ICYMI Multiple Sclerosis

BARCELONA—Revised consensus criteria have proposed that neuromyelitis optica spectrum disorder (NMOSD) become the new unifying term to replace neuromyelitis optica, and that the condition be further stratified based on serologic testing. In kind, NMOSD treatment may differ based on the goals of either relapse prevention or prevention of acute attacks. NMOSD diagnosis and treatment were discussed at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis.

NMOSD encompasses what previously has been diagnosed as neuromyelitis optica, an inflammatory CNS syndrome distinct from multiple sclerosis (MS), which requires clinical optic neuritis and myelitis. It also includes limited forms (eg, optic neuritis or myelitis alone) and a series of associated conditions such as area postrema syndrome and certain brain syndromes known to occur with other symptoms of neuromyelitis optica, said Brian G. Weinshenker, MD, Professor of Neurology at the Mayo Clinic in Rochester, Minnesota, and a member of the international panel that developed the NMOSD consensus criteria. The criteria were published in the July 14 issue of Neurology. The criteria also include patients who are aquaporin 4 (AQP4) seronegative but have otherwise typical clinical presentations.

Patients who are AQP4 antibody sero­positive should have at least one core clinical characteristic for a diagnosis of NMOSD, according to the criteria. The core clinical characteristics are optic neuritis, acute myelitis, area postrema syndrome (ie, otherwise unexplained hiccups or nausea), acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome with diencephalic lesions typical of NMOSD on MRI, and symptomatic cerebral syndrome.

“There are no exclusionary criteria, but our caveat is that there should be no better explanation for the symptoms,” Dr. Weinshenker noted. “Comorbidities such as lupus or Sjögren’s syndrome do not exclude NMOSD, but some syndromes or comorbidities raise red flags. These red flags are clinical and MRI features that might suggest a diagnosis of MS instead of NMOSD, as well as sarcoidosis, which can cause optic neuritis or myelitis.” Other red flags, according to the criteria, include cancer and chronic infection (eg, HIV or syphilis).

For patients who are AQP4 seronegative or those for whom serologic testing is unavailable, the criteria are similar, but more rigorous. Specifically, at least two core clinical characteristics are required, and one of them must be optic neuritis, acute myelitis with longitudinally extensive transverse myelitis (LETM) lesions, or area postrema syndrome.

“There must be evidence of dissemination in space, and we require additional MRI features to be present,” said Dr. Weinshenker. “For example, in patients with intractable vomiting, we require that they also have associated dorsal medulla/area postrema lesions.” Those with myelitis must have a long spinal cord lesion and those with acute optic neuritis must have a long optic nerve lesion that takes up half or more of the length of the optic nerve or affects the optic chiasm. “Again, there should be no better explanation for the findings,” he said.

The revised criteria align “with our contemporary view of what NMOSD is and captures current expert practice,” Dr. Weinshenker said. “It should facilitate clinical research by allowing for early diagnosis in a larger pool of patients who might be eligible for clinical trials.”

However, as is true for any set of diagnostic criteria, physicians will still need to exercise individual judgment, he said. He noted that despite the high accuracy of enzyme-linked immunosorbent assay (ELISA) testing, the most widely used serologic test in the United States for AQP4 antibodies, there is still about a 5% chance of false positives, particularly among patients with a low pretest probability of NMOSD. In addition, patients who are AQP4 seronegative, who make up approximately 30% of the total NMOSD population, are poorly characterized.

Among the AQP4 seropositive patients are those who have detectable serum myelin oligodendrocyte glycoprotein (MOG) antibodies. They tend to be younger, male, and less likely to relapse than those with AQP4 antibodies “Maybe MOG syndrome will ultimately be considered separately, but currently we consider it to be a form of NMOSD, and future versions of the diagnostic criteria will probably incorporate other biomarkers,” Dr. Weinshenker said.

NMOSD therapy can be stratified into two types: treatment of acute (ie, monophasic) attack and relapse prevention, said Jacqueline Palace, BM, DM, Consultant Neurologist at the University of Oxford, United Kingdom. She noted that her classifications for treatment purposes are not based on the newly revised NMOSD diagnostic criteria, but rather are slightly broader. She pointed out that her treatment recommendations are in line with 2010 guidelines by the European Federation of Neurological Societies.

“AQP4 antibody disease is a relapsing condition when untreated,” said Dr. Palace. “On the other hand, many MOG antibody seropositive patients have monophasic phenotypes.” Other monophasic conditions include LETM or idiopathic transverse myelitis, Devic’s disease, and severe or bilateral optic neuritis.

Patients in the monophasic group may go on to develop relapsing disease (ie, relapsing NMOSD, relapsing optic neuritis, and relapsing LETM), Dr. Palace noted. Among the difficult-to-treat patients are those who have overlap between MS and antibody-negative NMOSD.

Management of an acute attack across all of these monophasic syndromes is similar because the attacks tend to present with more severe relapses than patients with MS, and some patients are left with severe residual disability, said Dr. Palace. “We treat these patients urgently with IV methylprednisolone for three to five days to try to restore function. If there is poor response or significant disability, we follow with plasma exchange.” If plasma exchange is not feasible, patients may be given IV immunoglobulin (IVIG), she suggested. “There is a small proportion of patients who develop severe paraplegia that don’t appear to respond at all to treatment, even if given urgently. In my experience, these patients are monophasic and they are antibody negative for both MOG and AQP4.”

Patients with acute disseminated encephalomyelitis can rebound if given a short course of IV methylprednisolone. Dr. Palace recommended follow-on prednisolone for two months for patients who have such monophasic MOG and AQP4 antibody disorders to prevent rebound, and for longer (ie, six to 12 months) for monophasic patients with MOG antibodies.

Preventing relapse is probably the most important aspect of managing NMOSD. “AQP4 antibody disease is a relapsing condition, and there is no progressive phase as there is in MS,” Dr. Palace said. “There is a high morbidity and mortality associated with relapse.”

In a 2012 review of AQP4 antibody-seropositive patients—many of whom were on corticosteroids or other immunosuppression—researchers found that, among 59 patients in the UK with a median follow-up of five years, 22% had permanent bilateral visual loss with visual acuity of less than 6/36 in the better eye, and nearly 30% were wheelchair-dependent.

Prednisolone cover alone or in conjunction with a steroid-sparing drug (ie, azathioprine, mycophenolate, methotrexate, or rituximab) is the recommended first-line treatment for relapse prevention. “If patients have a relapse on an adequate dose tried for three to six months, then you might consider an alternative first-line drug or other less commonly used immunosuppressive agents such as ciclosporin/tacrolimus, cyclophosphamide, or mitoxantrone. Regular plasma exchange or IVIG is also an option,” said Dr. Palace. “We note that our patients appear less likely to relapse if they are kept on a low background dose of prednisolone when on other immunosuppressants. If they have a relapse, we may increase the background prednisolone dose rather than switch treatments.”

Some MS disease-modifying drugs have been reported to exacerbate NMOSD, including beta-interferon, natalizumab, and fingolimod. In addition, there is a theoretical risk of alemtuzumab being harmful because it is known to precipitate antibody-mediated disease, Dr. Palace said.

—Adriene Marshall

BARCELONA—Revised consensus criteria have proposed that neuromyelitis optica spectrum disorder (NMOSD) become the new unifying term to replace neuromyelitis optica, and that the condition be further stratified based on serologic testing. In kind, NMOSD treatment may differ based on the goals of either relapse prevention or prevention of acute attacks. NMOSD diagnosis and treatment were discussed at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis.

NMOSD encompasses what previously has been diagnosed as neuromyelitis optica, an inflammatory CNS syndrome distinct from multiple sclerosis (MS), which requires clinical optic neuritis and myelitis. It also includes limited forms (eg, optic neuritis or myelitis alone) and a series of associated conditions such as area postrema syndrome and certain brain syndromes known to occur with other symptoms of neuromyelitis optica, said Brian G. Weinshenker, MD, Professor of Neurology at the Mayo Clinic in Rochester, Minnesota, and a member of the international panel that developed the NMOSD consensus criteria. The criteria were published in the July 14 issue of Neurology. The criteria also include patients who are aquaporin 4 (AQP4) seronegative but have otherwise typical clinical presentations.

Patients who are AQP4 antibody sero­positive should have at least one core clinical characteristic for a diagnosis of NMOSD, according to the criteria. The core clinical characteristics are optic neuritis, acute myelitis, area postrema syndrome (ie, otherwise unexplained hiccups or nausea), acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome with diencephalic lesions typical of NMOSD on MRI, and symptomatic cerebral syndrome.

“There are no exclusionary criteria, but our caveat is that there should be no better explanation for the symptoms,” Dr. Weinshenker noted. “Comorbidities such as lupus or Sjögren’s syndrome do not exclude NMOSD, but some syndromes or comorbidities raise red flags. These red flags are clinical and MRI features that might suggest a diagnosis of MS instead of NMOSD, as well as sarcoidosis, which can cause optic neuritis or myelitis.” Other red flags, according to the criteria, include cancer and chronic infection (eg, HIV or syphilis).

For patients who are AQP4 seronegative or those for whom serologic testing is unavailable, the criteria are similar, but more rigorous. Specifically, at least two core clinical characteristics are required, and one of them must be optic neuritis, acute myelitis with longitudinally extensive transverse myelitis (LETM) lesions, or area postrema syndrome.

“There must be evidence of dissemination in space, and we require additional MRI features to be present,” said Dr. Weinshenker. “For example, in patients with intractable vomiting, we require that they also have associated dorsal medulla/area postrema lesions.” Those with myelitis must have a long spinal cord lesion and those with acute optic neuritis must have a long optic nerve lesion that takes up half or more of the length of the optic nerve or affects the optic chiasm. “Again, there should be no better explanation for the findings,” he said.

The revised criteria align “with our contemporary view of what NMOSD is and captures current expert practice,” Dr. Weinshenker said. “It should facilitate clinical research by allowing for early diagnosis in a larger pool of patients who might be eligible for clinical trials.”

However, as is true for any set of diagnostic criteria, physicians will still need to exercise individual judgment, he said. He noted that despite the high accuracy of enzyme-linked immunosorbent assay (ELISA) testing, the most widely used serologic test in the United States for AQP4 antibodies, there is still about a 5% chance of false positives, particularly among patients with a low pretest probability of NMOSD. In addition, patients who are AQP4 seronegative, who make up approximately 30% of the total NMOSD population, are poorly characterized.

Among the AQP4 seropositive patients are those who have detectable serum myelin oligodendrocyte glycoprotein (MOG) antibodies. They tend to be younger, male, and less likely to relapse than those with AQP4 antibodies “Maybe MOG syndrome will ultimately be considered separately, but currently we consider it to be a form of NMOSD, and future versions of the diagnostic criteria will probably incorporate other biomarkers,” Dr. Weinshenker said.

NMOSD therapy can be stratified into two types: treatment of acute (ie, monophasic) attack and relapse prevention, said Jacqueline Palace, BM, DM, Consultant Neurologist at the University of Oxford, United Kingdom. She noted that her classifications for treatment purposes are not based on the newly revised NMOSD diagnostic criteria, but rather are slightly broader. She pointed out that her treatment recommendations are in line with 2010 guidelines by the European Federation of Neurological Societies.

“AQP4 antibody disease is a relapsing condition when untreated,” said Dr. Palace. “On the other hand, many MOG antibody seropositive patients have monophasic phenotypes.” Other monophasic conditions include LETM or idiopathic transverse myelitis, Devic’s disease, and severe or bilateral optic neuritis.

Patients in the monophasic group may go on to develop relapsing disease (ie, relapsing NMOSD, relapsing optic neuritis, and relapsing LETM), Dr. Palace noted. Among the difficult-to-treat patients are those who have overlap between MS and antibody-negative NMOSD.

Management of an acute attack across all of these monophasic syndromes is similar because the attacks tend to present with more severe relapses than patients with MS, and some patients are left with severe residual disability, said Dr. Palace. “We treat these patients urgently with IV methylprednisolone for three to five days to try to restore function. If there is poor response or significant disability, we follow with plasma exchange.” If plasma exchange is not feasible, patients may be given IV immunoglobulin (IVIG), she suggested. “There is a small proportion of patients who develop severe paraplegia that don’t appear to respond at all to treatment, even if given urgently. In my experience, these patients are monophasic and they are antibody negative for both MOG and AQP4.”

Patients with acute disseminated encephalomyelitis can rebound if given a short course of IV methylprednisolone. Dr. Palace recommended follow-on prednisolone for two months for patients who have such monophasic MOG and AQP4 antibody disorders to prevent rebound, and for longer (ie, six to 12 months) for monophasic patients with MOG antibodies.

Preventing relapse is probably the most important aspect of managing NMOSD. “AQP4 antibody disease is a relapsing condition, and there is no progressive phase as there is in MS,” Dr. Palace said. “There is a high morbidity and mortality associated with relapse.”

In a 2012 review of AQP4 antibody-seropositive patients—many of whom were on corticosteroids or other immunosuppression—researchers found that, among 59 patients in the UK with a median follow-up of five years, 22% had permanent bilateral visual loss with visual acuity of less than 6/36 in the better eye, and nearly 30% were wheelchair-dependent.

