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Gary Cutter, PhD
Deborah Backus, PhD
Prospective studies needed to compare MS in African Americans and whites
DALLAS – There is a need for prospective, multicenter studies to examine the differences between African Americans and whites with multiple sclerosis and their response to therapy, according to Dr. Omar Khan.
The impact of education, disease awareness, and access to health care as covariates must also be included in future studies, "otherwise, this question will continue to come up, to find out whether these factors do or don’t have a bearing on disease severity and outcomes," said Dr. Khan, professor and chair of neurology at Wayne State University, Detroit, during a presentation at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
Another point to consider, especially in regard to trials evaluating response to disease-modifying therapies, is that African Americans continue to be a small proportion of participants in these trials, he said.
Up until recent decades, it was believed that multiple sclerosis didn’t affect African Americans. Even today, some resources, such as the National MS Society's website, try to bust that myth first before delving into other facts about multiple sclerosis.
Nearly 10 years ago, Dr. Bruce Cree and his colleagues presented a study about the clinical characteristics of multiple sclerosis in African Americans, compared with whites, and they showed that African American patients were more likely to have a more aggressive disease course, and a greater likelihood of developing opticospinal MS and transverse myelitis (Neurology 2004;63:2039-45).
The study showed that the median time from onset to diagnosis was 1 year in African Americans, compared with 2 years in whites. Also, the median time from onset to treatment was 4 years in African American patients, compared with 5 years in whites. The former group also had a significantly shorter median time to a Kurtzke Expanded Disability Status Scale (EDSS) score of greater than or equal to 6 and 7, compared with whites.
These findings have been consistently shown in later trials.
In 2004, a group in France showed that the MS course was more aggressive in North African than in European patients (Neurology 2007;68:29-32). Researchers found that the mean age of onset was younger in North Africans, compared with Europeans. They also found that the median times to EDSS scores of 4 and 6 were both significantly shorter in the former group.
"You’re going to see this theme in other studies," said Dr. Khan. "Clearly there wasn’t a delay in diagnosing the disease based on these studies."
Then in 2008, a study in France showed that North African migrants with MS appear to be as responsive as other MS patients are to disease-modifying therapies, although they received the treatment sooner than their white counterparts and had more frequent use of immunosuppressive drugs (Mult. Scler. 2008;14:933-9). The study showed that the mean time to an EDSS score of 6 was 6 years in North Africans, which was almost 10 years sooner than in white patients.
In 2009, in a retrospective study of pediatric-onset MS, Dr. Khan and his colleagues yet again found "a more aggressive disease phenotype among American blacks with adult-onset MS," and called for larger multicenter studies, which Dr. Khan continues to advocate for (Pediatr. Neurol. 2009;40:31-3). The group found an earlier onset of disease to initiation of disease-modifying therapy among African American patients, compared with whites, although the difference didn’t reach statistical significance. The relapse rate was also higher among the former group.
Another study on pediatric-onset MS showed that African American patients may be at higher risk for adverse cognitive impact on language and complex attention (Neurology 2010;75:2097-102).
Dr. Khan also pointed to several studies quantifying central nervous system tissue injury in African Americans with MS.
A 2012 study showed that African Americans had a significantly greater lesion volume, compared with white patients, but the brain volumes weren’t significantly different between the two groups. Researchers concluded that "a higher lesion accumulation, rather than a pronounced brain volume decrease, might explain the early progress to ambulatory assistance of [African Americans] with MS" (PLoS One 2012;7:e43061).
"I don’t think we should be arguing that there is a clear indication that African Americans have greater disability, CNS tissue injury, and possibly suboptimal response to therapy," compared with whites, Dr. Khan said.
Other quantitative studies have suggested differences in the disease biology. "And they provide more credence to these observations, despite the fact that almost all of them have been cross-sectional or retrospective," he said, stressing the need for prospectively designed multicenter studies.
"And I think it’s equally important to keep in mind [that] the impact of education, health awareness, and access to health care as covariates at a bare minimum must be included in these studies," Dr. Khan said.
His group conducted a study in 2012 to find out whether there was a difference between African Americans and whites with MS in terms of level of education, disease awareness, and disease severity, but they didn’t find any statistically significant differences.
Additional study is needed, he said.
Dr. Khan said he had no relevant financial disclosures.
On Twitter @naseemmiller
DALLAS – There is a need for prospective, multicenter studies to examine the differences between African Americans and whites with multiple sclerosis and their response to therapy, according to Dr. Omar Khan.
The impact of education, disease awareness, and access to health care as covariates must also be included in future studies, "otherwise, this question will continue to come up, to find out whether these factors do or don’t have a bearing on disease severity and outcomes," said Dr. Khan, professor and chair of neurology at Wayne State University, Detroit, during a presentation at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
Another point to consider, especially in regard to trials evaluating response to disease-modifying therapies, is that African Americans continue to be a small proportion of participants in these trials, he said.
Up until recent decades, it was believed that multiple sclerosis didn’t affect African Americans. Even today, some resources, such as the National MS Society's website, try to bust that myth first before delving into other facts about multiple sclerosis.
Nearly 10 years ago, Dr. Bruce Cree and his colleagues presented a study about the clinical characteristics of multiple sclerosis in African Americans, compared with whites, and they showed that African American patients were more likely to have a more aggressive disease course, and a greater likelihood of developing opticospinal MS and transverse myelitis (Neurology 2004;63:2039-45).
The study showed that the median time from onset to diagnosis was 1 year in African Americans, compared with 2 years in whites. Also, the median time from onset to treatment was 4 years in African American patients, compared with 5 years in whites. The former group also had a significantly shorter median time to a Kurtzke Expanded Disability Status Scale (EDSS) score of greater than or equal to 6 and 7, compared with whites.
These findings have been consistently shown in later trials.
In 2004, a group in France showed that the MS course was more aggressive in North African than in European patients (Neurology 2007;68:29-32). Researchers found that the mean age of onset was younger in North Africans, compared with Europeans. They also found that the median times to EDSS scores of 4 and 6 were both significantly shorter in the former group.
"You’re going to see this theme in other studies," said Dr. Khan. "Clearly there wasn’t a delay in diagnosing the disease based on these studies."
Then in 2008, a study in France showed that North African migrants with MS appear to be as responsive as other MS patients are to disease-modifying therapies, although they received the treatment sooner than their white counterparts and had more frequent use of immunosuppressive drugs (Mult. Scler. 2008;14:933-9). The study showed that the mean time to an EDSS score of 6 was 6 years in North Africans, which was almost 10 years sooner than in white patients.
In 2009, in a retrospective study of pediatric-onset MS, Dr. Khan and his colleagues yet again found "a more aggressive disease phenotype among American blacks with adult-onset MS," and called for larger multicenter studies, which Dr. Khan continues to advocate for (Pediatr. Neurol. 2009;40:31-3). The group found an earlier onset of disease to initiation of disease-modifying therapy among African American patients, compared with whites, although the difference didn’t reach statistical significance. The relapse rate was also higher among the former group.
Another study on pediatric-onset MS showed that African American patients may be at higher risk for adverse cognitive impact on language and complex attention (Neurology 2010;75:2097-102).
Dr. Khan also pointed to several studies quantifying central nervous system tissue injury in African Americans with MS.
A 2012 study showed that African Americans had a significantly greater lesion volume, compared with white patients, but the brain volumes weren’t significantly different between the two groups. Researchers concluded that "a higher lesion accumulation, rather than a pronounced brain volume decrease, might explain the early progress to ambulatory assistance of [African Americans] with MS" (PLoS One 2012;7:e43061).
"I don’t think we should be arguing that there is a clear indication that African Americans have greater disability, CNS tissue injury, and possibly suboptimal response to therapy," compared with whites, Dr. Khan said.
Other quantitative studies have suggested differences in the disease biology. "And they provide more credence to these observations, despite the fact that almost all of them have been cross-sectional or retrospective," he said, stressing the need for prospectively designed multicenter studies.
"And I think it’s equally important to keep in mind [that] the impact of education, health awareness, and access to health care as covariates at a bare minimum must be included in these studies," Dr. Khan said.
His group conducted a study in 2012 to find out whether there was a difference between African Americans and whites with MS in terms of level of education, disease awareness, and disease severity, but they didn’t find any statistically significant differences.
Additional study is needed, he said.
Dr. Khan said he had no relevant financial disclosures.
On Twitter @naseemmiller
DALLAS – There is a need for prospective, multicenter studies to examine the differences between African Americans and whites with multiple sclerosis and their response to therapy, according to Dr. Omar Khan.
The impact of education, disease awareness, and access to health care as covariates must also be included in future studies, "otherwise, this question will continue to come up, to find out whether these factors do or don’t have a bearing on disease severity and outcomes," said Dr. Khan, professor and chair of neurology at Wayne State University, Detroit, during a presentation at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
Another point to consider, especially in regard to trials evaluating response to disease-modifying therapies, is that African Americans continue to be a small proportion of participants in these trials, he said.
Up until recent decades, it was believed that multiple sclerosis didn’t affect African Americans. Even today, some resources, such as the National MS Society's website, try to bust that myth first before delving into other facts about multiple sclerosis.
Nearly 10 years ago, Dr. Bruce Cree and his colleagues presented a study about the clinical characteristics of multiple sclerosis in African Americans, compared with whites, and they showed that African American patients were more likely to have a more aggressive disease course, and a greater likelihood of developing opticospinal MS and transverse myelitis (Neurology 2004;63:2039-45).
The study showed that the median time from onset to diagnosis was 1 year in African Americans, compared with 2 years in whites. Also, the median time from onset to treatment was 4 years in African American patients, compared with 5 years in whites. The former group also had a significantly shorter median time to a Kurtzke Expanded Disability Status Scale (EDSS) score of greater than or equal to 6 and 7, compared with whites.
These findings have been consistently shown in later trials.
In 2004, a group in France showed that the MS course was more aggressive in North African than in European patients (Neurology 2007;68:29-32). Researchers found that the mean age of onset was younger in North Africans, compared with Europeans. They also found that the median times to EDSS scores of 4 and 6 were both significantly shorter in the former group.
"You’re going to see this theme in other studies," said Dr. Khan. "Clearly there wasn’t a delay in diagnosing the disease based on these studies."
