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Is Chronic Migraine More Common in the MS Population?
BOSTON—At Island Neurological Associates in Plainview, New York, researchers uncovered a prevalence of chronic migraine among their population of patients with multiple sclerosis (MS) that was higher than would be expected in the general population. They reported their results at the 59th Annual Scientific Meeting of the American Headache Society. “Since migraine as a whole is generally accepted to occur in about 12% of the population, it appears that our MS patient prevalence of 21% significantly exceeds this [prevalence],” said Ira Turner, MD, a headache subspecialist at the Long Island facility. Similarly, “chronic migraine is thought to occur in 1% to 2% of the general population, but [it occurs] in 7% of our MS population,” Dr. Turner said. 
Observing that MS and migraine are both chronic neurologic conditions in which inflammatory processes play an important role, Dr. Turner and colleagues sought evidence for increased migraine prevalence in the MS population. “Anecdotally, it has been our experience that there is a comorbidity of headache disorders in our MS patient population,” Dr. Turner said.
The investigators conducted a retrospective review of the electronic medical record (EMR) system at their community-based Comprehensive MS Center and Center for Headache Care and Research. They reviewed the EMR for all patients with a diagnosis of any form of MS. The EMR was then queried to determine which of the patients with MS had any headache diagnosis listed as a comorbidity. Those headache diagnoses were then reviewed and separated into those that met ICHD
The researchers found 610 active patients with a diagnosis of MS. Of these, 139 (23%) also had a headache diagnosis listed in the EMR as a comorbidity. Migraine without aura was coded in 62 patients (10%), migraine with aura in 26 (4%), and chronic migraine in 45 (7%). Combining these diagnoses yielded a prevalence of comorbid migraine of 21% in the MS population studied. Episodic cluster headache was diagnosed in one patient, tension-type headache in two patients, and nonspecific headache in four patients. The prevalence of these three diagnoses was less than 1% each.
“While there is a potential bias caused by our practice having both an MS center and a headache center, this increased prevalence seems to be of great interest and would appear to warrant further investigation,” Dr. Turner said.
—Glenn S. Williams
BOSTON—At Island Neurological Associates in Plainview, New York, researchers uncovered a prevalence of chronic migraine among their population of patients with multiple sclerosis (MS) that was higher than would be expected in the general population. They reported their results at the 59th Annual Scientific Meeting of the American Headache Society. “Since migraine as a whole is generally accepted to occur in about 12% of the population, it appears that our MS patient prevalence of 21% significantly exceeds this [prevalence],” said Ira Turner, MD, a headache subspecialist at the Long Island facility. Similarly, “chronic migraine is thought to occur in 1% to 2% of the general population, but [it occurs] in 7% of our MS population,” Dr. Turner said.
Observing that MS and migraine are both chronic neurologic conditions in which inflammatory processes play an important role, Dr. Turner and colleagues sought evidence for increased migraine prevalence in the MS population. “Anecdotally, it has been our experience that there is a comorbidity of headache disorders in our MS patient population,” Dr. Turner said.
The investigators conducted a retrospective review of the electronic medical record (EMR) system at their community-based Comprehensive MS Center and Center for Headache Care and Research. They reviewed the EMR for all patients with a diagnosis of any form of MS. The EMR was then queried to determine which of the patients with MS had any headache diagnosis listed as a comorbidity. Those headache diagnoses were then reviewed and separated into those that met ICHD
The researchers found 610 active patients with a diagnosis of MS. Of these, 139 (23%) also had a headache diagnosis listed in the EMR as a comorbidity. Migraine without aura was coded in 62 patients (10%), migraine with aura in 26 (4%), and chronic migraine in 45 (7%). Combining these diagnoses yielded a prevalence of comorbid migraine of 21% in the MS population studied. Episodic cluster headache was diagnosed in one patient, tension-type headache in two patients, and nonspecific headache in four patients. The prevalence of these three diagnoses was less than 1% each.
“While there is a potential bias caused by our practice having both an MS center and a headache center, this increased prevalence seems to be of great interest and would appear to warrant further investigation,” Dr. Turner said.
—Glenn S. Williams
BOSTON—At Island Neurological Associates in Plainview, New York, researchers uncovered a prevalence of chronic migraine among their population of patients with multiple sclerosis (MS) that was higher than would be expected in the general population. They reported their results at the 59th Annual Scientific Meeting of the American Headache Society. “Since migraine as a whole is generally accepted to occur in about 12% of the population, it appears that our MS patient prevalence of 21% significantly exceeds this [prevalence],” said Ira Turner, MD, a headache subspecialist at the Long Island facility. Similarly, “chronic migraine is thought to occur in 1% to 2% of the general population, but [it occurs] in 7% of our MS population,” Dr. Turner said.
Observing that MS and migraine are both chronic neurologic conditions in which inflammatory processes play an important role, Dr. Turner and colleagues sought evidence for increased migraine prevalence in the MS population. “Anecdotally, it has been our experience that there is a comorbidity of headache disorders in our MS patient population,” Dr. Turner said.
The investigators conducted a retrospective review of the electronic medical record (EMR) system at their community-based Comprehensive MS Center and Center for Headache Care and Research. They reviewed the EMR for all patients with a diagnosis of any form of MS. The EMR was then queried to determine which of the patients with MS had any headache diagnosis listed as a comorbidity. Those headache diagnoses were then reviewed and separated into those that met ICHD
The researchers found 610 active patients with a diagnosis of MS. Of these, 139 (23%) also had a headache diagnosis listed in the EMR as a comorbidity. Migraine without aura was coded in 62 patients (10%), migraine with aura in 26 (4%), and chronic migraine in 45 (7%). Combining these diagnoses yielded a prevalence of comorbid migraine of 21% in the MS population studied. Episodic cluster headache was diagnosed in one patient, tension-type headache in two patients, and nonspecific headache in four patients. The prevalence of these three diagnoses was less than 1% each.
“While there is a potential bias caused by our practice having both an MS center and a headache center, this increased prevalence seems to be of great interest and would appear to warrant further investigation,” Dr. Turner said.
—Glenn S. Williams
Disease-Modifying Drug Treatment Before, During, and After Pregnancy in Women With MS
NEW ORLEANS—In a population of women with multiple sclerosis (MS) and a live birth, the rate of disease-modifying drug treatment decreased before and during pregnancy and increased steadily post partum, according to a report presented at the 31st Annual Meeting of the Consortium of MS Centers. In a separate analysis by the same researchers, they reported that less than one-third of women with MS and a live birth initiated a disease-modifying treatment within one year after delivery. “The rate of disease-modifying drug initiation increased with the number of relapses the patient experienced prior to pregnancy,” said Maria K. Houtchens, MD, on behalf of her research collaborators. Dr. Houtchens is an Assistant Professor in the Department of Neurology at Harvard Medical School and Director of the Women’s Health Program at the Partners MS Center at Brigham and Women’s Hospital in Boston. 
Treatment Before, During, and After Pregnancy
To evaluate treatment patterns before, during, and after pregnancy in women with MS and a live birth, Dr. Houtchens and colleagues used a US administrative claims database to conduct a retrospective analysis of women ages 18 to 65 with MS, a claim indicative of a live birth, and one-year continuous eligibility before and after pregnancy in the IMS Health Real World Data Adjudicated Claims US database from January 1, 2006, to June 30, 2015. Disease-modifying drug treatment was evaluated during the year prior to pregnancy (at three-month intervals), the three trimesters of pregnancy, puerperium (six weeks post pregnancy), and one year post pregnancy (seven to 12 weeks post pregnancy and three to six, six to nine, and nine to 12 months post pregnancy). The researchers evaluated the proportion of women exposed to disease-modifying drug treatment during the 12 time periods. Results were also stratified by the number of relapses women experienced in the year prior to pregnancy.
Of 190,475 women with MS, 2,158 met eligibility criteria. Mean age was 30.26. Most women had commercial health insurance (98%) and were from the Midwest (32%), South (30%), or Northeast (29%) regions of the US.
The proportion of women with MS and a live birth treated with any disease-modifying drug was 20.48% at nine to 12 months pre-pregnancy, 21.46% at six to nine months pre-pregnancy, 20.62% at three to six months pre-pregnancy, and 17.75% at three months pre-pregnancy. During pregnancy, the proportion of women treated with a disease-modifying drug decreased to 12.05% during the first trimester and 1.90% during the second trimester, and then increased slightly to 2.97% during the third trimester. The proportion of women treated with disease-modifying drugs increased to 8.34% during puerperium, 12.93% during seven to 12 weeks post partum, 21.97% during three to six months post partum, 24.47% during six to nine months post partum, and 25.49% during nine to 12 months post partum. The majority of women (81.9%) had received disease-modifying drug treatment by six to nine months post partum. The proportion of women with disease-modifying drug treatment before and after pregnancy increased numerically with the number of relapses experienced before pregnancy.
Treatment After a Live Birth
In a separate analysis using the same cohort, Dr. Houtchens and colleagues looked closer at the time to initiation of disease-modifying drug treatment after a live birth in women with MS. Of the 2,094 women included in this analysis, the proportion with a live birth initiating a disease-modifying drug treatment within one year was 28.46%, and the proportion with no disease-modifying treatment within one year was 71.54%.
For those initiating a disease-modifying treatment within one year, mean time from live birth to first treatment was 118.98 days, and median time to first treatment was 93.50 days. A total of 16.11% received a disease-modifying drug less than 30 days after live birth, approximately half initiated a treatment within 90 days (47.82%), and three-quarters initiated a disease-modifying drug within six months (75.5%). The proportion of patients initiating treatment within one year after live birth increased with higher numbers of pre-pregnancy relapses (zero relapses, n = 441, 24.53%; one relapse, n = 108, 50.94%; two relapses, n = 33, 54.10%; three or more relapses, n = 14, 60.87%). The mean number of days until disease-modifying drug initiation for those receiving
This study was supported by EMD Serono.
NEW ORLEANS—In a population of women with multiple sclerosis (MS) and a live birth, the rate of disease-modifying drug treatment decreased before and during pregnancy and increased steadily post partum, according to a report presented at the 31st Annual Meeting of the Consortium of MS Centers. In a separate analysis by the same researchers, they reported that less than one-third of women with MS and a live birth initiated a disease-modifying treatment within one year after delivery. “The rate of disease-modifying drug initiation increased with the number of relapses the patient experienced prior to pregnancy,” said Maria K. Houtchens, MD, on behalf of her research collaborators. Dr. Houtchens is an Assistant Professor in the Department of Neurology at Harvard Medical School and Director of the Women’s Health Program at the Partners MS Center at Brigham and Women’s Hospital in Boston.
Treatment Before, During, and After Pregnancy
To evaluate treatment patterns before, during, and after pregnancy in women with MS and a live birth, Dr. Houtchens and colleagues used a US administrative claims database to conduct a retrospective analysis of women ages 18 to 65 with MS, a claim indicative of a live birth, and one-year continuous eligibility before and after pregnancy in the IMS Health Real World Data Adjudicated Claims US database from January 1, 2006, to June 30, 2015. Disease-modifying drug treatment was evaluated during the year prior to pregnancy (at three-month intervals), the three trimesters of pregnancy, puerperium (six weeks post pregnancy), and one year post pregnancy (seven to 12 weeks post pregnancy and three to six, six to nine, and nine to 12 months post pregnancy). The researchers evaluated the proportion of women exposed to disease-modifying drug treatment during the 12 time periods. Results were also stratified by the number of relapses women experienced in the year prior to pregnancy.
Of 190,475 women with MS, 2,158 met eligibility criteria. Mean age was 30.26. Most women had commercial health insurance (98%) and were from the Midwest (32%), South (30%), or Northeast (29%) regions of the US.
The proportion of women with MS and a live birth treated with any disease-modifying drug was 20.48% at nine to 12 months pre-pregnancy, 21.46% at six to nine months pre-pregnancy, 20.62% at three to six months pre-pregnancy, and 17.75% at three months pre-pregnancy. During pregnancy, the proportion of women treated with a disease-modifying drug decreased to 12.05% during the first trimester and 1.90% during the second trimester, and then increased slightly to 2.97% during the third trimester. The proportion of women treated with disease-modifying drugs increased to 8.34% during puerperium, 12.93% during seven to 12 weeks post partum, 21.97% during three to six months post partum, 24.47% during six to nine months post partum, and 25.49% during nine to 12 months post partum. The majority of women (81.9%) had received disease-modifying drug treatment by six to nine months post partum. The proportion of women with disease-modifying drug treatment before and after pregnancy increased numerically with the number of relapses experienced before pregnancy.
Treatment After a Live Birth
In a separate analysis using the same cohort, Dr. Houtchens and colleagues looked closer at the time to initiation of disease-modifying drug treatment after a live birth in women with MS. Of the 2,094 women included in this analysis, the proportion with a live birth initiating a disease-modifying drug treatment within one year was 28.46%, and the proportion with no disease-modifying treatment within one year was 71.54%.
For those initiating a disease-modifying treatment within one year, mean time from live birth to first treatment was 118.98 days, and median time to first treatment was 93.50 days. A total of 16.11% received a disease-modifying drug less than 30 days after live birth, approximately half initiated a treatment within 90 days (47.82%), and three-quarters initiated a disease-modifying drug within six months (75.5%). The proportion of patients initiating treatment within one year after live birth increased with higher numbers of pre-pregnancy relapses (zero relapses, n = 441, 24.53%; one relapse, n = 108, 50.94%; two relapses, n = 33, 54.10%; three or more relapses, n = 14, 60.87%). The mean number of days until disease-modifying drug initiation for those receiving
This study was supported by EMD Serono.
NEW ORLEANS—In a population of women with multiple sclerosis (MS) and a live birth, the rate of disease-modifying drug treatment decreased before and during pregnancy and increased steadily post partum, according to a report presented at the 31st Annual Meeting of the Consortium of MS Centers. In a separate analysis by the same researchers, they reported that less than one-third of women with MS and a live birth initiated a disease-modifying treatment within one year after delivery. “The rate of disease-modifying drug initiation increased with the number of relapses the patient experienced prior to pregnancy,” said Maria K. Houtchens, MD, on behalf of her research collaborators. Dr. Houtchens is an Assistant Professor in the Department of Neurology at Harvard Medical School and Director of the Women’s Health Program at the Partners MS Center at Brigham and Women’s Hospital in Boston.