Prednisolone cover alone or in conjunction with a steroid-sparing drug (ie, azathioprine, mycophenolate, methotrexate, or rituximab) is the recommended first-line treatment for relapse prevention. “If patients have a relapse on an adequate dose tried for three to six months, then you might consider an alternative first-line drug or other less commonly used immunosuppressive agents such as ciclosporin/tacrolimus, cyclophosphamide, or mitoxantrone. Regular plasma exchange or IVIG is also an option,” said Dr. Palace. “We note that our patients appear less likely to relapse if they are kept on a low background dose of prednisolone when on other immunosuppressants. If they have a relapse, we may increase the background prednisolone dose rather than switch treatments.”

Some MS disease-modifying drugs have been reported to exacerbate NMOSD, including beta-interferon, natalizumab, and fingolimod. In addition, there is a theoretical risk of alemtuzumab being harmful because it is known to precipitate antibody-mediated disease, Dr. Palace said.

—Adriene Marshall

BARCELONA—Revised consensus criteria have proposed that neuromyelitis optica spectrum disorder (NMOSD) become the new unifying term to replace neuromyelitis optica, and that the condition be further stratified based on serologic testing. In kind, NMOSD treatment may differ based on the goals of either relapse prevention or prevention of acute attacks. NMOSD diagnosis and treatment were discussed at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis.

NMOSD encompasses what previously has been diagnosed as neuromyelitis optica, an inflammatory CNS syndrome distinct from multiple sclerosis (MS), which requires clinical optic neuritis and myelitis. It also includes limited forms (eg, optic neuritis or myelitis alone) and a series of associated conditions such as area postrema syndrome and certain brain syndromes known to occur with other symptoms of neuromyelitis optica, said Brian G. Weinshenker, MD, Professor of Neurology at the Mayo Clinic in Rochester, Minnesota, and a member of the international panel that developed the NMOSD consensus criteria. The criteria were published in the July 14 issue of Neurology. The criteria also include patients who are aquaporin 4 (AQP4) seronegative but have otherwise typical clinical presentations.

Patients who are AQP4 antibody sero­positive should have at least one core clinical characteristic for a diagnosis of NMOSD, according to the criteria. The core clinical characteristics are optic neuritis, acute myelitis, area postrema syndrome (ie, otherwise unexplained hiccups or nausea), acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome with diencephalic lesions typical of NMOSD on MRI, and symptomatic cerebral syndrome.

“There are no exclusionary criteria, but our caveat is that there should be no better explanation for the symptoms,” Dr. Weinshenker noted. “Comorbidities such as lupus or Sjögren’s syndrome do not exclude NMOSD, but some syndromes or comorbidities raise red flags. These red flags are clinical and MRI features that might suggest a diagnosis of MS instead of NMOSD, as well as sarcoidosis, which can cause optic neuritis or myelitis.” Other red flags, according to the criteria, include cancer and chronic infection (eg, HIV or syphilis).

For patients who are AQP4 seronegative or those for whom serologic testing is unavailable, the criteria are similar, but more rigorous. Specifically, at least two core clinical characteristics are required, and one of them must be optic neuritis, acute myelitis with longitudinally extensive transverse myelitis (LETM) lesions, or area postrema syndrome.

“There must be evidence of dissemination in space, and we require additional MRI features to be present,” said Dr. Weinshenker. “For example, in patients with intractable vomiting, we require that they also have associated dorsal medulla/area postrema lesions.” Those with myelitis must have a long spinal cord lesion and those with acute optic neuritis must have a long optic nerve lesion that takes up half or more of the length of the optic nerve or affects the optic chiasm. “Again, there should be no better explanation for the findings,” he said.

The revised criteria align “with our contemporary view of what NMOSD is and captures current expert practice,” Dr. Weinshenker said. “It should facilitate clinical research by allowing for early diagnosis in a larger pool of patients who might be eligible for clinical trials.”

However, as is true for any set of diagnostic criteria, physicians will still need to exercise individual judgment, he said. He noted that despite the high accuracy of enzyme-linked immunosorbent assay (ELISA) testing, the most widely used serologic test in the United States for AQP4 antibodies, there is still about a 5% chance of false positives, particularly among patients with a low pretest probability of NMOSD. In addition, patients who are AQP4 seronegative, who make up approximately 30% of the total NMOSD population, are poorly characterized.

Among the AQP4 seropositive patients are those who have detectable serum myelin oligodendrocyte glycoprotein (MOG) antibodies. They tend to be younger, male, and less likely to relapse than those with AQP4 antibodies “Maybe MOG syndrome will ultimately be considered separately, but currently we consider it to be a form of NMOSD, and future versions of the diagnostic criteria will probably incorporate other biomarkers,” Dr. Weinshenker said.

NMOSD therapy can be stratified into two types: treatment of acute (ie, monophasic) attack and relapse prevention, said Jacqueline Palace, BM, DM, Consultant Neurologist at the University of Oxford, United Kingdom. She noted that her classifications for treatment purposes are not based on the newly revised NMOSD diagnostic criteria, but rather are slightly broader. She pointed out that her treatment recommendations are in line with 2010 guidelines by the European Federation of Neurological Societies.

“AQP4 antibody disease is a relapsing condition when untreated,” said Dr. Palace. “On the other hand, many MOG antibody seropositive patients have monophasic phenotypes.” Other monophasic conditions include LETM or idiopathic transverse myelitis, Devic’s disease, and severe or bilateral optic neuritis.

Patients in the monophasic group may go on to develop relapsing disease (ie, relapsing NMOSD, relapsing optic neuritis, and relapsing LETM), Dr. Palace noted. Among the difficult-to-treat patients are those who have overlap between MS and antibody-negative NMOSD.

Management of an acute attack across all of these monophasic syndromes is similar because the attacks tend to present with more severe relapses than patients with MS, and some patients are left with severe residual disability, said Dr. Palace. “We treat these patients urgently with IV methylprednisolone for three to five days to try to restore function. If there is poor response or significant disability, we follow with plasma exchange.” If plasma exchange is not feasible, patients may be given IV immunoglobulin (IVIG), she suggested. “There is a small proportion of patients who develop severe paraplegia that don’t appear to respond at all to treatment, even if given urgently. In my experience, these patients are monophasic and they are antibody negative for both MOG and AQP4.”

Patients with acute disseminated encephalomyelitis can rebound if given a short course of IV methylprednisolone. Dr. Palace recommended follow-on prednisolone for two months for patients who have such monophasic MOG and AQP4 antibody disorders to prevent rebound, and for longer (ie, six to 12 months) for monophasic patients with MOG antibodies.

Preventing relapse is probably the most important aspect of managing NMOSD. “AQP4 antibody disease is a relapsing condition, and there is no progressive phase as there is in MS,” Dr. Palace said. “There is a high morbidity and mortality associated with relapse.”

In a 2012 review of AQP4 antibody-seropositive patients—many of whom were on corticosteroids or other immunosuppression—researchers found that, among 59 patients in the UK with a median follow-up of five years, 22% had permanent bilateral visual loss with visual acuity of less than 6/36 in the better eye, and nearly 30% were wheelchair-dependent.

Prednisolone cover alone or in conjunction with a steroid-sparing drug (ie, azathioprine, mycophenolate, methotrexate, or rituximab) is the recommended first-line treatment for relapse prevention. “If patients have a relapse on an adequate dose tried for three to six months, then you might consider an alternative first-line drug or other less commonly used immunosuppressive agents such as ciclosporin/tacrolimus, cyclophosphamide, or mitoxantrone. Regular plasma exchange or IVIG is also an option,” said Dr. Palace. “We note that our patients appear less likely to relapse if they are kept on a low background dose of prednisolone when on other immunosuppressants. If they have a relapse, we may increase the background prednisolone dose rather than switch treatments.”

Some MS disease-modifying drugs have been reported to exacerbate NMOSD, including beta-interferon, natalizumab, and fingolimod. In addition, there is a theoretical risk of alemtuzumab being harmful because it is known to precipitate antibody-mediated disease, Dr. Palace said.

—Adriene Marshall

BARCELONA—The investigational compound amiselimod, which also is known as MT-1303, improves MRI outcomes and reduces annualized relapse rate among patients with relapsing-remitting multiple sclerosis (MS), according to data presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Results indicate that the drug is well tolerated and may reduce the loss of gray matter volume.

Ludwig Kappos, MD, Chair of Neurology at University Hospital in Basel, Switzerland, and colleagues conducted a phase II proof-of-concept study that compared three doses of amiselimod with placebo. The investigators enrolled 415 patients with relapsing-remitting MS into the study. Participants were randomized to receive placebo or 0.1 mg, 0.2 mg, or 0.4 mg of amiselimod. Each treatment group included approximately 100 people. Patients underwent MRI at baseline and at weeks four, eight, 12, 16, 20, and 24.

The trial’s primary end point was the number of gadolinium-enhancing lesions from weeks eight to 24. Secondary efficacy end points included the proportion of gadolinium-enhancing-lesion-free patients, the total number of new or enlarged T2 lesions, brain volume, gray matter volume, clinical outcomes, relapse rate, and Expanded Disability Status Scale (EDSS) score.

The study population had active MS and was in a relatively early stage of disease. Patients’ mean EDSS score at baseline ranged between 0.5 and 0.8. The treatment groups were well balanced in terms of demographic, clinical, and imaging variables. The proportion of patients with gadolinium enhancement at baseline, however, varied between 30% and 40% between groups. The group that received the lowest dose of amiselimod had the largest proportion of patients with gadolinium enhancement at baseline. Patients had a median number of two relapses in the previous two years. More than 90% of participants completed the study.

Amiselimod was associated with a dose-dependent reduction in the number of gadolinium-enhancing lesions. Patients who received 0.4 mg of amiselimod had a 77% reduction in gadolinium-enhancing lesions. Participants who received 0.1 mg of amiselimod had an approximately 50% reduction in gadolinium-enhancing lesions. In addition, the two highest doses were associated with a 70% reduction and a 55% reduction, respectively, in the number of new and enlarged T2 lesions.

All three doses of the drug reduced patients’ annualized relapse rate. After 24 weeks of treatment, the 0.4-mg dose of amiselimod reduced the risk of relapse by 0.18. The drug also increased the likelihood of relapse freedom, compared with placebo. The study, however, was not designed to show an effect of treatment on relapses, said Dr. Kappos. Furthermore, amiselimod provided a dose-dependent reduction in gray matter volume loss. The investigators found no difference in disability between treated patients and controls, perhaps because of the study’s short duration, said Dr. Kappos.

The investigators observed no difference in the rate of treatment-emergent adverse events between patients receiving amiselimod and those receiving placebo. Significantly, the researchers did not observe a higher rate of cardiac side effects among treated participants, said Dr. Kappos. Nor was amiselimod associated with a higher rate of infections.

—Erik Greb

BARCELONA—The investigational compound amiselimod, which also is known as MT-1303, improves MRI outcomes and reduces annualized relapse rate among patients with relapsing-remitting multiple sclerosis (MS), according to data presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Results indicate that the drug is well tolerated and may reduce the loss of gray matter volume.

Ludwig Kappos, MD, Chair of Neurology at University Hospital in Basel, Switzerland, and colleagues conducted a phase II proof-of-concept study that compared three doses of amiselimod with placebo. The investigators enrolled 415 patients with relapsing-remitting MS into the study. Participants were randomized to receive placebo or 0.1 mg, 0.2 mg, or 0.4 mg of amiselimod. Each treatment group included approximately 100 people. Patients underwent MRI at baseline and at weeks four, eight, 12, 16, 20, and 24.

The trial’s primary end point was the number of gadolinium-enhancing lesions from weeks eight to 24. Secondary efficacy end points included the proportion of gadolinium-enhancing-lesion-free patients, the total number of new or enlarged T2 lesions, brain volume, gray matter volume, clinical outcomes, relapse rate, and Expanded Disability Status Scale (EDSS) score.

The study population had active MS and was in a relatively early stage of disease. Patients’ mean EDSS score at baseline ranged between 0.5 and 0.8. The treatment groups were well balanced in terms of demographic, clinical, and imaging variables. The proportion of patients with gadolinium enhancement at baseline, however, varied between 30% and 40% between groups. The group that received the lowest dose of amiselimod had the largest proportion of patients with gadolinium enhancement at baseline. Patients had a median number of two relapses in the previous two years. More than 90% of participants completed the study.

Amiselimod was associated with a dose-dependent reduction in the number of gadolinium-enhancing lesions. Patients who received 0.4 mg of amiselimod had a 77% reduction in gadolinium-enhancing lesions. Participants who received 0.1 mg of amiselimod had an approximately 50% reduction in gadolinium-enhancing lesions. In addition, the two highest doses were associated with a 70% reduction and a 55% reduction, respectively, in the number of new and enlarged T2 lesions.

All three doses of the drug reduced patients’ annualized relapse rate. After 24 weeks of treatment, the 0.4-mg dose of amiselimod reduced the risk of relapse by 0.18. The drug also increased the likelihood of relapse freedom, compared with placebo. The study, however, was not designed to show an effect of treatment on relapses, said Dr. Kappos. Furthermore, amiselimod provided a dose-dependent reduction in gray matter volume loss. The investigators found no difference in disability between treated patients and controls, perhaps because of the study’s short duration, said Dr. Kappos.