Then in 2008, a study in France showed that North African migrants with MS appear to be as responsive as other MS patients are to disease-modifying therapies, although they received the treatment sooner than their white counterparts and had more frequent use of immunosuppressive drugs (Mult. Scler. 2008;14:933-9). The study showed that the mean time to an EDSS score of 6 was 6 years in North Africans, which was almost 10 years sooner than in white patients.
In 2009, in a retrospective study of pediatric-onset MS, Dr. Khan and his colleagues yet again found "a more aggressive disease phenotype among American blacks with adult-onset MS," and called for larger multicenter studies, which Dr. Khan continues to advocate for (Pediatr. Neurol. 2009;40:31-3). The group found an earlier onset of disease to initiation of disease-modifying therapy among African American patients, compared with whites, although the difference didn’t reach statistical significance. The relapse rate was also higher among the former group.
Another study on pediatric-onset MS showed that African American patients may be at higher risk for adverse cognitive impact on language and complex attention (Neurology 2010;75:2097-102).
Dr. Khan also pointed to several studies quantifying central nervous system tissue injury in African Americans with MS.
A 2012 study showed that African Americans had a significantly greater lesion volume, compared with white patients, but the brain volumes weren’t significantly different between the two groups. Researchers concluded that "a higher lesion accumulation, rather than a pronounced brain volume decrease, might explain the early progress to ambulatory assistance of [African Americans] with MS" (PLoS One 2012;7:e43061).
"I don’t think we should be arguing that there is a clear indication that African Americans have greater disability, CNS tissue injury, and possibly suboptimal response to therapy," compared with whites, Dr. Khan said.
Other quantitative studies have suggested differences in the disease biology. "And they provide more credence to these observations, despite the fact that almost all of them have been cross-sectional or retrospective," he said, stressing the need for prospectively designed multicenter studies.
"And I think it’s equally important to keep in mind [that] the impact of education, health awareness, and access to health care as covariates at a bare minimum must be included in these studies," Dr. Khan said.
His group conducted a study in 2012 to find out whether there was a difference between African Americans and whites with MS in terms of level of education, disease awareness, and disease severity, but they didn’t find any statistically significant differences.
Additional study is needed, he said.
Dr. Khan said he had no relevant financial disclosures.
On Twitter @naseemmiller
EXPERT ANALYSIS AT THE CMSC/ACTRIMS ANNUAL MEETING
Copaxone lipoatrophy far more common than reported
DALLAS – The risk of lipoatrophy with glatiramer acetate is greater than 60%, according to a review of 73 multiple sclerosis patients at one clinic.
The risk is "substantially higher than previously reported and [is] often the sole factor prompting patients to switch to another MS [disease-modifying therapy]. Our data also suggest that a heightened risk of lipoatrophy is an inherent autoimmune problem and is not necessarily mitigated by vigilant injection-site rotation. The psychological consequences may be significant," said investigator Dr. Ronald Bailey, director of the MS clinic at the Riverside (Calif.) Medical Clinic.
A total of 46 glatiramer acetate (GA, Copaxone) patients (63%) developed lipoatrophy, an injection-site indentation that can be deep and disfiguring; 35 (76%) of them used an autoinjector. Once noted, the dents didn’t improve during a 3-year observation period, which included photographic documentation and instructions on how to inject the drug every 3 months.
In some patients, lipoatrophy developed within the first 3 months of starting the shots and was noted at multiple injection sites, which prompted the team to suspect that an autoimmune reaction was at work. "Upon GA treatment discontinuation, lipoatrophy remained permanent," he noted.
Lipoatrophy "appears to progress, even when you stop the injections. It’s a pretty impressive disfiguration. It’s important to emphasize [with patients] that this isn’t necessarily going to be remedied with plastic surgery. [However,] if patients were stable, most of them thought that this was a small price to pay to be in remission," Dr. Bailey said at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
GA labeling reports the risk of lipoatrophy to be 2% with the 20-mg/mL daily formulation, which has been on the market for almost 2 decades, and 0.5% with the 40-mg/mL three times weekly option, which was approved by the Food and Drug Administration in 2014. Lipoatrophy "is thought to be permanent. There is no known therapy. To assist in possibly minimizing these events, the patient should be advised to follow proper injection technique and to rotate injection sites with each injection," according to the GA label, which is in contrast with the Riverside finding that site rotation wasn’t much help.
Most of the patients at the clinic were women, in keeping with MS epidemiology, and 40 (55%) opted for the autoinjector, specifically the Autoject 2; the device’s labeling notes that the autoinjector can "help with hard-to-reach areas on your body." Perhaps, by helping patients reach those difficult areas, the autoinjector makes it easier to miss the proper subcutaneous fat layer. That might have something to do with the problem, Dr. Bailey said, but the team simply reported their observations and didn’t report any statistical analysis of the findings, so it’s impossible to discern causes, he noted.
The findings aren’t new for some. The "prevalence of lipoatrophy [is] much higher than expected," one team noted several years ago (Can. J. Neurol. Sci. 2004;31:58-63).
No one knows why GA seems to cause lipoatrophy. Maybe "an elevation in tumor necrosis factor–alpha ... causes a dedifferentiation of adipocytes in [subcutaneous] tissue," Dr. Bailey said.
He is a paid spokesman for Genzyme, Biogen, and Teva, the maker of GA. There was no outside funding for the project.
autoimmune problem, vigilant injection-site rotation, Dr. Ronald Bailey, glatiramer acetate, GA, Copaxone, lipoatrophy, injection-site indentation, autoinjector, Lipoatrophy, Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis, Food and Drug Administration, proper injection technique,
DALLAS – The risk of lipoatrophy with glatiramer acetate is greater than 60%, according to a review of 73 multiple sclerosis patients at one clinic.
The risk is "substantially higher than previously reported and [is] often the sole factor prompting patients to switch to another MS [disease-modifying therapy]. Our data also suggest that a heightened risk of lipoatrophy is an inherent autoimmune problem and is not necessarily mitigated by vigilant injection-site rotation. The psychological consequences may be significant," said investigator Dr. Ronald Bailey, director of the MS clinic at the Riverside (Calif.) Medical Clinic.
A total of 46 glatiramer acetate (GA, Copaxone) patients (63%) developed lipoatrophy, an injection-site indentation that can be deep and disfiguring; 35 (76%) of them used an autoinjector. Once noted, the dents didn’t improve during a 3-year observation period, which included photographic documentation and instructions on how to inject the drug every 3 months.
In some patients, lipoatrophy developed within the first 3 months of starting the shots and was noted at multiple injection sites, which prompted the team to suspect that an autoimmune reaction was at work. "Upon GA treatment discontinuation, lipoatrophy remained permanent," he noted.
Lipoatrophy "appears to progress, even when you stop the injections. It’s a pretty impressive disfiguration. It’s important to emphasize [with patients] that this isn’t necessarily going to be remedied with plastic surgery. [However,] if patients were stable, most of them thought that this was a small price to pay to be in remission," Dr. Bailey said at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
GA labeling reports the risk of lipoatrophy to be 2% with the 20-mg/mL daily formulation, which has been on the market for almost 2 decades, and 0.5% with the 40-mg/mL three times weekly option, which was approved by the Food and Drug Administration in 2014. Lipoatrophy "is thought to be permanent. There is no known therapy. To assist in possibly minimizing these events, the patient should be advised to follow proper injection technique and to rotate injection sites with each injection," according to the GA label, which is in contrast with the Riverside finding that site rotation wasn’t much help.
Most of the patients at the clinic were women, in keeping with MS epidemiology, and 40 (55%) opted for the autoinjector, specifically the Autoject 2; the device’s labeling notes that the autoinjector can "help with hard-to-reach areas on your body." Perhaps, by helping patients reach those difficult areas, the autoinjector makes it easier to miss the proper subcutaneous fat layer. That might have something to do with the problem, Dr. Bailey said, but the team simply reported their observations and didn’t report any statistical analysis of the findings, so it’s impossible to discern causes, he noted.
The findings aren’t new for some. The "prevalence of lipoatrophy [is] much higher than expected," one team noted several years ago (Can. J. Neurol. Sci. 2004;31:58-63).
No one knows why GA seems to cause lipoatrophy. Maybe "an elevation in tumor necrosis factor–alpha ... causes a dedifferentiation of adipocytes in [subcutaneous] tissue," Dr. Bailey said.
He is a paid spokesman for Genzyme, Biogen, and Teva, the maker of GA. There was no outside funding for the project.
DALLAS – The risk of lipoatrophy with glatiramer acetate is greater than 60%, according to a review of 73 multiple sclerosis patients at one clinic.
The risk is "substantially higher than previously reported and [is] often the sole factor prompting patients to switch to another MS [disease-modifying therapy]. Our data also suggest that a heightened risk of lipoatrophy is an inherent autoimmune problem and is not necessarily mitigated by vigilant injection-site rotation. The psychological consequences may be significant," said investigator Dr. Ronald Bailey, director of the MS clinic at the Riverside (Calif.) Medical Clinic.
A total of 46 glatiramer acetate (GA, Copaxone) patients (63%) developed lipoatrophy, an injection-site indentation that can be deep and disfiguring; 35 (76%) of them used an autoinjector. Once noted, the dents didn’t improve during a 3-year observation period, which included photographic documentation and instructions on how to inject the drug every 3 months.
In some patients, lipoatrophy developed within the first 3 months of starting the shots and was noted at multiple injection sites, which prompted the team to suspect that an autoimmune reaction was at work. "Upon GA treatment discontinuation, lipoatrophy remained permanent," he noted.
Lipoatrophy "appears to progress, even when you stop the injections. It’s a pretty impressive disfiguration. It’s important to emphasize [with patients] that this isn’t necessarily going to be remedied with plastic surgery. [However,] if patients were stable, most of them thought that this was a small price to pay to be in remission," Dr. Bailey said at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
GA labeling reports the risk of lipoatrophy to be 2% with the 20-mg/mL daily formulation, which has been on the market for almost 2 decades, and 0.5% with the 40-mg/mL three times weekly option, which was approved by the Food and Drug Administration in 2014. Lipoatrophy "is thought to be permanent. There is no known therapy. To assist in possibly minimizing these events, the patient should be advised to follow proper injection technique and to rotate injection sites with each injection," according to the GA label, which is in contrast with the Riverside finding that site rotation wasn’t much help.