Treatment Before, During, and After Pregnancy
To evaluate treatment patterns before, during, and after pregnancy in women with MS and a live birth, Dr. Houtchens and colleagues used a US administrative claims database to conduct a retrospective analysis of women ages 18 to 65 with MS, a claim indicative of a live birth, and one-year continuous eligibility before and after pregnancy in the IMS Health Real World Data Adjudicated Claims US database from January 1, 2006, to June 30, 2015. Disease-modifying drug treatment was evaluated during the year prior to pregnancy (at three-month intervals), the three trimesters of pregnancy, puerperium (six weeks post pregnancy), and one year post pregnancy (seven to 12 weeks post pregnancy and three to six, six to nine, and nine to 12 months post pregnancy). The researchers evaluated the proportion of women exposed to disease-modifying drug treatment during the 12 time periods. Results were also stratified by the number of relapses women experienced in the year prior to pregnancy.
Of 190,475 women with MS, 2,158 met eligibility criteria. Mean age was 30.26. Most women had commercial health insurance (98%) and were from the Midwest (32%), South (30%), or Northeast (29%) regions of the US.
The proportion of women with MS and a live birth treated with any disease-modifying drug was 20.48% at nine to 12 months pre-pregnancy, 21.46% at six to nine months pre-pregnancy, 20.62% at three to six months pre-pregnancy, and 17.75% at three months pre-pregnancy. During pregnancy, the proportion of women treated with a disease-modifying drug decreased to 12.05% during the first trimester and 1.90% during the second trimester, and then increased slightly to 2.97% during the third trimester. The proportion of women treated with disease-modifying drugs increased to 8.34% during puerperium, 12.93% during seven to 12 weeks post partum, 21.97% during three to six months post partum, 24.47% during six to nine months post partum, and 25.49% during nine to 12 months post partum. The majority of women (81.9%) had received disease-modifying drug treatment by six to nine months post partum. The proportion of women with disease-modifying drug treatment before and after pregnancy increased numerically with the number of relapses experienced before pregnancy.
Treatment After a Live Birth
In a separate analysis using the same cohort, Dr. Houtchens and colleagues looked closer at the time to initiation of disease-modifying drug treatment after a live birth in women with MS. Of the 2,094 women included in this analysis, the proportion with a live birth initiating a disease-modifying drug treatment within one year was 28.46%, and the proportion with no disease-modifying treatment within one year was 71.54%.
For those initiating a disease-modifying treatment within one year, mean time from live birth to first treatment was 118.98 days, and median time to first treatment was 93.50 days. A total of 16.11% received a disease-modifying drug less than 30 days after live birth, approximately half initiated a treatment within 90 days (47.82%), and three-quarters initiated a disease-modifying drug within six months (75.5%). The proportion of patients initiating treatment within one year after live birth increased with higher numbers of pre-pregnancy relapses (zero relapses, n = 441, 24.53%; one relapse, n = 108, 50.94%; two relapses, n = 33, 54.10%; three or more relapses, n = 14, 60.87%). The mean number of days until disease-modifying drug initiation for those receiving
This study was supported by EMD Serono.
Integrative approach to MS care underused, expert says
NEW ORLEANS – The integration of lifestyle, alternative, and conventional medicine into the care of patients with multiple sclerosis can be transformative for patients and clinicians alike, according to Allen C. Bowling, MD, PhD.
This approach not only emphasizes health and wellness of the whole person, it supports the clinician-patient relationship since neurologists serve as point persons for MS patients, Dr. Bowling said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “It’s critical to not just think about MS the disease, but to think about the patient’s overall health, maintaining health,” he said. “That’s a big mind shift. I think sometimes people hear the term ‘integrative medicine’ and they start walking out of the room or think it’s getting ‘woo-woo,’ but there is a very evidence-based approach to integrative medicine. The core of it still is not familiar to a lot of physicians.”
Harness ‘built-in’ resources
Dr. Bowling, author of “Optimal Health With Multiple Sclerosis: A Guide to Integrating Lifestyle, Alternative, and Conventional Medicine” (New York: Demos Medical Publishing, 2014) and developer of a website devoted to integrative care and MS (www.neurologycare.net), said that some of best treatment approaches may be those that use the “built-in” resources of the human body and do not require any medications, supplements, devices, or technology. “The most effective and long-lasting changes in lifestyle may be those that are small and consistent,” he said. For example, when he first started applying integrative care principles to his practice more than 16 years ago, some patients told him that MS was “one of the best things that happened to them, and that it was a gift in that it helped them clean up their lifestyle.” In the summer of 2001, one such patient came to see Dr. Bowling and said, “Since my last appointment I’ve lost 20 pounds, bought a bike. I exercise four times weekly. My wife and I have changed our diet. This is real; I’m on it.”
“I said. ‘Very impressive. How did that happen? What motivated you?’ ”
“He said, ‘You did.’ This was like a turning point in his life.”
As of May 2017, this patient has maintained his healthy lifestyle changes.
Dr. Bowling told meeting attendees that early in his neurology career he didn’t always consider other ways he could impact MS patients beyond helping them determine the best disease-modifying treatment and/or assisting them in managing symptoms. Thinking to counsel them in areas such as a balanced diet, exercise, and emotional wellness “was a mind shift for me, and made me realize how narrow my focus was,” he said. “It transformed me to go back to thinking more about general medicine. I’m a detail-oriented guy, but I don’t think that’s in the best interests of our patients. I think we need to combine very disease-specific advice with very general advice. We’re at a very important place with our patients where we can potentially have a very significant impact with our recommendations about MS as well as other medical conditions and health maintenance.”
Take baby steps
Dr. Bowling recommended that clinicians take baby steps to incorporate aspects of integrated care, including use of brief, strong supportive statements; focusing on only one issue per visit; referring patients to information resources; and sharing or transferring responsibility/accountability with other providers. Excessive focus on one therapy – including unusual and unproven CAM therapies – may detract from, or be used to avoid, other valuable approaches. For example, some of Dr. Bowling’s patients may come in very enchanted with a particular dietary supplement yet their own diet is unhealthy. “I don’t scold them, but I say, ‘I don’t think this supplement’s going to hurt you but there’s much more evidence that we should shift the focus of your motivation and drive to dietary approaches.’ ”
Use leverage to tackle emotional health
In the area of emotional health, Dr. Bowling said that an MS diagnosis often serves as a springboard to help young patients develop emotional literacy so that they don’t develop high levels of stress and anxiety. “What I find are people on the verge of entering into depression or anxiety and not really knowing how to address those emotional issues or even to do basic identification and processing of emotions, and getting attached to mind-body approaches, which I think have a clear benefit, but for many patients it does not lead to emotional literacy,” he said. “I emphasize ‘I can’t be with you 24/7. That’s your piece of the equation.’ You can also help patients identify things that give them joy, meaning, and fun in life. That’s a motivator for a lot of them – to keep doing what they find joyful, meaningful, and fun.” Dr. Bowling said that this kind of approach brings “plain old common sense” to the clinician-patient relationship. “I think we all have lots of leverage with our patients, but there’s no cookbook or algorithm here; you need to start where patients are,” he said. “Our younger patients in particular are not really listening to their primary care doctor too much. They’re paying very close attention to what we’re talking about: disease-modifying therapies and symptomatic management.”
In Dr. Bowling’s clinical experience, men often struggle with emotional health and emotional literacy issues. “I have seen amazing transformations of men in their early 20s with very low emotional literacy, and working with them, sometimes with psychodynamic psychotherapy and other methods, sometimes just talking with friends and family – really encouraging them before there’s serious anxiety or depression.” One patient told him that MS “forced me to do a year of psychotherapy and some intensive introspection for a few years. This helped me and also my family.” He recommended that clinicians tread carefully when advising men about tobacco and alcohol use, and when advising women about weight management. “Be prepared; it’s a little different every time you bring those potential issues up,” he said.
Dr. Bowling added that MS often affects how patients view the aging process itself. “It can be a crash course in how to understand the body and best use it before people technically get to the aging years,” he said. “There’s also more acceptance of disability in people who are older.” In the setting of patients who experience disease flare-ups, they may ask you if there’s anything they can do from a lifestyle standpoint to make them go away. “Be primed for these teaching moments and opportunities where there’s a seed of motivation,” he advised.
Approach treats, prevents clinician burnout
Dr. Bowling described the integrative approach to treating MS patients as “an ever-changing skill set. There’s all this talk about neurologist burnout, which is very real. If you practice this way, this is a great treatment and preventive approach for clinician burnout because your patients check you out to see if you ‘walk the walk’ on advice you give them. My success with my patients in some of these areas is less than 50%. But when there’s a real change, it’s for the life of that person. That’s the most rewarding part of my career at this point.”
Dr. Bowling disclosed that he has received research, consulting, advising, and speaking fees from Acorda, Biogen, EMD Serono, Genentech, Genzyme, Sanofi-Aventis, Teva, the American Academy of Neurology, the CMSC, the Mandell Center for Multiple Sclerosis, and the National MS Society.
NEW ORLEANS – The integration of lifestyle, alternative, and conventional medicine into the care of patients with multiple sclerosis can be transformative for patients and clinicians alike, according to Allen C. Bowling, MD, PhD.
This approach not only emphasizes health and wellness of the whole person, it supports the clinician-patient relationship since neurologists serve as point persons for MS patients, Dr. Bowling said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “It’s critical to not just think about MS the disease, but to think about the patient’s overall health, maintaining health,” he said. “That’s a big mind shift. I think sometimes people hear the term ‘integrative medicine’ and they start walking out of the room or think it’s getting ‘woo-woo,’ but there is a very evidence-based approach to integrative medicine. The core of it still is not familiar to a lot of physicians.”
Harness ‘built-in’ resources
Dr. Bowling, author of “Optimal Health With Multiple Sclerosis: A Guide to Integrating Lifestyle, Alternative, and Conventional Medicine” (New York: Demos Medical Publishing, 2014) and developer of a website devoted to integrative care and MS (www.neurologycare.net), said that some of best treatment approaches may be those that use the “built-in” resources of the human body and do not require any medications, supplements, devices, or technology. “The most effective and long-lasting changes in lifestyle may be those that are small and consistent,” he said. For example, when he first started applying integrative care principles to his practice more than 16 years ago, some patients told him that MS was “one of the best things that happened to them, and that it was a gift in that it helped them clean up their lifestyle.” In the summer of 2001, one such patient came to see Dr. Bowling and said, “Since my last appointment I’ve lost 20 pounds, bought a bike. I exercise four times weekly. My wife and I have changed our diet. This is real; I’m on it.”
“I said. ‘Very impressive. How did that happen? What motivated you?’ ”
“He said, ‘You did.’ This was like a turning point in his life.”
As of May 2017, this patient has maintained his healthy lifestyle changes.
Dr. Bowling told meeting attendees that early in his neurology career he didn’t always consider other ways he could impact MS patients beyond helping them determine the best disease-modifying treatment and/or assisting them in managing symptoms. Thinking to counsel them in areas such as a balanced diet, exercise, and emotional wellness “was a mind shift for me, and made me realize how narrow my focus was,” he said. “It transformed me to go back to thinking more about general medicine. I’m a detail-oriented guy, but I don’t think that’s in the best interests of our patients. I think we need to combine very disease-specific advice with very general advice. We’re at a very important place with our patients where we can potentially have a very significant impact with our recommendations about MS as well as other medical conditions and health maintenance.”
Take baby steps
Dr. Bowling recommended that clinicians take baby steps to incorporate aspects of integrated care, including use of brief, strong supportive statements; focusing on only one issue per visit; referring patients to information resources; and sharing or transferring responsibility/accountability with other providers. Excessive focus on one therapy – including unusual and unproven CAM therapies – may detract from, or be used to avoid, other valuable approaches. For example, some of Dr. Bowling’s patients may come in very enchanted with a particular dietary supplement yet their own diet is unhealthy. “I don’t scold them, but I say, ‘I don’t think this supplement’s going to hurt you but there’s much more evidence that we should shift the focus of your motivation and drive to dietary approaches.’ ”
Use leverage to tackle emotional health
In the area of emotional health, Dr. Bowling said that an MS diagnosis often serves as a springboard to help young patients develop emotional literacy so that they don’t develop high levels of stress and anxiety. “What I find are people on the verge of entering into depression or anxiety and not really knowing how to address those emotional issues or even to do basic identification and processing of emotions, and getting attached to mind-body approaches, which I think have a clear benefit, but for many patients it does not lead to emotional literacy,” he said. “I emphasize ‘I can’t be with you 24/7. That’s your piece of the equation.’ You can also help patients identify things that give them joy, meaning, and fun in life. That’s a motivator for a lot of them – to keep doing what they find joyful, meaningful, and fun.” Dr. Bowling said that this kind of approach brings “plain old common sense” to the clinician-patient relationship. “I think we all have lots of leverage with our patients, but there’s no cookbook or algorithm here; you need to start where patients are,” he said. “Our younger patients in particular are not really listening to their primary care doctor too much. They’re paying very close attention to what we’re talking about: disease-modifying therapies and symptomatic management.”
In Dr. Bowling’s clinical experience, men often struggle with emotional health and emotional literacy issues. “I have seen amazing transformations of men in their early 20s with very low emotional literacy, and working with them, sometimes with psychodynamic psychotherapy and other methods, sometimes just talking with friends and family – really encouraging them before there’s serious anxiety or depression.” One patient told him that MS “forced me to do a year of psychotherapy and some intensive introspection for a few years. This helped me and also my family.” He recommended that clinicians tread carefully when advising men about tobacco and alcohol use, and when advising women about weight management. “Be prepared; it’s a little different every time you bring those potential issues up,” he said.
Dr. Bowling added that MS often affects how patients view the aging process itself. “It can be a crash course in how to understand the body and best use it before people technically get to the aging years,” he said. “There’s also more acceptance of disability in people who are older.” In the setting of patients who experience disease flare-ups, they may ask you if there’s anything they can do from a lifestyle standpoint to make them go away. “Be primed for these teaching moments and opportunities where there’s a seed of motivation,” he advised.
Approach treats, prevents clinician burnout
Dr. Bowling described the integrative approach to treating MS patients as “an ever-changing skill set. There’s all this talk about neurologist burnout, which is very real. If you practice this way, this is a great treatment and preventive approach for clinician burnout because your patients check you out to see if you ‘walk the walk’ on advice you give them. My success with my patients in some of these areas is less than 50%. But when there’s a real change, it’s for the life of that person. That’s the most rewarding part of my career at this point.”
Dr. Bowling disclosed that he has received research, consulting, advising, and speaking fees from Acorda, Biogen, EMD Serono, Genentech, Genzyme, Sanofi-Aventis, Teva, the American Academy of Neurology, the CMSC, the Mandell Center for Multiple Sclerosis, and the National MS Society.
