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Is FOXP3 Gene Polymorphism a Risk for MS?
Key clinical point: More studies are needed with larger samples and more ethnicities to support the study's findings.
Major finding: The FOXP3 gene rs3761548 was found to increase the risk for MS, with a higher risk found in Asian patients.
Study details: This was a meta-analysis of 5 studies from January 1980 to October 2018. The studies were used to evaluate the association between FOXP3 gene polymorphism and MS. For FOXP3 gene rs3761548, there were 1,276 MS patients and 1,447 controls; and for FOXP3 gene rs2232365, there were 600 MS patients and 640 controls.
Disclosures: None.
Citation: Zhang Y, et al. Medicine. 2019 Sep;98(38):e17224. doi: 10.1097/MD.0000000000017224.
Key clinical point: More studies are needed with larger samples and more ethnicities to support the study's findings.
Major finding: The FOXP3 gene rs3761548 was found to increase the risk for MS, with a higher risk found in Asian patients.
Study details: This was a meta-analysis of 5 studies from January 1980 to October 2018. The studies were used to evaluate the association between FOXP3 gene polymorphism and MS. For FOXP3 gene rs3761548, there were 1,276 MS patients and 1,447 controls; and for FOXP3 gene rs2232365, there were 600 MS patients and 640 controls.
Disclosures: None.
Citation: Zhang Y, et al. Medicine. 2019 Sep;98(38):e17224. doi: 10.1097/MD.0000000000017224.
Key clinical point: More studies are needed with larger samples and more ethnicities to support the study's findings.
Major finding: The FOXP3 gene rs3761548 was found to increase the risk for MS, with a higher risk found in Asian patients.
Study details: This was a meta-analysis of 5 studies from January 1980 to October 2018. The studies were used to evaluate the association between FOXP3 gene polymorphism and MS. For FOXP3 gene rs3761548, there were 1,276 MS patients and 1,447 controls; and for FOXP3 gene rs2232365, there were 600 MS patients and 640 controls.
Disclosures: None.
Citation: Zhang Y, et al. Medicine. 2019 Sep;98(38):e17224. doi: 10.1097/MD.0000000000017224.
Late-onset MS is often more severe than earlier-onset MS
ST. LOUIS –
Whether the pathophysiology is different, or if the disease is simply compounded by the effects of aging, is uncertain. It is likely, however, that patients with late onset are at greater risk of misdiagnosis and delayed treatment, said Mattia Wruble, a 4th-year medical student at the University of Virginia.
The reason is that MS usually presents in young women as relapsing-remitting disease, but late onset is more typically primary progressive, with a higher proportion of men, which is something that has been demonstrated in previous work and also found in the new study.
“What we didn’t expect to find,” however, was greater “disability and higher disability accrual rates” across all subtypes. Late-onset MS “is a worse disease, a more severe disease” that might even need different treatment options, Ms. Wruble said at the American Neurological Association annual meeting.
Ms. Wruble and colleagues compared the charts of 1,381 patients with MS onset before age 50 years, at a median age of 33 years, with 143 patients whose symptoms began at age 50 years or later, at a median of 55 years.
It was one of the largest late-onset MS samples to date. Incidence of the condition is on the rise, but research has been limited. The investigators hoped to address a need for “a better and more thorough characterization of” the disease to aid treatment and improve outcomes, Ms. Wruble said.
There was a higher proportion of men in the late-onset group, 38% vs. 26%. About 75% of patients with early onset had relapsing remitting disease, and 10% had primary progressive disease. The late-onset group was about evenly split between relapsing-remitting and primary progressive MS (P less than .001).
Patients with late onset MS also had a higher degree of disability at their most recent visit across all subtypes (median Expanded Disability Status Scale score of 5 versus 3), despite having a shorter duration of disease (mean 12 vs. 17 years from symptom onset).
Overall disease accrual rate in the late-onset group was twice that of early-onset group, a decline of 0.647 points per year on the EDSS versus 0.357 points (P less than .001). The finding held when limited to early and late relapsing-remitting cases. The accrual rate for late-onset primary and secondary progressive MS was 1.5 times that of early-onset cases.
Transition to secondary progressive disease also was faster in the late-onset group, a mean of about 7 years versus 15-19 years. Patients with late onset also were more likely to have a history of smoking.
The cerebrospinal fluid in late-onset MS generally has fewer unique oligoclonal bands, which are part of the McDonald diagnostic criteria for MS. “The McDonald criteria were made for patients between 20 and 50 years old; maybe they are not the best criteria to diagnose this late-onset group,” Ms. Wruble said.
There was no external funding, and Ms. Wruble had no disclosures.
SOURCE: Wruble M et al. ANA 2019. Abstract S234.
ST. LOUIS –
Whether the pathophysiology is different, or if the disease is simply compounded by the effects of aging, is uncertain. It is likely, however, that patients with late onset are at greater risk of misdiagnosis and delayed treatment, said Mattia Wruble, a 4th-year medical student at the University of Virginia.
The reason is that MS usually presents in young women as relapsing-remitting disease, but late onset is more typically primary progressive, with a higher proportion of men, which is something that has been demonstrated in previous work and also found in the new study.
“What we didn’t expect to find,” however, was greater “disability and higher disability accrual rates” across all subtypes. Late-onset MS “is a worse disease, a more severe disease” that might even need different treatment options, Ms. Wruble said at the American Neurological Association annual meeting.
Ms. Wruble and colleagues compared the charts of 1,381 patients with MS onset before age 50 years, at a median age of 33 years, with 143 patients whose symptoms began at age 50 years or later, at a median of 55 years.
It was one of the largest late-onset MS samples to date. Incidence of the condition is on the rise, but research has been limited. The investigators hoped to address a need for “a better and more thorough characterization of” the disease to aid treatment and improve outcomes, Ms. Wruble said.
There was a higher proportion of men in the late-onset group, 38% vs. 26%. About 75% of patients with early onset had relapsing remitting disease, and 10% had primary progressive disease. The late-onset group was about evenly split between relapsing-remitting and primary progressive MS (P less than .001).
Patients with late onset MS also had a higher degree of disability at their most recent visit across all subtypes (median Expanded Disability Status Scale score of 5 versus 3), despite having a shorter duration of disease (mean 12 vs. 17 years from symptom onset).
Overall disease accrual rate in the late-onset group was twice that of early-onset group, a decline of 0.647 points per year on the EDSS versus 0.357 points (P less than .001). The finding held when limited to early and late relapsing-remitting cases. The accrual rate for late-onset primary and secondary progressive MS was 1.5 times that of early-onset cases.
Transition to secondary progressive disease also was faster in the late-onset group, a mean of about 7 years versus 15-19 years. Patients with late onset also were more likely to have a history of smoking.
The cerebrospinal fluid in late-onset MS generally has fewer unique oligoclonal bands, which are part of the McDonald diagnostic criteria for MS. “The McDonald criteria were made for patients between 20 and 50 years old; maybe they are not the best criteria to diagnose this late-onset group,” Ms. Wruble said.
There was no external funding, and Ms. Wruble had no disclosures.
SOURCE: Wruble M et al. ANA 2019. Abstract S234.
ST. LOUIS –
Whether the pathophysiology is different, or if the disease is simply compounded by the effects of aging, is uncertain. It is likely, however, that patients with late onset are at greater risk of misdiagnosis and delayed treatment, said Mattia Wruble, a 4th-year medical student at the University of Virginia.
The reason is that MS usually presents in young women as relapsing-remitting disease, but late onset is more typically primary progressive, with a higher proportion of men, which is something that has been demonstrated in previous work and also found in the new study.
