Clinical Topics & News

Cladribine tablets (3.5 mg/kg) have a favorable adverse event profile and are safe as monotherapy for relapsing remitting multiple sclerosis, according to an integrated analysis of several clinical trials published in Multiple Sclerosis and Related Disorders.

The drug causes transient lymphopenia, as is to be expected from its mechanism of action, but most patients who receive cladribine do not have grade 3 or 4 lymphopenia, the authors wrote. In general, cladribine is not associated with an increased risk of infections or malignancy.

Data indicate that cladribine’s mechanism of action contributes to its durable clinical effect, despite the brief treatment periods. Clinical trials have provided information about the treatment’s safety and tolerability. To examine the treatment’s long-term safety, Stuart Cook, MD, of New Jersey Medical School, Newark, and his colleagues pooled data for patients with multiple sclerosis (MS) treated with cladribine tablets (3.5 mg/kg) as monotherapy or placebo in three phase 3 clinical trials (CLARITY, CLARITY Extension, and ORACLE-MS) and followed up in the PREMIERE registry. The investigators called these patients the monotherapy oral cohort.

To investigate the potential associations between cladribine and rarer adverse events such as malignancies, Dr. Cook and his colleagues examined data from patients with MS who received cladribine, regardless of the formulation or route of administration, or placebo (the all-exposed cohort). This cohort included data from the ONWARD trial, in which patients received cladribine tablets or placebo in combination with interferon-beta, as well as data from five trials in which patients received parenteral cladribine or placebo.

The monotherapy oral cohort included 923 patients who received cladribine and 641 who received placebo. The median age at enrollment in this cohort was approximately 36 years. The majority of patients were women and disease characteristics were balanced between arms. The all-exposed cohort included 1,926 patients who received cladribine and 802 who received placebo. The demographic characteristics of this cohort were similar to those of the monotherapy oral cohort.

In the monotherapy oral cohort, the incidence rate of treatment-emergent adverse events, in adjusted adverse events per 100 patient-years, was 103.29 for the active group versus 94.26 for controls. Lymphopenia (7.94 vs. 1.06) and decreased lymphocyte count (0.78 vs. 0.10) occurred more frequently in the active group than in the placebo group.

Herpes zoster also occurred more frequently in the cladribine group (0.83 vs. 0.20). However, cladribine was not associated with systemic serious disseminated herpes zoster. Furthermore, the investigators found no overall increased risk of infections, including opportunistic infections, with cladribine tablets versus placebo, except for herpes zoster.

In addition, Dr. Cook and his colleagues found no increase in malignancy rates among patients who received cladribine, compared with those who received placebo. They also found no increase in the incidence of malignancies over time in the cladribine group.

The adverse event profile for cladribine tablets (3.5 mg/kg) as monotherapy has been well characterized, the investigators wrote. The results of this analysis are broadly similar to the short-term adverse event results reported in the individual trials.

EMD Serono and Merck Serono, two affiliates of Merck in Darmstadt, Germany, sponsored the study. Merck manufactures cladribine.

[email protected]

SOURCE: Cook S et al. Mult Scler Relat Disord. 2018 Nov 18. doi: 10.1016/j.msard.2018.11.021.

Cladribine tablets (3.5 mg/kg) have a favorable adverse event profile and are safe as monotherapy for relapsing remitting multiple sclerosis, according to an integrated analysis of several clinical trials published in Multiple Sclerosis and Related Disorders.

The drug causes transient lymphopenia, as is to be expected from its mechanism of action, but most patients who receive cladribine do not have grade 3 or 4 lymphopenia, the authors wrote. In general, cladribine is not associated with an increased risk of infections or malignancy.

Data indicate that cladribine’s mechanism of action contributes to its durable clinical effect, despite the brief treatment periods. Clinical trials have provided information about the treatment’s safety and tolerability. To examine the treatment’s long-term safety, Stuart Cook, MD, of New Jersey Medical School, Newark, and his colleagues pooled data for patients with multiple sclerosis (MS) treated with cladribine tablets (3.5 mg/kg) as monotherapy or placebo in three phase 3 clinical trials (CLARITY, CLARITY Extension, and ORACLE-MS) and followed up in the PREMIERE registry. The investigators called these patients the monotherapy oral cohort.

To investigate the potential associations between cladribine and rarer adverse events such as malignancies, Dr. Cook and his colleagues examined data from patients with MS who received cladribine, regardless of the formulation or route of administration, or placebo (the all-exposed cohort). This cohort included data from the ONWARD trial, in which patients received cladribine tablets or placebo in combination with interferon-beta, as well as data from five trials in which patients received parenteral cladribine or placebo.

The monotherapy oral cohort included 923 patients who received cladribine and 641 who received placebo. The median age at enrollment in this cohort was approximately 36 years. The majority of patients were women and disease characteristics were balanced between arms. The all-exposed cohort included 1,926 patients who received cladribine and 802 who received placebo. The demographic characteristics of this cohort were similar to those of the monotherapy oral cohort.

In the monotherapy oral cohort, the incidence rate of treatment-emergent adverse events, in adjusted adverse events per 100 patient-years, was 103.29 for the active group versus 94.26 for controls. Lymphopenia (7.94 vs. 1.06) and decreased lymphocyte count (0.78 vs. 0.10) occurred more frequently in the active group than in the placebo group.

Herpes zoster also occurred more frequently in the cladribine group (0.83 vs. 0.20). However, cladribine was not associated with systemic serious disseminated herpes zoster. Furthermore, the investigators found no overall increased risk of infections, including opportunistic infections, with cladribine tablets versus placebo, except for herpes zoster.

In addition, Dr. Cook and his colleagues found no increase in malignancy rates among patients who received cladribine, compared with those who received placebo. They also found no increase in the incidence of malignancies over time in the cladribine group.

The adverse event profile for cladribine tablets (3.5 mg/kg) as monotherapy has been well characterized, the investigators wrote. The results of this analysis are broadly similar to the short-term adverse event results reported in the individual trials.

EMD Serono and Merck Serono, two affiliates of Merck in Darmstadt, Germany, sponsored the study. Merck manufactures cladribine.

[email protected]

SOURCE: Cook S et al. Mult Scler Relat Disord. 2018 Nov 18. doi: 10.1016/j.msard.2018.11.021.

Cladribine tablets (3.5 mg/kg) have a favorable adverse event profile and are safe as monotherapy for relapsing remitting multiple sclerosis, according to an integrated analysis of several clinical trials published in Multiple Sclerosis and Related Disorders.

The drug causes transient lymphopenia, as is to be expected from its mechanism of action, but most patients who receive cladribine do not have grade 3 or 4 lymphopenia, the authors wrote. In general, cladribine is not associated with an increased risk of infections or malignancy.

Data indicate that cladribine’s mechanism of action contributes to its durable clinical effect, despite the brief treatment periods. Clinical trials have provided information about the treatment’s safety and tolerability. To examine the treatment’s long-term safety, Stuart Cook, MD, of New Jersey Medical School, Newark, and his colleagues pooled data for patients with multiple sclerosis (MS) treated with cladribine tablets (3.5 mg/kg) as monotherapy or placebo in three phase 3 clinical trials (CLARITY, CLARITY Extension, and ORACLE-MS) and followed up in the PREMIERE registry. The investigators called these patients the monotherapy oral cohort.

To investigate the potential associations between cladribine and rarer adverse events such as malignancies, Dr. Cook and his colleagues examined data from patients with MS who received cladribine, regardless of the formulation or route of administration, or placebo (the all-exposed cohort). This cohort included data from the ONWARD trial, in which patients received cladribine tablets or placebo in combination with interferon-beta, as well as data from five trials in which patients received parenteral cladribine or placebo.

The monotherapy oral cohort included 923 patients who received cladribine and 641 who received placebo. The median age at enrollment in this cohort was approximately 36 years. The majority of patients were women and disease characteristics were balanced between arms. The all-exposed cohort included 1,926 patients who received cladribine and 802 who received placebo. The demographic characteristics of this cohort were similar to those of the monotherapy oral cohort.

In the monotherapy oral cohort, the incidence rate of treatment-emergent adverse events, in adjusted adverse events per 100 patient-years, was 103.29 for the active group versus 94.26 for controls. Lymphopenia (7.94 vs. 1.06) and decreased lymphocyte count (0.78 vs. 0.10) occurred more frequently in the active group than in the placebo group.

Herpes zoster also occurred more frequently in the cladribine group (0.83 vs. 0.20). However, cladribine was not associated with systemic serious disseminated herpes zoster. Furthermore, the investigators found no overall increased risk of infections, including opportunistic infections, with cladribine tablets versus placebo, except for herpes zoster.

In addition, Dr. Cook and his colleagues found no increase in malignancy rates among patients who received cladribine, compared with those who received placebo. They also found no increase in the incidence of malignancies over time in the cladribine group.

The adverse event profile for cladribine tablets (3.5 mg/kg) as monotherapy has been well characterized, the investigators wrote. The results of this analysis are broadly similar to the short-term adverse event results reported in the individual trials.

EMD Serono and Merck Serono, two affiliates of Merck in Darmstadt, Germany, sponsored the study. Merck manufactures cladribine.

[email protected]

SOURCE: Cook S et al. Mult Scler Relat Disord. 2018 Nov 18. doi: 10.1016/j.msard.2018.11.021.

Steven M. Baskin, PhD, a clinical psychologist at the New England Institute for Neurology and Headache in Stamford, Connecticut, recently answered the Migraine Resource Center’s questions about the benefits of behavioral therapy in the treatment of migraine and tension-type headache.
 

Alan M. Rapoport, MD: Could you please give a brief description of the 5 best modalities of behavioral therapy for migraine and tension-type headache? 
 

Steven M. Baskin, PhD: The most researched modalities that have a good evidence base for both migraine and tension-type headache (TTHA) are relaxation therapies that often combine abdominal breathing with some form of progressive relaxation, electromyography (EMG) biofeedback therapy where headache patients learn to decrease scalp and neck muscle tension utilizing muscular biofeedback, thermal biofeedback where migraine sufferers learn a way to warm their hands which often creates a low arousal state that may reduce brain hyperexcitability, and cognitive behavioral therapy (CBT) techniques to learn stress management. The combination of behavioral medicine techniques plus preventive pharmacological treatment has been showed to be more efficacious than either treatment alone. (Holroyd KA, et al. Effect of preventive (β blocker) treatment, behavioural migraine management, or their combination on outcomes of optimised acute treatment in frequent migraine: randomised controlled trial. BMJ. 2010;1-12)

CBT to treat insomnia has also been shown to reverse many chronic migraine sufferers back to episodic migraine. (Smitherman TA, et al. Cognitive-Behavioral Therapy for Insomnia to Reduce Chronic Migraine: A Sequential Bayesian Analysis. Headache 2018;58:1052-1059)
 

Dr. Rapoport: How do you identify a patient who may benefit from behavioral therapy over acute medication, and what is the first step that you suggest?
 

Dr. Baskin: Behavioral therapies for migraine management are typically preventive therapies that can and should be combined with medications to control acute attacks. There are behavioral principles that can maximize adherence to abortive agents in order to optimize acute care.
 

Dr. Rapoport: Which tends to work the best for migraine?
 

Dr. Baskin: What works best is to first do a good behavioral assessment of the frequency, duration, intensity, and disability level of their headaches as well as current stress levels, history, and adherence to drug and nondrug therapies, and psychiatric comorbidities. A program should then be developed that includes some combination of pharmacological and behavioral interventions to address these issues. It is important to increase self-efficacy: patients’ belief in the ability to control the headache, belief in the ability to manage emotional reactivity to pain, and belief that they can achieve functionality in the presence of a significant headache disorder.
 

Dr. Rapoport: Who should not have biofeedback therapy?
 

Dr. Baskin: Biofeedback has shown to be effective in treating migraine and TTHA. It has not been shown to be effective in treating trigeminal autonomic cephalgias (TACs) such as cluster headache. Like pharmacological therapies, it is less effective in chronic migraine that is daily and constant. A patient with severe psychiatric disorder should be treated for their psychiatric disorder before beginning biofeedback therapy.
 

Dr. Rapoport: Some doctors see patients twice per week for several months. What is your typical routine for behavioral therapy?
 

Dr. Baskin: We have a variety of programs. For complicated patients, we tend to see them weekly and have a very systematic program of biofeedback and CBT for approximately 12 to 15 sessions. This may include treating psychiatric comorbidities. We see many other patients for 1 or 2 sessions of biofeedback to try to effect physiological learning and for 1 or 2 sessions of CBT to help them manage stressors and learn coping skills that they can use to help manage migraines and life stress.
 

Dr. Rapoport: Does behavioral medicine work best in conjunction with preventive medications, or on its own?

Dr. Baskin: Many patients do well with a behavioral treatment as a preventive therapy and a pharmacologic agent to optimize acute care. I believe that many patients with higher frequency migraine with psychological issues or ongoing stressors do best with a combination of preventive pharmacologic therapy and behavior therapy. Any migraine patient with sleep issues should learn CBT for insomnia. 

Dr. Rapoport: Is there evidence that suggests behavioral therapy can help patients at various ages manage their migraines?

Dr. Baskin: There is both adult and child data on behavioral therapy for migraine.  An excellent study was done in children and adolescents by Powers et al. It showed that adding 10 sessions of CBT to preventive amitriptyline therapy, compared to adding headache education, significantly reduced the number of headache days, level of disability, and kids with a better than 50% decrease in days of headache compared to amitriptyline, plus headache education control in chronic migraine patients.  (Powers SW et al. Cognitive Behavioral Therapy Plus Amitriptyline for Chronic Migraine in Children and Adolescents: A Randomized Clinical Trial. JAMA 2013;310(24):2622-2630)

Dr. Rapoport: A recent MedPage Today article noted that “anxiety may complicate migraine more than depression with greater long-term persistence, greater headache-related disability, and reduced satisfaction with acute therapies.” Could you please elaborate on why this may be the case? 

Dr. Baskin: Anxiety disorders are often based on feeling threat. They are always associated with avoidance behaviors. Headache sufferers with significant anxiety tend to overestimate the probability of danger (migraine) and perceive it as more unmanageable and threatening than objective reality. They are often very sensitive to medication side effects and benign somatic sensations. They sometimes take medications pre-emptively, because of their fear of getting a migraine, which may lead to medication misuse or overuse. The lifetime prevalence of anxiety disorders in migraineurs (ranging from 51-58%) is almost twice that of major depression.

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, M.D.

Editor-in-Chief

Migraine Resource Center

Clinical Professor of Neurology

The David Geffen School of Medicine at UCLA

Los Angeles, California

Steven M. Baskin, PhD, a clinical psychologist at the New England Institute for Neurology and Headache in Stamford, Connecticut, recently answered the Migraine Resource Center’s questions about the benefits of behavioral therapy in the treatment of migraine and tension-type headache.
 

Alan M. Rapoport, MD: Could you please give a brief description of the 5 best modalities of behavioral therapy for migraine and tension-type headache? 
 

Steven M. Baskin, PhD: The most researched modalities that have a good evidence base for both migraine and tension-type headache (TTHA) are relaxation therapies that often combine abdominal breathing with some form of progressive relaxation, electromyography (EMG) biofeedback therapy where headache patients learn to decrease scalp and neck muscle tension utilizing muscular biofeedback, thermal biofeedback where migraine sufferers learn a way to warm their hands which often creates a low arousal state that may reduce brain hyperexcitability, and cognitive behavioral therapy (CBT) techniques to learn stress management. The combination of behavioral medicine techniques plus preventive pharmacological treatment has been showed to be more efficacious than either treatment alone. (Holroyd KA, et al. Effect of preventive (β blocker) treatment, behavioural migraine management, or their combination on outcomes of optimised acute treatment in frequent migraine: randomised controlled trial. BMJ. 2010;1-12)

CBT to treat insomnia has also been shown to reverse many chronic migraine sufferers back to episodic migraine. (Smitherman TA, et al. Cognitive-Behavioral Therapy for Insomnia to Reduce Chronic Migraine: A Sequential Bayesian Analysis. Headache 2018;58:1052-1059)
 

Dr. Rapoport: How do you identify a patient who may benefit from behavioral therapy over acute medication, and what is the first step that you suggest?
 

Dr. Baskin: Behavioral therapies for migraine management are typically preventive therapies that can and should be combined with medications to control acute attacks. There are behavioral principles that can maximize adherence to abortive agents in order to optimize acute care.
 

Dr. Rapoport: Which tends to work the best for migraine?
 