NEW ORLEANS – The integration of lifestyle, alternative, and conventional medicine into the care of patients with multiple sclerosis can be transformative for patients and clinicians alike, according to Allen C. Bowling, MD, PhD.
This approach not only emphasizes health and wellness of the whole person, it supports the clinician-patient relationship since neurologists serve as point persons for MS patients, Dr. Bowling said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “It’s critical to not just think about MS the disease, but to think about the patient’s overall health, maintaining health,” he said. “That’s a big mind shift. I think sometimes people hear the term ‘integrative medicine’ and they start walking out of the room or think it’s getting ‘woo-woo,’ but there is a very evidence-based approach to integrative medicine. The core of it still is not familiar to a lot of physicians.”
Harness ‘built-in’ resources
Dr. Bowling, author of “Optimal Health With Multiple Sclerosis: A Guide to Integrating Lifestyle, Alternative, and Conventional Medicine” (New York: Demos Medical Publishing, 2014) and developer of a website devoted to integrative care and MS (www.neurologycare.net), said that some of best treatment approaches may be those that use the “built-in” resources of the human body and do not require any medications, supplements, devices, or technology. “The most effective and long-lasting changes in lifestyle may be those that are small and consistent,” he said. For example, when he first started applying integrative care principles to his practice more than 16 years ago, some patients told him that MS was “one of the best things that happened to them, and that it was a gift in that it helped them clean up their lifestyle.” In the summer of 2001, one such patient came to see Dr. Bowling and said, “Since my last appointment I’ve lost 20 pounds, bought a bike. I exercise four times weekly. My wife and I have changed our diet. This is real; I’m on it.”
“I said. ‘Very impressive. How did that happen? What motivated you?’ ”
“He said, ‘You did.’ This was like a turning point in his life.”
As of May 2017, this patient has maintained his healthy lifestyle changes.
Dr. Bowling told meeting attendees that early in his neurology career he didn’t always consider other ways he could impact MS patients beyond helping them determine the best disease-modifying treatment and/or assisting them in managing symptoms. Thinking to counsel them in areas such as a balanced diet, exercise, and emotional wellness “was a mind shift for me, and made me realize how narrow my focus was,” he said. “It transformed me to go back to thinking more about general medicine. I’m a detail-oriented guy, but I don’t think that’s in the best interests of our patients. I think we need to combine very disease-specific advice with very general advice. We’re at a very important place with our patients where we can potentially have a very significant impact with our recommendations about MS as well as other medical conditions and health maintenance.”
Take baby steps
Dr. Bowling recommended that clinicians take baby steps to incorporate aspects of integrated care, including use of brief, strong supportive statements; focusing on only one issue per visit; referring patients to information resources; and sharing or transferring responsibility/accountability with other providers. Excessive focus on one therapy – including unusual and unproven CAM therapies – may detract from, or be used to avoid, other valuable approaches. For example, some of Dr. Bowling’s patients may come in very enchanted with a particular dietary supplement yet their own diet is unhealthy. “I don’t scold them, but I say, ‘I don’t think this supplement’s going to hurt you but there’s much more evidence that we should shift the focus of your motivation and drive to dietary approaches.’ ”
Use leverage to tackle emotional health
In the area of emotional health, Dr. Bowling said that an MS diagnosis often serves as a springboard to help young patients develop emotional literacy so that they don’t develop high levels of stress and anxiety. “What I find are people on the verge of entering into depression or anxiety and not really knowing how to address those emotional issues or even to do basic identification and processing of emotions, and getting attached to mind-body approaches, which I think have a clear benefit, but for many patients it does not lead to emotional literacy,” he said. “I emphasize ‘I can’t be with you 24/7. That’s your piece of the equation.’ You can also help patients identify things that give them joy, meaning, and fun in life. That’s a motivator for a lot of them – to keep doing what they find joyful, meaningful, and fun.” Dr. Bowling said that this kind of approach brings “plain old common sense” to the clinician-patient relationship. “I think we all have lots of leverage with our patients, but there’s no cookbook or algorithm here; you need to start where patients are,” he said. “Our younger patients in particular are not really listening to their primary care doctor too much. They’re paying very close attention to what we’re talking about: disease-modifying therapies and symptomatic management.”
In Dr. Bowling’s clinical experience, men often struggle with emotional health and emotional literacy issues. “I have seen amazing transformations of men in their early 20s with very low emotional literacy, and working with them, sometimes with psychodynamic psychotherapy and other methods, sometimes just talking with friends and family – really encouraging them before there’s serious anxiety or depression.” One patient told him that MS “forced me to do a year of psychotherapy and some intensive introspection for a few years. This helped me and also my family.” He recommended that clinicians tread carefully when advising men about tobacco and alcohol use, and when advising women about weight management. “Be prepared; it’s a little different every time you bring those potential issues up,” he said.
Dr. Bowling added that MS often affects how patients view the aging process itself. “It can be a crash course in how to understand the body and best use it before people technically get to the aging years,” he said. “There’s also more acceptance of disability in people who are older.” In the setting of patients who experience disease flare-ups, they may ask you if there’s anything they can do from a lifestyle standpoint to make them go away. “Be primed for these teaching moments and opportunities where there’s a seed of motivation,” he advised.
Approach treats, prevents clinician burnout
Dr. Bowling described the integrative approach to treating MS patients as “an ever-changing skill set. There’s all this talk about neurologist burnout, which is very real. If you practice this way, this is a great treatment and preventive approach for clinician burnout because your patients check you out to see if you ‘walk the walk’ on advice you give them. My success with my patients in some of these areas is less than 50%. But when there’s a real change, it’s for the life of that person. That’s the most rewarding part of my career at this point.”
Dr. Bowling disclosed that he has received research, consulting, advising, and speaking fees from Acorda, Biogen, EMD Serono, Genentech, Genzyme, Sanofi-Aventis, Teva, the American Academy of Neurology, the CMSC, the Mandell Center for Multiple Sclerosis, and the National MS Society.
EXPERT ANALYSIS FROM THE CMSC ANNUAL MEETING
Preliminary results promising from ublituximab phase II study for MS
NEW ORLEANS – The investigative agent ublituximab was well tolerated and demonstrated rapid B-cell depletion in patients with relapsing multiple sclerosis, results from an ongoing phase II trial showed.
“Ublituximab is a novel, chimeric monoclonal antibody targeting a unique epitope on the CD20 antigen, and glycoengineered to enhance affinity for all variants of FcyRIlla receptors, thereby demonstrating greater antibody-dependent cellular toxicity activity than rituximab and ofatumumab,” Amy Lovett-Racke, PhD, said at the annual meeting of the Consortium of Multiple Sclerosis Centers.
In a trial supported by TG Therapeutics, which is developing the agent, Dr. Lovett-Racke of the department of microbial infection and immunity at the Ohio State University Medical Center, Columbus, and her associates reported data from 24 patients who received ublituximab at doses markedly less than those used in ongoing phase III oncology studies, and at a range of infusion times, with a goal of rapid infusions.
The study ran for 48 weeks, and the primary endpoint was responders rate, defined as a percent of patients with at least a 95% reduction in peripheral CD19-positive B-cells within 2 weeks after the second infusion. All patients received the same total dose of 600 mg; only infusion times differed. (Ublituximab was administered on day 1, day 15, and week 24. Placebo IV infusion dose was administered on day 1 and day 15 only.)
The mean age of the study participants was 40 years, and the distribution of time from diagnosis was less than 5 years in 11 patients, 5-10 years in 7 patients, and greater than 10 years in 6 patients.
To date, ublituximab has been well tolerated, with only mild infusion reactions being observed, even with infusion times reduced to 1 hour. The researchers also found that ublituximab resulted in 99% B-cell depletion, meeting the study endpoint of greater than 95% depletion within 2 weeks of the second dose, which is comparable to ocrelizumab.
“Every patient has met the endpoint so far,” Dr. Lovett-Racke said. “Although there is a transient decrease in T cells after the initial dose of ublituximab, T-cell numbers are fairly stable over time. Memory B cells seem slightly more resistant to depletion, but are efficiently depleted in all patients. A comprehensive analysis of B- and T-cell profiles is being performed to understand how B-cell depletion influences T-cell profiles, and to characterize the B-cell repletion.”
TG Therapeutics funded the study. Dr. Lovett-Racke disclosed having received research grants from the National Institutes of Health, the National Multiple Sclerosis Society, and the Strategic Pharmaceutical Academic Research Consortium.
NEW ORLEANS – The investigative agent ublituximab was well tolerated and demonstrated rapid B-cell depletion in patients with relapsing multiple sclerosis, results from an ongoing phase II trial showed.
“Ublituximab is a novel, chimeric monoclonal antibody targeting a unique epitope on the CD20 antigen, and glycoengineered to enhance affinity for all variants of FcyRIlla receptors, thereby demonstrating greater antibody-dependent cellular toxicity activity than rituximab and ofatumumab,” Amy Lovett-Racke, PhD, said at the annual meeting of the Consortium of Multiple Sclerosis Centers.
In a trial supported by TG Therapeutics, which is developing the agent, Dr. Lovett-Racke of the department of microbial infection and immunity at the Ohio State University Medical Center, Columbus, and her associates reported data from 24 patients who received ublituximab at doses markedly less than those used in ongoing phase III oncology studies, and at a range of infusion times, with a goal of rapid infusions.
The study ran for 48 weeks, and the primary endpoint was responders rate, defined as a percent of patients with at least a 95% reduction in peripheral CD19-positive B-cells within 2 weeks after the second infusion. All patients received the same total dose of 600 mg; only infusion times differed. (Ublituximab was administered on day 1, day 15, and week 24. Placebo IV infusion dose was administered on day 1 and day 15 only.)
The mean age of the study participants was 40 years, and the distribution of time from diagnosis was less than 5 years in 11 patients, 5-10 years in 7 patients, and greater than 10 years in 6 patients.
To date, ublituximab has been well tolerated, with only mild infusion reactions being observed, even with infusion times reduced to 1 hour. The researchers also found that ublituximab resulted in 99% B-cell depletion, meeting the study endpoint of greater than 95% depletion within 2 weeks of the second dose, which is comparable to ocrelizumab.
“Every patient has met the endpoint so far,” Dr. Lovett-Racke said. “Although there is a transient decrease in T cells after the initial dose of ublituximab, T-cell numbers are fairly stable over time. Memory B cells seem slightly more resistant to depletion, but are efficiently depleted in all patients. A comprehensive analysis of B- and T-cell profiles is being performed to understand how B-cell depletion influences T-cell profiles, and to characterize the B-cell repletion.”
TG Therapeutics funded the study. Dr. Lovett-Racke disclosed having received research grants from the National Institutes of Health, the National Multiple Sclerosis Society, and the Strategic Pharmaceutical Academic Research Consortium.
NEW ORLEANS – The investigative agent ublituximab was well tolerated and demonstrated rapid B-cell depletion in patients with relapsing multiple sclerosis, results from an ongoing phase II trial showed.
“Ublituximab is a novel, chimeric monoclonal antibody targeting a unique epitope on the CD20 antigen, and glycoengineered to enhance affinity for all variants of FcyRIlla receptors, thereby demonstrating greater antibody-dependent cellular toxicity activity than rituximab and ofatumumab,” Amy Lovett-Racke, PhD, said at the annual meeting of the Consortium of Multiple Sclerosis Centers.
In a trial supported by TG Therapeutics, which is developing the agent, Dr. Lovett-Racke of the department of microbial infection and immunity at the Ohio State University Medical Center, Columbus, and her associates reported data from 24 patients who received ublituximab at doses markedly less than those used in ongoing phase III oncology studies, and at a range of infusion times, with a goal of rapid infusions.
The study ran for 48 weeks, and the primary endpoint was responders rate, defined as a percent of patients with at least a 95% reduction in peripheral CD19-positive B-cells within 2 weeks after the second infusion. All patients received the same total dose of 600 mg; only infusion times differed. (Ublituximab was administered on day 1, day 15, and week 24. Placebo IV infusion dose was administered on day 1 and day 15 only.)
The mean age of the study participants was 40 years, and the distribution of time from diagnosis was less than 5 years in 11 patients, 5-10 years in 7 patients, and greater than 10 years in 6 patients.
To date, ublituximab has been well tolerated, with only mild infusion reactions being observed, even with infusion times reduced to 1 hour. The researchers also found that ublituximab resulted in 99% B-cell depletion, meeting the study endpoint of greater than 95% depletion within 2 weeks of the second dose, which is comparable to ocrelizumab.
“Every patient has met the endpoint so far,” Dr. Lovett-Racke said. “Although there is a transient decrease in T cells after the initial dose of ublituximab, T-cell numbers are fairly stable over time. Memory B cells seem slightly more resistant to depletion, but are efficiently depleted in all patients. A comprehensive analysis of B- and T-cell profiles is being performed to understand how B-cell depletion influences T-cell profiles, and to characterize the B-cell repletion.”
TG Therapeutics funded the study. Dr. Lovett-Racke disclosed having received research grants from the National Institutes of Health, the National Multiple Sclerosis Society, and the Strategic Pharmaceutical Academic Research Consortium.
AT THE CMSC ANNUAL MEETING
Key clinical point:
Major finding: Use of ublituximab resulted in 99% B-cell depletion among patients with relapsing MS.
Data source: Preliminary results from a phase II placebo-controlled study of 24 MS patients who received ublituximab.
Disclosures: TG Therapeutics funded the study. Dr. Lovett-Racke disclosed having received research grants from the National Institutes of Health, the National Multiple Sclerosis Society, and the Strategic Pharmaceutical Academic Research Consortium.
Updated Analysis of Ocrelizumab’s Safety
NEW ORLEANS—The safety profile of ocrelizumab in ongoing open-label extension studies in relapsing multiple sclerosis (MS) and primary progressive MS is generally consistent with that observed in controlled clinical trials, according to a report presented at the 31st Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC). “A slight increase in the rate of serious infections was observed in patients with relapsing MS beyond two years, but the rates remained low,” reported Ludwig Kappos, MD, Chair of Neurology at University Hospital Basel in Switzerland, and colleagues. “This was not observed in patients with primary progressive MS, and additional exposure data are needed to determine if the risk increases with further dosing,” the researchers said. “Incidence rates of malignancies and breast cancer observed with ocrelizumab treatment in MS remain within the range of epidemiologic background data.” 