The investigators observed no difference in the rate of treatment-emergent adverse events between patients receiving amiselimod and those receiving placebo. Significantly, the researchers did not observe a higher rate of cardiac side effects among treated participants, said Dr. Kappos. Nor was amiselimod associated with a higher rate of infections.

—Erik Greb

BARCELONA—The investigational compound amiselimod, which also is known as MT-1303, improves MRI outcomes and reduces annualized relapse rate among patients with relapsing-remitting multiple sclerosis (MS), according to data presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Results indicate that the drug is well tolerated and may reduce the loss of gray matter volume.

Ludwig Kappos, MD, Chair of Neurology at University Hospital in Basel, Switzerland, and colleagues conducted a phase II proof-of-concept study that compared three doses of amiselimod with placebo. The investigators enrolled 415 patients with relapsing-remitting MS into the study. Participants were randomized to receive placebo or 0.1 mg, 0.2 mg, or 0.4 mg of amiselimod. Each treatment group included approximately 100 people. Patients underwent MRI at baseline and at weeks four, eight, 12, 16, 20, and 24.

The trial’s primary end point was the number of gadolinium-enhancing lesions from weeks eight to 24. Secondary efficacy end points included the proportion of gadolinium-enhancing-lesion-free patients, the total number of new or enlarged T2 lesions, brain volume, gray matter volume, clinical outcomes, relapse rate, and Expanded Disability Status Scale (EDSS) score.

The study population had active MS and was in a relatively early stage of disease. Patients’ mean EDSS score at baseline ranged between 0.5 and 0.8. The treatment groups were well balanced in terms of demographic, clinical, and imaging variables. The proportion of patients with gadolinium enhancement at baseline, however, varied between 30% and 40% between groups. The group that received the lowest dose of amiselimod had the largest proportion of patients with gadolinium enhancement at baseline. Patients had a median number of two relapses in the previous two years. More than 90% of participants completed the study.

Amiselimod was associated with a dose-dependent reduction in the number of gadolinium-enhancing lesions. Patients who received 0.4 mg of amiselimod had a 77% reduction in gadolinium-enhancing lesions. Participants who received 0.1 mg of amiselimod had an approximately 50% reduction in gadolinium-enhancing lesions. In addition, the two highest doses were associated with a 70% reduction and a 55% reduction, respectively, in the number of new and enlarged T2 lesions.

All three doses of the drug reduced patients’ annualized relapse rate. After 24 weeks of treatment, the 0.4-mg dose of amiselimod reduced the risk of relapse by 0.18. The drug also increased the likelihood of relapse freedom, compared with placebo. The study, however, was not designed to show an effect of treatment on relapses, said Dr. Kappos. Furthermore, amiselimod provided a dose-dependent reduction in gray matter volume loss. The investigators found no difference in disability between treated patients and controls, perhaps because of the study’s short duration, said Dr. Kappos.

The investigators observed no difference in the rate of treatment-emergent adverse events between patients receiving amiselimod and those receiving placebo. Significantly, the researchers did not observe a higher rate of cardiac side effects among treated participants, said Dr. Kappos. Nor was amiselimod associated with a higher rate of infections.

—Erik Greb

The findings of a multicenter, multinational cohort study of radiologically isolated syndrome (RIS) published online ahead of print November 24 in Annals of Neurology offer further evidence that the condition should be considered part of the multiple sclerosis (MS) treatment spectrum because of the rate at which patients progressed to primary progressive MS over the course of the study.

“This is the first report of the temporal course within the preprogression phase for an extremely rare group of subjects originally identified by MRI as having asymptomatic disease, who ultimately experienced progressive symptom evolution consistent with primary progressive MS that could not otherwise be explained by any other mechanism (excessive alcohol use, vitamin deficiencies, etc.),” said Orhun H. Kantarci, MD, Assistant Professor of Neurology at the Mayo Clinic in Rochester, Minnesota.

Dr. Kantarci and his coinvestigators evaluated 453 patients with RIS at 22 centers in the United States, France, Italy, Spain, and Turkey. The researchers also collected data on MRI, lesions, and CSF at baseline and during follow-up for as long as 20 years in certain cohorts. Demographic and clinical data were also analyzed for each patient enrolled.

Ultimately, 128 (28%) of the 453 patients with RIS developed symptomatic MS. Of these patients, 15 (12%) evolved to primary progressive MS and the remaining 113 patients “developed a first acute clinical event related to CNS demyelination consistent with clinically isolated syndrome [CIS]/MS diagnosis.” RIS occurred at a median age of 43.3, with an age range of 20 to 66, and evolved to primary progressive MS at a mean age of 49.1. The median time to conversion was 3.5 years over a median follow-up period of 5.8 years.

Nine patients with primary progressive MS were male, and the remaining six were female. Patients with primary progressive MS were more likely to be men, compared with patients who developed CIS/MS. In addition, median age at the onset of RIS and median age at symptomatic evolution were both older by about 10 years in patients with primary progressive MS versus patients who developed CIS/MS.“The 12% prevalence of primary progressive MS in this large RIS cohort, as well as age at primary progressive MS onset, is strikingly similar to that of large clinical studies in MS,” the authors noted. “Studying RIS, therefore, provides an opportunity to better understand the onset of clinical MS and to test early intervention.”Dr. Kantarci and his associates also pointed out that, in their study, the older age of primary progressive MS onset versus CIS/MS was “clearly” independent of individual follow-up times. Therefore, they also concluded that “age dependence of progressive MS development, in the absence of previous clinical relapses despite having clear subclinically active MS, suggests that biological aging mechanisms may be a significant contributor for development of progressive MS.”

—Deepak Chitnis

The findings of a multicenter, multinational cohort study of radiologically isolated syndrome (RIS) published online ahead of print November 24 in Annals of Neurology offer further evidence that the condition should be considered part of the multiple sclerosis (MS) treatment spectrum because of the rate at which patients progressed to primary progressive MS over the course of the study.

“This is the first report of the temporal course within the preprogression phase for an extremely rare group of subjects originally identified by MRI as having asymptomatic disease, who ultimately experienced progressive symptom evolution consistent with primary progressive MS that could not otherwise be explained by any other mechanism (excessive alcohol use, vitamin deficiencies, etc.),” said Orhun H. Kantarci, MD, Assistant Professor of Neurology at the Mayo Clinic in Rochester, Minnesota.

Dr. Kantarci and his coinvestigators evaluated 453 patients with RIS at 22 centers in the United States, France, Italy, Spain, and Turkey. The researchers also collected data on MRI, lesions, and CSF at baseline and during follow-up for as long as 20 years in certain cohorts. Demographic and clinical data were also analyzed for each patient enrolled.

Ultimately, 128 (28%) of the 453 patients with RIS developed symptomatic MS. Of these patients, 15 (12%) evolved to primary progressive MS and the remaining 113 patients “developed a first acute clinical event related to CNS demyelination consistent with clinically isolated syndrome [CIS]/MS diagnosis.” RIS occurred at a median age of 43.3, with an age range of 20 to 66, and evolved to primary progressive MS at a mean age of 49.1. The median time to conversion was 3.5 years over a median follow-up period of 5.8 years.

Nine patients with primary progressive MS were male, and the remaining six were female. Patients with primary progressive MS were more likely to be men, compared with patients who developed CIS/MS. In addition, median age at the onset of RIS and median age at symptomatic evolution were both older by about 10 years in patients with primary progressive MS versus patients who developed CIS/MS.“The 12% prevalence of primary progressive MS in this large RIS cohort, as well as age at primary progressive MS onset, is strikingly similar to that of large clinical studies in MS,” the authors noted. “Studying RIS, therefore, provides an opportunity to better understand the onset of clinical MS and to test early intervention.”Dr. Kantarci and his associates also pointed out that, in their study, the older age of primary progressive MS onset versus CIS/MS was “clearly” independent of individual follow-up times. Therefore, they also concluded that “age dependence of progressive MS development, in the absence of previous clinical relapses despite having clear subclinically active MS, suggests that biological aging mechanisms may be a significant contributor for development of progressive MS.”

—Deepak Chitnis

The findings of a multicenter, multinational cohort study of radiologically isolated syndrome (RIS) published online ahead of print November 24 in Annals of Neurology offer further evidence that the condition should be considered part of the multiple sclerosis (MS) treatment spectrum because of the rate at which patients progressed to primary progressive MS over the course of the study.

“This is the first report of the temporal course within the preprogression phase for an extremely rare group of subjects originally identified by MRI as having asymptomatic disease, who ultimately experienced progressive symptom evolution consistent with primary progressive MS that could not otherwise be explained by any other mechanism (excessive alcohol use, vitamin deficiencies, etc.),” said Orhun H. Kantarci, MD, Assistant Professor of Neurology at the Mayo Clinic in Rochester, Minnesota.

Dr. Kantarci and his coinvestigators evaluated 453 patients with RIS at 22 centers in the United States, France, Italy, Spain, and Turkey. The researchers also collected data on MRI, lesions, and CSF at baseline and during follow-up for as long as 20 years in certain cohorts. Demographic and clinical data were also analyzed for each patient enrolled.

Ultimately, 128 (28%) of the 453 patients with RIS developed symptomatic MS. Of these patients, 15 (12%) evolved to primary progressive MS and the remaining 113 patients “developed a first acute clinical event related to CNS demyelination consistent with clinically isolated syndrome [CIS]/MS diagnosis.” RIS occurred at a median age of 43.3, with an age range of 20 to 66, and evolved to primary progressive MS at a mean age of 49.1. The median time to conversion was 3.5 years over a median follow-up period of 5.8 years.

Nine patients with primary progressive MS were male, and the remaining six were female. Patients with primary progressive MS were more likely to be men, compared with patients who developed CIS/MS. In addition, median age at the onset of RIS and median age at symptomatic evolution were both older by about 10 years in patients with primary progressive MS versus patients who developed CIS/MS.“The 12% prevalence of primary progressive MS in this large RIS cohort, as well as age at primary progressive MS onset, is strikingly similar to that of large clinical studies in MS,” the authors noted. “Studying RIS, therefore, provides an opportunity to better understand the onset of clinical MS and to test early intervention.”Dr. Kantarci and his associates also pointed out that, in their study, the older age of primary progressive MS onset versus CIS/MS was “clearly” independent of individual follow-up times. Therefore, they also concluded that “age dependence of progressive MS development, in the absence of previous clinical relapses despite having clear subclinically active MS, suggests that biological aging mechanisms may be a significant contributor for development of progressive MS.”

—Deepak Chitnis

BARCELONA—Overall intake of polyunsaturated fatty acids (PUFAs) is associated with a lower risk of multiple sclerosis (MS), according to a prospective study described at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The association mainly results from the effect of plant-derived PUFAs, especially alpha-linolenic acid. Fish-derived fatty acids appear to have no significant association with MS risk.

“While confirmation from other studies is needed, low PUFA intake may be another modifiable risk factor for MS,” said Kjetil Bjørnevik, MD, a research fellow in the neuroepidemiology group at Harvard T.H. Chan School of Public Health in Boston.

For more than 50 years, investigators have been studying the role that fat intake may play in the development of MS. In a 1952 New England Journal of Medicine article, researchers proposed that differences in the incidence of MS in distinct regions of Norway resulted from differences in diet. Subsequent animal studies suggested that omega-6 PUFAs have disease-modifying effects. A recent Cochrane review of randomized controlled trials concluded that PUFAs play no major role on the clinical outcomes of MS. A recent study, however, found an inverse association between overall omega-3 PUFA intake and MS risk.

Dr. Bjørnevik and colleagues prospectively followed more than 175,000 participants in the Nurses’ Health Studies I and II. Participants received questionnaires every second year, and their diet was assessed every fourth year. Dr. Bjørnevik’s team used food-frequency questionnaires to assess the nurses’ intake of alpha-linolenic acid, linoleic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) at baseline (ie, in 1984 and 1991) and during follow-up. The questionnaires had been specifically validated for the intake of PUFAs. The study’s follow-up time spanned several decades. During follow-up, 479 participants developed MS. Each diagnosis of MS was confirmed by a treating neurologist or by medical records. The researchers used a Cox proportional h<hl name="5"/>azard model to calculate acid ratios in each cohort and adjusted all analyses for age, ethnicity, BMI at age 18, smoking, vitamin D intake from supplements, and total caloric intake.

The investigators found no significant association between overall fat intake and MS risk. Neither saturated fat intake nor monounsaturated fat intake was associated with MS. “This [result] is interesting, as it has been suggested that a diet rich in saturated fat could increase MS risk,” said Dr. Bjørnevik. PUFA intake, however, was significantly associated with lower MS risk. The hazard ratio of MS among participants in the top quintile of PUFA intake was 0.66. The researchers also observed a trend toward lower risk of MS in the other quintiles of PUFA intake. No such association obtained for any other fat studied.