Dr. Baskin: What works best is to first do a good behavioral assessment of the frequency, duration, intensity, and disability level of their headaches as well as current stress levels, history, and adherence to drug and nondrug therapies, and psychiatric comorbidities. A program should then be developed that includes some combination of pharmacological and behavioral interventions to address these issues. It is important to increase self-efficacy: patients’ belief in the ability to control the headache, belief in the ability to manage emotional reactivity to pain, and belief that they can achieve functionality in the presence of a significant headache disorder.
 

Dr. Rapoport: Who should not have biofeedback therapy?
 

Dr. Baskin: Biofeedback has shown to be effective in treating migraine and TTHA. It has not been shown to be effective in treating trigeminal autonomic cephalgias (TACs) such as cluster headache. Like pharmacological therapies, it is less effective in chronic migraine that is daily and constant. A patient with severe psychiatric disorder should be treated for their psychiatric disorder before beginning biofeedback therapy.
 

Dr. Rapoport: Some doctors see patients twice per week for several months. What is your typical routine for behavioral therapy?
 

Dr. Baskin: We have a variety of programs. For complicated patients, we tend to see them weekly and have a very systematic program of biofeedback and CBT for approximately 12 to 15 sessions. This may include treating psychiatric comorbidities. We see many other patients for 1 or 2 sessions of biofeedback to try to effect physiological learning and for 1 or 2 sessions of CBT to help them manage stressors and learn coping skills that they can use to help manage migraines and life stress.
 

Dr. Rapoport: Does behavioral medicine work best in conjunction with preventive medications, or on its own?

Dr. Baskin: Many patients do well with a behavioral treatment as a preventive therapy and a pharmacologic agent to optimize acute care. I believe that many patients with higher frequency migraine with psychological issues or ongoing stressors do best with a combination of preventive pharmacologic therapy and behavior therapy. Any migraine patient with sleep issues should learn CBT for insomnia. 

Dr. Rapoport: Is there evidence that suggests behavioral therapy can help patients at various ages manage their migraines?

Dr. Baskin: There is both adult and child data on behavioral therapy for migraine.  An excellent study was done in children and adolescents by Powers et al. It showed that adding 10 sessions of CBT to preventive amitriptyline therapy, compared to adding headache education, significantly reduced the number of headache days, level of disability, and kids with a better than 50% decrease in days of headache compared to amitriptyline, plus headache education control in chronic migraine patients.  (Powers SW et al. Cognitive Behavioral Therapy Plus Amitriptyline for Chronic Migraine in Children and Adolescents: A Randomized Clinical Trial. JAMA 2013;310(24):2622-2630)

Dr. Rapoport: A recent MedPage Today article noted that “anxiety may complicate migraine more than depression with greater long-term persistence, greater headache-related disability, and reduced satisfaction with acute therapies.” Could you please elaborate on why this may be the case? 

Dr. Baskin: Anxiety disorders are often based on feeling threat. They are always associated with avoidance behaviors. Headache sufferers with significant anxiety tend to overestimate the probability of danger (migraine) and perceive it as more unmanageable and threatening than objective reality. They are often very sensitive to medication side effects and benign somatic sensations. They sometimes take medications pre-emptively, because of their fear of getting a migraine, which may lead to medication misuse or overuse. The lifetime prevalence of anxiety disorders in migraineurs (ranging from 51-58%) is almost twice that of major depression.

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, M.D.

Editor-in-Chief

Migraine Resource Center

Clinical Professor of Neurology

The David Geffen School of Medicine at UCLA

Los Angeles, California

Steven M. Baskin, PhD, a clinical psychologist at the New England Institute for Neurology and Headache in Stamford, Connecticut, recently answered the Migraine Resource Center’s questions about the benefits of behavioral therapy in the treatment of migraine and tension-type headache.
 

Alan M. Rapoport, MD: Could you please give a brief description of the 5 best modalities of behavioral therapy for migraine and tension-type headache? 
 

Steven M. Baskin, PhD: The most researched modalities that have a good evidence base for both migraine and tension-type headache (TTHA) are relaxation therapies that often combine abdominal breathing with some form of progressive relaxation, electromyography (EMG) biofeedback therapy where headache patients learn to decrease scalp and neck muscle tension utilizing muscular biofeedback, thermal biofeedback where migraine sufferers learn a way to warm their hands which often creates a low arousal state that may reduce brain hyperexcitability, and cognitive behavioral therapy (CBT) techniques to learn stress management. The combination of behavioral medicine techniques plus preventive pharmacological treatment has been showed to be more efficacious than either treatment alone. (Holroyd KA, et al. Effect of preventive (β blocker) treatment, behavioural migraine management, or their combination on outcomes of optimised acute treatment in frequent migraine: randomised controlled trial. BMJ. 2010;1-12)

CBT to treat insomnia has also been shown to reverse many chronic migraine sufferers back to episodic migraine. (Smitherman TA, et al. Cognitive-Behavioral Therapy for Insomnia to Reduce Chronic Migraine: A Sequential Bayesian Analysis. Headache 2018;58:1052-1059)
 

Dr. Rapoport: How do you identify a patient who may benefit from behavioral therapy over acute medication, and what is the first step that you suggest?
 

Dr. Baskin: Behavioral therapies for migraine management are typically preventive therapies that can and should be combined with medications to control acute attacks. There are behavioral principles that can maximize adherence to abortive agents in order to optimize acute care.
 

Dr. Rapoport: Which tends to work the best for migraine?
 

Dr. Baskin: What works best is to first do a good behavioral assessment of the frequency, duration, intensity, and disability level of their headaches as well as current stress levels, history, and adherence to drug and nondrug therapies, and psychiatric comorbidities. A program should then be developed that includes some combination of pharmacological and behavioral interventions to address these issues. It is important to increase self-efficacy: patients’ belief in the ability to control the headache, belief in the ability to manage emotional reactivity to pain, and belief that they can achieve functionality in the presence of a significant headache disorder.
 

Dr. Rapoport: Who should not have biofeedback therapy?
 

Dr. Baskin: Biofeedback has shown to be effective in treating migraine and TTHA. It has not been shown to be effective in treating trigeminal autonomic cephalgias (TACs) such as cluster headache. Like pharmacological therapies, it is less effective in chronic migraine that is daily and constant. A patient with severe psychiatric disorder should be treated for their psychiatric disorder before beginning biofeedback therapy.
 

Dr. Rapoport: Some doctors see patients twice per week for several months. What is your typical routine for behavioral therapy?
 

Dr. Baskin: We have a variety of programs. For complicated patients, we tend to see them weekly and have a very systematic program of biofeedback and CBT for approximately 12 to 15 sessions. This may include treating psychiatric comorbidities. We see many other patients for 1 or 2 sessions of biofeedback to try to effect physiological learning and for 1 or 2 sessions of CBT to help them manage stressors and learn coping skills that they can use to help manage migraines and life stress.
 

Dr. Rapoport: Does behavioral medicine work best in conjunction with preventive medications, or on its own?

Dr. Baskin: Many patients do well with a behavioral treatment as a preventive therapy and a pharmacologic agent to optimize acute care. I believe that many patients with higher frequency migraine with psychological issues or ongoing stressors do best with a combination of preventive pharmacologic therapy and behavior therapy. Any migraine patient with sleep issues should learn CBT for insomnia. 

Dr. Rapoport: Is there evidence that suggests behavioral therapy can help patients at various ages manage their migraines?

Dr. Baskin: There is both adult and child data on behavioral therapy for migraine.  An excellent study was done in children and adolescents by Powers et al. It showed that adding 10 sessions of CBT to preventive amitriptyline therapy, compared to adding headache education, significantly reduced the number of headache days, level of disability, and kids with a better than 50% decrease in days of headache compared to amitriptyline, plus headache education control in chronic migraine patients.  (Powers SW et al. Cognitive Behavioral Therapy Plus Amitriptyline for Chronic Migraine in Children and Adolescents: A Randomized Clinical Trial. JAMA 2013;310(24):2622-2630)

Dr. Rapoport: A recent MedPage Today article noted that “anxiety may complicate migraine more than depression with greater long-term persistence, greater headache-related disability, and reduced satisfaction with acute therapies.” Could you please elaborate on why this may be the case? 

Dr. Baskin: Anxiety disorders are often based on feeling threat. They are always associated with avoidance behaviors. Headache sufferers with significant anxiety tend to overestimate the probability of danger (migraine) and perceive it as more unmanageable and threatening than objective reality. They are often very sensitive to medication side effects and benign somatic sensations. They sometimes take medications pre-emptively, because of their fear of getting a migraine, which may lead to medication misuse or overuse. The lifetime prevalence of anxiety disorders in migraineurs (ranging from 51-58%) is almost twice that of major depression.

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, M.D.

Editor-in-Chief

Migraine Resource Center

Clinical Professor of Neurology

The David Geffen School of Medicine at UCLA

Los Angeles, California

Patients with multiple sclerosis (MS) and food allergies had more relapses and gadolinium-enhancing lesions than patients with MS but no food allergies, according to a recent analysis of a longitudinal study.

Patients with food allergies had a 1.3-times higher rate for cumulative number of attacks and a 2.5-times higher likelihood of enhancing lesions on brain MRI in the analysis of patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women’s Hospital (CLIMB).

By contrast, there were no significant differences in relapse or lesion rates for patients with environmental or drug allergies when compared with those without allergies, reported Tanuja Chitnis, MD, of Partners Multiple Sclerosis Center at Brigham and Women’s Hospital, Boston, and her coinvestigators.

“Our findings suggest that MS patients with allergies have more active disease than those without allergies, and that this effect is driven by food allergies,” Dr. Tanuja and her coauthors wrote in their report, which appeared in the Journal of Neurology, Neurosurgery and Psychiatry.

Previous investigations have looked at whether allergy history increases risk of developing MS, with conflicting results, they added, noting a meta-analysis of 10 observational studies suggesting no such link.

By contrast, whether allergies lead to more or less intense MS activity has not been addressed, according to investigators, who said this is the first study tying allergy history to MS disease course using clinical and MRI variables.

Their study was based on a subset of 1,349 patients with a diagnosis of MS who were enrolled in CLIMB and completed a self-administered questionnaire on food, environmental, and drug allergies. Of those patients, 922 reported allergies, while 427 reported no known allergies.

Patients with food allergies had a significantly increased rate of cumulative number of attacks, compared with those with no allergies, according to investigators, even after adjusting the analysis for gender, age at symptom onset, disease category, and time on treatment (relapse rate ratio, 1.274; 95% confidence interval, 1.023-1.587; P = .0305).

Food allergy patients were more than twice as likely as no-allergy patients were to have gadolinium-enhancing lesions on brain MRI after adjusting for other covariates (odds ratio, 2.53; 95% CI, 1.25-5.11; P = .0096), they added.

Patients with environmental and drug allergies also appeared to have more relapses, compared with patients with no allergies, in univariate analysis, but the differences were not significant in the adjusted analysis, investigators said. Likewise, there were trends toward a link between number of lesions and presence of environmental or drug allergies that did not hold up on multivariate analysis.

It is unknown what underlying biological mechanisms might potentially link food allergies to MS disease severity; however, findings of experimental studies support the hypothesis that gut microbiota might affect the risk and course of MS, Dr. Chitnis and her coauthors wrote in their report.

The CLIMB study was supported by Merck Serono and the National MS Society Nancy Davis Center Without Walls. Dr. Chitnis reported consulting fees from Biogen Idec, Novartis, Sanofi, Bayer, and Celgene outside the submitted work. Coauthors provided additional disclosures related to Merck Serono, Genentech, Verily Life Sciences, EMD Serono, Biogen, Teva, Sanofi, and Novartis, among others.

SOURCE: Fakih R et al. J Neurol Neurosurg Psychiatry. 2018 Dec 18. doi: 10.1136/jnnp-2018-319301.

Patients with multiple sclerosis (MS) and food allergies had more relapses and gadolinium-enhancing lesions than patients with MS but no food allergies, according to a recent analysis of a longitudinal study.

Patients with food allergies had a 1.3-times higher rate for cumulative number of attacks and a 2.5-times higher likelihood of enhancing lesions on brain MRI in the analysis of patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women’s Hospital (CLIMB).

By contrast, there were no significant differences in relapse or lesion rates for patients with environmental or drug allergies when compared with those without allergies, reported Tanuja Chitnis, MD, of Partners Multiple Sclerosis Center at Brigham and Women’s Hospital, Boston, and her coinvestigators.

“Our findings suggest that MS patients with allergies have more active disease than those without allergies, and that this effect is driven by food allergies,” Dr. Tanuja and her coauthors wrote in their report, which appeared in the Journal of Neurology, Neurosurgery and Psychiatry.

Previous investigations have looked at whether allergy history increases risk of developing MS, with conflicting results, they added, noting a meta-analysis of 10 observational studies suggesting no such link.

By contrast, whether allergies lead to more or less intense MS activity has not been addressed, according to investigators, who said this is the first study tying allergy history to MS disease course using clinical and MRI variables.

Their study was based on a subset of 1,349 patients with a diagnosis of MS who were enrolled in CLIMB and completed a self-administered questionnaire on food, environmental, and drug allergies. Of those patients, 922 reported allergies, while 427 reported no known allergies.

Patients with food allergies had a significantly increased rate of cumulative number of attacks, compared with those with no allergies, according to investigators, even after adjusting the analysis for gender, age at symptom onset, disease category, and time on treatment (relapse rate ratio, 1.274; 95% confidence interval, 1.023-1.587; P = .0305).

Food allergy patients were more than twice as likely as no-allergy patients were to have gadolinium-enhancing lesions on brain MRI after adjusting for other covariates (odds ratio, 2.53; 95% CI, 1.25-5.11; P = .0096), they added.

Patients with environmental and drug allergies also appeared to have more relapses, compared with patients with no allergies, in univariate analysis, but the differences were not significant in the adjusted analysis, investigators said. Likewise, there were trends toward a link between number of lesions and presence of environmental or drug allergies that did not hold up on multivariate analysis.

It is unknown what underlying biological mechanisms might potentially link food allergies to MS disease severity; however, findings of experimental studies support the hypothesis that gut microbiota might affect the risk and course of MS, Dr. Chitnis and her coauthors wrote in their report.

The CLIMB study was supported by Merck Serono and the National MS Society Nancy Davis Center Without Walls. Dr. Chitnis reported consulting fees from Biogen Idec, Novartis, Sanofi, Bayer, and Celgene outside the submitted work. Coauthors provided additional disclosures related to Merck Serono, Genentech, Verily Life Sciences, EMD Serono, Biogen, Teva, Sanofi, and Novartis, among others.

SOURCE: Fakih R et al. J Neurol Neurosurg Psychiatry. 2018 Dec 18. doi: 10.1136/jnnp-2018-319301.

Patients with multiple sclerosis (MS) and food allergies had more relapses and gadolinium-enhancing lesions than patients with MS but no food allergies, according to a recent analysis of a longitudinal study.

Patients with food allergies had a 1.3-times higher rate for cumulative number of attacks and a 2.5-times higher likelihood of enhancing lesions on brain MRI in the analysis of patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women’s Hospital (CLIMB).

By contrast, there were no significant differences in relapse or lesion rates for patients with environmental or drug allergies when compared with those without allergies, reported Tanuja Chitnis, MD, of Partners Multiple Sclerosis Center at Brigham and Women’s Hospital, Boston, and her coinvestigators.

“Our findings suggest that MS patients with allergies have more active disease than those without allergies, and that this effect is driven by food allergies,” Dr. Tanuja and her coauthors wrote in their report, which appeared in the Journal of Neurology, Neurosurgery and Psychiatry.

Previous investigations have looked at whether allergy history increases risk of developing MS, with conflicting results, they added, noting a meta-analysis of 10 observational studies suggesting no such link.

By contrast, whether allergies lead to more or less intense MS activity has not been addressed, according to investigators, who said this is the first study tying allergy history to MS disease course using clinical and MRI variables.

Their study was based on a subset of 1,349 patients with a diagnosis of MS who were enrolled in CLIMB and completed a self-administered questionnaire on food, environmental, and drug allergies. Of those patients, 922 reported allergies, while 427 reported no known allergies.

Patients with food allergies had a significantly increased rate of cumulative number of attacks, compared with those with no allergies, according to investigators, even after adjusting the analysis for gender, age at symptom onset, disease category, and time on treatment (relapse rate ratio, 1.274; 95% confidence interval, 1.023-1.587; P = .0305).

Food allergy patients were more than twice as likely as no-allergy patients were to have gadolinium-enhancing lesions on brain MRI after adjusting for other covariates (odds ratio, 2.53; 95% CI, 1.25-5.11; P = .0096), they added.

Patients with environmental and drug allergies also appeared to have more relapses, compared with patients with no allergies, in univariate analysis, but the differences were not significant in the adjusted analysis, investigators said. Likewise, there were trends toward a link between number of lesions and presence of environmental or drug allergies that did not hold up on multivariate analysis.

