases such as systemic lupus. Although the current study is the largest in patients with MS that includes data about the microbiome and relapses, its findings require replication, said Mary Horton, a doctoral candidate in epidemiology at the University of California, Berkeley.

Gut microbes digest food, produce vitamins (for example, B12 and K), create a barrier against pathogens, and regulate the immune system, among other tasks. Most current knowledge about the gut microbiome in MS comes from studies of patients with adult-onset MS. In 2016, Tremlett et al. found an increase in Desulfovibrionaceae and a decrease in Lachnospiraceae and Ruminococcaceae in patients with pediatric-onset MS. They also found that a decrease in Fusobacteria was associated with risk of relapse in this population.
 

Advanced analytical methods

Using a larger sample size and newer analytical methods than in the study by Tremlett and colleagues, Ms. Horton’s group sought to determine whether features of the gut microbiome are associated with relapse. From 2014 to 2018, the investigators recruited 53 patients with pediatric-onset MS from the University of California, San Francisco, and six centers in the U.S. Network of Pediatric MS Centers. At baseline, they collected stool samples, blood samples, information about past relapses, medication records, demographics, and environmental factors. At each relapse, the investigators collected information about the patient’s current and past medication use and about relapses that the patient had had since the previous visit.

Ms. Horton and colleagues analyzed the stool samples using 16S rRNA sequencing of the V4 region. They identified amplicon sequence variants (ASVs), which are used to define species of bacteria, with the Divisive Amplicon Denoising Algorithm-2 (DADA2). Taxonomies were assigned using the naive Bayesian classifier method, and the read count was normalized using multiple rarefaction.

The investigators identified ASV clusters using weighted genetic correlation network analysis (WGCNA). To evaluate whether individual ASVs were associated with relapse, they used a Prentice, Williams, and Peterson (PWP) recurrent event model, an extension of the Cox proportional hazards model.
 

The role of methanogenesis

Ms. Horton and colleagues included 53 patients (72% girls) in their study. The population’s mean age was 14.3 years at disease onset and 15.5 years at stool sample collection. About 70% of patients were White, and about 36% were Hispanic. Mean disease duration was 1.3 years, and median Expanded Disability Status Scale score was 1.0.

Approximately 45% of participants had one relapse, and 30% had more than one relapse during the subsequent mean follow-up of 2.5 years. About 91% of patients used a disease-modifying therapy during follow-up.

Gut bacterial abundance was broadly similar between patients who relapsed during the study period and those who did not. Of 270 ASVs included in the analyses, 20 were nominally associated with risk of relapse. Blautia stercoris had the most significant association with relapse risk (hazard ratio, 2.50). Blautia massiliensis also was among the 20 ASVs associated with risk of relapse.

WGCNA identified six ASV clusters. Higher values of one cluster’s eigengene were significantly associated with higher relapse risk (HR, 1.23). The following four ASVs nominally associated with higher relapse risk were in this cluster: Blautia massiliensis, Dorea longicatena, Coprococcus comes, and an unknown species in genus Subdoligranulum.

When Ms. Horton and colleagues examined the pathways from these bacterial species, they found 10 that were significantly associated with the risk of relapse. Four of these 10 pathways are involved in methane production, which suggests the involvement of methanogenesis pathways in relapse.

Although the investigators used advanced techniques for genetic and statistical analysis, the study’s sample size is small, Ms. Horton acknowledged. In addition, the conclusions that can be drawn from observational data are limited.

These suggest several avenues for future research. “There is a big question about how the different treatments that people are on when they are experiencing relapses might impact the microbiome,” said Ms. Horton. “Is the microbiome impacting your treatment response, or is it the reverse?” Investigators also could examine why the methane production pathway is overrepresented among people with MS who have relapses. “Which specific archaea might be leading to that increase in methane is a ripe future study question. Just what that means for health is really unknown.”

The National MS Society and the National Institute of Neurological Disorders and Stroke provided funding for the study. Ms. Horton had no disclosures.

[email protected]

SOURCE: Horton M et al. MSVirtual2020, Abstract LB01.05.

In patients with pediatric-onset multiple sclerosis (MS), increased abundance of Blautia stercoris and its variants in the gut is associated with an increased risk of relapse. No broad differences in gut bacterial composition, however, are associated with risk of relapse, according to the investigators. The findings 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.

Previous research has found an association between Blautia stercoris and disease activity in other immune-mediated diseases such as systemic lupus. Although the current study is the largest in patients with MS that includes data about the microbiome and relapses, its findings require replication, said Mary Horton, a doctoral candidate in epidemiology at the University of California, Berkeley.

Gut microbes digest food, produce vitamins (for example, B12 and K), create a barrier against pathogens, and regulate the immune system, among other tasks. Most current knowledge about the gut microbiome in MS comes from studies of patients with adult-onset MS. In 2016, Tremlett et al. found an increase in Desulfovibrionaceae and a decrease in Lachnospiraceae and Ruminococcaceae in patients with pediatric-onset MS. They also found that a decrease in Fusobacteria was associated with risk of relapse in this population.
 

Advanced analytical methods

Using a larger sample size and newer analytical methods than in the study by Tremlett and colleagues, Ms. Horton’s group sought to determine whether features of the gut microbiome are associated with relapse. From 2014 to 2018, the investigators recruited 53 patients with pediatric-onset MS from the University of California, San Francisco, and six centers in the U.S. Network of Pediatric MS Centers. At baseline, they collected stool samples, blood samples, information about past relapses, medication records, demographics, and environmental factors. At each relapse, the investigators collected information about the patient’s current and past medication use and about relapses that the patient had had since the previous visit.

Ms. Horton and colleagues analyzed the stool samples using 16S rRNA sequencing of the V4 region. They identified amplicon sequence variants (ASVs), which are used to define species of bacteria, with the Divisive Amplicon Denoising Algorithm-2 (DADA2). Taxonomies were assigned using the naive Bayesian classifier method, and the read count was normalized using multiple rarefaction.

The investigators identified ASV clusters using weighted genetic correlation network analysis (WGCNA). To evaluate whether individual ASVs were associated with relapse, they used a Prentice, Williams, and Peterson (PWP) recurrent event model, an extension of the Cox proportional hazards model.
 

The role of methanogenesis

Ms. Horton and colleagues included 53 patients (72% girls) in their study. The population’s mean age was 14.3 years at disease onset and 15.5 years at stool sample collection. About 70% of patients were White, and about 36% were Hispanic. Mean disease duration was 1.3 years, and median Expanded Disability Status Scale score was 1.0.

Approximately 45% of participants had one relapse, and 30% had more than one relapse during the subsequent mean follow-up of 2.5 years. About 91% of patients used a disease-modifying therapy during follow-up.

Gut bacterial abundance was broadly similar between patients who relapsed during the study period and those who did not. Of 270 ASVs included in the analyses, 20 were nominally associated with risk of relapse. Blautia stercoris had the most significant association with relapse risk (hazard ratio, 2.50). Blautia massiliensis also was among the 20 ASVs associated with risk of relapse.

WGCNA identified six ASV clusters. Higher values of one cluster’s eigengene were significantly associated with higher relapse risk (HR, 1.23). The following four ASVs nominally associated with higher relapse risk were in this cluster: Blautia massiliensis, Dorea longicatena, Coprococcus comes, and an unknown species in genus Subdoligranulum.

When Ms. Horton and colleagues examined the pathways from these bacterial species, they found 10 that were significantly associated with the risk of relapse. Four of these 10 pathways are involved in methane production, which suggests the involvement of methanogenesis pathways in relapse.

Although the investigators used advanced techniques for genetic and statistical analysis, the study’s sample size is small, Ms. Horton acknowledged. In addition, the conclusions that can be drawn from observational data are limited.

These suggest several avenues for future research. “There is a big question about how the different treatments that people are on when they are experiencing relapses might impact the microbiome,” said Ms. Horton. “Is the microbiome impacting your treatment response, or is it the reverse?” Investigators also could examine why the methane production pathway is overrepresented among people with MS who have relapses. “Which specific archaea might be leading to that increase in methane is a ripe future study question. Just what that means for health is really unknown.”

The National MS Society and the National Institute of Neurological Disorders and Stroke provided funding for the study. Ms. Horton had no disclosures.

[email protected]

SOURCE: Horton M et al. MSVirtual2020, Abstract LB01.05.

In patients with pediatric-onset multiple sclerosis (MS), increased abundance of Blautia stercoris and its variants in the gut is associated with an increased risk of relapse. No broad differences in gut bacterial composition, however, are associated with risk of relapse, according to the investigators. The findings 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.

Previous research has found an association between Blautia stercoris and disease activity in other immune-mediated diseases such as systemic lupus. Although the current study is the largest in patients with MS that includes data about the microbiome and relapses, its findings require replication, said Mary Horton, a doctoral candidate in epidemiology at the University of California, Berkeley.

Gut microbes digest food, produce vitamins (for example, B12 and K), create a barrier against pathogens, and regulate the immune system, among other tasks. Most current knowledge about the gut microbiome in MS comes from studies of patients with adult-onset MS. In 2016, Tremlett et al. found an increase in Desulfovibrionaceae and a decrease in Lachnospiraceae and Ruminococcaceae in patients with pediatric-onset MS. They also found that a decrease in Fusobacteria was associated with risk of relapse in this population.
 

Advanced analytical methods

Using a larger sample size and newer analytical methods than in the study by Tremlett and colleagues, Ms. Horton’s group sought to determine whether features of the gut microbiome are associated with relapse. From 2014 to 2018, the investigators recruited 53 patients with pediatric-onset MS from the University of California, San Francisco, and six centers in the U.S. Network of Pediatric MS Centers. At baseline, they collected stool samples, blood samples, information about past relapses, medication records, demographics, and environmental factors. At each relapse, the investigators collected information about the patient’s current and past medication use and about relapses that the patient had had since the previous visit.

Ms. Horton and colleagues analyzed the stool samples using 16S rRNA sequencing of the V4 region. They identified amplicon sequence variants (ASVs), which are used to define species of bacteria, with the Divisive Amplicon Denoising Algorithm-2 (DADA2). Taxonomies were assigned using the naive Bayesian classifier method, and the read count was normalized using multiple rarefaction.

The investigators identified ASV clusters using weighted genetic correlation network analysis (WGCNA). To evaluate whether individual ASVs were associated with relapse, they used a Prentice, Williams, and Peterson (PWP) recurrent event model, an extension of the Cox proportional hazards model.
 

The role of methanogenesis

Ms. Horton and colleagues included 53 patients (72% girls) in their study. The population’s mean age was 14.3 years at disease onset and 15.5 years at stool sample collection. About 70% of patients were White, and about 36% were Hispanic. Mean disease duration was 1.3 years, and median Expanded Disability Status Scale score was 1.0.