When the group examined the specific types of PUFAs, they found no association between dietary intake of fatty-fish-derived PUFAs, including EPA and DHA, and MS risk. “It is mostly these fatty acids that have been suggested to be beneficial for MS risk,” said Dr. Bjørnevik. Both plant-derived PUFAs (ie, alpha-linolenic acid and linoleic acid), however, were associated with lower MS risk. The hazard ratio of MS for the top quintile of alpha-linolenic acid intake was 0.64.

Finally, Dr. Bjørnevik and colleagues compared the effect estimates for PUFA in the baseline analysis and in the cumulative analysis. The results of both analyses were similar. The overall intake of PUFAs was consistently associated with lower MS risk in both analyses. The fish-derived PUFAs were not significantly associated with MS risk in either analysis, but plant-derived PUFAs were associated with a lower MS risk in both analyses.

—Erik Greb

BARCELONA—Overall intake of polyunsaturated fatty acids (PUFAs) is associated with a lower risk of multiple sclerosis (MS), according to a prospective study described at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The association mainly results from the effect of plant-derived PUFAs, especially alpha-linolenic acid. Fish-derived fatty acids appear to have no significant association with MS risk.

“While confirmation from other studies is needed, low PUFA intake may be another modifiable risk factor for MS,” said Kjetil Bjørnevik, MD, a research fellow in the neuroepidemiology group at Harvard T.H. Chan School of Public Health in Boston.

For more than 50 years, investigators have been studying the role that fat intake may play in the development of MS. In a 1952 New England Journal of Medicine article, researchers proposed that differences in the incidence of MS in distinct regions of Norway resulted from differences in diet. Subsequent animal studies suggested that omega-6 PUFAs have disease-modifying effects. A recent Cochrane review of randomized controlled trials concluded that PUFAs play no major role on the clinical outcomes of MS. A recent study, however, found an inverse association between overall omega-3 PUFA intake and MS risk.

Dr. Bjørnevik and colleagues prospectively followed more than 175,000 participants in the Nurses’ Health Studies I and II. Participants received questionnaires every second year, and their diet was assessed every fourth year. Dr. Bjørnevik’s team used food-frequency questionnaires to assess the nurses’ intake of alpha-linolenic acid, linoleic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) at baseline (ie, in 1984 and 1991) and during follow-up. The questionnaires had been specifically validated for the intake of PUFAs. The study’s follow-up time spanned several decades. During follow-up, 479 participants developed MS. Each diagnosis of MS was confirmed by a treating neurologist or by medical records. The researchers used a Cox proportional h<hl name="5"/>azard model to calculate acid ratios in each cohort and adjusted all analyses for age, ethnicity, BMI at age 18, smoking, vitamin D intake from supplements, and total caloric intake.

The investigators found no significant association between overall fat intake and MS risk. Neither saturated fat intake nor monounsaturated fat intake was associated with MS. “This [result] is interesting, as it has been suggested that a diet rich in saturated fat could increase MS risk,” said Dr. Bjørnevik. PUFA intake, however, was significantly associated with lower MS risk. The hazard ratio of MS among participants in the top quintile of PUFA intake was 0.66. The researchers also observed a trend toward lower risk of MS in the other quintiles of PUFA intake. No such association obtained for any other fat studied.

When the group examined the specific types of PUFAs, they found no association between dietary intake of fatty-fish-derived PUFAs, including EPA and DHA, and MS risk. “It is mostly these fatty acids that have been suggested to be beneficial for MS risk,” said Dr. Bjørnevik. Both plant-derived PUFAs (ie, alpha-linolenic acid and linoleic acid), however, were associated with lower MS risk. The hazard ratio of MS for the top quintile of alpha-linolenic acid intake was 0.64.

Finally, Dr. Bjørnevik and colleagues compared the effect estimates for PUFA in the baseline analysis and in the cumulative analysis. The results of both analyses were similar. The overall intake of PUFAs was consistently associated with lower MS risk in both analyses. The fish-derived PUFAs were not significantly associated with MS risk in either analysis, but plant-derived PUFAs were associated with a lower MS risk in both analyses.

—Erik Greb

BARCELONA—Overall intake of polyunsaturated fatty acids (PUFAs) is associated with a lower risk of multiple sclerosis (MS), according to a prospective study described at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The association mainly results from the effect of plant-derived PUFAs, especially alpha-linolenic acid. Fish-derived fatty acids appear to have no significant association with MS risk.

“While confirmation from other studies is needed, low PUFA intake may be another modifiable risk factor for MS,” said Kjetil Bjørnevik, MD, a research fellow in the neuroepidemiology group at Harvard T.H. Chan School of Public Health in Boston.

For more than 50 years, investigators have been studying the role that fat intake may play in the development of MS. In a 1952 New England Journal of Medicine article, researchers proposed that differences in the incidence of MS in distinct regions of Norway resulted from differences in diet. Subsequent animal studies suggested that omega-6 PUFAs have disease-modifying effects. A recent Cochrane review of randomized controlled trials concluded that PUFAs play no major role on the clinical outcomes of MS. A recent study, however, found an inverse association between overall omega-3 PUFA intake and MS risk.

Dr. Bjørnevik and colleagues prospectively followed more than 175,000 participants in the Nurses’ Health Studies I and II. Participants received questionnaires every second year, and their diet was assessed every fourth year. Dr. Bjørnevik’s team used food-frequency questionnaires to assess the nurses’ intake of alpha-linolenic acid, linoleic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) at baseline (ie, in 1984 and 1991) and during follow-up. The questionnaires had been specifically validated for the intake of PUFAs. The study’s follow-up time spanned several decades. During follow-up, 479 participants developed MS. Each diagnosis of MS was confirmed by a treating neurologist or by medical records. The researchers used a Cox proportional h<hl name="5"/>azard model to calculate acid ratios in each cohort and adjusted all analyses for age, ethnicity, BMI at age 18, smoking, vitamin D intake from supplements, and total caloric intake.

The investigators found no significant association between overall fat intake and MS risk. Neither saturated fat intake nor monounsaturated fat intake was associated with MS. “This [result] is interesting, as it has been suggested that a diet rich in saturated fat could increase MS risk,” said Dr. Bjørnevik. PUFA intake, however, was significantly associated with lower MS risk. The hazard ratio of MS among participants in the top quintile of PUFA intake was 0.66. The researchers also observed a trend toward lower risk of MS in the other quintiles of PUFA intake. No such association obtained for any other fat studied.

When the group examined the specific types of PUFAs, they found no association between dietary intake of fatty-fish-derived PUFAs, including EPA and DHA, and MS risk. “It is mostly these fatty acids that have been suggested to be beneficial for MS risk,” said Dr. Bjørnevik. Both plant-derived PUFAs (ie, alpha-linolenic acid and linoleic acid), however, were associated with lower MS risk. The hazard ratio of MS for the top quintile of alpha-linolenic acid intake was 0.64.

Finally, Dr. Bjørnevik and colleagues compared the effect estimates for PUFA in the baseline analysis and in the cumulative analysis. The results of both analyses were similar. The overall intake of PUFAs was consistently associated with lower MS risk in both analyses. The fish-derived PUFAs were not significantly associated with MS risk in either analysis, but plant-derived PUFAs were associated with a lower MS risk in both analyses.

—Erik Greb

BARCELONA—Extended-interval dose therapy with natalizumab may reduce the risk of progressive multifocal leukoencephalopathy (PML), reduce annualized relapse rate, and decrease the likelihood of new T2 lesions in high-risk patients with multiple sclerosis (MS), according to Lana Zhovtis-Ryerson, MD, a neurologist at New York University Langone MS Comprehensive Care Center in New York City.

Previous attempts to mitigate the risk of PML associated with natalizumab by altering the optimal dosing frequency through drug holidays compromised the efficacy of treatment, Dr. Zhovtis-Ryerson explained at the 31st Congress of the European Committee for Treatment and Research in MS (ECTRIMS). “Our hypothesis is that extending the dosing frequency up to eight and a half weeks may be safely enacted without clinical or radiographic worsening, and perhaps reduce PML risk,” she said.

Rebound of MS clinical activity tends to occur at 10 to 12 weeks following natalizumab withdrawal, Dr. Zhovtis-Ryerson said, suggesting that natalizumab-receptor saturation may be more germane to the drug’s disease-modifying effects than serum concentration. “Less frequent natalizumab dosing may result in submaximal receptor saturation, leading to a balance where there is adequate exclusion of white blood cells from the CNS, allowing the drug to be MS-protective,” she reported. At the same time, a PML-protective effect may occur because enough of the cells are entering the CNS to maintain immune surveillance of the John Cunningham virus (JCV) that causes PML.

Dr. Zhovtis-Ryerson and colleagues at nine MS centers in the United States examined 1,093 patients with MS who received standard-interval dose therapy with natalizumab and 905 patients with MS who received extended-interval dose therapy with natalizumab. Patients in the standard-interval dose group received 300-mg infusions of natalizumab every four weeks, while those in the extended-interval dose group waited up to eight weeks and five days between doses.

None of the patients in the extended-interval dose group developed PML during the study period, compared with four participants who developed PML in the standard-interval dose group. The study population had a total of 1,052 JCV-positive patient years. Post-market algorithms as reported by Biogen show an expected incidence of 2.5 cases of PML per 1,000 patients who are JCV-antibody positive, said Dr. Zhovtis-Ryerson.

The results are not statistically significant, but demonstrate a distinct trend, she added. The extended-dose interval group in this study would be considered to be at theoretically high risk of PML because of a combination of several risk factors, including testing positive for the JC antibody and having a high JCV index, a history of prior immunosuppression, and longer duration of therapy (ie, more than 24 months).

Annualized relapse rates were low in both groups, but “surprisingly,” the number of patients who showed clinical relapses was slightly lower in the extended-interval dose group, Dr. Zhovtis-Ryerson observed. Extended-dose interval schedules may be considered for patients with MS who are treated with natalizumab and are at high risk for PML, she added.

The investigators plan to continue monitoring the current cohort and to add pharmacodynamic studies evaluating CD34 cells and receptor saturation and concentration, Dr. Zhovtis-Ryerson said. A prospective, randomized trial of extended interval dosing with natalizumab is also needed, she concluded.

—Linda Peckel

BARCELONA—Extended-interval dose therapy with natalizumab may reduce the risk of progressive multifocal leukoencephalopathy (PML), reduce annualized relapse rate, and decrease the likelihood of new T2 lesions in high-risk patients with multiple sclerosis (MS), according to Lana Zhovtis-Ryerson, MD, a neurologist at New York University Langone MS Comprehensive Care Center in New York City.

Previous attempts to mitigate the risk of PML associated with natalizumab by altering the optimal dosing frequency through drug holidays compromised the efficacy of treatment, Dr. Zhovtis-Ryerson explained at the 31st Congress of the European Committee for Treatment and Research in MS (ECTRIMS). “Our hypothesis is that extending the dosing frequency up to eight and a half weeks may be safely enacted without clinical or radiographic worsening, and perhaps reduce PML risk,” she said.

Rebound of MS clinical activity tends to occur at 10 to 12 weeks following natalizumab withdrawal, Dr. Zhovtis-Ryerson said, suggesting that natalizumab-receptor saturation may be more germane to the drug’s disease-modifying effects than serum concentration. “Less frequent natalizumab dosing may result in submaximal receptor saturation, leading to a balance where there is adequate exclusion of white blood cells from the CNS, allowing the drug to be MS-protective,” she reported. At the same time, a PML-protective effect may occur because enough of the cells are entering the CNS to maintain immune surveillance of the John Cunningham virus (JCV) that causes PML.

Dr. Zhovtis-Ryerson and colleagues at nine MS centers in the United States examined 1,093 patients with MS who received standard-interval dose therapy with natalizumab and 905 patients with MS who received extended-interval dose therapy with natalizumab. Patients in the standard-interval dose group received 300-mg infusions of natalizumab every four weeks, while those in the extended-interval dose group waited up to eight weeks and five days between doses.

None of the patients in the extended-interval dose group developed PML during the study period, compared with four participants who developed PML in the standard-interval dose group. The study population had a total of 1,052 JCV-positive patient years. Post-market algorithms as reported by Biogen show an expected incidence of 2.5 cases of PML per 1,000 patients who are JCV-antibody positive, said Dr. Zhovtis-Ryerson.

The results are not statistically significant, but demonstrate a distinct trend, she added. The extended-dose interval group in this study would be considered to be at theoretically high risk of PML because of a combination of several risk factors, including testing positive for the JC antibody and having a high JCV index, a history of prior immunosuppression, and longer duration of therapy (ie, more than 24 months).

Annualized relapse rates were low in both groups, but “surprisingly,” the number of patients who showed clinical relapses was slightly lower in the extended-interval dose group, Dr. Zhovtis-Ryerson observed. Extended-dose interval schedules may be considered for patients with MS who are treated with natalizumab and are at high risk for PML, she added.

The investigators plan to continue monitoring the current cohort and to add pharmacodynamic studies evaluating CD34 cells and receptor saturation and concentration, Dr. Zhovtis-Ryerson said. A prospective, randomized trial of extended interval dosing with natalizumab is also needed, she concluded.