It is unknown what underlying biological mechanisms might potentially link food allergies to MS disease severity; however, findings of experimental studies support the hypothesis that gut microbiota might affect the risk and course of MS, Dr. Chitnis and her coauthors wrote in their report.

The CLIMB study was supported by Merck Serono and the National MS Society Nancy Davis Center Without Walls. Dr. Chitnis reported consulting fees from Biogen Idec, Novartis, Sanofi, Bayer, and Celgene outside the submitted work. Coauthors provided additional disclosures related to Merck Serono, Genentech, Verily Life Sciences, EMD Serono, Biogen, Teva, Sanofi, and Novartis, among others.

SOURCE: Fakih R et al. J Neurol Neurosurg Psychiatry. 2018 Dec 18. doi: 10.1136/jnnp-2018-319301.

A significant number of patients who receive only a placebo in a clinical trial of cancer immunotherapy still experience grade three or grade four adverse events, research suggests.

Writing in JAMA Network Open, researchers reported the outcomes of a systematic review and meta-analysis of 10 randomized, double-blind, placebo-controlled, phase 3 trials of targeted therapy or immunotherapy drugs for cancer, in which patients in the placebo group were treated only with placebo and no other anticancer drugs.

Among the 4,873 patients who were randomized to placebo, a mean of 85.1% experienced some sort of placebo adverse event. The overall incidence of grade 3-4 placebo adverse events was 18% but was as high as 25% in two trials – one in renal cell carcinoma and one in melanoma – and as low as 11% in one trial.

Hypertension was the most frequent grade 3-4 adverse event among patients on placebo, experienced by a mean of 2.8% of patients, followed by fatigue (1%) and diarrhea (0.8%).

Neither route of administration nor cancer type made a significant difference in terms of the rate of placebo adverse events. No deaths attributed to the placebo were reported, but the mean rate of discontinuation due to placebo adverse events was 3.9%, and was higher than 5% for four trials.

The median duration of placebo administration ranged from 10 to 15 months for all but one study, and the authors noted that the longer the placebo exposure, the higher the proportion of grade 3-4 adverse events.

The investigators – Matías Rodrigo Chacón, MD, and his colleagues in the research department at the Argentine Association of Clinical Oncology – said that studies with a lower incidence of grade 3-4 adverse events in the treatment arm also had a lower incidence of grade 3-4 placebo adverse events, while the higher incidences of placebo adverse events were seen in studies that also had a higher incidence of treatment-related adverse events.

They suggested that “contextual factors,” such as the information given during the informed consent process, could contribute to negative expectations of adverse events.

“To illustrate this point, in an RCT [randomized controlled trial] of aspirin as a treatment for unstable angina, a higher incidence of gastrointestinal irritation was reported in centers that specified its potential occurrence in the informed consent compared with research units that did not include that risk,” they wrote.

They also suggested that patients may experience anxiety associated with the uncertainty about whether they had received active treatment or placebo, and this could also affect their distress levels.

No conflicts of interest were declared.

SOURCE: Chacón M et al. JAMA Network Open. 2018 Dec 7. doi: 10.1001/jamanetworkopen.2018.5617.

A significant number of patients who receive only a placebo in a clinical trial of cancer immunotherapy still experience grade three or grade four adverse events, research suggests.

Writing in JAMA Network Open, researchers reported the outcomes of a systematic review and meta-analysis of 10 randomized, double-blind, placebo-controlled, phase 3 trials of targeted therapy or immunotherapy drugs for cancer, in which patients in the placebo group were treated only with placebo and no other anticancer drugs.

Among the 4,873 patients who were randomized to placebo, a mean of 85.1% experienced some sort of placebo adverse event. The overall incidence of grade 3-4 placebo adverse events was 18% but was as high as 25% in two trials – one in renal cell carcinoma and one in melanoma – and as low as 11% in one trial.

Hypertension was the most frequent grade 3-4 adverse event among patients on placebo, experienced by a mean of 2.8% of patients, followed by fatigue (1%) and diarrhea (0.8%).

Neither route of administration nor cancer type made a significant difference in terms of the rate of placebo adverse events. No deaths attributed to the placebo were reported, but the mean rate of discontinuation due to placebo adverse events was 3.9%, and was higher than 5% for four trials.

The median duration of placebo administration ranged from 10 to 15 months for all but one study, and the authors noted that the longer the placebo exposure, the higher the proportion of grade 3-4 adverse events.

The investigators – Matías Rodrigo Chacón, MD, and his colleagues in the research department at the Argentine Association of Clinical Oncology – said that studies with a lower incidence of grade 3-4 adverse events in the treatment arm also had a lower incidence of grade 3-4 placebo adverse events, while the higher incidences of placebo adverse events were seen in studies that also had a higher incidence of treatment-related adverse events.

They suggested that “contextual factors,” such as the information given during the informed consent process, could contribute to negative expectations of adverse events.

“To illustrate this point, in an RCT [randomized controlled trial] of aspirin as a treatment for unstable angina, a higher incidence of gastrointestinal irritation was reported in centers that specified its potential occurrence in the informed consent compared with research units that did not include that risk,” they wrote.

They also suggested that patients may experience anxiety associated with the uncertainty about whether they had received active treatment or placebo, and this could also affect their distress levels.

No conflicts of interest were declared.

SOURCE: Chacón M et al. JAMA Network Open. 2018 Dec 7. doi: 10.1001/jamanetworkopen.2018.5617.

A significant number of patients who receive only a placebo in a clinical trial of cancer immunotherapy still experience grade three or grade four adverse events, research suggests.

Writing in JAMA Network Open, researchers reported the outcomes of a systematic review and meta-analysis of 10 randomized, double-blind, placebo-controlled, phase 3 trials of targeted therapy or immunotherapy drugs for cancer, in which patients in the placebo group were treated only with placebo and no other anticancer drugs.

Among the 4,873 patients who were randomized to placebo, a mean of 85.1% experienced some sort of placebo adverse event. The overall incidence of grade 3-4 placebo adverse events was 18% but was as high as 25% in two trials – one in renal cell carcinoma and one in melanoma – and as low as 11% in one trial.

Hypertension was the most frequent grade 3-4 adverse event among patients on placebo, experienced by a mean of 2.8% of patients, followed by fatigue (1%) and diarrhea (0.8%).

Neither route of administration nor cancer type made a significant difference in terms of the rate of placebo adverse events. No deaths attributed to the placebo were reported, but the mean rate of discontinuation due to placebo adverse events was 3.9%, and was higher than 5% for four trials.

The median duration of placebo administration ranged from 10 to 15 months for all but one study, and the authors noted that the longer the placebo exposure, the higher the proportion of grade 3-4 adverse events.

The investigators – Matías Rodrigo Chacón, MD, and his colleagues in the research department at the Argentine Association of Clinical Oncology – said that studies with a lower incidence of grade 3-4 adverse events in the treatment arm also had a lower incidence of grade 3-4 placebo adverse events, while the higher incidences of placebo adverse events were seen in studies that also had a higher incidence of treatment-related adverse events.

They suggested that “contextual factors,” such as the information given during the informed consent process, could contribute to negative expectations of adverse events.

“To illustrate this point, in an RCT [randomized controlled trial] of aspirin as a treatment for unstable angina, a higher incidence of gastrointestinal irritation was reported in centers that specified its potential occurrence in the informed consent compared with research units that did not include that risk,” they wrote.

They also suggested that patients may experience anxiety associated with the uncertainty about whether they had received active treatment or placebo, and this could also affect their distress levels.

No conflicts of interest were declared.

SOURCE: Chacón M et al. JAMA Network Open. 2018 Dec 7. doi: 10.1001/jamanetworkopen.2018.5617.

BERLIN – Real-world data from six postmarketing surveillance studies suggest that currently available disease-modifying treatments (DMTs) for relapsing-remitting multiple sclerosis (RRMS) have long-lasting effects that are matched by reasonable tolerability.

solitude72/iStockphoto

Long-term efficacy and safety data on natalizumab (Tysabri), fingolimod (Gilenya), alemtuzumab (Lemtrada), dimethyl fumarate (Tecfidera), and teriflunomide (Aubagio) from four Swedish studies, one French study, and one international study were reported during a poster session on long-term treatment monitoring at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

The IMSE 1 study with natalizumab

The Immunomodulation and Multiple Sclerosis Epidemiology (IMSE) studies are Swedish postmarketing surveillance studies that were started with the launch of various DMTs in Sweden: natalizumab since 2006 (IMSE 1), fingolimod in 2015 (IMSE 2), alemtuzumab in 2014 (IMSE 3), and dimethyl fumarate in 2014 (IMSE 5).

“Postmarketing surveillance is important for determination of long-term safety and effectiveness in a real-world setting,” Stina Kågström and her associates observed in their poster reporting some findings of the IMSE 1 study with natalizumab (Mult Scler. 2018;24[S2]:699-700, Abstract P1232).

Ms. Kågström of the department of clinical neuroscience at the Karolinska Institute in Stockholm and her colleagues reported that data on 3,108 patients who were seen at 54 Swedish clinics had been collated via the nationwide Swedish Quality Registry for Neurological Care (NEUROreg). NEUROreg started out as an MS register but has since widened its remit to include other neurologic diagnoses.

For the IMSE 1 study, prospectively recorded data regarding natalizumab treatment, adverse events, JC-virus (JCV) status and clinical effectiveness measures were obtained from NEUROreg for 2,225 women and 883 men. Just over one-third (37%, n = 1,150) were still receiving natalizumab at the time of the analysis.


The mean age at which natalizumab was started was 39 years, with treatment primarily given for RRMS (81% of patients) and less often for secondary progressive multiple sclerosis (SPMS, 15%) and rarely for other types of progressive MS. The mean treatment duration was just under 4 years (47.6 months).

JCV testing was introduced in 2011 in Sweden, and this “has led to fewer treated JCV-positive patients,” the IMSE 1 study investigators reported. “This likely explains a reduced incidence of PML [progressive multifocal leukoencephalopathy],” they suggested. There were nine PML cases diagnosed in Sweden from 2008 to the data cut-off point in 2018, one of which was fatal.

JCV status from 2011 onward was available for 1,269 patients, of whom 39% were JCV positive and 61% were JCV negative. The overall drug survival rate was 72% for JCV-negative and 14% for JCV-positive patients. Improved health status was seen, as measured by the Expanded Disability Status Scale (EDSS), the Multiple Sclerosis Severity Score (MSSS), and the physical and psychological Multiple Sclerosis Impact Scale–29 (MSIS-29) components.

A total of 644 of 1,269 patients discontinued treatment with natalizumab at some point, of whom 67% discontinued because of being JCV positive. The main reason for discontinuation in JCV-negative patients was pregnancy or planning a pregnancy (38%), with lack of effect (10%) and adverse events (11%) as other key reasons for stopping natalizumab.

Ms. Kågström and her associates concluded that natalizumab was “generally well tolerated with sustained effectiveness.”

The IMSE 2 study with fingolimod

Data on the long-term safety and efficacy of fingolimod were reported from the IMSE 2 study (Mult Scler. 2018;24[S2]:696-7, Abstract P1228). Lead author Anna Fält, also of the Karolinska Institute, and her associates analyzed data for 1,634 patients who had been treated with fingolimod from June 2015 to September 2018.

Most patients were older than 30 years (79%), and those aged 30 and older were predominantly female (69%), had an RRMS diagnosis (88%), and been treated for a mean of about 3 years (37 months). A total of 829 were being treated with fingolimod at the time of the analysis, with 844 having discontinued treatment at some point. The main reason for discontinuing treatment with fingolimod was a lack of effect (42% of cases) or an adverse effect (34%). The IMSE 2 study authors reported in their abstract that most patients were switched to rituximab after discontinuing fingolimod.

The number of relapses per 1,000 patient-years was reduced by fingolimod treatment from 280 to 82, comparing before and during treatment for all age groups studied. Relapse rate dropped from 694 per 1,000 patient-years before treatment to 138 during treatment in patients aged 20 years or younger, from 454 to 122 in those aged 21-30 years, and from 257 to 72 in those older than 31 years.

After 1 year of treatment, improvements were seen in the health status of patients as measured by various scales, including the EDSS, MSSS, MSIS-29 Physical, and MSIS-29 Psychological. When the researchers analyzed data by age groups, significant improvements were seen in patients aged 21-30 years and older than 30 years.

Ninety nonserious and 62 serious adverse events were reported in fingolimod-treated patients during the time of analysis. Of the latter, 13 serious adverse events involved cardiac disorders, 12 neoplasms, and 10 infections and infestations.

Overall, the IMSE 2 study investigators said that fingolimod was generally tolerable and reduced disease activity in MS.
 

French experience with fingolimod: The VIRGILE study

Real-world data on the long-term safety and efficacy of fingolimod in France from the VIRGILE study were reported by Christine Lebrun-Frenay, MD, PhD, and her associates (Mult Scler. 2018;24[S2]:698-9, Abstract P1231).

Dr. Lebrun-Frenay of Pasteur 2 Hospital in Nice and her coauthors noted that VIRGILE study included patients starting treatment with fingolimod between January 2014 and February 2016. A total of 1,047 patients were included, and another 330 patients treated with natalizumab were included at the behest of the French health authorities.

The annualized relapse rate after 2 years of follow-up was 0.30 in the fingolimod group. Dr. Lebrun-Frenay and her colleagues noted: “The 3-year data from this interim analysis provide evidence for sustained efficacy of fingolimod.” Indeed, they report that almost 60% of patients did not relapse and 64% had no worsening of disease. On average, EDSS was stable during the 3-year follow-up period.

“Safety and tolerability profiles of fingolimod were in line with previous clinical experience, with lymphopenia being the most frequent AE [adverse event] reported,” they added.
 

The IMSE 3 study with alemtuzumab

Long-term experience with alemtuzumab as a treatment for RRMS in the real-world setting is more limited as it only became available for use for this indication in 2014, but some insight is provided by the results of the IMSE 3 study (Mult Scler. 2018;24[S2]:706-7, Abstract P1240).

In total, there were 113 patients treated with alemtuzumab; the vast majority (94%) had RRMS and were aged a mean of 34 years at the start of treatment. Treatment was for more than 12 months in 101 patients, more than 24 months in 86 patients, and more than 36 months in 36 patients.

“In patients treated for at least 12 months, significant improvements were seen in several clinical parameters,” Dr. Fält and her associates observed in their poster at ECTRIMS. The mean baseline and 12-month values for the EDSS were 2.0 and 1.6, and for the MSSS they were 3.46 and 2.61. The mean baseline and 12-month values for the MSIS-29 Psychological subscale were 35.1 and 30.8, respectively, and for MSIS-29 Physical they were 22.7 and 17.7.

Overall, there were 14 nonserious and 11 serious adverse events, the most common of which were infections and infestations, metabolism and nutrition disorders, and immune system disorders.

“A longer follow-up period is needed to assess the real-world effectiveness and safety of alemtuzumab,” the IMSE 3 study authors noted.
 

The IMSE 5 study with dimethyl fumarate

Similarly, the authors of the IMSE 5 study (Mult Scler. 2018;24[S2]:701-2, Abstract 1234) concluded that a longer follow-up period is need to assess the real-world effectiveness of dimethyl fumarate. Selin Safer Demirbüker, also of the Karolinska Institute, and her associates looked at data on 2,108 patients treated with dimethyl fumarate between March 2014 and April 2018, of whom 1,150 were still receiving treatment at the time of their assessment.

The mean age of patients at the start of treatment was 41 years, 91% had RRMS, and 73% were female. The mean treatment duration was 22.3 months. The majority of patients (n = 867) had been previously treated with interferon and glatiramer acetate (Copaxone) prior to dimethyl fumarate, with 538 being naive to treatment.

“Dimethyl fumarate seems to have a positive effect for patients remaining on treatment,” wrote Ms. Safer Demirbüker and her colleagues. The overall 1-year drug survival reported in their abstract was 74%. Their poster showed a lower 2-year drug survival rate of 63.5% for men and 56.4% for women.

“Swedish patients show cognitive, psychological, and physical benefits after 2 or more years of treatment,” the IMSE 5 study authors further noted. Mean EDSS, MSSS, and MSIS-29 Psychological values all fell from baseline to 2 years.

Overall, 958 (47%) of patients discontinued treatment with dimethyl fumarate at some point, primarily (in 52% of cases) because of adverse events or lack of effect (29% of cases). Most patients (39%) switched to rituximab (15% had no new treatment registered), but 35% of patients continued treatment for 3 or more years.