Approximately 45% of participants had one relapse, and 30% had more than one relapse during the subsequent mean follow-up of 2.5 years. About 91% of patients used a disease-modifying therapy during follow-up.

Gut bacterial abundance was broadly similar between patients who relapsed during the study period and those who did not. Of 270 ASVs included in the analyses, 20 were nominally associated with risk of relapse. Blautia stercoris had the most significant association with relapse risk (hazard ratio, 2.50). Blautia massiliensis also was among the 20 ASVs associated with risk of relapse.

WGCNA identified six ASV clusters. Higher values of one cluster’s eigengene were significantly associated with higher relapse risk (HR, 1.23). The following four ASVs nominally associated with higher relapse risk were in this cluster: Blautia massiliensis, Dorea longicatena, Coprococcus comes, and an unknown species in genus Subdoligranulum.

When Ms. Horton and colleagues examined the pathways from these bacterial species, they found 10 that were significantly associated with the risk of relapse. Four of these 10 pathways are involved in methane production, which suggests the involvement of methanogenesis pathways in relapse.

Although the investigators used advanced techniques for genetic and statistical analysis, the study’s sample size is small, Ms. Horton acknowledged. In addition, the conclusions that can be drawn from observational data are limited.

These suggest several avenues for future research. “There is a big question about how the different treatments that people are on when they are experiencing relapses might impact the microbiome,” said Ms. Horton. “Is the microbiome impacting your treatment response, or is it the reverse?” Investigators also could examine why the methane production pathway is overrepresented among people with MS who have relapses. “Which specific archaea might be leading to that increase in methane is a ripe future study question. Just what that means for health is really unknown.”

The National MS Society and the National Institute of Neurological Disorders and Stroke provided funding for the study. Ms. Horton had no disclosures.

[email protected]

SOURCE: Horton M et al. MSVirtual2020, Abstract LB01.05.

The risk of severe outcomes from COVID-19 infection in patients with multiple sclerosis (MS) seems to align with that seen in the general population, new U.S. data suggest. A separate study from the United Kingdom also found similar trends of rates of COVID-19 infection in patients with MS and the general population.

Both studies were presented Sept. 26 at a special session on multiple sclerosis and COVID-19 at a final “Encore” event as part of 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.

The U.S. data appear consistent with studies from several other countries, in that worse COVID-19 outcomes increase with age and higher disability levels, both of which would be expected from findings in the general population.

The U.S. data also show a clear effect of race in MS, with higher rates of adverse COVID-19 outcomes in Black patients, again in line with what is seen in the general population.

“I would say the results from our study and in general do not suggest that MS itself is associated with higher risks of severe COVID-19 outcomes, compared with the general population,” said Amber Salter, PhD.

Dr. Salter, who is assistant professor of biostatistics at Washington University, St. Louis, presented data from the COViMS North American registry, set up for health care providers to report persons with MS who are infected with COVID-19.

The COViMS registry so far has information on 858 patients with MS who have COVID-19 (80% verified by a positive test), as reported from 150 different health care providers in the United States and Canada. The average age was 48 years, with average disease duration of 13.6 years. MS clinical course was reported as relapsing remitting in 78%, secondary progressive in 15%, and primary progressive in 5%. Most patients (72%) were fully ambulatory, 16% could walk with assistance, and 12% were nonambulatory.

Severe COVID-19 outcomes were classified as mortality (which occurred in 5.7% of the cohort), mortality/ICU admission (13.6%) and mortality/ICU admission/hospitalization (30.2%).

Results were adjusted for many different covariates, including sex, age, smoking, MS clinical course (relapsing, progressive), disease duration, ambulation, individual comorbidities (cardiovascular disease, cerebrovascular disease, chronic kidney disease, chronic lung disease, diabetes, hypertension, morbid obesity), and disease-modifying therapy use.

In multivariable logistic regression analyses, older age, having chronic renal disease, and being nonambulatory were consistently associated with increased odds of poorer outcomes. Chronic kidney disease had the strongest association with mortality (odds ratio, 28.6; P < .001). Other factors associated with mortality included cardiovascular disease (OR, 4.35; P = .009); age (OR per 10 years, 1.91; P = .012), and male sex (OR, 2.60; P = .041).

Patients who were nonambulatory had a higher risk of mortality/ICU admission/hospitalization (OR, 3.32; P = .003). This endpoint was also increased in patients on anti-CD20 drugs, compared with other disease-modifying treatment (OR, 2.31; P = .002), consistent with results from at least two other studies.

Disease-modifying therapy in general was not associated with an increased risk of worse outcomes. “There was some concern at the outset about the effect of disease-modifying therapies on COVID-19 outcomes, but most studies have not found an increased risk of worse outcomes in patients on such drug treatments, with the possible exception of anti-CD20 drugs,” Dr. Salter said.

“Some disease-modifying therapies may actually be protective (particularly interferon) and studies are investigating whether they may have a role in the treatment of COVID-19,” she added.

“The factors in MS patients that we and others have found to be associated with worse COVID-19 outcomes may not be specific to MS. Older age is known to be a primary risk factor for worse COVID-19 outcomes in the general population, and increasing disability presumably tracks with worse general heath,” Dr. Salter commented.

“I would say the overall data are fairly reassuring for MS patents,” she concluded.
 

Black patients have higher risk

One worrying finding in the North American data, however, was the effect of race. “We found an independent effect of race for worse COVID-19 outcomes in MS patients,” Dr. Slater said.

Of the 858 patients in the COViMS registry, 65.7% were White and 26.1% were Black. Black individuals were more likely to be younger, never smokers, have shorter MS duration, a relapsing MS course, and have comorbidities, compared with White patients. A higher proportion of Black patients had hypertension (40.2% vs 19.5%) and morbid obesity (17% vs. 9.5%).

Results showed that mortality rates were not statistically different between White and Black patients, but Black race was associated with increased risk of mortality and/or ICU admission, compared with White patients (16.9% vs. 12.8%), and multivariate logistic regression analysis showed Black race was independently associated with mortality/ICU admission after adjustments for covariates (OR, 3.7; P = .002).

Black race was also associated with increased risk of mortality/ICU admission/hospital admission (35.8% vs. 30.2%), and after adjustment for covariates this was found to be an independent predictor (OR, 1.7; P = .04).

“This higher COVID-19 risk in Black individuals is also seen in the general population, so these results are not that surprising and it doesn’t appear to be an effect specific to MS patients,” Dr. Salter commented.
 

U.K. data on risk of contracting COVID-19 

A U.K. study also suggested race to be an independent predictor in the risk of contracting COVID-19 in patients with MS.

The study of more than 5,000 patients with MS showed that those from a Black, Asian, and Minority Ethnic group were twice as likely to report having COVID-19 than those who were White.

The study, which was conducted during the U.K. lockdown, also found that the trend of COVID-19 infection in patients with MS is comparable with that of the U.K. general population.

Presenting the data, Afagh Garjani, MD, concluded: “During a period with strict physical distancing measures, patients with MS are not at an increased risk of contracting COVID-19.”

Dr. Garjani, a neurology clinical research fellow at the University of Nottingham, (England), explained that the COVID-19 pandemic has introduced uncertainties into the MS community, and the focus so far has been the severity of infection among people with MS who have COVID-19.

“This approach has left questions about the risk of contracting disease in people with MS unanswered, which has implications as society gradually returns to normal,” she said.

Dr. Garjani presented data from the United Kingdom MS Register (UKMSR), which has been collecting demographic and MS-related data since 2011 from patients with MS throughout the United Kingdom.

On March 17 – just before the lockdown in United Kingdom – existing participants of the UKMSR were asked to join the COVID-19 study. The study was also advertised through social media. In this ongoing study, people with MS answered a COVID-19–related survey at participation and a different follow-up survey every 2 weeks depending on whether they contracted COVID-19.

The COVID-19 study included 5,309 patients with MS. The mean age of the study population was 52.4 years, 76.1% were female, and 95.7% were White. Of the 5,309 patients, 535 (10%) reported a self-diagnosis of COVID-19. Because of limited availability of tests in the United Kingdom at the time, only 75 patents had a positive polymerase chain reaction result.

“To our knowledge, this is the largest community-based study of COVID-19 in patients with MS worldwide,” Dr. Garjani said. She presented results from the period March 23 to June 24, when the United Kingdom was in a period of lockdown with vulnerable groups encouraged to self-isolate completely.

In this MS cohort, 47% reported self-isolating at some point. Those at older age and higher Expanded Disability Status Scale (EDSS) score were more likely to have self-isolated.

The researchers did not find that patients with progressive MS or those on disease-modifying therapies in general isolated more, but patients on monoclonal antibody drugs and fingolimod were more likely to self-isolate versus those on other therapies. “This may be because there are concerns about infection with these drugs and patients on these therapies may be more concerned about contracting COVID-19,” Dr. Garjani suggested.

In terms of contracting COVID, the researchers found a reduced risk of COVID-19 (self-diagnosed) in patients with older age and higher EDSS. “This is not really surprising that these patients were more likely to self-isolate,” Dr. Garjani commented.

No association was seen between type of MS, disease duration, disease-modifying therapy in general, and risk of COVID-19. No individual drug treatment increased risk versus no therapy or versus self-injectables. But there was an increased risk of contracting the virus in patients whose race was Black, Asian, or Minority Ethnic (OR, 2.2), which is in line with findings from the general population.

“This study is unique – the denominator is all people with MS. We are looking primarily at the risk of contracting COVID-19. Other studies are focusing more on people with MS who have COVID and assessing risk of a severe COVID outcome. Our results are not contradicting the findings from those studies,” Dr. Garjani said.

The results were similar only when patients with a confirmed COVID-19 test were considered.

In terms of outcomes in those who reported COVID-19 infection, preliminary results have not shown any MS factors – such as EDSS, age, type of MS, drug therapy in general – to be associated with outcome.

“Since the COVID-19 outbreak started there has been concern among MS patients, especially among those on disease-modifying therapies, about whether they are at increased risk of infection and severe disease,” Dr. Garjani said.

“We found similar trends of rates of infection in MS patients and the general population, and no signal of increased risks in those with higher EDSS or progressive MS. The caveat is that this study was conducted in a period of lockdown, but we adjusted for self-isolating behavior in the multivariable regression analysis,” she noted.

Dr. Salter is a statistical editor for the American Heart Association journal Circulation: Cardiovascular Imaging. Dr. Garjani has disclosed no relevant financial relationships.

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

The risk of severe outcomes from COVID-19 infection in patients with multiple sclerosis (MS) seems to align with that seen in the general population, new U.S. data suggest. A separate study from the United Kingdom also found similar trends of rates of COVID-19 infection in patients with MS and the general population.

Both studies were presented Sept. 26 at a special session on multiple sclerosis and COVID-19 at a final “Encore” event as part of 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.

The U.S. data appear consistent with studies from several other countries, in that worse COVID-19 outcomes increase with age and higher disability levels, both of which would be expected from findings in the general population.