“What we didn’t expect to find,” however, was greater “disability and higher disability accrual rates” across all subtypes. Late-onset MS “is a worse disease, a more severe disease” that might even need different treatment options, Ms. Wruble said at the American Neurological Association annual meeting.
Ms. Wruble and colleagues compared the charts of 1,381 patients with MS onset before age 50 years, at a median age of 33 years, with 143 patients whose symptoms began at age 50 years or later, at a median of 55 years.
It was one of the largest late-onset MS samples to date. Incidence of the condition is on the rise, but research has been limited. The investigators hoped to address a need for “a better and more thorough characterization of” the disease to aid treatment and improve outcomes, Ms. Wruble said.
There was a higher proportion of men in the late-onset group, 38% vs. 26%. About 75% of patients with early onset had relapsing remitting disease, and 10% had primary progressive disease. The late-onset group was about evenly split between relapsing-remitting and primary progressive MS (P less than .001).
Patients with late onset MS also had a higher degree of disability at their most recent visit across all subtypes (median Expanded Disability Status Scale score of 5 versus 3), despite having a shorter duration of disease (mean 12 vs. 17 years from symptom onset).
Overall disease accrual rate in the late-onset group was twice that of early-onset group, a decline of 0.647 points per year on the EDSS versus 0.357 points (P less than .001). The finding held when limited to early and late relapsing-remitting cases. The accrual rate for late-onset primary and secondary progressive MS was 1.5 times that of early-onset cases.
Transition to secondary progressive disease also was faster in the late-onset group, a mean of about 7 years versus 15-19 years. Patients with late onset also were more likely to have a history of smoking.
The cerebrospinal fluid in late-onset MS generally has fewer unique oligoclonal bands, which are part of the McDonald diagnostic criteria for MS. “The McDonald criteria were made for patients between 20 and 50 years old; maybe they are not the best criteria to diagnose this late-onset group,” Ms. Wruble said.
There was no external funding, and Ms. Wruble had no disclosures.
SOURCE: Wruble M et al. ANA 2019. Abstract S234.
REPORTING FROM ANA 2019
Time to Disability Milestones in MS Is Lengthening
Key clinical point: Disability milestones are not being met as quickly for patients with multiple sclerosis (MS), as disease progression has slowed.
Major finding: In patients with relapsing-onset MS there was a decreased risk of reaching disability milestones by 3%, 6%, and 7% in Expanded Disability Status Score (EDSS) scores of 3.0, 4.0, and 6.0, respectively. In patients with progressive-onset MS there was no significant decrease.
Study details: This was a nationwide population-based retrospective cohort study of 12,512 patients in Sweden. Of those patients 7,331 (5,196 females) were diagnosed with MS at a mean age of 38.3 years between January 1995 and December 2010 and had 2 recorded EDSS scores.
Disclosures: Research was funded by the Swedish Research Council and the Swedish Brain Foundation.
Citation: Beiki O, et al. JAMA Neurol. 2019;76(6):665-671. doi: 10.1001/jamaneurol.2019.0330.
Key clinical point: Disability milestones are not being met as quickly for patients with multiple sclerosis (MS), as disease progression has slowed.
Major finding: In patients with relapsing-onset MS there was a decreased risk of reaching disability milestones by 3%, 6%, and 7% in Expanded Disability Status Score (EDSS) scores of 3.0, 4.0, and 6.0, respectively. In patients with progressive-onset MS there was no significant decrease.
Study details: This was a nationwide population-based retrospective cohort study of 12,512 patients in Sweden. Of those patients 7,331 (5,196 females) were diagnosed with MS at a mean age of 38.3 years between January 1995 and December 2010 and had 2 recorded EDSS scores.
Disclosures: Research was funded by the Swedish Research Council and the Swedish Brain Foundation.
Citation: Beiki O, et al. JAMA Neurol. 2019;76(6):665-671. doi: 10.1001/jamaneurol.2019.0330.
Key clinical point: Disability milestones are not being met as quickly for patients with multiple sclerosis (MS), as disease progression has slowed.
Major finding: In patients with relapsing-onset MS there was a decreased risk of reaching disability milestones by 3%, 6%, and 7% in Expanded Disability Status Score (EDSS) scores of 3.0, 4.0, and 6.0, respectively. In patients with progressive-onset MS there was no significant decrease.
Study details: This was a nationwide population-based retrospective cohort study of 12,512 patients in Sweden. Of those patients 7,331 (5,196 females) were diagnosed with MS at a mean age of 38.3 years between January 1995 and December 2010 and had 2 recorded EDSS scores.
Disclosures: Research was funded by the Swedish Research Council and the Swedish Brain Foundation.
Citation: Beiki O, et al. JAMA Neurol. 2019;76(6):665-671. doi: 10.1001/jamaneurol.2019.0330.
From DMTs to Secondary Progressive MS
Key clinical point: The use, type, and timing of disease-modifying therapies (DMTs) in relapsing-remitting multiple sclerosis (RRMS) patients may lead to secondary progressive MS.
Major finding: RRMS patients beginning DMTs of fingolimod, alemtuzumab, or natalizumab had a lower chance of secondary progressive MS, whereas patients taking glatiramer acetate or interferon beta had a higher chance.
Study details: This was a cohort study that examined 1,555 RRMS patients (1,123 females) across 21 countries that began DMTs (interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab) between 1988 and 2012.
Disclosures: This study was financially supported by the National Health and Medical Research Council of Australia, the University of Melbourne, a Next Generation Fellowship funded by the Grand Charity of the Freemason’s, and the MSBase 2017 Fellowship. Alemtuzumab studies done in Cambridge were supported by the NIHR Cambridge Biomedical Research Centre and the MS Society UK.
Citation: Brown JWL, et al. JAMA. 2019;321(2):175-187. doi: 10.1001/jama.2018.20588.
Key clinical point: The use, type, and timing of disease-modifying therapies (DMTs) in relapsing-remitting multiple sclerosis (RRMS) patients may lead to secondary progressive MS.
Major finding: RRMS patients beginning DMTs of fingolimod, alemtuzumab, or natalizumab had a lower chance of secondary progressive MS, whereas patients taking glatiramer acetate or interferon beta had a higher chance.
Study details: This was a cohort study that examined 1,555 RRMS patients (1,123 females) across 21 countries that began DMTs (interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab) between 1988 and 2012.
Disclosures: This study was financially supported by the National Health and Medical Research Council of Australia, the University of Melbourne, a Next Generation Fellowship funded by the Grand Charity of the Freemason’s, and the MSBase 2017 Fellowship. Alemtuzumab studies done in Cambridge were supported by the NIHR Cambridge Biomedical Research Centre and the MS Society UK.
Citation: Brown JWL, et al. JAMA. 2019;321(2):175-187. doi: 10.1001/jama.2018.20588.
Key clinical point: The use, type, and timing of disease-modifying therapies (DMTs) in relapsing-remitting multiple sclerosis (RRMS) patients may lead to secondary progressive MS.
Major finding: RRMS patients beginning DMTs of fingolimod, alemtuzumab, or natalizumab had a lower chance of secondary progressive MS, whereas patients taking glatiramer acetate or interferon beta had a higher chance.
Study details: This was a cohort study that examined 1,555 RRMS patients (1,123 females) across 21 countries that began DMTs (interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab) between 1988 and 2012.
Disclosures: This study was financially supported by the National Health and Medical Research Council of Australia, the University of Melbourne, a Next Generation Fellowship funded by the Grand Charity of the Freemason’s, and the MSBase 2017 Fellowship. Alemtuzumab studies done in Cambridge were supported by the NIHR Cambridge Biomedical Research Centre and the MS Society UK.
