Medical - MS
October 3, 2016 at 12:57 pm
(This post was last modified: October 3, 2016 at 3:34 pm by brewer.)
I know that we have at least a couple of MS diagnosed individuals. Thought this is interesting. Let me know if you can't view these from the links.
OTC supplement may impact MS brain atrophy. Small initial study.
OTC Supplement May Reduce Brain Atrophy in SPMS
LONDON — The oral antioxidant lipoic acid can decrease brain atrophy in patients with secondary progressive multiple sclerosis (SPMS) while sustaining safety and tolerability, new imaging research suggests.
The small, 51-patient pilot trial showed that those randomly assigned to 1200 mg of lipoic acid daily had a significantly lower annualized rate of whole-brain atrophy at 96 weeks, as measured by MRI, than the participants who were assigned to matching placebo.
In fact, the atrophy reduction rate was 66% in the active treatment group — and they had a trend toward a greater improvement in walking speed.
In addition, reports of adverse events (AEs) were mostly similar between the two treatment groups. Although those receiving lipoic acid had more cases of gastrointestinal upset than those receiving placebo (17% vs 3%, respectively), they had half as many falls (15% vs 38%). Rebecca Spain, MD, from the VA Portland Health Care System and the Department of Neurology at Oregon Health and Science University, told Medscape Medical News that "it's still early days" but the findings are exciting.
"In my patients with progressive MS who are motivated to take an over-the-counter supplement, I am now providing them with this data. Of course I'm also making it clear that we don't yet know if it will change the long-term course of MS," she added.
Dr Spain presented the results here at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016. Michael Hutchinson, MD, St Vincent's University Hospital, Dublin, Ireland, marked the trial as a "clinical highlight" during a presentation he gave at the meeting's end. "This was such an interesting study," said Dr Hutchinson, who was not involved with the research. "Lipoic acid looks like a potential molecule that we might be using more of."
Inexpensive, Readily Available
The agent "is an inexpensive antioxidant with multiple biological functions," explained Dr Spain during her presentation. "The r-enantiomer is produced endogenously in mitochondria, where it plays a key role in oxidative respiration." Animal models have shown that the antioxidant can reduce inflammation, as well as macular and spinal cord atrophy.
"There is a great unmet need to find a disease-modifying therapy for progressive MS. We wanted to look at lipoic acid as possibly filling this role since it's a small-molecule agent that, because of its low cost, could be readily available to anybody who needed it," said Dr Spain.
The current study included 51 patients with SPMS (61% women; 96% white; mean age, 58.5 years). Of these, 27 received lipoic acid and 24 received placebo.
The mean disease duration for the entire group at baseline was 29.6 years and the mean Expanded Disability Status Scale (EDSS) score was 5.5. All of the participants underwent yearly MRI.
The primary outcome measure was annualized percentage change in brain volume, with structural image evaluation using normalization of atrophy (SIENA).
At 96 weeks, the group receiving placebo had a whole-brain atrophy rate of 0.65% per year, "which is comparable to rates in other progressive MS natural history cohorts," said Dr Spain. On the other hand, use of lipoic acid resulted in a significantly lower annualized atrophy rate of 0.22%, which represented a 66% reduction vs placebo (P = .004).
Clinical Benefits Need Clarification
Those taking lipoic acid group also had greater improvement on the timed 25-foot walk test than the placebo group, although this result just missed significance (P = .057). There were no between-group differences in the other secondary outcomes, including total deep grey-matter volume, change in cortical thickness, or number who had stable or improved EDSS scores. On the basis of pill counts, treatment adherence was greater than 80%. And there were five study dropouts, all in the lipoic acid group. Two notable AEs in that cohort included one case of new-onset proteinuria and one of worsening renal function. "But a consulting nephrologist did not think either of those events were related to the lipoic acid," said Dr Spain. "And renal events have not been noted in other trials of this agent for other conditions."