The U.S. data also show a clear effect of race in MS, with higher rates of adverse COVID-19 outcomes in Black patients, again in line with what is seen in the general population.

“I would say the results from our study and in general do not suggest that MS itself is associated with higher risks of severe COVID-19 outcomes, compared with the general population,” said Amber Salter, PhD.

Dr. Salter, who is assistant professor of biostatistics at Washington University, St. Louis, presented data from the COViMS North American registry, set up for health care providers to report persons with MS who are infected with COVID-19.

The COViMS registry so far has information on 858 patients with MS who have COVID-19 (80% verified by a positive test), as reported from 150 different health care providers in the United States and Canada. The average age was 48 years, with average disease duration of 13.6 years. MS clinical course was reported as relapsing remitting in 78%, secondary progressive in 15%, and primary progressive in 5%. Most patients (72%) were fully ambulatory, 16% could walk with assistance, and 12% were nonambulatory.

Severe COVID-19 outcomes were classified as mortality (which occurred in 5.7% of the cohort), mortality/ICU admission (13.6%) and mortality/ICU admission/hospitalization (30.2%).

Results were adjusted for many different covariates, including sex, age, smoking, MS clinical course (relapsing, progressive), disease duration, ambulation, individual comorbidities (cardiovascular disease, cerebrovascular disease, chronic kidney disease, chronic lung disease, diabetes, hypertension, morbid obesity), and disease-modifying therapy use.

In multivariable logistic regression analyses, older age, having chronic renal disease, and being nonambulatory were consistently associated with increased odds of poorer outcomes. Chronic kidney disease had the strongest association with mortality (odds ratio, 28.6; P < .001). Other factors associated with mortality included cardiovascular disease (OR, 4.35; P = .009); age (OR per 10 years, 1.91; P = .012), and male sex (OR, 2.60; P = .041).

Patients who were nonambulatory had a higher risk of mortality/ICU admission/hospitalization (OR, 3.32; P = .003). This endpoint was also increased in patients on anti-CD20 drugs, compared with other disease-modifying treatment (OR, 2.31; P = .002), consistent with results from at least two other studies.

Disease-modifying therapy in general was not associated with an increased risk of worse outcomes. “There was some concern at the outset about the effect of disease-modifying therapies on COVID-19 outcomes, but most studies have not found an increased risk of worse outcomes in patients on such drug treatments, with the possible exception of anti-CD20 drugs,” Dr. Salter said.

“Some disease-modifying therapies may actually be protective (particularly interferon) and studies are investigating whether they may have a role in the treatment of COVID-19,” she added.

“The factors in MS patients that we and others have found to be associated with worse COVID-19 outcomes may not be specific to MS. Older age is known to be a primary risk factor for worse COVID-19 outcomes in the general population, and increasing disability presumably tracks with worse general heath,” Dr. Salter commented.

“I would say the overall data are fairly reassuring for MS patents,” she concluded.
 

Black patients have higher risk

One worrying finding in the North American data, however, was the effect of race. “We found an independent effect of race for worse COVID-19 outcomes in MS patients,” Dr. Slater said.

Of the 858 patients in the COViMS registry, 65.7% were White and 26.1% were Black. Black individuals were more likely to be younger, never smokers, have shorter MS duration, a relapsing MS course, and have comorbidities, compared with White patients. A higher proportion of Black patients had hypertension (40.2% vs 19.5%) and morbid obesity (17% vs. 9.5%).

Results showed that mortality rates were not statistically different between White and Black patients, but Black race was associated with increased risk of mortality and/or ICU admission, compared with White patients (16.9% vs. 12.8%), and multivariate logistic regression analysis showed Black race was independently associated with mortality/ICU admission after adjustments for covariates (OR, 3.7; P = .002).

Black race was also associated with increased risk of mortality/ICU admission/hospital admission (35.8% vs. 30.2%), and after adjustment for covariates this was found to be an independent predictor (OR, 1.7; P = .04).

“This higher COVID-19 risk in Black individuals is also seen in the general population, so these results are not that surprising and it doesn’t appear to be an effect specific to MS patients,” Dr. Salter commented.
 

U.K. data on risk of contracting COVID-19 

A U.K. study also suggested race to be an independent predictor in the risk of contracting COVID-19 in patients with MS.

The study of more than 5,000 patients with MS showed that those from a Black, Asian, and Minority Ethnic group were twice as likely to report having COVID-19 than those who were White.

The study, which was conducted during the U.K. lockdown, also found that the trend of COVID-19 infection in patients with MS is comparable with that of the U.K. general population.

Presenting the data, Afagh Garjani, MD, concluded: “During a period with strict physical distancing measures, patients with MS are not at an increased risk of contracting COVID-19.”

Dr. Garjani, a neurology clinical research fellow at the University of Nottingham, (England), explained that the COVID-19 pandemic has introduced uncertainties into the MS community, and the focus so far has been the severity of infection among people with MS who have COVID-19.

“This approach has left questions about the risk of contracting disease in people with MS unanswered, which has implications as society gradually returns to normal,” she said.

Dr. Garjani presented data from the United Kingdom MS Register (UKMSR), which has been collecting demographic and MS-related data since 2011 from patients with MS throughout the United Kingdom.

On March 17 – just before the lockdown in United Kingdom – existing participants of the UKMSR were asked to join the COVID-19 study. The study was also advertised through social media. In this ongoing study, people with MS answered a COVID-19–related survey at participation and a different follow-up survey every 2 weeks depending on whether they contracted COVID-19.

The COVID-19 study included 5,309 patients with MS. The mean age of the study population was 52.4 years, 76.1% were female, and 95.7% were White. Of the 5,309 patients, 535 (10%) reported a self-diagnosis of COVID-19. Because of limited availability of tests in the United Kingdom at the time, only 75 patents had a positive polymerase chain reaction result.

“To our knowledge, this is the largest community-based study of COVID-19 in patients with MS worldwide,” Dr. Garjani said. She presented results from the period March 23 to June 24, when the United Kingdom was in a period of lockdown with vulnerable groups encouraged to self-isolate completely.

In this MS cohort, 47% reported self-isolating at some point. Those at older age and higher Expanded Disability Status Scale (EDSS) score were more likely to have self-isolated.

The researchers did not find that patients with progressive MS or those on disease-modifying therapies in general isolated more, but patients on monoclonal antibody drugs and fingolimod were more likely to self-isolate versus those on other therapies. “This may be because there are concerns about infection with these drugs and patients on these therapies may be more concerned about contracting COVID-19,” Dr. Garjani suggested.

In terms of contracting COVID, the researchers found a reduced risk of COVID-19 (self-diagnosed) in patients with older age and higher EDSS. “This is not really surprising that these patients were more likely to self-isolate,” Dr. Garjani commented.

No association was seen between type of MS, disease duration, disease-modifying therapy in general, and risk of COVID-19. No individual drug treatment increased risk versus no therapy or versus self-injectables. But there was an increased risk of contracting the virus in patients whose race was Black, Asian, or Minority Ethnic (OR, 2.2), which is in line with findings from the general population.

“This study is unique – the denominator is all people with MS. We are looking primarily at the risk of contracting COVID-19. Other studies are focusing more on people with MS who have COVID and assessing risk of a severe COVID outcome. Our results are not contradicting the findings from those studies,” Dr. Garjani said.

The results were similar only when patients with a confirmed COVID-19 test were considered.

In terms of outcomes in those who reported COVID-19 infection, preliminary results have not shown any MS factors – such as EDSS, age, type of MS, drug therapy in general – to be associated with outcome.

“Since the COVID-19 outbreak started there has been concern among MS patients, especially among those on disease-modifying therapies, about whether they are at increased risk of infection and severe disease,” Dr. Garjani said.

“We found similar trends of rates of infection in MS patients and the general population, and no signal of increased risks in those with higher EDSS or progressive MS. The caveat is that this study was conducted in a period of lockdown, but we adjusted for self-isolating behavior in the multivariable regression analysis,” she noted.

Dr. Salter is a statistical editor for the American Heart Association journal Circulation: Cardiovascular Imaging. Dr. Garjani has disclosed no relevant financial relationships.

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

The risk of severe outcomes from COVID-19 infection in patients with multiple sclerosis (MS) seems to align with that seen in the general population, new U.S. data suggest. A separate study from the United Kingdom also found similar trends of rates of COVID-19 infection in patients with MS and the general population.

Both studies were presented Sept. 26 at a special session on multiple sclerosis and COVID-19 at a final “Encore” event as part of 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.

The U.S. data appear consistent with studies from several other countries, in that worse COVID-19 outcomes increase with age and higher disability levels, both of which would be expected from findings in the general population.

The U.S. data also show a clear effect of race in MS, with higher rates of adverse COVID-19 outcomes in Black patients, again in line with what is seen in the general population.

“I would say the results from our study and in general do not suggest that MS itself is associated with higher risks of severe COVID-19 outcomes, compared with the general population,” said Amber Salter, PhD.

Dr. Salter, who is assistant professor of biostatistics at Washington University, St. Louis, presented data from the COViMS North American registry, set up for health care providers to report persons with MS who are infected with COVID-19.

The COViMS registry so far has information on 858 patients with MS who have COVID-19 (80% verified by a positive test), as reported from 150 different health care providers in the United States and Canada. The average age was 48 years, with average disease duration of 13.6 years. MS clinical course was reported as relapsing remitting in 78%, secondary progressive in 15%, and primary progressive in 5%. Most patients (72%) were fully ambulatory, 16% could walk with assistance, and 12% were nonambulatory.

Severe COVID-19 outcomes were classified as mortality (which occurred in 5.7% of the cohort), mortality/ICU admission (13.6%) and mortality/ICU admission/hospitalization (30.2%).

Results were adjusted for many different covariates, including sex, age, smoking, MS clinical course (relapsing, progressive), disease duration, ambulation, individual comorbidities (cardiovascular disease, cerebrovascular disease, chronic kidney disease, chronic lung disease, diabetes, hypertension, morbid obesity), and disease-modifying therapy use.

In multivariable logistic regression analyses, older age, having chronic renal disease, and being nonambulatory were consistently associated with increased odds of poorer outcomes. Chronic kidney disease had the strongest association with mortality (odds ratio, 28.6; P < .001). Other factors associated with mortality included cardiovascular disease (OR, 4.35; P = .009); age (OR per 10 years, 1.91; P = .012), and male sex (OR, 2.60; P = .041).

Patients who were nonambulatory had a higher risk of mortality/ICU admission/hospitalization (OR, 3.32; P = .003). This endpoint was also increased in patients on anti-CD20 drugs, compared with other disease-modifying treatment (OR, 2.31; P = .002), consistent with results from at least two other studies.