Twelve-year follow-up of teriflunomide shows continued efficacy, safety

Mark Freedman, MD, of the University of Ottawa and the Ottawa Hospital Research Institute and his associates reported long-term follow-up data on the efficacy and safety of teriflunomide (Aubagio) in relapsing forms of MS (Mult Scler. 2018;24[S2]:700-1, Abstract P1233). After up to 12 years’ follow up, teriflunomide 14 mg was associated with an overall annualized relapse rate of 0.228.

Yearly annualized relapse rates were “low and stable,” Dr. Freedman and his coauthors from the United States, Spain, Italy, France, Germany, England, the Republic of Korea, and Australia noted in their poster.

“As of August 2018, over 93,000 patients were being treated with teriflunomide,” the authors stated. This represented a real-world exposure of approximately 186,000 patient-years up to December 2017, they added.

For the analysis, data from one phase 2 study and three phase 3 studies (TEMSO, TOWER, and TENERE) and their long-term extension studies were pooled. In all, there were 1,696 patients treated with 14 mg of teriflunomide in these studies.

Annualized relapse rates ranged from 0.321 in the first year of follow-up in the studies to 0.080 by the 12th year. The proportions of patients remaining relapse free “were high and stable (ranging from 0.75 in year 1 to 0.93 in years 8 and 9).” EDSS scores were 2.57 at baseline and 2.27 at year 12.

Importantly, no new safety signals were reported, Dr. Freedman and his colleagues wrote, adding that most adverse events were mild to moderate in severity.

Taken together, “these data demonstrate the long-term efficacy and safety of teriflunomide,” they concluded.
 

Study and author disclosures

The teriflunomide analysis was supported by Sanofi. Dr. Freedman disclosed receiving research or educational grant support from Bayer and Genzyme; honoraria/consulting fees from Bayer, Biogen, EMD Canada, Novartis, Sanofi, and Teva; and membership on company advisory boards/boards of directors/other similar groups for Bayer, Biogen, Chugai, Merck Serono, Novartis, Opexa Therapeutics, Sanofi, and Teva.

The IMSE 1 and 5 studies were supported by Biogen and the IMSE 2 and 3 studies by Novartis. The lead study authors for the IMSE studies – Dr. Kågström, Dr. Fält, and Dr. Safer Demirbüker – had nothing personal to disclose. Other authors included employees of the sponsoring companies or those who had received research funding or honoraria for consultancy work from the companies.

The VIRGILE study was supported by Novartis Pharma AG, Switzerland. Dr. Lebrun-Frenay disclosed receiving consultancy fees from Merck, Novartis, Biogen, MedDay, Roche, Teva, and Genzyme. Coauthors included Novartis employees.

BERLIN – Real-world data from six postmarketing surveillance studies suggest that currently available disease-modifying treatments (DMTs) for relapsing-remitting multiple sclerosis (RRMS) have long-lasting effects that are matched by reasonable tolerability.

solitude72/iStockphoto

Long-term efficacy and safety data on natalizumab (Tysabri), fingolimod (Gilenya), alemtuzumab (Lemtrada), dimethyl fumarate (Tecfidera), and teriflunomide (Aubagio) from four Swedish studies, one French study, and one international study were reported during a poster session on long-term treatment monitoring at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

The IMSE 1 study with natalizumab

The Immunomodulation and Multiple Sclerosis Epidemiology (IMSE) studies are Swedish postmarketing surveillance studies that were started with the launch of various DMTs in Sweden: natalizumab since 2006 (IMSE 1), fingolimod in 2015 (IMSE 2), alemtuzumab in 2014 (IMSE 3), and dimethyl fumarate in 2014 (IMSE 5).

“Postmarketing surveillance is important for determination of long-term safety and effectiveness in a real-world setting,” Stina Kågström and her associates observed in their poster reporting some findings of the IMSE 1 study with natalizumab (Mult Scler. 2018;24[S2]:699-700, Abstract P1232).

Ms. Kågström of the department of clinical neuroscience at the Karolinska Institute in Stockholm and her colleagues reported that data on 3,108 patients who were seen at 54 Swedish clinics had been collated via the nationwide Swedish Quality Registry for Neurological Care (NEUROreg). NEUROreg started out as an MS register but has since widened its remit to include other neurologic diagnoses.

For the IMSE 1 study, prospectively recorded data regarding natalizumab treatment, adverse events, JC-virus (JCV) status and clinical effectiveness measures were obtained from NEUROreg for 2,225 women and 883 men. Just over one-third (37%, n = 1,150) were still receiving natalizumab at the time of the analysis.


The mean age at which natalizumab was started was 39 years, with treatment primarily given for RRMS (81% of patients) and less often for secondary progressive multiple sclerosis (SPMS, 15%) and rarely for other types of progressive MS. The mean treatment duration was just under 4 years (47.6 months).

JCV testing was introduced in 2011 in Sweden, and this “has led to fewer treated JCV-positive patients,” the IMSE 1 study investigators reported. “This likely explains a reduced incidence of PML [progressive multifocal leukoencephalopathy],” they suggested. There were nine PML cases diagnosed in Sweden from 2008 to the data cut-off point in 2018, one of which was fatal.

JCV status from 2011 onward was available for 1,269 patients, of whom 39% were JCV positive and 61% were JCV negative. The overall drug survival rate was 72% for JCV-negative and 14% for JCV-positive patients. Improved health status was seen, as measured by the Expanded Disability Status Scale (EDSS), the Multiple Sclerosis Severity Score (MSSS), and the physical and psychological Multiple Sclerosis Impact Scale–29 (MSIS-29) components.

A total of 644 of 1,269 patients discontinued treatment with natalizumab at some point, of whom 67% discontinued because of being JCV positive. The main reason for discontinuation in JCV-negative patients was pregnancy or planning a pregnancy (38%), with lack of effect (10%) and adverse events (11%) as other key reasons for stopping natalizumab.

Ms. Kågström and her associates concluded that natalizumab was “generally well tolerated with sustained effectiveness.”

The IMSE 2 study with fingolimod

Data on the long-term safety and efficacy of fingolimod were reported from the IMSE 2 study (Mult Scler. 2018;24[S2]:696-7, Abstract P1228). Lead author Anna Fält, also of the Karolinska Institute, and her associates analyzed data for 1,634 patients who had been treated with fingolimod from June 2015 to September 2018.

Most patients were older than 30 years (79%), and those aged 30 and older were predominantly female (69%), had an RRMS diagnosis (88%), and been treated for a mean of about 3 years (37 months). A total of 829 were being treated with fingolimod at the time of the analysis, with 844 having discontinued treatment at some point. The main reason for discontinuing treatment with fingolimod was a lack of effect (42% of cases) or an adverse effect (34%). The IMSE 2 study authors reported in their abstract that most patients were switched to rituximab after discontinuing fingolimod.

The number of relapses per 1,000 patient-years was reduced by fingolimod treatment from 280 to 82, comparing before and during treatment for all age groups studied. Relapse rate dropped from 694 per 1,000 patient-years before treatment to 138 during treatment in patients aged 20 years or younger, from 454 to 122 in those aged 21-30 years, and from 257 to 72 in those older than 31 years.

After 1 year of treatment, improvements were seen in the health status of patients as measured by various scales, including the EDSS, MSSS, MSIS-29 Physical, and MSIS-29 Psychological. When the researchers analyzed data by age groups, significant improvements were seen in patients aged 21-30 years and older than 30 years.

Ninety nonserious and 62 serious adverse events were reported in fingolimod-treated patients during the time of analysis. Of the latter, 13 serious adverse events involved cardiac disorders, 12 neoplasms, and 10 infections and infestations.

Overall, the IMSE 2 study investigators said that fingolimod was generally tolerable and reduced disease activity in MS.
 

French experience with fingolimod: The VIRGILE study

Real-world data on the long-term safety and efficacy of fingolimod in France from the VIRGILE study were reported by Christine Lebrun-Frenay, MD, PhD, and her associates (Mult Scler. 2018;24[S2]:698-9, Abstract P1231).

Dr. Lebrun-Frenay of Pasteur 2 Hospital in Nice and her coauthors noted that VIRGILE study included patients starting treatment with fingolimod between January 2014 and February 2016. A total of 1,047 patients were included, and another 330 patients treated with natalizumab were included at the behest of the French health authorities.

The annualized relapse rate after 2 years of follow-up was 0.30 in the fingolimod group. Dr. Lebrun-Frenay and her colleagues noted: “The 3-year data from this interim analysis provide evidence for sustained efficacy of fingolimod.” Indeed, they report that almost 60% of patients did not relapse and 64% had no worsening of disease. On average, EDSS was stable during the 3-year follow-up period.

“Safety and tolerability profiles of fingolimod were in line with previous clinical experience, with lymphopenia being the most frequent AE [adverse event] reported,” they added.
 

The IMSE 3 study with alemtuzumab

Long-term experience with alemtuzumab as a treatment for RRMS in the real-world setting is more limited as it only became available for use for this indication in 2014, but some insight is provided by the results of the IMSE 3 study (Mult Scler. 2018;24[S2]:706-7, Abstract P1240).

In total, there were 113 patients treated with alemtuzumab; the vast majority (94%) had RRMS and were aged a mean of 34 years at the start of treatment. Treatment was for more than 12 months in 101 patients, more than 24 months in 86 patients, and more than 36 months in 36 patients.

“In patients treated for at least 12 months, significant improvements were seen in several clinical parameters,” Dr. Fält and her associates observed in their poster at ECTRIMS. The mean baseline and 12-month values for the EDSS were 2.0 and 1.6, and for the MSSS they were 3.46 and 2.61. The mean baseline and 12-month values for the MSIS-29 Psychological subscale were 35.1 and 30.8, respectively, and for MSIS-29 Physical they were 22.7 and 17.7.

Overall, there were 14 nonserious and 11 serious adverse events, the most common of which were infections and infestations, metabolism and nutrition disorders, and immune system disorders.

“A longer follow-up period is needed to assess the real-world effectiveness and safety of alemtuzumab,” the IMSE 3 study authors noted.
 

The IMSE 5 study with dimethyl fumarate

Similarly, the authors of the IMSE 5 study (Mult Scler. 2018;24[S2]:701-2, Abstract 1234) concluded that a longer follow-up period is need to assess the real-world effectiveness of dimethyl fumarate. Selin Safer Demirbüker, also of the Karolinska Institute, and her associates looked at data on 2,108 patients treated with dimethyl fumarate between March 2014 and April 2018, of whom 1,150 were still receiving treatment at the time of their assessment.

The mean age of patients at the start of treatment was 41 years, 91% had RRMS, and 73% were female. The mean treatment duration was 22.3 months. The majority of patients (n = 867) had been previously treated with interferon and glatiramer acetate (Copaxone) prior to dimethyl fumarate, with 538 being naive to treatment.

“Dimethyl fumarate seems to have a positive effect for patients remaining on treatment,” wrote Ms. Safer Demirbüker and her colleagues. The overall 1-year drug survival reported in their abstract was 74%. Their poster showed a lower 2-year drug survival rate of 63.5% for men and 56.4% for women.

“Swedish patients show cognitive, psychological, and physical benefits after 2 or more years of treatment,” the IMSE 5 study authors further noted. Mean EDSS, MSSS, and MSIS-29 Psychological values all fell from baseline to 2 years.

Overall, 958 (47%) of patients discontinued treatment with dimethyl fumarate at some point, primarily (in 52% of cases) because of adverse events or lack of effect (29% of cases). Most patients (39%) switched to rituximab (15% had no new treatment registered), but 35% of patients continued treatment for 3 or more years.

Twelve-year follow-up of teriflunomide shows continued efficacy, safety

Mark Freedman, MD, of the University of Ottawa and the Ottawa Hospital Research Institute and his associates reported long-term follow-up data on the efficacy and safety of teriflunomide (Aubagio) in relapsing forms of MS (Mult Scler. 2018;24[S2]:700-1, Abstract P1233). After up to 12 years’ follow up, teriflunomide 14 mg was associated with an overall annualized relapse rate of 0.228.

Yearly annualized relapse rates were “low and stable,” Dr. Freedman and his coauthors from the United States, Spain, Italy, France, Germany, England, the Republic of Korea, and Australia noted in their poster.

“As of August 2018, over 93,000 patients were being treated with teriflunomide,” the authors stated. This represented a real-world exposure of approximately 186,000 patient-years up to December 2017, they added.

For the analysis, data from one phase 2 study and three phase 3 studies (TEMSO, TOWER, and TENERE) and their long-term extension studies were pooled. In all, there were 1,696 patients treated with 14 mg of teriflunomide in these studies.

Annualized relapse rates ranged from 0.321 in the first year of follow-up in the studies to 0.080 by the 12th year. The proportions of patients remaining relapse free “were high and stable (ranging from 0.75 in year 1 to 0.93 in years 8 and 9).” EDSS scores were 2.57 at baseline and 2.27 at year 12.

Importantly, no new safety signals were reported, Dr. Freedman and his colleagues wrote, adding that most adverse events were mild to moderate in severity.

Taken together, “these data demonstrate the long-term efficacy and safety of teriflunomide,” they concluded.
 

Study and author disclosures

The teriflunomide analysis was supported by Sanofi. Dr. Freedman disclosed receiving research or educational grant support from Bayer and Genzyme; honoraria/consulting fees from Bayer, Biogen, EMD Canada, Novartis, Sanofi, and Teva; and membership on company advisory boards/boards of directors/other similar groups for Bayer, Biogen, Chugai, Merck Serono, Novartis, Opexa Therapeutics, Sanofi, and Teva.

The IMSE 1 and 5 studies were supported by Biogen and the IMSE 2 and 3 studies by Novartis. The lead study authors for the IMSE studies – Dr. Kågström, Dr. Fält, and Dr. Safer Demirbüker – had nothing personal to disclose. Other authors included employees of the sponsoring companies or those who had received research funding or honoraria for consultancy work from the companies.

The VIRGILE study was supported by Novartis Pharma AG, Switzerland. Dr. Lebrun-Frenay disclosed receiving consultancy fees from Merck, Novartis, Biogen, MedDay, Roche, Teva, and Genzyme. Coauthors included Novartis employees.

BERLIN – Real-world data from six postmarketing surveillance studies suggest that currently available disease-modifying treatments (DMTs) for relapsing-remitting multiple sclerosis (RRMS) have long-lasting effects that are matched by reasonable tolerability.

solitude72/iStockphoto

Long-term efficacy and safety data on natalizumab (Tysabri), fingolimod (Gilenya), alemtuzumab (Lemtrada), dimethyl fumarate (Tecfidera), and teriflunomide (Aubagio) from four Swedish studies, one French study, and one international study were reported during a poster session on long-term treatment monitoring at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

The IMSE 1 study with natalizumab

The Immunomodulation and Multiple Sclerosis Epidemiology (IMSE) studies are Swedish postmarketing surveillance studies that were started with the launch of various DMTs in Sweden: natalizumab since 2006 (IMSE 1), fingolimod in 2015 (IMSE 2), alemtuzumab in 2014 (IMSE 3), and dimethyl fumarate in 2014 (IMSE 5).

“Postmarketing surveillance is important for determination of long-term safety and effectiveness in a real-world setting,” Stina Kågström and her associates observed in their poster reporting some findings of the IMSE 1 study with natalizumab (Mult Scler. 2018;24[S2]:699-700, Abstract P1232).

Ms. Kågström of the department of clinical neuroscience at the Karolinska Institute in Stockholm and her colleagues reported that data on 3,108 patients who were seen at 54 Swedish clinics had been collated via the nationwide Swedish Quality Registry for Neurological Care (NEUROreg). NEUROreg started out as an MS register but has since widened its remit to include other neurologic diagnoses.

For the IMSE 1 study, prospectively recorded data regarding natalizumab treatment, adverse events, JC-virus (JCV) status and clinical effectiveness measures were obtained from NEUROreg for 2,225 women and 883 men. Just over one-third (37%, n = 1,150) were still receiving natalizumab at the time of the analysis.


The mean age at which natalizumab was started was 39 years, with treatment primarily given for RRMS (81% of patients) and less often for secondary progressive multiple sclerosis (SPMS, 15%) and rarely for other types of progressive MS. The mean treatment duration was just under 4 years (47.6 months).

JCV testing was introduced in 2011 in Sweden, and this “has led to fewer treated JCV-positive patients,” the IMSE 1 study investigators reported. “This likely explains a reduced incidence of PML [progressive multifocal leukoencephalopathy],” they suggested. There were nine PML cases diagnosed in Sweden from 2008 to the data cut-off point in 2018, one of which was fatal.

JCV status from 2011 onward was available for 1,269 patients, of whom 39% were JCV positive and 61% were JCV negative. The overall drug survival rate was 72% for JCV-negative and 14% for JCV-positive patients. Improved health status was seen, as measured by the Expanded Disability Status Scale (EDSS), the Multiple Sclerosis Severity Score (MSSS), and the physical and psychological Multiple Sclerosis Impact Scale–29 (MSIS-29) components.