She added that the positive primary findings now need "further exploration with a larger population to clarify the effect size, to determine the clinical benefits associated with reductions in brain atrophy, and to explore the underlying mechanisms of action of lipoic acid in progressive MS." Dr Spain noted that "SIENA is not a perfect measure" and that brain volume can be influenced by such things as a patient's dehydration status, which is not controlled for. "The only way to control for all these variables is to have a large trial, which will blunt the effect of the individual variations." She reported that such a trial is now in the planning stages, with an estimated patient population of around 115.
"Encouraging Results"
"This was a small study but it had a very marked outcome," Dr Hutchinson told Medscape Medical News. "Basically, lipoic acid significantly reduced the rate of atrophy," he said, noting that healthy brains atrophy at a rate of about 0.2%. For people with MS, particularly SPMS, "it's usually two to three times that. But in this case, people who were on lipoic acid had a rate of loss at 0.22%, whereas for those taking placebo it was 0.66%. So there was a three-fold difference." "It looks very encouraging," reiterated Dr Hutchinson. "And it's lovely to see all of these studies coming to address what was up until now a relatively intractable problem — progressive MS."
However, he said that the argument that will likely come out of this study and/or agent is: "Will you need to continue to use some sort of active anti-inflammatory drug, like siponimod, which was talked about earlier at this meeting, plus a neuroprotective?"
The study was supported by the Department of Veterans Affairs and the National Institutes of Health. Pure Encapsulations, which is located in Sudbury, Massachusetts, provided the lipoic acid and placebo. Dr Spain and Dr Hutchinson have disclosed no relevant financial relationships.
Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016. Parallel Session 12, oral presentation 222. Presented September 16, 2016. Plenary Session 2, oral presentation 258. Presented September 17, 2016.
Discussion of early induction therapy in treating MS.
Induction Therapy in Early MS: Is It Justified?
LONDON — With the availability of new potent immunosuppressive drugs for multiple sclerosis, a new hot topic discussion point in the field is whether these agents should be used as "induction therapy" in patients with early disease, with the idea that hitting the disease hard at the beginning may be the best way to prevent long-term progression. This was subject of a well-attended, lively debate on the first day of the Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016 here.
Protagonist of the induction therapy approach, Gilles Edan, MD, University Hospital of Rennes, France, explained: "At present we have many different drugs and there are two possible approaches to treatment: the traditional strategy of escalation therapy, where we start with the lowest-risk agent, like β interferon, and when the disease starts to progress, then we escalate therapy to a stronger medication; or induction therapy, where we go in hard at the start with a very potent immunosuppressant for a short time, then switch to a less potent maintenance therapy or no treatment for the long term." He said the challenge with escalation therapy is to define the exact suboptimal response threshold at which the next level therapeutic option should be introduced.
Appropriate for High-Risk Patients?
He presented data showing that induction therapy brings about earlier achievement of '"no evidence of disease activity," the new gold standard of MS treatment. But he cautioned that some patients may be needlessly exposed to serious side effects with induction therapy, so the "key is to use induction therapy for the minimum amount of time needed to gain control over disease activity and to select patients who would benefit the most."
"I believe induction therapy does have a role, but only for those patients who are at higher risk of developing disability — those who have frequent or severe relapses or the accumulation of lesions on MRI," he commented to Medscape Medical News. "But I do not believe that we are at the stage yet where we can recommend induction therapy for all, as many patents are well controlled for many years on the low-risk treatments, such as interferon β."
Taking the counter view, Emmanuelle Waubant, MD, University of California, San Francisco, said that while it seems sensible to use induction therapy in more severe patients, she does not believe the field is yet ready to use such potent medications in patients with very early disease. "We are like an apprentice — we are trying to do something that we don't fully understand," she stated.
Dr Waubant pointed out that many patients do well on standard therapy and do not need strong immunosuppressants, with 20% of patients having benign disease, defined as an Extended Disability Status Scale (EDSS) score less than 2 after 10 years, and 70% of those receiving interferon β since first symptoms having an EDSS score less than 3 by year 11.