Disease-modifying therapy in general was not associated with an increased risk of worse outcomes. “There was some concern at the outset about the effect of disease-modifying therapies on COVID-19 outcomes, but most studies have not found an increased risk of worse outcomes in patients on such drug treatments, with the possible exception of anti-CD20 drugs,” Dr. Salter said.

“Some disease-modifying therapies may actually be protective (particularly interferon) and studies are investigating whether they may have a role in the treatment of COVID-19,” she added.

“The factors in MS patients that we and others have found to be associated with worse COVID-19 outcomes may not be specific to MS. Older age is known to be a primary risk factor for worse COVID-19 outcomes in the general population, and increasing disability presumably tracks with worse general heath,” Dr. Salter commented.

“I would say the overall data are fairly reassuring for MS patents,” she concluded.
 

Black patients have higher risk

One worrying finding in the North American data, however, was the effect of race. “We found an independent effect of race for worse COVID-19 outcomes in MS patients,” Dr. Slater said.

Of the 858 patients in the COViMS registry, 65.7% were White and 26.1% were Black. Black individuals were more likely to be younger, never smokers, have shorter MS duration, a relapsing MS course, and have comorbidities, compared with White patients. A higher proportion of Black patients had hypertension (40.2% vs 19.5%) and morbid obesity (17% vs. 9.5%).

Results showed that mortality rates were not statistically different between White and Black patients, but Black race was associated with increased risk of mortality and/or ICU admission, compared with White patients (16.9% vs. 12.8%), and multivariate logistic regression analysis showed Black race was independently associated with mortality/ICU admission after adjustments for covariates (OR, 3.7; P = .002).

Black race was also associated with increased risk of mortality/ICU admission/hospital admission (35.8% vs. 30.2%), and after adjustment for covariates this was found to be an independent predictor (OR, 1.7; P = .04).

“This higher COVID-19 risk in Black individuals is also seen in the general population, so these results are not that surprising and it doesn’t appear to be an effect specific to MS patients,” Dr. Salter commented.
 

U.K. data on risk of contracting COVID-19 

A U.K. study also suggested race to be an independent predictor in the risk of contracting COVID-19 in patients with MS.

The study of more than 5,000 patients with MS showed that those from a Black, Asian, and Minority Ethnic group were twice as likely to report having COVID-19 than those who were White.

The study, which was conducted during the U.K. lockdown, also found that the trend of COVID-19 infection in patients with MS is comparable with that of the U.K. general population.

Presenting the data, Afagh Garjani, MD, concluded: “During a period with strict physical distancing measures, patients with MS are not at an increased risk of contracting COVID-19.”

Dr. Garjani, a neurology clinical research fellow at the University of Nottingham, (England), explained that the COVID-19 pandemic has introduced uncertainties into the MS community, and the focus so far has been the severity of infection among people with MS who have COVID-19.

“This approach has left questions about the risk of contracting disease in people with MS unanswered, which has implications as society gradually returns to normal,” she said.

Dr. Garjani presented data from the United Kingdom MS Register (UKMSR), which has been collecting demographic and MS-related data since 2011 from patients with MS throughout the United Kingdom.

On March 17 – just before the lockdown in United Kingdom – existing participants of the UKMSR were asked to join the COVID-19 study. The study was also advertised through social media. In this ongoing study, people with MS answered a COVID-19–related survey at participation and a different follow-up survey every 2 weeks depending on whether they contracted COVID-19.

The COVID-19 study included 5,309 patients with MS. The mean age of the study population was 52.4 years, 76.1% were female, and 95.7% were White. Of the 5,309 patients, 535 (10%) reported a self-diagnosis of COVID-19. Because of limited availability of tests in the United Kingdom at the time, only 75 patents had a positive polymerase chain reaction result.

“To our knowledge, this is the largest community-based study of COVID-19 in patients with MS worldwide,” Dr. Garjani said. She presented results from the period March 23 to June 24, when the United Kingdom was in a period of lockdown with vulnerable groups encouraged to self-isolate completely.

In this MS cohort, 47% reported self-isolating at some point. Those at older age and higher Expanded Disability Status Scale (EDSS) score were more likely to have self-isolated.

The researchers did not find that patients with progressive MS or those on disease-modifying therapies in general isolated more, but patients on monoclonal antibody drugs and fingolimod were more likely to self-isolate versus those on other therapies. “This may be because there are concerns about infection with these drugs and patients on these therapies may be more concerned about contracting COVID-19,” Dr. Garjani suggested.

In terms of contracting COVID, the researchers found a reduced risk of COVID-19 (self-diagnosed) in patients with older age and higher EDSS. “This is not really surprising that these patients were more likely to self-isolate,” Dr. Garjani commented.

No association was seen between type of MS, disease duration, disease-modifying therapy in general, and risk of COVID-19. No individual drug treatment increased risk versus no therapy or versus self-injectables. But there was an increased risk of contracting the virus in patients whose race was Black, Asian, or Minority Ethnic (OR, 2.2), which is in line with findings from the general population.

“This study is unique – the denominator is all people with MS. We are looking primarily at the risk of contracting COVID-19. Other studies are focusing more on people with MS who have COVID and assessing risk of a severe COVID outcome. Our results are not contradicting the findings from those studies,” Dr. Garjani said.

The results were similar only when patients with a confirmed COVID-19 test were considered.

In terms of outcomes in those who reported COVID-19 infection, preliminary results have not shown any MS factors – such as EDSS, age, type of MS, drug therapy in general – to be associated with outcome.

“Since the COVID-19 outbreak started there has been concern among MS patients, especially among those on disease-modifying therapies, about whether they are at increased risk of infection and severe disease,” Dr. Garjani said.

“We found similar trends of rates of infection in MS patients and the general population, and no signal of increased risks in those with higher EDSS or progressive MS. The caveat is that this study was conducted in a period of lockdown, but we adjusted for self-isolating behavior in the multivariable regression analysis,” she noted.

Dr. Salter is a statistical editor for the American Heart Association journal Circulation: Cardiovascular Imaging. Dr. Garjani has disclosed no relevant financial relationships.

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

Among women with multiple sclerosis (MS), levels of serum neurofilament light (sNfL) are higher during pregnancy and the postpartum period. The increase in sNfL is independent of relapses, which suggests that patients have increased subclinical disease activity during this period, according to the researchers.

When the investigators controlled their data for exposure to disease-modifying therapy (DMT), the effect of pregnancy on sNfL was no longer evident. These data were presented said 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.

The results suggest that “sNfL may qualify as a sensitive and minimally invasive measure of disease activity in pregnancy,” said Özgür Yaldizli, MD, consultant neurologist at University Hospital Basel (Switzerland). “Strategies allowing the continuation of DMT during pregnancy may be warranted.”

MS preferentially affects women in their reproductive years, said Dr. Yaldizli. Almost one-third of women with MS become pregnant after they receive their diagnosis. A decrease in disease activity is typical in the third trimester, as is an increase in relapse frequency post partum.

DMTs reduce the risk of relapse, but have potential side effects for the woman and the fetus. Some DMTs are immunosuppressants, and they increase the risk of infection during pregnancy. Other DMTs may harm the development of the fetus, particularly if administered early during pregnancy.

“There is an urgent need to identify patients with high disease activity during pregnancy,” said Dr. Yaldizli. Increased levels of NfL, a specific biomarker of neuroaxonal injury, are associated with relapses, MRI activity, and disability worsening among patients with MS. Response to DMT is associated with decreased NfL levels. But few data about sNfL during pregnancy or post partum are available.
 

Relapses were associated with increased sNfL

Dr. Yaldizli and colleagues examined data from the Swiss MS Cohort Study to describe DMT use before, during, and after pregnancy. They also sought to assess sNfL as a marker of disease activity during and after pregnancy and to evaluate whether interrupting DMT because of pregnancy leads to increased sNfL levels.

Eligible participants had prospectively documented pregnancies, and Dr. Yaldizli’s group excluded pregnancies with early termination from their analysis. Serum samples were collected every 6 or 12 months and analyzed using the Simoa NF-light assay. The investigators used univariable and multivariable mixed-effects models to investigate associations between clinical characteristics and longitudinal sNfL levels in women before pregnancy, during pregnancy, and post partum.

Dr. Yaldizli and colleagues included 72 pregnancies in 63 patients with relapsing MS in their analysis. Nine patients had two pregnancies during follow-up. The population’s median age was 31.4 years, and median disease duration was 7.1 years. Median Expanded Disability Status Scale (EDSS) score at last visit before birth was 1.5. Median follow-up time was 6 years.

Most patients were treated with DMT before or during pregnancy. For most patients (39), fingolimod or natalizumab was the last DMT given before birth. Four patients did not use DMT before, during, or after pregnancy. In 14 pregnancies, the patient continued DMT for more than 6 months.

The univariable analysis showed that sNfL levels were 22% higher during pregnancy, compared with outside the pregnancy and postpartum period. The investigators recorded 29 relapses during the pregnancy and postpartum period. Relapses were more likely to occur during the first trimester and the first 3 months post partum. In the multivariable analysis, relapses that occurred within 120 days before serum sampling were associated with 98% higher levels of sNfL. In addition, sNfL was 7% higher for each step increase in EDSS and 13% higher during the pregnancy and postpartum period, compared with outside of that period.

When the investigators included DMT exposure at sampling time in the model, however, the pregnancy and postpartum period no longer had an effect on sNfL. The sNfL levels were 12% lower among patients exposed to DMT, compared with patients without DMT exposure.

Some DMTs, such as interferon-beta, are relatively safe during pregnancy, but the greater the medication’s efficacy, the more problematic it can be, said Dr. Yaldizi. “There are medications that are given, for example, every 6 months, like ocrelizumab. There are other medications that have to be taken daily. Probably the safest medications are those that are not given so often during pregnancy.”

Future research should examine the escalation therapies (i.e., the newer and more effective DMTs) during pregnancy in patients with MS, he added. “Not only in pregnancy, but also in general, we have to look for ways to measure disease activity in patients who switch therapy, who deescalate therapy.”
 

Pregnancy may not forestall disease activity

“The results of this study demonstrate that DMT withdrawal in the context of pregnancy can lead to subclinical disease re-emergence, as evidenced by increased sNfL levels in the DMT-free period,” said Vilija G. Jokubaitis, PhD, senior research fellow in the department of neuroscience at Monash University, Melbourne. Dr. Jokubaitis was not involved in the study.

“Interestingly, the median EDSS score in this cohort was quite low, demonstrating that, even in women with mild disease, pregnancy may not be sufficient to protect against ongoing MS activity.” Nevertheless, 28 of the 63 women were exposed to monoclonal antibody therapy, so it is unclear whether these women have mild disease or well-managed disease on DMT, she added.

“This study provides further evidence that pregnancy planning requires advanced planning, and that therapy continuation into pregnancy should be considered, particularly in women with moderate disease activity, to protect against disease reactivation,” said Dr. Jokubaitis.

