Multiple Sclerosis Hub

HILTON HEAD, SC—Managing patient expectations is important when discussing new and pending treatments for multiple sclerosis (MS), according to a lecture given at the 39th Annual Contemporary Clinical Neurology Symposium. The FDA’s recent approval of daclizumab and ongoing priority review of ocrelizumab mean that neurologists likely will be discussing these therapies with patients in their clinics. Conversations may revolve around efficacy, laboratory monitoring, and risk of adverse events.

In the case of daclizumab (Zinbryta), which was approved in May 2016, patient counseling may focus on monthly laboratory monitoring requirements that are part of the drug’s risk evaluation and mitigation strategy (REMS) program and the potential for adverse events at any time during treatment, said Harold Moses Jr, MD, Associate Professor of Neurology at Vanderbilt University in Nashville.

Ocrelizumab (Ocrevus) could be the first drug approved for primary progressive MS and a new treatment option for patients with relapsing MS. Neurologists may need to temper patients’ expectations regarding the drug’s efficacy in patients with more advanced progressive disease.

“If this drug gets approved for progressive MS, you are going to have a number of patients coming to your clinics to ask for this drug,” he said. It is unclear, however, how beneficial the treatment might be for patients with advanced disease, based on the clinical trial conducted in primary progressive MS. “In my opinion, if someone is 65 to 70 years old and has had primary progressive MS for 15 to 20 years and has been wheelchair-confined for five or more years, it is unlikely that this drug is going to be very meaningful for them. Although, I do not know that for a fact. Therefore, my plan is to offer this [treatment], probably for approximately a year, and see what happens. We will continue to follow them and make a decision together about continuing therapy or stopping.”

“Remember, half the people in the world who have MS have progressive disease,” Dr. Moses said. “They have seen more than 20 years of therapies [approved] for relapsing MS, so they have a lot of pent-up expectations about a treatment option, and rightfully so. I just think this potential treatment has to be discussed in a broader context of how the study was done.”

Daclizumab

Daclizumab is an interleukin-2 receptor blocking humanized monoclonal antibody approved for use in relapsing forms of MS. It is self-administered as a subcutaneous injection once per month at a dose of 150 mg/mL. The drug’s label notes, “Because of its safety profile, the use of Zinbryta should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.” This FDA guidance is similar to that for alemtuzumab. “With more than a dozen drugs for MS, it is not too surprising we are seeing this,” Dr. Moses said.

The efficacy of the drug was demonstrated in two randomized, double-blind studies. One study compared daclizumab with interferon beta-1a. The other study compared daclizumab and placebo.

In the active comparator study, 919 patients received daclizumab and 922 received interferon beta-1a. Compared with interferon beta-1a, daclizumab had a statistically significant effect on annualized relapse rate (0.393 vs 0.216; relative reduction, 45%) and on the number of new or newly enlarging T2 hyperintense lesions. Treatment did not significantly affect 12-week confirmed disability progression.

In some patients, daclizumab has a significant impact on the liver. As a result, physicians are asked to assess transaminase levels and total bilirubin monthly during treatment and for six months after stopping therapy, Dr. Moses said.

Autoimmune hepatitis and other immune-mediated disorders, including lymphadenopathy, noninfectious colitis, and cutaneous adverse events, were seen with daclizumab treatment.

Dermatologic reactions to daclizumab can range from mild rashes to serious reactions, and can include psoriasiform nail changes, erythematous changes and swelling, and desquamation and erythema of the palms. Neurologists should advise patients that these reactions “could happen at any point while they are taking this medication,” Dr. Moses said. Some patients experienced reactions after receiving the therapy for nearly three years.Patients also experienced adverse events related to infection, including nasopharyngitis, bronchitis, and tonsillitis. “Daclizumab is the newest approved drug for relapsing MS,” Dr. Moses said. “It has a unique mechanism of action and a favorable dosing schedule. Challenges exist with monitoring requirements and potential serious adverse events.”

Ocrelizumab

Ocrelizumab is a humanized monoclonal antibody that depletes CD20+ B cells.

Two identical studies, OPERA I and II, evaluated ocrelizumab in patients with relapsing MS. Another trial, ORATORIO, assessed ocrelizumab in patients with primary progressive MS. In the trials, patients received 600 mg of ocrelizumab by IV infusion every 24 weeks.

In OPERA I and II, treatment with ocrelizumab resulted in a 46% and 47% reduction in annualized relapse rate, respectively, compared with interferon beta-1a. In addition, ocrelizumab reduced the risk of confirmed disability progression for 12 weeks by 43% and 37%, respectively. Ocrelizumab also dramatically reduced the number of T1 gadolinium-enhancing lesions and the number of new or enlarging T2 hyperintense lesions, compared with interferon beta-1a.

The ORATORIO study included 732 patients with primary progressive MS who received ocrelizumab or placebo. Patients were ages 18 to 55, had an Expanded Disability Status Scale score of 3.0 to 6.5, and had abnormal CSF. Patients were treated for at least 120 weeks. Investigators measured slowing of disability progression as the primary outcome. There was a 24% reduction in clinical disability sustained for at least 12 weeks, compared with placebo.

Ocrelizumab generally was well tolerated. In the clinical trials, a similar proportion of patients treated with ocrelizumab and controls experienced adverse events. In OPERA I and II, the most common adverse event associated with ocrelizumab was infusion-related reactions, which occurred in 34.3% of patients in the ocrelizumab arm, compared with 9.7% of patients in the interferon beta-1a arm.

In ORATORIO, more malignancies were reported in patients treated with ocrelizumab, compared with patients who received placebo (11 vs 2). The implications of that finding are unclear. “We will see how that plays out in terms of what the FDA thinks about that,” Dr. Moses said.

The FDA has granted a priority review designation to ocrelizumab, with a targeted action date of December 28, 2016. “Ocrelizumab remains on the horizon with a potential role in both relapsing and progressive MS,” Dr. Moses said.

—Jake Remaly

HILTON HEAD, SC—Managing patient expectations is important when discussing new and pending treatments for multiple sclerosis (MS), according to a lecture given at the 39th Annual Contemporary Clinical Neurology Symposium. The FDA’s recent approval of daclizumab and ongoing priority review of ocrelizumab mean that neurologists likely will be discussing these therapies with patients in their clinics. Conversations may revolve around efficacy, laboratory monitoring, and risk of adverse events.

In the case of daclizumab (Zinbryta), which was approved in May 2016, patient counseling may focus on monthly laboratory monitoring requirements that are part of the drug’s risk evaluation and mitigation strategy (REMS) program and the potential for adverse events at any time during treatment, said Harold Moses Jr, MD, Associate Professor of Neurology at Vanderbilt University in Nashville.

Ocrelizumab (Ocrevus) could be the first drug approved for primary progressive MS and a new treatment option for patients with relapsing MS. Neurologists may need to temper patients’ expectations regarding the drug’s efficacy in patients with more advanced progressive disease.

“If this drug gets approved for progressive MS, you are going to have a number of patients coming to your clinics to ask for this drug,” he said. It is unclear, however, how beneficial the treatment might be for patients with advanced disease, based on the clinical trial conducted in primary progressive MS. “In my opinion, if someone is 65 to 70 years old and has had primary progressive MS for 15 to 20 years and has been wheelchair-confined for five or more years, it is unlikely that this drug is going to be very meaningful for them. Although, I do not know that for a fact. Therefore, my plan is to offer this [treatment], probably for approximately a year, and see what happens. We will continue to follow them and make a decision together about continuing therapy or stopping.”

“Remember, half the people in the world who have MS have progressive disease,” Dr. Moses said. “They have seen more than 20 years of therapies [approved] for relapsing MS, so they have a lot of pent-up expectations about a treatment option, and rightfully so. I just think this potential treatment has to be discussed in a broader context of how the study was done.”

Daclizumab

Daclizumab is an interleukin-2 receptor blocking humanized monoclonal antibody approved for use in relapsing forms of MS. It is self-administered as a subcutaneous injection once per month at a dose of 150 mg/mL. The drug’s label notes, “Because of its safety profile, the use of Zinbryta should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.” This FDA guidance is similar to that for alemtuzumab. “With more than a dozen drugs for MS, it is not too surprising we are seeing this,” Dr. Moses said.

The efficacy of the drug was demonstrated in two randomized, double-blind studies. One study compared daclizumab with interferon beta-1a. The other study compared daclizumab and placebo.

In the active comparator study, 919 patients received daclizumab and 922 received interferon beta-1a. Compared with interferon beta-1a, daclizumab had a statistically significant effect on annualized relapse rate (0.393 vs 0.216; relative reduction, 45%) and on the number of new or newly enlarging T2 hyperintense lesions. Treatment did not significantly affect 12-week confirmed disability progression.

In some patients, daclizumab has a significant impact on the liver. As a result, physicians are asked to assess transaminase levels and total bilirubin monthly during treatment and for six months after stopping therapy, Dr. Moses said.

Autoimmune hepatitis and other immune-mediated disorders, including lymphadenopathy, noninfectious colitis, and cutaneous adverse events, were seen with daclizumab treatment.

Dermatologic reactions to daclizumab can range from mild rashes to serious reactions, and can include psoriasiform nail changes, erythematous changes and swelling, and desquamation and erythema of the palms. Neurologists should advise patients that these reactions “could happen at any point while they are taking this medication,” Dr. Moses said. Some patients experienced reactions after receiving the therapy for nearly three years.Patients also experienced adverse events related to infection, including nasopharyngitis, bronchitis, and tonsillitis. “Daclizumab is the newest approved drug for relapsing MS,” Dr. Moses said. “It has a unique mechanism of action and a favorable dosing schedule. Challenges exist with monitoring requirements and potential serious adverse events.”

Ocrelizumab

Ocrelizumab is a humanized monoclonal antibody that depletes CD20+ B cells.

Two identical studies, OPERA I and II, evaluated ocrelizumab in patients with relapsing MS. Another trial, ORATORIO, assessed ocrelizumab in patients with primary progressive MS. In the trials, patients received 600 mg of ocrelizumab by IV infusion every 24 weeks.

In OPERA I and II, treatment with ocrelizumab resulted in a 46% and 47% reduction in annualized relapse rate, respectively, compared with interferon beta-1a. In addition, ocrelizumab reduced the risk of confirmed disability progression for 12 weeks by 43% and 37%, respectively. Ocrelizumab also dramatically reduced the number of T1 gadolinium-enhancing lesions and the number of new or enlarging T2 hyperintense lesions, compared with interferon beta-1a.

The ORATORIO study included 732 patients with primary progressive MS who received ocrelizumab or placebo. Patients were ages 18 to 55, had an Expanded Disability Status Scale score of 3.0 to 6.5, and had abnormal CSF. Patients were treated for at least 120 weeks. Investigators measured slowing of disability progression as the primary outcome. There was a 24% reduction in clinical disability sustained for at least 12 weeks, compared with placebo.

Ocrelizumab generally was well tolerated. In the clinical trials, a similar proportion of patients treated with ocrelizumab and controls experienced adverse events. In OPERA I and II, the most common adverse event associated with ocrelizumab was infusion-related reactions, which occurred in 34.3% of patients in the ocrelizumab arm, compared with 9.7% of patients in the interferon beta-1a arm.