Citation: Brown JWL, et al. JAMA. 2019;321(2):175-187. doi: 10.1001/jama.2018.20588.
MS-related disability may be decreasing
STOCKHOLM – , according to an overview provided at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Data consistently indicate that the time that elapses before a patient requires a cane for ambulation has increased, and survival has likewise improved. “Some of the improvement can be attributed confidently to treatment effect,” said Ilya Kister, MD, associate professor of neurology at NYU Langone Health in New York. “We hope to see an even greater change with newer therapies.”
At the same time, neurologists appear to be diagnosing more cases of MS than they previously did, said Dr. Kister, which suggests that neurologists probably are diagnosing milder cases. The overall societal burden of MS remains high.
The relative prevalence of mild disability has increased
About 25 years have elapsed since the first disease-modifying treatment (DMT) for MS became available, and treatment has become widespread during that time. Dr. Kister and colleagues sought to determine whether the current clinical population of patients with MS, who for the most part receive DMTs, has less disability than do untreated patients or patients from natural history studies do. They identified the MS Severity Score (MSSS) as a measure with which to compare populations. The MSSS assigns a patient a ranking according to his or her level of disability, using a reference population of patients with the same disease duration for comparison. “MSSS can be conceptualized as rate of disability accumulation,” said Dr. Kister. “Lower MSSS corresponds to relatively slower disability accumulation, and higher MSSS to higher disability accumulation.”
The MSSS was developed using the Expanded Disability Status Scale (EDSS) score as a measure of disability. Because many neurologists do not routinely obtain EDSS scores for their patients, Dr. Kister and colleagues used the Patient-Determined Disease Steps (PDDS) to measure disability. As its name implies, the PDDS is a patient-reported outcome measure that mainly measures ambulation. It correlates strongly with EDSS, said Dr. Kister. He and colleagues used the PDDS to develop a reference table of MS disability, which they called the Patient-Derived MSSS.
The investigators examined a large sample of patients at NYU MS Center and Barnabas MS Center in Livingston, N.J. They grouped patients into sextiles according to their Patient-Derived MSSS. Dr. Kister and colleagues found that, rather than arriving at sextiles that contained equal numbers of patients, as would be expected if disability were distributed as in the reference population, they had significantly more patients in the two lowest sextiles and significantly fewer patients in the two highest sextiles. “This [result] suggests that the disability curve has indeed shifted toward the more benign end of the spectrum in the contemporary clinic population,” said Dr. Kister.
Other researchers have observed a similar phenomenon. George et al. published the results of a large, international collaboration in Neurology Genetics in 2016. After examining more than 7,000 patients, the investigators noted a similar overrepresentation of patients with milder severity scores and underrepresentation of patients with higher severity scores. These results support the hypothesis of a shift toward milder disability, said Dr. Kister.
Trend toward milder disability
The investigators next examined whether the rate of accumulation of disability among patients with MS had changed from year to year since DMTs were introduced. They conducted a univariate analysis of MSSS for 6,238 patients who were enrolled in the N.Y. State MS Consortium during 1996-2007. They found that patients who were enrolled in more recent years had significantly lower MSSS than patients who were enrolled in earlier years, regardless of disease duration. When Dr. Kister and colleagues replicated their analysis using EDSS, they found significantly lower levels of disability for patients enrolled in more recent years, except for patients with disease duration of 26-30 years. A multivariate analysis showed that the median MSSS of enrollees into the N.Y. State MS Consortium decreased from 5.04 in 1996 to 3.78 in 2006.
In a subsequent study, Dr. Kister and colleagues examined the age at which patients in the MSBase registry reached various disability milestones (e.g., EDSS of 6, which indicates the need of a cane to walk outdoors), according to their year of enrollment in the registry. They found a significant increase in age at milestone achievement with each subsequent calendar year. For example, for every consecutive year of enrollment, the age at which patients attained an EDSS of 6 increased by 0.38 years. These analyses were confirmed for the subgroups of patients diagnosed according to the Poser and McDonald criteria. The increase in age “is probably not just related to the shift in diagnostic criteria,” said Dr. Kister. When the researchers calculated the net average gains in years over the 13-year follow-up period, they found that patients who entered at the end of the enrollment period were 4.9 years older when they reached an EDSS of 6, compared with patients with an EDSS of 6 who entered at the beginning of the enrollment period.
International data show similar trends
Research conducted around the world shows similar trends, said Dr. Kister. In 2009, Veugelers et al. published the results of a study that included 1,752 patients with MS in Nova Scotia. Before the 1998 introduction of a drug insurance program that provides DMTs, the time to an EDSS of 6 was 14.4 years. After the introduction of this program, the time to EDSS of 6 was 18.6 years.
More recently, Capra et al. examined 1,324 patients with MS who attended an MS center in Brescia, Italy, during 1980-2010. They found that the age at which 50% of patients reached an EDSS of 6 was approximately 55 years in 1990. By 2010, the age at achieving this milestone had increased to approximately 63 years.
In a prospective study, Cree et al. examined the evolution of disability in 448 actively treated patients with relapsing-remitting MS and 69 patients with progressive MS. Approximately 45% of patients had no disability worsening during a 10-year follow-up period. Furthermore, a comparatively low 11% of patients had reached an EDSS of 6 at 10 years. The average disease duration of the cohort at that time was 17 years, said Dr. Kister. The results indicated that about 50% of patients would be expected to reach an EDSS of 6 after a disease duration of approximately 38 years, “which is much longer than in the natural history studies,” he added.
In 2019, Beiki et al. found that among patients with relapsing-remitting MS, the risk of reaching an EDSS of 6 decreased by 7% with each subsequent calendar year of diagnosis. The researchers did not observe a similar trend among patients with progressive MS. Their population-based, retrospective study included 7,331 patients in Sweden.
Two additional studies in Scandinavian populations add to the evidence of decreasing disability. In their examination of Swedish patients with MS who received a diagnosis of MS during 1968-2012, Burkill et al. found that the risk of death decreased over time. The hazard ratio of mortality for patients with MS, compared with a non-MS comparator group, decreased from 6.52 among those diagnosed during 1968-1980 to 2.08 for patients diagnosed during 2001-2012. The decrease in the risk of mortality was greater among patients with MS than in a matched comparator population. Similarly, in a nationwide, population-based study, Koch-Henriksen et al. found that all-cause excess mortality in Danish patients with MS decreased from 1950 through 1999.
The role of DMTs
The evidence suggests that DMTs are affecting the long-term progression of MS, said Dr. Kister. Palace et al. compared patients with MS in the UK who received treatment with interferon-beta with a modeled untreated cohort of patients in British Columbia. They found that treated patients reached an EDSS of 6 4 years later than did untreated patients.
Furthermore, an analysis by Brown et al. showed that the time to conversion to secondary progressive MS was longer among treated patients, compared with untreated patients. The risk of conversion was lower for patients treated with newer, more effective therapies (i.e., fingolimod, alemtuzumab, or natalizumab) than for those treated with glatiramer acetate or interferon beta.
Finally, Kingwell and colleagues examined the effect of treatment with interferon-beta on survival using an international cohort of approximately 6,000 patients with relapsing-remitting MS. They found that exposure to interferon-beta for more than 3 years was associated with a 32% reduction in the risk of mortality. They observed no similar risk reduction among patients exposed to interferon-beta for 6 months to 3 years.
Although these data are encouraging, other evidence indicates that the prevalence of MS in the United States has increased considerably in the past 40 years. Researchers estimate that 1 million Americans have MS, which “suggests that we are diagnosing many more mild cases,” said Dr. Kister. The burden of the disease remains high, he concluded.