The strengths of the study include its prospective design, the investigators’ ability to describe the various DMT exposures before and during pregnancy, and the multivariable mixed-effects modeling, she added. On the other hand, the results are at the group level, individual trajectories in sNfL level are not described, and the small sample size prevented the investigators from differentiating between the effects of various DMTs on sNfL outcomes. In addition, Dr. Yaldizli and colleagues did not take time off DMT into account in the models; they considered DMT exposure as a dichotomous variable.

“More work is needed to determine the therapeutic strategies that will give women with MS the greatest protection against disease reactivation in pregnancy and post partum, whilst also protecting fetal and neonatal outcomes,” said Dr. Jokubaitis. Group studies will enable researchers to identify trends, but neurologists ultimately need to provide individualized advice to their patients. “There is a need to look at [the effect of] DMT identity, timing, and duration of DMT withdrawal on fluctuation of sNfL levels, and how these relate to baseline disease severity,” Dr. Jokubaitis added. Furthermore, researchers must compare sNfL changes in pregnancy between patients with MS and healthy women in large cohorts.

The analysis by Dr. Yaldizli and colleagues was conducted without outside funding. The Swiss MS Cohort receives funding from the Swiss MS society, Biogen, Celgene, Sanofi, Merck, Novartis, Roche, and research associations such as the International Progressive MS Alliance and the Swiss National Science Foundation. Dr. Yaldizli received grants from ECTRIMS/MAGNIMS, the University of Basel, Pro Patient Stiftung, University Hospital Basel, Free Academy Basel, and the Swiss MS Society. He has received advisory board fees from Sanofi Genzyme, Biogen, Almirall, and Novartis. Dr. Jokubaitis has received conference travel support from Merck and Roche and speakers honoraria from Biogen and Roche. These relationships are not related to the current study. Dr. Jokubaitis receives research support from the Australian National Health and Medical Research Grant and MS Research Australia.

[email protected]

Among women with multiple sclerosis (MS), levels of serum neurofilament light (sNfL) are higher during pregnancy and the postpartum period. The increase in sNfL is independent of relapses, which suggests that patients have increased subclinical disease activity during this period, according to the researchers.

When the investigators controlled their data for exposure to disease-modifying therapy (DMT), the effect of pregnancy on sNfL was no longer evident. These data were presented said 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.

The results suggest that “sNfL may qualify as a sensitive and minimally invasive measure of disease activity in pregnancy,” said Özgür Yaldizli, MD, consultant neurologist at University Hospital Basel (Switzerland). “Strategies allowing the continuation of DMT during pregnancy may be warranted.”

MS preferentially affects women in their reproductive years, said Dr. Yaldizli. Almost one-third of women with MS become pregnant after they receive their diagnosis. A decrease in disease activity is typical in the third trimester, as is an increase in relapse frequency post partum.

DMTs reduce the risk of relapse, but have potential side effects for the woman and the fetus. Some DMTs are immunosuppressants, and they increase the risk of infection during pregnancy. Other DMTs may harm the development of the fetus, particularly if administered early during pregnancy.

“There is an urgent need to identify patients with high disease activity during pregnancy,” said Dr. Yaldizli. Increased levels of NfL, a specific biomarker of neuroaxonal injury, are associated with relapses, MRI activity, and disability worsening among patients with MS. Response to DMT is associated with decreased NfL levels. But few data about sNfL during pregnancy or post partum are available.
 

Relapses were associated with increased sNfL

Dr. Yaldizli and colleagues examined data from the Swiss MS Cohort Study to describe DMT use before, during, and after pregnancy. They also sought to assess sNfL as a marker of disease activity during and after pregnancy and to evaluate whether interrupting DMT because of pregnancy leads to increased sNfL levels.

Eligible participants had prospectively documented pregnancies, and Dr. Yaldizli’s group excluded pregnancies with early termination from their analysis. Serum samples were collected every 6 or 12 months and analyzed using the Simoa NF-light assay. The investigators used univariable and multivariable mixed-effects models to investigate associations between clinical characteristics and longitudinal sNfL levels in women before pregnancy, during pregnancy, and post partum.

Dr. Yaldizli and colleagues included 72 pregnancies in 63 patients with relapsing MS in their analysis. Nine patients had two pregnancies during follow-up. The population’s median age was 31.4 years, and median disease duration was 7.1 years. Median Expanded Disability Status Scale (EDSS) score at last visit before birth was 1.5. Median follow-up time was 6 years.

Most patients were treated with DMT before or during pregnancy. For most patients (39), fingolimod or natalizumab was the last DMT given before birth. Four patients did not use DMT before, during, or after pregnancy. In 14 pregnancies, the patient continued DMT for more than 6 months.

The univariable analysis showed that sNfL levels were 22% higher during pregnancy, compared with outside the pregnancy and postpartum period. The investigators recorded 29 relapses during the pregnancy and postpartum period. Relapses were more likely to occur during the first trimester and the first 3 months post partum. In the multivariable analysis, relapses that occurred within 120 days before serum sampling were associated with 98% higher levels of sNfL. In addition, sNfL was 7% higher for each step increase in EDSS and 13% higher during the pregnancy and postpartum period, compared with outside of that period.

When the investigators included DMT exposure at sampling time in the model, however, the pregnancy and postpartum period no longer had an effect on sNfL. The sNfL levels were 12% lower among patients exposed to DMT, compared with patients without DMT exposure.

Some DMTs, such as interferon-beta, are relatively safe during pregnancy, but the greater the medication’s efficacy, the more problematic it can be, said Dr. Yaldizi. “There are medications that are given, for example, every 6 months, like ocrelizumab. There are other medications that have to be taken daily. Probably the safest medications are those that are not given so often during pregnancy.”

Future research should examine the escalation therapies (i.e., the newer and more effective DMTs) during pregnancy in patients with MS, he added. “Not only in pregnancy, but also in general, we have to look for ways to measure disease activity in patients who switch therapy, who deescalate therapy.”
 

Pregnancy may not forestall disease activity

“The results of this study demonstrate that DMT withdrawal in the context of pregnancy can lead to subclinical disease re-emergence, as evidenced by increased sNfL levels in the DMT-free period,” said Vilija G. Jokubaitis, PhD, senior research fellow in the department of neuroscience at Monash University, Melbourne. Dr. Jokubaitis was not involved in the study.

“Interestingly, the median EDSS score in this cohort was quite low, demonstrating that, even in women with mild disease, pregnancy may not be sufficient to protect against ongoing MS activity.” Nevertheless, 28 of the 63 women were exposed to monoclonal antibody therapy, so it is unclear whether these women have mild disease or well-managed disease on DMT, she added.

“This study provides further evidence that pregnancy planning requires advanced planning, and that therapy continuation into pregnancy should be considered, particularly in women with moderate disease activity, to protect against disease reactivation,” said Dr. Jokubaitis.

The strengths of the study include its prospective design, the investigators’ ability to describe the various DMT exposures before and during pregnancy, and the multivariable mixed-effects modeling, she added. On the other hand, the results are at the group level, individual trajectories in sNfL level are not described, and the small sample size prevented the investigators from differentiating between the effects of various DMTs on sNfL outcomes. In addition, Dr. Yaldizli and colleagues did not take time off DMT into account in the models; they considered DMT exposure as a dichotomous variable.

“More work is needed to determine the therapeutic strategies that will give women with MS the greatest protection against disease reactivation in pregnancy and post partum, whilst also protecting fetal and neonatal outcomes,” said Dr. Jokubaitis. Group studies will enable researchers to identify trends, but neurologists ultimately need to provide individualized advice to their patients. “There is a need to look at [the effect of] DMT identity, timing, and duration of DMT withdrawal on fluctuation of sNfL levels, and how these relate to baseline disease severity,” Dr. Jokubaitis added. Furthermore, researchers must compare sNfL changes in pregnancy between patients with MS and healthy women in large cohorts.

The analysis by Dr. Yaldizli and colleagues was conducted without outside funding. The Swiss MS Cohort receives funding from the Swiss MS society, Biogen, Celgene, Sanofi, Merck, Novartis, Roche, and research associations such as the International Progressive MS Alliance and the Swiss National Science Foundation. Dr. Yaldizli received grants from ECTRIMS/MAGNIMS, the University of Basel, Pro Patient Stiftung, University Hospital Basel, Free Academy Basel, and the Swiss MS Society. He has received advisory board fees from Sanofi Genzyme, Biogen, Almirall, and Novartis. Dr. Jokubaitis has received conference travel support from Merck and Roche and speakers honoraria from Biogen and Roche. These relationships are not related to the current study. Dr. Jokubaitis receives research support from the Australian National Health and Medical Research Grant and MS Research Australia.

[email protected]

Among women with multiple sclerosis (MS), levels of serum neurofilament light (sNfL) are higher during pregnancy and the postpartum period. The increase in sNfL is independent of relapses, which suggests that patients have increased subclinical disease activity during this period, according to the researchers.

When the investigators controlled their data for exposure to disease-modifying therapy (DMT), the effect of pregnancy on sNfL was no longer evident. These data were presented said 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.

The results suggest that “sNfL may qualify as a sensitive and minimally invasive measure of disease activity in pregnancy,” said Özgür Yaldizli, MD, consultant neurologist at University Hospital Basel (Switzerland). “Strategies allowing the continuation of DMT during pregnancy may be warranted.”

MS preferentially affects women in their reproductive years, said Dr. Yaldizli. Almost one-third of women with MS become pregnant after they receive their diagnosis. A decrease in disease activity is typical in the third trimester, as is an increase in relapse frequency post partum.

DMTs reduce the risk of relapse, but have potential side effects for the woman and the fetus. Some DMTs are immunosuppressants, and they increase the risk of infection during pregnancy. Other DMTs may harm the development of the fetus, particularly if administered early during pregnancy.

“There is an urgent need to identify patients with high disease activity during pregnancy,” said Dr. Yaldizli. Increased levels of NfL, a specific biomarker of neuroaxonal injury, are associated with relapses, MRI activity, and disability worsening among patients with MS. Response to DMT is associated with decreased NfL levels. But few data about sNfL during pregnancy or post partum are available.
 

Relapses were associated with increased sNfL

Dr. Yaldizli and colleagues examined data from the Swiss MS Cohort Study to describe DMT use before, during, and after pregnancy. They also sought to assess sNfL as a marker of disease activity during and after pregnancy and to evaluate whether interrupting DMT because of pregnancy leads to increased sNfL levels.

Eligible participants had prospectively documented pregnancies, and Dr. Yaldizli’s group excluded pregnancies with early termination from their analysis. Serum samples were collected every 6 or 12 months and analyzed using the Simoa NF-light assay. The investigators used univariable and multivariable mixed-effects models to investigate associations between clinical characteristics and longitudinal sNfL levels in women before pregnancy, during pregnancy, and post partum.

