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Dr. Patricia Coyle’s Donald Paty Memorial Lecture covered current controversies in DMT use.
NASHVILLE—What guides decisions to start, stop, switch, or restart disease-modifying therapy (DMT) in patients with multiple sclerosis (MS)—particularly in the absence of extensive robust data? Because multiple treatment options exist, there is a higher bar for a DMT to be considered successful. Clinicians need to base individualized decisions on the best available evidence, according to a presentation at the 2018 CMSC Annual Meeting. 
“We have practice guidelines, but unfortunately they are almost always out of date,” said Patricia K. Coyle, MD, Professor and Vice Chair of Clinical Affairs and Director of the MS Comprehensive Care Center at Stony Brook University Hospital in New York. “Guidelines have a lot of good things to say and several things that I would not quite agree with, but at least they are a helpful start. In the future, as we use cooperative studies, databases, and meaningful observations on large numbers of patients with MS to maximize our information and data, we will ultimately resolve all of these DMT debates.”
Starting Treatment
Controversies surrounding initiation of DMTs include whether to treat patients with radiologically isolated syndrome, when to start treating relapsing forms of MS that are not active, and, in patients with primary progressive MS, when the monoclonal agent ocrelizumab is appropriate. Current American Academy of Neurology (AAN) practice guidelines recommend both prescribing a DMT to patients with clinically isolated syndrome (CIS), patients with a first attack who have at least two MRI lesions characteristic of MS, and offering DMTs to patients with relapsing forms of MS and recent attacks or MRI activity.
The AAN recommendations stem from the benefits seen with early treatment, Dr. Coyle emphasized. “There may be a critical window of opportunity in treating early,” she said. “If MS involves accumulating permanent damage to the CNS, wouldn’t you want to stop or minimize that as quickly as possible—not wait until there has already been significant injury?” Virtually all studies comparing early versus delayed treatment support early treatment—and “age probably matters.”
In a 2017 meta-analysis of 38 clinical trials that assessed disability worsening and disease progression in a total population of 28,000 subjects with MS, the authors found that DMT efficacy and impact on disability fell with advancing age. The model created from this study predicted that none of the DMTs would be efficacious on disability in patients older than 53. Evidence also suggested that, after patients reached age 40.5, high-efficacy DMTs (eg, ocrelizumab, natalizumab) no longer outperformed lower-efficacy oral agents (fingolimod, teriflunomide, dimethyl fumarate) or injectables (interferon betas and glatiramer acetates).
While skeptical of this latter finding, Dr. Coyle termed it “provocative” because it demonstrates that patients should be treated at a younger age. “When MS declares itself, the disease has probably existed for years, damaging CNS tissue,” she said. Older age at onset probably means that the disease has been present but silent for a long period of time. In addition, CNS and brain reserve become increasingly impaired with age. “The older you are, in theory, the less CNS reserve you have.”
Stopping Treatment
Potential reasons for stopping DMT include relapsing MS or CIS that has been inactive for years; secondary progressive MS that is distant from the relapsing phase and now in a purely neurodegenerative one; age older than 60; and pregnancy.
Citing just a handful of studies in this area, Dr. Coyle pointed to the MSBase Registry of patients with relapsing MS who, on injectables, had no relapse for five years or more. Among 485 patients who stopped DMT versus 854 who continued treatment, time to relapse was similar but time to confirmed disability was shorter in those who stopped treatment. Those who stopped treatment also had an increased risk for entering the progressive stage. In another study of two cohorts who stopped DMT, 11.7% of patients with secondary progressive MS who were stable for two to 20 years, versus 58.8% of patients with relapsing MS, had acute disease within one to two years. The authors noted the secondary progressive MS cohort was older with higher EDSS scores. A retrospective review of patients with MS older than 60 who had been on DMT for more than two years showed that, of the 29.7% who stopped DMT, only one relapsed and just 10.7% reinitiated DMT.
“I would not stop a well-tolerated DMT in relapsing MS,” said Dr. Coyle. “I would continue DMT in CIS if patients were at high risk, even if they had had no disease activity for years. I would discuss stopping therapy in patients with secondary progressive MS who were older than 60, and in very debilitated patients with progressive MS.”