Most of the patients at the clinic were women, in keeping with MS epidemiology, and 40 (55%) opted for the autoinjector, specifically the Autoject 2; the device’s labeling notes that the autoinjector can "help with hard-to-reach areas on your body." Perhaps, by helping patients reach those difficult areas, the autoinjector makes it easier to miss the proper subcutaneous fat layer. That might have something to do with the problem, Dr. Bailey said, but the team simply reported their observations and didn’t report any statistical analysis of the findings, so it’s impossible to discern causes, he noted.
The findings aren’t new for some. The "prevalence of lipoatrophy [is] much higher than expected," one team noted several years ago (Can. J. Neurol. Sci. 2004;31:58-63).
No one knows why GA seems to cause lipoatrophy. Maybe "an elevation in tumor necrosis factor–alpha ... causes a dedifferentiation of adipocytes in [subcutaneous] tissue," Dr. Bailey said.
He is a paid spokesman for Genzyme, Biogen, and Teva, the maker of GA. There was no outside funding for the project.
autoimmune problem, vigilant injection-site rotation, Dr. Ronald Bailey, glatiramer acetate, GA, Copaxone, lipoatrophy, injection-site indentation, autoinjector, Lipoatrophy, Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis, Food and Drug Administration, proper injection technique,
autoimmune problem, vigilant injection-site rotation, Dr. Ronald Bailey, glatiramer acetate, GA, Copaxone, lipoatrophy, injection-site indentation, autoinjector, Lipoatrophy, Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis, Food and Drug Administration, proper injection technique,
AT THE CMSC/ACTRIMS ANNUAL MEETING
Key clinical point: The rate of lipoatrophy with glatiramer acetate may be much higher than reported in the drug’s label.
Major finding: Of 73 glatiramer acetate patients, 46 (63%) developed lipoatrophy, sometimes within 3 months of starting the shots.
Data Source: Patient observation every 3 months for 3 years.
Disclosures: The lead investigator is a paid spokesman for Teva, the maker of Copaxone. There was no outside funding for the project.
When switching from natalizumab to teriflunomide, timing is key
DALLAS – Teriflunomide could be a safe and effective option when patients with multiple sclerosis need to be switched from natalizumab, especially when the oral treatment starts 1 month after the last natalizumab treatment, according to a small, retrospective study.
Multiple studies have shown that natalizumab (Tysabri) is a risk factor for progressive multifocal leukoencephalopathy (PML). "So, there’s always the question of when do we switch," said Dr. Francisco J. Gomez, coauthor of the study and a physician at the MS Center of Northeastern New York in Latham.
"If you don’t switch people [from natalizumab] earlier in the disease, you might end up giving them worsened outcomes," Dr. Gomez said at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
At the same time, he noted, "you’re limited on how to switch. So you’re caught between a rock and a hard place. You want to switch them, but you don’t want to lose the only opportunity you have in controlling their disease."
Dr. Gomez and his colleagues looked at the safety and efficacy of teriflunomide (Aubagio), which was approved by theFood and Drug Administration in 2012 and has been shown to cut the annual MS relapse rate by more than a third.
The investigators used the center’s database to conduct a 12-month retrospective study of 30 patients who switched to teriflunomide after receiving natalizumab for more than a year and were all clinically stable. Most patients began the new treatment within 4 weeks of their last natalizumab treatment.
Cranial MRI and a clinical exam were conducted at the time of last natalizumab, and at 3 and 6 months after natalizumab treatment, to check for possible PML and new MS activity.
Of the 30 patients, 11 were triple positive for PML, meaning that they had received more than 24 natalizumab treatments, had prior immunosuppression, and were positive for anti–John Cunningham virus antibody. Fifteen were positive for anti-JCV antibody, and four were negative for anti-JCV antibody.
The mean number of natalizumab treatments was 38, ranging from 14 to 81. The patients’ mean age was 50 years, and 80% were female. Their mean duration of treatment with teriflunomide after natalizumab discontinuation was 13 months, ranging from 6 to 13.
Of all patients, 23 are still on teriflunomide, Dr. Gomez said. None have developed PML. Two have moved away and were lost to follow-up.
Five patients discontinued the treatment, one of whom developed significant exacerbation, including severe optic neuritis 4 weeks after starting on teriflunomide. That patient also had a 3-month delay between last natalizumab dose and the initiation of teriflunomide, compared with the rest, who started within a month of the last natalizumab treatment.
So, "a reduced washout period after natalizumab may be important to lessen breakthrough disease," Dr. Gomez and his colleagues said in the poster presented at the meeting.
Two others discontinued treatment because of persistent diarrhea and abdominal cramps, and one patient withdrew due to hair thinning. Minor diarrhea and transient hair thinning occurred in seven and five patients, respectively.
Despite the clinical exacerbations, "MRI scans haven’t shown disease, so we feel" that the disease is under control, Dr. Gomez said.
He advised physicians "to make the switch as soon as possible, no more than 4 weeks from the last natalizumab infusion, and then monitor the patient closely for potential MS relapse and PML for the next 6 months. Also, we have only been looking at patients switching to teriflunomide who have been stable while on natalizumab. If the patient has had exacerbations while on natalizumab, we usually go to rituximab and perhaps, in the future, alemtuzumab."
Dr. Gomez reported having no disclosures.
On Twitter @naseemmiller
DALLAS – Teriflunomide could be a safe and effective option when patients with multiple sclerosis need to be switched from natalizumab, especially when the oral treatment starts 1 month after the last natalizumab treatment, according to a small, retrospective study.
Multiple studies have shown that natalizumab (Tysabri) is a risk factor for progressive multifocal leukoencephalopathy (PML). "So, there’s always the question of when do we switch," said Dr. Francisco J. Gomez, coauthor of the study and a physician at the MS Center of Northeastern New York in Latham.
"If you don’t switch people [from natalizumab] earlier in the disease, you might end up giving them worsened outcomes," Dr. Gomez said at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
At the same time, he noted, "you’re limited on how to switch. So you’re caught between a rock and a hard place. You want to switch them, but you don’t want to lose the only opportunity you have in controlling their disease."
Dr. Gomez and his colleagues looked at the safety and efficacy of teriflunomide (Aubagio), which was approved by theFood and Drug Administration in 2012 and has been shown to cut the annual MS relapse rate by more than a third.
The investigators used the center’s database to conduct a 12-month retrospective study of 30 patients who switched to teriflunomide after receiving natalizumab for more than a year and were all clinically stable. Most patients began the new treatment within 4 weeks of their last natalizumab treatment.
Cranial MRI and a clinical exam were conducted at the time of last natalizumab, and at 3 and 6 months after natalizumab treatment, to check for possible PML and new MS activity.
Of the 30 patients, 11 were triple positive for PML, meaning that they had received more than 24 natalizumab treatments, had prior immunosuppression, and were positive for anti–John Cunningham virus antibody. Fifteen were positive for anti-JCV antibody, and four were negative for anti-JCV antibody.
The mean number of natalizumab treatments was 38, ranging from 14 to 81. The patients’ mean age was 50 years, and 80% were female. Their mean duration of treatment with teriflunomide after natalizumab discontinuation was 13 months, ranging from 6 to 13.
Of all patients, 23 are still on teriflunomide, Dr. Gomez said. None have developed PML. Two have moved away and were lost to follow-up.
Five patients discontinued the treatment, one of whom developed significant exacerbation, including severe optic neuritis 4 weeks after starting on teriflunomide. That patient also had a 3-month delay between last natalizumab dose and the initiation of teriflunomide, compared with the rest, who started within a month of the last natalizumab treatment.
So, "a reduced washout period after natalizumab may be important to lessen breakthrough disease," Dr. Gomez and his colleagues said in the poster presented at the meeting.
Two others discontinued treatment because of persistent diarrhea and abdominal cramps, and one patient withdrew due to hair thinning. Minor diarrhea and transient hair thinning occurred in seven and five patients, respectively.
Despite the clinical exacerbations, "MRI scans haven’t shown disease, so we feel" that the disease is under control, Dr. Gomez said.
He advised physicians "to make the switch as soon as possible, no more than 4 weeks from the last natalizumab infusion, and then monitor the patient closely for potential MS relapse and PML for the next 6 months. Also, we have only been looking at patients switching to teriflunomide who have been stable while on natalizumab. If the patient has had exacerbations while on natalizumab, we usually go to rituximab and perhaps, in the future, alemtuzumab."
Dr. Gomez reported having no disclosures.
On Twitter @naseemmiller
DALLAS – Teriflunomide could be a safe and effective option when patients with multiple sclerosis need to be switched from natalizumab, especially when the oral treatment starts 1 month after the last natalizumab treatment, according to a small, retrospective study.
Multiple studies have shown that natalizumab (Tysabri) is a risk factor for progressive multifocal leukoencephalopathy (PML). "So, there’s always the question of when do we switch," said Dr. Francisco J. Gomez, coauthor of the study and a physician at the MS Center of Northeastern New York in Latham.
"If you don’t switch people [from natalizumab] earlier in the disease, you might end up giving them worsened outcomes," Dr. Gomez said at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
At the same time, he noted, "you’re limited on how to switch. So you’re caught between a rock and a hard place. You want to switch them, but you don’t want to lose the only opportunity you have in controlling their disease."
Dr. Gomez and his colleagues looked at the safety and efficacy of teriflunomide (Aubagio), which was approved by theFood and Drug Administration in 2012 and has been shown to cut the annual MS relapse rate by more than a third.
The investigators used the center’s database to conduct a 12-month retrospective study of 30 patients who switched to teriflunomide after receiving natalizumab for more than a year and were all clinically stable. Most patients began the new treatment within 4 weeks of their last natalizumab treatment.
Cranial MRI and a clinical exam were conducted at the time of last natalizumab, and at 3 and 6 months after natalizumab treatment, to check for possible PML and new MS activity.
Of the 30 patients, 11 were triple positive for PML, meaning that they had received more than 24 natalizumab treatments, had prior immunosuppression, and were positive for anti–John Cunningham virus antibody. Fifteen were positive for anti-JCV antibody, and four were negative for anti-JCV antibody.
The mean number of natalizumab treatments was 38, ranging from 14 to 81. The patients’ mean age was 50 years, and 80% were female. Their mean duration of treatment with teriflunomide after natalizumab discontinuation was 13 months, ranging from 6 to 13.
Of all patients, 23 are still on teriflunomide, Dr. Gomez said. None have developed PML. Two have moved away and were lost to follow-up.
