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LONDON—No evidence of disease activity (NEDA) is a worthy but potentially problematic goal in the care of patients with multiple sclerosis (MS), according to an overview provided at the 32nd Congress of the European Committee for Treatment and Research in MS. The definition of NEDA is evolving as neurologists adopt new metrics in clinical practice, and NEDA is a difficult outcome to sustain in the long term.
Studies of interferon beta suggest that a minimal amount of clinical or MRI activity is not necessarily associated with poor long-term outcomes. Such research raises the possibility that minimal evidence of disease activity (MEDA) could be an appropriate goal of treatment, said Mar Tintoré, MD, PhD, neurologist at the MS Centre of Catalonia in Barcelona. 
The Emergence of NEDA
A patient receiving treatment who has no sustained disability progression, no relapses, and no new T2 or gadolinium-enhancing lesions has NEDA, as the term was originally conceived. The outcome was rapidly adopted in clinical trials. NEDA also has been applied in the clinical setting. In one study of patients with MS treated in clinical practice, 54% had NEDA at one year. Researchers also found that NEDA may predict long-term outcomes. In one study, 78% of patients with NEDA at year two did not have disease progression at year seven.
A drawback of NEDA is that disease activity may be diffuse and may not manifest itself in relapses, new lesions, or disability progression. “It also may give a false sense of security to the doctor and to the patient,” said Dr. Tintoré.
A fourth factor, brain volume loss, recently was incorporated into NEDA, which has come to be called NEDA-4. Two studies have determined that a 0.4% annual rate of brain volume loss is the best threshold for distinguishing between people with MS and healthy controls.
The Difficulties of NEDA
The new conception of NEDA still omits several factors that neurologists may consider important. NEDA does not take cognition into account, but adding the MS Functional Composite to the NEDA criteria could change that. Patient-reported outcomes such as fatigue, depression, and quality of life also might be appropriate outcomes to incorporate into NEDA, said Dr. Tintoré. In addition, biomarkers such as CSF levels of neurofilament light indicate treatment response and could be added to NEDA.
Current clinical practice may make it difficult to assess whether a patient has NEDA. Many neurologists perform an MRI on a patient before initiating treatment and again at 12 months. “Many of the drugs that we are currently using are not active from baseline,” said Dr. Tintoré. Because changes in the first six months of treatment do not necessarily indicate treatment response, it may be necessary to perform another MRI after several months of treatment as a second baseline measurement, said Dr. Tintoré.
Furthermore, agreement between neuroradiologists is not high. Researchers have observed great variability between readers who had been asked to assess the presence of new T2 or gadolinium-enhancing lesions. And although standardized MRI protocols have been established, they may not be followed uniformly, perhaps because of difficulties specific to given facilities.
Is MEDA an Appropriate Goal?
One potential argument in favor of adopting NEDA as a goal of treatment is that disease activity often predicts poor long-term outcomes. Dr. Tintoré and colleagues assessed the treatment effect in patients with relapsing-remitting MS after two years of interferon therapy. They followed patients for 12 years. Clinical activity during the first two years of treatment was associated with increased risks of developing secondary progressive MS, of reaching an Expanded Disability Status Scale (EDSS) score of 7, and of having a five-point increase on the EDSS at 12 years.
Yet patients with little disease activity may still have good long-term outcomes. In a separate study, Dr. Tintoré and colleagues assessed the presence of MRI lesions after one year in patients with relapsing-remitting MS who were receiving interferon treatment. Participants were followed for eight years, and the primary end point was an increase of at least two points on EDSS after eight years. The investigators found no difference in outcome at eight years between patients who had one gadolinium-enhancing lesion at one year and those who had none at one year. Patients who had two or more gadolinium-enhancing lesions at one year, however, were more likely to reach the primary end point than patients who had fewer than two gadolinium-enhancing lesions at one year.
Results were similar for new T2 lesions. There was no difference in outcome at eight years between participants with no new T2 lesions at one year and those with one or two new T2 lesions at one year. Patients with three or more new T2 lesions at one year, however, were more likely to reach the primary end point. The Rio score was able to predict which patients would have more disability progression, but NEDA was not able to do so, said Dr. Tintoré. These results are similar to those of the MRI in MS (MAGNIMS) data set, in which a low level of disease activity was not associated with poor long-term outcome.