A total of 644 of 1,269 patients discontinued treatment with natalizumab at some point, of whom 67% discontinued because of being JCV positive. The main reason for discontinuation in JCV-negative patients was pregnancy or planning a pregnancy (38%), with lack of effect (10%) and adverse events (11%) as other key reasons for stopping natalizumab.

Ms. Kågström and her associates concluded that natalizumab was “generally well tolerated with sustained effectiveness.”

The IMSE 2 study with fingolimod

Data on the long-term safety and efficacy of fingolimod were reported from the IMSE 2 study (Mult Scler. 2018;24[S2]:696-7, Abstract P1228). Lead author Anna Fält, also of the Karolinska Institute, and her associates analyzed data for 1,634 patients who had been treated with fingolimod from June 2015 to September 2018.

Most patients were older than 30 years (79%), and those aged 30 and older were predominantly female (69%), had an RRMS diagnosis (88%), and been treated for a mean of about 3 years (37 months). A total of 829 were being treated with fingolimod at the time of the analysis, with 844 having discontinued treatment at some point. The main reason for discontinuing treatment with fingolimod was a lack of effect (42% of cases) or an adverse effect (34%). The IMSE 2 study authors reported in their abstract that most patients were switched to rituximab after discontinuing fingolimod.

The number of relapses per 1,000 patient-years was reduced by fingolimod treatment from 280 to 82, comparing before and during treatment for all age groups studied. Relapse rate dropped from 694 per 1,000 patient-years before treatment to 138 during treatment in patients aged 20 years or younger, from 454 to 122 in those aged 21-30 years, and from 257 to 72 in those older than 31 years.

After 1 year of treatment, improvements were seen in the health status of patients as measured by various scales, including the EDSS, MSSS, MSIS-29 Physical, and MSIS-29 Psychological. When the researchers analyzed data by age groups, significant improvements were seen in patients aged 21-30 years and older than 30 years.

Ninety nonserious and 62 serious adverse events were reported in fingolimod-treated patients during the time of analysis. Of the latter, 13 serious adverse events involved cardiac disorders, 12 neoplasms, and 10 infections and infestations.

Overall, the IMSE 2 study investigators said that fingolimod was generally tolerable and reduced disease activity in MS.
 

French experience with fingolimod: The VIRGILE study

Real-world data on the long-term safety and efficacy of fingolimod in France from the VIRGILE study were reported by Christine Lebrun-Frenay, MD, PhD, and her associates (Mult Scler. 2018;24[S2]:698-9, Abstract P1231).

Dr. Lebrun-Frenay of Pasteur 2 Hospital in Nice and her coauthors noted that VIRGILE study included patients starting treatment with fingolimod between January 2014 and February 2016. A total of 1,047 patients were included, and another 330 patients treated with natalizumab were included at the behest of the French health authorities.

The annualized relapse rate after 2 years of follow-up was 0.30 in the fingolimod group. Dr. Lebrun-Frenay and her colleagues noted: “The 3-year data from this interim analysis provide evidence for sustained efficacy of fingolimod.” Indeed, they report that almost 60% of patients did not relapse and 64% had no worsening of disease. On average, EDSS was stable during the 3-year follow-up period.

“Safety and tolerability profiles of fingolimod were in line with previous clinical experience, with lymphopenia being the most frequent AE [adverse event] reported,” they added.
 

The IMSE 3 study with alemtuzumab

Long-term experience with alemtuzumab as a treatment for RRMS in the real-world setting is more limited as it only became available for use for this indication in 2014, but some insight is provided by the results of the IMSE 3 study (Mult Scler. 2018;24[S2]:706-7, Abstract P1240).

In total, there were 113 patients treated with alemtuzumab; the vast majority (94%) had RRMS and were aged a mean of 34 years at the start of treatment. Treatment was for more than 12 months in 101 patients, more than 24 months in 86 patients, and more than 36 months in 36 patients.

“In patients treated for at least 12 months, significant improvements were seen in several clinical parameters,” Dr. Fält and her associates observed in their poster at ECTRIMS. The mean baseline and 12-month values for the EDSS were 2.0 and 1.6, and for the MSSS they were 3.46 and 2.61. The mean baseline and 12-month values for the MSIS-29 Psychological subscale were 35.1 and 30.8, respectively, and for MSIS-29 Physical they were 22.7 and 17.7.

Overall, there were 14 nonserious and 11 serious adverse events, the most common of which were infections and infestations, metabolism and nutrition disorders, and immune system disorders.

“A longer follow-up period is needed to assess the real-world effectiveness and safety of alemtuzumab,” the IMSE 3 study authors noted.
 

The IMSE 5 study with dimethyl fumarate

Similarly, the authors of the IMSE 5 study (Mult Scler. 2018;24[S2]:701-2, Abstract 1234) concluded that a longer follow-up period is need to assess the real-world effectiveness of dimethyl fumarate. Selin Safer Demirbüker, also of the Karolinska Institute, and her associates looked at data on 2,108 patients treated with dimethyl fumarate between March 2014 and April 2018, of whom 1,150 were still receiving treatment at the time of their assessment.

The mean age of patients at the start of treatment was 41 years, 91% had RRMS, and 73% were female. The mean treatment duration was 22.3 months. The majority of patients (n = 867) had been previously treated with interferon and glatiramer acetate (Copaxone) prior to dimethyl fumarate, with 538 being naive to treatment.

“Dimethyl fumarate seems to have a positive effect for patients remaining on treatment,” wrote Ms. Safer Demirbüker and her colleagues. The overall 1-year drug survival reported in their abstract was 74%. Their poster showed a lower 2-year drug survival rate of 63.5% for men and 56.4% for women.

“Swedish patients show cognitive, psychological, and physical benefits after 2 or more years of treatment,” the IMSE 5 study authors further noted. Mean EDSS, MSSS, and MSIS-29 Psychological values all fell from baseline to 2 years.

Overall, 958 (47%) of patients discontinued treatment with dimethyl fumarate at some point, primarily (in 52% of cases) because of adverse events or lack of effect (29% of cases). Most patients (39%) switched to rituximab (15% had no new treatment registered), but 35% of patients continued treatment for 3 or more years.

Twelve-year follow-up of teriflunomide shows continued efficacy, safety

Mark Freedman, MD, of the University of Ottawa and the Ottawa Hospital Research Institute and his associates reported long-term follow-up data on the efficacy and safety of teriflunomide (Aubagio) in relapsing forms of MS (Mult Scler. 2018;24[S2]:700-1, Abstract P1233). After up to 12 years’ follow up, teriflunomide 14 mg was associated with an overall annualized relapse rate of 0.228.

Yearly annualized relapse rates were “low and stable,” Dr. Freedman and his coauthors from the United States, Spain, Italy, France, Germany, England, the Republic of Korea, and Australia noted in their poster.

“As of August 2018, over 93,000 patients were being treated with teriflunomide,” the authors stated. This represented a real-world exposure of approximately 186,000 patient-years up to December 2017, they added.

For the analysis, data from one phase 2 study and three phase 3 studies (TEMSO, TOWER, and TENERE) and their long-term extension studies were pooled. In all, there were 1,696 patients treated with 14 mg of teriflunomide in these studies.

Annualized relapse rates ranged from 0.321 in the first year of follow-up in the studies to 0.080 by the 12th year. The proportions of patients remaining relapse free “were high and stable (ranging from 0.75 in year 1 to 0.93 in years 8 and 9).” EDSS scores were 2.57 at baseline and 2.27 at year 12.

Importantly, no new safety signals were reported, Dr. Freedman and his colleagues wrote, adding that most adverse events were mild to moderate in severity.

Taken together, “these data demonstrate the long-term efficacy and safety of teriflunomide,” they concluded.
 

Study and author disclosures

The teriflunomide analysis was supported by Sanofi. Dr. Freedman disclosed receiving research or educational grant support from Bayer and Genzyme; honoraria/consulting fees from Bayer, Biogen, EMD Canada, Novartis, Sanofi, and Teva; and membership on company advisory boards/boards of directors/other similar groups for Bayer, Biogen, Chugai, Merck Serono, Novartis, Opexa Therapeutics, Sanofi, and Teva.

The IMSE 1 and 5 studies were supported by Biogen and the IMSE 2 and 3 studies by Novartis. The lead study authors for the IMSE studies – Dr. Kågström, Dr. Fält, and Dr. Safer Demirbüker – had nothing personal to disclose. Other authors included employees of the sponsoring companies or those who had received research funding or honoraria for consultancy work from the companies.

The VIRGILE study was supported by Novartis Pharma AG, Switzerland. Dr. Lebrun-Frenay disclosed receiving consultancy fees from Merck, Novartis, Biogen, MedDay, Roche, Teva, and Genzyme. Coauthors included Novartis employees.

Infusion of allogeneic BK virus-specific T cells may be an effective treatment for patients with progressive multifocal leukoencephalopathy (PML), according to a report in the October 11 New England Journal of Medicine. The infusion cleared JC virus from the CSF of two patients and reduced viral load in the third, reported lead author Muharrem Muftuoglu, MD, of the Department of Stem Cell Transplantation and Cellular Therapy at the University of Texas MD Anderson Cancer Center in Houston, and colleagues. One of the patients completely recovered and returned to work; this outcome was unprecedented in PML therapy.

“Several approaches for the treatment of PML, including the use of antiviral medications and mirtazapine, have been tested, with poor results,” the investigators said. Although virus-specific T-cell infusion is a novel approach to treating PML, this method has been used for other conditions. “Several groups, including ours, have successfully used viral-specific T cells to treat BK virus infection after stem-cell transplantation,” the investigators said. “Because BK virus and JC virus are genetically similar to one another and share a number of immunogenic proteins with a substantial degree of sequence homology ... we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”

This hypothesis proved correct. The investigators infused three patients with PML with “cryopreserved, third-party–produced, viral-specific T cells that had been designed for the treatment of patients with BK virus infection after stem-cell transplantation.” Each patient presented with a different condition and PML-precipitating therapy. The first patient was a 32-year-old woman with high-risk acute myeloid leukemia who had received a cord-blood transplantation, the second a 73-year-old woman with JAK2-positive myeloproliferative neoplasia on ruxolitinib therapy, and the third a 35-year-old man with HIV who had received highly active antiretroviral therapy.

T-cell infusions cleared JC virus from the CSF of the woman with leukemia (three infusions) and the man with HIV (four infusions). These patients recovered to different degrees.The woman had full resolution of symptoms, while the man had slurred speech and walked with a cane. Treatment reduced JC viral load in the elderly woman with myeloproliferative neoplasia (two infusions), but she did not clear the virus and died about eight months later.

No adverse events occurred, but two patients developed immune reconstitution inflammatory syndrome. This outcome was likely caused by the T-cell infusion, since absolute T-cell counts remained steady and white matter enhancement was detected on MRI within four weeks of treatment. Still, the investigators were optimistic about future potential.

“Third-party–produced, ‘off-the-shelf,’ partially HLA-matched, BK virus–specific T cells may serve as therapy for PML,” the investigators concluded. “Further study in a larger group of patients is required to determine the success rate, durability, and longer-term adverse events associated with this treatment.”

The study was funded by the MD Anderson Cancer Center Moon Shots Program and the National Institutes of Health.

—Will Pass

Suggested Reading

Muftuoglu M, Olson A, Marin D, et al. Allogeneic BK specific T cells for progressive multifocal leukoencephalopathy. N Engl J Med. 2018;379(15):1443-1451.

Infusion of allogeneic BK virus-specific T cells may be an effective treatment for patients with progressive multifocal leukoencephalopathy (PML), according to a report in the October 11 New England Journal of Medicine. The infusion cleared JC virus from the CSF of two patients and reduced viral load in the third, reported lead author Muharrem Muftuoglu, MD, of the Department of Stem Cell Transplantation and Cellular Therapy at the University of Texas MD Anderson Cancer Center in Houston, and colleagues. One of the patients completely recovered and returned to work; this outcome was unprecedented in PML therapy.

“Several approaches for the treatment of PML, including the use of antiviral medications and mirtazapine, have been tested, with poor results,” the investigators said. Although virus-specific T-cell infusion is a novel approach to treating PML, this method has been used for other conditions. “Several groups, including ours, have successfully used viral-specific T cells to treat BK virus infection after stem-cell transplantation,” the investigators said. “Because BK virus and JC virus are genetically similar to one another and share a number of immunogenic proteins with a substantial degree of sequence homology ... we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”

This hypothesis proved correct. The investigators infused three patients with PML with “cryopreserved, third-party–produced, viral-specific T cells that had been designed for the treatment of patients with BK virus infection after stem-cell transplantation.” Each patient presented with a different condition and PML-precipitating therapy. The first patient was a 32-year-old woman with high-risk acute myeloid leukemia who had received a cord-blood transplantation, the second a 73-year-old woman with JAK2-positive myeloproliferative neoplasia on ruxolitinib therapy, and the third a 35-year-old man with HIV who had received highly active antiretroviral therapy.

T-cell infusions cleared JC virus from the CSF of the woman with leukemia (three infusions) and the man with HIV (four infusions). These patients recovered to different degrees.The woman had full resolution of symptoms, while the man had slurred speech and walked with a cane. Treatment reduced JC viral load in the elderly woman with myeloproliferative neoplasia (two infusions), but she did not clear the virus and died about eight months later.

No adverse events occurred, but two patients developed immune reconstitution inflammatory syndrome. This outcome was likely caused by the T-cell infusion, since absolute T-cell counts remained steady and white matter enhancement was detected on MRI within four weeks of treatment. Still, the investigators were optimistic about future potential.

“Third-party–produced, ‘off-the-shelf,’ partially HLA-matched, BK virus–specific T cells may serve as therapy for PML,” the investigators concluded. “Further study in a larger group of patients is required to determine the success rate, durability, and longer-term adverse events associated with this treatment.”

The study was funded by the MD Anderson Cancer Center Moon Shots Program and the National Institutes of Health.

—Will Pass

Suggested Reading

Muftuoglu M, Olson A, Marin D, et al. Allogeneic BK specific T cells for progressive multifocal leukoencephalopathy. N Engl J Med. 2018;379(15):1443-1451.

Infusion of allogeneic BK virus-specific T cells may be an effective treatment for patients with progressive multifocal leukoencephalopathy (PML), according to a report in the October 11 New England Journal of Medicine. The infusion cleared JC virus from the CSF of two patients and reduced viral load in the third, reported lead author Muharrem Muftuoglu, MD, of the Department of Stem Cell Transplantation and Cellular Therapy at the University of Texas MD Anderson Cancer Center in Houston, and colleagues. One of the patients completely recovered and returned to work; this outcome was unprecedented in PML therapy.

“Several approaches for the treatment of PML, including the use of antiviral medications and mirtazapine, have been tested, with poor results,” the investigators said. Although virus-specific T-cell infusion is a novel approach to treating PML, this method has been used for other conditions. “Several groups, including ours, have successfully used viral-specific T cells to treat BK virus infection after stem-cell transplantation,” the investigators said. “Because BK virus and JC virus are genetically similar to one another and share a number of immunogenic proteins with a substantial degree of sequence homology ... we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”

This hypothesis proved correct. The investigators infused three patients with PML with “cryopreserved, third-party–produced, viral-specific T cells that had been designed for the treatment of patients with BK virus infection after stem-cell transplantation.” Each patient presented with a different condition and PML-precipitating therapy. The first patient was a 32-year-old woman with high-risk acute myeloid leukemia who had received a cord-blood transplantation, the second a 73-year-old woman with JAK2-positive myeloproliferative neoplasia on ruxolitinib therapy, and the third a 35-year-old man with HIV who had received highly active antiretroviral therapy.

T-cell infusions cleared JC virus from the CSF of the woman with leukemia (three infusions) and the man with HIV (four infusions). These patients recovered to different degrees.The woman had full resolution of symptoms, while the man had slurred speech and walked with a cane. Treatment reduced JC viral load in the elderly woman with myeloproliferative neoplasia (two infusions), but she did not clear the virus and died about eight months later.

No adverse events occurred, but two patients developed immune reconstitution inflammatory syndrome. This outcome was likely caused by the T-cell infusion, since absolute T-cell counts remained steady and white matter enhancement was detected on MRI within four weeks of treatment. Still, the investigators were optimistic about future potential.

“Third-party–produced, ‘off-the-shelf,’ partially HLA-matched, BK virus–specific T cells may serve as therapy for PML,” the investigators concluded. “Further study in a larger group of patients is required to determine the success rate, durability, and longer-term adverse events associated with this treatment.”