—Linda Peckel

BARCELONA—Extended-interval dose therapy with natalizumab may reduce the risk of progressive multifocal leukoencephalopathy (PML), reduce annualized relapse rate, and decrease the likelihood of new T2 lesions in high-risk patients with multiple sclerosis (MS), according to Lana Zhovtis-Ryerson, MD, a neurologist at New York University Langone MS Comprehensive Care Center in New York City.

Previous attempts to mitigate the risk of PML associated with natalizumab by altering the optimal dosing frequency through drug holidays compromised the efficacy of treatment, Dr. Zhovtis-Ryerson explained at the 31st Congress of the European Committee for Treatment and Research in MS (ECTRIMS). “Our hypothesis is that extending the dosing frequency up to eight and a half weeks may be safely enacted without clinical or radiographic worsening, and perhaps reduce PML risk,” she said.

Rebound of MS clinical activity tends to occur at 10 to 12 weeks following natalizumab withdrawal, Dr. Zhovtis-Ryerson said, suggesting that natalizumab-receptor saturation may be more germane to the drug’s disease-modifying effects than serum concentration. “Less frequent natalizumab dosing may result in submaximal receptor saturation, leading to a balance where there is adequate exclusion of white blood cells from the CNS, allowing the drug to be MS-protective,” she reported. At the same time, a PML-protective effect may occur because enough of the cells are entering the CNS to maintain immune surveillance of the John Cunningham virus (JCV) that causes PML.

Dr. Zhovtis-Ryerson and colleagues at nine MS centers in the United States examined 1,093 patients with MS who received standard-interval dose therapy with natalizumab and 905 patients with MS who received extended-interval dose therapy with natalizumab. Patients in the standard-interval dose group received 300-mg infusions of natalizumab every four weeks, while those in the extended-interval dose group waited up to eight weeks and five days between doses.

None of the patients in the extended-interval dose group developed PML during the study period, compared with four participants who developed PML in the standard-interval dose group. The study population had a total of 1,052 JCV-positive patient years. Post-market algorithms as reported by Biogen show an expected incidence of 2.5 cases of PML per 1,000 patients who are JCV-antibody positive, said Dr. Zhovtis-Ryerson.

The results are not statistically significant, but demonstrate a distinct trend, she added. The extended-dose interval group in this study would be considered to be at theoretically high risk of PML because of a combination of several risk factors, including testing positive for the JC antibody and having a high JCV index, a history of prior immunosuppression, and longer duration of therapy (ie, more than 24 months).

Annualized relapse rates were low in both groups, but “surprisingly,” the number of patients who showed clinical relapses was slightly lower in the extended-interval dose group, Dr. Zhovtis-Ryerson observed. Extended-dose interval schedules may be considered for patients with MS who are treated with natalizumab and are at high risk for PML, she added.

The investigators plan to continue monitoring the current cohort and to add pharmacodynamic studies evaluating CD34 cells and receptor saturation and concentration, Dr. Zhovtis-Ryerson said. A prospective, randomized trial of extended interval dosing with natalizumab is also needed, she concluded.

—Linda Peckel

BARCELONA—Neurologists can predict outcomes in patients with relapsing-remitting multiple sclerosis (MS) more accurately by adopting an expanded conception of no evidence of disease activity (NEDA), according to data presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). In addition to relapses, disability progression, and MRI activity, NEDA-4 includes change in brain volume over time. A patient’s NEDA-4 status at one year has advantages over the conventional NEDA-3 for predicting subsequent disability and structural damage for as long as seven years. NEDA-3 status at one year, however, is more closely correlated with relapses and new or enlarging T2 lesions than NEDA-4 status is.

Achieving NEDA reduces the probability of subsequent clinical and MRI disease activity. “These findings support the use of NEDA-4 as a more comprehensive and balanced measure for predicting long-term disease evolution in relapsing MS,” said Ludwig Kappos, MD, Chair of Neurology at University Hospital in Basel, Switzerland. “The finding needs further confirmation with longer follow-up and also other groups of patients.”

An Analysis of FREEDOMS Data

Dr. Kappos and colleagues examined data from the FREEDOMS extension studies, which compared fingolimod with placebo, to determine whether adding brain-volume change to NEDA-3 improved the latter’s predictive value. The disease outcomes that the researchers chose to study were confirmed relapse, new or enlarging T2 lesions on MRI, six-month confirmed disability progression, confirmed Expanded Disability Status Scale (EDSS) score of 6 or greater, and mean annual brain volume loss. Dr. Kappos and colleagues examined participants’ NEDA-4 and NEDA-3 statuses after one year of observation and after two years of observation. They analyzed the data with Cox regression analysis and the Akaike information criterion to evaluate the respective predictive values of NEDA-4 and NEDA-3.

The investigators found that NEDA-4 status at one year and NEDA-3 status at one year predicted time to first relapse, although NEDA-3 status was associated with a higher hazard ratio of first relapse than NEDA-4 was. Similarly, NEDA-4 status at one year and NEDA-3 status at one year predicted time to new T2 lesion activity, but NEDA-3 predicted this outcome slightly better than NEDA-4 did. NEDA-3 status was associated with a hazard ratio of 1.4 for six-month confirmed disability progression, and NEDA-4 was associated with a 1.6 hazard ratio for this outcome.

Few participants reached an EDSS of 6 or greater, which was the most stringent and perhaps the most clinically relevant criterion of the study, said Dr. Kappos. Failure to achieve NEDA-3 at one year increased the risk of this outcome by a hazard ratio of 1.6, and failure to achieve NEDA-4 at one year increased the risk of this outcome by a hazard ratio of 2.8. Likewise, failure to achieve NEDA-4 at one year was more closely correlated with continuous brain volume loss over the observation period than failure to achieve NEDA-3 at one year was.

Imaging Affects NEDA’s Predictive Value

The investigators obtained similar results when they examined patients’ NEDA-4 and NEDA-3 status at two years. NEDA-4 status at two years predicted brain volume change and attainment of an EDSS score of 6 or greater with more accuracy than did NEDA-3 status at two years. NEDA-3 status at two years had advantages over NEDA-4 status at two years for predicting new and enhancing lesions and confirmed relapses. Both methods of statistical analysis indicated similar conclusions.

Dr. Kappos acknowledged that MRI in the clinical setting has not been standardized. This lack of uniformity may affect the relative predictive value of new and enlarging T2 lesions, compared with gadolinium enhancement, which is more easily detected in nonstandardized scans, he added. The measurement of brain volume change depends to an even greater extent on a stringent methodology of the assessments and high-quality scans.

—Erik Greb

BARCELONA—Neurologists can predict outcomes in patients with relapsing-remitting multiple sclerosis (MS) more accurately by adopting an expanded conception of no evidence of disease activity (NEDA), according to data presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). In addition to relapses, disability progression, and MRI activity, NEDA-4 includes change in brain volume over time. A patient’s NEDA-4 status at one year has advantages over the conventional NEDA-3 for predicting subsequent disability and structural damage for as long as seven years. NEDA-3 status at one year, however, is more closely correlated with relapses and new or enlarging T2 lesions than NEDA-4 status is.

Achieving NEDA reduces the probability of subsequent clinical and MRI disease activity. “These findings support the use of NEDA-4 as a more comprehensive and balanced measure for predicting long-term disease evolution in relapsing MS,” said Ludwig Kappos, MD, Chair of Neurology at University Hospital in Basel, Switzerland. “The finding needs further confirmation with longer follow-up and also other groups of patients.”

An Analysis of FREEDOMS Data

Dr. Kappos and colleagues examined data from the FREEDOMS extension studies, which compared fingolimod with placebo, to determine whether adding brain-volume change to NEDA-3 improved the latter’s predictive value. The disease outcomes that the researchers chose to study were confirmed relapse, new or enlarging T2 lesions on MRI, six-month confirmed disability progression, confirmed Expanded Disability Status Scale (EDSS) score of 6 or greater, and mean annual brain volume loss. Dr. Kappos and colleagues examined participants’ NEDA-4 and NEDA-3 statuses after one year of observation and after two years of observation. They analyzed the data with Cox regression analysis and the Akaike information criterion to evaluate the respective predictive values of NEDA-4 and NEDA-3.

The investigators found that NEDA-4 status at one year and NEDA-3 status at one year predicted time to first relapse, although NEDA-3 status was associated with a higher hazard ratio of first relapse than NEDA-4 was. Similarly, NEDA-4 status at one year and NEDA-3 status at one year predicted time to new T2 lesion activity, but NEDA-3 predicted this outcome slightly better than NEDA-4 did. NEDA-3 status was associated with a hazard ratio of 1.4 for six-month confirmed disability progression, and NEDA-4 was associated with a 1.6 hazard ratio for this outcome.

Few participants reached an EDSS of 6 or greater, which was the most stringent and perhaps the most clinically relevant criterion of the study, said Dr. Kappos. Failure to achieve NEDA-3 at one year increased the risk of this outcome by a hazard ratio of 1.6, and failure to achieve NEDA-4 at one year increased the risk of this outcome by a hazard ratio of 2.8. Likewise, failure to achieve NEDA-4 at one year was more closely correlated with continuous brain volume loss over the observation period than failure to achieve NEDA-3 at one year was.

Imaging Affects NEDA’s Predictive Value

The investigators obtained similar results when they examined patients’ NEDA-4 and NEDA-3 status at two years. NEDA-4 status at two years predicted brain volume change and attainment of an EDSS score of 6 or greater with more accuracy than did NEDA-3 status at two years. NEDA-3 status at two years had advantages over NEDA-4 status at two years for predicting new and enhancing lesions and confirmed relapses. Both methods of statistical analysis indicated similar conclusions.

Dr. Kappos acknowledged that MRI in the clinical setting has not been standardized. This lack of uniformity may affect the relative predictive value of new and enlarging T2 lesions, compared with gadolinium enhancement, which is more easily detected in nonstandardized scans, he added. The measurement of brain volume change depends to an even greater extent on a stringent methodology of the assessments and high-quality scans.

—Erik Greb

BARCELONA—Neurologists can predict outcomes in patients with relapsing-remitting multiple sclerosis (MS) more accurately by adopting an expanded conception of no evidence of disease activity (NEDA), according to data presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). In addition to relapses, disability progression, and MRI activity, NEDA-4 includes change in brain volume over time. A patient’s NEDA-4 status at one year has advantages over the conventional NEDA-3 for predicting subsequent disability and structural damage for as long as seven years. NEDA-3 status at one year, however, is more closely correlated with relapses and new or enlarging T2 lesions than NEDA-4 status is.

Achieving NEDA reduces the probability of subsequent clinical and MRI disease activity. “These findings support the use of NEDA-4 as a more comprehensive and balanced measure for predicting long-term disease evolution in relapsing MS,” said Ludwig Kappos, MD, Chair of Neurology at University Hospital in Basel, Switzerland. “The finding needs further confirmation with longer follow-up and also other groups of patients.”

An Analysis of FREEDOMS Data

Dr. Kappos and colleagues examined data from the FREEDOMS extension studies, which compared fingolimod with placebo, to determine whether adding brain-volume change to NEDA-3 improved the latter’s predictive value. The disease outcomes that the researchers chose to study were confirmed relapse, new or enlarging T2 lesions on MRI, six-month confirmed disability progression, confirmed Expanded Disability Status Scale (EDSS) score of 6 or greater, and mean annual brain volume loss. Dr. Kappos and colleagues examined participants’ NEDA-4 and NEDA-3 statuses after one year of observation and after two years of observation. They analyzed the data with Cox regression analysis and the Akaike information criterion to evaluate the respective predictive values of NEDA-4 and NEDA-3.

The investigators found that NEDA-4 status at one year and NEDA-3 status at one year predicted time to first relapse, although NEDA-3 status was associated with a higher hazard ratio of first relapse than NEDA-4 was. Similarly, NEDA-4 status at one year and NEDA-3 status at one year predicted time to new T2 lesion activity, but NEDA-3 predicted this outcome slightly better than NEDA-4 did. NEDA-3 status was associated with a hazard ratio of 1.4 for six-month confirmed disability progression, and NEDA-4 was associated with a 1.6 hazard ratio for this outcome.

Few participants reached an EDSS of 6 or greater, which was the most stringent and perhaps the most clinically relevant criterion of the study, said Dr. Kappos. Failure to achieve NEDA-3 at one year increased the risk of this outcome by a hazard ratio of 1.6, and failure to achieve NEDA-4 at one year increased the risk of this outcome by a hazard ratio of 2.8. Likewise, failure to achieve NEDA-4 at one year was more closely correlated with continuous brain volume loss over the observation period than failure to achieve NEDA-3 at one year was.

Imaging Affects NEDA’s Predictive Value

The investigators obtained similar results when they examined patients’ NEDA-4 and NEDA-3 status at two years. NEDA-4 status at two years predicted brain volume change and attainment of an EDSS score of 6 or greater with more accuracy than did NEDA-3 status at two years. NEDA-3 status at two years had advantages over NEDA-4 status at two years for predicting new and enhancing lesions and confirmed relapses. Both methods of statistical analysis indicated similar conclusions.