In ORATORIO, more malignancies were reported in patients treated with ocrelizumab, compared with patients who received placebo (11 vs 2). The implications of that finding are unclear. “We will see how that plays out in terms of what the FDA thinks about that,” Dr. Moses said.

The FDA has granted a priority review designation to ocrelizumab, with a targeted action date of December 28, 2016. “Ocrelizumab remains on the horizon with a potential role in both relapsing and progressive MS,” Dr. Moses said.

—Jake Remaly

HILTON HEAD, SC—Managing patient expectations is important when discussing new and pending treatments for multiple sclerosis (MS), according to a lecture given at the 39th Annual Contemporary Clinical Neurology Symposium. The FDA’s recent approval of daclizumab and ongoing priority review of ocrelizumab mean that neurologists likely will be discussing these therapies with patients in their clinics. Conversations may revolve around efficacy, laboratory monitoring, and risk of adverse events.

In the case of daclizumab (Zinbryta), which was approved in May 2016, patient counseling may focus on monthly laboratory monitoring requirements that are part of the drug’s risk evaluation and mitigation strategy (REMS) program and the potential for adverse events at any time during treatment, said Harold Moses Jr, MD, Associate Professor of Neurology at Vanderbilt University in Nashville.

Ocrelizumab (Ocrevus) could be the first drug approved for primary progressive MS and a new treatment option for patients with relapsing MS. Neurologists may need to temper patients’ expectations regarding the drug’s efficacy in patients with more advanced progressive disease.

“If this drug gets approved for progressive MS, you are going to have a number of patients coming to your clinics to ask for this drug,” he said. It is unclear, however, how beneficial the treatment might be for patients with advanced disease, based on the clinical trial conducted in primary progressive MS. “In my opinion, if someone is 65 to 70 years old and has had primary progressive MS for 15 to 20 years and has been wheelchair-confined for five or more years, it is unlikely that this drug is going to be very meaningful for them. Although, I do not know that for a fact. Therefore, my plan is to offer this [treatment], probably for approximately a year, and see what happens. We will continue to follow them and make a decision together about continuing therapy or stopping.”

“Remember, half the people in the world who have MS have progressive disease,” Dr. Moses said. “They have seen more than 20 years of therapies [approved] for relapsing MS, so they have a lot of pent-up expectations about a treatment option, and rightfully so. I just think this potential treatment has to be discussed in a broader context of how the study was done.”

Daclizumab

Daclizumab is an interleukin-2 receptor blocking humanized monoclonal antibody approved for use in relapsing forms of MS. It is self-administered as a subcutaneous injection once per month at a dose of 150 mg/mL. The drug’s label notes, “Because of its safety profile, the use of Zinbryta should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.” This FDA guidance is similar to that for alemtuzumab. “With more than a dozen drugs for MS, it is not too surprising we are seeing this,” Dr. Moses said.

The efficacy of the drug was demonstrated in two randomized, double-blind studies. One study compared daclizumab with interferon beta-1a. The other study compared daclizumab and placebo.

In the active comparator study, 919 patients received daclizumab and 922 received interferon beta-1a. Compared with interferon beta-1a, daclizumab had a statistically significant effect on annualized relapse rate (0.393 vs 0.216; relative reduction, 45%) and on the number of new or newly enlarging T2 hyperintense lesions. Treatment did not significantly affect 12-week confirmed disability progression.

In some patients, daclizumab has a significant impact on the liver. As a result, physicians are asked to assess transaminase levels and total bilirubin monthly during treatment and for six months after stopping therapy, Dr. Moses said.

Autoimmune hepatitis and other immune-mediated disorders, including lymphadenopathy, noninfectious colitis, and cutaneous adverse events, were seen with daclizumab treatment.

Dermatologic reactions to daclizumab can range from mild rashes to serious reactions, and can include psoriasiform nail changes, erythematous changes and swelling, and desquamation and erythema of the palms. Neurologists should advise patients that these reactions “could happen at any point while they are taking this medication,” Dr. Moses said. Some patients experienced reactions after receiving the therapy for nearly three years.Patients also experienced adverse events related to infection, including nasopharyngitis, bronchitis, and tonsillitis. “Daclizumab is the newest approved drug for relapsing MS,” Dr. Moses said. “It has a unique mechanism of action and a favorable dosing schedule. Challenges exist with monitoring requirements and potential serious adverse events.”

Ocrelizumab

Ocrelizumab is a humanized monoclonal antibody that depletes CD20+ B cells.

Two identical studies, OPERA I and II, evaluated ocrelizumab in patients with relapsing MS. Another trial, ORATORIO, assessed ocrelizumab in patients with primary progressive MS. In the trials, patients received 600 mg of ocrelizumab by IV infusion every 24 weeks.

In OPERA I and II, treatment with ocrelizumab resulted in a 46% and 47% reduction in annualized relapse rate, respectively, compared with interferon beta-1a. In addition, ocrelizumab reduced the risk of confirmed disability progression for 12 weeks by 43% and 37%, respectively. Ocrelizumab also dramatically reduced the number of T1 gadolinium-enhancing lesions and the number of new or enlarging T2 hyperintense lesions, compared with interferon beta-1a.

The ORATORIO study included 732 patients with primary progressive MS who received ocrelizumab or placebo. Patients were ages 18 to 55, had an Expanded Disability Status Scale score of 3.0 to 6.5, and had abnormal CSF. Patients were treated for at least 120 weeks. Investigators measured slowing of disability progression as the primary outcome. There was a 24% reduction in clinical disability sustained for at least 12 weeks, compared with placebo.

Ocrelizumab generally was well tolerated. In the clinical trials, a similar proportion of patients treated with ocrelizumab and controls experienced adverse events. In OPERA I and II, the most common adverse event associated with ocrelizumab was infusion-related reactions, which occurred in 34.3% of patients in the ocrelizumab arm, compared with 9.7% of patients in the interferon beta-1a arm.

In ORATORIO, more malignancies were reported in patients treated with ocrelizumab, compared with patients who received placebo (11 vs 2). The implications of that finding are unclear. “We will see how that plays out in terms of what the FDA thinks about that,” Dr. Moses said.

The FDA has granted a priority review designation to ocrelizumab, with a targeted action date of December 28, 2016. “Ocrelizumab remains on the horizon with a potential role in both relapsing and progressive MS,” Dr. Moses said.

—Jake Remaly

HILTON HEAD—Multiple sclerosis (MS) is the most common demyelinating disease, and its mimics are rare, according to an overview provided at the 39th Annual Contemporary Clinical Neurology Symposium. Given that the treatments and outcomes for MS and its mimics are so different, neurologists should take care to establish a diagnosis early, said Sid Pawate, MD, Assistant Professor of Neurology at Vanderbilt University School of Medicine in Nashville.

Because of the varied clinical presentation of MS, a wide variety of conditions enter the differential diagnosis. Because of the central role that MRI plays in MS diagnosis, imaging mimics that cause white matter lesions also need to be considered, said Dr. Pawate. Typically, the white matter lesions seen in MS are periventricular, juxtacortical, and callososeptal in location. Infratentorially, cerebellar peduncles are a common site. The lesions tend to be ovoid, are 3 mm to 5 mm or larger, and appear hyperintense on T2 and FLAIR sequences. Acute lesions may show restricted diffusion or enhancement after the administration of gadolinium contrast.

Typical Presentations of MS

The three most common presentations of MS are transverse myelitis, optic neuritis, and brainstem–cerebellar dysfunction. Acute partial transverse myelitis is “the most classic” form of transverse myelitis among patients with MS, said Dr. Pawate. Acute complete transverse myelitis, on the other hand, may be postinfectious or idiopathic, or seen as part of acute disseminated encephalomyelitis (ADEM). Similarly, longitudinally extensive transverse myelitis is more suggestive of neuromyelitis optica spectrum disorders (NMOSD) than MS.

The most typical presentation of MS optic neuritis is unilateral and has acute or subacute onset. Patients often have retrobulbar, “gritty” pain when they move their eye. Complete blindness is unusual, and complete recovery occurs in nearly all patients. Hyperacute onset suggests a vascular process rather than optic neuritis, said Dr. Pawate. Slow, insidious onset may indicate an infiltrative process such as neoplasm or sarcoidosis. Painless vision loss may indicate ischemic optic neuropathy, and severe blindness without recovery may result from NMOSD.

The most pathognomonic brainstem dysfunction in MS is intranuclear ophthalmoplegia (INO), especially when it is bilateral. Other brainstem symptoms typical of MS include ataxia, painless diplopia, facial numbness, and trigeminal neuralgia in a young patient. Hyperacute or insidious onset of brainstem symptoms is unlikely to indicate MS. Symptoms that localize to a vascular territory usually result from a stroke. In addition, multiple cranial neuropathy is more suggestive of infections such as Lyme disease, sarcoidosis, or carcinomic ulcers.

Unusual Presentations of MS

Certain variants of MS do not present with the typical periventricular ovoid lesions. Tumefactive MS often presents with a large (ie, larger than 2 cm), solitary demyelinating lesion. These lesions usually are biopsied. Treatment with steroids usually brings improvement. After this first manifestation, the patient’s course is typical of relapsing-remitting MS. “Rarely do patients have tumefactive lesions in the middle of their MS course,” said Dr. Pawate.

Another unusual presentation is concentric rings of demyelination, sometimes with mass effect. This variant is called Balo’s concentric sclerosis, and the patient may have typical MS lesions in addition to the rings. “Historically, Balo’s concentric sclerosis was thought to be a severe disease with a poor prognosis,” said Dr. Pawate. “With the advent of MRI, we know that these [rings] are more common than we initially thought, and more benign—not much different from any other MS lesions.”

Patients also may present with multiple large lesions and aggressive disease onset. Such patients need early treatment. “When I see something like this, I treat aggressively using plasma exchange and IV steroids,” said Dr. Pawate. This treatment may be followed by natalizumab infusions, and the patients may make a good recovery. “Historically, this aggressive MS onset was called Marburg variant and was fatal,” said Dr. Pawate.

MS Mimics

ADEM is more common in children than in adults, and imaging can distinguish it from MS. One distinguishing feature of ADEM is that the patient has many lesions that appear to be of the same age. Lesions may appear on the basal ganglia and the thalamus, which is atypical for MS. Spinal cord lesions tend to be longer in ADEM, compared with those in MS. ADEM tends to have a monophasic course, and patients usually present with encephalopathy, headaches, and vomiting. Patients often have a history of preceding vaccination or infection.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) also can mimic MS on MRI. What distinguishes it from MS are lacunar infarcts, involvement in sites like the thalamus and basal ganglia, and gray matter involvement. CADASIL affects middle-aged adults and leads to disability and dementia.

If a patient referred for suspected MS has bilaterally symmetric confluent lesions, “think more in terms of leukodystrophies,” said Dr. Pawate. The absence of gadolinium enhancement is typical in leukodystrophies. The disorders may involve the U-fibers, the brainstem, or the cerebellum, and patients may present with cognitive decline.

Susac’s syndrome is a triad of branch retinal artery occlusion, sensorineural hearing loss, and encephalopathy. The syndrome is associated with a characteristic MRI that includes “spokes” (ie, linear lesions) and “snowballs” (ie, globular lesions) in the corpus callosum, as well as a “string of pearls” (ie, microinfarcts) in the internal capsule. In the eye, the most pathognomonic finding is hyperfluorescence of the arterial wall on fluorescein angiogram. Early treatment can produce good outcomes, but missing the diagnosis may quickly result in dementia, vision loss, and hearing loss.