Dr. Yaldizli and colleagues included 72 pregnancies in 63 patients with relapsing MS in their analysis. Nine patients had two pregnancies during follow-up. The population’s median age was 31.4 years, and median disease duration was 7.1 years. Median Expanded Disability Status Scale (EDSS) score at last visit before birth was 1.5. Median follow-up time was 6 years.

Most patients were treated with DMT before or during pregnancy. For most patients (39), fingolimod or natalizumab was the last DMT given before birth. Four patients did not use DMT before, during, or after pregnancy. In 14 pregnancies, the patient continued DMT for more than 6 months.

The univariable analysis showed that sNfL levels were 22% higher during pregnancy, compared with outside the pregnancy and postpartum period. The investigators recorded 29 relapses during the pregnancy and postpartum period. Relapses were more likely to occur during the first trimester and the first 3 months post partum. In the multivariable analysis, relapses that occurred within 120 days before serum sampling were associated with 98% higher levels of sNfL. In addition, sNfL was 7% higher for each step increase in EDSS and 13% higher during the pregnancy and postpartum period, compared with outside of that period.

When the investigators included DMT exposure at sampling time in the model, however, the pregnancy and postpartum period no longer had an effect on sNfL. The sNfL levels were 12% lower among patients exposed to DMT, compared with patients without DMT exposure.

Some DMTs, such as interferon-beta, are relatively safe during pregnancy, but the greater the medication’s efficacy, the more problematic it can be, said Dr. Yaldizi. “There are medications that are given, for example, every 6 months, like ocrelizumab. There are other medications that have to be taken daily. Probably the safest medications are those that are not given so often during pregnancy.”

Future research should examine the escalation therapies (i.e., the newer and more effective DMTs) during pregnancy in patients with MS, he added. “Not only in pregnancy, but also in general, we have to look for ways to measure disease activity in patients who switch therapy, who deescalate therapy.”
 

Pregnancy may not forestall disease activity

“The results of this study demonstrate that DMT withdrawal in the context of pregnancy can lead to subclinical disease re-emergence, as evidenced by increased sNfL levels in the DMT-free period,” said Vilija G. Jokubaitis, PhD, senior research fellow in the department of neuroscience at Monash University, Melbourne. Dr. Jokubaitis was not involved in the study.

“Interestingly, the median EDSS score in this cohort was quite low, demonstrating that, even in women with mild disease, pregnancy may not be sufficient to protect against ongoing MS activity.” Nevertheless, 28 of the 63 women were exposed to monoclonal antibody therapy, so it is unclear whether these women have mild disease or well-managed disease on DMT, she added.

“This study provides further evidence that pregnancy planning requires advanced planning, and that therapy continuation into pregnancy should be considered, particularly in women with moderate disease activity, to protect against disease reactivation,” said Dr. Jokubaitis.

The strengths of the study include its prospective design, the investigators’ ability to describe the various DMT exposures before and during pregnancy, and the multivariable mixed-effects modeling, she added. On the other hand, the results are at the group level, individual trajectories in sNfL level are not described, and the small sample size prevented the investigators from differentiating between the effects of various DMTs on sNfL outcomes. In addition, Dr. Yaldizli and colleagues did not take time off DMT into account in the models; they considered DMT exposure as a dichotomous variable.

“More work is needed to determine the therapeutic strategies that will give women with MS the greatest protection against disease reactivation in pregnancy and post partum, whilst also protecting fetal and neonatal outcomes,” said Dr. Jokubaitis. Group studies will enable researchers to identify trends, but neurologists ultimately need to provide individualized advice to their patients. “There is a need to look at [the effect of] DMT identity, timing, and duration of DMT withdrawal on fluctuation of sNfL levels, and how these relate to baseline disease severity,” Dr. Jokubaitis added. Furthermore, researchers must compare sNfL changes in pregnancy between patients with MS and healthy women in large cohorts.

The analysis by Dr. Yaldizli and colleagues was conducted without outside funding. The Swiss MS Cohort receives funding from the Swiss MS society, Biogen, Celgene, Sanofi, Merck, Novartis, Roche, and research associations such as the International Progressive MS Alliance and the Swiss National Science Foundation. Dr. Yaldizli received grants from ECTRIMS/MAGNIMS, the University of Basel, Pro Patient Stiftung, University Hospital Basel, Free Academy Basel, and the Swiss MS Society. He has received advisory board fees from Sanofi Genzyme, Biogen, Almirall, and Novartis. Dr. Jokubaitis has received conference travel support from Merck and Roche and speakers honoraria from Biogen and Roche. These relationships are not related to the current study. Dr. Jokubaitis receives research support from the Australian National Health and Medical Research Grant and MS Research Australia.

[email protected]

Further data suggesting that a lower dose of rituximab seems to offer similar effectiveness with a better safety profile than higher doses commonly used in multiple sclerosis (MS), according to a new observational study. “We showed similar numbers of relapses, MRI new/active lesions, and effects on disability with a higher and lower dose of rituximab over a median follow of 16 months,” said lead author, Luciana Midaglia, MD, Multiple Sclerosis Centre of Catalonia (Cemcat) at Vall d’Hebron University Hospital, Barcelona. “But adverse effects – particularly frequency of infection – were increased in the high-dose group.”

Dr. Midaglia presented the findings at the recent 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 haven’t been large studies of rituximab in MS as the company [Genentech/Roche] prioritized development of ocrelizumab over rituximab,” she explained. Rituximab has, therefore, never been approved for this indication. But it is available for several other conditions, and it is often used off label for MS.

“Although we now have a lot of experience with rituximab in MS, a dosage regimen has not been standardized,” Dr. Midaglia noted.

The current study was conducted to compare the efficacy and safety of two different dosage regimens of rituximab used at two different Catalan MS centers.

In the Barcelona center, 249 patients received a regimen of 2 g IV for the first three 6-month cycles followed by 1 g every 6 months thereafter (higher-dose group). In the Girona center, 54 patients received just one loading dose of 2 g followed by 500 mg every 6 months thereafter (lower-dose group).

Patients were followed up clinically every 6 months, and MRI brain scans were performed at baseline and yearly thereafter. Blood samples for safety and B cell/immunoglobulin monitoring were drawn at 3 months after rituximab infusions.

Results showed that the annualized relapse rate reduced by 87% (from 0.4 to 0.05; P < .001) in the higher-dose cohort, and by 90% (from 0.31 to 0.03; P = .018) in the lower-dose cohort.

The Expanded Disability Status Scale score remained stable or improved in 83% of the higher-dose group versus 72% of the lower-dose group (P = .09).

Contrast-enhancing lesions were reduced by 92% by 12 months and by 100% by 36 months in the higher-dose group and by 81% and 100%, respectively, in the lower-dose group.

New T2 lesions were present in 19% of patients at 12 months and in 12% at 36 months in the higher-dose group and in 16% and 0%, respectively, in the lower-dose group.

Reductions in B cell levels were similar with both doses. However, a reduced rate of adverse effects, mainly infections, was seen in the lower-dose group.

Infections were reported in 7.2% of the higher-dose group and 3.7% of the lower-dose group at 1 year, in 9.7% versus 0% in the second year, and in 9.7% versus 0% in the third year. Urinary tract infections, followed by respiratory infections, were the most prevalent.

A randomized phase 3 study is now underway testing an even lower dose of rituximab. The trial, known as RIDOSE-MS, is comparing maintenance doses of 500 mg every 6 months and 500 mg every 12 months.

Dr. Midaglia said that most centers are using higher doses of rituximab – similar to the Barcelona cohort in this study.

“After this study, we will we now start a new protocol and use the lower dose for all MS patients,” she said.

She reported that her hospital has been using rituximab extensively in MS.

“There were delays to ocrelizumab being introduced in Spain, and while we were waiting, we started using rituximab,” she said. “We believe it is similarly effective to ocrelizumab. It has exactly the same mechanism of action. The only difference is that rituximab is a chimeric antibody while ocrelizumab is fully humanized.”

While rituximab has not had the validation of a full phase 3 trial, she added, “there are data available from several smaller studies and we feel we have learned how to use it in the real world, but we don’t have an approved dosage schedule. We started off using the dose approved for use in rheumatological and hematological conditions.”

Now that ocrelizumab is approved, Dr. Midaglia said they are using that drug for the patients who meet the approved criteria, but there are many patients who don’t qualify.

“For example, in progressive MS, ocrelizumab has quite a narrow indication – it is not reimbursed for patients without any inflammatory activity. So for these patients, we tend to use rituximab,” she noted.

“While there is no good data on its efficacy in these patients, we believe it has some effect and there is no other option at present. Rituximab is an inexpensive drug and has a long safety record in other conditions, so we feel it’s worth a try,” Dr. Midaglia concluded. “And now we have better data on the optimal dosage.”

Commenting on the study, Daniel Ontaneda, MD, comoderator of the session at which the study was presented, said: “Rituximab is not an [Food and Drug Administration]–approved medication for MS, but it has been used in clinical practice quite extensively in the U.S. and also in Europe. The study is of interest as it showed that the lower dose of rituximab achieved good control of disease activity.”

Dr. Ontaneda, a neurologist at the Mellen Center for MS at the Cleveland Clinic, Ohio, added: “Many centers have been using lower doses or less frequent infusions and this study supports this practice. Some degree of residual confounding in the study in the differences in side effects may be related to the two different sites, but overall I think these results add to the real-world observational data now available for anti-CD20 therapies.”

Dr. Midaglia reported receiving travel funding from Genzyme, Roche, Biogen Idec, and Novartis, and personal fees for lectures from Roche.
 

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

Further data suggesting that a lower dose of rituximab seems to offer similar effectiveness with a better safety profile than higher doses commonly used in multiple sclerosis (MS), according to a new observational study. “We showed similar numbers of relapses, MRI new/active lesions, and effects on disability with a higher and lower dose of rituximab over a median follow of 16 months,” said lead author, Luciana Midaglia, MD, Multiple Sclerosis Centre of Catalonia (Cemcat) at Vall d’Hebron University Hospital, Barcelona. “But adverse effects – particularly frequency of infection – were increased in the high-dose group.”

Dr. Midaglia presented the findings at the recent 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 haven’t been large studies of rituximab in MS as the company [Genentech/Roche] prioritized development of ocrelizumab over rituximab,” she explained. Rituximab has, therefore, never been approved for this indication. But it is available for several other conditions, and it is often used off label for MS.

“Although we now have a lot of experience with rituximab in MS, a dosage regimen has not been standardized,” Dr. Midaglia noted.

The current study was conducted to compare the efficacy and safety of two different dosage regimens of rituximab used at two different Catalan MS centers.

In the Barcelona center, 249 patients received a regimen of 2 g IV for the first three 6-month cycles followed by 1 g every 6 months thereafter (higher-dose group). In the Girona center, 54 patients received just one loading dose of 2 g followed by 500 mg every 6 months thereafter (lower-dose group).