The study was funded by the MD Anderson Cancer Center Moon Shots Program and the National Institutes of Health.

—Will Pass

Suggested Reading

Muftuoglu M, Olson A, Marin D, et al. Allogeneic BK specific T cells for progressive multifocal leukoencephalopathy. N Engl J Med. 2018;379(15):1443-1451.

Myth: Psoriasis Is Only a Skin Problem

Psoriasis is predominantly regarded as a skin disease because of the outward clinical presentation of the condition. However, psoriasis is a disorder of the immune system and its damage may be more than skin deep.

Psoriasis commonly presents on the skin and nails, but a growing body of evidence has suggested that psoriasis is associated with systemic comorbidities. Up to 25% of psoriasis patients develop joint inflammation, and psoriatic arthritis (PsA) may precede skin involvement. There also is a risk for cardiovascular complications. Because of the emotional distress caused by psoriasis, patients may develop psychosocial disorders. Other conditions in patients with psoriasis include diabetes mellitus, high blood pressure, Crohn disease, and the metabolic syndrome.

Results from surveys conducted by the National Psoriasis Foundation from 2003 to 2011 found that the diagnosis of psoriasis preceded PsA in the majority of patients by a mean period of 14.6 years. Patients with moderate to severe psoriasis were more likely to develop PsA than patients with mild psoriasis. Furthermore, patients with severe psoriasis were more likely to develop diabetes mellitus and cardiovascular disease.

In a Cutis editorial, Dr. Jeffrey Weinberg emphasizes that the role of the dermatologist “is to identify and educate patients with psoriasis who are at risk of systemic complications and ensure appropriate follow-up for their treatment and overall health.” An infographic created by the American Academy of Dermatology illustrates areas of the body that may be impacted by psoriasis beyond the skin; for example, patients may develop eye problems, weight gain, or mood changes. Consider distributing this infographic to patients to show how psoriasis can affect more than their skin.

More Cutis content is available on psoriasis comorbidities:

• Do Psoriasis Patients Engage In Vigorous Physical Activity?
• The Role of Biologic Therapy for Psoriasis in Cardiovascular Risk Reduction
• VIDEO: Psoriasis and Internal Disease
• Uveitis and Psoriasis
• VIDEO: Update on Psoriasis Comorbidities

Myth: Psoriasis Is Only a Skin Problem

Psoriasis is predominantly regarded as a skin disease because of the outward clinical presentation of the condition. However, psoriasis is a disorder of the immune system and its damage may be more than skin deep.

Psoriasis commonly presents on the skin and nails, but a growing body of evidence has suggested that psoriasis is associated with systemic comorbidities. Up to 25% of psoriasis patients develop joint inflammation, and psoriatic arthritis (PsA) may precede skin involvement. There also is a risk for cardiovascular complications. Because of the emotional distress caused by psoriasis, patients may develop psychosocial disorders. Other conditions in patients with psoriasis include diabetes mellitus, high blood pressure, Crohn disease, and the metabolic syndrome.

Results from surveys conducted by the National Psoriasis Foundation from 2003 to 2011 found that the diagnosis of psoriasis preceded PsA in the majority of patients by a mean period of 14.6 years. Patients with moderate to severe psoriasis were more likely to develop PsA than patients with mild psoriasis. Furthermore, patients with severe psoriasis were more likely to develop diabetes mellitus and cardiovascular disease.

In a Cutis editorial, Dr. Jeffrey Weinberg emphasizes that the role of the dermatologist “is to identify and educate patients with psoriasis who are at risk of systemic complications and ensure appropriate follow-up for their treatment and overall health.” An infographic created by the American Academy of Dermatology illustrates areas of the body that may be impacted by psoriasis beyond the skin; for example, patients may develop eye problems, weight gain, or mood changes. Consider distributing this infographic to patients to show how psoriasis can affect more than their skin.

More Cutis content is available on psoriasis comorbidities:

• Do Psoriasis Patients Engage In Vigorous Physical Activity?
• The Role of Biologic Therapy for Psoriasis in Cardiovascular Risk Reduction
• VIDEO: Psoriasis and Internal Disease
• Uveitis and Psoriasis
• VIDEO: Update on Psoriasis Comorbidities

Myth: Psoriasis Is Only a Skin Problem

Psoriasis is predominantly regarded as a skin disease because of the outward clinical presentation of the condition. However, psoriasis is a disorder of the immune system and its damage may be more than skin deep.

Psoriasis commonly presents on the skin and nails, but a growing body of evidence has suggested that psoriasis is associated with systemic comorbidities. Up to 25% of psoriasis patients develop joint inflammation, and psoriatic arthritis (PsA) may precede skin involvement. There also is a risk for cardiovascular complications. Because of the emotional distress caused by psoriasis, patients may develop psychosocial disorders. Other conditions in patients with psoriasis include diabetes mellitus, high blood pressure, Crohn disease, and the metabolic syndrome.

Results from surveys conducted by the National Psoriasis Foundation from 2003 to 2011 found that the diagnosis of psoriasis preceded PsA in the majority of patients by a mean period of 14.6 years. Patients with moderate to severe psoriasis were more likely to develop PsA than patients with mild psoriasis. Furthermore, patients with severe psoriasis were more likely to develop diabetes mellitus and cardiovascular disease.

In a Cutis editorial, Dr. Jeffrey Weinberg emphasizes that the role of the dermatologist “is to identify and educate patients with psoriasis who are at risk of systemic complications and ensure appropriate follow-up for their treatment and overall health.” An infographic created by the American Academy of Dermatology illustrates areas of the body that may be impacted by psoriasis beyond the skin; for example, patients may develop eye problems, weight gain, or mood changes. Consider distributing this infographic to patients to show how psoriasis can affect more than their skin.

More Cutis content is available on psoriasis comorbidities:

• Do Psoriasis Patients Engage In Vigorous Physical Activity?
• The Role of Biologic Therapy for Psoriasis in Cardiovascular Risk Reduction
• VIDEO: Psoriasis and Internal Disease
• Uveitis and Psoriasis
• VIDEO: Update on Psoriasis Comorbidities

BERLIN – In the changing multiple sclerosis landscape, more women are having babies, and more are asking questions. With these women, what’s the best way to address the complicated interplay among pregnancy, relapse risk, breastfeeding, and medication resumption? A starting point is to recognize that “women with MS are very different today than they were 25 years ago,” said Annette Langer-Gould, MD, PhD. Not only have diagnostic criteria changed but also highly effective treatments now exist that were not available when the first pregnancy cohorts were studied, she pointed out, speaking at the annual congress of the European Committee on Treatment and Research in Multiple Sclerosis.

SelectStock/Getty Images

The existing literature, said Dr. Langer-Gould, has addressed one controversy: “Most women with MS can have normal pregnancies – and breastfeed – without incurring harm,” though it’s true that severe rebound relapses are possible if natalizumab (Tysabri) or fingolimod (Gilenya) are stopped before pregnancy. In any case, new small-molecule MS medications need to be stopped during pregnancy and breastfeeding, she pointed out. “We didn’t have to worry about that too much when we only had injectables and monoclonal antibodies because they were larger and didn’t cross the placenta.”

Since the 1980s, the conversation about pregnancy and MS has moved from asking “Is pregnancy bad for women with MS?” to the current MS landscape, in which sicker women are able to become pregnant, Dr. Langer-Gould said, adding that how women with MS fare through pregnancy and in the postpartum period is changing over time as well. She and her colleagues’ experience with pregnancy in a cohort of women with MS in the Kaiser Permanente care system, where she is a clinical neurologist and regional research lead, revealed a relapse rate of 8.4%. “So it was pretty rare for a woman to have a relapse during pregnancy,” Dr. Langer-Gould said.

Most women with MS who become pregnant, whether their care is received in a referral center or is community based, are now doing so while on a disease-modifying therapy (DMT), Dr. Langer-Gould said. On these highly effective treatments, “women who were too sick to get pregnant are now well controlled and having babies.”

As more women with MS become pregnant, more conversations about breastfeeding will inevitably crop up, she said. And the discussion about breastfeeding has now begun to acknowledge the “strong benefits to mom and the baby of not just breastfeeding, but longer breastfeeding,” as well.

“Because of this baby-friendly push in a lot of hospitals in the United States, where they’re trying to encourage all women to breastfeed,” a full 87% of women breastfed their infants at least some of the time, and over a third of women (35%) breastfed exclusively for at least 2 months, Dr. Langer-Gould said.

“There’s no one clear explanation of why the women seem to be healthier and doing better through pregnancy as a group, but it’s probably a combination of having milder disease, breastfeeding more, and they’ve got better controlled disease before pregnancy,” she said.


At least eight studies to date have examined the relationship between postpartum MS relapses and breastfeeding, Dr. Langer-Gould said.

“The thing to take away ... is that, even though we’ve studied this many, many times, no one can show that it’s harmful,” she said. For mothers who want to breastfeed, “you can support them in the breastfeeding choice, because they are not going to have more severe disease because of that.”

Whether breastfeeding is exclusive or not has not always been tracked in studies of childbearing women with MS, but when it was captured in the data, exclusive breastfeeding has exerted a protective effect, with about a 50% reduction in risk for postpartum relapse seen in one study (JAMA Neurol. 2015 Oct;72[10]:1132-8).

There is a hormonal rationale for exclusive breastfeeding exerting a protective effect on MS: With exclusive breastfeeding comes more frequent, intense suckling, with more profound elevations in prolactin, and larger drops in follicle-stimulating hormone, luteinizing hormone, progesterone, and estradiol. All these hormonal changes work together to produce more prolonged amenorrhea and anovulation, Dr. Langer-Gould said, with potentially beneficial immunologic effects.

When other, more general maternal and infant health benefits of breastfeeding also are taken into account, there’s strong evidence for the benefits of breastfeeding for women with MS whose medication profile allows them to breastfeed, she said.

However, the “treatment” effect of exclusive breastfeeding is only effective until the infant starts taking regular supplemental feedings, including the introduction of table food at around 6 months of age. “Once regular supplemental feedings are introduced, relapses return,” Dr. Langer-Gould said.

There is some suggestion that, in women without MS, prolonged breastfeeding may be associated with reduced risk of MS. In the MS Sunshine study, breastfeeding for 15 months or longer decreased the risk of later MS by 23%-53% (Nutrients. 2018 Feb 27;10[3]:268). The investigators, led by Dr. Langer-Gould, summed the total months of breastfeeding across all children, so that the 15-month threshold could be reached by breastfeeding one child for 15 months, or three children for 5 months each. “It’s a single study; I wouldn’t make too much out of it,” Dr. Langer-Gould said.

Open questions still remain, she said: “So far, no one has been able to demonstrate a clear beneficial effect in reducing the risk of postpartum relapse if they resume their DMT early in the postpartum period.” Dr. Langer-Gould noted that the literature in this area is hampered by heterogeneity and by the fact that newer, more highly active DMTs have not been well studied.

Also, the link between postpartum relapses and long-term prognosis is not completely delineated. Indirect evidence, she said, points to a postpartum relapse as being “overall, a low-impact event.”

Dr. Langer-Gould reported that she has been the site principal investigator for clinical trials sponsored by Roche and Biogen.

[email protected]

SOURCE: Langer-Gould A. ECTRIMS 2018, Abstract 5.

BERLIN – In the changing multiple sclerosis landscape, more women are having babies, and more are asking questions. With these women, what’s the best way to address the complicated interplay among pregnancy, relapse risk, breastfeeding, and medication resumption? A starting point is to recognize that “women with MS are very different today than they were 25 years ago,” said Annette Langer-Gould, MD, PhD. Not only have diagnostic criteria changed but also highly effective treatments now exist that were not available when the first pregnancy cohorts were studied, she pointed out, speaking at the annual congress of the European Committee on Treatment and Research in Multiple Sclerosis.

SelectStock/Getty Images

The existing literature, said Dr. Langer-Gould, has addressed one controversy: “Most women with MS can have normal pregnancies – and breastfeed – without incurring harm,” though it’s true that severe rebound relapses are possible if natalizumab (Tysabri) or fingolimod (Gilenya) are stopped before pregnancy. In any case, new small-molecule MS medications need to be stopped during pregnancy and breastfeeding, she pointed out. “We didn’t have to worry about that too much when we only had injectables and monoclonal antibodies because they were larger and didn’t cross the placenta.”

Since the 1980s, the conversation about pregnancy and MS has moved from asking “Is pregnancy bad for women with MS?” to the current MS landscape, in which sicker women are able to become pregnant, Dr. Langer-Gould said, adding that how women with MS fare through pregnancy and in the postpartum period is changing over time as well. She and her colleagues’ experience with pregnancy in a cohort of women with MS in the Kaiser Permanente care system, where she is a clinical neurologist and regional research lead, revealed a relapse rate of 8.4%. “So it was pretty rare for a woman to have a relapse during pregnancy,” Dr. Langer-Gould said.

Most women with MS who become pregnant, whether their care is received in a referral center or is community based, are now doing so while on a disease-modifying therapy (DMT), Dr. Langer-Gould said. On these highly effective treatments, “women who were too sick to get pregnant are now well controlled and having babies.”

As more women with MS become pregnant, more conversations about breastfeeding will inevitably crop up, she said. And the discussion about breastfeeding has now begun to acknowledge the “strong benefits to mom and the baby of not just breastfeeding, but longer breastfeeding,” as well.

“Because of this baby-friendly push in a lot of hospitals in the United States, where they’re trying to encourage all women to breastfeed,” a full 87% of women breastfed their infants at least some of the time, and over a third of women (35%) breastfed exclusively for at least 2 months, Dr. Langer-Gould said.

“There’s no one clear explanation of why the women seem to be healthier and doing better through pregnancy as a group, but it’s probably a combination of having milder disease, breastfeeding more, and they’ve got better controlled disease before pregnancy,” she said.


At least eight studies to date have examined the relationship between postpartum MS relapses and breastfeeding, Dr. Langer-Gould said.

“The thing to take away ... is that, even though we’ve studied this many, many times, no one can show that it’s harmful,” she said. For mothers who want to breastfeed, “you can support them in the breastfeeding choice, because they are not going to have more severe disease because of that.”

Whether breastfeeding is exclusive or not has not always been tracked in studies of childbearing women with MS, but when it was captured in the data, exclusive breastfeeding has exerted a protective effect, with about a 50% reduction in risk for postpartum relapse seen in one study (JAMA Neurol. 2015 Oct;72[10]:1132-8).

There is a hormonal rationale for exclusive breastfeeding exerting a protective effect on MS: With exclusive breastfeeding comes more frequent, intense suckling, with more profound elevations in prolactin, and larger drops in follicle-stimulating hormone, luteinizing hormone, progesterone, and estradiol. All these hormonal changes work together to produce more prolonged amenorrhea and anovulation, Dr. Langer-Gould said, with potentially beneficial immunologic effects.

When other, more general maternal and infant health benefits of breastfeeding also are taken into account, there’s strong evidence for the benefits of breastfeeding for women with MS whose medication profile allows them to breastfeed, she said.

However, the “treatment” effect of exclusive breastfeeding is only effective until the infant starts taking regular supplemental feedings, including the introduction of table food at around 6 months of age. “Once regular supplemental feedings are introduced, relapses return,” Dr. Langer-Gould said.

There is some suggestion that, in women without MS, prolonged breastfeeding may be associated with reduced risk of MS. In the MS Sunshine study, breastfeeding for 15 months or longer decreased the risk of later MS by 23%-53% (Nutrients. 2018 Feb 27;10[3]:268). The investigators, led by Dr. Langer-Gould, summed the total months of breastfeeding across all children, so that the 15-month threshold could be reached by breastfeeding one child for 15 months, or three children for 5 months each. “It’s a single study; I wouldn’t make too much out of it,” Dr. Langer-Gould said.

Open questions still remain, she said: “So far, no one has been able to demonstrate a clear beneficial effect in reducing the risk of postpartum relapse if they resume their DMT early in the postpartum period.” Dr. Langer-Gould noted that the literature in this area is hampered by heterogeneity and by the fact that newer, more highly active DMTs have not been well studied.

Also, the link between postpartum relapses and long-term prognosis is not completely delineated. Indirect evidence, she said, points to a postpartum relapse as being “overall, a low-impact event.”

Dr. Langer-Gould reported that she has been the site principal investigator for clinical trials sponsored by Roche and Biogen.

[email protected]

SOURCE: Langer-Gould A. ECTRIMS 2018, Abstract 5.