Dr. Kister reported receiving consulting fees or research grants from Biogen, Roche, Genzyme and Genentech.
SOURCE: Kister I et al. ECTRIMS 2019. Abstract 281754.
STOCKHOLM – , according to an overview provided at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Data consistently indicate that the time that elapses before a patient requires a cane for ambulation has increased, and survival has likewise improved. “Some of the improvement can be attributed confidently to treatment effect,” said Ilya Kister, MD, associate professor of neurology at NYU Langone Health in New York. “We hope to see an even greater change with newer therapies.”
At the same time, neurologists appear to be diagnosing more cases of MS than they previously did, said Dr. Kister, which suggests that neurologists probably are diagnosing milder cases. The overall societal burden of MS remains high.
The relative prevalence of mild disability has increased
About 25 years have elapsed since the first disease-modifying treatment (DMT) for MS became available, and treatment has become widespread during that time. Dr. Kister and colleagues sought to determine whether the current clinical population of patients with MS, who for the most part receive DMTs, has less disability than do untreated patients or patients from natural history studies do. They identified the MS Severity Score (MSSS) as a measure with which to compare populations. The MSSS assigns a patient a ranking according to his or her level of disability, using a reference population of patients with the same disease duration for comparison. “MSSS can be conceptualized as rate of disability accumulation,” said Dr. Kister. “Lower MSSS corresponds to relatively slower disability accumulation, and higher MSSS to higher disability accumulation.”
The MSSS was developed using the Expanded Disability Status Scale (EDSS) score as a measure of disability. Because many neurologists do not routinely obtain EDSS scores for their patients, Dr. Kister and colleagues used the Patient-Determined Disease Steps (PDDS) to measure disability. As its name implies, the PDDS is a patient-reported outcome measure that mainly measures ambulation. It correlates strongly with EDSS, said Dr. Kister. He and colleagues used the PDDS to develop a reference table of MS disability, which they called the Patient-Derived MSSS.
The investigators examined a large sample of patients at NYU MS Center and Barnabas MS Center in Livingston, N.J. They grouped patients into sextiles according to their Patient-Derived MSSS. Dr. Kister and colleagues found that, rather than arriving at sextiles that contained equal numbers of patients, as would be expected if disability were distributed as in the reference population, they had significantly more patients in the two lowest sextiles and significantly fewer patients in the two highest sextiles. “This [result] suggests that the disability curve has indeed shifted toward the more benign end of the spectrum in the contemporary clinic population,” said Dr. Kister.
Other researchers have observed a similar phenomenon. George et al. published the results of a large, international collaboration in Neurology Genetics in 2016. After examining more than 7,000 patients, the investigators noted a similar overrepresentation of patients with milder severity scores and underrepresentation of patients with higher severity scores. These results support the hypothesis of a shift toward milder disability, said Dr. Kister.
Trend toward milder disability
The investigators next examined whether the rate of accumulation of disability among patients with MS had changed from year to year since DMTs were introduced. They conducted a univariate analysis of MSSS for 6,238 patients who were enrolled in the N.Y. State MS Consortium during 1996-2007. They found that patients who were enrolled in more recent years had significantly lower MSSS than patients who were enrolled in earlier years, regardless of disease duration. When Dr. Kister and colleagues replicated their analysis using EDSS, they found significantly lower levels of disability for patients enrolled in more recent years, except for patients with disease duration of 26-30 years. A multivariate analysis showed that the median MSSS of enrollees into the N.Y. State MS Consortium decreased from 5.04 in 1996 to 3.78 in 2006.
In a subsequent study, Dr. Kister and colleagues examined the age at which patients in the MSBase registry reached various disability milestones (e.g., EDSS of 6, which indicates the need of a cane to walk outdoors), according to their year of enrollment in the registry. They found a significant increase in age at milestone achievement with each subsequent calendar year. For example, for every consecutive year of enrollment, the age at which patients attained an EDSS of 6 increased by 0.38 years. These analyses were confirmed for the subgroups of patients diagnosed according to the Poser and McDonald criteria. The increase in age “is probably not just related to the shift in diagnostic criteria,” said Dr. Kister. When the researchers calculated the net average gains in years over the 13-year follow-up period, they found that patients who entered at the end of the enrollment period were 4.9 years older when they reached an EDSS of 6, compared with patients with an EDSS of 6 who entered at the beginning of the enrollment period.
International data show similar trends
Research conducted around the world shows similar trends, said Dr. Kister. In 2009, Veugelers et al. published the results of a study that included 1,752 patients with MS in Nova Scotia. Before the 1998 introduction of a drug insurance program that provides DMTs, the time to an EDSS of 6 was 14.4 years. After the introduction of this program, the time to EDSS of 6 was 18.6 years.
More recently, Capra et al. examined 1,324 patients with MS who attended an MS center in Brescia, Italy, during 1980-2010. They found that the age at which 50% of patients reached an EDSS of 6 was approximately 55 years in 1990. By 2010, the age at achieving this milestone had increased to approximately 63 years.
In a prospective study, Cree et al. examined the evolution of disability in 448 actively treated patients with relapsing-remitting MS and 69 patients with progressive MS. Approximately 45% of patients had no disability worsening during a 10-year follow-up period. Furthermore, a comparatively low 11% of patients had reached an EDSS of 6 at 10 years. The average disease duration of the cohort at that time was 17 years, said Dr. Kister. The results indicated that about 50% of patients would be expected to reach an EDSS of 6 after a disease duration of approximately 38 years, “which is much longer than in the natural history studies,” he added.
In 2019, Beiki et al. found that among patients with relapsing-remitting MS, the risk of reaching an EDSS of 6 decreased by 7% with each subsequent calendar year of diagnosis. The researchers did not observe a similar trend among patients with progressive MS. Their population-based, retrospective study included 7,331 patients in Sweden.
Two additional studies in Scandinavian populations add to the evidence of decreasing disability. In their examination of Swedish patients with MS who received a diagnosis of MS during 1968-2012, Burkill et al. found that the risk of death decreased over time. The hazard ratio of mortality for patients with MS, compared with a non-MS comparator group, decreased from 6.52 among those diagnosed during 1968-1980 to 2.08 for patients diagnosed during 2001-2012. The decrease in the risk of mortality was greater among patients with MS than in a matched comparator population. Similarly, in a nationwide, population-based study, Koch-Henriksen et al. found that all-cause excess mortality in Danish patients with MS decreased from 1950 through 1999.
The role of DMTs
The evidence suggests that DMTs are affecting the long-term progression of MS, said Dr. Kister. Palace et al. compared patients with MS in the UK who received treatment with interferon-beta with a modeled untreated cohort of patients in British Columbia. They found that treated patients reached an EDSS of 6 4 years later than did untreated patients.
Furthermore, an analysis by Brown et al. showed that the time to conversion to secondary progressive MS was longer among treated patients, compared with untreated patients. The risk of conversion was lower for patients treated with newer, more effective therapies (i.e., fingolimod, alemtuzumab, or natalizumab) than for those treated with glatiramer acetate or interferon beta.
Finally, Kingwell and colleagues examined the effect of treatment with interferon-beta on survival using an international cohort of approximately 6,000 patients with relapsing-remitting MS. They found that exposure to interferon-beta for more than 3 years was associated with a 32% reduction in the risk of mortality. They observed no similar risk reduction among patients exposed to interferon-beta for 6 months to 3 years.
Although these data are encouraging, other evidence indicates that the prevalence of MS in the United States has increased considerably in the past 40 years. Researchers estimate that 1 million Americans have MS, which “suggests that we are diagnosing many more mild cases,” said Dr. Kister. The burden of the disease remains high, he concluded.