Dr. Kappos acknowledged that MRI in the clinical setting has not been standardized. This lack of uniformity may affect the relative predictive value of new and enlarging T2 lesions, compared with gadolinium enhancement, which is more easily detected in nonstandardized scans, he added. The measurement of brain volume change depends to an even greater extent on a stringent methodology of the assessments and high-quality scans.

—Erik Greb

BARCELONA—Monitoring for relapses and MRI activity is the best means of predicting treatment response in patients with multiple sclerosis (MS), according to research presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Relapses are less frequent than MRI activity, however, especially among newly diagnosed patients.

Isolated MRI activity may help assess treatment response, but technical issues such as variability in image acquisition and scan comparison may make this approach difficult. “There is not a magic threshold for the number of new T2 lesions to be tolerated,” said Luca Prosperini, MD, PhD, Researcher in the Department of Neurology and Psychiatry at Sapienza University in Rome. The location of the lesions may be more relevant for defining treatment response than their number, he added.

Soon after disease onset, neurologists should monitor the patient for signs of aggressive disease, although this MS phenotype is less frequent. Characterizing clinical and MRI features is important because patients with aggressive disease may require aggressive treatment such as the induction approach, said Dr. Prosperini.

Examining MRI Activity

“MRI activity is probably the most sensitive tool to detect biological disease activity, even a few months after the treatment starts,” said Dr. Prosperini. Various published studies, in which patients underwent MRI at six to 12 months after treatment initiation, support early on-treatment MRI assessment as a way to predict future response to treatment, future relapses, and future disability in the medium and long terms.

In a 2004 post hoc analysis of the pivotal trial of interferon beta-1a, the investigators found that on-treatment MRI activity, especially new T2 lesions, was associated with increased disability and increased brain atrophy at the end of the two-year follow-up in the active group, but not in the placebo group. In a 2013 post hoc analysis that included data from the pivotal trial’s extension phase, patients who accumulated the highest level of disability at 15 years after treatment initiation had had gadolinium-enhancing lesions after one year of treatment.

In a 2009 study of 394 patients with relapsing-remitting MS who started different formulations of interferon beta and were reassessed after one year, Dr. Prosperini and colleagues found a clear dose-effect relationship between new T2 lesions and the risk of future disability. “The greater the number of new T2 lesions, the higher the risk of disability progression over a follow-up time of four or five years,” said Dr. Prosperini. “It’s even more relevant that this statistical figure can be replicated even after removing patients who relapsed in the first year. In other words, the dose-effect phenomenon of new T2 lesions assessed at one year is independent of early clinical disease activity.”

In 2013, Dr. Prosperini and colleagues compared two criteria for assessing nonresponse to treatment. They used the European Medicines Agency criteria for escalating to a second-line therapy, as well as the isolated MRI activity criteria (ie, patients with one or more gadolinium-enhancing lesion or two or more T2 lesions). Both sets of criteria predicted patients’ risk of future disability worsening with similarly high accuracy.

Monitoring Clinical and MRI Activity

In 2015, Boster et al presented a post hoc analysis of data from the FREEDOMS I and II trials, which followed 1,693 patients with relapsing-remitting MS who received fingolimod. The study’s follow-up lasted four years. On-treatment relapses, MRI activity, and a combination of both factors effectively predicted future relapses and future disability. In addition, focal MRI activity, defined as one or more gadolinium-enhancing lesion or two or more new T2 lesions, was the strongest predictor of failure to achieve no evidence of disease activity.

Some neurologists believe that isolated MRI activity is insufficient reason to change treatment, and a 2011 post hoc analysis by Sormani et al supports this idea. The researchers examined 560 patients with relapsing-remitting MS in the PRISMS trial of interferon beta-1a. The combination of relapses and new T2 lesions fully estimated the treatment effect at the end of two years, but each of these measures alone estimated only about 63% of the treatment effect.

Next, Sormani and colleagues developed a statistically optimized version of the Rio score in 2013 and analyzed how accurately it could classify patients’ risk of disability worsening after one year of treatment with interferon beta. Their data indicated that patients with a modified Rio score of 2 or greater have a high risk (ie, 50%) of disability worsening. A score of 2 corresponds to having at least two relapses in the first year or one relapse and at least five new T2 lesions, said Dr. Prosperini. Because patients at medium risk (ie, those with a modified Rio score of 1) are the most difficult to classify, in terms of treatment response, Sormani suggested that they be reassessed at 18 months of treatment. If these patients have one or more relapse, or two or more new T2 lesions, they should be considered nonresponders, the researchers concluded.

The amount of MRI activity to be tolerated remains a matter of debate. To investigate this question, Sormani and colleagues examined a large amount of data from the MRI in MS network about patients treated with interferon beta. The investigators determined that patients with two or more relapses or one relapse and three or more new T2 lesions were at highest risk of disability worsening. The investigators initially classified 130 patients as being at high risk, but the final number of patients who had sustained disability worsening was more than 300. “So, this score suffered from a low sensitivity,” said Dr. Prosperini.

Lesion Location May Predict Outcomes

“Another important question is the topography of the new lesions,” he continued. Galassi et al presented a study at ECTRIMS of 390 patients with relapsing-remitting MS who initiated treatment with interferon beta and were assessed at one year. Follow-up lasted for four years. When the researchers chose disability worsening as their final outcome and performed multivariable Cox regression analysis, they found that new infratentorial lesions and new spinal cord lesions were independent predictors of disability worsening. Lesion count, however, did not contribute to model fit.

For patients with a good prognosis, early and safe treatment should be the goals, said Dr. Prosperini. Early and effective treatment should be the goals for patients with a bad prognosis, he added. “Consider induction strategy in aggressive MS, even if it’s the less frequent phenotype. After treatment starts, we should assess patients correctly and regularly.”

—Erik Greb

BARCELONA—Monitoring for relapses and MRI activity is the best means of predicting treatment response in patients with multiple sclerosis (MS), according to research presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Relapses are less frequent than MRI activity, however, especially among newly diagnosed patients.

Isolated MRI activity may help assess treatment response, but technical issues such as variability in image acquisition and scan comparison may make this approach difficult. “There is not a magic threshold for the number of new T2 lesions to be tolerated,” said Luca Prosperini, MD, PhD, Researcher in the Department of Neurology and Psychiatry at Sapienza University in Rome. The location of the lesions may be more relevant for defining treatment response than their number, he added.

Soon after disease onset, neurologists should monitor the patient for signs of aggressive disease, although this MS phenotype is less frequent. Characterizing clinical and MRI features is important because patients with aggressive disease may require aggressive treatment such as the induction approach, said Dr. Prosperini.

Examining MRI Activity

“MRI activity is probably the most sensitive tool to detect biological disease activity, even a few months after the treatment starts,” said Dr. Prosperini. Various published studies, in which patients underwent MRI at six to 12 months after treatment initiation, support early on-treatment MRI assessment as a way to predict future response to treatment, future relapses, and future disability in the medium and long terms.

In a 2004 post hoc analysis of the pivotal trial of interferon beta-1a, the investigators found that on-treatment MRI activity, especially new T2 lesions, was associated with increased disability and increased brain atrophy at the end of the two-year follow-up in the active group, but not in the placebo group. In a 2013 post hoc analysis that included data from the pivotal trial’s extension phase, patients who accumulated the highest level of disability at 15 years after treatment initiation had had gadolinium-enhancing lesions after one year of treatment.

In a 2009 study of 394 patients with relapsing-remitting MS who started different formulations of interferon beta and were reassessed after one year, Dr. Prosperini and colleagues found a clear dose-effect relationship between new T2 lesions and the risk of future disability. “The greater the number of new T2 lesions, the higher the risk of disability progression over a follow-up time of four or five years,” said Dr. Prosperini. “It’s even more relevant that this statistical figure can be replicated even after removing patients who relapsed in the first year. In other words, the dose-effect phenomenon of new T2 lesions assessed at one year is independent of early clinical disease activity.”

In 2013, Dr. Prosperini and colleagues compared two criteria for assessing nonresponse to treatment. They used the European Medicines Agency criteria for escalating to a second-line therapy, as well as the isolated MRI activity criteria (ie, patients with one or more gadolinium-enhancing lesion or two or more T2 lesions). Both sets of criteria predicted patients’ risk of future disability worsening with similarly high accuracy.

Monitoring Clinical and MRI Activity

In 2015, Boster et al presented a post hoc analysis of data from the FREEDOMS I and II trials, which followed 1,693 patients with relapsing-remitting MS who received fingolimod. The study’s follow-up lasted four years. On-treatment relapses, MRI activity, and a combination of both factors effectively predicted future relapses and future disability. In addition, focal MRI activity, defined as one or more gadolinium-enhancing lesion or two or more new T2 lesions, was the strongest predictor of failure to achieve no evidence of disease activity.

Some neurologists believe that isolated MRI activity is insufficient reason to change treatment, and a 2011 post hoc analysis by Sormani et al supports this idea. The researchers examined 560 patients with relapsing-remitting MS in the PRISMS trial of interferon beta-1a. The combination of relapses and new T2 lesions fully estimated the treatment effect at the end of two years, but each of these measures alone estimated only about 63% of the treatment effect.

Next, Sormani and colleagues developed a statistically optimized version of the Rio score in 2013 and analyzed how accurately it could classify patients’ risk of disability worsening after one year of treatment with interferon beta. Their data indicated that patients with a modified Rio score of 2 or greater have a high risk (ie, 50%) of disability worsening. A score of 2 corresponds to having at least two relapses in the first year or one relapse and at least five new T2 lesions, said Dr. Prosperini. Because patients at medium risk (ie, those with a modified Rio score of 1) are the most difficult to classify, in terms of treatment response, Sormani suggested that they be reassessed at 18 months of treatment. If these patients have one or more relapse, or two or more new T2 lesions, they should be considered nonresponders, the researchers concluded.

The amount of MRI activity to be tolerated remains a matter of debate. To investigate this question, Sormani and colleagues examined a large amount of data from the MRI in MS network about patients treated with interferon beta. The investigators determined that patients with two or more relapses or one relapse and three or more new T2 lesions were at highest risk of disability worsening. The investigators initially classified 130 patients as being at high risk, but the final number of patients who had sustained disability worsening was more than 300. “So, this score suffered from a low sensitivity,” said Dr. Prosperini.

Lesion Location May Predict Outcomes

“Another important question is the topography of the new lesions,” he continued. Galassi et al presented a study at ECTRIMS of 390 patients with relapsing-remitting MS who initiated treatment with interferon beta and were assessed at one year. Follow-up lasted for four years. When the researchers chose disability worsening as their final outcome and performed multivariable Cox regression analysis, they found that new infratentorial lesions and new spinal cord lesions were independent predictors of disability worsening. Lesion count, however, did not contribute to model fit.

For patients with a good prognosis, early and safe treatment should be the goals, said Dr. Prosperini. Early and effective treatment should be the goals for patients with a bad prognosis, he added. “Consider induction strategy in aggressive MS, even if it’s the less frequent phenotype. After treatment starts, we should assess patients correctly and regularly.”

—Erik Greb

BARCELONA—Monitoring for relapses and MRI activity is the best means of predicting treatment response in patients with multiple sclerosis (MS), according to research presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Relapses are less frequent than MRI activity, however, especially among newly diagnosed patients.

Isolated MRI activity may help assess treatment response, but technical issues such as variability in image acquisition and scan comparison may make this approach difficult. “There is not a magic threshold for the number of new T2 lesions to be tolerated,” said Luca Prosperini, MD, PhD, Researcher in the Department of Neurology and Psychiatry at Sapienza University in Rome. The location of the lesions may be more relevant for defining treatment response than their number, he added.

Soon after disease onset, neurologists should monitor the patient for signs of aggressive disease, although this MS phenotype is less frequent. Characterizing clinical and MRI features is important because patients with aggressive disease may require aggressive treatment such as the induction approach, said Dr. Prosperini.

Examining MRI Activity

“MRI activity is probably the most sensitive tool to detect biological disease activity, even a few months after the treatment starts,” said Dr. Prosperini. Various published studies, in which patients underwent MRI at six to 12 months after treatment initiation, support early on-treatment MRI assessment as a way to predict future response to treatment, future relapses, and future disability in the medium and long terms.

In a 2004 post hoc analysis of the pivotal trial of interferon beta-1a, the investigators found that on-treatment MRI activity, especially new T2 lesions, was associated with increased disability and increased brain atrophy at the end of the two-year follow-up in the active group, but not in the placebo group. In a 2013 post hoc analysis that included data from the pivotal trial’s extension phase, patients who accumulated the highest level of disability at 15 years after treatment initiation had had gadolinium-enhancing lesions after one year of treatment.

In a 2009 study of 394 patients with relapsing-remitting MS who started different formulations of interferon beta and were reassessed after one year, Dr. Prosperini and colleagues found a clear dose-effect relationship between new T2 lesions and the risk of future disability. “The greater the number of new T2 lesions, the higher the risk of disability progression over a follow-up time of four or five years,” said Dr. Prosperini. “It’s even more relevant that this statistical figure can be replicated even after removing patients who relapsed in the first year. In other words, the dose-effect phenomenon of new T2 lesions assessed at one year is independent of early clinical disease activity.”