She also noted the lack of randomized trials testing the benefit and safety of early induction therapy, and she called for new carefully designed large trials of induction therapy with the drugs most likely to achieve this goal with long-term follow-up.
Dr Edan argued that patients with aggressive disease needed aggressive treatment, and, with the availability of new potent drugs and the latest-generation MRI technology, it is possible to target highly active therapies to patients with highly active disease. "But we have to monitor patients closely to identify those that need these more potent agents."
He reported that recent studies have shown that monitoring patients closely over the first few years significantly refines prediction and facilitates the selection of those requiring aggressive treatment.
"MRI is a key prognostic marker. We need to be monitoring newly diagnosed patients closely for signs of disease activity, including regular standardized MRI scans. This is starting to happen now," he said. "We have several studies showing regular MRI scans increase the predictability of disease in terms of worsening of disability. I would recommend another MRI scan after 6 months of diagnosis and then yearly."
He listed factors suggesting suitability for early induction therapy were pure relapsing-remitting MS, age under 40 years, two or more relapses within the previous 12 months or a severe relapse resulting in an EDSS score greater than 4, a worsening EDSS score due to relapse (an increase of 2 or more points within previous 12 months), or two or more additional gadolinium-enhancing lesions on recent MRI.
As to which drugs to use for induction therapy, Dr Edan said he would consider mitoxantrone or alemtuzumab, both of which have shown strong effects on relapse rates and disease activity after a short treatment course. "Mitoxantrone is an older drug, but it is a strong immunosuppressant and has been studied in MS," he noted. "It can be given for a few months and then the patient can be switched to maintenance therapy with a less potent agent. Alemtuzumab is a new drug, but data so far are encouraging, with around 40% of patients free of disease activity at 5 years after one course of treatment. Because the effect of alemtuzumab lasts for so long there is no need to use any maintenance therapy."
He added that the new B cell–targeting agent, ocrelizumab, may also be suitable for induction therapy when it becomes available, but he does not recommend natalizumab for induction because of the risk for progressive multifocal leukoencephalopathy.
Cladribine Making a Comeback?
In a separate presentation immediately after the debate, Professor Giancarlo Comi, Vita-Salute San Raffaele University, Milan, Italy, suggested that cladribine could also be a suitable induction agent. This older drug has been studied in clinical trials for MS and has shown impressive efficacy but was not pursued because of concerns over possible cancers. However, latest data have been reassuring in this regard, and the drug is now under consideration for use in MS at the European Medicines Agency (EMA), he reported.
Dr Edan told Medscape Medical News that the short-term data with cladribine showed impressive efficacy, but long-term data are lacking. "I will wait to see what the EMA does and if it is approved for use in MS then I might consider it as induction therapy for 1 to 2 years," he commented. He added: "I think we should use induction therapy at the start in the high-risk patients but only for a short time. We don't have data on how safe any of these drugs are over the long term. But we know that any medicine started early in the course of MS — after the first clinical event — is more effective than when started later. That is a general rule."
Too Many Questions
But Dr Waubant urged caution, pointing out that it was still hard to know which individual patient could be classified as high risk. "Several MRI and clinical predictors may have been shown to be associated with poor outcomes in cohorts but not in individuals." She said there were too many questions to be able to go ahead confidently with induction."
There is a lack of immunological markers of disease initiation and progression — we do not have a biological target for induction therapy — do we wipe out all the white blood cells or just specific ones? Also, how do we measure effectiveness of the treatment? And most importantly, these potent treatments available for induction are associated with long-tern biological changes, but it is unclear whether these will change the course of disease in the long term, and what the long-term side effects will be. I would like to see data out to 15 or 20 years on cancer rates to have confidence in their long-term safety," she concluded.
A show of hands in the audience after the debate suggested a split vote, with no clear consensus on which approach was most popular.
Summing up, co-chair of the session Ludwig Kappos, Basel University Hospital, Switzerland, said it was up to each clinician to decide with each individual patient which approach to use. He stressed the need for more data and urged physicians to enroll patients in cohorts and registry studies so that comprehensive follow-up data could be collected.
Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016. Abstracts 68, 69 and 70. Presented September 14, 2016.
OTC supplement may impact MS brain atrophy. Small initial study.
OTC Supplement May Reduce Brain Atrophy in SPMS
LONDON — The oral antioxidant lipoic acid can decrease brain atrophy in patients with secondary progressive multiple sclerosis (SPMS) while sustaining safety and tolerability, new imaging research suggests.
The small, 51-patient pilot trial showed that those randomly assigned to 1200 mg of lipoic acid daily had a significantly lower annualized rate of whole-brain atrophy at 96 weeks, as measured by MRI, than the participants who were assigned to matching placebo.
In fact, the atrophy reduction rate was 66% in the active treatment group — and they had a trend toward a greater improvement in walking speed.
In addition, reports of adverse events (AEs) were mostly similar between the two treatment groups. Although those receiving lipoic acid had more cases of gastrointestinal upset than those receiving placebo (17% vs 3%, respectively), they had half as many falls (15% vs 38%). Rebecca Spain, MD, from the VA Portland Health Care System and the Department of Neurology at Oregon Health and Science University, told Medscape Medical News that "it's still early days" but the findings are exciting.
"In my patients with progressive MS who are motivated to take an over-the-counter supplement, I am now providing them with this data. Of course I'm also making it clear that we don't yet know if it will change the long-term course of MS," she added.
Dr Spain presented the results here at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016. Michael Hutchinson, MD, St Vincent's University Hospital, Dublin, Ireland, marked the trial as a "clinical highlight" during a presentation he gave at the meeting's end. "This was such an interesting study," said Dr Hutchinson, who was not involved with the research. "Lipoic acid looks like a potential molecule that we might be using more of."
Inexpensive, Readily Available
The agent "is an inexpensive antioxidant with multiple biological functions," explained Dr Spain during her presentation. "The r-enantiomer is produced endogenously in mitochondria, where it plays a key role in oxidative respiration." Animal models have shown that the antioxidant can reduce inflammation, as well as macular and spinal cord atrophy.
"There is a great unmet need to find a disease-modifying therapy for progressive MS. We wanted to look at lipoic acid as possibly filling this role since it's a small-molecule agent that, because of its low cost, could be readily available to anybody who needed it," said Dr Spain.
The current study included 51 patients with SPMS (61% women; 96% white; mean age, 58.5 years). Of these, 27 received lipoic acid and 24 received placebo.
The mean disease duration for the entire group at baseline was 29.6 years and the mean Expanded Disability Status Scale (EDSS) score was 5.5. All of the participants underwent yearly MRI.
The primary outcome measure was annualized percentage change in brain volume, with structural image evaluation using normalization of atrophy (SIENA).
At 96 weeks, the group receiving placebo had a whole-brain atrophy rate of 0.65% per year, "which is comparable to rates in other progressive MS natural history cohorts," said Dr Spain. On the other hand, use of lipoic acid resulted in a significantly lower annualized atrophy rate of 0.22%, which represented a 66% reduction vs placebo (P = .004).
Clinical Benefits Need Clarification
Those taking lipoic acid group also had greater improvement on the timed 25-foot walk test than the placebo group, although this result just missed significance (P = .057). There were no between-group differences in the other secondary outcomes, including total deep grey-matter volume, change in cortical thickness, or number who had stable or improved EDSS scores. On the basis of pill counts, treatment adherence was greater than 80%. And there were five study dropouts, all in the lipoic acid group. Two notable AEs in that cohort included one case of new-onset proteinuria and one of worsening renal function. "But a consulting nephrologist did not think either of those events were related to the lipoic acid," said Dr Spain. "And renal events have not been noted in other trials of this agent for other conditions."
She added that the positive primary findings now need "further exploration with a larger population to clarify the effect size, to determine the clinical benefits associated with reductions in brain atrophy, and to explore the underlying mechanisms of action of lipoic acid in progressive MS." Dr Spain noted that "SIENA is not a perfect measure" and that brain volume can be influenced by such things as a patient's dehydration status, which is not controlled for. "The only way to control for all these variables is to have a large trial, which will blunt the effect of the individual variations." She reported that such a trial is now in the planning stages, with an estimated patient population of around 115.