Switching DMTs
In terms of switching, a suboptimal response is likely magnified by delaying therapy, not matching patients well to their initial DMT, and not identifying poor response quickly,” said Dr. Coyle.
Reasons to switch include breakthrough activity—ie, the minimal evidence of disease activity (MEDA) or no evidence of disease activity (NEDA) target not met; MRI activity; poor tolerability; and abnormal laboratory data or clinical complications. Clinicians should consult the AAN practice guidelines for recommendations on when and which DMTs to switch.
Dr. Coyle again cited the MSBase Registry, in which three studies were conducted involving patients with MS who were on interferon beta or glatiramer acetate who had breakthrough attacks or disability. “In one study they switched them to another injectable or fingolimod,” she said. “They did better if they got to fingolimod. Another study involved switching to another injectable or natalizumab. They did better if they were on natalizumab. A third study looked at switching to fingolimod or natalizumab. They did better with natalizumab.”
Dr. Coyle observed that the first one to two years after initiating DMT may be the most important for determining whether a patient is doing well. “A DMT takes a few months to be fully operational,” she said. “If you are switching for breakthrough activity, you need to go to a higher-efficacy DMT. My treat-to target is not NEDA, it is MEDA.”
—Fred Balzac
Suggested Reading
Berkovich R. Clinical and MRI outcomes after stopping or switching disease-modifying therapy in stable MS patients: a case series report. Mult Scler Relat Disord. 2017;17:123-127.
Birnbaum G. Stopping disease-modifying therapy in nonrelapsing multiple sclerosis: experience from a clinical practice. Int J MS Care. 2017;19(1):11-14.
Coyle PK. Switching therapies in multiple sclerosis. CNS Drugs. 2013;27(4):239-247.
Hua LH, Fan TH, Conway D, et al. Discontinuation of disease-modifying therapy in patients with multiple sclerosis over age 60. Mult Scler. 2018 Mar 1 [Epub ahead of print].
Kappos L, Radue EW, Comi G, et al, for the TOFINGO study group. Switching from natalizumab to fingolimod: a randomized, placebo-controlled study in RRMS. Neurology. 2015;85(1):29-39.
Kister I, Spelman T, Alroughani R, et al, for the MSBase Study Group. Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: a propensity score-matched study. J Neurol Neurosurg Psychiatry. 2016;87(10):1133-1137.
Maillart E, Vidal JS, Brassat D, et al. Natalizumab-PML survivors with subsequent MS treatment: clinico-radiologic outcome. Neurol Neuroimmunol Neuroinflamm. 2017;4(3):e346.
Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(17):777-788.
Weideman AM, Tapia-Maltos MA, Johnson K, et al. Meta-analysis of the age-dependent efficacy of multiple sclerosis treatments. Front Neurol. 2017;8:577.
Dr. Patricia Coyle’s Donald Paty Memorial Lecture covered current controversies in DMT use.
Dr. Patricia Coyle’s Donald Paty Memorial Lecture covered current controversies in DMT use.
NASHVILLE—What guides decisions to start, stop, switch, or restart disease-modifying therapy (DMT) in patients with multiple sclerosis (MS)—particularly in the absence of extensive robust data? Because multiple treatment options exist, there is a higher bar for a DMT to be considered successful. Clinicians need to base individualized decisions on the best available evidence, according to a presentation at the 2018 CMSC Annual Meeting.
“We have practice guidelines, but unfortunately they are almost always out of date,” said Patricia K. Coyle, MD, Professor and Vice Chair of Clinical Affairs and Director of the MS Comprehensive Care Center at Stony Brook University Hospital in New York. “Guidelines have a lot of good things to say and several things that I would not quite agree with, but at least they are a helpful start. In the future, as we use cooperative studies, databases, and meaningful observations on large numbers of patients with MS to maximize our information and data, we will ultimately resolve all of these DMT debates.”
Starting Treatment
Controversies surrounding initiation of DMTs include whether to treat patients with radiologically isolated syndrome, when to start treating relapsing forms of MS that are not active, and, in patients with primary progressive MS, when the monoclonal agent ocrelizumab is appropriate. Current American Academy of Neurology (AAN) practice guidelines recommend both prescribing a DMT to patients with clinically isolated syndrome (CIS), patients with a first attack who have at least two MRI lesions characteristic of MS, and offering DMTs to patients with relapsing forms of MS and recent attacks or MRI activity.