Lupus can cause CNS manifestations, including cerebritis, vasculitis, and myelitis. “Primary CNS vasculitis can mimic MS on MRI sometimes, but the red flags are that the patient may have headache and infarcts on MRI, which are not seen in MS,” said Dr. Pawate. The white matter lesions in neurosarcoidosis can be similar to those in MS, but neurosarcoidosis also causes leptomeningeal enhancement and cranial nerve enhancement, which are not seen in MS.

—Erik Greb

Suggested Reading

Costello DJ, Eichler AF, Eichler FS. Leukodystrophies: classification, diagnosis, and treatment. Neurologist. 2009;15(6):319-328.

Kleinfeld K, Mobley B, Hedera P, et al. Adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia: report of five cases and a new mutation. J Neurol. 2013;260(2):558-571.

Pawate S, Agarwal A, Moses H, Sriram S. The spectrum of Susac’s syndrome. Neurol Sci. 2009;30(1):59-64.

HILTON HEAD—Multiple sclerosis (MS) is the most common demyelinating disease, and its mimics are rare, according to an overview provided at the 39th Annual Contemporary Clinical Neurology Symposium. Given that the treatments and outcomes for MS and its mimics are so different, neurologists should take care to establish a diagnosis early, said Sid Pawate, MD, Assistant Professor of Neurology at Vanderbilt University School of Medicine in Nashville.

Because of the varied clinical presentation of MS, a wide variety of conditions enter the differential diagnosis. Because of the central role that MRI plays in MS diagnosis, imaging mimics that cause white matter lesions also need to be considered, said Dr. Pawate. Typically, the white matter lesions seen in MS are periventricular, juxtacortical, and callososeptal in location. Infratentorially, cerebellar peduncles are a common site. The lesions tend to be ovoid, are 3 mm to 5 mm or larger, and appear hyperintense on T2 and FLAIR sequences. Acute lesions may show restricted diffusion or enhancement after the administration of gadolinium contrast.

Typical Presentations of MS

The three most common presentations of MS are transverse myelitis, optic neuritis, and brainstem–cerebellar dysfunction. Acute partial transverse myelitis is “the most classic” form of transverse myelitis among patients with MS, said Dr. Pawate. Acute complete transverse myelitis, on the other hand, may be postinfectious or idiopathic, or seen as part of acute disseminated encephalomyelitis (ADEM). Similarly, longitudinally extensive transverse myelitis is more suggestive of neuromyelitis optica spectrum disorders (NMOSD) than MS.

The most typical presentation of MS optic neuritis is unilateral and has acute or subacute onset. Patients often have retrobulbar, “gritty” pain when they move their eye. Complete blindness is unusual, and complete recovery occurs in nearly all patients. Hyperacute onset suggests a vascular process rather than optic neuritis, said Dr. Pawate. Slow, insidious onset may indicate an infiltrative process such as neoplasm or sarcoidosis. Painless vision loss may indicate ischemic optic neuropathy, and severe blindness without recovery may result from NMOSD.

The most pathognomonic brainstem dysfunction in MS is intranuclear ophthalmoplegia (INO), especially when it is bilateral. Other brainstem symptoms typical of MS include ataxia, painless diplopia, facial numbness, and trigeminal neuralgia in a young patient. Hyperacute or insidious onset of brainstem symptoms is unlikely to indicate MS. Symptoms that localize to a vascular territory usually result from a stroke. In addition, multiple cranial neuropathy is more suggestive of infections such as Lyme disease, sarcoidosis, or carcinomic ulcers.

Unusual Presentations of MS

Certain variants of MS do not present with the typical periventricular ovoid lesions. Tumefactive MS often presents with a large (ie, larger than 2 cm), solitary demyelinating lesion. These lesions usually are biopsied. Treatment with steroids usually brings improvement. After this first manifestation, the patient’s course is typical of relapsing-remitting MS. “Rarely do patients have tumefactive lesions in the middle of their MS course,” said Dr. Pawate.

Another unusual presentation is concentric rings of demyelination, sometimes with mass effect. This variant is called Balo’s concentric sclerosis, and the patient may have typical MS lesions in addition to the rings. “Historically, Balo’s concentric sclerosis was thought to be a severe disease with a poor prognosis,” said Dr. Pawate. “With the advent of MRI, we know that these [rings] are more common than we initially thought, and more benign—not much different from any other MS lesions.”

Patients also may present with multiple large lesions and aggressive disease onset. Such patients need early treatment. “When I see something like this, I treat aggressively using plasma exchange and IV steroids,” said Dr. Pawate. This treatment may be followed by natalizumab infusions, and the patients may make a good recovery. “Historically, this aggressive MS onset was called Marburg variant and was fatal,” said Dr. Pawate.

MS Mimics

ADEM is more common in children than in adults, and imaging can distinguish it from MS. One distinguishing feature of ADEM is that the patient has many lesions that appear to be of the same age. Lesions may appear on the basal ganglia and the thalamus, which is atypical for MS. Spinal cord lesions tend to be longer in ADEM, compared with those in MS. ADEM tends to have a monophasic course, and patients usually present with encephalopathy, headaches, and vomiting. Patients often have a history of preceding vaccination or infection.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) also can mimic MS on MRI. What distinguishes it from MS are lacunar infarcts, involvement in sites like the thalamus and basal ganglia, and gray matter involvement. CADASIL affects middle-aged adults and leads to disability and dementia.

If a patient referred for suspected MS has bilaterally symmetric confluent lesions, “think more in terms of leukodystrophies,” said Dr. Pawate. The absence of gadolinium enhancement is typical in leukodystrophies. The disorders may involve the U-fibers, the brainstem, or the cerebellum, and patients may present with cognitive decline.

Susac’s syndrome is a triad of branch retinal artery occlusion, sensorineural hearing loss, and encephalopathy. The syndrome is associated with a characteristic MRI that includes “spokes” (ie, linear lesions) and “snowballs” (ie, globular lesions) in the corpus callosum, as well as a “string of pearls” (ie, microinfarcts) in the internal capsule. In the eye, the most pathognomonic finding is hyperfluorescence of the arterial wall on fluorescein angiogram. Early treatment can produce good outcomes, but missing the diagnosis may quickly result in dementia, vision loss, and hearing loss.

Lupus can cause CNS manifestations, including cerebritis, vasculitis, and myelitis. “Primary CNS vasculitis can mimic MS on MRI sometimes, but the red flags are that the patient may have headache and infarcts on MRI, which are not seen in MS,” said Dr. Pawate. The white matter lesions in neurosarcoidosis can be similar to those in MS, but neurosarcoidosis also causes leptomeningeal enhancement and cranial nerve enhancement, which are not seen in MS.

—Erik Greb

Suggested Reading

Costello DJ, Eichler AF, Eichler FS. Leukodystrophies: classification, diagnosis, and treatment. Neurologist. 2009;15(6):319-328.

Kleinfeld K, Mobley B, Hedera P, et al. Adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia: report of five cases and a new mutation. J Neurol. 2013;260(2):558-571.

Pawate S, Agarwal A, Moses H, Sriram S. The spectrum of Susac’s syndrome. Neurol Sci. 2009;30(1):59-64.

HILTON HEAD—Multiple sclerosis (MS) is the most common demyelinating disease, and its mimics are rare, according to an overview provided at the 39th Annual Contemporary Clinical Neurology Symposium. Given that the treatments and outcomes for MS and its mimics are so different, neurologists should take care to establish a diagnosis early, said Sid Pawate, MD, Assistant Professor of Neurology at Vanderbilt University School of Medicine in Nashville.

Because of the varied clinical presentation of MS, a wide variety of conditions enter the differential diagnosis. Because of the central role that MRI plays in MS diagnosis, imaging mimics that cause white matter lesions also need to be considered, said Dr. Pawate. Typically, the white matter lesions seen in MS are periventricular, juxtacortical, and callososeptal in location. Infratentorially, cerebellar peduncles are a common site. The lesions tend to be ovoid, are 3 mm to 5 mm or larger, and appear hyperintense on T2 and FLAIR sequences. Acute lesions may show restricted diffusion or enhancement after the administration of gadolinium contrast.

Typical Presentations of MS

The three most common presentations of MS are transverse myelitis, optic neuritis, and brainstem–cerebellar dysfunction. Acute partial transverse myelitis is “the most classic” form of transverse myelitis among patients with MS, said Dr. Pawate. Acute complete transverse myelitis, on the other hand, may be postinfectious or idiopathic, or seen as part of acute disseminated encephalomyelitis (ADEM). Similarly, longitudinally extensive transverse myelitis is more suggestive of neuromyelitis optica spectrum disorders (NMOSD) than MS.

The most typical presentation of MS optic neuritis is unilateral and has acute or subacute onset. Patients often have retrobulbar, “gritty” pain when they move their eye. Complete blindness is unusual, and complete recovery occurs in nearly all patients. Hyperacute onset suggests a vascular process rather than optic neuritis, said Dr. Pawate. Slow, insidious onset may indicate an infiltrative process such as neoplasm or sarcoidosis. Painless vision loss may indicate ischemic optic neuropathy, and severe blindness without recovery may result from NMOSD.

The most pathognomonic brainstem dysfunction in MS is intranuclear ophthalmoplegia (INO), especially when it is bilateral. Other brainstem symptoms typical of MS include ataxia, painless diplopia, facial numbness, and trigeminal neuralgia in a young patient. Hyperacute or insidious onset of brainstem symptoms is unlikely to indicate MS. Symptoms that localize to a vascular territory usually result from a stroke. In addition, multiple cranial neuropathy is more suggestive of infections such as Lyme disease, sarcoidosis, or carcinomic ulcers.

Unusual Presentations of MS

Certain variants of MS do not present with the typical periventricular ovoid lesions. Tumefactive MS often presents with a large (ie, larger than 2 cm), solitary demyelinating lesion. These lesions usually are biopsied. Treatment with steroids usually brings improvement. After this first manifestation, the patient’s course is typical of relapsing-remitting MS. “Rarely do patients have tumefactive lesions in the middle of their MS course,” said Dr. Pawate.

Another unusual presentation is concentric rings of demyelination, sometimes with mass effect. This variant is called Balo’s concentric sclerosis, and the patient may have typical MS lesions in addition to the rings. “Historically, Balo’s concentric sclerosis was thought to be a severe disease with a poor prognosis,” said Dr. Pawate. “With the advent of MRI, we know that these [rings] are more common than we initially thought, and more benign—not much different from any other MS lesions.”

Patients also may present with multiple large lesions and aggressive disease onset. Such patients need early treatment. “When I see something like this, I treat aggressively using plasma exchange and IV steroids,” said Dr. Pawate. This treatment may be followed by natalizumab infusions, and the patients may make a good recovery. “Historically, this aggressive MS onset was called Marburg variant and was fatal,” said Dr. Pawate.