The safety and efficacy of ocrelizumab previously have been characterized in a phase II study in patients with relapsing-remitting MS and in phase III studies in patients with relapsing MS (OPERA I and OPERA II) and in patients with primary progressive MS (ORATORIO). Results from these trials showed that ocrelizumab reduced clinical and MRI evidence of disease activity, compared with placebo and interferon beta-1a. The most common adverse events associated with ocrelizumab during the double-blind periods of the phase III trials included infusion-related reactions, nasopharyngitis, upper respiratory tract infections, headache, and urinary tract infections. During the double-blind treatment period in the phase III trials in relapsing MS, serious adverse events, serious infections, and malignancies were reported in 6.9%, 1.3%, and 0.5% of ocrelizumab-treated patients, respectively (vs 8.7%, 2.9%, and 0.2% of patients treated with interferon beta-1a). In the phase III trial in primary progressive MS, these events were reported in 20.4%, 6.2%, and 2.3% of ocrelizumab-treated patients (vs 22.2%, 5.9%, and 0.8% of patients who received placebo). Across studies, few patients who received ocrelizumab (in the range of 2% to 4%) had adverse event–related treatment withdrawals.
At the CMSC annual meeting, data from controlled and open-label extension periods of the clinical trials of ocrelizumab in relapsing MS and primary progressive MS were presented.
Upon completion of a double-blind treatment period, patients from all studies were eligible to enter a long-term open-label extension in which they received ocrelizumab treatment. Safety analyses were based on integrated data from the phase II and phase III studies. The primary analysis was based on the clinical cutoff dates of the individual studies (phase II, January 22, 2015; OPERA I, April 2, 2015; OPERA II, May 12, 2015; ORATORIO, July 24, 2015). The present updated analysis includes all patients who received one or more dose of ocrelizumab during the controlled or open-label periods of the phase II and phase III studies (ie, the ocrelizumab all-exposure population) as of January 20, 2016. Additional data cutoffs of June 30, 2016, and September 15, 2016, were presented for malignancies to demonstrate changes with increasing ocrelizumab exposure.
The ocrelizumab all-exposure group included 2,279 patients. Patients’ mean age was 40.1, and 61.3% were female. Time since MS symptom onset was 6.67 years, and time since MS diagnosis was 3.66 years.
Overall Adverse Events
As of January 20, 2016, the majority (81%) of patients who received ocrelizumab experienced at least one adverse event, corresponding to a rate of 242 events per 100 patient-years. The most common adverse events included nasopharyngitis, upper respiratory tract infection, urinary tract infection, infusion-related reactions, and headache. Serious adverse events were reported in 12% of patients, corresponding to 6.97 events per 100 patient-years, and most commonly included infections. Treatment withdrawal because of an adverse event occurred in 3.3% of patients (rate, 1.40 per 100 patient-years) and primarily included infusion-related reactions (0.9%) and events coded as neoplasms (0.6%) or infections (0.4%).
Infections
As of January 20, 2016, 56.9% of the ocrelizumab all-exposure population reported one or more infection with ocrelizumab, corresponding to a rate of 73.6 per 100 patient-years. “These findings are consistent with the 75.6 rate observed at the primary analysis cutoff date,” the researchers reported. Infections were reported at the highest rate following the first dose and declined with subsequent dosing. Infections reported in 5% or more of patients included nasopharyngitis, upper respiratory tract infection, urinary tract infection, bronchitis, and influenza. In the ocrelizumab all-exposure population, the rate per 100 patient-years of serious infections (1.80) as of January 20, 2016, was comparable with the rate at the primary analysis cutoff date (1.74). Data for the pooled relapsing MS population showed a slight increase in the rate per 100 patient-years of serious infections (1.45) as of January 20, 2016, compared with the rate at the primary analysis cutoff date (1.08); “however, rates remained low, and further exposure is needed to make any interpretation,” the researchers said.
Among patients with primary progressive MS, the rate per 100 patient-years of serious infections remained stable (2.74) as of January 20, 2016, compared with the rate at the primary analysis cutoff date (2.97). The most common serious infection reported was pneumonia. No infections were identified as opportunistic in nature.
Malignancies
In the MS clinical trial program, an imbalance in the crude incidence of malignancies was observed between the ocrelizumab- and comparator-treated patients, which was associated with a cluster of breast cancer events in the ocrelizumab group. Over time, the crude incidence rate of malignancy per 100 patient-years in the ocrelizumab all-exposure population fluctuated but remained within the epidemiologic range of patients with MS. An observed change in the crude incidence rate of malignancy from June to September is attributed to the crude incidence rate of non-melanoma skin cancer, which increased from 0.090 at the primary analysis cutoff date to 0.145 at the September 15, 2016, data cutoff, due to six new cases of basal cell carcinoma. The crude incidence rate of breast cancer remained stable through the September 15, 2016, data cutoff.
More Recent Developments
In late May 2017, Genentech, the maker of ocrelizumab, notified physicians of
—Glenn S. Williams
NEW ORLEANS—The safety profile of ocrelizumab in ongoing open-label extension studies in relapsing multiple sclerosis (MS) and primary progressive MS is generally consistent with that observed in controlled clinical trials, according to a report presented at the 31st Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC). “A slight increase in the rate of serious infections was observed in patients with relapsing MS beyond two years, but the rates remained low,” reported Ludwig Kappos, MD, Chair of Neurology at University Hospital Basel in Switzerland, and colleagues. “This was not observed in patients with primary progressive MS, and additional exposure data are needed to determine if the risk increases with further dosing,” the researchers said. “Incidence rates of malignancies and breast cancer observed with ocrelizumab treatment in MS remain within the range of epidemiologic background data.”
The safety and efficacy of ocrelizumab previously have been characterized in a phase II study in patients with relapsing-remitting MS and in phase III studies in patients with relapsing MS (OPERA I and OPERA II) and in patients with primary progressive MS (ORATORIO). Results from these trials showed that ocrelizumab reduced clinical and MRI evidence of disease activity, compared with placebo and interferon beta-1a. The most common adverse events associated with ocrelizumab during the double-blind periods of the phase III trials included infusion-related reactions, nasopharyngitis, upper respiratory tract infections, headache, and urinary tract infections. During the double-blind treatment period in the phase III trials in relapsing MS, serious adverse events, serious infections, and malignancies were reported in 6.9%, 1.3%, and 0.5% of ocrelizumab-treated patients, respectively (vs 8.7%, 2.9%, and 0.2% of patients treated with interferon beta-1a). In the phase III trial in primary progressive MS, these events were reported in 20.4%, 6.2%, and 2.3% of ocrelizumab-treated patients (vs 22.2%, 5.9%, and 0.8% of patients who received placebo). Across studies, few patients who received ocrelizumab (in the range of 2% to 4%) had adverse event–related treatment withdrawals.
At the CMSC annual meeting, data from controlled and open-label extension periods of the clinical trials of ocrelizumab in relapsing MS and primary progressive MS were presented.
Upon completion of a double-blind treatment period, patients from all studies were eligible to enter a long-term open-label extension in which they received ocrelizumab treatment. Safety analyses were based on integrated data from the phase II and phase III studies. The primary analysis was based on the clinical cutoff dates of the individual studies (phase II, January 22, 2015; OPERA I, April 2, 2015; OPERA II, May 12, 2015; ORATORIO, July 24, 2015). The present updated analysis includes all patients who received one or more dose of ocrelizumab during the controlled or open-label periods of the phase II and phase III studies (ie, the ocrelizumab all-exposure population) as of January 20, 2016. Additional data cutoffs of June 30, 2016, and September 15, 2016, were presented for malignancies to demonstrate changes with increasing ocrelizumab exposure.
The ocrelizumab all-exposure group included 2,279 patients. Patients’ mean age was 40.1, and 61.3% were female. Time since MS symptom onset was 6.67 years, and time since MS diagnosis was 3.66 years.
Overall Adverse Events
As of January 20, 2016, the majority (81%) of patients who received ocrelizumab experienced at least one adverse event, corresponding to a rate of 242 events per 100 patient-years. The most common adverse events included nasopharyngitis, upper respiratory tract infection, urinary tract infection, infusion-related reactions, and headache. Serious adverse events were reported in 12% of patients, corresponding to 6.97 events per 100 patient-years, and most commonly included infections. Treatment withdrawal because of an adverse event occurred in 3.3% of patients (rate, 1.40 per 100 patient-years) and primarily included infusion-related reactions (0.9%) and events coded as neoplasms (0.6%) or infections (0.4%).
Infections
As of January 20, 2016, 56.9% of the ocrelizumab all-exposure population reported one or more infection with ocrelizumab, corresponding to a rate of 73.6 per 100 patient-years. “These findings are consistent with the 75.6 rate observed at the primary analysis cutoff date,” the researchers reported. Infections were reported at the highest rate following the first dose and declined with subsequent dosing. Infections reported in 5% or more of patients included nasopharyngitis, upper respiratory tract infection, urinary tract infection, bronchitis, and influenza. In the ocrelizumab all-exposure population, the rate per 100 patient-years of serious infections (1.80) as of January 20, 2016, was comparable with the rate at the primary analysis cutoff date (1.74). Data for the pooled relapsing MS population showed a slight increase in the rate per 100 patient-years of serious infections (1.45) as of January 20, 2016, compared with the rate at the primary analysis cutoff date (1.08); “however, rates remained low, and further exposure is needed to make any interpretation,” the researchers said.
Among patients with primary progressive MS, the rate per 100 patient-years of serious infections remained stable (2.74) as of January 20, 2016, compared with the rate at the primary analysis cutoff date (2.97). The most common serious infection reported was pneumonia. No infections were identified as opportunistic in nature.
Malignancies
In the MS clinical trial program, an imbalance in the crude incidence of malignancies was observed between the ocrelizumab- and comparator-treated patients, which was associated with a cluster of breast cancer events in the ocrelizumab group. Over time, the crude incidence rate of malignancy per 100 patient-years in the ocrelizumab all-exposure population fluctuated but remained within the epidemiologic range of patients with MS. An observed change in the crude incidence rate of malignancy from June to September is attributed to the crude incidence rate of non-melanoma skin cancer, which increased from 0.090 at the primary analysis cutoff date to 0.145 at the September 15, 2016, data cutoff, due to six new cases of basal cell carcinoma. The crude incidence rate of breast cancer remained stable through the September 15, 2016, data cutoff.
More Recent Developments
In late May 2017, Genentech, the maker of ocrelizumab, notified physicians of
—Glenn S. Williams
NEW ORLEANS—The safety profile of ocrelizumab in ongoing open-label extension studies in relapsing multiple sclerosis (MS) and primary progressive MS is generally consistent with that observed in controlled clinical trials, according to a report presented at the 31st Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC). “A slight increase in the rate of serious infections was observed in patients with relapsing MS beyond two years, but the rates remained low,” reported Ludwig Kappos, MD, Chair of Neurology at University Hospital Basel in Switzerland, and colleagues. “This was not observed in patients with primary progressive MS, and additional exposure data are needed to determine if the risk increases with further dosing,” the researchers said. “Incidence rates of malignancies and breast cancer observed with ocrelizumab treatment in MS remain within the range of epidemiologic background data.”
The safety and efficacy of ocrelizumab previously have been characterized in a phase II study in patients with relapsing-remitting MS and in phase III studies in patients with relapsing MS (OPERA I and OPERA II) and in patients with primary progressive MS (ORATORIO). Results from these trials showed that ocrelizumab reduced clinical and MRI evidence of disease activity, compared with placebo and interferon beta-1a. The most common adverse events associated with ocrelizumab during the double-blind periods of the phase III trials included infusion-related reactions, nasopharyngitis, upper respiratory tract infections, headache, and urinary tract infections. During the double-blind treatment period in the phase III trials in relapsing MS, serious adverse events, serious infections, and malignancies were reported in 6.9%, 1.3%, and 0.5% of ocrelizumab-treated patients, respectively (vs 8.7%, 2.9%, and 0.2% of patients treated with interferon beta-1a). In the phase III trial in primary progressive MS, these events were reported in 20.4%, 6.2%, and 2.3% of ocrelizumab-treated patients (vs 22.2%, 5.9%, and 0.8% of patients who received placebo). Across studies, few patients who received ocrelizumab (in the range of 2% to 4%) had adverse event–related treatment withdrawals.
At the CMSC annual meeting, data from controlled and open-label extension periods of the clinical trials of ocrelizumab in relapsing MS and primary progressive MS were presented.
Upon completion of a double-blind treatment period, patients from all studies were eligible to enter a long-term open-label extension in which they received ocrelizumab treatment. Safety analyses were based on integrated data from the phase II and phase III studies. The primary analysis was based on the clinical cutoff dates of the individual studies (phase II, January 22, 2015; OPERA I, April 2, 2015; OPERA II, May 12, 2015; ORATORIO, July 24, 2015). The present updated analysis includes all patients who received one or more dose of ocrelizumab during the controlled or open-label periods of the phase II and phase III studies (ie, the ocrelizumab all-exposure population) as of January 20, 2016. Additional data cutoffs of June 30, 2016, and September 15, 2016, were presented for malignancies to demonstrate changes with increasing ocrelizumab exposure.
The ocrelizumab all-exposure group included 2,279 patients. Patients’ mean age was 40.1, and 61.3% were female. Time since MS symptom onset was 6.67 years, and time since MS diagnosis was 3.66 years.
Overall Adverse Events
As of January 20, 2016, the majority (81%) of patients who received ocrelizumab experienced at least one adverse event, corresponding to a rate of 242 events per 100 patient-years. The most common adverse events included nasopharyngitis, upper respiratory tract infection, urinary tract infection, infusion-related reactions, and headache. Serious adverse events were reported in 12% of patients, corresponding to 6.97 events per 100 patient-years, and most commonly included infections. Treatment withdrawal because of an adverse event occurred in 3.3% of patients (rate, 1.40 per 100 patient-years) and primarily included infusion-related reactions (0.9%) and events coded as neoplasms (0.6%) or infections (0.4%).
Infections
As of January 20, 2016, 56.9% of the ocrelizumab all-exposure population reported one or more infection with ocrelizumab, corresponding to a rate of 73.6 per 100 patient-years. “These findings are consistent with the 75.6 rate observed at the primary analysis cutoff date,” the researchers reported. Infections were reported at the highest rate following the first dose and declined with subsequent dosing. Infections reported in 5% or more of patients included nasopharyngitis, upper respiratory tract infection, urinary tract infection, bronchitis, and influenza. In the ocrelizumab all-exposure population, the rate per 100 patient-years of serious infections (1.80) as of January 20, 2016, was comparable with the rate at the primary analysis cutoff date (1.74). Data for the pooled relapsing MS population showed a slight increase in the rate per 100 patient-years of serious infections (1.45) as of January 20, 2016, compared with the rate at the primary analysis cutoff date (1.08); “however, rates remained low, and further exposure is needed to make any interpretation,” the researchers said.