Patients were followed up clinically every 6 months, and MRI brain scans were performed at baseline and yearly thereafter. Blood samples for safety and B cell/immunoglobulin monitoring were drawn at 3 months after rituximab infusions.

Results showed that the annualized relapse rate reduced by 87% (from 0.4 to 0.05; P < .001) in the higher-dose cohort, and by 90% (from 0.31 to 0.03; P = .018) in the lower-dose cohort.

The Expanded Disability Status Scale score remained stable or improved in 83% of the higher-dose group versus 72% of the lower-dose group (P = .09).

Contrast-enhancing lesions were reduced by 92% by 12 months and by 100% by 36 months in the higher-dose group and by 81% and 100%, respectively, in the lower-dose group.

New T2 lesions were present in 19% of patients at 12 months and in 12% at 36 months in the higher-dose group and in 16% and 0%, respectively, in the lower-dose group.

Reductions in B cell levels were similar with both doses. However, a reduced rate of adverse effects, mainly infections, was seen in the lower-dose group.

Infections were reported in 7.2% of the higher-dose group and 3.7% of the lower-dose group at 1 year, in 9.7% versus 0% in the second year, and in 9.7% versus 0% in the third year. Urinary tract infections, followed by respiratory infections, were the most prevalent.

A randomized phase 3 study is now underway testing an even lower dose of rituximab. The trial, known as RIDOSE-MS, is comparing maintenance doses of 500 mg every 6 months and 500 mg every 12 months.

Dr. Midaglia said that most centers are using higher doses of rituximab – similar to the Barcelona cohort in this study.

“After this study, we will we now start a new protocol and use the lower dose for all MS patients,” she said.

She reported that her hospital has been using rituximab extensively in MS.

“There were delays to ocrelizumab being introduced in Spain, and while we were waiting, we started using rituximab,” she said. “We believe it is similarly effective to ocrelizumab. It has exactly the same mechanism of action. The only difference is that rituximab is a chimeric antibody while ocrelizumab is fully humanized.”

While rituximab has not had the validation of a full phase 3 trial, she added, “there are data available from several smaller studies and we feel we have learned how to use it in the real world, but we don’t have an approved dosage schedule. We started off using the dose approved for use in rheumatological and hematological conditions.”

Now that ocrelizumab is approved, Dr. Midaglia said they are using that drug for the patients who meet the approved criteria, but there are many patients who don’t qualify.

“For example, in progressive MS, ocrelizumab has quite a narrow indication – it is not reimbursed for patients without any inflammatory activity. So for these patients, we tend to use rituximab,” she noted.

“While there is no good data on its efficacy in these patients, we believe it has some effect and there is no other option at present. Rituximab is an inexpensive drug and has a long safety record in other conditions, so we feel it’s worth a try,” Dr. Midaglia concluded. “And now we have better data on the optimal dosage.”

Commenting on the study, Daniel Ontaneda, MD, comoderator of the session at which the study was presented, said: “Rituximab is not an [Food and Drug Administration]–approved medication for MS, but it has been used in clinical practice quite extensively in the U.S. and also in Europe. The study is of interest as it showed that the lower dose of rituximab achieved good control of disease activity.”

Dr. Ontaneda, a neurologist at the Mellen Center for MS at the Cleveland Clinic, Ohio, added: “Many centers have been using lower doses or less frequent infusions and this study supports this practice. Some degree of residual confounding in the study in the differences in side effects may be related to the two different sites, but overall I think these results add to the real-world observational data now available for anti-CD20 therapies.”

Dr. Midaglia reported receiving travel funding from Genzyme, Roche, Biogen Idec, and Novartis, and personal fees for lectures from Roche.
 

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

Further data suggesting that a lower dose of rituximab seems to offer similar effectiveness with a better safety profile than higher doses commonly used in multiple sclerosis (MS), according to a new observational study. “We showed similar numbers of relapses, MRI new/active lesions, and effects on disability with a higher and lower dose of rituximab over a median follow of 16 months,” said lead author, Luciana Midaglia, MD, Multiple Sclerosis Centre of Catalonia (Cemcat) at Vall d’Hebron University Hospital, Barcelona. “But adverse effects – particularly frequency of infection – were increased in the high-dose group.”

Dr. Midaglia presented the findings at the recent 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 haven’t been large studies of rituximab in MS as the company [Genentech/Roche] prioritized development of ocrelizumab over rituximab,” she explained. Rituximab has, therefore, never been approved for this indication. But it is available for several other conditions, and it is often used off label for MS.

“Although we now have a lot of experience with rituximab in MS, a dosage regimen has not been standardized,” Dr. Midaglia noted.

The current study was conducted to compare the efficacy and safety of two different dosage regimens of rituximab used at two different Catalan MS centers.

In the Barcelona center, 249 patients received a regimen of 2 g IV for the first three 6-month cycles followed by 1 g every 6 months thereafter (higher-dose group). In the Girona center, 54 patients received just one loading dose of 2 g followed by 500 mg every 6 months thereafter (lower-dose group).

Patients were followed up clinically every 6 months, and MRI brain scans were performed at baseline and yearly thereafter. Blood samples for safety and B cell/immunoglobulin monitoring were drawn at 3 months after rituximab infusions.

Results showed that the annualized relapse rate reduced by 87% (from 0.4 to 0.05; P < .001) in the higher-dose cohort, and by 90% (from 0.31 to 0.03; P = .018) in the lower-dose cohort.

The Expanded Disability Status Scale score remained stable or improved in 83% of the higher-dose group versus 72% of the lower-dose group (P = .09).

Contrast-enhancing lesions were reduced by 92% by 12 months and by 100% by 36 months in the higher-dose group and by 81% and 100%, respectively, in the lower-dose group.

New T2 lesions were present in 19% of patients at 12 months and in 12% at 36 months in the higher-dose group and in 16% and 0%, respectively, in the lower-dose group.

Reductions in B cell levels were similar with both doses. However, a reduced rate of adverse effects, mainly infections, was seen in the lower-dose group.

Infections were reported in 7.2% of the higher-dose group and 3.7% of the lower-dose group at 1 year, in 9.7% versus 0% in the second year, and in 9.7% versus 0% in the third year. Urinary tract infections, followed by respiratory infections, were the most prevalent.

A randomized phase 3 study is now underway testing an even lower dose of rituximab. The trial, known as RIDOSE-MS, is comparing maintenance doses of 500 mg every 6 months and 500 mg every 12 months.

Dr. Midaglia said that most centers are using higher doses of rituximab – similar to the Barcelona cohort in this study.

“After this study, we will we now start a new protocol and use the lower dose for all MS patients,” she said.

She reported that her hospital has been using rituximab extensively in MS.

“There were delays to ocrelizumab being introduced in Spain, and while we were waiting, we started using rituximab,” she said. “We believe it is similarly effective to ocrelizumab. It has exactly the same mechanism of action. The only difference is that rituximab is a chimeric antibody while ocrelizumab is fully humanized.”

While rituximab has not had the validation of a full phase 3 trial, she added, “there are data available from several smaller studies and we feel we have learned how to use it in the real world, but we don’t have an approved dosage schedule. We started off using the dose approved for use in rheumatological and hematological conditions.”

Now that ocrelizumab is approved, Dr. Midaglia said they are using that drug for the patients who meet the approved criteria, but there are many patients who don’t qualify.

“For example, in progressive MS, ocrelizumab has quite a narrow indication – it is not reimbursed for patients without any inflammatory activity. So for these patients, we tend to use rituximab,” she noted.

“While there is no good data on its efficacy in these patients, we believe it has some effect and there is no other option at present. Rituximab is an inexpensive drug and has a long safety record in other conditions, so we feel it’s worth a try,” Dr. Midaglia concluded. “And now we have better data on the optimal dosage.”

Commenting on the study, Daniel Ontaneda, MD, comoderator of the session at which the study was presented, said: “Rituximab is not an [Food and Drug Administration]–approved medication for MS, but it has been used in clinical practice quite extensively in the U.S. and also in Europe. The study is of interest as it showed that the lower dose of rituximab achieved good control of disease activity.”

Dr. Ontaneda, a neurologist at the Mellen Center for MS at the Cleveland Clinic, Ohio, added: “Many centers have been using lower doses or less frequent infusions and this study supports this practice. Some degree of residual confounding in the study in the differences in side effects may be related to the two different sites, but overall I think these results add to the real-world observational data now available for anti-CD20 therapies.”

Dr. Midaglia reported receiving travel funding from Genzyme, Roche, Biogen Idec, and Novartis, and personal fees for lectures from Roche.
 

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

There is no evidence to support the idea that previous autoimmunity before or after alemtuzumab treatment predicts subsequent rare but serious and possibly life-threatening autoimmune events that have recently been linked to the drug, a new study has shown.

These latest data were reported by Alasdair J. Coles, MD, University of Cambridge (England), 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.

Dr. Coles, who led the initial research to develop alemtuzumab in partnership with Genzyme, explained that autoimmune disease is a well-described and common adverse event with the drug, manifesting mainly as autoimmune thyroid events that can occur in up to 40% of patients.

But as postmarketing experience has grown, it has become clear that there is a low frequency of more serious autoimmune disease, he noted. In an effort to understand this better, regulators have suggested that the presence of non–multiple sclerosis (MS) autoimmune disease before alemtuzumab treatment and the emergence of autoimmune disease after alemtuzumab treatment may define a group that is at higher risk of one of the rare but serious autoimmune events for those on the drug.

To investigate if this was the case, Dr. Coles and colleagues analyzed data on 1,216 patients who received alemtuzumab in the clinical development program. Of these, 96 had preexisting non-MS autoimmunity.

Results showed that up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) versus without (35.3%) preexisting autoimmunity.

Similar percentages of patients with versus without preexisting autoimmunity had two or more new autoimmune events (5.2% vs. 8.2%, respectively). And most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab.

In addition, treatment-emergent thyroid autoimmunity after the first alemtuzumab course was not associated with subsequent nonthyroid autoimmunity after the second course. Similarly, thyroid autoimmunity after the second course did not predict non-thyroid autoimmunity after the third course.

In another analysis of the incidence of serious autoimmune events from postmarketing data on 25,292 patients treated with alemtuzumab, immune thrombocytopenic purpura was reported in 43 patients, newly identified autoimmune hepatitis in 11 patients, and hemophagocytic lymphohistiocytosis in 9 patients.

There was “no hint at all” that baseline thyroid disorders or postalemtuzumab thyroid disorders are associated with increased risk of these serious autoimmune adverse events, Dr. Coles said.

He calculated that the incidence of serious autoimmune diseases that could be life-threatening after alemtuzumab treatment was 10.7 per 10,000 patients treated for autoimmune hepatitis and 2.7 per 10,000 patients treated for hemophagocytic lymphohistiocytosis.