Five patients discontinued the treatment, one of whom developed significant exacerbation, including severe optic neuritis 4 weeks after starting on teriflunomide. That patient also had a 3-month delay between last natalizumab dose and the initiation of teriflunomide, compared with the rest, who started within a month of the last natalizumab treatment.
So, "a reduced washout period after natalizumab may be important to lessen breakthrough disease," Dr. Gomez and his colleagues said in the poster presented at the meeting.
Two others discontinued treatment because of persistent diarrhea and abdominal cramps, and one patient withdrew due to hair thinning. Minor diarrhea and transient hair thinning occurred in seven and five patients, respectively.
Despite the clinical exacerbations, "MRI scans haven’t shown disease, so we feel" that the disease is under control, Dr. Gomez said.
He advised physicians "to make the switch as soon as possible, no more than 4 weeks from the last natalizumab infusion, and then monitor the patient closely for potential MS relapse and PML for the next 6 months. Also, we have only been looking at patients switching to teriflunomide who have been stable while on natalizumab. If the patient has had exacerbations while on natalizumab, we usually go to rituximab and perhaps, in the future, alemtuzumab."
Dr. Gomez reported having no disclosures.
On Twitter @naseemmiller
AT THE CMSC/ACTRIMS ANNUAL MEETING
Key clinical point: Make the switch as soon as possible – no more than 4 weeks from the last natalizumab infusion – and then monitor the patient closely.
Major finding: Despite clinical exacerbations in five patients, MRI scans remained stable.
Data source: A 12-month retrospective study involving 30 patients who switched to teriflunomide after receiving natalizumab for more than a year.
Disclosures: Dr. Gomez reported having no disclosures.
Aquatic therapy deemed beneficial for MS patients
DALLAS – Aquatic exercise can be beneficial for individuals with multiple sclerosis, and it can be considered as an adjunct to other therapies, according to a systematic review and a small randomized, controlled trial presented by the same group at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
In the systematic review, all 11 studies had positive outcomes in patients with multiple sclerosis (MS), and none identified any exacerbation or adverse changes in neurologic status, reported Yasser Salem, Ph.D., of the University of North Texas Health Science Center’s Physical Therapy Program, Fort Worth.
Dr. Salem and his colleagues also conducted a single-blind randomized, controlled trial of 20 patients and found better overall scores in all outcome measures in individuals with MS who received aquatic therapy, compared with those who didn’t.
Aquatic therapy has started receiving attention in recent years and is "now recommended by many physicians, therapists, and the National Multiple Sclerosis Society [NMSS] as an adjunct treatment for individuals with multiple sclerosis," Dr. Salem said in an interview.
The therapy uses the unique aspects and natural properties of water and is generally a well-tolerated form of exercise, Dr. Salem said. "There is no specific contraindication to aquatic therapy other than general contraindications associated with exercise and immersion in water such as fever and severe cardiac diseases," he said.
For their systematic review, Dr. Salem and his colleagues analyzed 11 studies that totaled 141 participants with MS. They said this is the first time such a systematic review has been done.
Of the 11 studies, 3 were randomized, controlled trials; 5 had a single-subject design; and 3 were case studies. The length of treatment ranged from 5 to 12 weeks, and the frequency ranged from 1 to 3 times per week. Most studies didn’t report the duration of the workout sessions, but the longest duration was 1 hour. The exercises included stretching, strength training, aerobics, endurance, balance, and general exercises.
All studies indicated that individuals with MS benefited from aquatic therapy, including increases in mobility and muscle strength, improved quality of life, cardiovascular fitness, and grip strength.
"There is a need for more studies with longer-term follow-up to determine if any gains are retained" on a long-term basis, Dr. Salem and his associates wrote in their unpublished study, which was presented as a poster.
Their single-blind randomized, controlled trial included 20 people with chronic MS, and examined the effects of a 10-week aquatic training program on mobility function, strength, fatigue, and quality of life.
Ten participants were in the exercise group and 10 in the control group. The training included strength, balance, walking, and aerobic training, originally designed by the NMSS and implemented at several local community settings sponsored by the local chapter of NMSS, according to the authors.
Participants were assessed 1 week before and after the training by a blinded investigator. Primary outcomes included a self-paced 10-m walk test, timed Up & Go (TUG) test, Berg Balance Scale, grip strength measured by a hand-held dynamometer, Modified Fatigue Impact Scale, Quality of Life using the MS Quality of Life 54 test (MSQOL-54), and a survey and interview.
The average attendance at the training sessions was 78%. No MS-related exacerbations were reported. "Participants reported better overall scores in all outcome measures, compared with participants in the control group," the authors wrote in the poster. The majority were also extremely satisfied with the program.
Currently, there’s not enough evidence to show whether aquatic therapy is superior to land therapy or whether it can substitute for land therapy. But Dr. Salem said that based on the current literature, it can be an adjunct to other forms of therapy. "When properly performed, aquatic therapy is a gentle and invigorating exercise with little or no adverse effects," he said.
Dr. Salem highly recommends the American Physical Therapy Association’s (APTA’s) Aquatic Physical Therapy Section website, aquaticpt.org, and its "Find an Aquatic PT Clinic" feature to search for places that offer aquatic therapy in your state.
In addition, some local support groups offer free aquatic classes for people with MS. For example, some local offices of the NMSS sponsor aquatic exercise programs designed for individuals with MS. An MS Navigator, available at 1-800-344-4867, can be used to find out if other resources are available in your area.
Dr. Salem reported having no financial disclosures.
On Twitter @naseemmiller
DALLAS – Aquatic exercise can be beneficial for individuals with multiple sclerosis, and it can be considered as an adjunct to other therapies, according to a systematic review and a small randomized, controlled trial presented by the same group at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
In the systematic review, all 11 studies had positive outcomes in patients with multiple sclerosis (MS), and none identified any exacerbation or adverse changes in neurologic status, reported Yasser Salem, Ph.D., of the University of North Texas Health Science Center’s Physical Therapy Program, Fort Worth.
Dr. Salem and his colleagues also conducted a single-blind randomized, controlled trial of 20 patients and found better overall scores in all outcome measures in individuals with MS who received aquatic therapy, compared with those who didn’t.
Aquatic therapy has started receiving attention in recent years and is "now recommended by many physicians, therapists, and the National Multiple Sclerosis Society [NMSS] as an adjunct treatment for individuals with multiple sclerosis," Dr. Salem said in an interview.
The therapy uses the unique aspects and natural properties of water and is generally a well-tolerated form of exercise, Dr. Salem said. "There is no specific contraindication to aquatic therapy other than general contraindications associated with exercise and immersion in water such as fever and severe cardiac diseases," he said.
For their systematic review, Dr. Salem and his colleagues analyzed 11 studies that totaled 141 participants with MS. They said this is the first time such a systematic review has been done.
Of the 11 studies, 3 were randomized, controlled trials; 5 had a single-subject design; and 3 were case studies. The length of treatment ranged from 5 to 12 weeks, and the frequency ranged from 1 to 3 times per week. Most studies didn’t report the duration of the workout sessions, but the longest duration was 1 hour. The exercises included stretching, strength training, aerobics, endurance, balance, and general exercises.
All studies indicated that individuals with MS benefited from aquatic therapy, including increases in mobility and muscle strength, improved quality of life, cardiovascular fitness, and grip strength.
"There is a need for more studies with longer-term follow-up to determine if any gains are retained" on a long-term basis, Dr. Salem and his associates wrote in their unpublished study, which was presented as a poster.
Their single-blind randomized, controlled trial included 20 people with chronic MS, and examined the effects of a 10-week aquatic training program on mobility function, strength, fatigue, and quality of life.
Ten participants were in the exercise group and 10 in the control group. The training included strength, balance, walking, and aerobic training, originally designed by the NMSS and implemented at several local community settings sponsored by the local chapter of NMSS, according to the authors.
Participants were assessed 1 week before and after the training by a blinded investigator. Primary outcomes included a self-paced 10-m walk test, timed Up & Go (TUG) test, Berg Balance Scale, grip strength measured by a hand-held dynamometer, Modified Fatigue Impact Scale, Quality of Life using the MS Quality of Life 54 test (MSQOL-54), and a survey and interview.
The average attendance at the training sessions was 78%. No MS-related exacerbations were reported. "Participants reported better overall scores in all outcome measures, compared with participants in the control group," the authors wrote in the poster. The majority were also extremely satisfied with the program.
Currently, there’s not enough evidence to show whether aquatic therapy is superior to land therapy or whether it can substitute for land therapy. But Dr. Salem said that based on the current literature, it can be an adjunct to other forms of therapy. "When properly performed, aquatic therapy is a gentle and invigorating exercise with little or no adverse effects," he said.
Dr. Salem highly recommends the American Physical Therapy Association’s (APTA’s) Aquatic Physical Therapy Section website, aquaticpt.org, and its "Find an Aquatic PT Clinic" feature to search for places that offer aquatic therapy in your state.
In addition, some local support groups offer free aquatic classes for people with MS. For example, some local offices of the NMSS sponsor aquatic exercise programs designed for individuals with MS. An MS Navigator, available at 1-800-344-4867, can be used to find out if other resources are available in your area.
Dr. Salem reported having no financial disclosures.
On Twitter @naseemmiller
DALLAS – Aquatic exercise can be beneficial for individuals with multiple sclerosis, and it can be considered as an adjunct to other therapies, according to a systematic review and a small randomized, controlled trial presented by the same group at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
In the systematic review, all 11 studies had positive outcomes in patients with multiple sclerosis (MS), and none identified any exacerbation or adverse changes in neurologic status, reported Yasser Salem, Ph.D., of the University of North Texas Health Science Center’s Physical Therapy Program, Fort Worth.
Dr. Salem and his colleagues also conducted a single-blind randomized, controlled trial of 20 patients and found better overall scores in all outcome measures in individuals with MS who received aquatic therapy, compared with those who didn’t.
Aquatic therapy has started receiving attention in recent years and is "now recommended by many physicians, therapists, and the National Multiple Sclerosis Society [NMSS] as an adjunct treatment for individuals with multiple sclerosis," Dr. Salem said in an interview.
The therapy uses the unique aspects and natural properties of water and is generally a well-tolerated form of exercise, Dr. Salem said. "There is no specific contraindication to aquatic therapy other than general contraindications associated with exercise and immersion in water such as fever and severe cardiac diseases," he said.