Among patients with primary progressive MS, the rate per 100 patient-years of serious infections remained stable (2.74) as of January 20, 2016, compared with the rate at the primary analysis cutoff date (2.97). The most common serious infection reported was pneumonia. No infections were identified as opportunistic in nature.
Malignancies
In the MS clinical trial program, an imbalance in the crude incidence of malignancies was observed between the ocrelizumab- and comparator-treated patients, which was associated with a cluster of breast cancer events in the ocrelizumab group. Over time, the crude incidence rate of malignancy per 100 patient-years in the ocrelizumab all-exposure population fluctuated but remained within the epidemiologic range of patients with MS. An observed change in the crude incidence rate of malignancy from June to September is attributed to the crude incidence rate of non-melanoma skin cancer, which increased from 0.090 at the primary analysis cutoff date to 0.145 at the September 15, 2016, data cutoff, due to six new cases of basal cell carcinoma. The crude incidence rate of breast cancer remained stable through the September 15, 2016, data cutoff.
More Recent Developments
In late May 2017, Genentech, the maker of ocrelizumab, notified physicians of
—Glenn S. Williams
Can Exercise Boost Cognitive Performance in Patients With MS?
NEW ORLEANS—A single bout of treadmill walking might affect cognitive processing to a greater degree than stationary cycling, particularly among those with multiple sclerosis (MS) who demonstrate low aerobic fitness, according to a report presented at the 31st Annual Meeting of the Consortium of MS Centers. "This [finding] highlights the importance of targeting those with low aerobic fitness in treadmill walking exercise training interventions for improving cognition in persons with MS, as improving aerobic fitness may be beneficial for reducing MS-related cognitive-motor interference," said Brian M. Sandroff, PhD, of the Kessler Foundation in West Orange, New Jersey, and colleagues. 
The mechanisms by which treadmill walking improves cognition in patients with MS are not well understood. Researchers have hypothesized that treadmill walking is essentially a complex cognitive task that requires more attentional resources than other modalities of aerobic exercise (eg, cycle ergometry), and that repeated exposure trains the person in cognitive-motor processing. If this hypothesis is true, then patients with MS should demonstrate worse cognitive performance during treadmill walking than during cycle ergometry, as more attentional resources would presumably be devoted to walking on a treadmill than to cycling on a stationary bicycle. Furthermore, it is unknown whether better aerobic fitness attenuates such cognitive-motor interference in patients with MS.
Dr. Sandroff and colleagues conducted a pilot study to examine cognitive performance before and during acute bouts of treadmill walking, stationary cycling, and seated quiet rest in 12 fully ambulatory patients with MS with high or low aerobic fitness using a within-subjects, repeated-measures design.
Participants underwent a baseline incremental exercise test to exhaustion for measurement of aerobic fitness (ie, VO2peak). Participants further completed three experimental conditions that consisted of 20 minutes of moderate- to vigorous-intensity treadmill walking exercise, moderate- to vigorous-intensity cycle ergometer exercise, and seated quiet rest in a randomized, counterbalanced order. Participants underwent the three-second Paced Auditory Serial Addition Test (PASAT) as a measure of cognitive performance prior to and during each condition.
Overall, decreases in PASAT performance during treadmill walking were not larger than those during cycle ergometry, relative to quiet rest. However, decreases in PASAT performance were larger for those with lower aerobic fitness during treadmill walking than during cycle ergometry, compared with quiet rest.
NEW ORLEANS—A single bout of treadmill walking might affect cognitive processing to a greater degree than stationary cycling, particularly among those with multiple sclerosis (MS) who demonstrate low aerobic fitness, according to a report presented at the 31st Annual Meeting of the Consortium of MS Centers. "This [finding] highlights the importance of targeting those with low aerobic fitness in treadmill walking exercise training interventions for improving cognition in persons with MS, as improving aerobic fitness may be beneficial for reducing MS-related cognitive-motor interference," said Brian M. Sandroff, PhD, of the Kessler Foundation in West Orange, New Jersey, and colleagues.
The mechanisms by which treadmill walking improves cognition in patients with MS are not well understood. Researchers have hypothesized that treadmill walking is essentially a complex cognitive task that requires more attentional resources than other modalities of aerobic exercise (eg, cycle ergometry), and that repeated exposure trains the person in cognitive-motor processing. If this hypothesis is true, then patients with MS should demonstrate worse cognitive performance during treadmill walking than during cycle ergometry, as more attentional resources would presumably be devoted to walking on a treadmill than to cycling on a stationary bicycle. Furthermore, it is unknown whether better aerobic fitness attenuates such cognitive-motor interference in patients with MS.
Dr. Sandroff and colleagues conducted a pilot study to examine cognitive performance before and during acute bouts of treadmill walking, stationary cycling, and seated quiet rest in 12 fully ambulatory patients with MS with high or low aerobic fitness using a within-subjects, repeated-measures design.
Participants underwent a baseline incremental exercise test to exhaustion for measurement of aerobic fitness (ie, VO2peak). Participants further completed three experimental conditions that consisted of 20 minutes of moderate- to vigorous-intensity treadmill walking exercise, moderate- to vigorous-intensity cycle ergometer exercise, and seated quiet rest in a randomized, counterbalanced order. Participants underwent the three-second Paced Auditory Serial Addition Test (PASAT) as a measure of cognitive performance prior to and during each condition.
Overall, decreases in PASAT performance during treadmill walking were not larger than those during cycle ergometry, relative to quiet rest. However, decreases in PASAT performance were larger for those with lower aerobic fitness during treadmill walking than during cycle ergometry, compared with quiet rest.
NEW ORLEANS—A single bout of treadmill walking might affect cognitive processing to a greater degree than stationary cycling, particularly among those with multiple sclerosis (MS) who demonstrate low aerobic fitness, according to a report presented at the 31st Annual Meeting of the Consortium of MS Centers. "This [finding] highlights the importance of targeting those with low aerobic fitness in treadmill walking exercise training interventions for improving cognition in persons with MS, as improving aerobic fitness may be beneficial for reducing MS-related cognitive-motor interference," said Brian M. Sandroff, PhD, of the Kessler Foundation in West Orange, New Jersey, and colleagues.
The mechanisms by which treadmill walking improves cognition in patients with MS are not well understood. Researchers have hypothesized that treadmill walking is essentially a complex cognitive task that requires more attentional resources than other modalities of aerobic exercise (eg, cycle ergometry), and that repeated exposure trains the person in cognitive-motor processing. If this hypothesis is true, then patients with MS should demonstrate worse cognitive performance during treadmill walking than during cycle ergometry, as more attentional resources would presumably be devoted to walking on a treadmill than to cycling on a stationary bicycle. Furthermore, it is unknown whether better aerobic fitness attenuates such cognitive-motor interference in patients with MS.
Dr. Sandroff and colleagues conducted a pilot study to examine cognitive performance before and during acute bouts of treadmill walking, stationary cycling, and seated quiet rest in 12 fully ambulatory patients with MS with high or low aerobic fitness using a within-subjects, repeated-measures design.
Participants underwent a baseline incremental exercise test to exhaustion for measurement of aerobic fitness (ie, VO2peak). Participants further completed three experimental conditions that consisted of 20 minutes of moderate- to vigorous-intensity treadmill walking exercise, moderate- to vigorous-intensity cycle ergometer exercise, and seated quiet rest in a randomized, counterbalanced order. Participants underwent the three-second Paced Auditory Serial Addition Test (PASAT) as a measure of cognitive performance prior to and during each condition.
Overall, decreases in PASAT performance during treadmill walking were not larger than those during cycle ergometry, relative to quiet rest. However, decreases in PASAT performance were larger for those with lower aerobic fitness during treadmill walking than during cycle ergometry, compared with quiet rest.
Researchers Compare Three Escalation Therapies for MS
A Retrospective Chart Review
Ms. Vollmer and colleagues conducted a retrospective study to compare the discontinuation rates and efficacy of fingolimod and dimethyl fumarate to those of natalizumab. In a retrospective chart review, they identified patients with multiple sclerosis (MS) who presented to the Rocky Mountain MS Center in Aurora, Colorado. Eligible participants initiated drug therapy between January 2010 and October 2013. Patients who initiated natalizumab had to be negative for the John Cunningham virus (JCV) at baseline. Ms. Vollmer and colleagues retrospectively collected clinician-recorded data.
The study’s primary outcome was discontinuation at 24 months. Secondary outcomes included reasons for discontinuation, relapse activity, MRI activity, and a composite disease activity measure that comprised clinical relapse, contrast enhancement, and new T2 lesions on follow-up MRI. Ms. Vollmer and colleagues identified 1,302 patients who initiated insurance paperwork for natalizumab. To reduce the size of this sample, they randomly selected 800 patients, of whom 270 met the inclusion criteria. In all, 440 participants initiated paperwork for fingolimod, of whom 271 met the inclusion criteria. For dimethyl fumarate, the researchers found 592 participants who initiated the paperwork, and 342 met the inclusion criteria.
Patients receiving natalizumab were significantly younger (mean age, 39.8) than patients receiving fingolimod (42.5) or dimethyl fumarate (45.8). Furthermore, patients treated with natalizumab were more likely to be female (77.8%) than patients treated with fingolimod (72.0%) or dimethyl fumarate (69.6%). Patients receiving natalizumab also were more likely to have contrast enhancement on baseline MRI (31.2%) than were participants receiving fingolimod (24.6%) or dimethyl fumarate (14.6%). Mean disease duration was approximately 12 years for all groups.
Discontinuation and Disease Activity
The rate of discontinuation was similar for natalizumab (33.3%) and fingolimod (34.3%), but the researchers observed a significant difference between natalizumab and dimethyl fumarate (47.1%). Disease activity and adverse events were the most common reasons for discontinuation of fingolimod and dimethyl fumarate, and JCV positivity was the most common reason for discontinuation of natalizumab. Of the seven participants who discontinued natalizumab because of disease activity, five had neutralizing antibodies. Of the 20 patients who discontinued natalizumab because of adverse events, nine had rashes during infusion, eight of whom tested positive for neutralizing antibodies.
Ms. Vollmer and colleagues found no significant difference between natalizumab and fingolimod in the rate of patients with a clinical relapse (5.6% and 8.9%, respectively), but they observed a significant difference between dimethyl fumarate (12.9%) and natalizumab for this outcome. Contrast enhancement was less common among patients receiving natalizumab (6.6%), compared with fingolimod (13.1%), but there was no significant difference between natalizumab and dimethyl fumarate (10.0%).
The rate of new T2 lesions was lower with natalizumab (21.4%), compared with fingolimod (35.0%) and dimethyl fumarate (31.5%). Similarly, the composite disease activity measure was less common with natalizumab (20.7%), compared with fingolimod (34.7%) and dimethyl fumarate (33.6%). Data adjustments indicated that discontinuation was equally likely among patients receiving fingolimod and those receiving natalizumab. Patients receiving dimethyl fumarate, however, were approximately twice as likely to discontinue treatment, compared with patients receiving natalizumab.
Furthermore, patients receiving fingolimod were approximately twice as likely to discontinue treatment because of adverse events, compared with patients receiving natalizumab. Patients treated with dimethyl fumarate were approximately four times as likely to discontinue because of adverse events, compared with patients treated with natalizumab. In addition, patients were approximately twice as likely to have disease activity on fingolimod or dimethyl fumarate, compared with natalizumab.
—Erik Greb
Suggested Reading
Barbin L, Rousseau C, Jousset N, et al. Comparative efficacy of fingolimod vs natalizumab: A French multicenter observational study. Neurology. 2016;86(8):771-778.
A Retrospective Chart Review
Ms. Vollmer and colleagues conducted a retrospective study to compare the discontinuation rates and efficacy of fingolimod and dimethyl fumarate to those of natalizumab. In a retrospective chart review, they identified patients with multiple sclerosis (MS) who presented to the Rocky Mountain MS Center in Aurora, Colorado. Eligible participants initiated drug therapy between January 2010 and October 2013. Patients who initiated natalizumab had to be negative for the John Cunningham virus (JCV) at baseline. Ms. Vollmer and colleagues retrospectively collected clinician-recorded data.
The study’s primary outcome was discontinuation at 24 months. Secondary outcomes included reasons for discontinuation, relapse activity, MRI activity, and a composite disease activity measure that comprised clinical relapse, contrast enhancement, and new T2 lesions on follow-up MRI. Ms. Vollmer and colleagues identified 1,302 patients who initiated insurance paperwork for natalizumab. To reduce the size of this sample, they randomly selected 800 patients, of whom 270 met the inclusion criteria. In all, 440 participants initiated paperwork for fingolimod, of whom 271 met the inclusion criteria. For dimethyl fumarate, the researchers found 592 participants who initiated the paperwork, and 342 met the inclusion criteria.
Patients receiving natalizumab were significantly younger (mean age, 39.8) than patients receiving fingolimod (42.5) or dimethyl fumarate (45.8). Furthermore, patients treated with natalizumab were more likely to be female (77.8%) than patients treated with fingolimod (72.0%) or dimethyl fumarate (69.6%). Patients receiving natalizumab also were more likely to have contrast enhancement on baseline MRI (31.2%) than were participants receiving fingolimod (24.6%) or dimethyl fumarate (14.6%). Mean disease duration was approximately 12 years for all groups.
Discontinuation and Disease Activity
The rate of discontinuation was similar for natalizumab (33.3%) and fingolimod (34.3%), but the researchers observed a significant difference between natalizumab and dimethyl fumarate (47.1%). Disease activity and adverse events were the most common reasons for discontinuation of fingolimod and dimethyl fumarate, and JCV positivity was the most common reason for discontinuation of natalizumab. Of the seven participants who discontinued natalizumab because of disease activity, five had neutralizing antibodies. Of the 20 patients who discontinued natalizumab because of adverse events, nine had rashes during infusion, eight of whom tested positive for neutralizing antibodies.
Ms. Vollmer and colleagues found no significant difference between natalizumab and fingolimod in the rate of patients with a clinical relapse (5.6% and 8.9%, respectively), but they observed a significant difference between dimethyl fumarate (12.9%) and natalizumab for this outcome. Contrast enhancement was less common among patients receiving natalizumab (6.6%), compared with fingolimod (13.1%), but there was no significant difference between natalizumab and dimethyl fumarate (10.0%).