The AAN recommendations stem from the benefits seen with early treatment, Dr. Coyle emphasized. “There may be a critical window of opportunity in treating early,” she said. “If MS involves accumulating permanent damage to the CNS, wouldn’t you want to stop or minimize that as quickly as possible—not wait until there has already been significant injury?” Virtually all studies comparing early versus delayed treatment support early treatment—and “age probably matters.”
In a 2017 meta-analysis of 38 clinical trials that assessed disability worsening and disease progression in a total population of 28,000 subjects with MS, the authors found that DMT efficacy and impact on disability fell with advancing age. The model created from this study predicted that none of the DMTs would be efficacious on disability in patients older than 53. Evidence also suggested that, after patients reached age 40.5, high-efficacy DMTs (eg, ocrelizumab, natalizumab) no longer outperformed lower-efficacy oral agents (fingolimod, teriflunomide, dimethyl fumarate) or injectables (interferon betas and glatiramer acetates).
While skeptical of this latter finding, Dr. Coyle termed it “provocative” because it demonstrates that patients should be treated at a younger age. “When MS declares itself, the disease has probably existed for years, damaging CNS tissue,” she said. Older age at onset probably means that the disease has been present but silent for a long period of time. In addition, CNS and brain reserve become increasingly impaired with age. “The older you are, in theory, the less CNS reserve you have.”
Stopping Treatment
Potential reasons for stopping DMT include relapsing MS or CIS that has been inactive for years; secondary progressive MS that is distant from the relapsing phase and now in a purely neurodegenerative one; age older than 60; and pregnancy.
Citing just a handful of studies in this area, Dr. Coyle pointed to the MSBase Registry of patients with relapsing MS who, on injectables, had no relapse for five years or more. Among 485 patients who stopped DMT versus 854 who continued treatment, time to relapse was similar but time to confirmed disability was shorter in those who stopped treatment. Those who stopped treatment also had an increased risk for entering the progressive stage. In another study of two cohorts who stopped DMT, 11.7% of patients with secondary progressive MS who were stable for two to 20 years, versus 58.8% of patients with relapsing MS, had acute disease within one to two years. The authors noted the secondary progressive MS cohort was older with higher EDSS scores. A retrospective review of patients with MS older than 60 who had been on DMT for more than two years showed that, of the 29.7% who stopped DMT, only one relapsed and just 10.7% reinitiated DMT.
“I would not stop a well-tolerated DMT in relapsing MS,” said Dr. Coyle. “I would continue DMT in CIS if patients were at high risk, even if they had had no disease activity for years. I would discuss stopping therapy in patients with secondary progressive MS who were older than 60, and in very debilitated patients with progressive MS.”
Switching DMTs
In terms of switching, a suboptimal response is likely magnified by delaying therapy, not matching patients well to their initial DMT, and not identifying poor response quickly,” said Dr. Coyle.
Reasons to switch include breakthrough activity—ie, the minimal evidence of disease activity (MEDA) or no evidence of disease activity (NEDA) target not met; MRI activity; poor tolerability; and abnormal laboratory data or clinical complications. Clinicians should consult the AAN practice guidelines for recommendations on when and which DMTs to switch.
Dr. Coyle again cited the MSBase Registry, in which three studies were conducted involving patients with MS who were on interferon beta or glatiramer acetate who had breakthrough attacks or disability. “In one study they switched them to another injectable or fingolimod,” she said. “They did better if they got to fingolimod. Another study involved switching to another injectable or natalizumab. They did better if they were on natalizumab. A third study looked at switching to fingolimod or natalizumab. They did better with natalizumab.”
Dr. Coyle observed that the first one to two years after initiating DMT may be the most important for determining whether a patient is doing well. “A DMT takes a few months to be fully operational,” she said. “If you are switching for breakthrough activity, you need to go to a higher-efficacy DMT. My treat-to target is not NEDA, it is MEDA.”