MS Mimics

ADEM is more common in children than in adults, and imaging can distinguish it from MS. One distinguishing feature of ADEM is that the patient has many lesions that appear to be of the same age. Lesions may appear on the basal ganglia and the thalamus, which is atypical for MS. Spinal cord lesions tend to be longer in ADEM, compared with those in MS. ADEM tends to have a monophasic course, and patients usually present with encephalopathy, headaches, and vomiting. Patients often have a history of preceding vaccination or infection.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) also can mimic MS on MRI. What distinguishes it from MS are lacunar infarcts, involvement in sites like the thalamus and basal ganglia, and gray matter involvement. CADASIL affects middle-aged adults and leads to disability and dementia.

If a patient referred for suspected MS has bilaterally symmetric confluent lesions, “think more in terms of leukodystrophies,” said Dr. Pawate. The absence of gadolinium enhancement is typical in leukodystrophies. The disorders may involve the U-fibers, the brainstem, or the cerebellum, and patients may present with cognitive decline.

Susac’s syndrome is a triad of branch retinal artery occlusion, sensorineural hearing loss, and encephalopathy. The syndrome is associated with a characteristic MRI that includes “spokes” (ie, linear lesions) and “snowballs” (ie, globular lesions) in the corpus callosum, as well as a “string of pearls” (ie, microinfarcts) in the internal capsule. In the eye, the most pathognomonic finding is hyperfluorescence of the arterial wall on fluorescein angiogram. Early treatment can produce good outcomes, but missing the diagnosis may quickly result in dementia, vision loss, and hearing loss.

Lupus can cause CNS manifestations, including cerebritis, vasculitis, and myelitis. “Primary CNS vasculitis can mimic MS on MRI sometimes, but the red flags are that the patient may have headache and infarcts on MRI, which are not seen in MS,” said Dr. Pawate. The white matter lesions in neurosarcoidosis can be similar to those in MS, but neurosarcoidosis also causes leptomeningeal enhancement and cranial nerve enhancement, which are not seen in MS.

—Erik Greb

Suggested Reading

Costello DJ, Eichler AF, Eichler FS. Leukodystrophies: classification, diagnosis, and treatment. Neurologist. 2009;15(6):319-328.

Kleinfeld K, Mobley B, Hedera P, et al. Adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia: report of five cases and a new mutation. J Neurol. 2013;260(2):558-571.

Pawate S, Agarwal A, Moses H, Sriram S. The spectrum of Susac’s syndrome. Neurol Sci. 2009;30(1):59-64.

LONDON – Real-world data show that the disease-modifying multiple sclerosis drug alemtuzumab is as effective as natalizumab for preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.

Three separate analyses of data involving more than 4,000 patients included in the MSBase Registry and from seven European MS centers showed that alemtuzumab (Lemtrada) was also more effective than subcutaneous interferon beta-1a (IFN beta-1a; Rebif) and fingolimod (Gilenya) for relapse prevention.

“We have seen that alemtuzumab is superior to IFN beta-1a subcutaneous administration in suppressing relapse activity and, in patients with a perilously high level of relapse activity, also in suppressing the probability of reaching disability progression and increasing the probability of reaching disability regression,” Tomas Kalincik, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Furthermore, “alemtuzumab was superior to fingolimod in suppressing annualized relapse rates, and comparable to natalizumab (Tysabri) in controlling relapse activity and limiting the probability of disability progression,” said Dr. Kalincik of the University of Melbourne.

Head-to-head trials of MS therapies are lacking, so the aim of the observational study was to compare the treatment effectiveness of alemtuzumab versus natalizumab, IFN beta-1a, and fingolimod. Specifically, the aim was to look at the annualized relapse rate (ARR), cumulative hazard of relapses, and 6-month Expanded Disability Scale Score (EDSS) progression and regression. Propensity score matching was used to make the comparisons between alemtuzumab and the other MS treatments.

Patient data were retrospectively taken from the MSbase database, which includes prospectively collected data from more than 41,000 patients with MS treated at 119 centers in 35 countries. For inclusion in the present analysis, patients had to have definite relapsing-remitting multiple sclerosis, a baseline EDSS of 0-5.5, age of 65 years or younger, and duration of MS of 10 years or less, as well as one or more relapses in the previous year. Patients also needed to have a minimum follow-up of 12 months before and 6 months after they started treatment, and a minimum of two post-baseline visits that were 6 months apart.

Of 15,763 patients with definite MS who commenced treatment with one of the four MS therapies being considered, 4,332 met all the inclusion criteria. Of these, 189 were treated with alemtuzumab, 1,160 with natalizumab, 2,155 with IFN beta-1a, and 828 with fingolimod. Dr. Kalincik noted that the alemtuzumab patient data were combined from seven European MS centers and not the MSBase database.

Versus interferon beta-1a

The first data analysis involved 124 alemtuzumab-treated patients and 219 IFN beta-1a-treated patients with 5 years’ follow-up. Compared with IFN beta-1a, alemtuzumab was associated with an overall lower 5-year ARR of 0.2 versus 0.5 (P less than .001). The annual relapse rates by each individual year were also all significantly lower with alemtuzumab, and the cumulative hazard ratio (HR) of relapses was 0.42 (P less than .001), indicating an almost 60% reduction in relapses over time.

In terms of disability progression, alemtuzumab did not show an advantage over IFN beta-1a, which is in contrast to the findings of its pivotal trials, Dr. Kalincik observed. However, alemtuzumab was found to have an advantage over IFN beta-1a therapy in a secondary analysis if patients had highly active disease, defined as either three or more relapses over a 2-year period or two or more relapses over a 1-year period. The HR for confirmed disability progression was 0.64 (P = .016). Patients with on-treatment relapses within the previous year also fared better if treated with alemtuzumab, with a HR of 3.9 (P = .028) for confirmed disability regression.

Versus fingolimod

The second data analysis involved 114 alemtuzumab-treated patients and 195 fingolimod-treated patients with 3 years’ follow-up. When compared with fingolimod, there was again a much lower ARR overall (0.15 vs. 0.3; P less than .001) at 3 years, and at years 1, 2, and 3 individually (P less than .05). There was a nonsignificant 40% reduction in the relapse rate over time.

“For the disability outcomes, we haven’t seen any statistically significant difference, neither between the 6-month confirmed disability progression nor the 6-month confirmed disability regression,” Dr. Kalincik reported.

Versus natalizumab

The third and final analysis involved 138 alemtuzumab-treated patients and 223 natalizumab-treated patients with 4 years’ follow-up. There were no significant differences found in either the ARR overall (0.2 for both treatments; P = .8) or by follow-up year, and the cumulative hazard of relapses was the same.

Although there was no significant difference in confirmed disability progression at 6 months between the two treatments, there was a significant difference observed for the confirmed 6-month disability regression that favored natalizumab during the first year of treatment, Dr. Kalincik said. After 1 year, this potential advantage disappeared, he observed.

A large number of sensitivity analyses were performed and “largely confirm” the outcomes of the primary analyses.

Limitations include the lack of MRI data, and it was not possible to evaluate the relative safety of treatments.

Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.

LONDON – Real-world data show that the disease-modifying multiple sclerosis drug alemtuzumab is as effective as natalizumab for preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.

Three separate analyses of data involving more than 4,000 patients included in the MSBase Registry and from seven European MS centers showed that alemtuzumab (Lemtrada) was also more effective than subcutaneous interferon beta-1a (IFN beta-1a; Rebif) and fingolimod (Gilenya) for relapse prevention.

“We have seen that alemtuzumab is superior to IFN beta-1a subcutaneous administration in suppressing relapse activity and, in patients with a perilously high level of relapse activity, also in suppressing the probability of reaching disability progression and increasing the probability of reaching disability regression,” Tomas Kalincik, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Furthermore, “alemtuzumab was superior to fingolimod in suppressing annualized relapse rates, and comparable to natalizumab (Tysabri) in controlling relapse activity and limiting the probability of disability progression,” said Dr. Kalincik of the University of Melbourne.

Head-to-head trials of MS therapies are lacking, so the aim of the observational study was to compare the treatment effectiveness of alemtuzumab versus natalizumab, IFN beta-1a, and fingolimod. Specifically, the aim was to look at the annualized relapse rate (ARR), cumulative hazard of relapses, and 6-month Expanded Disability Scale Score (EDSS) progression and regression. Propensity score matching was used to make the comparisons between alemtuzumab and the other MS treatments.

Patient data were retrospectively taken from the MSbase database, which includes prospectively collected data from more than 41,000 patients with MS treated at 119 centers in 35 countries. For inclusion in the present analysis, patients had to have definite relapsing-remitting multiple sclerosis, a baseline EDSS of 0-5.5, age of 65 years or younger, and duration of MS of 10 years or less, as well as one or more relapses in the previous year. Patients also needed to have a minimum follow-up of 12 months before and 6 months after they started treatment, and a minimum of two post-baseline visits that were 6 months apart.

Of 15,763 patients with definite MS who commenced treatment with one of the four MS therapies being considered, 4,332 met all the inclusion criteria. Of these, 189 were treated with alemtuzumab, 1,160 with natalizumab, 2,155 with IFN beta-1a, and 828 with fingolimod. Dr. Kalincik noted that the alemtuzumab patient data were combined from seven European MS centers and not the MSBase database.

Versus interferon beta-1a

The first data analysis involved 124 alemtuzumab-treated patients and 219 IFN beta-1a-treated patients with 5 years’ follow-up. Compared with IFN beta-1a, alemtuzumab was associated with an overall lower 5-year ARR of 0.2 versus 0.5 (P less than .001). The annual relapse rates by each individual year were also all significantly lower with alemtuzumab, and the cumulative hazard ratio (HR) of relapses was 0.42 (P less than .001), indicating an almost 60% reduction in relapses over time.

In terms of disability progression, alemtuzumab did not show an advantage over IFN beta-1a, which is in contrast to the findings of its pivotal trials, Dr. Kalincik observed. However, alemtuzumab was found to have an advantage over IFN beta-1a therapy in a secondary analysis if patients had highly active disease, defined as either three or more relapses over a 2-year period or two or more relapses over a 1-year period. The HR for confirmed disability progression was 0.64 (P = .016). Patients with on-treatment relapses within the previous year also fared better if treated with alemtuzumab, with a HR of 3.9 (P = .028) for confirmed disability regression.

Versus fingolimod

The second data analysis involved 114 alemtuzumab-treated patients and 195 fingolimod-treated patients with 3 years’ follow-up. When compared with fingolimod, there was again a much lower ARR overall (0.15 vs. 0.3; P less than .001) at 3 years, and at years 1, 2, and 3 individually (P less than .05). There was a nonsignificant 40% reduction in the relapse rate over time.

“For the disability outcomes, we haven’t seen any statistically significant difference, neither between the 6-month confirmed disability progression nor the 6-month confirmed disability regression,” Dr. Kalincik reported.

Versus natalizumab

The third and final analysis involved 138 alemtuzumab-treated patients and 223 natalizumab-treated patients with 4 years’ follow-up. There were no significant differences found in either the ARR overall (0.2 for both treatments; P = .8) or by follow-up year, and the cumulative hazard of relapses was the same.

Although there was no significant difference in confirmed disability progression at 6 months between the two treatments, there was a significant difference observed for the confirmed 6-month disability regression that favored natalizumab during the first year of treatment, Dr. Kalincik said. After 1 year, this potential advantage disappeared, he observed.

A large number of sensitivity analyses were performed and “largely confirm” the outcomes of the primary analyses.

Limitations include the lack of MRI data, and it was not possible to evaluate the relative safety of treatments.

Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.

LONDON – Real-world data show that the disease-modifying multiple sclerosis drug alemtuzumab is as effective as natalizumab for preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.

Three separate analyses of data involving more than 4,000 patients included in the MSBase Registry and from seven European MS centers showed that alemtuzumab (Lemtrada) was also more effective than subcutaneous interferon beta-1a (IFN beta-1a; Rebif) and fingolimod (Gilenya) for relapse prevention.

“We have seen that alemtuzumab is superior to IFN beta-1a subcutaneous administration in suppressing relapse activity and, in patients with a perilously high level of relapse activity, also in suppressing the probability of reaching disability progression and increasing the probability of reaching disability regression,” Tomas Kalincik, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Furthermore, “alemtuzumab was superior to fingolimod in suppressing annualized relapse rates, and comparable to natalizumab (Tysabri) in controlling relapse activity and limiting the probability of disability progression,” said Dr. Kalincik of the University of Melbourne.

Head-to-head trials of MS therapies are lacking, so the aim of the observational study was to compare the treatment effectiveness of alemtuzumab versus natalizumab, IFN beta-1a, and fingolimod. Specifically, the aim was to look at the annualized relapse rate (ARR), cumulative hazard of relapses, and 6-month Expanded Disability Scale Score (EDSS) progression and regression. Propensity score matching was used to make the comparisons between alemtuzumab and the other MS treatments.

Patient data were retrospectively taken from the MSbase database, which includes prospectively collected data from more than 41,000 patients with MS treated at 119 centers in 35 countries. For inclusion in the present analysis, patients had to have definite relapsing-remitting multiple sclerosis, a baseline EDSS of 0-5.5, age of 65 years or younger, and duration of MS of 10 years or less, as well as one or more relapses in the previous year. Patients also needed to have a minimum follow-up of 12 months before and 6 months after they started treatment, and a minimum of two post-baseline visits that were 6 months apart.

Of 15,763 patients with definite MS who commenced treatment with one of the four MS therapies being considered, 4,332 met all the inclusion criteria. Of these, 189 were treated with alemtuzumab, 1,160 with natalizumab, 2,155 with IFN beta-1a, and 828 with fingolimod. Dr. Kalincik noted that the alemtuzumab patient data were combined from seven European MS centers and not the MSBase database.

Versus interferon beta-1a

The first data analysis involved 124 alemtuzumab-treated patients and 219 IFN beta-1a-treated patients with 5 years’ follow-up. Compared with IFN beta-1a, alemtuzumab was associated with an overall lower 5-year ARR of 0.2 versus 0.5 (P less than .001). The annual relapse rates by each individual year were also all significantly lower with alemtuzumab, and the cumulative hazard ratio (HR) of relapses was 0.42 (P less than .001), indicating an almost 60% reduction in relapses over time.

In terms of disability progression, alemtuzumab did not show an advantage over IFN beta-1a, which is in contrast to the findings of its pivotal trials, Dr. Kalincik observed. However, alemtuzumab was found to have an advantage over IFN beta-1a therapy in a secondary analysis if patients had highly active disease, defined as either three or more relapses over a 2-year period or two or more relapses over a 1-year period. The HR for confirmed disability progression was 0.64 (P = .016). Patients with on-treatment relapses within the previous year also fared better if treated with alemtuzumab, with a HR of 3.9 (P = .028) for confirmed disability regression.

Versus fingolimod

The second data analysis involved 114 alemtuzumab-treated patients and 195 fingolimod-treated patients with 3 years’ follow-up. When compared with fingolimod, there was again a much lower ARR overall (0.15 vs. 0.3; P less than .001) at 3 years, and at years 1, 2, and 3 individually (P less than .05). There was a nonsignificant 40% reduction in the relapse rate over time.

“For the disability outcomes, we haven’t seen any statistically significant difference, neither between the 6-month confirmed disability progression nor the 6-month confirmed disability regression,” Dr. Kalincik reported.

Versus natalizumab

The third and final analysis involved 138 alemtuzumab-treated patients and 223 natalizumab-treated patients with 4 years’ follow-up. There were no significant differences found in either the ARR overall (0.2 for both treatments; P = .8) or by follow-up year, and the cumulative hazard of relapses was the same.

Although there was no significant difference in confirmed disability progression at 6 months between the two treatments, there was a significant difference observed for the confirmed 6-month disability regression that favored natalizumab during the first year of treatment, Dr. Kalincik said. After 1 year, this potential advantage disappeared, he observed.

A large number of sensitivity analyses were performed and “largely confirm” the outcomes of the primary analyses.

Limitations include the lack of MRI data, and it was not possible to evaluate the relative safety of treatments.

Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.

Primary progressive MS is characterized by steadily increasing, objectively documented neurologic dysfunction or disability without recovery, although patients may have fluctuations and phases of stability.

Primary progressive MS remains a severely disabling condition with high unmet medical need. Investigators believe that B cells contribute to the pathogenesis of MS, including primary progressive MS. Ocrelizumab, a recombinant humanized monoclonal antibody that selectively targets CD20⁺ B cells, showed superior efficacy and favorable safety, compared with placebo, in the phase III ORATORIO study in patients with primary progressive MS.

Xavier Montalban, MD, PhD, Chair of the Department of Neurology-Neuroimmunology and Director of the Multiple Sclerosis Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, and colleagues sought to assess the effect of ocrelizumab from baseline to Week 120 on the proportion of patients with NEP in the ORATORIO study.

In all, 732 patients were randomized (2:1) to receive 600 mg of ocrelizumab as two 300-mg IV infusions 14 days apart, or placebo every 24 weeks for at least 120 weeks until a prespecified number of 12-week confirmed disability progression events (as measured by Expanded Disability Status Scale score) occurred. Patients with NEP were defined as having no 12-week confirmed disability progression, and no 12-week confirmed progression of 20% or more on the timed 25-foot walk test and on the nine-hole peg test. A total of 230 placebo-treated patients and 461 ocrelizumab-treated patients were evaluable in this exploratory analysis of the ORATORIO trial.

Compared with placebo, ocrelizumab significantly increased the proportion of patients with NEP at Week 120. The relative risk of NEP for ocrelizumab versus placebo was 1.47. The proportions of ocrelizumab- and placebo-treated patients with NEP up to Week 120 were 42.7% and 29.1%, respectively. This result represents a 47% relative increase in the ocrelizumab group. The proportions of ocrelizumab- and placebo-treated patients with NEP for the individual components of NEP up to Week 120 were 68.5% and 63.0%, respectively, for 12-week confirmed disability progression; 51.0% and 38.7%, respectively, for the timed 25-foot walk test; and 82.2% and 71.3%, respectively for the nine-hole peg test.

The study was sponsored by F. Hoffmann-La Roche.

Primary progressive MS is characterized by steadily increasing, objectively documented neurologic dysfunction or disability without recovery, although patients may have fluctuations and phases of stability.

Primary progressive MS remains a severely disabling condition with high unmet medical need. Investigators believe that B cells contribute to the pathogenesis of MS, including primary progressive MS. Ocrelizumab, a recombinant humanized monoclonal antibody that selectively targets CD20⁺ B cells, showed superior efficacy and favorable safety, compared with placebo, in the phase III ORATORIO study in patients with primary progressive MS.

Xavier Montalban, MD, PhD, Chair of the Department of Neurology-Neuroimmunology and Director of the Multiple Sclerosis Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, and colleagues sought to assess the effect of ocrelizumab from baseline to Week 120 on the proportion of patients with NEP in the ORATORIO study.

In all, 732 patients were randomized (2:1) to receive 600 mg of ocrelizumab as two 300-mg IV infusions 14 days apart, or placebo every 24 weeks for at least 120 weeks until a prespecified number of 12-week confirmed disability progression events (as measured by Expanded Disability Status Scale score) occurred. Patients with NEP were defined as having no 12-week confirmed disability progression, and no 12-week confirmed progression of 20% or more on the timed 25-foot walk test and on the nine-hole peg test. A total of 230 placebo-treated patients and 461 ocrelizumab-treated patients were evaluable in this exploratory analysis of the ORATORIO trial.

Compared with placebo, ocrelizumab significantly increased the proportion of patients with NEP at Week 120. The relative risk of NEP for ocrelizumab versus placebo was 1.47. The proportions of ocrelizumab- and placebo-treated patients with NEP up to Week 120 were 42.7% and 29.1%, respectively. This result represents a 47% relative increase in the ocrelizumab group. The proportions of ocrelizumab- and placebo-treated patients with NEP for the individual components of NEP up to Week 120 were 68.5% and 63.0%, respectively, for 12-week confirmed disability progression; 51.0% and 38.7%, respectively, for the timed 25-foot walk test; and 82.2% and 71.3%, respectively for the nine-hole peg test.

The study was sponsored by F. Hoffmann-La Roche.

Primary progressive MS is characterized by steadily increasing, objectively documented neurologic dysfunction or disability without recovery, although patients may have fluctuations and phases of stability.

Primary progressive MS remains a severely disabling condition with high unmet medical need. Investigators believe that B cells contribute to the pathogenesis of MS, including primary progressive MS. Ocrelizumab, a recombinant humanized monoclonal antibody that selectively targets CD20⁺ B cells, showed superior efficacy and favorable safety, compared with placebo, in the phase III ORATORIO study in patients with primary progressive MS.

Xavier Montalban, MD, PhD, Chair of the Department of Neurology-Neuroimmunology and Director of the Multiple Sclerosis Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, and colleagues sought to assess the effect of ocrelizumab from baseline to Week 120 on the proportion of patients with NEP in the ORATORIO study.

In all, 732 patients were randomized (2:1) to receive 600 mg of ocrelizumab as two 300-mg IV infusions 14 days apart, or placebo every 24 weeks for at least 120 weeks until a prespecified number of 12-week confirmed disability progression events (as measured by Expanded Disability Status Scale score) occurred. Patients with NEP were defined as having no 12-week confirmed disability progression, and no 12-week confirmed progression of 20% or more on the timed 25-foot walk test and on the nine-hole peg test. A total of 230 placebo-treated patients and 461 ocrelizumab-treated patients were evaluable in this exploratory analysis of the ORATORIO trial.

Compared with placebo, ocrelizumab significantly increased the proportion of patients with NEP at Week 120. The relative risk of NEP for ocrelizumab versus placebo was 1.47. The proportions of ocrelizumab- and placebo-treated patients with NEP up to Week 120 were 42.7% and 29.1%, respectively. This result represents a 47% relative increase in the ocrelizumab group. The proportions of ocrelizumab- and placebo-treated patients with NEP for the individual components of NEP up to Week 120 were 68.5% and 63.0%, respectively, for 12-week confirmed disability progression; 51.0% and 38.7%, respectively, for the timed 25-foot walk test; and 82.2% and 71.3%, respectively for the nine-hole peg test.

The study was sponsored by F. Hoffmann-La Roche.

Spasticity is common in MS and is associated with significant morbidity. The standard treatment is oral administration of baclofen, a γ-aminobutyric acid-b (GABA-b) receptor agonist. Baclofen is a racemic mixture, and its efficacy is thought to result from the R-enantiomer (arbaclofen). Therapeutic doses of baclofen can cause CNS side effects, decreased adherence, and decreased tolerability. Arbaclofen extended-release tablets potentially could reduce dosing frequency and adverse events.