The rate of new T2 lesions was lower with natalizumab (21.4%), compared with fingolimod (35.0%) and dimethyl fumarate (31.5%). Similarly, the composite disease activity measure was less common with natalizumab (20.7%), compared with fingolimod (34.7%) and dimethyl fumarate (33.6%). Data adjustments indicated that discontinuation was equally likely among patients receiving fingolimod and those receiving natalizumab. Patients receiving dimethyl fumarate, however, were approximately twice as likely to discontinue treatment, compared with patients receiving natalizumab.
Furthermore, patients receiving fingolimod were approximately twice as likely to discontinue treatment because of adverse events, compared with patients receiving natalizumab. Patients treated with dimethyl fumarate were approximately four times as likely to discontinue because of adverse events, compared with patients treated with natalizumab. In addition, patients were approximately twice as likely to have disease activity on fingolimod or dimethyl fumarate, compared with natalizumab.
—Erik Greb
Suggested Reading
Barbin L, Rousseau C, Jousset N, et al. Comparative efficacy of fingolimod vs natalizumab: A French multicenter observational study. Neurology. 2016;86(8):771-778.
A Retrospective Chart Review
Ms. Vollmer and colleagues conducted a retrospective study to compare the discontinuation rates and efficacy of fingolimod and dimethyl fumarate to those of natalizumab. In a retrospective chart review, they identified patients with multiple sclerosis (MS) who presented to the Rocky Mountain MS Center in Aurora, Colorado. Eligible participants initiated drug therapy between January 2010 and October 2013. Patients who initiated natalizumab had to be negative for the John Cunningham virus (JCV) at baseline. Ms. Vollmer and colleagues retrospectively collected clinician-recorded data.
The study’s primary outcome was discontinuation at 24 months. Secondary outcomes included reasons for discontinuation, relapse activity, MRI activity, and a composite disease activity measure that comprised clinical relapse, contrast enhancement, and new T2 lesions on follow-up MRI. Ms. Vollmer and colleagues identified 1,302 patients who initiated insurance paperwork for natalizumab. To reduce the size of this sample, they randomly selected 800 patients, of whom 270 met the inclusion criteria. In all, 440 participants initiated paperwork for fingolimod, of whom 271 met the inclusion criteria. For dimethyl fumarate, the researchers found 592 participants who initiated the paperwork, and 342 met the inclusion criteria.
Patients receiving natalizumab were significantly younger (mean age, 39.8) than patients receiving fingolimod (42.5) or dimethyl fumarate (45.8). Furthermore, patients treated with natalizumab were more likely to be female (77.8%) than patients treated with fingolimod (72.0%) or dimethyl fumarate (69.6%). Patients receiving natalizumab also were more likely to have contrast enhancement on baseline MRI (31.2%) than were participants receiving fingolimod (24.6%) or dimethyl fumarate (14.6%). Mean disease duration was approximately 12 years for all groups.
Discontinuation and Disease Activity
The rate of discontinuation was similar for natalizumab (33.3%) and fingolimod (34.3%), but the researchers observed a significant difference between natalizumab and dimethyl fumarate (47.1%). Disease activity and adverse events were the most common reasons for discontinuation of fingolimod and dimethyl fumarate, and JCV positivity was the most common reason for discontinuation of natalizumab. Of the seven participants who discontinued natalizumab because of disease activity, five had neutralizing antibodies. Of the 20 patients who discontinued natalizumab because of adverse events, nine had rashes during infusion, eight of whom tested positive for neutralizing antibodies.
Ms. Vollmer and colleagues found no significant difference between natalizumab and fingolimod in the rate of patients with a clinical relapse (5.6% and 8.9%, respectively), but they observed a significant difference between dimethyl fumarate (12.9%) and natalizumab for this outcome. Contrast enhancement was less common among patients receiving natalizumab (6.6%), compared with fingolimod (13.1%), but there was no significant difference between natalizumab and dimethyl fumarate (10.0%).
The rate of new T2 lesions was lower with natalizumab (21.4%), compared with fingolimod (35.0%) and dimethyl fumarate (31.5%). Similarly, the composite disease activity measure was less common with natalizumab (20.7%), compared with fingolimod (34.7%) and dimethyl fumarate (33.6%). Data adjustments indicated that discontinuation was equally likely among patients receiving fingolimod and those receiving natalizumab. Patients receiving dimethyl fumarate, however, were approximately twice as likely to discontinue treatment, compared with patients receiving natalizumab.
Furthermore, patients receiving fingolimod were approximately twice as likely to discontinue treatment because of adverse events, compared with patients receiving natalizumab. Patients treated with dimethyl fumarate were approximately four times as likely to discontinue because of adverse events, compared with patients treated with natalizumab. In addition, patients were approximately twice as likely to have disease activity on fingolimod or dimethyl fumarate, compared with natalizumab.
—Erik Greb
Suggested Reading
Barbin L, Rousseau C, Jousset N, et al. Comparative efficacy of fingolimod vs natalizumab: A French multicenter observational study. Neurology. 2016;86(8):771-778.
When Should Neurologists Discontinue Disease-Modifying Treatments in Patients With MS?
NEW ORLEANS—Discontinuation of disease-modifying treatments (DMTs) may be considered for patients with secondary progressive multiple sclerosis (SPMS) age 55 or older with ongoing progression and no clinical relapses or new MRI lesions consistent with MS in the previous five years, according to research presented at the 31st Annual Meeting of the Consortium of MS Centers. Data from the study also suggest that it is reasonable to consider discontinuing DMTs for patients in the same age range with stable relapsing remitting (RR) MS who have had no clinical relapses or new MRI lesions consistent with MS in the previous five years.
Although DMTs can reduce relapse rates and progression of disability early in the course of RRMS, it remains unknown whether these treatments maintain efficacy late in the course of RRMS, in SPMS, or in older patients. Considerations for discontinuing treatment include potential inefficacy of DMTs and adverse effects in this cohort, said the authors.
Devyn Parsons, a medical student at the University of British Columbia in Vancouver, Canada, working with Anthony Traboulsee, MD, and colleagues, conducted a systematic search to examine literature relevant to the discontinuation of DMTs and to provide guidance about when DMTs may be discontinued. The investigators used the keywords “multiple sclerosis,” “disease modifying treatments,” “treatment withdrawal,” “stopping medication,” and “medication withdrawal” to search PubMed, Embase, and the Cochrane Database of Systematic Reviews. The search included articles up to June 2016 and was limited to English-language publications.
The review yielded what Ms. Parsons described as a “paucity of information.” The investigators found evidence that disease activity in RRMS declined with increasing age and longer disease duration. Some observational studies suggested that older patients who continuously receive DMT and are free of disease activity for several years might be good candidates for discontinuation of DMTs. Since DMTs are associated with adverse events that may affect quality of life or pose serious safety risks, it is important to consider patient preference, said the authors.
Safety monitoring following discontinuation of DMTs should include annual clinical assessment and annual brain MRIs for two to five years, with consideration of reinitiation of DMTs if evidence of new clinical relapse emerges or more than two new MRI lesions consistent with MS appear, said the researchers.
This study was supported by Sanofi Genzyme.
NEW ORLEANS—Discontinuation of disease-modifying treatments (DMTs) may be considered for patients with secondary progressive multiple sclerosis (SPMS) age 55 or older with ongoing progression and no clinical relapses or new MRI lesions consistent with MS in the previous five years, according to research presented at the 31st Annual Meeting of the Consortium of MS Centers. Data from the study also suggest that it is reasonable to consider discontinuing DMTs for patients in the same age range with stable relapsing remitting (RR) MS who have had no clinical relapses or new MRI lesions consistent with MS in the previous five years.
Although DMTs can reduce relapse rates and progression of disability early in the course of RRMS, it remains unknown whether these treatments maintain efficacy late in the course of RRMS, in SPMS, or in older patients. Considerations for discontinuing treatment include potential inefficacy of DMTs and adverse effects in this cohort, said the authors.
Devyn Parsons, a medical student at the University of British Columbia in Vancouver, Canada, working with Anthony Traboulsee, MD, and colleagues, conducted a systematic search to examine literature relevant to the discontinuation of DMTs and to provide guidance about when DMTs may be discontinued. The investigators used the keywords “multiple sclerosis,” “disease modifying treatments,” “treatment withdrawal,” “stopping medication,” and “medication withdrawal” to search PubMed, Embase, and the Cochrane Database of Systematic Reviews. The search included articles up to June 2016 and was limited to English-language publications.
The review yielded what Ms. Parsons described as a “paucity of information.” The investigators found evidence that disease activity in RRMS declined with increasing age and longer disease duration. Some observational studies suggested that older patients who continuously receive DMT and are free of disease activity for several years might be good candidates for discontinuation of DMTs. Since DMTs are associated with adverse events that may affect quality of life or pose serious safety risks, it is important to consider patient preference, said the authors.
Safety monitoring following discontinuation of DMTs should include annual clinical assessment and annual brain MRIs for two to five years, with consideration of reinitiation of DMTs if evidence of new clinical relapse emerges or more than two new MRI lesions consistent with MS appear, said the researchers.
This study was supported by Sanofi Genzyme.
NEW ORLEANS—Discontinuation of disease-modifying treatments (DMTs) may be considered for patients with secondary progressive multiple sclerosis (SPMS) age 55 or older with ongoing progression and no clinical relapses or new MRI lesions consistent with MS in the previous five years, according to research presented at the 31st Annual Meeting of the Consortium of MS Centers. Data from the study also suggest that it is reasonable to consider discontinuing DMTs for patients in the same age range with stable relapsing remitting (RR) MS who have had no clinical relapses or new MRI lesions consistent with MS in the previous five years.
Although DMTs can reduce relapse rates and progression of disability early in the course of RRMS, it remains unknown whether these treatments maintain efficacy late in the course of RRMS, in SPMS, or in older patients. Considerations for discontinuing treatment include potential inefficacy of DMTs and adverse effects in this cohort, said the authors.
Devyn Parsons, a medical student at the University of British Columbia in Vancouver, Canada, working with Anthony Traboulsee, MD, and colleagues, conducted a systematic search to examine literature relevant to the discontinuation of DMTs and to provide guidance about when DMTs may be discontinued. The investigators used the keywords “multiple sclerosis,” “disease modifying treatments,” “treatment withdrawal,” “stopping medication,” and “medication withdrawal” to search PubMed, Embase, and the Cochrane Database of Systematic Reviews. The search included articles up to June 2016 and was limited to English-language publications.
The review yielded what Ms. Parsons described as a “paucity of information.” The investigators found evidence that disease activity in RRMS declined with increasing age and longer disease duration. Some observational studies suggested that older patients who continuously receive DMT and are free of disease activity for several years might be good candidates for discontinuation of DMTs. Since DMTs are associated with adverse events that may affect quality of life or pose serious safety risks, it is important to consider patient preference, said the authors.
Safety monitoring following discontinuation of DMTs should include annual clinical assessment and annual brain MRIs for two to five years, with consideration of reinitiation of DMTs if evidence of new clinical relapse emerges or more than two new MRI lesions consistent with MS appear, said the researchers.
This study was supported by Sanofi Genzyme.
Pregnancy and MS: How do they affect each other?
NEW ORLEANS – Multiple sclerosis has little to no impact on the ability to conceive, on pregnancy, or on fetal status, according to Patricia K. Coyle, MD.
“That’s very reassuring,” Dr. Coyle said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “We don’t see an increase in birth defects just because the mother has MS. There is no consistent increase in abortions, ectopic pregnancies, or assisted vaginal/cesarean deliveries.”
Dr. Coyle, director of the MS Comprehensive Care Center at Stony Brook (N.Y.) University Medical Center, said that the most dramatic changes for pregnant patients with MS occur in the final trimester and mainly involve rising levels of multiple hormones: estrogens, cortisol, progesterone, norepinephrine, and 1,25-dihydroxyvitamin D, which increase late in pregnancy, then rapidly drop off postpartum. This has led to the evaluation of sex hormone therapy for MS.
The impact of other pregnancy factors on MS disease activity remains unknown. One is microchimerism, a maternal-fetal exchange of cells and DNA. “These cells can last for a long time; you can find them in the blood, as well as in the [central nervous system],” Dr. Coyle said. “It’s been reported that fetal microchimerism may be increased in immune-mediated diseases like MS, but we really don’t have a lot of good data.”
Researchers also are studying the impact of changes in the gut microbiota that occur during pregnancy. “Could this be a potential target for MS therapy?” Dr. Coyle asked. “This is in its infancy.”
Counseling tips
She went on to share counseling tips for MS patients of childbearing age, including the fact that some studies report slightly smaller babies born to mothers with MS, while others have not found that association. “This is a question mark, but it doesn’t seem to be a major issue,” she said. One thing you can tell patients for certain is that MS is not inherited. “There are well over 230 genes linked to MS, so there’s a genetic enrichment that can make somebody vulnerable to MS, but there’s no gene that passes on MS,” Dr. Coyle said. “The risk is slightly higher for a first-degree relative, so when a parent has MS, the risk for the child is in the range of 2% to 2.5%, compared with the expected 0.13% in the general population. But there’s a slightly higher risk when you’re a sibling than when you’re a parent – 2.7% – which is speaking to environmental factors having an important impact on genes.”
Controversial data exist as to whether a maternal deficiency in vitamin D poses a risk of MS in the offspring. Dr. Coyle makes it a point to “normalize” vitamin D levels in pregnant MS patients, particularly in white patients. “You’d want to have them on prenatal vitamins and folic acid and tell them not to smoke, to limit their alcohol use, and advise them to have good sleep hygiene.”
Dr. Coyle, vice chair of clinical affairs at Stony Brook University Medical Center, said that up until the 1950s, physicians advised women with MS against having children. “They were told not to get pregnant or to have an abortion, because it was thought to make MS worse,” she said. “It turns out that was fiction. That was completely wrong. Pregnancy has no negative effect on long-term MS prognosis. It may have long-term benefits for relapsing MS, but there are not enough data to comment on its impact on progressive MS. Pregnancy makes it less likely that someone will develop a clinically isolated syndrome, but it may increase the radiologically isolated syndrome risk for clinical attack. That’s based on 7 pregnant patients out of a cohort of 60, so we need further data to explain that.”
Disease-modifying therapies
When it comes to washouts of disease-modifying therapies (DMTs), no one-size-fits-all approach exists. Interferon betas and glatiramer acetate have more than 1,000 pregnancy exposures that yield no evidence for teratogenicity or negative fetal impact. No washout is needed prior to pregnancy. “These agents can be used during pregnancy and breastfeeding,” she said.