"Encouraging Results"
"This was a small study but it had a very marked outcome," Dr Hutchinson told Medscape Medical News. "Basically, lipoic acid significantly reduced the rate of atrophy," he said, noting that healthy brains atrophy at a rate of about 0.2%. For people with MS, particularly SPMS, "it's usually two to three times that. But in this case, people who were on lipoic acid had a rate of loss at 0.22%, whereas for those taking placebo it was 0.66%. So there was a three-fold difference." "It looks very encouraging," reiterated Dr Hutchinson. "And it's lovely to see all of these studies coming to address what was up until now a relatively intractable problem — progressive MS."
However, he said that the argument that will likely come out of this study and/or agent is: "Will you need to continue to use some sort of active anti-inflammatory drug, like siponimod, which was talked about earlier at this meeting, plus a neuroprotective?"
The study was supported by the Department of Veterans Affairs and the National Institutes of Health. Pure Encapsulations, which is located in Sudbury, Massachusetts, provided the lipoic acid and placebo. Dr Spain and Dr Hutchinson have disclosed no relevant financial relationships.
Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016. Parallel Session 12, oral presentation 222. Presented September 16, 2016. Plenary Session 2, oral presentation 258. Presented September 17, 2016.
Discussion of early induction therapy in treating MS.
Induction Therapy in Early MS: Is It Justified?
LONDON — With the availability of new potent immunosuppressive drugs for multiple sclerosis, a new hot topic discussion point in the field is whether these agents should be used as "induction therapy" in patients with early disease, with the idea that hitting the disease hard at the beginning may be the best way to prevent long-term progression. This was subject of a well-attended, lively debate on the first day of the Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016 here.
Protagonist of the induction therapy approach, Gilles Edan, MD, University Hospital of Rennes, France, explained: "At present we have many different drugs and there are two possible approaches to treatment: the traditional strategy of escalation therapy, where we start with the lowest-risk agent, like β interferon, and when the disease starts to progress, then we escalate therapy to a stronger medication; or induction therapy, where we go in hard at the start with a very potent immunosuppressant for a short time, then switch to a less potent maintenance therapy or no treatment for the long term." He said the challenge with escalation therapy is to define the exact suboptimal response threshold at which the next level therapeutic option should be introduced.
Appropriate for High-Risk Patients?
He presented data showing that induction therapy brings about earlier achievement of '"no evidence of disease activity," the new gold standard of MS treatment. But he cautioned that some patients may be needlessly exposed to serious side effects with induction therapy, so the "key is to use induction therapy for the minimum amount of time needed to gain control over disease activity and to select patients who would benefit the most."
"I believe induction therapy does have a role, but only for those patients who are at higher risk of developing disability — those who have frequent or severe relapses or the accumulation of lesions on MRI," he commented to Medscape Medical News. "But I do not believe that we are at the stage yet where we can recommend induction therapy for all, as many patents are well controlled for many years on the low-risk treatments, such as interferon β."
Taking the counter view, Emmanuelle Waubant, MD, University of California, San Francisco, said that while it seems sensible to use induction therapy in more severe patients, she does not believe the field is yet ready to use such potent medications in patients with very early disease. "We are like an apprentice — we are trying to do something that we don't fully understand," she stated.
Dr Waubant pointed out that many patients do well on standard therapy and do not need strong immunosuppressants, with 20% of patients having benign disease, defined as an Extended Disability Status Scale (EDSS) score less than 2 after 10 years, and 70% of those receiving interferon β since first symptoms having an EDSS score less than 3 by year 11.
She also noted the lack of randomized trials testing the benefit and safety of early induction therapy, and she called for new carefully designed large trials of induction therapy with the drugs most likely to achieve this goal with long-term follow-up.