—Fred Balzac
Suggested Reading
Berkovich R. Clinical and MRI outcomes after stopping or switching disease-modifying therapy in stable MS patients: a case series report. Mult Scler Relat Disord. 2017;17:123-127.
Birnbaum G. Stopping disease-modifying therapy in nonrelapsing multiple sclerosis: experience from a clinical practice. Int J MS Care. 2017;19(1):11-14.
Coyle PK. Switching therapies in multiple sclerosis. CNS Drugs. 2013;27(4):239-247.
Hua LH, Fan TH, Conway D, et al. Discontinuation of disease-modifying therapy in patients with multiple sclerosis over age 60. Mult Scler. 2018 Mar 1 [Epub ahead of print].
Kappos L, Radue EW, Comi G, et al, for the TOFINGO study group. Switching from natalizumab to fingolimod: a randomized, placebo-controlled study in RRMS. Neurology. 2015;85(1):29-39.
Kister I, Spelman T, Alroughani R, et al, for the MSBase Study Group. Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: a propensity score-matched study. J Neurol Neurosurg Psychiatry. 2016;87(10):1133-1137.
Maillart E, Vidal JS, Brassat D, et al. Natalizumab-PML survivors with subsequent MS treatment: clinico-radiologic outcome. Neurol Neuroimmunol Neuroinflamm. 2017;4(3):e346.
Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(17):777-788.
Weideman AM, Tapia-Maltos MA, Johnson K, et al. Meta-analysis of the age-dependent efficacy of multiple sclerosis treatments. Front Neurol. 2017;8:577.
NASHVILLE—What guides decisions to start, stop, switch, or restart disease-modifying therapy (DMT) in patients with multiple sclerosis (MS)—particularly in the absence of extensive robust data? Because multiple treatment options exist, there is a higher bar for a DMT to be considered successful. Clinicians need to base individualized decisions on the best available evidence, according to a presentation at the 2018 CMSC Annual Meeting.
“We have practice guidelines, but unfortunately they are almost always out of date,” said Patricia K. Coyle, MD, Professor and Vice Chair of Clinical Affairs and Director of the MS Comprehensive Care Center at Stony Brook University Hospital in New York. “Guidelines have a lot of good things to say and several things that I would not quite agree with, but at least they are a helpful start. In the future, as we use cooperative studies, databases, and meaningful observations on large numbers of patients with MS to maximize our information and data, we will ultimately resolve all of these DMT debates.”
Starting Treatment
Controversies surrounding initiation of DMTs include whether to treat patients with radiologically isolated syndrome, when to start treating relapsing forms of MS that are not active, and, in patients with primary progressive MS, when the monoclonal agent ocrelizumab is appropriate. Current American Academy of Neurology (AAN) practice guidelines recommend both prescribing a DMT to patients with clinically isolated syndrome (CIS), patients with a first attack who have at least two MRI lesions characteristic of MS, and offering DMTs to patients with relapsing forms of MS and recent attacks or MRI activity.
The AAN recommendations stem from the benefits seen with early treatment, Dr. Coyle emphasized. “There may be a critical window of opportunity in treating early,” she said. “If MS involves accumulating permanent damage to the CNS, wouldn’t you want to stop or minimize that as quickly as possible—not wait until there has already been significant injury?” Virtually all studies comparing early versus delayed treatment support early treatment—and “age probably matters.”
In a 2017 meta-analysis of 38 clinical trials that assessed disability worsening and disease progression in a total population of 28,000 subjects with MS, the authors found that DMT efficacy and impact on disability fell with advancing age. The model created from this study predicted that none of the DMTs would be efficacious on disability in patients older than 53. Evidence also suggested that, after patients reached age 40.5, high-efficacy DMTs (eg, ocrelizumab, natalizumab) no longer outperformed lower-efficacy oral agents (fingolimod, teriflunomide, dimethyl fumarate) or injectables (interferon betas and glatiramer acetates).
While skeptical of this latter finding, Dr. Coyle termed it “provocative” because it demonstrates that patients should be treated at a younger age. “When MS declares itself, the disease has probably existed for years, damaging CNS tissue,” she said. Older age at onset probably means that the disease has been present but silent for a long period of time. In addition, CNS and brain reserve become increasingly impaired with age. “The older you are, in theory, the less CNS reserve you have.”