The other DMTs paint a somewhat different picture. “There is insufficient pregnancy exposure to the three available oral DMTs to comment definitively on their safety, but there is no clear human teratogenicity to date,” Dr. Coyle said. The conventional washout for fingolimod is 8 weeks. In Dr. Coyle’s opinion, no washout is required with dimethyl fumarate. “The half-life is 40 minutes. There are no good signs of issues. For teriflunomide, it can hang around in individuals for 18-24 months. You should go through an accelerated elimination procedure with oral cholestyramine 8 mg three times a day for 11 days until blood level of the agent is less than 0.02 mcg/mL. Avoid all the orals with breastfeeding.”
Monoclonal antibodies – another form of DMTs – lack sufficient pregnancy exposures to merit comment on safety, but they should not be used during breastfeeding. Natalizumab is a humanized IgG4 antibody that crosses the placenta. “This has been used in several dozen pregnancies because the patients got so bad when they were taken off that it required reinstituting natalizumab even though they were pregnant,” Dr. Coyle said. “Human pregnancy exposures have been associated with transient hematologic issues in the newborn, including anemia, thrombocytopenia, and pancytopenia.” Data indicate that the rate of spontaneous abortion among pregnant women treated with natalizumab was 9%, the rate of major birth defects was 5.05%, and no malformation pattern was observed. The drug is detected in human breast milk and has a half-life of 11 days.
Alemtuzumab is a humanized IgG1 monoclonal antibody that crosses the placenta. The half-life elimination is about 14 days. In transgenic mice, giving alemtuzumab during organogenesis was found to be embryolethal. In human pregnancy, hypothyroidism is a concern. “The recommendation has been to wait 4 months after the last treatment before you try to become pregnant. Alemtuzumab is considered a two-cycle treatment. You don’t get the maximum benefit after the first cycle of 5 days. The complete treatment is the second cycle 3 days.”
Daclizumab, another humanized IgG1 monoclonal antibody, also crosses the placenta. Monkey exposure during gestation led to embryofetal death and decreased fetal growth, “but this was at greater than 30 times the human dose,” she said. “It was found to be excreted in monkey breast milk and the half-life is 21 days.” In humans, there have been 36 exposed women who had 38 pregnancies and 20 live births. The rate of spontaneous abortions/miscarriages was 11%, there were eight elective terminations, two ectopic pregnancies, and one congenital heart defect. “This is very limited data, but nothing that would raise the level of concern,” Dr. Coyle said.
Ocrelizumab, another humanized IgG1 monoclonal antibody, was approved by the Food and Drug Administration in March 2017. Prior studies of anti-CD20 antibodies in human pregnancy noted transient lymphocytopenia and peripheral B cell depletion in the newborns. In studies of pregnant monkeys that used 2 and 10 times human doses during organogenesis, it was associated with B cell depletion in spleen/lymph nodes, Dr. Coyle said. “During organogenesis and throughout the neonatal period, treatment could be associated with perinatal death, some associated with bacterial infection; glomerulonephropathy with inflammation; a decrease in circulating B cells, a decrease in testicular weight, and bone marrow lymphoid follicle formation.” Ocrelizumab is excreted in monkey breast milk and the prescription label suggests a 6-month delay in pregnancy. The drug’s half-life is 26 days.
Dr. Coyle reported that she has served as a consultant for Accordant, Acorda, Bayer, Biogen, Celgene, Genentech/Roche, Genzyme/Sanofi, Novartis, Serono, and Teva. She has also received research support from Actelion, Alkermes, Genentech/Roche, MedDay, the National Institute of Neurological Disorders and Stroke, and Novartis.
NEW ORLEANS – Multiple sclerosis has little to no impact on the ability to conceive, on pregnancy, or on fetal status, according to Patricia K. Coyle, MD.
“That’s very reassuring,” Dr. Coyle said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “We don’t see an increase in birth defects just because the mother has MS. There is no consistent increase in abortions, ectopic pregnancies, or assisted vaginal/cesarean deliveries.”
Dr. Coyle, director of the MS Comprehensive Care Center at Stony Brook (N.Y.) University Medical Center, said that the most dramatic changes for pregnant patients with MS occur in the final trimester and mainly involve rising levels of multiple hormones: estrogens, cortisol, progesterone, norepinephrine, and 1,25-dihydroxyvitamin D, which increase late in pregnancy, then rapidly drop off postpartum. This has led to the evaluation of sex hormone therapy for MS.
The impact of other pregnancy factors on MS disease activity remains unknown. One is microchimerism, a maternal-fetal exchange of cells and DNA. “These cells can last for a long time; you can find them in the blood, as well as in the [central nervous system],” Dr. Coyle said. “It’s been reported that fetal microchimerism may be increased in immune-mediated diseases like MS, but we really don’t have a lot of good data.”
Researchers also are studying the impact of changes in the gut microbiota that occur during pregnancy. “Could this be a potential target for MS therapy?” Dr. Coyle asked. “This is in its infancy.”
Counseling tips
She went on to share counseling tips for MS patients of childbearing age, including the fact that some studies report slightly smaller babies born to mothers with MS, while others have not found that association. “This is a question mark, but it doesn’t seem to be a major issue,” she said. One thing you can tell patients for certain is that MS is not inherited. “There are well over 230 genes linked to MS, so there’s a genetic enrichment that can make somebody vulnerable to MS, but there’s no gene that passes on MS,” Dr. Coyle said. “The risk is slightly higher for a first-degree relative, so when a parent has MS, the risk for the child is in the range of 2% to 2.5%, compared with the expected 0.13% in the general population. But there’s a slightly higher risk when you’re a sibling than when you’re a parent – 2.7% – which is speaking to environmental factors having an important impact on genes.”
Controversial data exist as to whether a maternal deficiency in vitamin D poses a risk of MS in the offspring. Dr. Coyle makes it a point to “normalize” vitamin D levels in pregnant MS patients, particularly in white patients. “You’d want to have them on prenatal vitamins and folic acid and tell them not to smoke, to limit their alcohol use, and advise them to have good sleep hygiene.”
Dr. Coyle, vice chair of clinical affairs at Stony Brook University Medical Center, said that up until the 1950s, physicians advised women with MS against having children. “They were told not to get pregnant or to have an abortion, because it was thought to make MS worse,” she said. “It turns out that was fiction. That was completely wrong. Pregnancy has no negative effect on long-term MS prognosis. It may have long-term benefits for relapsing MS, but there are not enough data to comment on its impact on progressive MS. Pregnancy makes it less likely that someone will develop a clinically isolated syndrome, but it may increase the radiologically isolated syndrome risk for clinical attack. That’s based on 7 pregnant patients out of a cohort of 60, so we need further data to explain that.”
Disease-modifying therapies
When it comes to washouts of disease-modifying therapies (DMTs), no one-size-fits-all approach exists. Interferon betas and glatiramer acetate have more than 1,000 pregnancy exposures that yield no evidence for teratogenicity or negative fetal impact. No washout is needed prior to pregnancy. “These agents can be used during pregnancy and breastfeeding,” she said.
The other DMTs paint a somewhat different picture. “There is insufficient pregnancy exposure to the three available oral DMTs to comment definitively on their safety, but there is no clear human teratogenicity to date,” Dr. Coyle said. The conventional washout for fingolimod is 8 weeks. In Dr. Coyle’s opinion, no washout is required with dimethyl fumarate. “The half-life is 40 minutes. There are no good signs of issues. For teriflunomide, it can hang around in individuals for 18-24 months. You should go through an accelerated elimination procedure with oral cholestyramine 8 mg three times a day for 11 days until blood level of the agent is less than 0.02 mcg/mL. Avoid all the orals with breastfeeding.”
Monoclonal antibodies – another form of DMTs – lack sufficient pregnancy exposures to merit comment on safety, but they should not be used during breastfeeding. Natalizumab is a humanized IgG4 antibody that crosses the placenta. “This has been used in several dozen pregnancies because the patients got so bad when they were taken off that it required reinstituting natalizumab even though they were pregnant,” Dr. Coyle said. “Human pregnancy exposures have been associated with transient hematologic issues in the newborn, including anemia, thrombocytopenia, and pancytopenia.” Data indicate that the rate of spontaneous abortion among pregnant women treated with natalizumab was 9%, the rate of major birth defects was 5.05%, and no malformation pattern was observed. The drug is detected in human breast milk and has a half-life of 11 days.
Alemtuzumab is a humanized IgG1 monoclonal antibody that crosses the placenta. The half-life elimination is about 14 days. In transgenic mice, giving alemtuzumab during organogenesis was found to be embryolethal. In human pregnancy, hypothyroidism is a concern. “The recommendation has been to wait 4 months after the last treatment before you try to become pregnant. Alemtuzumab is considered a two-cycle treatment. You don’t get the maximum benefit after the first cycle of 5 days. The complete treatment is the second cycle 3 days.”
Daclizumab, another humanized IgG1 monoclonal antibody, also crosses the placenta. Monkey exposure during gestation led to embryofetal death and decreased fetal growth, “but this was at greater than 30 times the human dose,” she said. “It was found to be excreted in monkey breast milk and the half-life is 21 days.” In humans, there have been 36 exposed women who had 38 pregnancies and 20 live births. The rate of spontaneous abortions/miscarriages was 11%, there were eight elective terminations, two ectopic pregnancies, and one congenital heart defect. “This is very limited data, but nothing that would raise the level of concern,” Dr. Coyle said.
Ocrelizumab, another humanized IgG1 monoclonal antibody, was approved by the Food and Drug Administration in March 2017. Prior studies of anti-CD20 antibodies in human pregnancy noted transient lymphocytopenia and peripheral B cell depletion in the newborns. In studies of pregnant monkeys that used 2 and 10 times human doses during organogenesis, it was associated with B cell depletion in spleen/lymph nodes, Dr. Coyle said. “During organogenesis and throughout the neonatal period, treatment could be associated with perinatal death, some associated with bacterial infection; glomerulonephropathy with inflammation; a decrease in circulating B cells, a decrease in testicular weight, and bone marrow lymphoid follicle formation.” Ocrelizumab is excreted in monkey breast milk and the prescription label suggests a 6-month delay in pregnancy. The drug’s half-life is 26 days.
Dr. Coyle reported that she has served as a consultant for Accordant, Acorda, Bayer, Biogen, Celgene, Genentech/Roche, Genzyme/Sanofi, Novartis, Serono, and Teva. She has also received research support from Actelion, Alkermes, Genentech/Roche, MedDay, the National Institute of Neurological Disorders and Stroke, and Novartis.
NEW ORLEANS – Multiple sclerosis has little to no impact on the ability to conceive, on pregnancy, or on fetal status, according to Patricia K. Coyle, MD.
“That’s very reassuring,” Dr. Coyle said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “We don’t see an increase in birth defects just because the mother has MS. There is no consistent increase in abortions, ectopic pregnancies, or assisted vaginal/cesarean deliveries.”
Dr. Coyle, director of the MS Comprehensive Care Center at Stony Brook (N.Y.) University Medical Center, said that the most dramatic changes for pregnant patients with MS occur in the final trimester and mainly involve rising levels of multiple hormones: estrogens, cortisol, progesterone, norepinephrine, and 1,25-dihydroxyvitamin D, which increase late in pregnancy, then rapidly drop off postpartum. This has led to the evaluation of sex hormone therapy for MS.
The impact of other pregnancy factors on MS disease activity remains unknown. One is microchimerism, a maternal-fetal exchange of cells and DNA. “These cells can last for a long time; you can find them in the blood, as well as in the [central nervous system],” Dr. Coyle said. “It’s been reported that fetal microchimerism may be increased in immune-mediated diseases like MS, but we really don’t have a lot of good data.”
Researchers also are studying the impact of changes in the gut microbiota that occur during pregnancy. “Could this be a potential target for MS therapy?” Dr. Coyle asked. “This is in its infancy.”
Counseling tips
She went on to share counseling tips for MS patients of childbearing age, including the fact that some studies report slightly smaller babies born to mothers with MS, while others have not found that association. “This is a question mark, but it doesn’t seem to be a major issue,” she said. One thing you can tell patients for certain is that MS is not inherited. “There are well over 230 genes linked to MS, so there’s a genetic enrichment that can make somebody vulnerable to MS, but there’s no gene that passes on MS,” Dr. Coyle said. “The risk is slightly higher for a first-degree relative, so when a parent has MS, the risk for the child is in the range of 2% to 2.5%, compared with the expected 0.13% in the general population. But there’s a slightly higher risk when you’re a sibling than when you’re a parent – 2.7% – which is speaking to environmental factors having an important impact on genes.”
Controversial data exist as to whether a maternal deficiency in vitamin D poses a risk of MS in the offspring. Dr. Coyle makes it a point to “normalize” vitamin D levels in pregnant MS patients, particularly in white patients. “You’d want to have them on prenatal vitamins and folic acid and tell them not to smoke, to limit their alcohol use, and advise them to have good sleep hygiene.”
Dr. Coyle, vice chair of clinical affairs at Stony Brook University Medical Center, said that up until the 1950s, physicians advised women with MS against having children. “They were told not to get pregnant or to have an abortion, because it was thought to make MS worse,” she said. “It turns out that was fiction. That was completely wrong. Pregnancy has no negative effect on long-term MS prognosis. It may have long-term benefits for relapsing MS, but there are not enough data to comment on its impact on progressive MS. Pregnancy makes it less likely that someone will develop a clinically isolated syndrome, but it may increase the radiologically isolated syndrome risk for clinical attack. That’s based on 7 pregnant patients out of a cohort of 60, so we need further data to explain that.”
Disease-modifying therapies
When it comes to washouts of disease-modifying therapies (DMTs), no one-size-fits-all approach exists. Interferon betas and glatiramer acetate have more than 1,000 pregnancy exposures that yield no evidence for teratogenicity or negative fetal impact. No washout is needed prior to pregnancy. “These agents can be used during pregnancy and breastfeeding,” she said.
The other DMTs paint a somewhat different picture. “There is insufficient pregnancy exposure to the three available oral DMTs to comment definitively on their safety, but there is no clear human teratogenicity to date,” Dr. Coyle said. The conventional washout for fingolimod is 8 weeks. In Dr. Coyle’s opinion, no washout is required with dimethyl fumarate. “The half-life is 40 minutes. There are no good signs of issues. For teriflunomide, it can hang around in individuals for 18-24 months. You should go through an accelerated elimination procedure with oral cholestyramine 8 mg three times a day for 11 days until blood level of the agent is less than 0.02 mcg/mL. Avoid all the orals with breastfeeding.”