For their systematic review, Dr. Salem and his colleagues analyzed 11 studies that totaled 141 participants with MS. They said this is the first time such a systematic review has been done.
Of the 11 studies, 3 were randomized, controlled trials; 5 had a single-subject design; and 3 were case studies. The length of treatment ranged from 5 to 12 weeks, and the frequency ranged from 1 to 3 times per week. Most studies didn’t report the duration of the workout sessions, but the longest duration was 1 hour. The exercises included stretching, strength training, aerobics, endurance, balance, and general exercises.
All studies indicated that individuals with MS benefited from aquatic therapy, including increases in mobility and muscle strength, improved quality of life, cardiovascular fitness, and grip strength.
"There is a need for more studies with longer-term follow-up to determine if any gains are retained" on a long-term basis, Dr. Salem and his associates wrote in their unpublished study, which was presented as a poster.
Their single-blind randomized, controlled trial included 20 people with chronic MS, and examined the effects of a 10-week aquatic training program on mobility function, strength, fatigue, and quality of life.
Ten participants were in the exercise group and 10 in the control group. The training included strength, balance, walking, and aerobic training, originally designed by the NMSS and implemented at several local community settings sponsored by the local chapter of NMSS, according to the authors.
Participants were assessed 1 week before and after the training by a blinded investigator. Primary outcomes included a self-paced 10-m walk test, timed Up & Go (TUG) test, Berg Balance Scale, grip strength measured by a hand-held dynamometer, Modified Fatigue Impact Scale, Quality of Life using the MS Quality of Life 54 test (MSQOL-54), and a survey and interview.
The average attendance at the training sessions was 78%. No MS-related exacerbations were reported. "Participants reported better overall scores in all outcome measures, compared with participants in the control group," the authors wrote in the poster. The majority were also extremely satisfied with the program.
Currently, there’s not enough evidence to show whether aquatic therapy is superior to land therapy or whether it can substitute for land therapy. But Dr. Salem said that based on the current literature, it can be an adjunct to other forms of therapy. "When properly performed, aquatic therapy is a gentle and invigorating exercise with little or no adverse effects," he said.
Dr. Salem highly recommends the American Physical Therapy Association’s (APTA’s) Aquatic Physical Therapy Section website, aquaticpt.org, and its "Find an Aquatic PT Clinic" feature to search for places that offer aquatic therapy in your state.
In addition, some local support groups offer free aquatic classes for people with MS. For example, some local offices of the NMSS sponsor aquatic exercise programs designed for individuals with MS. An MS Navigator, available at 1-800-344-4867, can be used to find out if other resources are available in your area.
Dr. Salem reported having no financial disclosures.
On Twitter @naseemmiller
AT THE CMSC/ACTRIMS ANNUAL MEETING
Key clinical point: An aquatic exercise regimen may benefit many areas of life for patients with MS without adverse effects.
Major finding: In a review, 11 studies showed positive results for MS patients who received aquatic therapy. A small randomized, controlled trial also showed benefits.
Data source: Systematic review of 11 studies and a single-blind randomized, controlled study of 20 patients.
Disclosures: Dr. Salem reported having no financial disclosures.
MS experts battle over alemtuzumab’s value
DALLAS – Should clinicians favor safety or efficacy when choosing whether to use the controversial drug alemtuzumab to treat patients with relapsing-remitting multiple sclerosis?
This was the question at the heart of an impassioned debate during a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
Safety is ‘relative’
"Safety is a relative thing," session panel member Dr. Olaf Stüve told the standing-room-only, and occasionally obstreperous, crowd.
"I think what we’re all struggling with is, ‘What is a good ratio between efficacy and safety that benefits patients more than it hurts them?’" said Dr. Stüve of the department of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center in Dallas. "I would argue strongly that alemtuzumab has a very good efficacy profile that really outweighs potential safety issues."
Dr. Stüve, who is also chief of the neurology section of Veterans Affairs North Texas Health Care Systems, Dallas, added that because natalizumab (Tysabri) is the current first-line therapy for patients with refractory disease and has its own safety issues, "for that reason alone, we need another player for patients who don’t respond to disease-modifying therapies."
Off-label, off market, ... for now
Until late 2012, clinicians in the United States had been off-label prescribing alemtuzumab, a monoclonal antibody that binds to antigen CD52 that was originally approved and marketed as Campath, a treatment for chronic lymphocytic leukemia. In order to submit the drug to the Food and Drug Administration (FDA) for approval under the name Lemtrada with a specific MS indication, Genzyme pulled alemtuzumab from the U.S. market. Many in the MS community expected the drug to be approved with an MS indication, based on how well it had performed as an off-label treatment.
Alemtuzumab is approved in Europe, Canada, and Australia for use in MS patients. Currently, the only first-line therapy for refractory MS that is available in the United States is natalizumab, although among its drawbacks is the increased risk of progressive multifocal leukoencephalopathy (PML) in patients who test positive for the John Cunningham (JC) virus antibody.
To the surprise and outrage of many, including the MS Coalition, the FDA rejected Genzyme’s bid to market Lemtrada late last year, citing the lack of double blinding in the CARE MS I and II trials (Comparison of Alemtuzumab and Rebif Efficacy) and concerns over safety.
"It would have been possible to design a double-blinded trial," Dr. Stüve said in an interview. "However, [nearly all] patients are aware which intervention they are receiving based on any flulike symptoms. Similarly, an incidence of 90%-99% infusion-related reactions under alemtuzumab would likely make it impossible to blind for that agent."
Dr. Stüve also said he believed that because the relapse rate was "fairly consistent in the phase II and phase III programs," there was a reduced risk that outcomes were "substantially affected by the trial design."
Genzyme was largely expected to appeal the decision, but instead recently resubmitted its request for approval of Lemtrada, based on additional data and supplemental analyses, including results presented at this year’s American Academy of Neurology annual meeting. In a company statement, Genzyme said it expects FDA action in the fourth quarter of this year.
Lethal ‘poison’
"Alemtuzumab is more poison than good," panel member Dr. Mitchell T. Wallin told the audience at the CMSC/ACTRIMS meeting. An associate professor of neurology at Georgetown University in Washington, and a neurologist at the Veterans Affairs Medical Center, also in Washington, Dr. Wallin said, "My vote is to not approve it."
"I think there is some question about how well this drug actually controls disability progression," said Dr. Wallin, referring to the disparate findings of the CARE MS I and II studies – the former trial failed to show a change in the progression of the expanded disability status scale (EDSS) scores, while the latter trial did.
Data from the CARE studies, FDA reviews, and data presented late last year by Genzyme to the FDA during an advisory panel meeting indicated "there are good efficacy data in terms of MRI and relapse rates, so that impacts the efficacy equation," Dr. Wallin said during the discussion. When asked in an interview about the extended CARE MS trial data, he said, "These data seem to show the stabilization of the MRI out to 3 years."
"There are often lethal consequences to this drug," Dr. Wallin told the audience. Citing data from the alemtuzumab trials, Dr. Wallin said there was a greater than 2% occurrence of a distinctive form of immune thrombocytopenia (ITP), which in one case resulted in death.
Approximately 1% of those studied also had dangerously low platelet counts, putting them at high risk for bleeding complications, he said. Opportunistic infections, kidney failure, fetal complications, and even suicidal ideation were all reported adverse events that soured Dr. Wallin’s view of alemtuzumab as a front-runner for first-line therapy. "You give one dose, and the effects probably last at least a year, and some of these effects are seen beyond that."
Why be ‘squeamish’?
This long-lasting effect is precisely what Dr. Stüve said makes alemtuzumab an imperative treatment. "This is a therapy we don’t have to treat patients with indefinitely, or even long term. There is a detectable, dramatic benefit in patients who receive short-term therapy," he said. And because the CARE MS extension data indicated that 20% of patients who’d received alemtuzumab received sequential disease-modifying therapy (DMT) with no increase in adverse events, "it shows that alemtuzumab could potentially be used as a very effective induction therapy, up-front and for a limited amount of time, followed by a safe DMT, without added safety concerns. I think this is something many of us have really been waiting for to treat patients who declare themselves early on as having aggressive disease."
Although Dr. Stüve did cite his concerns about ITP, opportunistic infections associated with alemtuzumab, and the occurrence of various malignancies, particularly thyroid kinds, the extension trial data indicated that these adverse events tend to occur in the third year of treatment, which allows clinicians to possibly anticipate and monitor these conditions and subsequently treat them.
When Dr. Stüve was challenged by panel moderator Dr. Dennis Bourdette, director of the Multiple Sclerosis and Neuroimmunology Center at Oregon Health & Science University, Portland, he responded that when viewed within the entire current treatment landscape, the risks of alemtuzumab were worth the benefits. "The other player is natalizumab, which has a 1 in 250 chance of PML, and 20% of those patients die. So I don’t see why I should be squeamish about ITP," which he said was, like thyroid disease, treatable.
"We should not withhold these kinds of drugs from patients who really need them," he concluded.
The ‘1 percent’
When asked in an interview whether Americans would benefit from seeking treatment with alemtuzumab out of the country, Dr. Bourdette rejected the idea.
"In my opinion, most patients with MS should not be treated with alemtuzumab, so I see very little need for anyone to go out of the country to receive it." And if they did, he warned, they would need extensive follow-up treatment for "autoimmune disease, particularly thyroid disease, platelet abnormalities, kidney dysfunction, and cancer."
"I personally consider this to be a very toxic drug that should be used with great caution and in a very small group of patients with very active and difficult-to-control disease, perhaps 1% to 2% of cases at most," he said.
Dr. Stüve said he had no relevant disclosures. Dr. Wallin declared that he has done research for Biogen Idec. Dr. Bourdette declared that he had no relevant disclosures.
On Twitter @whitneymcknight
DALLAS – Should clinicians favor safety or efficacy when choosing whether to use the controversial drug alemtuzumab to treat patients with relapsing-remitting multiple sclerosis?
This was the question at the heart of an impassioned debate during a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
Safety is ‘relative’
"Safety is a relative thing," session panel member Dr. Olaf Stüve told the standing-room-only, and occasionally obstreperous, crowd.
"I think what we’re all struggling with is, ‘What is a good ratio between efficacy and safety that benefits patients more than it hurts them?’" said Dr. Stüve of the department of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center in Dallas. "I would argue strongly that alemtuzumab has a very good efficacy profile that really outweighs potential safety issues."