Stopping Treatment
Potential reasons for stopping DMT include relapsing MS or CIS that has been inactive for years; secondary progressive MS that is distant from the relapsing phase and now in a purely neurodegenerative one; age older than 60; and pregnancy.
Citing just a handful of studies in this area, Dr. Coyle pointed to the MSBase Registry of patients with relapsing MS who, on injectables, had no relapse for five years or more. Among 485 patients who stopped DMT versus 854 who continued treatment, time to relapse was similar but time to confirmed disability was shorter in those who stopped treatment. Those who stopped treatment also had an increased risk for entering the progressive stage. In another study of two cohorts who stopped DMT, 11.7% of patients with secondary progressive MS who were stable for two to 20 years, versus 58.8% of patients with relapsing MS, had acute disease within one to two years. The authors noted the secondary progressive MS cohort was older with higher EDSS scores. A retrospective review of patients with MS older than 60 who had been on DMT for more than two years showed that, of the 29.7% who stopped DMT, only one relapsed and just 10.7% reinitiated DMT.
“I would not stop a well-tolerated DMT in relapsing MS,” said Dr. Coyle. “I would continue DMT in CIS if patients were at high risk, even if they had had no disease activity for years. I would discuss stopping therapy in patients with secondary progressive MS who were older than 60, and in very debilitated patients with progressive MS.”
Switching DMTs
In terms of switching, a suboptimal response is likely magnified by delaying therapy, not matching patients well to their initial DMT, and not identifying poor response quickly,” said Dr. Coyle.
Reasons to switch include breakthrough activity—ie, the minimal evidence of disease activity (MEDA) or no evidence of disease activity (NEDA) target not met; MRI activity; poor tolerability; and abnormal laboratory data or clinical complications. Clinicians should consult the AAN practice guidelines for recommendations on when and which DMTs to switch.
Dr. Coyle again cited the MSBase Registry, in which three studies were conducted involving patients with MS who were on interferon beta or glatiramer acetate who had breakthrough attacks or disability. “In one study they switched them to another injectable or fingolimod,” she said. “They did better if they got to fingolimod. Another study involved switching to another injectable or natalizumab. They did better if they were on natalizumab. A third study looked at switching to fingolimod or natalizumab. They did better with natalizumab.”
Dr. Coyle observed that the first one to two years after initiating DMT may be the most important for determining whether a patient is doing well. “A DMT takes a few months to be fully operational,” she said. “If you are switching for breakthrough activity, you need to go to a higher-efficacy DMT. My treat-to target is not NEDA, it is MEDA.”
—Fred Balzac
Suggested Reading
Berkovich R. Clinical and MRI outcomes after stopping or switching disease-modifying therapy in stable MS patients: a case series report. Mult Scler Relat Disord. 2017;17:123-127.
Birnbaum G. Stopping disease-modifying therapy in nonrelapsing multiple sclerosis: experience from a clinical practice. Int J MS Care. 2017;19(1):11-14.
Coyle PK. Switching therapies in multiple sclerosis. CNS Drugs. 2013;27(4):239-247.
Hua LH, Fan TH, Conway D, et al. Discontinuation of disease-modifying therapy in patients with multiple sclerosis over age 60. Mult Scler. 2018 Mar 1 [Epub ahead of print].
Kappos L, Radue EW, Comi G, et al, for the TOFINGO study group. Switching from natalizumab to fingolimod: a randomized, placebo-controlled study in RRMS. Neurology. 2015;85(1):29-39.
Kister I, Spelman T, Alroughani R, et al, for the MSBase Study Group. Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: a propensity score-matched study. J Neurol Neurosurg Psychiatry. 2016;87(10):1133-1137.
Maillart E, Vidal JS, Brassat D, et al. Natalizumab-PML survivors with subsequent MS treatment: clinico-radiologic outcome. Neurol Neuroimmunol Neuroinflamm. 2017;4(3):e346.
Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(17):777-788.
Weideman AM, Tapia-Maltos MA, Johnson K, et al. Meta-analysis of the age-dependent efficacy of multiple sclerosis treatments. Front Neurol. 2017;8:577.