“From two separate data sources – phase 2/3 trials populations combined and postmarketing data – there is no evidence to support the hypothesis that preexisting non-MS autoimmunity predisposes to the serious but rare autoimmune events that have newly been described, nor does thyroid autoimmunity following the use of alemtuzumab,” Dr. Coles stated.

“In my opinion it is not appropriate to preclude the use of alemtuzumab to patients who have had previous autoimmune disease before treatment or who develop thyroid autoimmunity after alemtuzumab,” he said.

“It remains in my view a reasonable treatment option for patients with active MS to receive this highly effective therapy in the face of well-managed, well-understood thyroid autoimmunity and the very unlikely, rare, but serious autoimmune disease,” he concluded.
 

Risk stratification

Commenting on the presentation, Robert J. Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis, Cleveland Clinic, Ohio, explained that, whenever there is a serious risk of a complication, clinicians like to try to stratify that risk.

“We like to identify those at higher risk [and perhaps not use the therapy] and those at lower risk [and perhaps consider more likely the use of that therapy],” he said.

With regard to alemtuzumab, Dr. Fox noted: “We’d like to stratify the risk of autoimmune complications, which could help guide us regarding the patients in whom therapy may be safer. Unfortunately, these findings did not point to a risk stratification to help guide its use towards lower-risk patients.

“I view this as an unfortunate result, because it leaves me without a way to stratify the risks of alemtuzumab, which are quite significant and currently limit my use of that MS therapy only to those with no other treatment options,” he added.

On Dr. Coles’ view of alemtuzumab as a “reasonable” treatment option, Dr. Fox commented: “I guess it depends upon how that’s interpreted. Given the risks of serious, life-threatening immune and infectious complications, I only consider alemtuzumab when all other immune-modulating therapies have been tried or are not a reasonable treatment option. So, yes, I see it as ‘reasonable,’ but only when there are no other available treatment options.”

The current work was supported by Sanofi and Bayer HealthCare. Dr. Coles reported sitting on advisory boards for Genzyme (Sanofi). He is credited as an inventor on several patents related to the technology on which alemtuzumab is based. Dr. Fox has disclosed no relevant financial relationships.
 

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

There is no evidence to support the idea that previous autoimmunity before or after alemtuzumab treatment predicts subsequent rare but serious and possibly life-threatening autoimmune events that have recently been linked to the drug, a new study has shown.

These latest data were reported by Alasdair J. Coles, MD, University of Cambridge (England), 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.

Dr. Coles, who led the initial research to develop alemtuzumab in partnership with Genzyme, explained that autoimmune disease is a well-described and common adverse event with the drug, manifesting mainly as autoimmune thyroid events that can occur in up to 40% of patients.

But as postmarketing experience has grown, it has become clear that there is a low frequency of more serious autoimmune disease, he noted. In an effort to understand this better, regulators have suggested that the presence of non–multiple sclerosis (MS) autoimmune disease before alemtuzumab treatment and the emergence of autoimmune disease after alemtuzumab treatment may define a group that is at higher risk of one of the rare but serious autoimmune events for those on the drug.

To investigate if this was the case, Dr. Coles and colleagues analyzed data on 1,216 patients who received alemtuzumab in the clinical development program. Of these, 96 had preexisting non-MS autoimmunity.

Results showed that up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) versus without (35.3%) preexisting autoimmunity.

Similar percentages of patients with versus without preexisting autoimmunity had two or more new autoimmune events (5.2% vs. 8.2%, respectively). And most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab.

In addition, treatment-emergent thyroid autoimmunity after the first alemtuzumab course was not associated with subsequent nonthyroid autoimmunity after the second course. Similarly, thyroid autoimmunity after the second course did not predict non-thyroid autoimmunity after the third course.

In another analysis of the incidence of serious autoimmune events from postmarketing data on 25,292 patients treated with alemtuzumab, immune thrombocytopenic purpura was reported in 43 patients, newly identified autoimmune hepatitis in 11 patients, and hemophagocytic lymphohistiocytosis in 9 patients.

There was “no hint at all” that baseline thyroid disorders or postalemtuzumab thyroid disorders are associated with increased risk of these serious autoimmune adverse events, Dr. Coles said.

He calculated that the incidence of serious autoimmune diseases that could be life-threatening after alemtuzumab treatment was 10.7 per 10,000 patients treated for autoimmune hepatitis and 2.7 per 10,000 patients treated for hemophagocytic lymphohistiocytosis.

“From two separate data sources – phase 2/3 trials populations combined and postmarketing data – there is no evidence to support the hypothesis that preexisting non-MS autoimmunity predisposes to the serious but rare autoimmune events that have newly been described, nor does thyroid autoimmunity following the use of alemtuzumab,” Dr. Coles stated.

“In my opinion it is not appropriate to preclude the use of alemtuzumab to patients who have had previous autoimmune disease before treatment or who develop thyroid autoimmunity after alemtuzumab,” he said.

“It remains in my view a reasonable treatment option for patients with active MS to receive this highly effective therapy in the face of well-managed, well-understood thyroid autoimmunity and the very unlikely, rare, but serious autoimmune disease,” he concluded.
 

Risk stratification

Commenting on the presentation, Robert J. Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis, Cleveland Clinic, Ohio, explained that, whenever there is a serious risk of a complication, clinicians like to try to stratify that risk.

“We like to identify those at higher risk [and perhaps not use the therapy] and those at lower risk [and perhaps consider more likely the use of that therapy],” he said.

With regard to alemtuzumab, Dr. Fox noted: “We’d like to stratify the risk of autoimmune complications, which could help guide us regarding the patients in whom therapy may be safer. Unfortunately, these findings did not point to a risk stratification to help guide its use towards lower-risk patients.

“I view this as an unfortunate result, because it leaves me without a way to stratify the risks of alemtuzumab, which are quite significant and currently limit my use of that MS therapy only to those with no other treatment options,” he added.

On Dr. Coles’ view of alemtuzumab as a “reasonable” treatment option, Dr. Fox commented: “I guess it depends upon how that’s interpreted. Given the risks of serious, life-threatening immune and infectious complications, I only consider alemtuzumab when all other immune-modulating therapies have been tried or are not a reasonable treatment option. So, yes, I see it as ‘reasonable,’ but only when there are no other available treatment options.”

The current work was supported by Sanofi and Bayer HealthCare. Dr. Coles reported sitting on advisory boards for Genzyme (Sanofi). He is credited as an inventor on several patents related to the technology on which alemtuzumab is based. Dr. Fox has disclosed no relevant financial relationships.
 

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

There is no evidence to support the idea that previous autoimmunity before or after alemtuzumab treatment predicts subsequent rare but serious and possibly life-threatening autoimmune events that have recently been linked to the drug, a new study has shown.

These latest data were reported by Alasdair J. Coles, MD, University of Cambridge (England), 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.

Dr. Coles, who led the initial research to develop alemtuzumab in partnership with Genzyme, explained that autoimmune disease is a well-described and common adverse event with the drug, manifesting mainly as autoimmune thyroid events that can occur in up to 40% of patients.

But as postmarketing experience has grown, it has become clear that there is a low frequency of more serious autoimmune disease, he noted. In an effort to understand this better, regulators have suggested that the presence of non–multiple sclerosis (MS) autoimmune disease before alemtuzumab treatment and the emergence of autoimmune disease after alemtuzumab treatment may define a group that is at higher risk of one of the rare but serious autoimmune events for those on the drug.

To investigate if this was the case, Dr. Coles and colleagues analyzed data on 1,216 patients who received alemtuzumab in the clinical development program. Of these, 96 had preexisting non-MS autoimmunity.

Results showed that up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) versus without (35.3%) preexisting autoimmunity.

Similar percentages of patients with versus without preexisting autoimmunity had two or more new autoimmune events (5.2% vs. 8.2%, respectively). And most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab.

In addition, treatment-emergent thyroid autoimmunity after the first alemtuzumab course was not associated with subsequent nonthyroid autoimmunity after the second course. Similarly, thyroid autoimmunity after the second course did not predict non-thyroid autoimmunity after the third course.

In another analysis of the incidence of serious autoimmune events from postmarketing data on 25,292 patients treated with alemtuzumab, immune thrombocytopenic purpura was reported in 43 patients, newly identified autoimmune hepatitis in 11 patients, and hemophagocytic lymphohistiocytosis in 9 patients.

There was “no hint at all” that baseline thyroid disorders or postalemtuzumab thyroid disorders are associated with increased risk of these serious autoimmune adverse events, Dr. Coles said.

He calculated that the incidence of serious autoimmune diseases that could be life-threatening after alemtuzumab treatment was 10.7 per 10,000 patients treated for autoimmune hepatitis and 2.7 per 10,000 patients treated for hemophagocytic lymphohistiocytosis.

“From two separate data sources – phase 2/3 trials populations combined and postmarketing data – there is no evidence to support the hypothesis that preexisting non-MS autoimmunity predisposes to the serious but rare autoimmune events that have newly been described, nor does thyroid autoimmunity following the use of alemtuzumab,” Dr. Coles stated.

“In my opinion it is not appropriate to preclude the use of alemtuzumab to patients who have had previous autoimmune disease before treatment or who develop thyroid autoimmunity after alemtuzumab,” he said.

“It remains in my view a reasonable treatment option for patients with active MS to receive this highly effective therapy in the face of well-managed, well-understood thyroid autoimmunity and the very unlikely, rare, but serious autoimmune disease,” he concluded.
 

Risk stratification

Commenting on the presentation, Robert J. Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis, Cleveland Clinic, Ohio, explained that, whenever there is a serious risk of a complication, clinicians like to try to stratify that risk.

“We like to identify those at higher risk [and perhaps not use the therapy] and those at lower risk [and perhaps consider more likely the use of that therapy],” he said.

With regard to alemtuzumab, Dr. Fox noted: “We’d like to stratify the risk of autoimmune complications, which could help guide us regarding the patients in whom therapy may be safer. Unfortunately, these findings did not point to a risk stratification to help guide its use towards lower-risk patients.

“I view this as an unfortunate result, because it leaves me without a way to stratify the risks of alemtuzumab, which are quite significant and currently limit my use of that MS therapy only to those with no other treatment options,” he added.

On Dr. Coles’ view of alemtuzumab as a “reasonable” treatment option, Dr. Fox commented: “I guess it depends upon how that’s interpreted. Given the risks of serious, life-threatening immune and infectious complications, I only consider alemtuzumab when all other immune-modulating therapies have been tried or are not a reasonable treatment option. So, yes, I see it as ‘reasonable,’ but only when there are no other available treatment options.”

The current work was supported by Sanofi and Bayer HealthCare. Dr. Coles reported sitting on advisory boards for Genzyme (Sanofi). He is credited as an inventor on several patents related to the technology on which alemtuzumab is based. Dr. Fox has disclosed no relevant financial relationships.
 

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