Dr. Stüve, who is also chief of the neurology section of Veterans Affairs North Texas Health Care Systems, Dallas, added that because natalizumab (Tysabri) is the current first-line therapy for patients with refractory disease and has its own safety issues, "for that reason alone, we need another player for patients who don’t respond to disease-modifying therapies."
Off-label, off market, ... for now
Until late 2012, clinicians in the United States had been off-label prescribing alemtuzumab, a monoclonal antibody that binds to antigen CD52 that was originally approved and marketed as Campath, a treatment for chronic lymphocytic leukemia. In order to submit the drug to the Food and Drug Administration (FDA) for approval under the name Lemtrada with a specific MS indication, Genzyme pulled alemtuzumab from the U.S. market. Many in the MS community expected the drug to be approved with an MS indication, based on how well it had performed as an off-label treatment.
Alemtuzumab is approved in Europe, Canada, and Australia for use in MS patients. Currently, the only first-line therapy for refractory MS that is available in the United States is natalizumab, although among its drawbacks is the increased risk of progressive multifocal leukoencephalopathy (PML) in patients who test positive for the John Cunningham (JC) virus antibody.
To the surprise and outrage of many, including the MS Coalition, the FDA rejected Genzyme’s bid to market Lemtrada late last year, citing the lack of double blinding in the CARE MS I and II trials (Comparison of Alemtuzumab and Rebif Efficacy) and concerns over safety.
"It would have been possible to design a double-blinded trial," Dr. Stüve said in an interview. "However, [nearly all] patients are aware which intervention they are receiving based on any flulike symptoms. Similarly, an incidence of 90%-99% infusion-related reactions under alemtuzumab would likely make it impossible to blind for that agent."
Dr. Stüve also said he believed that because the relapse rate was "fairly consistent in the phase II and phase III programs," there was a reduced risk that outcomes were "substantially affected by the trial design."
Genzyme was largely expected to appeal the decision, but instead recently resubmitted its request for approval of Lemtrada, based on additional data and supplemental analyses, including results presented at this year’s American Academy of Neurology annual meeting. In a company statement, Genzyme said it expects FDA action in the fourth quarter of this year.
Lethal ‘poison’
"Alemtuzumab is more poison than good," panel member Dr. Mitchell T. Wallin told the audience at the CMSC/ACTRIMS meeting. An associate professor of neurology at Georgetown University in Washington, and a neurologist at the Veterans Affairs Medical Center, also in Washington, Dr. Wallin said, "My vote is to not approve it."
"I think there is some question about how well this drug actually controls disability progression," said Dr. Wallin, referring to the disparate findings of the CARE MS I and II studies – the former trial failed to show a change in the progression of the expanded disability status scale (EDSS) scores, while the latter trial did.
Data from the CARE studies, FDA reviews, and data presented late last year by Genzyme to the FDA during an advisory panel meeting indicated "there are good efficacy data in terms of MRI and relapse rates, so that impacts the efficacy equation," Dr. Wallin said during the discussion. When asked in an interview about the extended CARE MS trial data, he said, "These data seem to show the stabilization of the MRI out to 3 years."
"There are often lethal consequences to this drug," Dr. Wallin told the audience. Citing data from the alemtuzumab trials, Dr. Wallin said there was a greater than 2% occurrence of a distinctive form of immune thrombocytopenia (ITP), which in one case resulted in death.
Approximately 1% of those studied also had dangerously low platelet counts, putting them at high risk for bleeding complications, he said. Opportunistic infections, kidney failure, fetal complications, and even suicidal ideation were all reported adverse events that soured Dr. Wallin’s view of alemtuzumab as a front-runner for first-line therapy. "You give one dose, and the effects probably last at least a year, and some of these effects are seen beyond that."
Why be ‘squeamish’?
This long-lasting effect is precisely what Dr. Stüve said makes alemtuzumab an imperative treatment. "This is a therapy we don’t have to treat patients with indefinitely, or even long term. There is a detectable, dramatic benefit in patients who receive short-term therapy," he said. And because the CARE MS extension data indicated that 20% of patients who’d received alemtuzumab received sequential disease-modifying therapy (DMT) with no increase in adverse events, "it shows that alemtuzumab could potentially be used as a very effective induction therapy, up-front and for a limited amount of time, followed by a safe DMT, without added safety concerns. I think this is something many of us have really been waiting for to treat patients who declare themselves early on as having aggressive disease."
Although Dr. Stüve did cite his concerns about ITP, opportunistic infections associated with alemtuzumab, and the occurrence of various malignancies, particularly thyroid kinds, the extension trial data indicated that these adverse events tend to occur in the third year of treatment, which allows clinicians to possibly anticipate and monitor these conditions and subsequently treat them.
When Dr. Stüve was challenged by panel moderator Dr. Dennis Bourdette, director of the Multiple Sclerosis and Neuroimmunology Center at Oregon Health & Science University, Portland, he responded that when viewed within the entire current treatment landscape, the risks of alemtuzumab were worth the benefits. "The other player is natalizumab, which has a 1 in 250 chance of PML, and 20% of those patients die. So I don’t see why I should be squeamish about ITP," which he said was, like thyroid disease, treatable.
"We should not withhold these kinds of drugs from patients who really need them," he concluded.
The ‘1 percent’
When asked in an interview whether Americans would benefit from seeking treatment with alemtuzumab out of the country, Dr. Bourdette rejected the idea.
"In my opinion, most patients with MS should not be treated with alemtuzumab, so I see very little need for anyone to go out of the country to receive it." And if they did, he warned, they would need extensive follow-up treatment for "autoimmune disease, particularly thyroid disease, platelet abnormalities, kidney dysfunction, and cancer."
"I personally consider this to be a very toxic drug that should be used with great caution and in a very small group of patients with very active and difficult-to-control disease, perhaps 1% to 2% of cases at most," he said.
Dr. Stüve said he had no relevant disclosures. Dr. Wallin declared that he has done research for Biogen Idec. Dr. Bourdette declared that he had no relevant disclosures.
On Twitter @whitneymcknight
DALLAS – Should clinicians favor safety or efficacy when choosing whether to use the controversial drug alemtuzumab to treat patients with relapsing-remitting multiple sclerosis?
This was the question at the heart of an impassioned debate during a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
Safety is ‘relative’
"Safety is a relative thing," session panel member Dr. Olaf Stüve told the standing-room-only, and occasionally obstreperous, crowd.
"I think what we’re all struggling with is, ‘What is a good ratio between efficacy and safety that benefits patients more than it hurts them?’" said Dr. Stüve of the department of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center in Dallas. "I would argue strongly that alemtuzumab has a very good efficacy profile that really outweighs potential safety issues."
Dr. Stüve, who is also chief of the neurology section of Veterans Affairs North Texas Health Care Systems, Dallas, added that because natalizumab (Tysabri) is the current first-line therapy for patients with refractory disease and has its own safety issues, "for that reason alone, we need another player for patients who don’t respond to disease-modifying therapies."
Off-label, off market, ... for now
Until late 2012, clinicians in the United States had been off-label prescribing alemtuzumab, a monoclonal antibody that binds to antigen CD52 that was originally approved and marketed as Campath, a treatment for chronic lymphocytic leukemia. In order to submit the drug to the Food and Drug Administration (FDA) for approval under the name Lemtrada with a specific MS indication, Genzyme pulled alemtuzumab from the U.S. market. Many in the MS community expected the drug to be approved with an MS indication, based on how well it had performed as an off-label treatment.
Alemtuzumab is approved in Europe, Canada, and Australia for use in MS patients. Currently, the only first-line therapy for refractory MS that is available in the United States is natalizumab, although among its drawbacks is the increased risk of progressive multifocal leukoencephalopathy (PML) in patients who test positive for the John Cunningham (JC) virus antibody.
To the surprise and outrage of many, including the MS Coalition, the FDA rejected Genzyme’s bid to market Lemtrada late last year, citing the lack of double blinding in the CARE MS I and II trials (Comparison of Alemtuzumab and Rebif Efficacy) and concerns over safety.
"It would have been possible to design a double-blinded trial," Dr. Stüve said in an interview. "However, [nearly all] patients are aware which intervention they are receiving based on any flulike symptoms. Similarly, an incidence of 90%-99% infusion-related reactions under alemtuzumab would likely make it impossible to blind for that agent."
Dr. Stüve also said he believed that because the relapse rate was "fairly consistent in the phase II and phase III programs," there was a reduced risk that outcomes were "substantially affected by the trial design."
Genzyme was largely expected to appeal the decision, but instead recently resubmitted its request for approval of Lemtrada, based on additional data and supplemental analyses, including results presented at this year’s American Academy of Neurology annual meeting. In a company statement, Genzyme said it expects FDA action in the fourth quarter of this year.
Lethal ‘poison’
"Alemtuzumab is more poison than good," panel member Dr. Mitchell T. Wallin told the audience at the CMSC/ACTRIMS meeting. An associate professor of neurology at Georgetown University in Washington, and a neurologist at the Veterans Affairs Medical Center, also in Washington, Dr. Wallin said, "My vote is to not approve it."
"I think there is some question about how well this drug actually controls disability progression," said Dr. Wallin, referring to the disparate findings of the CARE MS I and II studies – the former trial failed to show a change in the progression of the expanded disability status scale (EDSS) scores, while the latter trial did.
Data from the CARE studies, FDA reviews, and data presented late last year by Genzyme to the FDA during an advisory panel meeting indicated "there are good efficacy data in terms of MRI and relapse rates, so that impacts the efficacy equation," Dr. Wallin said during the discussion. When asked in an interview about the extended CARE MS trial data, he said, "These data seem to show the stabilization of the MRI out to 3 years."
"There are often lethal consequences to this drug," Dr. Wallin told the audience. Citing data from the alemtuzumab trials, Dr. Wallin said there was a greater than 2% occurrence of a distinctive form of immune thrombocytopenia (ITP), which in one case resulted in death.
Approximately 1% of those studied also had dangerously low platelet counts, putting them at high risk for bleeding complications, he said. Opportunistic infections, kidney failure, fetal complications, and even suicidal ideation were all reported adverse events that soured Dr. Wallin’s view of alemtuzumab as a front-runner for first-line therapy. "You give one dose, and the effects probably last at least a year, and some of these effects are seen beyond that."
Why be ‘squeamish’?