“Combined clinical and MRI scores allow us to integrate disease activity data into individual therapeutic decisions for our patients with MS,” said Dr. Tintoré. Newer therapies have made NEDA attainable for more patients, but not for all patients. Because minimal clinical or MRI activity is not necessarily associated with a poor response in the long term, neurologists may debate whether or when MEDA is an acceptable goal of treatment.
—Erik Greb
Suggested Reading
Giovannoni G, Turner B, Gnanapavan S, et al. Is it time to target no evident disease activity (NEDA) in multiple sclerosis? Mult Scler Relat Disord. 2015;4(4):329-333.
Kappos L, De Stefano N, Freedman MS, et al. Inclusion of brain volume loss in a revised measure of ‘no evidence of disease activity’ (NEDA-4) in relapsing-remitting multiple sclerosis. Mult Scler. 2016;22(10):1297-1305.
Río J, Castilló J, Rovira A, et al. Measures in the first year of therapy predict the response to interferon beta in MS. Mult Scler. 2009;15(7):848-853.
Uher T, Havrdova E, Sobisek L, et al. Is no evidence of disease activity an achievable goal in MS patients on intramuscular interferon beta-1a treatment over long-term follow-up? Mult Scler. 2016 May 26 [Epub ahead of print].
LONDON—No evidence of disease activity (NEDA) is a worthy but potentially problematic goal in the care of patients with multiple sclerosis (MS), according to an overview provided at the 32nd Congress of the European Committee for Treatment and Research in MS. The definition of NEDA is evolving as neurologists adopt new metrics in clinical practice, and NEDA is a difficult outcome to sustain in the long term.
Studies of interferon beta suggest that a minimal amount of clinical or MRI activity is not necessarily associated with poor long-term outcomes. Such research raises the possibility that minimal evidence of disease activity (MEDA) could be an appropriate goal of treatment, said Mar Tintoré, MD, PhD, neurologist at the MS Centre of Catalonia in Barcelona.
The Emergence of NEDA
A patient receiving treatment who has no sustained disability progression, no relapses, and no new T2 or gadolinium-enhancing lesions has NEDA, as the term was originally conceived. The outcome was rapidly adopted in clinical trials. NEDA also has been applied in the clinical setting. In one study of patients with MS treated in clinical practice, 54% had NEDA at one year. Researchers also found that NEDA may predict long-term outcomes. In one study, 78% of patients with NEDA at year two did not have disease progression at year seven.
A drawback of NEDA is that disease activity may be diffuse and may not manifest itself in relapses, new lesions, or disability progression. “It also may give a false sense of security to the doctor and to the patient,” said Dr. Tintoré.
A fourth factor, brain volume loss, recently was incorporated into NEDA, which has come to be called NEDA-4. Two studies have determined that a 0.4% annual rate of brain volume loss is the best threshold for distinguishing between people with MS and healthy controls.
The Difficulties of NEDA
The new conception of NEDA still omits several factors that neurologists may consider important. NEDA does not take cognition into account, but adding the MS Functional Composite to the NEDA criteria could change that. Patient-reported outcomes such as fatigue, depression, and quality of life also might be appropriate outcomes to incorporate into NEDA, said Dr. Tintoré. In addition, biomarkers such as CSF levels of neurofilament light indicate treatment response and could be added to NEDA.
Current clinical practice may make it difficult to assess whether a patient has NEDA. Many neurologists perform an MRI on a patient before initiating treatment and again at 12 months. “Many of the drugs that we are currently using are not active from baseline,” said Dr. Tintoré. Because changes in the first six months of treatment do not necessarily indicate treatment response, it may be necessary to perform another MRI after several months of treatment as a second baseline measurement, said Dr. Tintoré.
Furthermore, agreement between neuroradiologists is not high. Researchers have observed great variability between readers who had been asked to assess the presence of new T2 or gadolinium-enhancing lesions. And although standardized MRI protocols have been established, they may not be followed uniformly, perhaps because of difficulties specific to given facilities.
Is MEDA an Appropriate Goal?