Dr. Kister reported receiving consulting fees or research grants from Biogen, Roche, Genzyme and Genentech.
SOURCE: Kister I et al. ECTRIMS 2019. Abstract 281754.
STOCKHOLM – , according to an overview provided at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Data consistently indicate that the time that elapses before a patient requires a cane for ambulation has increased, and survival has likewise improved. “Some of the improvement can be attributed confidently to treatment effect,” said Ilya Kister, MD, associate professor of neurology at NYU Langone Health in New York. “We hope to see an even greater change with newer therapies.”
At the same time, neurologists appear to be diagnosing more cases of MS than they previously did, said Dr. Kister, which suggests that neurologists probably are diagnosing milder cases. The overall societal burden of MS remains high.
The relative prevalence of mild disability has increased
About 25 years have elapsed since the first disease-modifying treatment (DMT) for MS became available, and treatment has become widespread during that time. Dr. Kister and colleagues sought to determine whether the current clinical population of patients with MS, who for the most part receive DMTs, has less disability than do untreated patients or patients from natural history studies do. They identified the MS Severity Score (MSSS) as a measure with which to compare populations. The MSSS assigns a patient a ranking according to his or her level of disability, using a reference population of patients with the same disease duration for comparison. “MSSS can be conceptualized as rate of disability accumulation,” said Dr. Kister. “Lower MSSS corresponds to relatively slower disability accumulation, and higher MSSS to higher disability accumulation.”
The MSSS was developed using the Expanded Disability Status Scale (EDSS) score as a measure of disability. Because many neurologists do not routinely obtain EDSS scores for their patients, Dr. Kister and colleagues used the Patient-Determined Disease Steps (PDDS) to measure disability. As its name implies, the PDDS is a patient-reported outcome measure that mainly measures ambulation. It correlates strongly with EDSS, said Dr. Kister. He and colleagues used the PDDS to develop a reference table of MS disability, which they called the Patient-Derived MSSS.
The investigators examined a large sample of patients at NYU MS Center and Barnabas MS Center in Livingston, N.J. They grouped patients into sextiles according to their Patient-Derived MSSS. Dr. Kister and colleagues found that, rather than arriving at sextiles that contained equal numbers of patients, as would be expected if disability were distributed as in the reference population, they had significantly more patients in the two lowest sextiles and significantly fewer patients in the two highest sextiles. “This [result] suggests that the disability curve has indeed shifted toward the more benign end of the spectrum in the contemporary clinic population,” said Dr. Kister.
Other researchers have observed a similar phenomenon. George et al. published the results of a large, international collaboration in Neurology Genetics in 2016. After examining more than 7,000 patients, the investigators noted a similar overrepresentation of patients with milder severity scores and underrepresentation of patients with higher severity scores. These results support the hypothesis of a shift toward milder disability, said Dr. Kister.
Trend toward milder disability
The investigators next examined whether the rate of accumulation of disability among patients with MS had changed from year to year since DMTs were introduced. They conducted a univariate analysis of MSSS for 6,238 patients who were enrolled in the N.Y. State MS Consortium during 1996-2007. They found that patients who were enrolled in more recent years had significantly lower MSSS than patients who were enrolled in earlier years, regardless of disease duration. When Dr. Kister and colleagues replicated their analysis using EDSS, they found significantly lower levels of disability for patients enrolled in more recent years, except for patients with disease duration of 26-30 years. A multivariate analysis showed that the median MSSS of enrollees into the N.Y. State MS Consortium decreased from 5.04 in 1996 to 3.78 in 2006.
In a subsequent study, Dr. Kister and colleagues examined the age at which patients in the MSBase registry reached various disability milestones (e.g., EDSS of 6, which indicates the need of a cane to walk outdoors), according to their year of enrollment in the registry. They found a significant increase in age at milestone achievement with each subsequent calendar year. For example, for every consecutive year of enrollment, the age at which patients attained an EDSS of 6 increased by 0.38 years. These analyses were confirmed for the subgroups of patients diagnosed according to the Poser and McDonald criteria. The increase in age “is probably not just related to the shift in diagnostic criteria,” said Dr. Kister. When the researchers calculated the net average gains in years over the 13-year follow-up period, they found that patients who entered at the end of the enrollment period were 4.9 years older when they reached an EDSS of 6, compared with patients with an EDSS of 6 who entered at the beginning of the enrollment period.
International data show similar trends
Research conducted around the world shows similar trends, said Dr. Kister. In 2009, Veugelers et al. published the results of a study that included 1,752 patients with MS in Nova Scotia. Before the 1998 introduction of a drug insurance program that provides DMTs, the time to an EDSS of 6 was 14.4 years. After the introduction of this program, the time to EDSS of 6 was 18.6 years.
More recently, Capra et al. examined 1,324 patients with MS who attended an MS center in Brescia, Italy, during 1980-2010. They found that the age at which 50% of patients reached an EDSS of 6 was approximately 55 years in 1990. By 2010, the age at achieving this milestone had increased to approximately 63 years.
In a prospective study, Cree et al. examined the evolution of disability in 448 actively treated patients with relapsing-remitting MS and 69 patients with progressive MS. Approximately 45% of patients had no disability worsening during a 10-year follow-up period. Furthermore, a comparatively low 11% of patients had reached an EDSS of 6 at 10 years. The average disease duration of the cohort at that time was 17 years, said Dr. Kister. The results indicated that about 50% of patients would be expected to reach an EDSS of 6 after a disease duration of approximately 38 years, “which is much longer than in the natural history studies,” he added.
In 2019, Beiki et al. found that among patients with relapsing-remitting MS, the risk of reaching an EDSS of 6 decreased by 7% with each subsequent calendar year of diagnosis. The researchers did not observe a similar trend among patients with progressive MS. Their population-based, retrospective study included 7,331 patients in Sweden.
Two additional studies in Scandinavian populations add to the evidence of decreasing disability. In their examination of Swedish patients with MS who received a diagnosis of MS during 1968-2012, Burkill et al. found that the risk of death decreased over time. The hazard ratio of mortality for patients with MS, compared with a non-MS comparator group, decreased from 6.52 among those diagnosed during 1968-1980 to 2.08 for patients diagnosed during 2001-2012. The decrease in the risk of mortality was greater among patients with MS than in a matched comparator population. Similarly, in a nationwide, population-based study, Koch-Henriksen et al. found that all-cause excess mortality in Danish patients with MS decreased from 1950 through 1999.
The role of DMTs
The evidence suggests that DMTs are affecting the long-term progression of MS, said Dr. Kister. Palace et al. compared patients with MS in the UK who received treatment with interferon-beta with a modeled untreated cohort of patients in British Columbia. They found that treated patients reached an EDSS of 6 4 years later than did untreated patients.
Furthermore, an analysis by Brown et al. showed that the time to conversion to secondary progressive MS was longer among treated patients, compared with untreated patients. The risk of conversion was lower for patients treated with newer, more effective therapies (i.e., fingolimod, alemtuzumab, or natalizumab) than for those treated with glatiramer acetate or interferon beta.
Finally, Kingwell and colleagues examined the effect of treatment with interferon-beta on survival using an international cohort of approximately 6,000 patients with relapsing-remitting MS. They found that exposure to interferon-beta for more than 3 years was associated with a 32% reduction in the risk of mortality. They observed no similar risk reduction among patients exposed to interferon-beta for 6 months to 3 years.