This long-lasting effect is precisely what Dr. Stüve said makes alemtuzumab an imperative treatment. "This is a therapy we don’t have to treat patients with indefinitely, or even long term. There is a detectable, dramatic benefit in patients who receive short-term therapy," he said. And because the CARE MS extension data indicated that 20% of patients who’d received alemtuzumab received sequential disease-modifying therapy (DMT) with no increase in adverse events, "it shows that alemtuzumab could potentially be used as a very effective induction therapy, up-front and for a limited amount of time, followed by a safe DMT, without added safety concerns. I think this is something many of us have really been waiting for to treat patients who declare themselves early on as having aggressive disease."
Although Dr. Stüve did cite his concerns about ITP, opportunistic infections associated with alemtuzumab, and the occurrence of various malignancies, particularly thyroid kinds, the extension trial data indicated that these adverse events tend to occur in the third year of treatment, which allows clinicians to possibly anticipate and monitor these conditions and subsequently treat them.
When Dr. Stüve was challenged by panel moderator Dr. Dennis Bourdette, director of the Multiple Sclerosis and Neuroimmunology Center at Oregon Health & Science University, Portland, he responded that when viewed within the entire current treatment landscape, the risks of alemtuzumab were worth the benefits. "The other player is natalizumab, which has a 1 in 250 chance of PML, and 20% of those patients die. So I don’t see why I should be squeamish about ITP," which he said was, like thyroid disease, treatable.
"We should not withhold these kinds of drugs from patients who really need them," he concluded.
The ‘1 percent’
When asked in an interview whether Americans would benefit from seeking treatment with alemtuzumab out of the country, Dr. Bourdette rejected the idea.
"In my opinion, most patients with MS should not be treated with alemtuzumab, so I see very little need for anyone to go out of the country to receive it." And if they did, he warned, they would need extensive follow-up treatment for "autoimmune disease, particularly thyroid disease, platelet abnormalities, kidney dysfunction, and cancer."
"I personally consider this to be a very toxic drug that should be used with great caution and in a very small group of patients with very active and difficult-to-control disease, perhaps 1% to 2% of cases at most," he said.
Dr. Stüve said he had no relevant disclosures. Dr. Wallin declared that he has done research for Biogen Idec. Dr. Bourdette declared that he had no relevant disclosures.
On Twitter @whitneymcknight
EXPERT ANALYSIS FROM THE CMSC/ACTRIMS ANNUAL MEETING
VIDEO: Vitamin D helps with optic neuritis, too
DALLAS – Sufficient vitamin D levels – serum 25-hydroxyvitamin D concentrations greater than 80 nmol/L – appeared to protect against edema of the retinal nerve fiber layer in a prospective cohort study of patients with acute optic neuritis.
An adequate vitamin D level also protected against thinning of the retinal nerve fiber layer (RNFL) ganglion cell layer and other poor outcomes after 6 months in the study of 49 patients (some of whom had multiple sclerosis), according to researchers at the University of Calgary (Alta.).
The team correlated vitamin D levels with optical coherence tomography findings. Vitamin D is known to have anti-inflammatory effects, so it’s the chronic benefit that was surprising, lead investigator Dr. Jodie Burton explained at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
It’s just one more reason that it’s a good idea to check vitamin D levels, and supplement them if necessary, Dr. Burton said.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
DALLAS – Sufficient vitamin D levels – serum 25-hydroxyvitamin D concentrations greater than 80 nmol/L – appeared to protect against edema of the retinal nerve fiber layer in a prospective cohort study of patients with acute optic neuritis.
An adequate vitamin D level also protected against thinning of the retinal nerve fiber layer (RNFL) ganglion cell layer and other poor outcomes after 6 months in the study of 49 patients (some of whom had multiple sclerosis), according to researchers at the University of Calgary (Alta.).
The team correlated vitamin D levels with optical coherence tomography findings. Vitamin D is known to have anti-inflammatory effects, so it’s the chronic benefit that was surprising, lead investigator Dr. Jodie Burton explained at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
It’s just one more reason that it’s a good idea to check vitamin D levels, and supplement them if necessary, Dr. Burton said.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
DALLAS – Sufficient vitamin D levels – serum 25-hydroxyvitamin D concentrations greater than 80 nmol/L – appeared to protect against edema of the retinal nerve fiber layer in a prospective cohort study of patients with acute optic neuritis.
An adequate vitamin D level also protected against thinning of the retinal nerve fiber layer (RNFL) ganglion cell layer and other poor outcomes after 6 months in the study of 49 patients (some of whom had multiple sclerosis), according to researchers at the University of Calgary (Alta.).
The team correlated vitamin D levels with optical coherence tomography findings. Vitamin D is known to have anti-inflammatory effects, so it’s the chronic benefit that was surprising, lead investigator Dr. Jodie Burton explained at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
It’s just one more reason that it’s a good idea to check vitamin D levels, and supplement them if necessary, Dr. Burton said.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT THE CMSC/ACTRIMS ANNUAL MEETING
A Personalized Management Plan of Fingolimod Titration May Benefit Some Patients With MS
DALLAS—Long-term data demonstrating the success of interferon titration suggests that a similar strategy could be effective for a select group of patients who struggle tolerating the initial recommended 0.5 mg daily fingolimod dose. Data presented at the 2014 Cooperative Meeting of CMSC and ACTRIMS suggest that there may be a role for fingolimod 0.25 mg/day, however the optimal recommended therapeutic dose of 0.5 mg/day is achievable for many patients if side effects and titration is efficiently and effectively managed.
A major Australian tertiary teaching hospital with a large multiple sclerosis (MS) clinic anticipated that patients starting on fingolimod and experiencing poor drug tolerability would request, or simply decide on their own, to cease their medication. Historical experience with inferferon prompted discussions with the neurologist and MS nursing staff. Through consultation in relation to dosing alternatives, it was identified that there was an opportunity to explore individualized oral drug titration. Select patients whose quality of life was being disrupted by unwanted side effects were offered a titration and monitoring opportunity. The goal of the “go slow” approach was to achieve the full recommended daily dose regime and establish confidence with a nonexistent or minimal acceptable side effect profile.
Susanne Baker and Meena Sharma from the MS Clinic at Liverpool Hospital in Sydney, Australia, in collaboration with neurologists, endeavored to manage side effects and titrate the fingolimod dose according to side effects experienced. Patient who chose to withdraw from fingolimod treatment were given the option of a personalized management plan. No clinical assessment tool was used to grade the severity of the adverse events and all supportive care was given based on the patients’ self-report of discomfort. The program offered regular monitoring and side effect management for lymphopenia, gastrointestinal disturbance, headache, and a feeling of being generally unwell. Ongoing consultation with the neurologist by the MS nursing staff was maintained along with fingolimod dose adjustments. Supportive medication included, but was not limited to, paracetamol, ibuprofen, ranitidine, metoclopramide, and loperamide.
In total, 209 patients were treated with fingolimod at the MS clinic at Liverpool Hospital and 51 (24.4%) significant adverse events (eg, lymphopenia, herpes zoster, malignancy, headache, ophthalmologic symptoms, gastrointestinal disturbance, and a feeling of being generally unwell) were reported. From this patient group, 24 (47%) were offered a side effect management and drug titration plan. Sixteen patients (66.7%) chose to participate in the proposed plan. Of these, 10 were able to achieve the full dose and remain on treatment, two (12.5%) discontinued treatment due to poor tolerance, and four (25%) continued to remain on drug titration. No relapses were observed or reported during the titration period.
—Glenn S. Williams
DALLAS—Long-term data demonstrating the success of interferon titration suggests that a similar strategy could be effective for a select group of patients who struggle tolerating the initial recommended 0.5 mg daily fingolimod dose. Data presented at the 2014 Cooperative Meeting of CMSC and ACTRIMS suggest that there may be a role for fingolimod 0.25 mg/day, however the optimal recommended therapeutic dose of 0.5 mg/day is achievable for many patients if side effects and titration is efficiently and effectively managed.
A major Australian tertiary teaching hospital with a large multiple sclerosis (MS) clinic anticipated that patients starting on fingolimod and experiencing poor drug tolerability would request, or simply decide on their own, to cease their medication. Historical experience with inferferon prompted discussions with the neurologist and MS nursing staff. Through consultation in relation to dosing alternatives, it was identified that there was an opportunity to explore individualized oral drug titration. Select patients whose quality of life was being disrupted by unwanted side effects were offered a titration and monitoring opportunity. The goal of the “go slow” approach was to achieve the full recommended daily dose regime and establish confidence with a nonexistent or minimal acceptable side effect profile.
Susanne Baker and Meena Sharma from the MS Clinic at Liverpool Hospital in Sydney, Australia, in collaboration with neurologists, endeavored to manage side effects and titrate the fingolimod dose according to side effects experienced. Patient who chose to withdraw from fingolimod treatment were given the option of a personalized management plan. No clinical assessment tool was used to grade the severity of the adverse events and all supportive care was given based on the patients’ self-report of discomfort. The program offered regular monitoring and side effect management for lymphopenia, gastrointestinal disturbance, headache, and a feeling of being generally unwell. Ongoing consultation with the neurologist by the MS nursing staff was maintained along with fingolimod dose adjustments. Supportive medication included, but was not limited to, paracetamol, ibuprofen, ranitidine, metoclopramide, and loperamide.
In total, 209 patients were treated with fingolimod at the MS clinic at Liverpool Hospital and 51 (24.4%) significant adverse events (eg, lymphopenia, herpes zoster, malignancy, headache, ophthalmologic symptoms, gastrointestinal disturbance, and a feeling of being generally unwell) were reported. From this patient group, 24 (47%) were offered a side effect management and drug titration plan. Sixteen patients (66.7%) chose to participate in the proposed plan. Of these, 10 were able to achieve the full dose and remain on treatment, two (12.5%) discontinued treatment due to poor tolerance, and four (25%) continued to remain on drug titration. No relapses were observed or reported during the titration period.
—Glenn S. Williams
DALLAS—Long-term data demonstrating the success of interferon titration suggests that a similar strategy could be effective for a select group of patients who struggle tolerating the initial recommended 0.5 mg daily fingolimod dose. Data presented at the 2014 Cooperative Meeting of CMSC and ACTRIMS suggest that there may be a role for fingolimod 0.25 mg/day, however the optimal recommended therapeutic dose of 0.5 mg/day is achievable for many patients if side effects and titration is efficiently and effectively managed.