In 2013, Dr. Prosperini and colleagues compared two criteria for assessing nonresponse to treatment. They used the European Medicines Agency criteria for escalating to a second-line therapy, as well as the isolated MRI activity criteria (ie, patients with one or more gadolinium-enhancing lesion or two or more T2 lesions). Both sets of criteria predicted patients’ risk of future disability worsening with similarly high accuracy.

Monitoring Clinical and MRI Activity

In 2015, Boster et al presented a post hoc analysis of data from the FREEDOMS I and II trials, which followed 1,693 patients with relapsing-remitting MS who received fingolimod. The study’s follow-up lasted four years. On-treatment relapses, MRI activity, and a combination of both factors effectively predicted future relapses and future disability. In addition, focal MRI activity, defined as one or more gadolinium-enhancing lesion or two or more new T2 lesions, was the strongest predictor of failure to achieve no evidence of disease activity.

Some neurologists believe that isolated MRI activity is insufficient reason to change treatment, and a 2011 post hoc analysis by Sormani et al supports this idea. The researchers examined 560 patients with relapsing-remitting MS in the PRISMS trial of interferon beta-1a. The combination of relapses and new T2 lesions fully estimated the treatment effect at the end of two years, but each of these measures alone estimated only about 63% of the treatment effect.

Next, Sormani and colleagues developed a statistically optimized version of the Rio score in 2013 and analyzed how accurately it could classify patients’ risk of disability worsening after one year of treatment with interferon beta. Their data indicated that patients with a modified Rio score of 2 or greater have a high risk (ie, 50%) of disability worsening. A score of 2 corresponds to having at least two relapses in the first year or one relapse and at least five new T2 lesions, said Dr. Prosperini. Because patients at medium risk (ie, those with a modified Rio score of 1) are the most difficult to classify, in terms of treatment response, Sormani suggested that they be reassessed at 18 months of treatment. If these patients have one or more relapse, or two or more new T2 lesions, they should be considered nonresponders, the researchers concluded.

The amount of MRI activity to be tolerated remains a matter of debate. To investigate this question, Sormani and colleagues examined a large amount of data from the MRI in MS network about patients treated with interferon beta. The investigators determined that patients with two or more relapses or one relapse and three or more new T2 lesions were at highest risk of disability worsening. The investigators initially classified 130 patients as being at high risk, but the final number of patients who had sustained disability worsening was more than 300. “So, this score suffered from a low sensitivity,” said Dr. Prosperini.

Lesion Location May Predict Outcomes

“Another important question is the topography of the new lesions,” he continued. Galassi et al presented a study at ECTRIMS of 390 patients with relapsing-remitting MS who initiated treatment with interferon beta and were assessed at one year. Follow-up lasted for four years. When the researchers chose disability worsening as their final outcome and performed multivariable Cox regression analysis, they found that new infratentorial lesions and new spinal cord lesions were independent predictors of disability worsening. Lesion count, however, did not contribute to model fit.

For patients with a good prognosis, early and safe treatment should be the goals, said Dr. Prosperini. Early and effective treatment should be the goals for patients with a bad prognosis, he added. “Consider induction strategy in aggressive MS, even if it’s the less frequent phenotype. After treatment starts, we should assess patients correctly and regularly.”

—Erik Greb

BARCELONA—Researchers are actively seeking means of promoting myelin repair in patients with multiple sclerosis (MS), and some drugs have advanced from the preclinical to the clinical phase, according to an overview presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The therapy furthest along in development is the anti-LINGO1 monoclonal antibody, which promotes endogenous remyelination. Exogenous strategies for myelin repair are still in preclinical stages, and perhaps the most promising of these methods relies on induced pluripotent stem cells.

“There is still a crucial need of markers: clinical markers of repair, biomarkers of repair, [and] imaging markers of repair,” said Catherine Lubetzki, MD, PhD, Professor of Neurology at Pierre and Marie Curie University in Paris. Trial designs for remyelinating strategies also need to be optimized, she added.

Exogenous Strategies

Exogenous strategies introduce myelinating cells into the patient. Oligodendrocyte progenitor cells (OPCs), Schwann cells, and neuronal stem cells are under investigation as potential exogenous methods of remyelination.

Induced pluripotent stem cells have been the major advance in this area in the past several years, said Dr. Lubetzki. Investigators use a mixture of transcription factors to induce skin fibroblasts to become stem cells, and then reprogram them into an oligodendrocyte cell phase. This method can enable autologous grafts. Goldman and colleagues transplanted OPCs generated from human fibroblasts into the brains of dysmyelinating mutant mice. The OPCs promoted extensive remyelination and improved the mice’s survival.

Selecting Candidates Based on Their Mechanisms

One method of selecting drug candidates that could promote endogenous remyelination is based on the molecules’ mechanisms of action. Dr. Lubetzki and colleagues studied eliprodil because of its known neuroprotective properties. In 1999, they demonstrated that eliprodil strongly stimulated CNS myelination in an in vitro system of myelination.

More recently, Dr. Lubetzki and colleagues have been investigating molecules that guide OPCs to demyelinated areas. In a proof-of-concept study, the investigators found that semaphorin 3F performs such a function. They also concluded that speeding the recruitment of OPCs to demyelinated plaques results in accelerated remyelination. Approximately one year ago, the team began an ongoing preclinical study in which they are overexpressing semaphorin 3F at lesion sites to speed the recruitment of OPCs and accelerate the remyelination process. The goal is to stimulate remyelination during the window of time when axonal damage is reversible, said Dr. Lubetzki.

Perhaps the best-known investigational strategy for promoting endogenous repair involves the protein LINGO1. Researchers at Biogen found that when LINGO1 is expressed at the surface of immature oligodendrocytes, the protein blocks their maturation and prevents myelination. They developed a monoclonal antibody to suppress the expression of LINGO1, thus allowing oligodendrocytes’ maturation to proceed and improving myelination and remyelination.

The anti-LINGO1 monoclonal anti­body yielded positive results in experimental models, and investigators subsequently began two phase II studies of the treatment in humans. Results of the first study were reported at ECTRIMS; the monoclonal antibody improved full-field visual evoked potential latency in patients with acute optic neuritis, and this result was consistent with improved remyelination. The other phase II study includes 419 patients with relapsing-remitting MS and is ongoing.

Screening Banks of Molecules

The other main approach to selecting drug candidates that could promote endogenous remyelination is to screen a large bank of molecules. This approach “will lead to an increasing number of candidates and new screening tools,” said Dr. Lubetzki.

Several years ago, Tesar and colleagues developed a method of deriving OPCs from epiblast stem cells. The investigators recently used this cellular model to perform high-throughput screening of a large library of bioactive small molecules. They identified seven compounds that, at low concentrations, enhanced the generation of mature oligodendrocytes from OPCs. After they validated this method in various models, Tesar and colleagues identified two drug candidates: miconazole, an antifungal drug, and clobetasol, an immunosuppressant. The researchers now have “a strong rationale for translation into human subjects with MS,” said Dr. Lubetzki.

In 2014, Chan et al developed a micropillar array system for screening molecules. Oligodendrocytes placed in the array are able to wrap membrane around the micropillars, and investigators can measure the thickness of the membrane. The method thus is a binary indicant of the presence or absence of myelination. When Chan and colleagues used the micropillar array model to perform high-throughput screening, they identified a cluster of antimuscarinic compounds that enhanced oligodendrocyte differentiation. One of these drugs was clemastine, an antihistaminic compound that promotes myelination. Researchers are studying clemastine as a remyelinating agent in an ongoing phase II study of 50 patients with relapsing-remitting MS.

Finally, Zalc and colleagues developed a method of medium-throughput screening based on a transgenic tadpole model. Adding metronidazole to the water bath in which the tadpole swims causes a drastic reduction in the number of oligodendrocytes within the tadpole’s optic nerve. When researchers remove the metronidazole from the bath, new oligodendrocytes form within the optic nerve. Zalc and colleagues have used the model to analyze drugs that appear to promote remyelination, such as clemastine, benztropine, and retinoic acid.

One question that researchers have not resolved yet is whether newly formed myelin, which is thinner than normal myelin, is as durable as myelin formed in the normal way. “Twenty years after remyelination, will this myelin be as resistant as the normally made myelin? We don’t know. But at least for the short term or the medium term, this newly formed myelin seems to be as efficient as the usually formed myelin,” concluded Dr. Lubetzki.

—Erik Greb

BARCELONA—Researchers are actively seeking means of promoting myelin repair in patients with multiple sclerosis (MS), and some drugs have advanced from the preclinical to the clinical phase, according to an overview presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The therapy furthest along in development is the anti-LINGO1 monoclonal antibody, which promotes endogenous remyelination. Exogenous strategies for myelin repair are still in preclinical stages, and perhaps the most promising of these methods relies on induced pluripotent stem cells.

“There is still a crucial need of markers: clinical markers of repair, biomarkers of repair, [and] imaging markers of repair,” said Catherine Lubetzki, MD, PhD, Professor of Neurology at Pierre and Marie Curie University in Paris. Trial designs for remyelinating strategies also need to be optimized, she added.

Exogenous Strategies

Exogenous strategies introduce myelinating cells into the patient. Oligodendrocyte progenitor cells (OPCs), Schwann cells, and neuronal stem cells are under investigation as potential exogenous methods of remyelination.

Induced pluripotent stem cells have been the major advance in this area in the past several years, said Dr. Lubetzki. Investigators use a mixture of transcription factors to induce skin fibroblasts to become stem cells, and then reprogram them into an oligodendrocyte cell phase. This method can enable autologous grafts. Goldman and colleagues transplanted OPCs generated from human fibroblasts into the brains of dysmyelinating mutant mice. The OPCs promoted extensive remyelination and improved the mice’s survival.

Selecting Candidates Based on Their Mechanisms

One method of selecting drug candidates that could promote endogenous remyelination is based on the molecules’ mechanisms of action. Dr. Lubetzki and colleagues studied eliprodil because of its known neuroprotective properties. In 1999, they demonstrated that eliprodil strongly stimulated CNS myelination in an in vitro system of myelination.

More recently, Dr. Lubetzki and colleagues have been investigating molecules that guide OPCs to demyelinated areas. In a proof-of-concept study, the investigators found that semaphorin 3F performs such a function. They also concluded that speeding the recruitment of OPCs to demyelinated plaques results in accelerated remyelination. Approximately one year ago, the team began an ongoing preclinical study in which they are overexpressing semaphorin 3F at lesion sites to speed the recruitment of OPCs and accelerate the remyelination process. The goal is to stimulate remyelination during the window of time when axonal damage is reversible, said Dr. Lubetzki.

Perhaps the best-known investigational strategy for promoting endogenous repair involves the protein LINGO1. Researchers at Biogen found that when LINGO1 is expressed at the surface of immature oligodendrocytes, the protein blocks their maturation and prevents myelination. They developed a monoclonal antibody to suppress the expression of LINGO1, thus allowing oligodendrocytes’ maturation to proceed and improving myelination and remyelination.

The anti-LINGO1 monoclonal anti­body yielded positive results in experimental models, and investigators subsequently began two phase II studies of the treatment in humans. Results of the first study were reported at ECTRIMS; the monoclonal antibody improved full-field visual evoked potential latency in patients with acute optic neuritis, and this result was consistent with improved remyelination. The other phase II study includes 419 patients with relapsing-remitting MS and is ongoing.

Screening Banks of Molecules

The other main approach to selecting drug candidates that could promote endogenous remyelination is to screen a large bank of molecules. This approach “will lead to an increasing number of candidates and new screening tools,” said Dr. Lubetzki.

Several years ago, Tesar and colleagues developed a method of deriving OPCs from epiblast stem cells. The investigators recently used this cellular model to perform high-throughput screening of a large library of bioactive small molecules. They identified seven compounds that, at low concentrations, enhanced the generation of mature oligodendrocytes from OPCs. After they validated this method in various models, Tesar and colleagues identified two drug candidates: miconazole, an antifungal drug, and clobetasol, an immunosuppressant. The researchers now have “a strong rationale for translation into human subjects with MS,” said Dr. Lubetzki.

In 2014, Chan et al developed a micropillar array system for screening molecules. Oligodendrocytes placed in the array are able to wrap membrane around the micropillars, and investigators can measure the thickness of the membrane. The method thus is a binary indicant of the presence or absence of myelination. When Chan and colleagues used the micropillar array model to perform high-throughput screening, they identified a cluster of antimuscarinic compounds that enhanced oligodendrocyte differentiation. One of these drugs was clemastine, an antihistaminic compound that promotes myelination. Researchers are studying clemastine as a remyelinating agent in an ongoing phase II study of 50 patients with relapsing-remitting MS.

Finally, Zalc and colleagues developed a method of medium-throughput screening based on a transgenic tadpole model. Adding metronidazole to the water bath in which the tadpole swims causes a drastic reduction in the number of oligodendrocytes within the tadpole’s optic nerve. When researchers remove the metronidazole from the bath, new oligodendrocytes form within the optic nerve. Zalc and colleagues have used the model to analyze drugs that appear to promote remyelination, such as clemastine, benztropine, and retinoic acid.