Although these data are encouraging, other evidence indicates that the prevalence of MS in the United States has increased considerably in the past 40 years. Researchers estimate that 1 million Americans have MS, which “suggests that we are diagnosing many more mild cases,” said Dr. Kister. The burden of the disease remains high, he concluded.
Dr. Kister reported receiving consulting fees or research grants from Biogen, Roche, Genzyme and Genentech.
SOURCE: Kister I et al. ECTRIMS 2019. Abstract 281754.
EXPERT ANALYSIS FROM ECTRIMS 2019
Cost-effective treatment for relapsing MS patients
Key clinical point: Teriflunomide may be more cost effective than interferon beta-1b for relapsing MS patients.
Major finding: Over the course of 20 years, the cost of treatment with teriflunomide would cost $567,767, compared with the cost of treatment for interferon beta of $620,191 for patients in China.
Study details: A Markov cost model was developed for the study. Eleven neurologists were surveyed throughout China about costs related to treatment for RMS including acquisition and administration, patient monitoring, treating relapse, and the management of adverse events.
Disclosures: This study was funded by Sanofi China. Two study investigators reported being employees of the company.
Citation: Xu Y, et al. Clin Drug Investig. 2019 Mar;39(3):331-340. doi: 10.1007/s40261-019-00750-3.
Key clinical point: Teriflunomide may be more cost effective than interferon beta-1b for relapsing MS patients.
Major finding: Over the course of 20 years, the cost of treatment with teriflunomide would cost $567,767, compared with the cost of treatment for interferon beta of $620,191 for patients in China.
Study details: A Markov cost model was developed for the study. Eleven neurologists were surveyed throughout China about costs related to treatment for RMS including acquisition and administration, patient monitoring, treating relapse, and the management of adverse events.
Disclosures: This study was funded by Sanofi China. Two study investigators reported being employees of the company.
Citation: Xu Y, et al. Clin Drug Investig. 2019 Mar;39(3):331-340. doi: 10.1007/s40261-019-00750-3.
Key clinical point: Teriflunomide may be more cost effective than interferon beta-1b for relapsing MS patients.
Major finding: Over the course of 20 years, the cost of treatment with teriflunomide would cost $567,767, compared with the cost of treatment for interferon beta of $620,191 for patients in China.
Study details: A Markov cost model was developed for the study. Eleven neurologists were surveyed throughout China about costs related to treatment for RMS including acquisition and administration, patient monitoring, treating relapse, and the management of adverse events.
Disclosures: This study was funded by Sanofi China. Two study investigators reported being employees of the company.
Citation: Xu Y, et al. Clin Drug Investig. 2019 Mar;39(3):331-340. doi: 10.1007/s40261-019-00750-3.
Impact of polypharmacy in RRMS
Key clinical point: Polypharmacy frequency can have a negative effect on relapsing-remitting multiple sclerosis (RRMS) patients.
Major finding: The proportion of polypharmacy among patients with a secondary illness to RRMS was four times higher than in patients without a secondary illness. Patients with polypharmacy were older, had a lower level of education, and had higher comorbidities than patients without polypharmacy.
Study details: Subgroups of 145 RRMS patients were analyzed. The subgroups were patients with polypharmacy, patients without polypharmacy, patients with secondary illness, and patients without secondary illness.
Disclosures: Michael Hecker support from Bayer HealthCare, Biogen, Novartis and Teva. Uwe Klaus Zettl received support from Almirall, Bayer HealthCare, Biogen, Merck Serono, Novartis, Sanofi and Teva. Niklas Frahm has no relevant conflicts of interest.
Citation: Frahm N, et al. PLoS One. 2019 Jan 24;14(1):e0211120. doi: 10.1371/journal.pone.0211120.
Key clinical point: Polypharmacy frequency can have a negative effect on relapsing-remitting multiple sclerosis (RRMS) patients.
Major finding: The proportion of polypharmacy among patients with a secondary illness to RRMS was four times higher than in patients without a secondary illness. Patients with polypharmacy were older, had a lower level of education, and had higher comorbidities than patients without polypharmacy.
Study details: Subgroups of 145 RRMS patients were analyzed. The subgroups were patients with polypharmacy, patients without polypharmacy, patients with secondary illness, and patients without secondary illness.
Disclosures: Michael Hecker support from Bayer HealthCare, Biogen, Novartis and Teva. Uwe Klaus Zettl received support from Almirall, Bayer HealthCare, Biogen, Merck Serono, Novartis, Sanofi and Teva. Niklas Frahm has no relevant conflicts of interest.
Citation: Frahm N, et al. PLoS One. 2019 Jan 24;14(1):e0211120. doi: 10.1371/journal.pone.0211120.
Key clinical point: Polypharmacy frequency can have a negative effect on relapsing-remitting multiple sclerosis (RRMS) patients.
Major finding: The proportion of polypharmacy among patients with a secondary illness to RRMS was four times higher than in patients without a secondary illness. Patients with polypharmacy were older, had a lower level of education, and had higher comorbidities than patients without polypharmacy.
Study details: Subgroups of 145 RRMS patients were analyzed. The subgroups were patients with polypharmacy, patients without polypharmacy, patients with secondary illness, and patients without secondary illness.
Disclosures: Michael Hecker support from Bayer HealthCare, Biogen, Novartis and Teva. Uwe Klaus Zettl received support from Almirall, Bayer HealthCare, Biogen, Merck Serono, Novartis, Sanofi and Teva. Niklas Frahm has no relevant conflicts of interest.
Citation: Frahm N, et al. PLoS One. 2019 Jan 24;14(1):e0211120. doi: 10.1371/journal.pone.0211120.
Algorithms help identify RRMS patients
Key clinical point: Two algorithms identified in a new study can be used for future clinical research of relapsing-remitting multiple sclerosis (RRMS). Major finding: Using EHRs and the coded health care claims of 5,308 patients with possible MS, 837 and 2,271 were identified as having RRMS, respectively. There were also 779 patients identified using both algorithms.
Study details: Two different algorithms “unstructured clinical notes (EHR clinical notes-based algorithm) and structured/coded data (claims-based algorithms)” were used to identify patients with RRMS.
Disclosures: The investigators reported no conflicts of interest.
Citation: Van Le H, et al. Value Health. 2019 Jan;22(1):77-84. doi: 10.1016/j.jval.2018.06.014.
Key clinical point: Two algorithms identified in a new study can be used for future clinical research of relapsing-remitting multiple sclerosis (RRMS). Major finding: Using EHRs and the coded health care claims of 5,308 patients with possible MS, 837 and 2,271 were identified as having RRMS, respectively. There were also 779 patients identified using both algorithms.
Study details: Two different algorithms “unstructured clinical notes (EHR clinical notes-based algorithm) and structured/coded data (claims-based algorithms)” were used to identify patients with RRMS.
Disclosures: The investigators reported no conflicts of interest.
Citation: Van Le H, et al. Value Health. 2019 Jan;22(1):77-84. doi: 10.1016/j.jval.2018.06.014.
Key clinical point: Two algorithms identified in a new study can be used for future clinical research of relapsing-remitting multiple sclerosis (RRMS). Major finding: Using EHRs and the coded health care claims of 5,308 patients with possible MS, 837 and 2,271 were identified as having RRMS, respectively. There were also 779 patients identified using both algorithms.
Study details: Two different algorithms “unstructured clinical notes (EHR clinical notes-based algorithm) and structured/coded data (claims-based algorithms)” were used to identify patients with RRMS.
Disclosures: The investigators reported no conflicts of interest.
Citation: Van Le H, et al. Value Health. 2019 Jan;22(1):77-84. doi: 10.1016/j.jval.2018.06.014.