BERLIN – In the changing multiple sclerosis landscape, more women are having babies, and more are asking questions. With these women, what’s the best way to address the complicated interplay among pregnancy, relapse risk, breastfeeding, and medication resumption? A starting point is to recognize that “women with MS are very different today than they were 25 years ago,” said Annette Langer-Gould, MD, PhD. Not only have diagnostic criteria changed but also highly effective treatments now exist that were not available when the first pregnancy cohorts were studied, she pointed out, speaking at the annual congress of the European Committee on Treatment and Research in Multiple Sclerosis.

SelectStock/Getty Images

The existing literature, said Dr. Langer-Gould, has addressed one controversy: “Most women with MS can have normal pregnancies – and breastfeed – without incurring harm,” though it’s true that severe rebound relapses are possible if natalizumab (Tysabri) or fingolimod (Gilenya) are stopped before pregnancy. In any case, new small-molecule MS medications need to be stopped during pregnancy and breastfeeding, she pointed out. “We didn’t have to worry about that too much when we only had injectables and monoclonal antibodies because they were larger and didn’t cross the placenta.”

Since the 1980s, the conversation about pregnancy and MS has moved from asking “Is pregnancy bad for women with MS?” to the current MS landscape, in which sicker women are able to become pregnant, Dr. Langer-Gould said, adding that how women with MS fare through pregnancy and in the postpartum period is changing over time as well. She and her colleagues’ experience with pregnancy in a cohort of women with MS in the Kaiser Permanente care system, where she is a clinical neurologist and regional research lead, revealed a relapse rate of 8.4%. “So it was pretty rare for a woman to have a relapse during pregnancy,” Dr. Langer-Gould said.

Most women with MS who become pregnant, whether their care is received in a referral center or is community based, are now doing so while on a disease-modifying therapy (DMT), Dr. Langer-Gould said. On these highly effective treatments, “women who were too sick to get pregnant are now well controlled and having babies.”

As more women with MS become pregnant, more conversations about breastfeeding will inevitably crop up, she said. And the discussion about breastfeeding has now begun to acknowledge the “strong benefits to mom and the baby of not just breastfeeding, but longer breastfeeding,” as well.

“Because of this baby-friendly push in a lot of hospitals in the United States, where they’re trying to encourage all women to breastfeed,” a full 87% of women breastfed their infants at least some of the time, and over a third of women (35%) breastfed exclusively for at least 2 months, Dr. Langer-Gould said.

“There’s no one clear explanation of why the women seem to be healthier and doing better through pregnancy as a group, but it’s probably a combination of having milder disease, breastfeeding more, and they’ve got better controlled disease before pregnancy,” she said.


At least eight studies to date have examined the relationship between postpartum MS relapses and breastfeeding, Dr. Langer-Gould said.

“The thing to take away ... is that, even though we’ve studied this many, many times, no one can show that it’s harmful,” she said. For mothers who want to breastfeed, “you can support them in the breastfeeding choice, because they are not going to have more severe disease because of that.”

Whether breastfeeding is exclusive or not has not always been tracked in studies of childbearing women with MS, but when it was captured in the data, exclusive breastfeeding has exerted a protective effect, with about a 50% reduction in risk for postpartum relapse seen in one study (JAMA Neurol. 2015 Oct;72[10]:1132-8).

There is a hormonal rationale for exclusive breastfeeding exerting a protective effect on MS: With exclusive breastfeeding comes more frequent, intense suckling, with more profound elevations in prolactin, and larger drops in follicle-stimulating hormone, luteinizing hormone, progesterone, and estradiol. All these hormonal changes work together to produce more prolonged amenorrhea and anovulation, Dr. Langer-Gould said, with potentially beneficial immunologic effects.

When other, more general maternal and infant health benefits of breastfeeding also are taken into account, there’s strong evidence for the benefits of breastfeeding for women with MS whose medication profile allows them to breastfeed, she said.

However, the “treatment” effect of exclusive breastfeeding is only effective until the infant starts taking regular supplemental feedings, including the introduction of table food at around 6 months of age. “Once regular supplemental feedings are introduced, relapses return,” Dr. Langer-Gould said.

There is some suggestion that, in women without MS, prolonged breastfeeding may be associated with reduced risk of MS. In the MS Sunshine study, breastfeeding for 15 months or longer decreased the risk of later MS by 23%-53% (Nutrients. 2018 Feb 27;10[3]:268). The investigators, led by Dr. Langer-Gould, summed the total months of breastfeeding across all children, so that the 15-month threshold could be reached by breastfeeding one child for 15 months, or three children for 5 months each. “It’s a single study; I wouldn’t make too much out of it,” Dr. Langer-Gould said.

Open questions still remain, she said: “So far, no one has been able to demonstrate a clear beneficial effect in reducing the risk of postpartum relapse if they resume their DMT early in the postpartum period.” Dr. Langer-Gould noted that the literature in this area is hampered by heterogeneity and by the fact that newer, more highly active DMTs have not been well studied.

Also, the link between postpartum relapses and long-term prognosis is not completely delineated. Indirect evidence, she said, points to a postpartum relapse as being “overall, a low-impact event.”

Dr. Langer-Gould reported that she has been the site principal investigator for clinical trials sponsored by Roche and Biogen.

[email protected]

SOURCE: Langer-Gould A. ECTRIMS 2018, Abstract 5.

Instances of stroke and arterial dissection in the head and neck have been reported in some multiple sclerosis patients soon after an infusion of alemtuzumab (Lemtrada), according to a safety announcement issued by the Food and Drug Administration on Nov. 29.

Wikimedia Commons/FitzColinGerald/Creative Commons License

Since the FDA approved alemtuzumab in 2014 for relapsing forms of MS, 13 cases of ischemic and hemorrhagic stroke or arterial dissection have been reported worldwide via the FDA Adverse Event Reporting System, but “additional cases we are unaware of may have occurred,” the FDA said in the announcement.

Most of the patients who developed stroke or arterial lining tears showed symptoms within a day of taking the medication, although one patient reported symptoms three days after treatment. The drug is given via intravenous infusion and is generally reserved for patients with relapsing MS who have not responded adequately to other approved MS medications, according to the FDA.

Symptoms include sudden onset of the following: severe headache or neck pain; numbness or weakness in the arms or legs, especially on only one side of the body; confusion or trouble speaking or understanding speech; vision problems in one or both eyes; and dizziness, loss of balance, or difficulty walking.

As a result of the reports, the FDA has updated the drug label prescribing information and the patient Medication Guide to reflect these risks, and added the risk of stroke to the medication’s existing boxed warning.

Health care providers should remind patients of the potential for stroke and arterial dissection at each treatment visit and advise them to seek immediate medical attention if they experience any of the symptoms reported in previous cases. “The diagnosis is often complicated because early symptoms such as headache and neck pain are not specific,” according to the agency, but patients complaining of such symptoms should be evaluated immediately.

Alemtuzumab was also approved in May 2001 for treating B-cell chronic lymphocytic leukemia (B-CLL) under the brand name Campath. The FDA will update the Campath label to reflect the new warnings and risks.

Instances of stroke and arterial dissection in the head and neck have been reported in some multiple sclerosis patients soon after an infusion of alemtuzumab (Lemtrada), according to a safety announcement issued by the Food and Drug Administration on Nov. 29.

Wikimedia Commons/FitzColinGerald/Creative Commons License

Since the FDA approved alemtuzumab in 2014 for relapsing forms of MS, 13 cases of ischemic and hemorrhagic stroke or arterial dissection have been reported worldwide via the FDA Adverse Event Reporting System, but “additional cases we are unaware of may have occurred,” the FDA said in the announcement.

Most of the patients who developed stroke or arterial lining tears showed symptoms within a day of taking the medication, although one patient reported symptoms three days after treatment. The drug is given via intravenous infusion and is generally reserved for patients with relapsing MS who have not responded adequately to other approved MS medications, according to the FDA.

Symptoms include sudden onset of the following: severe headache or neck pain; numbness or weakness in the arms or legs, especially on only one side of the body; confusion or trouble speaking or understanding speech; vision problems in one or both eyes; and dizziness, loss of balance, or difficulty walking.

As a result of the reports, the FDA has updated the drug label prescribing information and the patient Medication Guide to reflect these risks, and added the risk of stroke to the medication’s existing boxed warning.

Health care providers should remind patients of the potential for stroke and arterial dissection at each treatment visit and advise them to seek immediate medical attention if they experience any of the symptoms reported in previous cases. “The diagnosis is often complicated because early symptoms such as headache and neck pain are not specific,” according to the agency, but patients complaining of such symptoms should be evaluated immediately.

Alemtuzumab was also approved in May 2001 for treating B-cell chronic lymphocytic leukemia (B-CLL) under the brand name Campath. The FDA will update the Campath label to reflect the new warnings and risks.

Instances of stroke and arterial dissection in the head and neck have been reported in some multiple sclerosis patients soon after an infusion of alemtuzumab (Lemtrada), according to a safety announcement issued by the Food and Drug Administration on Nov. 29.

Wikimedia Commons/FitzColinGerald/Creative Commons License

Since the FDA approved alemtuzumab in 2014 for relapsing forms of MS, 13 cases of ischemic and hemorrhagic stroke or arterial dissection have been reported worldwide via the FDA Adverse Event Reporting System, but “additional cases we are unaware of may have occurred,” the FDA said in the announcement.

Most of the patients who developed stroke or arterial lining tears showed symptoms within a day of taking the medication, although one patient reported symptoms three days after treatment. The drug is given via intravenous infusion and is generally reserved for patients with relapsing MS who have not responded adequately to other approved MS medications, according to the FDA.

Symptoms include sudden onset of the following: severe headache or neck pain; numbness or weakness in the arms or legs, especially on only one side of the body; confusion or trouble speaking or understanding speech; vision problems in one or both eyes; and dizziness, loss of balance, or difficulty walking.

As a result of the reports, the FDA has updated the drug label prescribing information and the patient Medication Guide to reflect these risks, and added the risk of stroke to the medication’s existing boxed warning.

Health care providers should remind patients of the potential for stroke and arterial dissection at each treatment visit and advise them to seek immediate medical attention if they experience any of the symptoms reported in previous cases. “The diagnosis is often complicated because early symptoms such as headache and neck pain are not specific,” according to the agency, but patients complaining of such symptoms should be evaluated immediately.

Alemtuzumab was also approved in May 2001 for treating B-cell chronic lymphocytic leukemia (B-CLL) under the brand name Campath. The FDA will update the Campath label to reflect the new warnings and risks.

BERLIN – In addition to the pain, motor and sensory impairments, and cognitive dysfunction that can stalk multiple sclerosis (MS) patients, for many, there’s also the challenge of an invisible, tough-to-quantify entity: fatigue.

©RusN/Thinkstock.com

“Approximately 80% of patients suffer from fatigue, so it’s an immense problem in MS. There’s no real clear relationship with disease severity,” Vincent de Groot, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. “Despite what a lot of people think, there’s no clear or strong relationship between fatigue and the amount of physical activity people undertake daily,” he noted.

“Patients all know what we are talking about when we ask about fatigue,” but there are a variety of definitions of fatigue used in research, a fact that has limited progress in the field, said Dr. de Groot.

Primary fatigue is related to the pathophysiology of MS itself, while secondary fatigue can result from MS symptoms, such as poor sleep from spasms. Secondary fatigue can also be a side effect of MS medications; baclofen, used for spasticity, is a good example, said Dr. de Groot. “We must not underestimate how many problems these drugs can give people.”

What’s the mechanism by which MS causes primary fatigue? “The simple answer is that we do not know,” said Dr. de Groot, a physiatrist and researcher at Vrije University, Amsterdam.

Though immune-mediated fatigue had been proposed as a factor for patients with MS, Dr. de Groot said that his own lab’s work has not found any connection between fatigue levels and any immune-related biomarkers. “So I don’t think the immune hypothesis has a lot of evidence.”

Similarly, though there might be mechanistic reasons to suspect the hypothalamic-pituitary-adrenal (HPA) axis as a culprit for MS fatigue, no consistent association has been found between any markers for HPA axis disruption and fatigue ratings, Dr. de Groot said.

Newer theories center on MS-related disruptions in brain connectivity, with imaging studies now able to detect some of these disruptions in functional connectivity that correlate with fatigue. “Right now, I think this is the hypothesis to bet money on,” Dr. de Groot said.

Many factors come into play, including environmental and psychological factors, he said.

“What can we do to treat MS-related fatigue?” Though several drugs have been used, “if you carefully look at the systematic reviews, the evidence is very, very disappointing,” Dr. de Groot said. For both amantadine and modafinil, “there is no evidence that these drugs are effective,” he said, citing a systematic review and meta-analysis that found a pooled effect size of 0.07 (95% confidence interval, –0.22 to 0.37) for medications (Mult Scler Int. 2014 May; doi: 10.1155/2014/798285).

Only two trials have looked at multidisciplinary rehabilitation for MS-related fatigue, Dr. de Groot said. Two studies that looked at multidisciplinary strategies that pulled in a variety of disciplines to help develop tailored fatigue management strategies saw no between-group effect when the multidisciplinary intervention was compared with nurse-provided information or with non–fatigue-related rehabilitation.

In an effort to determine whether MS-related fatigue is truly refractory to treatment, Dr. de Groot said that he and his colleagues decided to take “three steps back” to look at the individual interventions that make up a multidisciplinary approach to tackling fatigue. “So, we looked at exercise therapy, energy conservation management, and cognitive-behavioral therapy,” beginning with a literature review, he said.

Members of his research group found that effect sizes ranged from small to moderate for the three approaches, but there were methodologic problems with many of the studies; in the case of cognitive-behavioral therapy (CBT), the effect size waned over time, Dr. de Groot said. A newer randomized, controlled trial showed a relatively robust effect size of 0.52 for Internet-delivered CBT, which may provide a promising and practical approach (J Neurol Neurosurg Psychiatry. 2018 Sep;89[9]:970-6. doi: 10.1136/jnnp-2017-317463).

Looking at fatigue and societal participation, Dr. de Groot and his colleagues examined what effect aerobic training, energy conservation management, and CBT had on the two outcome measures. The three interventions were studied in three stand-alone trials, he said.

Patients were assessed at baseline, and at 8, 16, 26, and 52 weeks. The assessments were performed by a blinded researcher and were the same across trials: For fatigue, researchers used the Checklist Individual Strength–fatigue (CIS20R-fatigue), and for societal participation, they administered the Impact on Participation and Autonomy (IPA).

Each trial included 90 patients, randomized 1:1 to receive high- or low-intensity treatment. Patients had to have MS with no exacerbations within the prior 6 months and an Expanded Disability Status Scale score of 6 or less. However, the included patients had severe fatigue, with a CIS20R-fatigue subscore of 35 or higher, and the fatigue could not be attributable to such secondary causes as infection, depression, or thyroid or sleep problems. Finally, patients could not have been treated for fatigue in the 3 months prior to enrollment.

Those in the high-intensity treatment group received 12 sessions focused on the particular intervention over 4 months, provided by an expert therapist. Each type of intervention had a treatment protocol that was followed over the 4 months. Patients receiving low-intensity treatment saw an MS-specialized nurse three times over 4 months.

The aerobic training intervention had patients performing high-intensity exercise on a cycle ergometer for 30 minutes, three times weekly for 16 weeks. In addition to the 12 supervised sessions, patients also completed 36 home-based sessions. The level of intensity for each patient was personalized based on their baseline cardiopulmonary exercise test, Dr. de Groot said.

At the end of 1 year, patients in the high-intensity group and those in the low-intensity group reported virtually the same fatigue scores. Though there was an initial drop in fatigue for those in the high-intensity group, compared with baseline and with the low-intensity participants, values on the CIS20R never dropped below 35, the “severe fatigue” cutoff.

And, Dr. de Groot said, there was no effect on societal participation or in other fatigue scores. In sum, the effect size was barely significant at –0.54 (95% CI, –1.00 to –0.06), with a number needed to treat of 9.

Adherence to attempting the workouts was fairly good for participants in the high-intensity group; 74% completed the sessions, with 71% doing so at the prescribed workload. The median rate of perceived exertion on a 1-20 scale was 14.

However, the thrice-weekly exercise bouts didn’t improve aerobic fitness parameters: Neither V0₂peak, V0₂peak adjusted for body mass, nor anaerobic threshold changed for those in the high-intensity group. Peak power did increase by 11.7 watts (P = .048).

Energy conservation education, whether delivered in high- or low-intensity format, had almost no effect on fatigue scores, with a number needed to treat of 158 – a figure that is “neither significant nor clinically meaningful,” Dr. de Groot said. Other fatigue scores and societal participation levels also went unchanged.