One question that researchers have not resolved yet is whether newly formed myelin, which is thinner than normal myelin, is as durable as myelin formed in the normal way. “Twenty years after remyelination, will this myelin be as resistant as the normally made myelin? We don’t know. But at least for the short term or the medium term, this newly formed myelin seems to be as efficient as the usually formed myelin,” concluded Dr. Lubetzki.

—Erik Greb

BARCELONA—Researchers are actively seeking means of promoting myelin repair in patients with multiple sclerosis (MS), and some drugs have advanced from the preclinical to the clinical phase, according to an overview presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The therapy furthest along in development is the anti-LINGO1 monoclonal antibody, which promotes endogenous remyelination. Exogenous strategies for myelin repair are still in preclinical stages, and perhaps the most promising of these methods relies on induced pluripotent stem cells.

“There is still a crucial need of markers: clinical markers of repair, biomarkers of repair, [and] imaging markers of repair,” said Catherine Lubetzki, MD, PhD, Professor of Neurology at Pierre and Marie Curie University in Paris. Trial designs for remyelinating strategies also need to be optimized, she added.

Exogenous Strategies

Exogenous strategies introduce myelinating cells into the patient. Oligodendrocyte progenitor cells (OPCs), Schwann cells, and neuronal stem cells are under investigation as potential exogenous methods of remyelination.

Induced pluripotent stem cells have been the major advance in this area in the past several years, said Dr. Lubetzki. Investigators use a mixture of transcription factors to induce skin fibroblasts to become stem cells, and then reprogram them into an oligodendrocyte cell phase. This method can enable autologous grafts. Goldman and colleagues transplanted OPCs generated from human fibroblasts into the brains of dysmyelinating mutant mice. The OPCs promoted extensive remyelination and improved the mice’s survival.

Selecting Candidates Based on Their Mechanisms

One method of selecting drug candidates that could promote endogenous remyelination is based on the molecules’ mechanisms of action. Dr. Lubetzki and colleagues studied eliprodil because of its known neuroprotective properties. In 1999, they demonstrated that eliprodil strongly stimulated CNS myelination in an in vitro system of myelination.

More recently, Dr. Lubetzki and colleagues have been investigating molecules that guide OPCs to demyelinated areas. In a proof-of-concept study, the investigators found that semaphorin 3F performs such a function. They also concluded that speeding the recruitment of OPCs to demyelinated plaques results in accelerated remyelination. Approximately one year ago, the team began an ongoing preclinical study in which they are overexpressing semaphorin 3F at lesion sites to speed the recruitment of OPCs and accelerate the remyelination process. The goal is to stimulate remyelination during the window of time when axonal damage is reversible, said Dr. Lubetzki.

Perhaps the best-known investigational strategy for promoting endogenous repair involves the protein LINGO1. Researchers at Biogen found that when LINGO1 is expressed at the surface of immature oligodendrocytes, the protein blocks their maturation and prevents myelination. They developed a monoclonal antibody to suppress the expression of LINGO1, thus allowing oligodendrocytes’ maturation to proceed and improving myelination and remyelination.

The anti-LINGO1 monoclonal anti­body yielded positive results in experimental models, and investigators subsequently began two phase II studies of the treatment in humans. Results of the first study were reported at ECTRIMS; the monoclonal antibody improved full-field visual evoked potential latency in patients with acute optic neuritis, and this result was consistent with improved remyelination. The other phase II study includes 419 patients with relapsing-remitting MS and is ongoing.

Screening Banks of Molecules

The other main approach to selecting drug candidates that could promote endogenous remyelination is to screen a large bank of molecules. This approach “will lead to an increasing number of candidates and new screening tools,” said Dr. Lubetzki.

Several years ago, Tesar and colleagues developed a method of deriving OPCs from epiblast stem cells. The investigators recently used this cellular model to perform high-throughput screening of a large library of bioactive small molecules. They identified seven compounds that, at low concentrations, enhanced the generation of mature oligodendrocytes from OPCs. After they validated this method in various models, Tesar and colleagues identified two drug candidates: miconazole, an antifungal drug, and clobetasol, an immunosuppressant. The researchers now have “a strong rationale for translation into human subjects with MS,” said Dr. Lubetzki.

In 2014, Chan et al developed a micropillar array system for screening molecules. Oligodendrocytes placed in the array are able to wrap membrane around the micropillars, and investigators can measure the thickness of the membrane. The method thus is a binary indicant of the presence or absence of myelination. When Chan and colleagues used the micropillar array model to perform high-throughput screening, they identified a cluster of antimuscarinic compounds that enhanced oligodendrocyte differentiation. One of these drugs was clemastine, an antihistaminic compound that promotes myelination. Researchers are studying clemastine as a remyelinating agent in an ongoing phase II study of 50 patients with relapsing-remitting MS.

Finally, Zalc and colleagues developed a method of medium-throughput screening based on a transgenic tadpole model. Adding metronidazole to the water bath in which the tadpole swims causes a drastic reduction in the number of oligodendrocytes within the tadpole’s optic nerve. When researchers remove the metronidazole from the bath, new oligodendrocytes form within the optic nerve. Zalc and colleagues have used the model to analyze drugs that appear to promote remyelination, such as clemastine, benztropine, and retinoic acid.

One question that researchers have not resolved yet is whether newly formed myelin, which is thinner than normal myelin, is as durable as myelin formed in the normal way. “Twenty years after remyelination, will this myelin be as resistant as the normally made myelin? We don’t know. But at least for the short term or the medium term, this newly formed myelin seems to be as efficient as the usually formed myelin,” concluded Dr. Lubetzki.

—Erik Greb

BARCELONA—In the months following a first clinical event suggestive of multiple sclerosis (MS), MRI findings and Expanded Disability Status Scale (EDSS) score can help predict which patients will have sustained disability progression, according to the results of a longitudinal study presented at the 31st Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The significance of these findings lies in the fact that MS is a heterogeneous disease with a broad spectrum of phenotypes, which makes it difficult to predict disease course, said Tomas Uher, MD, a neurologist at Charles University in Prague. Thus, early identification of patients with MS who are at the highest risk of disease progression may help guide therapeutic decision making.

Testing MRI and Clinical Indicators

The current investigation was a substudy of the Study of Early Interferon β1-a Treatment in High Risk Subjects after Clinically Isolated Syndrome (SET). The primary outcome was sustained disability progression, defined as a 1.0-point increase in the EDSS confirmed after 12 months or, if the EDSS score was 0 at baseline, an increase of 1.5 points.

A total of 210 patients who had had a first clinical event suggestive of MS within the previous four months were included in the analysis. Subjects had a baseline EDSS score of 3.5 or lower, at least two T2 lesions as seen on brain MRI, and at least two CSF-restricted oligoclonal bands. In addition to MRI assessment at baseline, six months, and 12 months, patients underwent clinical visits every three months and were followed for a minimum of four years, with an average follow-up duration of six years. Sixty-six percent of participants were women, and the population’s mean age was 29.

A total of 42 clinical and MRI predictors were analyzed, including the MS Functional Composite and gray matter and white matter volume change. Results were adjusted for age, sex, and disease duration.

Significantly Increased Risks

By study’s end, 61% of subjects had experienced a new relapse, and 20% had experienced sustained disability progression. Statistically significant factors shown to be the best predictors of disease progression were any new relapse, any change in EDSS score, and T1 lesion volume greater than 1.25 mL at six months or at 12 months; a decrease in corpus callosum volume greater than 0.5% and whole-brain volume change greater than 0.4% at six months; and corpus callosum change greater than 0.7% at 12 months.

“When we looked at individual predictors, we found that patients had a twofold to as much as a fivefold greater risk of disability progression, compared with patients who didn’t fulfill the criteria,” Dr. Uher noted. For example, the hazard ratio for sustained disease progression was 2.2 for new relapse at six months, 3.3 for corpus callosum volume decrease at six months, and 4.9 for EDSS change at 12 months.

Further studies are needed to confirm these results, as well as to determine which disease-modifying therapies would prevent disability progression in patients at highest risk. Additional studies also are needed to evaluate the feasibility of MRI volumetry in clinical practice, Dr. Uher concluded.

—Adriene Marshall

BARCELONA—In the months following a first clinical event suggestive of multiple sclerosis (MS), MRI findings and Expanded Disability Status Scale (EDSS) score can help predict which patients will have sustained disability progression, according to the results of a longitudinal study presented at the 31st Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The significance of these findings lies in the fact that MS is a heterogeneous disease with a broad spectrum of phenotypes, which makes it difficult to predict disease course, said Tomas Uher, MD, a neurologist at Charles University in Prague. Thus, early identification of patients with MS who are at the highest risk of disease progression may help guide therapeutic decision making.

Testing MRI and Clinical Indicators

The current investigation was a substudy of the Study of Early Interferon β1-a Treatment in High Risk Subjects after Clinically Isolated Syndrome (SET). The primary outcome was sustained disability progression, defined as a 1.0-point increase in the EDSS confirmed after 12 months or, if the EDSS score was 0 at baseline, an increase of 1.5 points.

A total of 210 patients who had had a first clinical event suggestive of MS within the previous four months were included in the analysis. Subjects had a baseline EDSS score of 3.5 or lower, at least two T2 lesions as seen on brain MRI, and at least two CSF-restricted oligoclonal bands. In addition to MRI assessment at baseline, six months, and 12 months, patients underwent clinical visits every three months and were followed for a minimum of four years, with an average follow-up duration of six years. Sixty-six percent of participants were women, and the population’s mean age was 29.

A total of 42 clinical and MRI predictors were analyzed, including the MS Functional Composite and gray matter and white matter volume change. Results were adjusted for age, sex, and disease duration.

Significantly Increased Risks

By study’s end, 61% of subjects had experienced a new relapse, and 20% had experienced sustained disability progression. Statistically significant factors shown to be the best predictors of disease progression were any new relapse, any change in EDSS score, and T1 lesion volume greater than 1.25 mL at six months or at 12 months; a decrease in corpus callosum volume greater than 0.5% and whole-brain volume change greater than 0.4% at six months; and corpus callosum change greater than 0.7% at 12 months.

“When we looked at individual predictors, we found that patients had a twofold to as much as a fivefold greater risk of disability progression, compared with patients who didn’t fulfill the criteria,” Dr. Uher noted. For example, the hazard ratio for sustained disease progression was 2.2 for new relapse at six months, 3.3 for corpus callosum volume decrease at six months, and 4.9 for EDSS change at 12 months.

Further studies are needed to confirm these results, as well as to determine which disease-modifying therapies would prevent disability progression in patients at highest risk. Additional studies also are needed to evaluate the feasibility of MRI volumetry in clinical practice, Dr. Uher concluded.

—Adriene Marshall

BARCELONA—In the months following a first clinical event suggestive of multiple sclerosis (MS), MRI findings and Expanded Disability Status Scale (EDSS) score can help predict which patients will have sustained disability progression, according to the results of a longitudinal study presented at the 31st Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The significance of these findings lies in the fact that MS is a heterogeneous disease with a broad spectrum of phenotypes, which makes it difficult to predict disease course, said Tomas Uher, MD, a neurologist at Charles University in Prague. Thus, early identification of patients with MS who are at the highest risk of disease progression may help guide therapeutic decision making.

Testing MRI and Clinical Indicators

The current investigation was a substudy of the Study of Early Interferon β1-a Treatment in High Risk Subjects after Clinically Isolated Syndrome (SET). The primary outcome was sustained disability progression, defined as a 1.0-point increase in the EDSS confirmed after 12 months or, if the EDSS score was 0 at baseline, an increase of 1.5 points.

A total of 210 patients who had had a first clinical event suggestive of MS within the previous four months were included in the analysis. Subjects had a baseline EDSS score of 3.5 or lower, at least two T2 lesions as seen on brain MRI, and at least two CSF-restricted oligoclonal bands. In addition to MRI assessment at baseline, six months, and 12 months, patients underwent clinical visits every three months and were followed for a minimum of four years, with an average follow-up duration of six years. Sixty-six percent of participants were women, and the population’s mean age was 29.

A total of 42 clinical and MRI predictors were analyzed, including the MS Functional Composite and gray matter and white matter volume change. Results were adjusted for age, sex, and disease duration.

Significantly Increased Risks

By study’s end, 61% of subjects had experienced a new relapse, and 20% had experienced sustained disability progression. Statistically significant factors shown to be the best predictors of disease progression were any new relapse, any change in EDSS score, and T1 lesion volume greater than 1.25 mL at six months or at 12 months; a decrease in corpus callosum volume greater than 0.5% and whole-brain volume change greater than 0.4% at six months; and corpus callosum change greater than 0.7% at 12 months.

“When we looked at individual predictors, we found that patients had a twofold to as much as a fivefold greater risk of disability progression, compared with patients who didn’t fulfill the criteria,” Dr. Uher noted. For example, the hazard ratio for sustained disease progression was 2.2 for new relapse at six months, 3.3 for corpus callosum volume decrease at six months, and 4.9 for EDSS change at 12 months.

Further studies are needed to confirm these results, as well as to determine which disease-modifying therapies would prevent disability progression in patients at highest risk. Additional studies also are needed to evaluate the feasibility of MRI volumetry in clinical practice, Dr. Uher concluded.

—Adriene Marshall