Daniel Kantor, MD, a neurologist from Coconut Creek, Florida, and colleagues conducted a multicenter, randomized, double-blind, parallel-group study to compare the efficacy and safety of arbaclofen extended-release tablets to those of placebo and baclofen over 12 weeks of treatment in patients with spasticity due to MS. Participants were randomized to receive 20 mg of arbaclofen bid, 20 mg of baclofen tablets qid, or matching placebo. The dose was titrated over four weeks, followed by a 12-week maintenance period. The primary end points were the mean changes in Total Numeric-transformed Modified Ashworth Scale (TNmAS) and Clinician Global Impression of Change (CGIC) at the end of the maintenance period.

Of 354 randomized participants, 59.0% had relapsing-remitting MS and 36.7% had secondary progressive MS. The average baseline TNmAS score was 7.78. Mean changes in TNmAS and CGIC were significantly greater for patients receiving arbaclofen, compared with patients receiving placebo. The researchers observed a greater difference in CGIC between arbaclofen and placebo, compared with that between baclofen and placebo, perhaps because of improved tolerability of arbaclofen, compared with baclofen. Differences between arbaclofen and baclofen were not statistically significant. MS Spasticity Scale (MSSS-88) showed a statistically significant improvement among patients receiving arbaclofen, compared with those receiving placebo. Epworth Sleepiness Scale (ESS) showed a statistically significant increase in sleepiness in the baclofen group, but not in the arbaclofen group, compared with placebo. Drowsiness and dizziness were less frequent in the arbaclofen group, compared with baclofen.

The study was supported by Osmotica Pharmaceutical.

Spasticity is common in MS and is associated with significant morbidity. The standard treatment is oral administration of baclofen, a γ-aminobutyric acid-b (GABA-b) receptor agonist. Baclofen is a racemic mixture, and its efficacy is thought to result from the R-enantiomer (arbaclofen). Therapeutic doses of baclofen can cause CNS side effects, decreased adherence, and decreased tolerability. Arbaclofen extended-release tablets potentially could reduce dosing frequency and adverse events.

Daniel Kantor, MD, a neurologist from Coconut Creek, Florida, and colleagues conducted a multicenter, randomized, double-blind, parallel-group study to compare the efficacy and safety of arbaclofen extended-release tablets to those of placebo and baclofen over 12 weeks of treatment in patients with spasticity due to MS. Participants were randomized to receive 20 mg of arbaclofen bid, 20 mg of baclofen tablets qid, or matching placebo. The dose was titrated over four weeks, followed by a 12-week maintenance period. The primary end points were the mean changes in Total Numeric-transformed Modified Ashworth Scale (TNmAS) and Clinician Global Impression of Change (CGIC) at the end of the maintenance period.

Of 354 randomized participants, 59.0% had relapsing-remitting MS and 36.7% had secondary progressive MS. The average baseline TNmAS score was 7.78. Mean changes in TNmAS and CGIC were significantly greater for patients receiving arbaclofen, compared with patients receiving placebo. The researchers observed a greater difference in CGIC between arbaclofen and placebo, compared with that between baclofen and placebo, perhaps because of improved tolerability of arbaclofen, compared with baclofen. Differences between arbaclofen and baclofen were not statistically significant. MS Spasticity Scale (MSSS-88) showed a statistically significant improvement among patients receiving arbaclofen, compared with those receiving placebo. Epworth Sleepiness Scale (ESS) showed a statistically significant increase in sleepiness in the baclofen group, but not in the arbaclofen group, compared with placebo. Drowsiness and dizziness were less frequent in the arbaclofen group, compared with baclofen.

The study was supported by Osmotica Pharmaceutical.

Spasticity is common in MS and is associated with significant morbidity. The standard treatment is oral administration of baclofen, a γ-aminobutyric acid-b (GABA-b) receptor agonist. Baclofen is a racemic mixture, and its efficacy is thought to result from the R-enantiomer (arbaclofen). Therapeutic doses of baclofen can cause CNS side effects, decreased adherence, and decreased tolerability. Arbaclofen extended-release tablets potentially could reduce dosing frequency and adverse events.

Daniel Kantor, MD, a neurologist from Coconut Creek, Florida, and colleagues conducted a multicenter, randomized, double-blind, parallel-group study to compare the efficacy and safety of arbaclofen extended-release tablets to those of placebo and baclofen over 12 weeks of treatment in patients with spasticity due to MS. Participants were randomized to receive 20 mg of arbaclofen bid, 20 mg of baclofen tablets qid, or matching placebo. The dose was titrated over four weeks, followed by a 12-week maintenance period. The primary end points were the mean changes in Total Numeric-transformed Modified Ashworth Scale (TNmAS) and Clinician Global Impression of Change (CGIC) at the end of the maintenance period.

Of 354 randomized participants, 59.0% had relapsing-remitting MS and 36.7% had secondary progressive MS. The average baseline TNmAS score was 7.78. Mean changes in TNmAS and CGIC were significantly greater for patients receiving arbaclofen, compared with patients receiving placebo. The researchers observed a greater difference in CGIC between arbaclofen and placebo, compared with that between baclofen and placebo, perhaps because of improved tolerability of arbaclofen, compared with baclofen. Differences between arbaclofen and baclofen were not statistically significant. MS Spasticity Scale (MSSS-88) showed a statistically significant improvement among patients receiving arbaclofen, compared with those receiving placebo. Epworth Sleepiness Scale (ESS) showed a statistically significant increase in sleepiness in the baclofen group, but not in the arbaclofen group, compared with placebo. Drowsiness and dizziness were less frequent in the arbaclofen group, compared with baclofen.

The study was supported by Osmotica Pharmaceutical.

LONDON – Siponimod delayed disability progression in patients with secondary progressive multiple sclerosis, according to top-line findings from the phase III EXPAND study.

Siponimod reduced the primary endpoint of the time to 3-month confirmed disease progression (CDP) assessed via the Expanded Disability Status Scale (EDSS) by 21%, compared with placebo (P = .013).

“It is reassuring that this primary outcome is supported by an important secondary outcome of the time to CDP at 6 months,” presenting author Ludwig Kappos, MD, of University Hospital Basel (Switzerland), said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

He reported that a 26% reduction in the 6-month CDP was also observed comparing the active and placebo treatments (P = .006) in the multicenter, randomized, double-blind trial that involved 1,646 patients “with the whole spectrum” of secondary progressive multiple sclerosis (SPMS).

The findings build on those of the phase II BOLD study in patients with relapsing-remitting MS (RRMS) (Lancet Neurol. 2013;12[8]:756-67) and showed a reduction in relapse rates and a reduction in the number of brain lesions seen on MRI scans for siponimod, compared with placebo.

Recently reported data from the 24-month extension of the BOLD phase II trial (JAMA Neurol. 2016;73[9]:1089-98) also showed that disease activity was low in patients treated with siponimod, and that there were no new safety signals. Dose reduction during initiation mitigated cardiac adverse effects, an approach that was also used successfully in the phase III study.

Siponimod is a once-daily oral treatment being developed by Novartis for the treatment of MS. Like fingolimod (Gilenya), which is licensed for the treatment of RRMS, siponimod is a selective sphingosine 1-phosphate receptor (S1P) modulator. Unlike fingolimod, which targets S1P subtypes 1, 3, 4, and 5, siponimod only targets the S1P 1 and 5 subtypes.

Fingolimod is also known to cause temporary changes in heart rate, heartbeat, and blood pressure, which necessitates early electrocardiographic monitoring during the first 6 hours when the drug is first given. At the present time, it doesn’t seem that siponimod will have unwanted cardiac effects, but longer-term follow-up data are needed.

“Adverse events were as you would expect with an S1P receptor modulator,” Dr. Kappos said, noting that there was nothing new. Overall, any adverse event occurred in 88% of actively-treated and 81% of placebo-treated patients. The rate of serious adverse events was similar in the siponimod (3.8%) and placebo (3.7%) arms, and a similar percentage of patients were reported to have infections (48% and 49%, respectively).

Analysis of all the various secondary endpoints is still ongoing; Dr. Kappos noted that the primary endpoint data had just recently become available. Some initial findings, however, show benefit for siponimod over placebo.

The change in T2 lesion volume from baseline to both 12 and 24 months was significantly less with siponimod than with placebo, at a 79.1% lower average change (P less than .0001).

The annualized relapse rate was reduced by 55% with the active treatment versus placebo, and there was less percent change in brain volume with active therapy versus placebo from baseline to 12 and 24 months’ follow-up (23.4% lower average change, P = .0002).

The time to 3-month confirmed worsening by 20% or more from baseline in the timed 25-foot walk test was reduced by 6.2%. Although not significant, the trend was “in the right direction,” Dr. Kappos said.

The mean age of recruited patients was 48 years, with an average duration of MS of 16-17 years, and just under 4 years since their conversion to SPMS. Baseline EDSS was a mean of 5.4, around 35%-37% had one or more relapses in the 2 years before screening, and 20% had gadolinium-enhancing lesions at baseline.

A variety of predefined subgroup analyses showed a benefit for siponimod over placebo. These included analyses looking at the effect by the number of gadolinium-enhancing lesions at baseline, previous disease-modifying treatment, whether patients’ MS was rapidly progressing, whether patients’ disease was moderate or severe, the baseline EDSS, and the duration of MS since the first recognition of symptoms.

“What is the optimal patient population?” an audience member asked Dr. Kappos during the Q&A period following his presentation at the ECTRIMS meeting. He responded: “I think younger patients with the more active disease will certainly be the best candidates.” But, he added, it was reassuring to note that the drug seems to work equally well in all patient subtypes.

Novartis funded the study. Dr. Kappos disclosed that his institution has received financial support for research purposes from multiple MS drug manufacturers – including Novartis – and charitable organizations.

LONDON – Siponimod delayed disability progression in patients with secondary progressive multiple sclerosis, according to top-line findings from the phase III EXPAND study.

Siponimod reduced the primary endpoint of the time to 3-month confirmed disease progression (CDP) assessed via the Expanded Disability Status Scale (EDSS) by 21%, compared with placebo (P = .013).

“It is reassuring that this primary outcome is supported by an important secondary outcome of the time to CDP at 6 months,” presenting author Ludwig Kappos, MD, of University Hospital Basel (Switzerland), said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

He reported that a 26% reduction in the 6-month CDP was also observed comparing the active and placebo treatments (P = .006) in the multicenter, randomized, double-blind trial that involved 1,646 patients “with the whole spectrum” of secondary progressive multiple sclerosis (SPMS).

The findings build on those of the phase II BOLD study in patients with relapsing-remitting MS (RRMS) (Lancet Neurol. 2013;12[8]:756-67) and showed a reduction in relapse rates and a reduction in the number of brain lesions seen on MRI scans for siponimod, compared with placebo.

Recently reported data from the 24-month extension of the BOLD phase II trial (JAMA Neurol. 2016;73[9]:1089-98) also showed that disease activity was low in patients treated with siponimod, and that there were no new safety signals. Dose reduction during initiation mitigated cardiac adverse effects, an approach that was also used successfully in the phase III study.