A major Australian tertiary teaching hospital with a large multiple sclerosis (MS) clinic anticipated that patients starting on fingolimod and experiencing poor drug tolerability would request, or simply decide on their own, to cease their medication. Historical experience with inferferon prompted discussions with the neurologist and MS nursing staff. Through consultation in relation to dosing alternatives, it was identified that there was an opportunity to explore individualized oral drug titration. Select patients whose quality of life was being disrupted by unwanted side effects were offered a titration and monitoring opportunity. The goal of the “go slow” approach was to achieve the full recommended daily dose regime and establish confidence with a nonexistent or minimal acceptable side effect profile.
Susanne Baker and Meena Sharma from the MS Clinic at Liverpool Hospital in Sydney, Australia, in collaboration with neurologists, endeavored to manage side effects and titrate the fingolimod dose according to side effects experienced. Patient who chose to withdraw from fingolimod treatment were given the option of a personalized management plan. No clinical assessment tool was used to grade the severity of the adverse events and all supportive care was given based on the patients’ self-report of discomfort. The program offered regular monitoring and side effect management for lymphopenia, gastrointestinal disturbance, headache, and a feeling of being generally unwell. Ongoing consultation with the neurologist by the MS nursing staff was maintained along with fingolimod dose adjustments. Supportive medication included, but was not limited to, paracetamol, ibuprofen, ranitidine, metoclopramide, and loperamide.
In total, 209 patients were treated with fingolimod at the MS clinic at Liverpool Hospital and 51 (24.4%) significant adverse events (eg, lymphopenia, herpes zoster, malignancy, headache, ophthalmologic symptoms, gastrointestinal disturbance, and a feeling of being generally unwell) were reported. From this patient group, 24 (47%) were offered a side effect management and drug titration plan. Sixteen patients (66.7%) chose to participate in the proposed plan. Of these, 10 were able to achieve the full dose and remain on treatment, two (12.5%) discontinued treatment due to poor tolerance, and four (25%) continued to remain on drug titration. No relapses were observed or reported during the titration period.
—Glenn S. Williams
Vitamin D Deficiency Predicts Long-Term Disease Activity in Patients Taking Interferon Beta-1b
DALLAS—Correcting vitamin D deficiency early in the course of treatment with interferon beta-1b is likely to improve the outcome for patients with multiple sclerosis (MS), according to data presented at the 2014 Cooperative Meeting of CMSC and ACTRIMS. “The results of this study support the importance of identifying and correcting 25(OH)D insufficiency early in the course of MS,” said Alberto Ascherio, MD, DrPH, and colleagues. “The effects are likely additive to therapy with interferon beta-1b without decreasing its tolerability.”
Dr. Ascherio, from the Harvard School of Public Health in Boston, and colleagues sought to examine the predictive effect of serum 25(OH)D levels on disease activity and progression in patients with clinically isolated syndrome starting interferon beta-1b therapy. They also examined the effect of serum 25(OH)D levels on the occurrence of flu-like symptoms, a common side-effect of interferon beta-1b.
Drawing their study cohort from the BEtaferon/BEtaseron in Newly Emerging MS for Initial Treatment (BENEFIT) study, the researchers randomized patients with clinically isolated syndrome and two or more clinically silent brain MRI lesions to 250 mcg of interferon beta-1b (early treatment) or placebo (late treatment) subcutaneously every other day. Serum 25(OH)D concentration measurements were taken at baseline and at six, 12, and 24 months. Cox proportional hazard models or generalized mixed effects models were used to relate season-adjusted 25(OH)D concentrations to clinical and MRI outcomes up to five years. Occurrence of flu-like symptoms in the early treatment group with high or low serum 25(OH)D levels were compared by chi-square test.
Data from 216 patients in the early treatment group and 118 patients in the delayed treatment group were analyzed. When analyzed as a continuous variable, increases in 25(OH)D led to a lower probability of conversion to McDonald MS, with a trend toward lower probability of conversion to clinically definite MS. Increases in 25(OH)D also led to lower rates of newly active lesions, relapses, annual percent change in T2 volume, and annual percent change in brain volume. Dichotomous 25(OH)D levels were strongly and inversely associated with probability of conversion to clinically definite MS, cumulative number of new lesions on MRI, percent change in T2 volume, and percent change in brain volume. Occurrence of flu-like symptoms did not differ between patients in the early treatment group with high or low serum 25(OH)D levels at months 6, 12, and 24.
Dr. Ascherio and colleagues concluded that among patients who started interferon beta-1b treatment right after clinically isolated syndrome, incremental increases of 25(OH)D levels were associated with reduction of long-term MS disease activity and severity. “These results also suggest that early treatment with interferon beta-1b has an additive effect with 25(OH)D to reduce disease severity and progression on both clinical and imaging outcomes.”
Further research would be needed, the researchers said, to determine whether these results apply to patients with different MS subtypes or those treated with drugs other than interferon beta-1b.
DALLAS—Correcting vitamin D deficiency early in the course of treatment with interferon beta-1b is likely to improve the outcome for patients with multiple sclerosis (MS), according to data presented at the 2014 Cooperative Meeting of CMSC and ACTRIMS. “The results of this study support the importance of identifying and correcting 25(OH)D insufficiency early in the course of MS,” said Alberto Ascherio, MD, DrPH, and colleagues. “The effects are likely additive to therapy with interferon beta-1b without decreasing its tolerability.”
Dr. Ascherio, from the Harvard School of Public Health in Boston, and colleagues sought to examine the predictive effect of serum 25(OH)D levels on disease activity and progression in patients with clinically isolated syndrome starting interferon beta-1b therapy. They also examined the effect of serum 25(OH)D levels on the occurrence of flu-like symptoms, a common side-effect of interferon beta-1b.
Drawing their study cohort from the BEtaferon/BEtaseron in Newly Emerging MS for Initial Treatment (BENEFIT) study, the researchers randomized patients with clinically isolated syndrome and two or more clinically silent brain MRI lesions to 250 mcg of interferon beta-1b (early treatment) or placebo (late treatment) subcutaneously every other day. Serum 25(OH)D concentration measurements were taken at baseline and at six, 12, and 24 months. Cox proportional hazard models or generalized mixed effects models were used to relate season-adjusted 25(OH)D concentrations to clinical and MRI outcomes up to five years. Occurrence of flu-like symptoms in the early treatment group with high or low serum 25(OH)D levels were compared by chi-square test.
Data from 216 patients in the early treatment group and 118 patients in the delayed treatment group were analyzed. When analyzed as a continuous variable, increases in 25(OH)D led to a lower probability of conversion to McDonald MS, with a trend toward lower probability of conversion to clinically definite MS. Increases in 25(OH)D also led to lower rates of newly active lesions, relapses, annual percent change in T2 volume, and annual percent change in brain volume. Dichotomous 25(OH)D levels were strongly and inversely associated with probability of conversion to clinically definite MS, cumulative number of new lesions on MRI, percent change in T2 volume, and percent change in brain volume. Occurrence of flu-like symptoms did not differ between patients in the early treatment group with high or low serum 25(OH)D levels at months 6, 12, and 24.
Dr. Ascherio and colleagues concluded that among patients who started interferon beta-1b treatment right after clinically isolated syndrome, incremental increases of 25(OH)D levels were associated with reduction of long-term MS disease activity and severity. “These results also suggest that early treatment with interferon beta-1b has an additive effect with 25(OH)D to reduce disease severity and progression on both clinical and imaging outcomes.”
Further research would be needed, the researchers said, to determine whether these results apply to patients with different MS subtypes or those treated with drugs other than interferon beta-1b.
DALLAS—Correcting vitamin D deficiency early in the course of treatment with interferon beta-1b is likely to improve the outcome for patients with multiple sclerosis (MS), according to data presented at the 2014 Cooperative Meeting of CMSC and ACTRIMS. “The results of this study support the importance of identifying and correcting 25(OH)D insufficiency early in the course of MS,” said Alberto Ascherio, MD, DrPH, and colleagues. “The effects are likely additive to therapy with interferon beta-1b without decreasing its tolerability.”
Dr. Ascherio, from the Harvard School of Public Health in Boston, and colleagues sought to examine the predictive effect of serum 25(OH)D levels on disease activity and progression in patients with clinically isolated syndrome starting interferon beta-1b therapy. They also examined the effect of serum 25(OH)D levels on the occurrence of flu-like symptoms, a common side-effect of interferon beta-1b.
Drawing their study cohort from the BEtaferon/BEtaseron in Newly Emerging MS for Initial Treatment (BENEFIT) study, the researchers randomized patients with clinically isolated syndrome and two or more clinically silent brain MRI lesions to 250 mcg of interferon beta-1b (early treatment) or placebo (late treatment) subcutaneously every other day. Serum 25(OH)D concentration measurements were taken at baseline and at six, 12, and 24 months. Cox proportional hazard models or generalized mixed effects models were used to relate season-adjusted 25(OH)D concentrations to clinical and MRI outcomes up to five years. Occurrence of flu-like symptoms in the early treatment group with high or low serum 25(OH)D levels were compared by chi-square test.
Data from 216 patients in the early treatment group and 118 patients in the delayed treatment group were analyzed. When analyzed as a continuous variable, increases in 25(OH)D led to a lower probability of conversion to McDonald MS, with a trend toward lower probability of conversion to clinically definite MS. Increases in 25(OH)D also led to lower rates of newly active lesions, relapses, annual percent change in T2 volume, and annual percent change in brain volume. Dichotomous 25(OH)D levels were strongly and inversely associated with probability of conversion to clinically definite MS, cumulative number of new lesions on MRI, percent change in T2 volume, and percent change in brain volume. Occurrence of flu-like symptoms did not differ between patients in the early treatment group with high or low serum 25(OH)D levels at months 6, 12, and 24.
Dr. Ascherio and colleagues concluded that among patients who started interferon beta-1b treatment right after clinically isolated syndrome, incremental increases of 25(OH)D levels were associated with reduction of long-term MS disease activity and severity. “These results also suggest that early treatment with interferon beta-1b has an additive effect with 25(OH)D to reduce disease severity and progression on both clinical and imaging outcomes.”
Further research would be needed, the researchers said, to determine whether these results apply to patients with different MS subtypes or those treated with drugs other than interferon beta-1b.