Dr Edan argued that patients with aggressive disease needed aggressive treatment, and, with the availability of new potent drugs and the latest-generation MRI technology, it is possible to target highly active therapies to patients with highly active disease. "But we have to monitor patients closely to identify those that need these more potent agents."
He reported that recent studies have shown that monitoring patients closely over the first few years significantly refines prediction and facilitates the selection of those requiring aggressive treatment.
"MRI is a key prognostic marker. We need to be monitoring newly diagnosed patients closely for signs of disease activity, including regular standardized MRI scans. This is starting to happen now," he said. "We have several studies showing regular MRI scans increase the predictability of disease in terms of worsening of disability. I would recommend another MRI scan after 6 months of diagnosis and then yearly."
He listed factors suggesting suitability for early induction therapy were pure relapsing-remitting MS, age under 40 years, two or more relapses within the previous 12 months or a severe relapse resulting in an EDSS score greater than 4, a worsening EDSS score due to relapse (an increase of 2 or more points within previous 12 months), or two or more additional gadolinium-enhancing lesions on recent MRI.
As to which drugs to use for induction therapy, Dr Edan said he would consider mitoxantrone or alemtuzumab, both of which have shown strong effects on relapse rates and disease activity after a short treatment course. "Mitoxantrone is an older drug, but it is a strong immunosuppressant and has been studied in MS," he noted. "It can be given for a few months and then the patient can be switched to maintenance therapy with a less potent agent. Alemtuzumab is a new drug, but data so far are encouraging, with around 40% of patients free of disease activity at 5 years after one course of treatment. Because the effect of alemtuzumab lasts for so long there is no need to use any maintenance therapy."
He added that the new B cell–targeting agent, ocrelizumab, may also be suitable for induction therapy when it becomes available, but he does not recommend natalizumab for induction because of the risk for progressive multifocal leukoencephalopathy.
Cladribine Making a Comeback?
In a separate presentation immediately after the debate, Professor Giancarlo Comi, Vita-Salute San Raffaele University, Milan, Italy, suggested that cladribine could also be a suitable induction agent. This older drug has been studied in clinical trials for MS and has shown impressive efficacy but was not pursued because of concerns over possible cancers. However, latest data have been reassuring in this regard, and the drug is now under consideration for use in MS at the European Medicines Agency (EMA), he reported.
Dr Edan told Medscape Medical News that the short-term data with cladribine showed impressive efficacy, but long-term data are lacking. "I will wait to see what the EMA does and if it is approved for use in MS then I might consider it as induction therapy for 1 to 2 years," he commented. He added: "I think we should use induction therapy at the start in the high-risk patients but only for a short time. We don't have data on how safe any of these drugs are over the long term. But we know that any medicine started early in the course of MS — after the first clinical event — is more effective than when started later. That is a general rule."
Too Many Questions
But Dr Waubant urged caution, pointing out that it was still hard to know which individual patient could be classified as high risk. "Several MRI and clinical predictors may have been shown to be associated with poor outcomes in cohorts but not in individuals." She said there were too many questions to be able to go ahead confidently with induction."
There is a lack of immunological markers of disease initiation and progression — we do not have a biological target for induction therapy — do we wipe out all the white blood cells or just specific ones? Also, how do we measure effectiveness of the treatment? And most importantly, these potent treatments available for induction are associated with long-tern biological changes, but it is unclear whether these will change the course of disease in the long term, and what the long-term side effects will be. I would like to see data out to 15 or 20 years on cancer rates to have confidence in their long-term safety," she concluded.
A show of hands in the audience after the debate suggested a split vote, with no clear consensus on which approach was most popular.
Summing up, co-chair of the session Ludwig Kappos, Basel University Hospital, Switzerland, said it was up to each clinician to decide with each individual patient which approach to use. He stressed the need for more data and urged physicians to enroll patients in cohorts and registry studies so that comprehensive follow-up data could be collected.
Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016. Abstracts 68, 69 and 70. Presented September 14, 2016.
I don't have an anger problem, I have an idiot problem.