Siponimod is a once-daily oral treatment being developed by Novartis for the treatment of MS. Like fingolimod (Gilenya), which is licensed for the treatment of RRMS, siponimod is a selective sphingosine 1-phosphate receptor (S1P) modulator. Unlike fingolimod, which targets S1P subtypes 1, 3, 4, and 5, siponimod only targets the S1P 1 and 5 subtypes.

Fingolimod is also known to cause temporary changes in heart rate, heartbeat, and blood pressure, which necessitates early electrocardiographic monitoring during the first 6 hours when the drug is first given. At the present time, it doesn’t seem that siponimod will have unwanted cardiac effects, but longer-term follow-up data are needed.

“Adverse events were as you would expect with an S1P receptor modulator,” Dr. Kappos said, noting that there was nothing new. Overall, any adverse event occurred in 88% of actively-treated and 81% of placebo-treated patients. The rate of serious adverse events was similar in the siponimod (3.8%) and placebo (3.7%) arms, and a similar percentage of patients were reported to have infections (48% and 49%, respectively).

Analysis of all the various secondary endpoints is still ongoing; Dr. Kappos noted that the primary endpoint data had just recently become available. Some initial findings, however, show benefit for siponimod over placebo.

The change in T2 lesion volume from baseline to both 12 and 24 months was significantly less with siponimod than with placebo, at a 79.1% lower average change (P less than .0001).

The annualized relapse rate was reduced by 55% with the active treatment versus placebo, and there was less percent change in brain volume with active therapy versus placebo from baseline to 12 and 24 months’ follow-up (23.4% lower average change, P = .0002).

The time to 3-month confirmed worsening by 20% or more from baseline in the timed 25-foot walk test was reduced by 6.2%. Although not significant, the trend was “in the right direction,” Dr. Kappos said.

The mean age of recruited patients was 48 years, with an average duration of MS of 16-17 years, and just under 4 years since their conversion to SPMS. Baseline EDSS was a mean of 5.4, around 35%-37% had one or more relapses in the 2 years before screening, and 20% had gadolinium-enhancing lesions at baseline.

A variety of predefined subgroup analyses showed a benefit for siponimod over placebo. These included analyses looking at the effect by the number of gadolinium-enhancing lesions at baseline, previous disease-modifying treatment, whether patients’ MS was rapidly progressing, whether patients’ disease was moderate or severe, the baseline EDSS, and the duration of MS since the first recognition of symptoms.

“What is the optimal patient population?” an audience member asked Dr. Kappos during the Q&A period following his presentation at the ECTRIMS meeting. He responded: “I think younger patients with the more active disease will certainly be the best candidates.” But, he added, it was reassuring to note that the drug seems to work equally well in all patient subtypes.

Novartis funded the study. Dr. Kappos disclosed that his institution has received financial support for research purposes from multiple MS drug manufacturers – including Novartis – and charitable organizations.

LONDON – Siponimod delayed disability progression in patients with secondary progressive multiple sclerosis, according to top-line findings from the phase III EXPAND study.

Siponimod reduced the primary endpoint of the time to 3-month confirmed disease progression (CDP) assessed via the Expanded Disability Status Scale (EDSS) by 21%, compared with placebo (P = .013).

“It is reassuring that this primary outcome is supported by an important secondary outcome of the time to CDP at 6 months,” presenting author Ludwig Kappos, MD, of University Hospital Basel (Switzerland), said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

He reported that a 26% reduction in the 6-month CDP was also observed comparing the active and placebo treatments (P = .006) in the multicenter, randomized, double-blind trial that involved 1,646 patients “with the whole spectrum” of secondary progressive multiple sclerosis (SPMS).

The findings build on those of the phase II BOLD study in patients with relapsing-remitting MS (RRMS) (Lancet Neurol. 2013;12[8]:756-67) and showed a reduction in relapse rates and a reduction in the number of brain lesions seen on MRI scans for siponimod, compared with placebo.

Recently reported data from the 24-month extension of the BOLD phase II trial (JAMA Neurol. 2016;73[9]:1089-98) also showed that disease activity was low in patients treated with siponimod, and that there were no new safety signals. Dose reduction during initiation mitigated cardiac adverse effects, an approach that was also used successfully in the phase III study.

Siponimod is a once-daily oral treatment being developed by Novartis for the treatment of MS. Like fingolimod (Gilenya), which is licensed for the treatment of RRMS, siponimod is a selective sphingosine 1-phosphate receptor (S1P) modulator. Unlike fingolimod, which targets S1P subtypes 1, 3, 4, and 5, siponimod only targets the S1P 1 and 5 subtypes.

Fingolimod is also known to cause temporary changes in heart rate, heartbeat, and blood pressure, which necessitates early electrocardiographic monitoring during the first 6 hours when the drug is first given. At the present time, it doesn’t seem that siponimod will have unwanted cardiac effects, but longer-term follow-up data are needed.

“Adverse events were as you would expect with an S1P receptor modulator,” Dr. Kappos said, noting that there was nothing new. Overall, any adverse event occurred in 88% of actively-treated and 81% of placebo-treated patients. The rate of serious adverse events was similar in the siponimod (3.8%) and placebo (3.7%) arms, and a similar percentage of patients were reported to have infections (48% and 49%, respectively).

Analysis of all the various secondary endpoints is still ongoing; Dr. Kappos noted that the primary endpoint data had just recently become available. Some initial findings, however, show benefit for siponimod over placebo.

The change in T2 lesion volume from baseline to both 12 and 24 months was significantly less with siponimod than with placebo, at a 79.1% lower average change (P less than .0001).

The annualized relapse rate was reduced by 55% with the active treatment versus placebo, and there was less percent change in brain volume with active therapy versus placebo from baseline to 12 and 24 months’ follow-up (23.4% lower average change, P = .0002).

The time to 3-month confirmed worsening by 20% or more from baseline in the timed 25-foot walk test was reduced by 6.2%. Although not significant, the trend was “in the right direction,” Dr. Kappos said.

The mean age of recruited patients was 48 years, with an average duration of MS of 16-17 years, and just under 4 years since their conversion to SPMS. Baseline EDSS was a mean of 5.4, around 35%-37% had one or more relapses in the 2 years before screening, and 20% had gadolinium-enhancing lesions at baseline.

A variety of predefined subgroup analyses showed a benefit for siponimod over placebo. These included analyses looking at the effect by the number of gadolinium-enhancing lesions at baseline, previous disease-modifying treatment, whether patients’ MS was rapidly progressing, whether patients’ disease was moderate or severe, the baseline EDSS, and the duration of MS since the first recognition of symptoms.

“What is the optimal patient population?” an audience member asked Dr. Kappos during the Q&A period following his presentation at the ECTRIMS meeting. He responded: “I think younger patients with the more active disease will certainly be the best candidates.” But, he added, it was reassuring to note that the drug seems to work equally well in all patient subtypes.

Novartis funded the study. Dr. Kappos disclosed that his institution has received financial support for research purposes from multiple MS drug manufacturers – including Novartis – and charitable organizations.

LONDON—Autoimmune adverse events over five years were generally mild or moderate in intensity in alemtuzumab-treated patients from the CARE-MS trials, according to data presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “No patients withdrew from the extension studies due to autoimmune adverse events,” said Colin Dayan, MD, PhD, Clinical Professor, Cardiff University School of Medicine, Cardiff, United Kingdom, and his research colleagues. “Consistent with previous reports, most autoimmune adverse events were thyroid-related events.”

Alemtuzumab significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a over two years in patients with relapsing-remitting multiple sclerosis (MS) who were treatment-naive in the CARE-MS I trial or had an inadequate response (ie, one or more relapses) to prior therapy at baseline in the CARE-MS II trial. Durable efficacy over five years was observed in an extension study in the absence of continuous treatment. The most frequent adverse events with alemtuzumab were infusion-associated reactions; other adverse events included autoimmune adverse events. According to researchers, patient education and the drug’s safety monitoring program enable timely detection and treatment of autoimmune adverse events in patients treated with alemtuzumab.

The goal of the present study was to evaluate the occurrence of autoimmune adverse events over five years in patients with relapsing-remitting MS treated with alemtuzumab.

Patients participating in the study received two courses of alemtuzumab 12 mg (Month 0: 5 days; Month 12: 3 days) in the CARE-MS core studies, with as-needed alemtuzumab for relapse or MRI activity in the extension. Patients were monitored for autoimmune adverse events. Safety measures included quarterly thyroid function testing, monthly complete blood counts with platelets and symptom monitoring for immune thrombocytopenia, and monthly serum creatinine and urinalysis.

Results were reported for pooled data from the CARE-MS I and II studies. A total of 811 patients received alemtuzumab 12 mg in the CARE-MS I and II core studies; 742 (91%) entered the extension, and 692 (93%) of those remained in the study at five years. Most autoimmune adverse events were mild or moderate in intensity. Serious autoimmune adverse events were uncommon (67 events; 1.8/100 patient-years over five years). None of the adverse events led to study withdrawal. The most common autoimmune adverse events were thyroid adverse events, the rate of which peaked in Year 3 (227 events; 31.3/100 patient-years) and subsequently declined in Years 4 (126 events; 17.6/100 patient-years) and 5 (95 events; 13.6/100 patient-years). Serious thyroid adverse event rates remained low. Over Years 0-5, 22 immune thrombocytopenia events were observed (cumulative rate: 0.59) with no fatalities. Two nephropathies were reported over Years 0-5 (cumulative rate: 0.05); serum creatinine remained normal in both cases.

This study was supported by Sanofi Genzyme and Bayer HealthCare Pharmaceuticals.

—Glenn S. Williams

LONDON—Autoimmune adverse events over five years were generally mild or moderate in intensity in alemtuzumab-treated patients from the CARE-MS trials, according to data presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “No patients withdrew from the extension studies due to autoimmune adverse events,” said Colin Dayan, MD, PhD, Clinical Professor, Cardiff University School of Medicine, Cardiff, United Kingdom, and his research colleagues. “Consistent with previous reports, most autoimmune adverse events were thyroid-related events.”

Alemtuzumab significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a over two years in patients with relapsing-remitting multiple sclerosis (MS) who were treatment-naive in the CARE-MS I trial or had an inadequate response (ie, one or more relapses) to prior therapy at baseline in the CARE-MS II trial. Durable efficacy over five years was observed in an extension study in the absence of continuous treatment. The most frequent adverse events with alemtuzumab were infusion-associated reactions; other adverse events included autoimmune adverse events. According to researchers, patient education and the drug’s safety monitoring program enable timely detection and treatment of autoimmune adverse events in patients treated with alemtuzumab.

The goal of the present study was to evaluate the occurrence of autoimmune adverse events over five years in patients with relapsing-remitting MS treated with alemtuzumab.

Patients participating in the study received two courses of alemtuzumab 12 mg (Month 0: 5 days; Month 12: 3 days) in the CARE-MS core studies, with as-needed alemtuzumab for relapse or MRI activity in the extension. Patients were monitored for autoimmune adverse events. Safety measures included quarterly thyroid function testing, monthly complete blood counts with platelets and symptom monitoring for immune thrombocytopenia, and monthly serum creatinine and urinalysis.