One potential argument in favor of adopting NEDA as a goal of treatment is that disease activity often predicts poor long-term outcomes. Dr. Tintoré and colleagues assessed the treatment effect in patients with relapsing-remitting MS after two years of interferon therapy. They followed patients for 12 years. Clinical activity during the first two years of treatment was associated with increased risks of developing secondary progressive MS, of reaching an Expanded Disability Status Scale (EDSS) score of 7, and of having a five-point increase on the EDSS at 12 years.
Yet patients with little disease activity may still have good long-term outcomes. In a separate study, Dr. Tintoré and colleagues assessed the presence of MRI lesions after one year in patients with relapsing-remitting MS who were receiving interferon treatment. Participants were followed for eight years, and the primary end point was an increase of at least two points on EDSS after eight years. The investigators found no difference in outcome at eight years between patients who had one gadolinium-enhancing lesion at one year and those who had none at one year. Patients who had two or more gadolinium-enhancing lesions at one year, however, were more likely to reach the primary end point than patients who had fewer than two gadolinium-enhancing lesions at one year.
Results were similar for new T2 lesions. There was no difference in outcome at eight years between participants with no new T2 lesions at one year and those with one or two new T2 lesions at one year. Patients with three or more new T2 lesions at one year, however, were more likely to reach the primary end point. The Rio score was able to predict which patients would have more disability progression, but NEDA was not able to do so, said Dr. Tintoré. These results are similar to those of the MRI in MS (MAGNIMS) data set, in which a low level of disease activity was not associated with poor long-term outcome.
“Combined clinical and MRI scores allow us to integrate disease activity data into individual therapeutic decisions for our patients with MS,” said Dr. Tintoré. Newer therapies have made NEDA attainable for more patients, but not for all patients. Because minimal clinical or MRI activity is not necessarily associated with a poor response in the long term, neurologists may debate whether or when MEDA is an acceptable goal of treatment.
—Erik Greb
Suggested Reading
Giovannoni G, Turner B, Gnanapavan S, et al. Is it time to target no evident disease activity (NEDA) in multiple sclerosis? Mult Scler Relat Disord. 2015;4(4):329-333.
Kappos L, De Stefano N, Freedman MS, et al. Inclusion of brain volume loss in a revised measure of ‘no evidence of disease activity’ (NEDA-4) in relapsing-remitting multiple sclerosis. Mult Scler. 2016;22(10):1297-1305.
Río J, Castilló J, Rovira A, et al. Measures in the first year of therapy predict the response to interferon beta in MS. Mult Scler. 2009;15(7):848-853.
Uher T, Havrdova E, Sobisek L, et al. Is no evidence of disease activity an achievable goal in MS patients on intramuscular interferon beta-1a treatment over long-term follow-up? Mult Scler. 2016 May 26 [Epub ahead of print].
LONDON—No evidence of disease activity (NEDA) is a worthy but potentially problematic goal in the care of patients with multiple sclerosis (MS), according to an overview provided at the 32nd Congress of the European Committee for Treatment and Research in MS. The definition of NEDA is evolving as neurologists adopt new metrics in clinical practice, and NEDA is a difficult outcome to sustain in the long term.
Studies of interferon beta suggest that a minimal amount of clinical or MRI activity is not necessarily associated with poor long-term outcomes. Such research raises the possibility that minimal evidence of disease activity (MEDA) could be an appropriate goal of treatment, said Mar Tintoré, MD, PhD, neurologist at the MS Centre of Catalonia in Barcelona.
The Emergence of NEDA
A patient receiving treatment who has no sustained disability progression, no relapses, and no new T2 or gadolinium-enhancing lesions has NEDA, as the term was originally conceived. The outcome was rapidly adopted in clinical trials. NEDA also has been applied in the clinical setting. In one study of patients with MS treated in clinical practice, 54% had NEDA at one year. Researchers also found that NEDA may predict long-term outcomes. In one study, 78% of patients with NEDA at year two did not have disease progression at year seven.
A drawback of NEDA is that disease activity may be diffuse and may not manifest itself in relapses, new lesions, or disability progression. “It also may give a false sense of security to the doctor and to the patient,” said Dr. Tintoré.