However, CBT delivered in a series of 10 modules to address various beliefs and coping mechanisms about MS, fatigue, pain, and activity regulation did have a positive effect on fatigue. Here, the effect size was –0.79 (95% CI, –1.26 to –0.32). The number needed to treat was 3, and CIS20R values did dip below the “severe fatigue” threshold during treatment. A similar effect, Dr. de Groot said, was seen for other fatigue and quality of life measures, though societal participation scores didn’t change. No significant improvement was seen for the low-intensity CBT group.

“Severe MS-related fatigue can be reduced effectively with CBT in the short term. More research is needed on how to maintain this effect in the long term,” Dr. de Groot said. Still, “it’s currently the best treatment option,” he said.

The fact that patients reverted to their preintervention fatigue levels regardless of the intervention shows that effective treatment for MS-related fatigue should probably be ongoing, viewed more as a process than an occurrence, Dr. de Groot said.

To that end, Dr. de Groot and his colleagues are conducting a randomized, controlled trial that includes 166 MS patients with fatigue. The study has two arms: The first is a noninferiority trial comparing face-to-face CBT with e-learning delivery of the content, and the second looks at the efficacy of ongoing booster sessions after initial CBT.

An online database of randomized, controlled trials of rehabilitation for MS patients can be found at www.appeco.net.

The study was funded by Fonds NutsOhra, a private Dutch foundation. Dr. de Groot reported no relevant conflicts of interest.

[email protected]

SOURCE: de Groot V. Mult Scler. 2018;24(S2):83, Abstract 225.

BERLIN – In addition to the pain, motor and sensory impairments, and cognitive dysfunction that can stalk multiple sclerosis (MS) patients, for many, there’s also the challenge of an invisible, tough-to-quantify entity: fatigue.

©RusN/Thinkstock.com

“Approximately 80% of patients suffer from fatigue, so it’s an immense problem in MS. There’s no real clear relationship with disease severity,” Vincent de Groot, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. “Despite what a lot of people think, there’s no clear or strong relationship between fatigue and the amount of physical activity people undertake daily,” he noted.

“Patients all know what we are talking about when we ask about fatigue,” but there are a variety of definitions of fatigue used in research, a fact that has limited progress in the field, said Dr. de Groot.

Primary fatigue is related to the pathophysiology of MS itself, while secondary fatigue can result from MS symptoms, such as poor sleep from spasms. Secondary fatigue can also be a side effect of MS medications; baclofen, used for spasticity, is a good example, said Dr. de Groot. “We must not underestimate how many problems these drugs can give people.”

What’s the mechanism by which MS causes primary fatigue? “The simple answer is that we do not know,” said Dr. de Groot, a physiatrist and researcher at Vrije University, Amsterdam.

Though immune-mediated fatigue had been proposed as a factor for patients with MS, Dr. de Groot said that his own lab’s work has not found any connection between fatigue levels and any immune-related biomarkers. “So I don’t think the immune hypothesis has a lot of evidence.”

Similarly, though there might be mechanistic reasons to suspect the hypothalamic-pituitary-adrenal (HPA) axis as a culprit for MS fatigue, no consistent association has been found between any markers for HPA axis disruption and fatigue ratings, Dr. de Groot said.

Newer theories center on MS-related disruptions in brain connectivity, with imaging studies now able to detect some of these disruptions in functional connectivity that correlate with fatigue. “Right now, I think this is the hypothesis to bet money on,” Dr. de Groot said.

Many factors come into play, including environmental and psychological factors, he said.

“What can we do to treat MS-related fatigue?” Though several drugs have been used, “if you carefully look at the systematic reviews, the evidence is very, very disappointing,” Dr. de Groot said. For both amantadine and modafinil, “there is no evidence that these drugs are effective,” he said, citing a systematic review and meta-analysis that found a pooled effect size of 0.07 (95% confidence interval, –0.22 to 0.37) for medications (Mult Scler Int. 2014 May; doi: 10.1155/2014/798285).

Only two trials have looked at multidisciplinary rehabilitation for MS-related fatigue, Dr. de Groot said. Two studies that looked at multidisciplinary strategies that pulled in a variety of disciplines to help develop tailored fatigue management strategies saw no between-group effect when the multidisciplinary intervention was compared with nurse-provided information or with non–fatigue-related rehabilitation.

In an effort to determine whether MS-related fatigue is truly refractory to treatment, Dr. de Groot said that he and his colleagues decided to take “three steps back” to look at the individual interventions that make up a multidisciplinary approach to tackling fatigue. “So, we looked at exercise therapy, energy conservation management, and cognitive-behavioral therapy,” beginning with a literature review, he said.

Members of his research group found that effect sizes ranged from small to moderate for the three approaches, but there were methodologic problems with many of the studies; in the case of cognitive-behavioral therapy (CBT), the effect size waned over time, Dr. de Groot said. A newer randomized, controlled trial showed a relatively robust effect size of 0.52 for Internet-delivered CBT, which may provide a promising and practical approach (J Neurol Neurosurg Psychiatry. 2018 Sep;89[9]:970-6. doi: 10.1136/jnnp-2017-317463).

Looking at fatigue and societal participation, Dr. de Groot and his colleagues examined what effect aerobic training, energy conservation management, and CBT had on the two outcome measures. The three interventions were studied in three stand-alone trials, he said.

Patients were assessed at baseline, and at 8, 16, 26, and 52 weeks. The assessments were performed by a blinded researcher and were the same across trials: For fatigue, researchers used the Checklist Individual Strength–fatigue (CIS20R-fatigue), and for societal participation, they administered the Impact on Participation and Autonomy (IPA).

Each trial included 90 patients, randomized 1:1 to receive high- or low-intensity treatment. Patients had to have MS with no exacerbations within the prior 6 months and an Expanded Disability Status Scale score of 6 or less. However, the included patients had severe fatigue, with a CIS20R-fatigue subscore of 35 or higher, and the fatigue could not be attributable to such secondary causes as infection, depression, or thyroid or sleep problems. Finally, patients could not have been treated for fatigue in the 3 months prior to enrollment.

Those in the high-intensity treatment group received 12 sessions focused on the particular intervention over 4 months, provided by an expert therapist. Each type of intervention had a treatment protocol that was followed over the 4 months. Patients receiving low-intensity treatment saw an MS-specialized nurse three times over 4 months.

The aerobic training intervention had patients performing high-intensity exercise on a cycle ergometer for 30 minutes, three times weekly for 16 weeks. In addition to the 12 supervised sessions, patients also completed 36 home-based sessions. The level of intensity for each patient was personalized based on their baseline cardiopulmonary exercise test, Dr. de Groot said.

At the end of 1 year, patients in the high-intensity group and those in the low-intensity group reported virtually the same fatigue scores. Though there was an initial drop in fatigue for those in the high-intensity group, compared with baseline and with the low-intensity participants, values on the CIS20R never dropped below 35, the “severe fatigue” cutoff.

And, Dr. de Groot said, there was no effect on societal participation or in other fatigue scores. In sum, the effect size was barely significant at –0.54 (95% CI, –1.00 to –0.06), with a number needed to treat of 9.

Adherence to attempting the workouts was fairly good for participants in the high-intensity group; 74% completed the sessions, with 71% doing so at the prescribed workload. The median rate of perceived exertion on a 1-20 scale was 14.

However, the thrice-weekly exercise bouts didn’t improve aerobic fitness parameters: Neither V0₂peak, V0₂peak adjusted for body mass, nor anaerobic threshold changed for those in the high-intensity group. Peak power did increase by 11.7 watts (P = .048).

Energy conservation education, whether delivered in high- or low-intensity format, had almost no effect on fatigue scores, with a number needed to treat of 158 – a figure that is “neither significant nor clinically meaningful,” Dr. de Groot said. Other fatigue scores and societal participation levels also went unchanged.

However, CBT delivered in a series of 10 modules to address various beliefs and coping mechanisms about MS, fatigue, pain, and activity regulation did have a positive effect on fatigue. Here, the effect size was –0.79 (95% CI, –1.26 to –0.32). The number needed to treat was 3, and CIS20R values did dip below the “severe fatigue” threshold during treatment. A similar effect, Dr. de Groot said, was seen for other fatigue and quality of life measures, though societal participation scores didn’t change. No significant improvement was seen for the low-intensity CBT group.

“Severe MS-related fatigue can be reduced effectively with CBT in the short term. More research is needed on how to maintain this effect in the long term,” Dr. de Groot said. Still, “it’s currently the best treatment option,” he said.

The fact that patients reverted to their preintervention fatigue levels regardless of the intervention shows that effective treatment for MS-related fatigue should probably be ongoing, viewed more as a process than an occurrence, Dr. de Groot said.

To that end, Dr. de Groot and his colleagues are conducting a randomized, controlled trial that includes 166 MS patients with fatigue. The study has two arms: The first is a noninferiority trial comparing face-to-face CBT with e-learning delivery of the content, and the second looks at the efficacy of ongoing booster sessions after initial CBT.

An online database of randomized, controlled trials of rehabilitation for MS patients can be found at www.appeco.net.

The study was funded by Fonds NutsOhra, a private Dutch foundation. Dr. de Groot reported no relevant conflicts of interest.

[email protected]

SOURCE: de Groot V. Mult Scler. 2018;24(S2):83, Abstract 225.

BERLIN – In addition to the pain, motor and sensory impairments, and cognitive dysfunction that can stalk multiple sclerosis (MS) patients, for many, there’s also the challenge of an invisible, tough-to-quantify entity: fatigue.

©RusN/Thinkstock.com

“Approximately 80% of patients suffer from fatigue, so it’s an immense problem in MS. There’s no real clear relationship with disease severity,” Vincent de Groot, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. “Despite what a lot of people think, there’s no clear or strong relationship between fatigue and the amount of physical activity people undertake daily,” he noted.

“Patients all know what we are talking about when we ask about fatigue,” but there are a variety of definitions of fatigue used in research, a fact that has limited progress in the field, said Dr. de Groot.

Primary fatigue is related to the pathophysiology of MS itself, while secondary fatigue can result from MS symptoms, such as poor sleep from spasms. Secondary fatigue can also be a side effect of MS medications; baclofen, used for spasticity, is a good example, said Dr. de Groot. “We must not underestimate how many problems these drugs can give people.”

What’s the mechanism by which MS causes primary fatigue? “The simple answer is that we do not know,” said Dr. de Groot, a physiatrist and researcher at Vrije University, Amsterdam.

Though immune-mediated fatigue had been proposed as a factor for patients with MS, Dr. de Groot said that his own lab’s work has not found any connection between fatigue levels and any immune-related biomarkers. “So I don’t think the immune hypothesis has a lot of evidence.”

Similarly, though there might be mechanistic reasons to suspect the hypothalamic-pituitary-adrenal (HPA) axis as a culprit for MS fatigue, no consistent association has been found between any markers for HPA axis disruption and fatigue ratings, Dr. de Groot said.

Newer theories center on MS-related disruptions in brain connectivity, with imaging studies now able to detect some of these disruptions in functional connectivity that correlate with fatigue. “Right now, I think this is the hypothesis to bet money on,” Dr. de Groot said.

Many factors come into play, including environmental and psychological factors, he said.

“What can we do to treat MS-related fatigue?” Though several drugs have been used, “if you carefully look at the systematic reviews, the evidence is very, very disappointing,” Dr. de Groot said. For both amantadine and modafinil, “there is no evidence that these drugs are effective,” he said, citing a systematic review and meta-analysis that found a pooled effect size of 0.07 (95% confidence interval, –0.22 to 0.37) for medications (Mult Scler Int. 2014 May; doi: 10.1155/2014/798285).

Only two trials have looked at multidisciplinary rehabilitation for MS-related fatigue, Dr. de Groot said. Two studies that looked at multidisciplinary strategies that pulled in a variety of disciplines to help develop tailored fatigue management strategies saw no between-group effect when the multidisciplinary intervention was compared with nurse-provided information or with non–fatigue-related rehabilitation.

In an effort to determine whether MS-related fatigue is truly refractory to treatment, Dr. de Groot said that he and his colleagues decided to take “three steps back” to look at the individual interventions that make up a multidisciplinary approach to tackling fatigue. “So, we looked at exercise therapy, energy conservation management, and cognitive-behavioral therapy,” beginning with a literature review, he said.

Members of his research group found that effect sizes ranged from small to moderate for the three approaches, but there were methodologic problems with many of the studies; in the case of cognitive-behavioral therapy (CBT), the effect size waned over time, Dr. de Groot said. A newer randomized, controlled trial showed a relatively robust effect size of 0.52 for Internet-delivered CBT, which may provide a promising and practical approach (J Neurol Neurosurg Psychiatry. 2018 Sep;89[9]:970-6. doi: 10.1136/jnnp-2017-317463).

Looking at fatigue and societal participation, Dr. de Groot and his colleagues examined what effect aerobic training, energy conservation management, and CBT had on the two outcome measures. The three interventions were studied in three stand-alone trials, he said.

Patients were assessed at baseline, and at 8, 16, 26, and 52 weeks. The assessments were performed by a blinded researcher and were the same across trials: For fatigue, researchers used the Checklist Individual Strength–fatigue (CIS20R-fatigue), and for societal participation, they administered the Impact on Participation and Autonomy (IPA).

Each trial included 90 patients, randomized 1:1 to receive high- or low-intensity treatment. Patients had to have MS with no exacerbations within the prior 6 months and an Expanded Disability Status Scale score of 6 or less. However, the included patients had severe fatigue, with a CIS20R-fatigue subscore of 35 or higher, and the fatigue could not be attributable to such secondary causes as infection, depression, or thyroid or sleep problems. Finally, patients could not have been treated for fatigue in the 3 months prior to enrollment.

Those in the high-intensity treatment group received 12 sessions focused on the particular intervention over 4 months, provided by an expert therapist. Each type of intervention had a treatment protocol that was followed over the 4 months. Patients receiving low-intensity treatment saw an MS-specialized nurse three times over 4 months.

The aerobic training intervention had patients performing high-intensity exercise on a cycle ergometer for 30 minutes, three times weekly for 16 weeks. In addition to the 12 supervised sessions, patients also completed 36 home-based sessions. The level of intensity for each patient was personalized based on their baseline cardiopulmonary exercise test, Dr. de Groot said.

At the end of 1 year, patients in the high-intensity group and those in the low-intensity group reported virtually the same fatigue scores. Though there was an initial drop in fatigue for those in the high-intensity group, compared with baseline and with the low-intensity participants, values on the CIS20R never dropped below 35, the “severe fatigue” cutoff.

And, Dr. de Groot said, there was no effect on societal participation or in other fatigue scores. In sum, the effect size was barely significant at –0.54 (95% CI, –1.00 to –0.06), with a number needed to treat of 9.

Adherence to attempting the workouts was fairly good for participants in the high-intensity group; 74% completed the sessions, with 71% doing so at the prescribed workload. The median rate of perceived exertion on a 1-20 scale was 14.

However, the thrice-weekly exercise bouts didn’t improve aerobic fitness parameters: Neither V0₂peak, V0₂peak adjusted for body mass, nor anaerobic threshold changed for those in the high-intensity group. Peak power did increase by 11.7 watts (P = .048).

Energy conservation education, whether delivered in high- or low-intensity format, had almost no effect on fatigue scores, with a number needed to treat of 158 – a figure that is “neither significant nor clinically meaningful,” Dr. de Groot said. Other fatigue scores and societal participation levels also went unchanged.

However, CBT delivered in a series of 10 modules to address various beliefs and coping mechanisms about MS, fatigue, pain, and activity regulation did have a positive effect on fatigue. Here, the effect size was –0.79 (95% CI, –1.26 to –0.32). The number needed to treat was 3, and CIS20R values did dip below the “severe fatigue” threshold during treatment. A similar effect, Dr. de Groot said, was seen for other fatigue and quality of life measures, though societal participation scores didn’t change. No significant improvement was seen for the low-intensity CBT group.

“Severe MS-related fatigue can be reduced effectively with CBT in the short term. More research is needed on how to maintain this effect in the long term,” Dr. de Groot said. Still, “it’s currently the best treatment option,” he said.

The fact that patients reverted to their preintervention fatigue levels regardless of the intervention shows that effective treatment for MS-related fatigue should probably be ongoing, viewed more as a process than an occurrence, Dr. de Groot said.

To that end, Dr. de Groot and his colleagues are conducting a randomized, controlled trial that includes 166 MS patients with fatigue. The study has two arms: The first is a noninferiority trial comparing face-to-face CBT with e-learning delivery of the content, and the second looks at the efficacy of ongoing booster sessions after initial CBT.

An online database of randomized, controlled trials of rehabilitation for MS patients can be found at www.appeco.net.

The study was funded by Fonds NutsOhra, a private Dutch foundation. Dr. de Groot reported no relevant conflicts of interest.

[email protected]

SOURCE: de Groot V. Mult Scler. 2018;24(S2):83, Abstract 225.