Monoclonal antibodies – another form of DMTs – lack sufficient pregnancy exposures to merit comment on safety, but they should not be used during breastfeeding. Natalizumab is a humanized IgG4 antibody that crosses the placenta. “This has been used in several dozen pregnancies because the patients got so bad when they were taken off that it required reinstituting natalizumab even though they were pregnant,” Dr. Coyle said. “Human pregnancy exposures have been associated with transient hematologic issues in the newborn, including anemia, thrombocytopenia, and pancytopenia.” Data indicate that the rate of spontaneous abortion among pregnant women treated with natalizumab was 9%, the rate of major birth defects was 5.05%, and no malformation pattern was observed. The drug is detected in human breast milk and has a half-life of 11 days.
Alemtuzumab is a humanized IgG1 monoclonal antibody that crosses the placenta. The half-life elimination is about 14 days. In transgenic mice, giving alemtuzumab during organogenesis was found to be embryolethal. In human pregnancy, hypothyroidism is a concern. “The recommendation has been to wait 4 months after the last treatment before you try to become pregnant. Alemtuzumab is considered a two-cycle treatment. You don’t get the maximum benefit after the first cycle of 5 days. The complete treatment is the second cycle 3 days.”
Daclizumab, another humanized IgG1 monoclonal antibody, also crosses the placenta. Monkey exposure during gestation led to embryofetal death and decreased fetal growth, “but this was at greater than 30 times the human dose,” she said. “It was found to be excreted in monkey breast milk and the half-life is 21 days.” In humans, there have been 36 exposed women who had 38 pregnancies and 20 live births. The rate of spontaneous abortions/miscarriages was 11%, there were eight elective terminations, two ectopic pregnancies, and one congenital heart defect. “This is very limited data, but nothing that would raise the level of concern,” Dr. Coyle said.
Ocrelizumab, another humanized IgG1 monoclonal antibody, was approved by the Food and Drug Administration in March 2017. Prior studies of anti-CD20 antibodies in human pregnancy noted transient lymphocytopenia and peripheral B cell depletion in the newborns. In studies of pregnant monkeys that used 2 and 10 times human doses during organogenesis, it was associated with B cell depletion in spleen/lymph nodes, Dr. Coyle said. “During organogenesis and throughout the neonatal period, treatment could be associated with perinatal death, some associated with bacterial infection; glomerulonephropathy with inflammation; a decrease in circulating B cells, a decrease in testicular weight, and bone marrow lymphoid follicle formation.” Ocrelizumab is excreted in monkey breast milk and the prescription label suggests a 6-month delay in pregnancy. The drug’s half-life is 26 days.
Dr. Coyle reported that she has served as a consultant for Accordant, Acorda, Bayer, Biogen, Celgene, Genentech/Roche, Genzyme/Sanofi, Novartis, Serono, and Teva. She has also received research support from Actelion, Alkermes, Genentech/Roche, MedDay, the National Institute of Neurological Disorders and Stroke, and Novartis.
EXPERT ANALYSIS AT THE CMSC ANNUAL MEETING
Study sheds light on pregnancy outcomes following ocrelizumab treatment
NEW ORLEANS – Data from the ocrelizumab clinical development program gives clinicians a first look at pregnancy outcomes after exposure to the drug, but the small size limits the ability to draw firm conclusions.
In the United States, prescribing information for ocrelizumab states that women of childbearing potential should use contraception while receiving ocrelizumab and for 6 months after the last infusion. At the annual meeting of the Consortium of Multiple Sclerosis Centers, researchers led by Sibyl Wray, MD, set out to assess the pregnancy, fetal, neonatal and infant outcomes in patients who became pregnant during ocrelizumab trials in MS, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) through Sept. 15, 2015.
The analysis included ocrelizumab-exposed women in primarily European-based clinical trials in patients with MS, RA, or SLE, in whom doses ranged from 20 mg to 2,000 mg. These included three randomized trials of its use in MS, totaling 1,876 patients with a mean age of 40 years; four trials of its use in RA, totaling 2,759 patients with a mean age of 53 years; and one trial of its use in SLE, totaling 381 patients with a mean age of 31 years. Between 2008 and Sept. 14, 2015, a total of 48 women who were enrolled in the trials reported pregnancies.
MS data
Of the 15 pregnancies in the MS trials, three involved the delivery of full term, healthy newborns. In one case, the last ocrelizumab infusion was given 28 months before conception. In the second case, an infusion was given 20 weeks before conception, and a further infusion was given 17 days after conception. In the third case, the last ocrelizumab infusion was given 26.5 weeks before conception.
One live term birth occurred with an abnormal finding. In this case, the last infusion of ocrelizumab was 23 weeks prior to the last menstrual period or about 6 months prior to conception. The embryo/fetus was not exposed to the drug in utero. The researchers also found that seven elective terminations occurred among MS patients and that four pregnancies were ongoing at the time of this report.
“We have to be cautious because we don’t have enough data yet to know, but it’s encouraging to see that, if you follow the guidelines, the patient population and the newborns seem to be healthy in these exposed individuals,” Dr. Wray said.
RA data
Data from the RA clinical trials revealed 22 pregnancies in 21 patients exposed to ocrelizumab. Of these, eight pregnancies resulted in healthy term babies; four resulted in live births with abnormal findings (structural malformation, growth abnormality) or preterm birth; and eight pregnancies in seven women resulted in spontaneous abortion (one patient experienced a spontaneous abortion on two occasions), missed abortion, or an embryonic pregnancy. One pregnancy was lost to follow-up and another resulted in elective termination.
SLE data
During the SLE trials, 11 pregnancies occurred in 10 patients. Three pregnancies in two women resulted in healthy term babies. Three other pregnancies resulted in live births with an abnormal finding (structural malformation, functional deficit, growth abnormality) and/or preterm birth. Two pregnancies resulted in spontaneous/missed abortion. One pregnancy resulted in fetal death at 7.5 months’ gestation secondary to fatal pulmonary embolism in the mother; one pregnancy resulted in elective termination; and one pregnancy resulted in a healthy baby born at an unknown gestational week.
Dr. Wray emphasized that the small numbers of patients studied make it difficult to draw conclusions about pregnancy outcomes following ocrelizumab in patients with MS and other autoimmune diseases. “We need to pay attention to the half-life of this drug, the time it takes to clear, and how to plan pregnancies around that,” she said. She noted that pregnancy outcomes in ongoing ocrelizumab studies and postmarketing experiences will continue to be collected and assessed.
The study was funded by Roche, Basel, Switzerland. Dr. Wray reported that she has received honoraria and/or research funding from Actelion, Alkermes, Biogen, Celgene, EMD Serono, Genentech/Roche, Genzyme/Sanofi, Novartis, and TG Therapeutics.
NEW ORLEANS – Data from the ocrelizumab clinical development program gives clinicians a first look at pregnancy outcomes after exposure to the drug, but the small size limits the ability to draw firm conclusions.
In the United States, prescribing information for ocrelizumab states that women of childbearing potential should use contraception while receiving ocrelizumab and for 6 months after the last infusion. At the annual meeting of the Consortium of Multiple Sclerosis Centers, researchers led by Sibyl Wray, MD, set out to assess the pregnancy, fetal, neonatal and infant outcomes in patients who became pregnant during ocrelizumab trials in MS, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) through Sept. 15, 2015.
The analysis included ocrelizumab-exposed women in primarily European-based clinical trials in patients with MS, RA, or SLE, in whom doses ranged from 20 mg to 2,000 mg. These included three randomized trials of its use in MS, totaling 1,876 patients with a mean age of 40 years; four trials of its use in RA, totaling 2,759 patients with a mean age of 53 years; and one trial of its use in SLE, totaling 381 patients with a mean age of 31 years. Between 2008 and Sept. 14, 2015, a total of 48 women who were enrolled in the trials reported pregnancies.
MS data
Of the 15 pregnancies in the MS trials, three involved the delivery of full term, healthy newborns. In one case, the last ocrelizumab infusion was given 28 months before conception. In the second case, an infusion was given 20 weeks before conception, and a further infusion was given 17 days after conception. In the third case, the last ocrelizumab infusion was given 26.5 weeks before conception.
One live term birth occurred with an abnormal finding. In this case, the last infusion of ocrelizumab was 23 weeks prior to the last menstrual period or about 6 months prior to conception. The embryo/fetus was not exposed to the drug in utero. The researchers also found that seven elective terminations occurred among MS patients and that four pregnancies were ongoing at the time of this report.
“We have to be cautious because we don’t have enough data yet to know, but it’s encouraging to see that, if you follow the guidelines, the patient population and the newborns seem to be healthy in these exposed individuals,” Dr. Wray said.
RA data
Data from the RA clinical trials revealed 22 pregnancies in 21 patients exposed to ocrelizumab. Of these, eight pregnancies resulted in healthy term babies; four resulted in live births with abnormal findings (structural malformation, growth abnormality) or preterm birth; and eight pregnancies in seven women resulted in spontaneous abortion (one patient experienced a spontaneous abortion on two occasions), missed abortion, or an embryonic pregnancy. One pregnancy was lost to follow-up and another resulted in elective termination.
SLE data
During the SLE trials, 11 pregnancies occurred in 10 patients. Three pregnancies in two women resulted in healthy term babies. Three other pregnancies resulted in live births with an abnormal finding (structural malformation, functional deficit, growth abnormality) and/or preterm birth. Two pregnancies resulted in spontaneous/missed abortion. One pregnancy resulted in fetal death at 7.5 months’ gestation secondary to fatal pulmonary embolism in the mother; one pregnancy resulted in elective termination; and one pregnancy resulted in a healthy baby born at an unknown gestational week.
Dr. Wray emphasized that the small numbers of patients studied make it difficult to draw conclusions about pregnancy outcomes following ocrelizumab in patients with MS and other autoimmune diseases. “We need to pay attention to the half-life of this drug, the time it takes to clear, and how to plan pregnancies around that,” she said. She noted that pregnancy outcomes in ongoing ocrelizumab studies and postmarketing experiences will continue to be collected and assessed.
The study was funded by Roche, Basel, Switzerland. Dr. Wray reported that she has received honoraria and/or research funding from Actelion, Alkermes, Biogen, Celgene, EMD Serono, Genentech/Roche, Genzyme/Sanofi, Novartis, and TG Therapeutics.
NEW ORLEANS – Data from the ocrelizumab clinical development program gives clinicians a first look at pregnancy outcomes after exposure to the drug, but the small size limits the ability to draw firm conclusions.
In the United States, prescribing information for ocrelizumab states that women of childbearing potential should use contraception while receiving ocrelizumab and for 6 months after the last infusion. At the annual meeting of the Consortium of Multiple Sclerosis Centers, researchers led by Sibyl Wray, MD, set out to assess the pregnancy, fetal, neonatal and infant outcomes in patients who became pregnant during ocrelizumab trials in MS, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) through Sept. 15, 2015.
The analysis included ocrelizumab-exposed women in primarily European-based clinical trials in patients with MS, RA, or SLE, in whom doses ranged from 20 mg to 2,000 mg. These included three randomized trials of its use in MS, totaling 1,876 patients with a mean age of 40 years; four trials of its use in RA, totaling 2,759 patients with a mean age of 53 years; and one trial of its use in SLE, totaling 381 patients with a mean age of 31 years. Between 2008 and Sept. 14, 2015, a total of 48 women who were enrolled in the trials reported pregnancies.
MS data
Of the 15 pregnancies in the MS trials, three involved the delivery of full term, healthy newborns. In one case, the last ocrelizumab infusion was given 28 months before conception. In the second case, an infusion was given 20 weeks before conception, and a further infusion was given 17 days after conception. In the third case, the last ocrelizumab infusion was given 26.5 weeks before conception.
One live term birth occurred with an abnormal finding. In this case, the last infusion of ocrelizumab was 23 weeks prior to the last menstrual period or about 6 months prior to conception. The embryo/fetus was not exposed to the drug in utero. The researchers also found that seven elective terminations occurred among MS patients and that four pregnancies were ongoing at the time of this report.
“We have to be cautious because we don’t have enough data yet to know, but it’s encouraging to see that, if you follow the guidelines, the patient population and the newborns seem to be healthy in these exposed individuals,” Dr. Wray said.
RA data
Data from the RA clinical trials revealed 22 pregnancies in 21 patients exposed to ocrelizumab. Of these, eight pregnancies resulted in healthy term babies; four resulted in live births with abnormal findings (structural malformation, growth abnormality) or preterm birth; and eight pregnancies in seven women resulted in spontaneous abortion (one patient experienced a spontaneous abortion on two occasions), missed abortion, or an embryonic pregnancy. One pregnancy was lost to follow-up and another resulted in elective termination.
SLE data
During the SLE trials, 11 pregnancies occurred in 10 patients. Three pregnancies in two women resulted in healthy term babies. Three other pregnancies resulted in live births with an abnormal finding (structural malformation, functional deficit, growth abnormality) and/or preterm birth. Two pregnancies resulted in spontaneous/missed abortion. One pregnancy resulted in fetal death at 7.5 months’ gestation secondary to fatal pulmonary embolism in the mother; one pregnancy resulted in elective termination; and one pregnancy resulted in a healthy baby born at an unknown gestational week.
Dr. Wray emphasized that the small numbers of patients studied make it difficult to draw conclusions about pregnancy outcomes following ocrelizumab in patients with MS and other autoimmune diseases. “We need to pay attention to the half-life of this drug, the time it takes to clear, and how to plan pregnancies around that,” she said. She noted that pregnancy outcomes in ongoing ocrelizumab studies and postmarketing experiences will continue to be collected and assessed.
The study was funded by Roche, Basel, Switzerland. Dr. Wray reported that she has received honoraria and/or research funding from Actelion, Alkermes, Biogen, Celgene, EMD Serono, Genentech/Roche, Genzyme/Sanofi, Novartis, and TG Therapeutics.
AT THE CMSC ANNUAL MEETING
Key clinical point:
Major finding: Of 15 pregnancies in the MS trials, three involved the delivery of three full term, healthy newborns; one live term birth occurred with an abnormal finding; seven elective terminations occurred; and four pregnancies were ongoing.
Data source: A review of 48 pregnancies among women enrolled in clinical trials for ocrelizumab in MS, rheumatoid arthritis, and systemic lupus erythematosus.
Disclosures: The study was funded by Roche, Basel, Switzerland. Dr. Wray reported that she has received honoraria and/or research funding from Actelion, Alkermes, Biogen, Celgene, EMD Serono, Genentech/Roche, Genzyme/Sanofi, Novartis, and TG Therapeutics.