A fourth factor, brain volume loss, recently was incorporated into NEDA, which has come to be called NEDA-4. Two studies have determined that a 0.4% annual rate of brain volume loss is the best threshold for distinguishing between people with MS and healthy controls.
The Difficulties of NEDA
The new conception of NEDA still omits several factors that neurologists may consider important. NEDA does not take cognition into account, but adding the MS Functional Composite to the NEDA criteria could change that. Patient-reported outcomes such as fatigue, depression, and quality of life also might be appropriate outcomes to incorporate into NEDA, said Dr. Tintoré. In addition, biomarkers such as CSF levels of neurofilament light indicate treatment response and could be added to NEDA.
Current clinical practice may make it difficult to assess whether a patient has NEDA. Many neurologists perform an MRI on a patient before initiating treatment and again at 12 months. “Many of the drugs that we are currently using are not active from baseline,” said Dr. Tintoré. Because changes in the first six months of treatment do not necessarily indicate treatment response, it may be necessary to perform another MRI after several months of treatment as a second baseline measurement, said Dr. Tintoré.
Furthermore, agreement between neuroradiologists is not high. Researchers have observed great variability between readers who had been asked to assess the presence of new T2 or gadolinium-enhancing lesions. And although standardized MRI protocols have been established, they may not be followed uniformly, perhaps because of difficulties specific to given facilities.
Is MEDA an Appropriate Goal?
One potential argument in favor of adopting NEDA as a goal of treatment is that disease activity often predicts poor long-term outcomes. Dr. Tintoré and colleagues assessed the treatment effect in patients with relapsing-remitting MS after two years of interferon therapy. They followed patients for 12 years. Clinical activity during the first two years of treatment was associated with increased risks of developing secondary progressive MS, of reaching an Expanded Disability Status Scale (EDSS) score of 7, and of having a five-point increase on the EDSS at 12 years.
Yet patients with little disease activity may still have good long-term outcomes. In a separate study, Dr. Tintoré and colleagues assessed the presence of MRI lesions after one year in patients with relapsing-remitting MS who were receiving interferon treatment. Participants were followed for eight years, and the primary end point was an increase of at least two points on EDSS after eight years. The investigators found no difference in outcome at eight years between patients who had one gadolinium-enhancing lesion at one year and those who had none at one year. Patients who had two or more gadolinium-enhancing lesions at one year, however, were more likely to reach the primary end point than patients who had fewer than two gadolinium-enhancing lesions at one year.
Results were similar for new T2 lesions. There was no difference in outcome at eight years between participants with no new T2 lesions at one year and those with one or two new T2 lesions at one year. Patients with three or more new T2 lesions at one year, however, were more likely to reach the primary end point. The Rio score was able to predict which patients would have more disability progression, but NEDA was not able to do so, said Dr. Tintoré. These results are similar to those of the MRI in MS (MAGNIMS) data set, in which a low level of disease activity was not associated with poor long-term outcome.
“Combined clinical and MRI scores allow us to integrate disease activity data into individual therapeutic decisions for our patients with MS,” said Dr. Tintoré. Newer therapies have made NEDA attainable for more patients, but not for all patients. Because minimal clinical or MRI activity is not necessarily associated with a poor response in the long term, neurologists may debate whether or when MEDA is an acceptable goal of treatment.
—Erik Greb
Suggested Reading
Giovannoni G, Turner B, Gnanapavan S, et al. Is it time to target no evident disease activity (NEDA) in multiple sclerosis? Mult Scler Relat Disord. 2015;4(4):329-333.
Kappos L, De Stefano N, Freedman MS, et al. Inclusion of brain volume loss in a revised measure of ‘no evidence of disease activity’ (NEDA-4) in relapsing-remitting multiple sclerosis. Mult Scler. 2016;22(10):1297-1305.
Río J, Castilló J, Rovira A, et al. Measures in the first year of therapy predict the response to interferon beta in MS. Mult Scler. 2009;15(7):848-853.
Uher T, Havrdova E, Sobisek L, et al. Is no evidence of disease activity an achievable goal in MS patients on intramuscular interferon beta-1a treatment over long-term follow-up? Mult Scler. 2016 May 26 [Epub ahead of print].