Results were reported for pooled data from the CARE-MS I and II studies. A total of 811 patients received alemtuzumab 12 mg in the CARE-MS I and II core studies; 742 (91%) entered the extension, and 692 (93%) of those remained in the study at five years. Most autoimmune adverse events were mild or moderate in intensity. Serious autoimmune adverse events were uncommon (67 events; 1.8/100 patient-years over five years). None of the adverse events led to study withdrawal. The most common autoimmune adverse events were thyroid adverse events, the rate of which peaked in Year 3 (227 events; 31.3/100 patient-years) and subsequently declined in Years 4 (126 events; 17.6/100 patient-years) and 5 (95 events; 13.6/100 patient-years). Serious thyroid adverse event rates remained low. Over Years 0-5, 22 immune thrombocytopenia events were observed (cumulative rate: 0.59) with no fatalities. Two nephropathies were reported over Years 0-5 (cumulative rate: 0.05); serum creatinine remained normal in both cases.

This study was supported by Sanofi Genzyme and Bayer HealthCare Pharmaceuticals.

—Glenn S. Williams

LONDON—Autoimmune adverse events over five years were generally mild or moderate in intensity in alemtuzumab-treated patients from the CARE-MS trials, according to data presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “No patients withdrew from the extension studies due to autoimmune adverse events,” said Colin Dayan, MD, PhD, Clinical Professor, Cardiff University School of Medicine, Cardiff, United Kingdom, and his research colleagues. “Consistent with previous reports, most autoimmune adverse events were thyroid-related events.”

Alemtuzumab significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a over two years in patients with relapsing-remitting multiple sclerosis (MS) who were treatment-naive in the CARE-MS I trial or had an inadequate response (ie, one or more relapses) to prior therapy at baseline in the CARE-MS II trial. Durable efficacy over five years was observed in an extension study in the absence of continuous treatment. The most frequent adverse events with alemtuzumab were infusion-associated reactions; other adverse events included autoimmune adverse events. According to researchers, patient education and the drug’s safety monitoring program enable timely detection and treatment of autoimmune adverse events in patients treated with alemtuzumab.

The goal of the present study was to evaluate the occurrence of autoimmune adverse events over five years in patients with relapsing-remitting MS treated with alemtuzumab.

Patients participating in the study received two courses of alemtuzumab 12 mg (Month 0: 5 days; Month 12: 3 days) in the CARE-MS core studies, with as-needed alemtuzumab for relapse or MRI activity in the extension. Patients were monitored for autoimmune adverse events. Safety measures included quarterly thyroid function testing, monthly complete blood counts with platelets and symptom monitoring for immune thrombocytopenia, and monthly serum creatinine and urinalysis.

Results were reported for pooled data from the CARE-MS I and II studies. A total of 811 patients received alemtuzumab 12 mg in the CARE-MS I and II core studies; 742 (91%) entered the extension, and 692 (93%) of those remained in the study at five years. Most autoimmune adverse events were mild or moderate in intensity. Serious autoimmune adverse events were uncommon (67 events; 1.8/100 patient-years over five years). None of the adverse events led to study withdrawal. The most common autoimmune adverse events were thyroid adverse events, the rate of which peaked in Year 3 (227 events; 31.3/100 patient-years) and subsequently declined in Years 4 (126 events; 17.6/100 patient-years) and 5 (95 events; 13.6/100 patient-years). Serious thyroid adverse event rates remained low. Over Years 0-5, 22 immune thrombocytopenia events were observed (cumulative rate: 0.59) with no fatalities. Two nephropathies were reported over Years 0-5 (cumulative rate: 0.05); serum creatinine remained normal in both cases.

This study was supported by Sanofi Genzyme and Bayer HealthCare Pharmaceuticals.

—Glenn S. Williams

LONDON—The Expanded Disability Status Scale (EDSS) is largely insensitive to cognitive ability in patients with multiple sclerosis (MS) and does not comprehensively capture accumulated cognitive disability, according to research presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “The EDSS’s use as the gold standard in measuring accumulated disability in patients with MS should be reconsidered as cognitive impairment–related disability can occur independent of EDSS,” said Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, New York.

MS is typically measured by MRI changes, relapse rates, and EDSS. Changes in EDSS score are primarily driven by motor and walking impairment. According to Dr. Gudesblatt and colleagues, cognitive impairment, independent of EDSS, in patients with MS impacts employment, driving, fall risk, and quality of life. “Although the EDSS is universally accepted to measure treatment efficacy, cognitive function does not impact EDSS. Cognitive function greatly varies independently of walking ability and is an important aspect of disease impact for patients with MS,” Dr. Gudesblatt said.

To investigate the sensitivity of the EDSS in measuring cognitive ability in patients with MS, Dr. Gudesblatt and colleagues asked a group of patients with MS to complete a computerized cognitive assessment battery (NeuroTrax) with analysis of cognitive domain scores (ie, memory, executive function, visual spatial, and verbal function, attention, information processing, and motor skills). The average of these domain scores was defined as the global cognitive score. The number of cognitive domains impaired greater than one standard deviation from age- and education-matched norms were also recorded for each assessment battery. A certified grader assigned EDSS scores to participants at the date of their cognitive testing. EDSS groups were defined as low (EDSS 0 to 2.5), moderate (EDSS 3 to 4.5), high (EDSS 5 to 6.5), and severe (EDSS > 7). Percent overlap of NeuroTrax cognitive scores were calculated across EDSS both adjacent (low and moderate, moderate and high, high and severe) and extreme (low and severe) groups.

A total of 258 patients with MS were enrolled in the study; 72.5% were women and the average age was 46.2. For the global cognitive score in patients with MS, there was an average 65% overlap across adjacent EDSS groups and a 42.5% overlap across extreme EDSS groups. The overlap of the cognitive domain scores were: memory (65.3% average adjacent, 65.3% extreme), executive function (65.1% average adjacent, 35.1% extreme), attention (60.3% average adjacent, 38.1% extreme), information processing speed (58.0% average adjacent, 42.5% extreme), visual spatial (65.6% average adjacent, 63.2% extreme), verbal function (70.1% average adjacent, 66.4% extreme), motor skills (55.2% average adjacent, 32.3% extreme). The overlap of number of cognitive domains impaired one standard deviation or more below the normative means was 72.2% across EDSS adjacent groups and 38.1% across extreme EDSS groups.

—Glenn S. Williams

LONDON—The Expanded Disability Status Scale (EDSS) is largely insensitive to cognitive ability in patients with multiple sclerosis (MS) and does not comprehensively capture accumulated cognitive disability, according to research presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “The EDSS’s use as the gold standard in measuring accumulated disability in patients with MS should be reconsidered as cognitive impairment–related disability can occur independent of EDSS,” said Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, New York.

MS is typically measured by MRI changes, relapse rates, and EDSS. Changes in EDSS score are primarily driven by motor and walking impairment. According to Dr. Gudesblatt and colleagues, cognitive impairment, independent of EDSS, in patients with MS impacts employment, driving, fall risk, and quality of life. “Although the EDSS is universally accepted to measure treatment efficacy, cognitive function does not impact EDSS. Cognitive function greatly varies independently of walking ability and is an important aspect of disease impact for patients with MS,” Dr. Gudesblatt said.

To investigate the sensitivity of the EDSS in measuring cognitive ability in patients with MS, Dr. Gudesblatt and colleagues asked a group of patients with MS to complete a computerized cognitive assessment battery (NeuroTrax) with analysis of cognitive domain scores (ie, memory, executive function, visual spatial, and verbal function, attention, information processing, and motor skills). The average of these domain scores was defined as the global cognitive score. The number of cognitive domains impaired greater than one standard deviation from age- and education-matched norms were also recorded for each assessment battery. A certified grader assigned EDSS scores to participants at the date of their cognitive testing. EDSS groups were defined as low (EDSS 0 to 2.5), moderate (EDSS 3 to 4.5), high (EDSS 5 to 6.5), and severe (EDSS > 7). Percent overlap of NeuroTrax cognitive scores were calculated across EDSS both adjacent (low and moderate, moderate and high, high and severe) and extreme (low and severe) groups.

A total of 258 patients with MS were enrolled in the study; 72.5% were women and the average age was 46.2. For the global cognitive score in patients with MS, there was an average 65% overlap across adjacent EDSS groups and a 42.5% overlap across extreme EDSS groups. The overlap of the cognitive domain scores were: memory (65.3% average adjacent, 65.3% extreme), executive function (65.1% average adjacent, 35.1% extreme), attention (60.3% average adjacent, 38.1% extreme), information processing speed (58.0% average adjacent, 42.5% extreme), visual spatial (65.6% average adjacent, 63.2% extreme), verbal function (70.1% average adjacent, 66.4% extreme), motor skills (55.2% average adjacent, 32.3% extreme). The overlap of number of cognitive domains impaired one standard deviation or more below the normative means was 72.2% across EDSS adjacent groups and 38.1% across extreme EDSS groups.

—Glenn S. Williams

LONDON—The Expanded Disability Status Scale (EDSS) is largely insensitive to cognitive ability in patients with multiple sclerosis (MS) and does not comprehensively capture accumulated cognitive disability, according to research presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “The EDSS’s use as the gold standard in measuring accumulated disability in patients with MS should be reconsidered as cognitive impairment–related disability can occur independent of EDSS,” said Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, New York.

MS is typically measured by MRI changes, relapse rates, and EDSS. Changes in EDSS score are primarily driven by motor and walking impairment. According to Dr. Gudesblatt and colleagues, cognitive impairment, independent of EDSS, in patients with MS impacts employment, driving, fall risk, and quality of life. “Although the EDSS is universally accepted to measure treatment efficacy, cognitive function does not impact EDSS. Cognitive function greatly varies independently of walking ability and is an important aspect of disease impact for patients with MS,” Dr. Gudesblatt said.

To investigate the sensitivity of the EDSS in measuring cognitive ability in patients with MS, Dr. Gudesblatt and colleagues asked a group of patients with MS to complete a computerized cognitive assessment battery (NeuroTrax) with analysis of cognitive domain scores (ie, memory, executive function, visual spatial, and verbal function, attention, information processing, and motor skills). The average of these domain scores was defined as the global cognitive score. The number of cognitive domains impaired greater than one standard deviation from age- and education-matched norms were also recorded for each assessment battery. A certified grader assigned EDSS scores to participants at the date of their cognitive testing. EDSS groups were defined as low (EDSS 0 to 2.5), moderate (EDSS 3 to 4.5), high (EDSS 5 to 6.5), and severe (EDSS > 7). Percent overlap of NeuroTrax cognitive scores were calculated across EDSS both adjacent (low and moderate, moderate and high, high and severe) and extreme (low and severe) groups.

A total of 258 patients with MS were enrolled in the study; 72.5% were women and the average age was 46.2. For the global cognitive score in patients with MS, there was an average 65% overlap across adjacent EDSS groups and a 42.5% overlap across extreme EDSS groups. The overlap of the cognitive domain scores were: memory (65.3% average adjacent, 65.3% extreme), executive function (65.1% average adjacent, 35.1% extreme), attention (60.3% average adjacent, 38.1% extreme), information processing speed (58.0% average adjacent, 42.5% extreme), visual spatial (65.6% average adjacent, 63.2% extreme), verbal function (70.1% average adjacent, 66.4% extreme), motor skills (55.2% average adjacent, 32.3% extreme). The overlap of number of cognitive domains impaired one standard deviation or more below the normative means was 72.2% across EDSS adjacent groups and 38.1% across extreme EDSS groups.

—Glenn S. Williams