Interview with Clyde E. Markowitz, MD on switching therapies during MS treatment
Clyde E. Markowitz, MD, is the director of the Multiple Sclerosis Center at Penn Neuroscience Center and an Associate Professor of Neurology at the Perelman School of Medicine at the University of Pennsylvania. We sat down with Dr. Markowitz to talk about different multiple sclerosis (MS) therapies and how to determine when it might be time to switch a patient’s current regimen.
Why would an MS specialist switch a patient from one drug therapy to another?
The main reason we switch a patient from one treatment to another is usually related to an inadequate response to their current treatment. This can be seen when a patient is having new clinical symptoms suggestive of a relapse. Additional situations which would cause us to consider a switch in treatment include if the patient has had a new abnormalities seen on MRI scans, such as new T2 lesions or gadolinium- enhancing lesions. We might also switch a patient due to intolerance towards the medication they are on. For example, if they are experiencing flu-like symptoms or having Gastrointestinal issues.
In addition, the expectation that the treatment should slow the rate of progression may not be adequately demonstrating the desired effect. In that setting, we may consider a switch to a drug with a different mechanism of action to hopefully better control disease progression.
Laboratory abnormalities while on treatment might also be a consideration for a switch in therapy. Elevated LFTs, or low WBCs can occur on DMTs and may require a change in treatment. Patients on Natalizumab, require JC virus antibody testing. If the patient’s JCV Ab status changes from negative to positive or a rising index may require a change in therapy to avoid the development of PML.
What are some special considerations for patients during a switch in therapy?
We need to take into consideration the patient’s comorbidities. Does the patient have a history of diabetes, hypertension, cardiac concerns or a risk for infectious complications? What is the patient’s age? As individuals age the immune system becomes less robust at fighting infections or surveillance for malignancies. Some of the medications are immunosuppressive and might increase the risk of developing opportunistic infections or cancers.
Family planning should be taken into consideration during the discussion of which medications might be appropriate. Is the patient planning to have a pregnancy in the near future? Some medications might not be appropriate in that case.
Route of administration could be a factor to consider, since there are several medications that are administered as an infusion in a medical office or hospital setting. This could create issues for some patients who are employed and may have to miss work during these infusions. This could be as frequent as monthly or 2-3 times per year. Some patients just starting a new job, may feel uncomfortable taking time off or disclosing that they have MS leading to concerns for job security.
We also consider the side effects of the new treatment. What side effects and safety monitoring are required for a particular medication? Are there frequent blood tests, cardiac monitoring, dermatologic and ophthalmologic monitoring? How will this impact the patient’s quality of life?
In the end, it comes down to the level of monitoring required for a particular treatment, where the patient is in his or her life, and where he or she is in the disease course.
What are some potential complications when switching therapies?
When switching therapies, one of the bigger concerns is how quickly can we get the patient on the new therapy. Some medications when stopped can lead to return of disease activity or possibly lead to a rebound phenomenon with significant inflammatory activity. We focus on transitioning a patient quickly to a new drug that has a rapid mechanism of action thus limiting the amount of time that a patient is without a treatment. However, based on the mechanism of action of the drug you must consider if a wash out is necessary. The question is how quickly can the patient start the new drug thus preventing a rebound phenomenon. Ideally, no wash out would protect the patient best but might have safety concerns depending on the switch drug profile. If the switch was related to concerns for high JC virus antibody titer going off of natalizumab, there may be a need to make sure the patient does not have PML before making the switch. This may require MRIs and CSF analysis prior to switching.
Ultimately, we consider whether the drug we are switching the patient to is going to be more efficacious than the drug that the patient was previously on. We consider the safety and side effect profile of the new medication. We balance the risk of the disease with the risk of the medication. We must factor in the patient’s tolerance for risk as well and make the best decision with all the available factors considered.
Clyde E. Markowitz, MD, is the director of the Multiple Sclerosis Center at Penn Neuroscience Center and an Associate Professor of Neurology at the Perelman School of Medicine at the University of Pennsylvania. We sat down with Dr. Markowitz to talk about different multiple sclerosis (MS) therapies and how to determine when it might be time to switch a patient’s current regimen.
Why would an MS specialist switch a patient from one drug therapy to another?
The main reason we switch a patient from one treatment to another is usually related to an inadequate response to their current treatment. This can be seen when a patient is having new clinical symptoms suggestive of a relapse. Additional situations which would cause us to consider a switch in treatment include if the patient has had a new abnormalities seen on MRI scans, such as new T2 lesions or gadolinium- enhancing lesions. We might also switch a patient due to intolerance towards the medication they are on. For example, if they are experiencing flu-like symptoms or having Gastrointestinal issues.
In addition, the expectation that the treatment should slow the rate of progression may not be adequately demonstrating the desired effect. In that setting, we may consider a switch to a drug with a different mechanism of action to hopefully better control disease progression.
Laboratory abnormalities while on treatment might also be a consideration for a switch in therapy. Elevated LFTs, or low WBCs can occur on DMTs and may require a change in treatment. Patients on Natalizumab, require JC virus antibody testing. If the patient’s JCV Ab status changes from negative to positive or a rising index may require a change in therapy to avoid the development of PML.
What are some special considerations for patients during a switch in therapy?
We need to take into consideration the patient’s comorbidities. Does the patient have a history of diabetes, hypertension, cardiac concerns or a risk for infectious complications? What is the patient’s age? As individuals age the immune system becomes less robust at fighting infections or surveillance for malignancies. Some of the medications are immunosuppressive and might increase the risk of developing opportunistic infections or cancers.
Family planning should be taken into consideration during the discussion of which medications might be appropriate. Is the patient planning to have a pregnancy in the near future? Some medications might not be appropriate in that case.
Route of administration could be a factor to consider, since there are several medications that are administered as an infusion in a medical office or hospital setting. This could create issues for some patients who are employed and may have to miss work during these infusions. This could be as frequent as monthly or 2-3 times per year. Some patients just starting a new job, may feel uncomfortable taking time off or disclosing that they have MS leading to concerns for job security.
We also consider the side effects of the new treatment. What side effects and safety monitoring are required for a particular medication? Are there frequent blood tests, cardiac monitoring, dermatologic and ophthalmologic monitoring? How will this impact the patient’s quality of life?
In the end, it comes down to the level of monitoring required for a particular treatment, where the patient is in his or her life, and where he or she is in the disease course.
What are some potential complications when switching therapies?
When switching therapies, one of the bigger concerns is how quickly can we get the patient on the new therapy. Some medications when stopped can lead to return of disease activity or possibly lead to a rebound phenomenon with significant inflammatory activity. We focus on transitioning a patient quickly to a new drug that has a rapid mechanism of action thus limiting the amount of time that a patient is without a treatment. However, based on the mechanism of action of the drug you must consider if a wash out is necessary. The question is how quickly can the patient start the new drug thus preventing a rebound phenomenon. Ideally, no wash out would protect the patient best but might have safety concerns depending on the switch drug profile. If the switch was related to concerns for high JC virus antibody titer going off of natalizumab, there may be a need to make sure the patient does not have PML before making the switch. This may require MRIs and CSF analysis prior to switching.
Ultimately, we consider whether the drug we are switching the patient to is going to be more efficacious than the drug that the patient was previously on. We consider the safety and side effect profile of the new medication. We balance the risk of the disease with the risk of the medication. We must factor in the patient’s tolerance for risk as well and make the best decision with all the available factors considered.
Clyde E. Markowitz, MD, is the director of the Multiple Sclerosis Center at Penn Neuroscience Center and an Associate Professor of Neurology at the Perelman School of Medicine at the University of Pennsylvania. We sat down with Dr. Markowitz to talk about different multiple sclerosis (MS) therapies and how to determine when it might be time to switch a patient’s current regimen.
Why would an MS specialist switch a patient from one drug therapy to another?
The main reason we switch a patient from one treatment to another is usually related to an inadequate response to their current treatment. This can be seen when a patient is having new clinical symptoms suggestive of a relapse. Additional situations which would cause us to consider a switch in treatment include if the patient has had a new abnormalities seen on MRI scans, such as new T2 lesions or gadolinium- enhancing lesions. We might also switch a patient due to intolerance towards the medication they are on. For example, if they are experiencing flu-like symptoms or having Gastrointestinal issues.
In addition, the expectation that the treatment should slow the rate of progression may not be adequately demonstrating the desired effect. In that setting, we may consider a switch to a drug with a different mechanism of action to hopefully better control disease progression.
Laboratory abnormalities while on treatment might also be a consideration for a switch in therapy. Elevated LFTs, or low WBCs can occur on DMTs and may require a change in treatment. Patients on Natalizumab, require JC virus antibody testing. If the patient’s JCV Ab status changes from negative to positive or a rising index may require a change in therapy to avoid the development of PML.
What are some special considerations for patients during a switch in therapy?
We need to take into consideration the patient’s comorbidities. Does the patient have a history of diabetes, hypertension, cardiac concerns or a risk for infectious complications? What is the patient’s age? As individuals age the immune system becomes less robust at fighting infections or surveillance for malignancies. Some of the medications are immunosuppressive and might increase the risk of developing opportunistic infections or cancers.
Family planning should be taken into consideration during the discussion of which medications might be appropriate. Is the patient planning to have a pregnancy in the near future? Some medications might not be appropriate in that case.
Route of administration could be a factor to consider, since there are several medications that are administered as an infusion in a medical office or hospital setting. This could create issues for some patients who are employed and may have to miss work during these infusions. This could be as frequent as monthly or 2-3 times per year. Some patients just starting a new job, may feel uncomfortable taking time off or disclosing that they have MS leading to concerns for job security.
We also consider the side effects of the new treatment. What side effects and safety monitoring are required for a particular medication? Are there frequent blood tests, cardiac monitoring, dermatologic and ophthalmologic monitoring? How will this impact the patient’s quality of life?
In the end, it comes down to the level of monitoring required for a particular treatment, where the patient is in his or her life, and where he or she is in the disease course.
What are some potential complications when switching therapies?
When switching therapies, one of the bigger concerns is how quickly can we get the patient on the new therapy. Some medications when stopped can lead to return of disease activity or possibly lead to a rebound phenomenon with significant inflammatory activity. We focus on transitioning a patient quickly to a new drug that has a rapid mechanism of action thus limiting the amount of time that a patient is without a treatment. However, based on the mechanism of action of the drug you must consider if a wash out is necessary. The question is how quickly can the patient start the new drug thus preventing a rebound phenomenon. Ideally, no wash out would protect the patient best but might have safety concerns depending on the switch drug profile. If the switch was related to concerns for high JC virus antibody titer going off of natalizumab, there may be a need to make sure the patient does not have PML before making the switch. This may require MRIs and CSF analysis prior to switching.
Ultimately, we consider whether the drug we are switching the patient to is going to be more efficacious than the drug that the patient was previously on. We consider the safety and side effect profile of the new medication. We balance the risk of the disease with the risk of the medication. We must factor in the patient’s tolerance for risk as well and make the best decision with all the available factors considered.
FDA approves diroximel fumarate for relapsing MS
The Food and Drug Administration has approved diroximel fumarate (Vumerity) for the treatment of relapsing forms of multiple sclerosis (MS) in adults, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, according to an Oct. 30 announcement from its developers, Biogen and Alkermes.
The approval is based on pharmacokinetic studies that established the bioequivalence of diroximel fumarate and dimethyl fumarate (Tecfidera), and it relied in part on the safety and efficacy data for dimethyl fumarate, which was approved in 2013. Diroximel fumarate rapidly converts to monomethyl fumarate, the same active metabolite as dimethyl fumarate.
Diroximel fumarate may be better tolerated than dimethyl fumarate. A trial found that the newer drug has significantly better gastrointestinal tolerability, the developers of the drug announced in July. In addition, the drug application for diroximel fumarate included interim data from EVOLVE-MS-1, an ongoing, open-label, 2-year safety study evaluating diroximel fumarate in patients with relapsing-remitting MS. Researchers found a 6.3% rate of treatment discontinuation attributable to adverse events. Less than 1% of patients discontinued treatment because of gastrointestinal adverse events.
Serious side effects of diroximel fumarate may include allergic reaction, progressive multifocal leukoencephalopathy, decreases in white blood cell count, and liver problems. Flushing and stomach problems are the most common side effects, which may decrease over time.
Biogen plans to make diroximel fumarate available in the United States in the near future, the company said. Prescribing information is available online.
The Food and Drug Administration has approved diroximel fumarate (Vumerity) for the treatment of relapsing forms of multiple sclerosis (MS) in adults, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, according to an Oct. 30 announcement from its developers, Biogen and Alkermes.
The approval is based on pharmacokinetic studies that established the bioequivalence of diroximel fumarate and dimethyl fumarate (Tecfidera), and it relied in part on the safety and efficacy data for dimethyl fumarate, which was approved in 2013. Diroximel fumarate rapidly converts to monomethyl fumarate, the same active metabolite as dimethyl fumarate.
Diroximel fumarate may be better tolerated than dimethyl fumarate. A trial found that the newer drug has significantly better gastrointestinal tolerability, the developers of the drug announced in July. In addition, the drug application for diroximel fumarate included interim data from EVOLVE-MS-1, an ongoing, open-label, 2-year safety study evaluating diroximel fumarate in patients with relapsing-remitting MS. Researchers found a 6.3% rate of treatment discontinuation attributable to adverse events. Less than 1% of patients discontinued treatment because of gastrointestinal adverse events.
Serious side effects of diroximel fumarate may include allergic reaction, progressive multifocal leukoencephalopathy, decreases in white blood cell count, and liver problems. Flushing and stomach problems are the most common side effects, which may decrease over time.
Biogen plans to make diroximel fumarate available in the United States in the near future, the company said. Prescribing information is available online.
The Food and Drug Administration has approved diroximel fumarate (Vumerity) for the treatment of relapsing forms of multiple sclerosis (MS) in adults, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, according to an Oct. 30 announcement from its developers, Biogen and Alkermes.
The approval is based on pharmacokinetic studies that established the bioequivalence of diroximel fumarate and dimethyl fumarate (Tecfidera), and it relied in part on the safety and efficacy data for dimethyl fumarate, which was approved in 2013. Diroximel fumarate rapidly converts to monomethyl fumarate, the same active metabolite as dimethyl fumarate.
Diroximel fumarate may be better tolerated than dimethyl fumarate. A trial found that the newer drug has significantly better gastrointestinal tolerability, the developers of the drug announced in July. In addition, the drug application for diroximel fumarate included interim data from EVOLVE-MS-1, an ongoing, open-label, 2-year safety study evaluating diroximel fumarate in patients with relapsing-remitting MS. Researchers found a 6.3% rate of treatment discontinuation attributable to adverse events. Less than 1% of patients discontinued treatment because of gastrointestinal adverse events.
Serious side effects of diroximel fumarate may include allergic reaction, progressive multifocal leukoencephalopathy, decreases in white blood cell count, and liver problems. Flushing and stomach problems are the most common side effects, which may decrease over time.
Biogen plans to make diroximel fumarate available in the United States in the near future, the company said. Prescribing information is available online.